Sue Sutter

The Food and Drug Administration approved Stribild on Aug. 27, the product’s user fee date, to treat HIV-1 infection in adults who have never been treated for HIV.

Quad is the moniker by which the four-drug, fixed-dose combination (elvitegravir/cobicistat/emtricitabine/tenofovir) has become widely known. The product combines the novel HIV integrase inhibitor elvitegravir with a novel "boosting" agent, cobicistat, and Gilead’s dual nucleoside/nucleotide reverse transcriptase inhibitor regimen Truvada (emtricitabine/tenofovir).

The approval makes Stribild the first fixed-dose combination HIV drug approved before its individual novel components. Gilead filed the Quad New Drug Application (NDA) in October 2011. The company announced the NDA submissions for single-agent elvitegravir on June 27 and cobicistat 1 day later.

The FDA highlighted the product’s streamlined, once-daily regimen in announcing Stribild’s approval.

"Through continued research and drug development, treatment for those infected with HIV has evolved from multi-pill regimens to single-pill regimens," FDA Office of Antimicrobial Products Director Dr. Edward Cox said in an agency release. "New combination HIV drugs like Stribild help simplify treatment regimens."

Gilead has previously said that Quad would take over the first-line position in the company’s HIV detailing efforts, bumping the triple-combination Complera, which is partnered with Johnson & Johnson’s Tibotec, to second position. Approved in August 2011, Complera combines the non-nucleoside reverse transcriptase inhibitor Edurant (rilpivirine) with Truvada.

An Easy Review

Quad sailed through its May 11 review by the FDA’s Antiviral Drugs Advisory Committee. The panel voted 13-1 in favor of approval, despite renal toxicity concerns and calls for postmarketing studies to better define the drug’s efficacy and safety. The meeting was a relative breeze for Gilead, the FDA, and the committee compared to the panel’s marathon review a day earlier of a pre-exposure prophylaxis indication for Truvada.

At the time of the advisory committee, the FDA appeared to harbor no major efficacy concerns about Quad.

The NDA filing was based upon two similarly designed, phase III studies in which Quad was shown to be noninferior to Gilead/Bristol-Myers Squibb’s Atripla (efavirenz/emtricitabine/tenofovir) and atazanavir/ritonavir plus Truvada.

The agency’s presentation to the committee primarily focused on safety, particularly renal effects and the risk of proximal renal tubulopathy.

Tenofovir has been associated with adverse renal effects. Gilead asserted that cobicistat can cause a modest elevation in serum creatinine, resulting in a decrease in the estimated glomerular filtration rate. However, the company maintained that actual GFR is not affected.

The FDA presented data from the pooled phase III studies showing that eight subjects who received Quad discontinued the study drug due to renal adverse events, four of whom developed proximal renal tubular dysfunction. The agency also presented high-level safety data from a phase III trial of single-agent cobicistat, in which five subjects receiving the boosting agent experienced proximal tubulopathy.

Given the renal adverse events seen with Quad and single-agent cobicistat, the FDA questioned whether two discrete processes were at work: a nonpathologic decrease in eGFR, as suggested by Gilead, and a bona fide increased risk of renal dysfunction.

Panel members generally found the potential renal toxicities were real but manageable with the help of enhanced monitoring. Nephrologists on the panel generally supported the FDA’s proposal that renal function be monitored for all patients, not just those with, or at risk for, renal impairment, as had been suggested by Gilead.

Labeling includes a warning about acute renal failure and Fanconi syndrome with the use of tenofovir and Stribild. It also contains detailed instructions for health care providers: "Monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment. Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; patients with an increase in serum creatinine greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. Do not initiate Stribild in patients with CrCl below 70 mL/min. Discontinue Stribild if CrCl declines below 50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent."

There is also a boxed warning about lactic acidosis and severe hepatomegaly with steatosis with the use of nucleoside analogues, including tenofovir, when used in combination with other antiretrovirals.

Committee members suggested that postmarketing studies should evaluate the best means for detecting renal injury early, and evaluate long-term effects of Quad on renal and bone parameters. The panel also called for further studies on drug-drug interactions and use in women, who represented only 8%-12% of the population in the pivotal trials.

The FDA’s release said that Gilead must conduct postmarketing studies "to help further characterize the drug’s safety in women and children, how resistance develops to Stribild, and the possibility of interactions between Stribild and other drugs."

Concerns About Price

Despite the novelty of a four-in-one, single-dose HIV treatment, not everyone in the HIV/AIDS community has been enthusiastic about the prospects for the drug’s approval, particularly one expected to be priced at a premium to existing regimens.

On Aug. 17, the AIDS Healthcare Foundation (AHF) announced it was requesting that state Medicaid and AIDS Drug Assistance Programs (ADAPs), as well as private insurers, place Quad on prior authorization because the four-drug combination has not been shown to have a significant efficacy or safety advantage over existing treatments.

Prior authorization will "ensure that Quad is only prescribed to patients when there is a documented need for it, and also will help ensure access for people with HIV/AIDS to these safety net programs," AHF said, adding that it has worked with other groups in urging Gilead not to price Quad higher than Atripla, which is currently the most prescribed HIV/AIDS medication.

Gilead’s press release on the approval reports that the company is working with the ADAP Crisis Task Force to provide discounts in state ADAPs, and notes that Stribild will be covered by the company’s Advancing Access Patient Assistance Program as well as the firm’s copay coupon programs for patients with private insurance.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

The Food and Drug Administration approved Stribild on Aug. 27, the product’s user fee date, to treat HIV-1 infection in adults who have never been treated for HIV.

Quad is the moniker by which the four-drug, fixed-dose combination (elvitegravir/cobicistat/emtricitabine/tenofovir) has become widely known. The product combines the novel HIV integrase inhibitor elvitegravir with a novel "boosting" agent, cobicistat, and Gilead’s dual nucleoside/nucleotide reverse transcriptase inhibitor regimen Truvada (emtricitabine/tenofovir).

The approval makes Stribild the first fixed-dose combination HIV drug approved before its individual novel components. Gilead filed the Quad New Drug Application (NDA) in October 2011. The company announced the NDA submissions for single-agent elvitegravir on June 27 and cobicistat 1 day later.

The FDA highlighted the product’s streamlined, once-daily regimen in announcing Stribild’s approval.

"Through continued research and drug development, treatment for those infected with HIV has evolved from multi-pill regimens to single-pill regimens," FDA Office of Antimicrobial Products Director Dr. Edward Cox said in an agency release. "New combination HIV drugs like Stribild help simplify treatment regimens."

Gilead has previously said that Quad would take over the first-line position in the company’s HIV detailing efforts, bumping the triple-combination Complera, which is partnered with Johnson & Johnson’s Tibotec, to second position. Approved in August 2011, Complera combines the non-nucleoside reverse transcriptase inhibitor Edurant (rilpivirine) with Truvada.

An Easy Review

Quad sailed through its May 11 review by the FDA’s Antiviral Drugs Advisory Committee. The panel voted 13-1 in favor of approval, despite renal toxicity concerns and calls for postmarketing studies to better define the drug’s efficacy and safety. The meeting was a relative breeze for Gilead, the FDA, and the committee compared to the panel’s marathon review a day earlier of a pre-exposure prophylaxis indication for Truvada.

At the time of the advisory committee, the FDA appeared to harbor no major efficacy concerns about Quad.

The NDA filing was based upon two similarly designed, phase III studies in which Quad was shown to be noninferior to Gilead/Bristol-Myers Squibb’s Atripla (efavirenz/emtricitabine/tenofovir) and atazanavir/ritonavir plus Truvada.

The agency’s presentation to the committee primarily focused on safety, particularly renal effects and the risk of proximal renal tubulopathy.

Tenofovir has been associated with adverse renal effects. Gilead asserted that cobicistat can cause a modest elevation in serum creatinine, resulting in a decrease in the estimated glomerular filtration rate. However, the company maintained that actual GFR is not affected.

The FDA presented data from the pooled phase III studies showing that eight subjects who received Quad discontinued the study drug due to renal adverse events, four of whom developed proximal renal tubular dysfunction. The agency also presented high-level safety data from a phase III trial of single-agent cobicistat, in which five subjects receiving the boosting agent experienced proximal tubulopathy.

Given the renal adverse events seen with Quad and single-agent cobicistat, the FDA questioned whether two discrete processes were at work: a nonpathologic decrease in eGFR, as suggested by Gilead, and a bona fide increased risk of renal dysfunction.

Panel members generally found the potential renal toxicities were real but manageable with the help of enhanced monitoring. Nephrologists on the panel generally supported the FDA’s proposal that renal function be monitored for all patients, not just those with, or at risk for, renal impairment, as had been suggested by Gilead.

Labeling includes a warning about acute renal failure and Fanconi syndrome with the use of tenofovir and Stribild. It also contains detailed instructions for health care providers: "Monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment. Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; patients with an increase in serum creatinine greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. Do not initiate Stribild in patients with CrCl below 70 mL/min. Discontinue Stribild if CrCl declines below 50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent."

There is also a boxed warning about lactic acidosis and severe hepatomegaly with steatosis with the use of nucleoside analogues, including tenofovir, when used in combination with other antiretrovirals.

Committee members suggested that postmarketing studies should evaluate the best means for detecting renal injury early, and evaluate long-term effects of Quad on renal and bone parameters. The panel also called for further studies on drug-drug interactions and use in women, who represented only 8%-12% of the population in the pivotal trials.

The FDA’s release said that Gilead must conduct postmarketing studies "to help further characterize the drug’s safety in women and children, how resistance develops to Stribild, and the possibility of interactions between Stribild and other drugs."

Concerns About Price

Despite the novelty of a four-in-one, single-dose HIV treatment, not everyone in the HIV/AIDS community has been enthusiastic about the prospects for the drug’s approval, particularly one expected to be priced at a premium to existing regimens.

On Aug. 17, the AIDS Healthcare Foundation (AHF) announced it was requesting that state Medicaid and AIDS Drug Assistance Programs (ADAPs), as well as private insurers, place Quad on prior authorization because the four-drug combination has not been shown to have a significant efficacy or safety advantage over existing treatments.

Prior authorization will "ensure that Quad is only prescribed to patients when there is a documented need for it, and also will help ensure access for people with HIV/AIDS to these safety net programs," AHF said, adding that it has worked with other groups in urging Gilead not to price Quad higher than Atripla, which is currently the most prescribed HIV/AIDS medication.

Gilead’s press release on the approval reports that the company is working with the ADAP Crisis Task Force to provide discounts in state ADAPs, and notes that Stribild will be covered by the company’s Advancing Access Patient Assistance Program as well as the firm’s copay coupon programs for patients with private insurance.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

The Food and Drug Administration approved Stribild on Aug. 27, the product’s user fee date, to treat HIV-1 infection in adults who have never been treated for HIV.

Quad is the moniker by which the four-drug, fixed-dose combination (elvitegravir/cobicistat/emtricitabine/tenofovir) has become widely known. The product combines the novel HIV integrase inhibitor elvitegravir with a novel "boosting" agent, cobicistat, and Gilead’s dual nucleoside/nucleotide reverse transcriptase inhibitor regimen Truvada (emtricitabine/tenofovir).

The approval makes Stribild the first fixed-dose combination HIV drug approved before its individual novel components. Gilead filed the Quad New Drug Application (NDA) in October 2011. The company announced the NDA submissions for single-agent elvitegravir on June 27 and cobicistat 1 day later.

The FDA highlighted the product’s streamlined, once-daily regimen in announcing Stribild’s approval.

"Through continued research and drug development, treatment for those infected with HIV has evolved from multi-pill regimens to single-pill regimens," FDA Office of Antimicrobial Products Director Dr. Edward Cox said in an agency release. "New combination HIV drugs like Stribild help simplify treatment regimens."

Gilead has previously said that Quad would take over the first-line position in the company’s HIV detailing efforts, bumping the triple-combination Complera, which is partnered with Johnson & Johnson’s Tibotec, to second position. Approved in August 2011, Complera combines the non-nucleoside reverse transcriptase inhibitor Edurant (rilpivirine) with Truvada.

An Easy Review

Quad sailed through its May 11 review by the FDA’s Antiviral Drugs Advisory Committee. The panel voted 13-1 in favor of approval, despite renal toxicity concerns and calls for postmarketing studies to better define the drug’s efficacy and safety. The meeting was a relative breeze for Gilead, the FDA, and the committee compared to the panel’s marathon review a day earlier of a pre-exposure prophylaxis indication for Truvada.

At the time of the advisory committee, the FDA appeared to harbor no major efficacy concerns about Quad.

The NDA filing was based upon two similarly designed, phase III studies in which Quad was shown to be noninferior to Gilead/Bristol-Myers Squibb’s Atripla (efavirenz/emtricitabine/tenofovir) and atazanavir/ritonavir plus Truvada.

The agency’s presentation to the committee primarily focused on safety, particularly renal effects and the risk of proximal renal tubulopathy.

Tenofovir has been associated with adverse renal effects. Gilead asserted that cobicistat can cause a modest elevation in serum creatinine, resulting in a decrease in the estimated glomerular filtration rate. However, the company maintained that actual GFR is not affected.

The FDA presented data from the pooled phase III studies showing that eight subjects who received Quad discontinued the study drug due to renal adverse events, four of whom developed proximal renal tubular dysfunction. The agency also presented high-level safety data from a phase III trial of single-agent cobicistat, in which five subjects receiving the boosting agent experienced proximal tubulopathy.

Given the renal adverse events seen with Quad and single-agent cobicistat, the FDA questioned whether two discrete processes were at work: a nonpathologic decrease in eGFR, as suggested by Gilead, and a bona fide increased risk of renal dysfunction.

Panel members generally found the potential renal toxicities were real but manageable with the help of enhanced monitoring. Nephrologists on the panel generally supported the FDA’s proposal that renal function be monitored for all patients, not just those with, or at risk for, renal impairment, as had been suggested by Gilead.

Labeling includes a warning about acute renal failure and Fanconi syndrome with the use of tenofovir and Stribild. It also contains detailed instructions for health care providers: "Monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment. Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; patients with an increase in serum creatinine greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. Do not initiate Stribild in patients with CrCl below 70 mL/min. Discontinue Stribild if CrCl declines below 50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent."

There is also a boxed warning about lactic acidosis and severe hepatomegaly with steatosis with the use of nucleoside analogues, including tenofovir, when used in combination with other antiretrovirals.

Committee members suggested that postmarketing studies should evaluate the best means for detecting renal injury early, and evaluate long-term effects of Quad on renal and bone parameters. The panel also called for further studies on drug-drug interactions and use in women, who represented only 8%-12% of the population in the pivotal trials.

The FDA’s release said that Gilead must conduct postmarketing studies "to help further characterize the drug’s safety in women and children, how resistance develops to Stribild, and the possibility of interactions between Stribild and other drugs."

Concerns About Price

Despite the novelty of a four-in-one, single-dose HIV treatment, not everyone in the HIV/AIDS community has been enthusiastic about the prospects for the drug’s approval, particularly one expected to be priced at a premium to existing regimens.

On Aug. 17, the AIDS Healthcare Foundation (AHF) announced it was requesting that state Medicaid and AIDS Drug Assistance Programs (ADAPs), as well as private insurers, place Quad on prior authorization because the four-drug combination has not been shown to have a significant efficacy or safety advantage over existing treatments.

Prior authorization will "ensure that Quad is only prescribed to patients when there is a documented need for it, and also will help ensure access for people with HIV/AIDS to these safety net programs," AHF said, adding that it has worked with other groups in urging Gilead not to price Quad higher than Atripla, which is currently the most prescribed HIV/AIDS medication.

Gilead’s press release on the approval reports that the company is working with the ADAP Crisis Task Force to provide discounts in state ADAPs, and notes that Stribild will be covered by the company’s Advancing Access Patient Assistance Program as well as the firm’s copay coupon programs for patients with private insurance.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

GlaxoSmithKline PLC pulled its application for a new indication for lapatinib less than 2 weeks before a scheduled advisory committee review – a decision that may have stemmed from Food and Drug Administration questions about the breast cancer drug’s efficacy.

GSK announced on July 12 that it had withdrawn the sNDA (supplemental New Drug Application) for lapatinib (Tykerb) in combination with trastuzumab (Herceptin) for use in patients with HER2-positive metastatic breast cancer who received prior trastuzumab therapy.

The application was scheduled for review by the FDA’s Oncologic Drugs Advisory Committee (ODAC) on the morning of July 24. Because GSK would have received the agency’s briefing package for that meeting 2-3 weeks ahead of time, the timing of the withdrawal announcement suggests that the application garnered a negative evaluation by oncology division reviewers and faced a challenging ODAC meeting.

"Our discussions [with the FDA] highlighted questions that could not be addressed with the data currently available," GSK Oncology R&D Head Rafael Amado said in a press release. "We have decided to withdraw our application [in the United States] with the intent to wait for ongoing studies testing the combination of lapatinib with trastuzumab."

Regulatory reviews of the combination use of lapatinib and trastuzumab are ongoing in the European Union and other regions, the company said.

The sNDA was aimed at adding a third indication to the label of lapatinib, which gained initial approval in March 2007. The kinase inhibitor is currently indicated for use with capecitabine (Xeloda) in patients with advanced or metastatic HER2-positive breast cancer who have received prior therapy, including an anthracycline, a taxane, and trastuzumab; and with letrozole (Femara) for the treatment of postmenopausal women with hormone receptor–positive, HER2-positive metastatic breast cancer for whom hormonal therapy is indicated.

The lapatinib-trastuzumab combination would have been the second FDA-approved combination of two targeted agents against HER2-positive breast cancer. In June, the agency approved pertuzumab (Perjeta), in combination with trastuzumab and chemotherapy, for first-line treatment of HER2-positive metastatic breast cancer.

A 4-Week PFS Advantage ...

GSK declined to comment further on the FDA’s observations about the data in the sNDA, saying that its discussions with the agency are proprietary and confidential. Nevertheless, the pivotal trial’s published results suggest the agency may have questioned whether the lapatinib-trastuzumab combination’s efficacy was sufficiently robust and clinically meaningful.

The filing was based on the results of an open-label, phase III study of 296 patients with HER2-positive metastatic breast cancer whose disease had progressed on trastuzumab-containing regimens. The study results were presented at the 2008 American Society of Clinical Oncology (ASCO) annual meeting.

Subjects were randomized 1:1 to receive either lapatinib monotherapy or lapatinib in combination with trastuzumab. Efficacy assessments were performed every 4 weeks through week 16 and every 8 weeks thereafter. Patients with disease progression after receiving at least 4 weeks of study treatment with lapatinib monotherapy were permitted to cross over to the combination treatment, according to published study results (J. Clin. Oncol. 2010;28:1124-30).

The primary end point was progression-free survival based on investigator assessment, with supporting data provided through an independent review. Secondary end points included overall response rate, clinical benefit response rate, overall survival, quality of life, and safety.

According to the published results, the lapatinib-trastuzumab combination was associated with a statistically significant 27% reduced risk of progression or death, compared with lapatinib monotherapy, based upon investigator assessment (hazard ratio, 0.73; 95% confidence interval, 0.57-0.93; P = .008). Median progression-free survival with the combination was 12.0 weeks, compared with 8.1 weeks for lapatinib monotherapy. Independent review verified a statistically significant improvement (HR, 0.71; 95% CI, 0.52-0.98; P = .027).

Median overall survival was 51.6 weeks in the combination group, compared with 39.0 weeks in the lapatinib monotherapy arm. "Although these data are not mature (56% censoring rate), they show a trend in improved overall survival after combination therapy (HR, 0.75; 95% CI, 0.53-1.07; P = .106)," the study’s authors, led by Dr. Kimberly Blackwell of Duke University in Durham, N.C., wrote.

The overall incidence of adverse events was similar between the two groups, although the incidence of diarrhea was significantly higher with combination therapy.

... May Not Have Been Enough for the FDA

The results, as published, appear to raise several red flags from an FDA review perspective. Specifically, oncology review staff may have questioned whether a median progression-free survival advantage of 4 weeks is clinically meaningful.

This was the crux of the issue in the agency’s decision to withdraw the metastatic breast cancer indication from the label of bevacizumab (Avastin). Accelerated approval was originally granted for a bevacizumab breast cancer claim on the basis of the open-label ECOG (Eastern Cooperative Oncology Group) 2100 trial, which demonstrated a median progression-free survival advantage of 5.5 months; however, confirmatory trials showed smaller median improvements ranging from 0.9-2.9 months, and the agency determined these subsequent studies failed to verify the magnitude of benefit seen in ECOG 2100.

The agency also may have had concerns about the lapatinib study’s use of a primary end point based upon investigator assessment.

For open-label trials using progression-free survival as the primary end point, the agency generally requires 100% blinded independent review of progression determinations, although it has indicated a willingness to consider relaxing this requirement. During the afternoon session of ODAC’s July 24 meeting, the committee will discuss the feasibility of conducting independent audits of only a subgroup of patient scans in trials using this end point.

The fact that independent blinded review was not the lapatinib trial’s primary end point might have been a concern for the agency, as might related issues such as missing data or informative censoring. Furthermore, the upper limit of the 95% confidence interval for the independent review results fell just below 1.0, according to the published results, and this statistical result may not have held up under further scrutiny by agency reviewers.

Waiting on Other Studies

Although GSK said that it would await the results from other studies that will provide additional information about the combination of lapatinib with trastuzumab, it declined to highlight any one study in particular.

The ClinicalTrials.gov database lists numerous breast cancer studies, currently in recruitment, for which both lapatinib and trastuzumab are study interventions.

These include a randomized, open-label, phase III trial evaluating the efficacy and safety of lapatinib in combination with trastuzumab vs. trastuzumab alone as maintenance therapy in women with HER2-positive metastatic breast cancer. The 280-patient study, which is being conducted in the United States and Canada, is expected to complete in August 2014.

Another phase III trial is comparing the safety and efficacy of an aromatase inhibitor in combination with lapatinib, trastuzumab or both for the treatment of hormone receptor–positive, HER2-positive metastatic breast cancer. The estimated completion date for the 525-patient study is December 2017.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

GlaxoSmithKline PLC pulled its application for a new indication for lapatinib less than 2 weeks before a scheduled advisory committee review – a decision that may have stemmed from Food and Drug Administration questions about the breast cancer drug’s efficacy.

GSK announced on July 12 that it had withdrawn the sNDA (supplemental New Drug Application) for lapatinib (Tykerb) in combination with trastuzumab (Herceptin) for use in patients with HER2-positive metastatic breast cancer who received prior trastuzumab therapy.

The application was scheduled for review by the FDA’s Oncologic Drugs Advisory Committee (ODAC) on the morning of July 24. Because GSK would have received the agency’s briefing package for that meeting 2-3 weeks ahead of time, the timing of the withdrawal announcement suggests that the application garnered a negative evaluation by oncology division reviewers and faced a challenging ODAC meeting.

"Our discussions [with the FDA] highlighted questions that could not be addressed with the data currently available," GSK Oncology R&D Head Rafael Amado said in a press release. "We have decided to withdraw our application [in the United States] with the intent to wait for ongoing studies testing the combination of lapatinib with trastuzumab."

Regulatory reviews of the combination use of lapatinib and trastuzumab are ongoing in the European Union and other regions, the company said.

The sNDA was aimed at adding a third indication to the label of lapatinib, which gained initial approval in March 2007. The kinase inhibitor is currently indicated for use with capecitabine (Xeloda) in patients with advanced or metastatic HER2-positive breast cancer who have received prior therapy, including an anthracycline, a taxane, and trastuzumab; and with letrozole (Femara) for the treatment of postmenopausal women with hormone receptor–positive, HER2-positive metastatic breast cancer for whom hormonal therapy is indicated.

The lapatinib-trastuzumab combination would have been the second FDA-approved combination of two targeted agents against HER2-positive breast cancer. In June, the agency approved pertuzumab (Perjeta), in combination with trastuzumab and chemotherapy, for first-line treatment of HER2-positive metastatic breast cancer.

A 4-Week PFS Advantage ...

GSK declined to comment further on the FDA’s observations about the data in the sNDA, saying that its discussions with the agency are proprietary and confidential. Nevertheless, the pivotal trial’s published results suggest the agency may have questioned whether the lapatinib-trastuzumab combination’s efficacy was sufficiently robust and clinically meaningful.

The filing was based on the results of an open-label, phase III study of 296 patients with HER2-positive metastatic breast cancer whose disease had progressed on trastuzumab-containing regimens. The study results were presented at the 2008 American Society of Clinical Oncology (ASCO) annual meeting.

Subjects were randomized 1:1 to receive either lapatinib monotherapy or lapatinib in combination with trastuzumab. Efficacy assessments were performed every 4 weeks through week 16 and every 8 weeks thereafter. Patients with disease progression after receiving at least 4 weeks of study treatment with lapatinib monotherapy were permitted to cross over to the combination treatment, according to published study results (J. Clin. Oncol. 2010;28:1124-30).

The primary end point was progression-free survival based on investigator assessment, with supporting data provided through an independent review. Secondary end points included overall response rate, clinical benefit response rate, overall survival, quality of life, and safety.

According to the published results, the lapatinib-trastuzumab combination was associated with a statistically significant 27% reduced risk of progression or death, compared with lapatinib monotherapy, based upon investigator assessment (hazard ratio, 0.73; 95% confidence interval, 0.57-0.93; P = .008). Median progression-free survival with the combination was 12.0 weeks, compared with 8.1 weeks for lapatinib monotherapy. Independent review verified a statistically significant improvement (HR, 0.71; 95% CI, 0.52-0.98; P = .027).

Median overall survival was 51.6 weeks in the combination group, compared with 39.0 weeks in the lapatinib monotherapy arm. "Although these data are not mature (56% censoring rate), they show a trend in improved overall survival after combination therapy (HR, 0.75; 95% CI, 0.53-1.07; P = .106)," the study’s authors, led by Dr. Kimberly Blackwell of Duke University in Durham, N.C., wrote.

The overall incidence of adverse events was similar between the two groups, although the incidence of diarrhea was significantly higher with combination therapy.

... May Not Have Been Enough for the FDA

The results, as published, appear to raise several red flags from an FDA review perspective. Specifically, oncology review staff may have questioned whether a median progression-free survival advantage of 4 weeks is clinically meaningful.

This was the crux of the issue in the agency’s decision to withdraw the metastatic breast cancer indication from the label of bevacizumab (Avastin). Accelerated approval was originally granted for a bevacizumab breast cancer claim on the basis of the open-label ECOG (Eastern Cooperative Oncology Group) 2100 trial, which demonstrated a median progression-free survival advantage of 5.5 months; however, confirmatory trials showed smaller median improvements ranging from 0.9-2.9 months, and the agency determined these subsequent studies failed to verify the magnitude of benefit seen in ECOG 2100.

The agency also may have had concerns about the lapatinib study’s use of a primary end point based upon investigator assessment.

For open-label trials using progression-free survival as the primary end point, the agency generally requires 100% blinded independent review of progression determinations, although it has indicated a willingness to consider relaxing this requirement. During the afternoon session of ODAC’s July 24 meeting, the committee will discuss the feasibility of conducting independent audits of only a subgroup of patient scans in trials using this end point.

The fact that independent blinded review was not the lapatinib trial’s primary end point might have been a concern for the agency, as might related issues such as missing data or informative censoring. Furthermore, the upper limit of the 95% confidence interval for the independent review results fell just below 1.0, according to the published results, and this statistical result may not have held up under further scrutiny by agency reviewers.

Waiting on Other Studies

Although GSK said that it would await the results from other studies that will provide additional information about the combination of lapatinib with trastuzumab, it declined to highlight any one study in particular.

The ClinicalTrials.gov database lists numerous breast cancer studies, currently in recruitment, for which both lapatinib and trastuzumab are study interventions.

These include a randomized, open-label, phase III trial evaluating the efficacy and safety of lapatinib in combination with trastuzumab vs. trastuzumab alone as maintenance therapy in women with HER2-positive metastatic breast cancer. The 280-patient study, which is being conducted in the United States and Canada, is expected to complete in August 2014.

Another phase III trial is comparing the safety and efficacy of an aromatase inhibitor in combination with lapatinib, trastuzumab or both for the treatment of hormone receptor–positive, HER2-positive metastatic breast cancer. The estimated completion date for the 525-patient study is December 2017.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

GlaxoSmithKline PLC pulled its application for a new indication for lapatinib less than 2 weeks before a scheduled advisory committee review – a decision that may have stemmed from Food and Drug Administration questions about the breast cancer drug’s efficacy.

GSK announced on July 12 that it had withdrawn the sNDA (supplemental New Drug Application) for lapatinib (Tykerb) in combination with trastuzumab (Herceptin) for use in patients with HER2-positive metastatic breast cancer who received prior trastuzumab therapy.

The application was scheduled for review by the FDA’s Oncologic Drugs Advisory Committee (ODAC) on the morning of July 24. Because GSK would have received the agency’s briefing package for that meeting 2-3 weeks ahead of time, the timing of the withdrawal announcement suggests that the application garnered a negative evaluation by oncology division reviewers and faced a challenging ODAC meeting.

"Our discussions [with the FDA] highlighted questions that could not be addressed with the data currently available," GSK Oncology R&D Head Rafael Amado said in a press release. "We have decided to withdraw our application [in the United States] with the intent to wait for ongoing studies testing the combination of lapatinib with trastuzumab."

Regulatory reviews of the combination use of lapatinib and trastuzumab are ongoing in the European Union and other regions, the company said.

The sNDA was aimed at adding a third indication to the label of lapatinib, which gained initial approval in March 2007. The kinase inhibitor is currently indicated for use with capecitabine (Xeloda) in patients with advanced or metastatic HER2-positive breast cancer who have received prior therapy, including an anthracycline, a taxane, and trastuzumab; and with letrozole (Femara) for the treatment of postmenopausal women with hormone receptor–positive, HER2-positive metastatic breast cancer for whom hormonal therapy is indicated.

The lapatinib-trastuzumab combination would have been the second FDA-approved combination of two targeted agents against HER2-positive breast cancer. In June, the agency approved pertuzumab (Perjeta), in combination with trastuzumab and chemotherapy, for first-line treatment of HER2-positive metastatic breast cancer.

A 4-Week PFS Advantage ...

GSK declined to comment further on the FDA’s observations about the data in the sNDA, saying that its discussions with the agency are proprietary and confidential. Nevertheless, the pivotal trial’s published results suggest the agency may have questioned whether the lapatinib-trastuzumab combination’s efficacy was sufficiently robust and clinically meaningful.

The filing was based on the results of an open-label, phase III study of 296 patients with HER2-positive metastatic breast cancer whose disease had progressed on trastuzumab-containing regimens. The study results were presented at the 2008 American Society of Clinical Oncology (ASCO) annual meeting.

Subjects were randomized 1:1 to receive either lapatinib monotherapy or lapatinib in combination with trastuzumab. Efficacy assessments were performed every 4 weeks through week 16 and every 8 weeks thereafter. Patients with disease progression after receiving at least 4 weeks of study treatment with lapatinib monotherapy were permitted to cross over to the combination treatment, according to published study results (J. Clin. Oncol. 2010;28:1124-30).

The primary end point was progression-free survival based on investigator assessment, with supporting data provided through an independent review. Secondary end points included overall response rate, clinical benefit response rate, overall survival, quality of life, and safety.

According to the published results, the lapatinib-trastuzumab combination was associated with a statistically significant 27% reduced risk of progression or death, compared with lapatinib monotherapy, based upon investigator assessment (hazard ratio, 0.73; 95% confidence interval, 0.57-0.93; P = .008). Median progression-free survival with the combination was 12.0 weeks, compared with 8.1 weeks for lapatinib monotherapy. Independent review verified a statistically significant improvement (HR, 0.71; 95% CI, 0.52-0.98; P = .027).

Median overall survival was 51.6 weeks in the combination group, compared with 39.0 weeks in the lapatinib monotherapy arm. "Although these data are not mature (56% censoring rate), they show a trend in improved overall survival after combination therapy (HR, 0.75; 95% CI, 0.53-1.07; P = .106)," the study’s authors, led by Dr. Kimberly Blackwell of Duke University in Durham, N.C., wrote.

The overall incidence of adverse events was similar between the two groups, although the incidence of diarrhea was significantly higher with combination therapy.

... May Not Have Been Enough for the FDA

The results, as published, appear to raise several red flags from an FDA review perspective. Specifically, oncology review staff may have questioned whether a median progression-free survival advantage of 4 weeks is clinically meaningful.

This was the crux of the issue in the agency’s decision to withdraw the metastatic breast cancer indication from the label of bevacizumab (Avastin). Accelerated approval was originally granted for a bevacizumab breast cancer claim on the basis of the open-label ECOG (Eastern Cooperative Oncology Group) 2100 trial, which demonstrated a median progression-free survival advantage of 5.5 months; however, confirmatory trials showed smaller median improvements ranging from 0.9-2.9 months, and the agency determined these subsequent studies failed to verify the magnitude of benefit seen in ECOG 2100.

The agency also may have had concerns about the lapatinib study’s use of a primary end point based upon investigator assessment.

For open-label trials using progression-free survival as the primary end point, the agency generally requires 100% blinded independent review of progression determinations, although it has indicated a willingness to consider relaxing this requirement. During the afternoon session of ODAC’s July 24 meeting, the committee will discuss the feasibility of conducting independent audits of only a subgroup of patient scans in trials using this end point.

The fact that independent blinded review was not the lapatinib trial’s primary end point might have been a concern for the agency, as might related issues such as missing data or informative censoring. Furthermore, the upper limit of the 95% confidence interval for the independent review results fell just below 1.0, according to the published results, and this statistical result may not have held up under further scrutiny by agency reviewers.

Waiting on Other Studies

Although GSK said that it would await the results from other studies that will provide additional information about the combination of lapatinib with trastuzumab, it declined to highlight any one study in particular.

The ClinicalTrials.gov database lists numerous breast cancer studies, currently in recruitment, for which both lapatinib and trastuzumab are study interventions.

These include a randomized, open-label, phase III trial evaluating the efficacy and safety of lapatinib in combination with trastuzumab vs. trastuzumab alone as maintenance therapy in women with HER2-positive metastatic breast cancer. The 280-patient study, which is being conducted in the United States and Canada, is expected to complete in August 2014.

Another phase III trial is comparing the safety and efficacy of an aromatase inhibitor in combination with lapatinib, trastuzumab or both for the treatment of hormone receptor–positive, HER2-positive metastatic breast cancer. The estimated completion date for the 525-patient study is December 2017.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.

In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.

The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.

The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.

Benefit Over Existing Therapies

Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.

The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.

The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.

"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).

The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.

The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.

The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."

Deaths, SAEs, and Discontinuations

There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.

Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.

The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.

"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."

Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.

"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."

The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.

Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."

Phase III Trials Underway

Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.

In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.

The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.

The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.

Benefit Over Existing Therapies

Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.

The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.

The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.

"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).

The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.

The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.

The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."

Deaths, SAEs, and Discontinuations

There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.

Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.

The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.

"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."

Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.

"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."

The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.

Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."

Phase III Trials Underway

Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.

In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.

The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.

The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.

Benefit Over Existing Therapies

Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.

The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.

The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.

"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).

The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.

The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.

The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."

Deaths, SAEs, and Discontinuations

There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.

Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.

The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.

"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."

Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.

"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."

The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.

Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."

Phase III Trials Underway

Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee will be asked at a May 23 meeting whether the advantage seen with Johnson & Johnson/Bayer HealthCare AG’s Xarelto (rivaroxaban) in acute coronary syndromes is undermined by the extent of missing data in the pivotal trial.

In background briefing materials released May 21, the FDA said the pivotal ATLAS ACS 2-TIMI 51 trial had substantial missing data, including lack of vital status, because of the withdrawal of consent. In its draft questions for discussion, the FDA’s Division of Cardiovascular and Renal Drug Products seeks the committee’s views on how the missing data affected interpretation of the ATLAS efficacy results. In that study, rivaroxaban was associated with a statistically significant reduction in the risk of the composite end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, though with significantly increased bleeding.

The review division appears interested in using rivaroxaban as the platform for a broader discussion on issues surrounding missing data in cardiovascular studies. According to the draft questions, the committee will be asked whether the agency should prespecify trial standards for data quality in the same way it prespecifies standards for demonstrating statistical significance.

The committee will be asked to vote on whether rivaroxaban should be approved in ACS and, if so, how it should be labeled.

Finally, the division plans to ask committee members the unusual question of whether, if the ACS claim is approved, they will use rivaroxaban for such patients in clinical practice.

Three Indications, Three Advisory Committees

Johnson & Johnson’s Janssen Pharmaceuticals division is seeking approval of the Factor Xa inhibitor to reduce the risk of thrombotic CV events in patients with acute ACS – defined as ST elevation myocardial infarction (STEMI), non-STEMI, or unstable angina – in combination with aspirin alone or aspirin plus clopidogrel or ticlopidine. The proposed dose is 2.5 mg twice daily.

The supplemental new drug application is undergoing a priority review, with a June 29 Prescription Drug User Fee Act (PDUFA) date. If approved, the ACS indication would be the third for rivaroxaban. The drug gained its initial approval in July 2011 for prevention of deep vein thrombosis and pulmonary embolism after hip or knee replacement surgery. In November, it added a claim for stroke risk reduction in patients with atrial fibrillation.

The ACS claim marks the third advisory committee meeting for rivaroxaban; the cardiorenal panel previously recommended approval for the deep vein thrombosis prophylaxis and atrial fibrillation indications.

ACS Claim Rests on the Shoulders of ATLAS

The proposed indication is based on the phase III, 15,526-patient ATLAS trial, the results of which were published in the New England Journal of Medicine in November (2011;366:9-19 [doi:10.1056/NEJMoa1112277]).

The trial randomized ACS patients to rivaroxaban 2.5 mg twice daily, 5 mg twice daily, or placebo; patients were stratified based upon whether they received concomitant aspirin alone (stratum 1) or aspirin with a thienopyridine (stratum 2). In her April 30 clinical review, medical officer Karen Hicks said stratum 2 was the most clinically relevant stratum for U.S. ACS patients.

Dr. Hicks said she recommended approval of rivaroxaban in ACS, finding efficacy to have been demonstrated under numerous different analyses.

"In all strata, including subjects treated with aspirin (stratum 1) and subjects treated with aspirin plus a thienopyridine (stratum 2), on-treatment plus 30 days (sponsor’s modified intent to treat) and intent to treat analyses ... demonstrated that rivaroxaban (combined, 2.5 mg twice daily, and 5 mg twice daily) significantly reduced the occurrence of the composite primary end point of cardiovascular death, myocardial infarction or stroke, compared with placebo, in ACS subjects stabilized 1-7 days post index event," Dr. Hicks said. "Numerous sensitivity analyses confirmed these results."

These efficacy results were statistically significant, regardless of whether data from three Indian clinical trial sites were included or excluded. The sponsors proposed to exclude the sites because of Good Clinical Practice violations.

Risk reductions for the 2.5-mg dose ranged from 16%-18% across all strata and 15%-18% in stratum 2.

The findings in all strata and stratum 2 were driven primarily by a reduction in CV deaths, particularly on the 2.5 mg dose, and to a lesser extent by a reduction in MI, Dr. Hicks said. "Compared to 2.5 mg BID [twice daily], rivaroxaban 5 mg BID increased the risk of all bleeding events without providing additional efficacy. Further, rivaroxaban 5 mg BID improved MI but not CV death, which was somewhat unexpected."

The 2.5-mg dose was associated with an all-cause mortality benefit that was nominally statistically significant. However, the 5-mg dose demonstrated no mortality advantage, and the two doses combined did not produce a statistically robust benefit. "Given the inconsistent results between rivaroxaban 2.5 mg BID and rivaroxaban 5 mg BID with respect to CV death and all-cause mortality, I do not recommend a mortality claim," Dr. Hicks said.

Significant Increases in Bleeding

On the safety side, rivaroxaban significantly increased the risk of all bleeding events, compared with placebo.

Across all strata, the 2.5-mg dose significantly increased the risk of the following TIMI classifications of bleeding: major, major or minor, life-threatening, intracranial hemorrhage, minor, clinically significant, and warranting medical attention. In stratum 2, the 2.5-mg dose significantly increased all TIMI major or minor bleeding, major bleeding, life-threatening bleeding, clinically significant bleeding, and medical attention bleeding. The 2.5-mg dose did not significantly increase the risk of TIMI major fatal bleeding or fatal intracranial hemorrhage.

In stratum 2, the 2.5-mg dose reduced the rate of the primary end point by 15% while increasing the rate of bleeding not related to coronary artery bypass graft surgery, Dr. Hicks said. "There was a twofold increase in TIMI major fatal bleeding and threefold increases in TIMI major bleeding, intracranial hemorrhage, hemorrhagic stroke, TIMI life-threatening bleeding, and TIMI major or minor bleeding. There was also an 18% increase in the risk of fatal stroke. Although the hazard ratios were increased, the absolute incidence of these events was low."

Subjects aged 75 years and older, and individuals weighing less than 60 kg, had an increased risk of bleeding events.

ACS subjects appeared to have a more pronounced tendency for liver injury than did populations studied in the atrial fibrillation and deep vein thrombosis prophylaxis studies. "Therefore, rivaroxaban, even in lower doses than what is recommended for other uses, appears possibly to cause mild liver injury in some patients. This finding likely reflects some increased susceptibility to drug-induced liver injury in patients with ACS," Dr. Hicks said.

Data Quality as a Counterargument to Approval

Dr. Hicks said that in arriving at her approval recommendation, she considered the argument that the amount of missing data from the ATLAS study weighed against approval.

Across all strata, 2,402 subjects (15.5%) discontinued the study prematurely, including 1,294 subjects (8%) who withdrew consent. "There were [more than] 1,000 subjects at the end of the trial with unknown vital status," Dr. Hicks said. Additionally, there were incomplete follow-up and uncounted deaths. "The quantity of missing data in ATLAS could affect the overall interpretability of the trial."

Nevertheless, Dr. Hicks suggested she was satisfied with the sponsors’ attempt to obtain vital status information on missing subjects and its responses to the FDA’s information requests on the issue. She also pointed to the broader problem of missing data in the setting of CV outcomes studies.

Shades of Ticagrelor

However, Dr. Thomas Marciniak, the review division’s medical team leader on the rivaroxaban application, takes a tougher stand on the issue of missing data and its ramifications for approval. In an April 26 memo, Dr. Marciniak suggests that the data quality may not support the favorable statistical results reported with the 2.5-mg dose.

The percentage of patients with incomplete follow-up in the study was high, averaging about 12%, he noted. "This percentage is far higher than the differences between the placebo and rivaroxaban arms in end point rates, which typically are about 1%-1.5%. The difference between placebo and rivaroxaban for bad follow-up rates matches these differences in end point rates. By [Johnson & Johnson’s] patient status statistics, there appears to be plenty of opportunity for incomplete data to obscure or magnify any differences in end points."

Furthermore, the rates of patients with unknown vital status exceed the reported differences in mortality rates, Dr. Marciniak said, asserting, "We cannot have confidence that the claimed mortality benefits are real."

He also challenged the sponsors’ approach to censoring patients and their classification of deaths that occurred after withdrawal of consent, saying this may have led to an overstatement of rivaroxaban’s efficacy.

"Because of the extent of missing follow-up in ATLAS, we cannot have confidence in either the calculated mortality or CV endpoint benefits," he said.

Marciniak’s criticisms about ATLAS are reminiscent of his attacks on the pivotal efficacy study for AstraZeneca PLC’s ticagrelor (Brilinta). During a July 2010 advisory committee review of the antiplatelet agent, Dr. Marciniak criticized the sponsor for inadequate end point and vital status follow-up in the 18,624-patient PLATO trial.

Dr. Marciniak’s criticisms were even more strenuous in his written reviews, in which he cited inadequate data collection and analyses, poor follow-up, faulty adverse event reporting, failure to adjudicate potential end points, an inappropriate primary end point, and censoring problems. The review division approved ticagrelor in July 2011 despite Dr. Marciniak’s recommendation against approval.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee will be asked at a May 23 meeting whether the advantage seen with Johnson & Johnson/Bayer HealthCare AG’s Xarelto (rivaroxaban) in acute coronary syndromes is undermined by the extent of missing data in the pivotal trial.

In background briefing materials released May 21, the FDA said the pivotal ATLAS ACS 2-TIMI 51 trial had substantial missing data, including lack of vital status, because of the withdrawal of consent. In its draft questions for discussion, the FDA’s Division of Cardiovascular and Renal Drug Products seeks the committee’s views on how the missing data affected interpretation of the ATLAS efficacy results. In that study, rivaroxaban was associated with a statistically significant reduction in the risk of the composite end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, though with significantly increased bleeding.

The review division appears interested in using rivaroxaban as the platform for a broader discussion on issues surrounding missing data in cardiovascular studies. According to the draft questions, the committee will be asked whether the agency should prespecify trial standards for data quality in the same way it prespecifies standards for demonstrating statistical significance.

The committee will be asked to vote on whether rivaroxaban should be approved in ACS and, if so, how it should be labeled.

Finally, the division plans to ask committee members the unusual question of whether, if the ACS claim is approved, they will use rivaroxaban for such patients in clinical practice.

Three Indications, Three Advisory Committees

Johnson & Johnson’s Janssen Pharmaceuticals division is seeking approval of the Factor Xa inhibitor to reduce the risk of thrombotic CV events in patients with acute ACS – defined as ST elevation myocardial infarction (STEMI), non-STEMI, or unstable angina – in combination with aspirin alone or aspirin plus clopidogrel or ticlopidine. The proposed dose is 2.5 mg twice daily.

The supplemental new drug application is undergoing a priority review, with a June 29 Prescription Drug User Fee Act (PDUFA) date. If approved, the ACS indication would be the third for rivaroxaban. The drug gained its initial approval in July 2011 for prevention of deep vein thrombosis and pulmonary embolism after hip or knee replacement surgery. In November, it added a claim for stroke risk reduction in patients with atrial fibrillation.

The ACS claim marks the third advisory committee meeting for rivaroxaban; the cardiorenal panel previously recommended approval for the deep vein thrombosis prophylaxis and atrial fibrillation indications.

ACS Claim Rests on the Shoulders of ATLAS

The proposed indication is based on the phase III, 15,526-patient ATLAS trial, the results of which were published in the New England Journal of Medicine in November (2011;366:9-19 [doi:10.1056/NEJMoa1112277]).

The trial randomized ACS patients to rivaroxaban 2.5 mg twice daily, 5 mg twice daily, or placebo; patients were stratified based upon whether they received concomitant aspirin alone (stratum 1) or aspirin with a thienopyridine (stratum 2). In her April 30 clinical review, medical officer Karen Hicks said stratum 2 was the most clinically relevant stratum for U.S. ACS patients.

Dr. Hicks said she recommended approval of rivaroxaban in ACS, finding efficacy to have been demonstrated under numerous different analyses.

"In all strata, including subjects treated with aspirin (stratum 1) and subjects treated with aspirin plus a thienopyridine (stratum 2), on-treatment plus 30 days (sponsor’s modified intent to treat) and intent to treat analyses ... demonstrated that rivaroxaban (combined, 2.5 mg twice daily, and 5 mg twice daily) significantly reduced the occurrence of the composite primary end point of cardiovascular death, myocardial infarction or stroke, compared with placebo, in ACS subjects stabilized 1-7 days post index event," Dr. Hicks said. "Numerous sensitivity analyses confirmed these results."

These efficacy results were statistically significant, regardless of whether data from three Indian clinical trial sites were included or excluded. The sponsors proposed to exclude the sites because of Good Clinical Practice violations.

Risk reductions for the 2.5-mg dose ranged from 16%-18% across all strata and 15%-18% in stratum 2.

The findings in all strata and stratum 2 were driven primarily by a reduction in CV deaths, particularly on the 2.5 mg dose, and to a lesser extent by a reduction in MI, Dr. Hicks said. "Compared to 2.5 mg BID [twice daily], rivaroxaban 5 mg BID increased the risk of all bleeding events without providing additional efficacy. Further, rivaroxaban 5 mg BID improved MI but not CV death, which was somewhat unexpected."

The 2.5-mg dose was associated with an all-cause mortality benefit that was nominally statistically significant. However, the 5-mg dose demonstrated no mortality advantage, and the two doses combined did not produce a statistically robust benefit. "Given the inconsistent results between rivaroxaban 2.5 mg BID and rivaroxaban 5 mg BID with respect to CV death and all-cause mortality, I do not recommend a mortality claim," Dr. Hicks said.

Significant Increases in Bleeding

On the safety side, rivaroxaban significantly increased the risk of all bleeding events, compared with placebo.

Across all strata, the 2.5-mg dose significantly increased the risk of the following TIMI classifications of bleeding: major, major or minor, life-threatening, intracranial hemorrhage, minor, clinically significant, and warranting medical attention. In stratum 2, the 2.5-mg dose significantly increased all TIMI major or minor bleeding, major bleeding, life-threatening bleeding, clinically significant bleeding, and medical attention bleeding. The 2.5-mg dose did not significantly increase the risk of TIMI major fatal bleeding or fatal intracranial hemorrhage.

In stratum 2, the 2.5-mg dose reduced the rate of the primary end point by 15% while increasing the rate of bleeding not related to coronary artery bypass graft surgery, Dr. Hicks said. "There was a twofold increase in TIMI major fatal bleeding and threefold increases in TIMI major bleeding, intracranial hemorrhage, hemorrhagic stroke, TIMI life-threatening bleeding, and TIMI major or minor bleeding. There was also an 18% increase in the risk of fatal stroke. Although the hazard ratios were increased, the absolute incidence of these events was low."

Subjects aged 75 years and older, and individuals weighing less than 60 kg, had an increased risk of bleeding events.

ACS subjects appeared to have a more pronounced tendency for liver injury than did populations studied in the atrial fibrillation and deep vein thrombosis prophylaxis studies. "Therefore, rivaroxaban, even in lower doses than what is recommended for other uses, appears possibly to cause mild liver injury in some patients. This finding likely reflects some increased susceptibility to drug-induced liver injury in patients with ACS," Dr. Hicks said.

Data Quality as a Counterargument to Approval

Dr. Hicks said that in arriving at her approval recommendation, she considered the argument that the amount of missing data from the ATLAS study weighed against approval.

Across all strata, 2,402 subjects (15.5%) discontinued the study prematurely, including 1,294 subjects (8%) who withdrew consent. "There were [more than] 1,000 subjects at the end of the trial with unknown vital status," Dr. Hicks said. Additionally, there were incomplete follow-up and uncounted deaths. "The quantity of missing data in ATLAS could affect the overall interpretability of the trial."

Nevertheless, Dr. Hicks suggested she was satisfied with the sponsors’ attempt to obtain vital status information on missing subjects and its responses to the FDA’s information requests on the issue. She also pointed to the broader problem of missing data in the setting of CV outcomes studies.

Shades of Ticagrelor

However, Dr. Thomas Marciniak, the review division’s medical team leader on the rivaroxaban application, takes a tougher stand on the issue of missing data and its ramifications for approval. In an April 26 memo, Dr. Marciniak suggests that the data quality may not support the favorable statistical results reported with the 2.5-mg dose.

The percentage of patients with incomplete follow-up in the study was high, averaging about 12%, he noted. "This percentage is far higher than the differences between the placebo and rivaroxaban arms in end point rates, which typically are about 1%-1.5%. The difference between placebo and rivaroxaban for bad follow-up rates matches these differences in end point rates. By [Johnson & Johnson’s] patient status statistics, there appears to be plenty of opportunity for incomplete data to obscure or magnify any differences in end points."

Furthermore, the rates of patients with unknown vital status exceed the reported differences in mortality rates, Dr. Marciniak said, asserting, "We cannot have confidence that the claimed mortality benefits are real."

He also challenged the sponsors’ approach to censoring patients and their classification of deaths that occurred after withdrawal of consent, saying this may have led to an overstatement of rivaroxaban’s efficacy.

"Because of the extent of missing follow-up in ATLAS, we cannot have confidence in either the calculated mortality or CV endpoint benefits," he said.

Marciniak’s criticisms about ATLAS are reminiscent of his attacks on the pivotal efficacy study for AstraZeneca PLC’s ticagrelor (Brilinta). During a July 2010 advisory committee review of the antiplatelet agent, Dr. Marciniak criticized the sponsor for inadequate end point and vital status follow-up in the 18,624-patient PLATO trial.

Dr. Marciniak’s criticisms were even more strenuous in his written reviews, in which he cited inadequate data collection and analyses, poor follow-up, faulty adverse event reporting, failure to adjudicate potential end points, an inappropriate primary end point, and censoring problems. The review division approved ticagrelor in July 2011 despite Dr. Marciniak’s recommendation against approval.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee will be asked at a May 23 meeting whether the advantage seen with Johnson & Johnson/Bayer HealthCare AG’s Xarelto (rivaroxaban) in acute coronary syndromes is undermined by the extent of missing data in the pivotal trial.

In background briefing materials released May 21, the FDA said the pivotal ATLAS ACS 2-TIMI 51 trial had substantial missing data, including lack of vital status, because of the withdrawal of consent. In its draft questions for discussion, the FDA’s Division of Cardiovascular and Renal Drug Products seeks the committee’s views on how the missing data affected interpretation of the ATLAS efficacy results. In that study, rivaroxaban was associated with a statistically significant reduction in the risk of the composite end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, though with significantly increased bleeding.

The review division appears interested in using rivaroxaban as the platform for a broader discussion on issues surrounding missing data in cardiovascular studies. According to the draft questions, the committee will be asked whether the agency should prespecify trial standards for data quality in the same way it prespecifies standards for demonstrating statistical significance.

The committee will be asked to vote on whether rivaroxaban should be approved in ACS and, if so, how it should be labeled.

Finally, the division plans to ask committee members the unusual question of whether, if the ACS claim is approved, they will use rivaroxaban for such patients in clinical practice.

Three Indications, Three Advisory Committees

Johnson & Johnson’s Janssen Pharmaceuticals division is seeking approval of the Factor Xa inhibitor to reduce the risk of thrombotic CV events in patients with acute ACS – defined as ST elevation myocardial infarction (STEMI), non-STEMI, or unstable angina – in combination with aspirin alone or aspirin plus clopidogrel or ticlopidine. The proposed dose is 2.5 mg twice daily.

The supplemental new drug application is undergoing a priority review, with a June 29 Prescription Drug User Fee Act (PDUFA) date. If approved, the ACS indication would be the third for rivaroxaban. The drug gained its initial approval in July 2011 for prevention of deep vein thrombosis and pulmonary embolism after hip or knee replacement surgery. In November, it added a claim for stroke risk reduction in patients with atrial fibrillation.

The ACS claim marks the third advisory committee meeting for rivaroxaban; the cardiorenal panel previously recommended approval for the deep vein thrombosis prophylaxis and atrial fibrillation indications.

ACS Claim Rests on the Shoulders of ATLAS

The proposed indication is based on the phase III, 15,526-patient ATLAS trial, the results of which were published in the New England Journal of Medicine in November (2011;366:9-19 [doi:10.1056/NEJMoa1112277]).

The trial randomized ACS patients to rivaroxaban 2.5 mg twice daily, 5 mg twice daily, or placebo; patients were stratified based upon whether they received concomitant aspirin alone (stratum 1) or aspirin with a thienopyridine (stratum 2). In her April 30 clinical review, medical officer Karen Hicks said stratum 2 was the most clinically relevant stratum for U.S. ACS patients.

Dr. Hicks said she recommended approval of rivaroxaban in ACS, finding efficacy to have been demonstrated under numerous different analyses.

"In all strata, including subjects treated with aspirin (stratum 1) and subjects treated with aspirin plus a thienopyridine (stratum 2), on-treatment plus 30 days (sponsor’s modified intent to treat) and intent to treat analyses ... demonstrated that rivaroxaban (combined, 2.5 mg twice daily, and 5 mg twice daily) significantly reduced the occurrence of the composite primary end point of cardiovascular death, myocardial infarction or stroke, compared with placebo, in ACS subjects stabilized 1-7 days post index event," Dr. Hicks said. "Numerous sensitivity analyses confirmed these results."

These efficacy results were statistically significant, regardless of whether data from three Indian clinical trial sites were included or excluded. The sponsors proposed to exclude the sites because of Good Clinical Practice violations.

Risk reductions for the 2.5-mg dose ranged from 16%-18% across all strata and 15%-18% in stratum 2.

The findings in all strata and stratum 2 were driven primarily by a reduction in CV deaths, particularly on the 2.5 mg dose, and to a lesser extent by a reduction in MI, Dr. Hicks said. "Compared to 2.5 mg BID [twice daily], rivaroxaban 5 mg BID increased the risk of all bleeding events without providing additional efficacy. Further, rivaroxaban 5 mg BID improved MI but not CV death, which was somewhat unexpected."

The 2.5-mg dose was associated with an all-cause mortality benefit that was nominally statistically significant. However, the 5-mg dose demonstrated no mortality advantage, and the two doses combined did not produce a statistically robust benefit. "Given the inconsistent results between rivaroxaban 2.5 mg BID and rivaroxaban 5 mg BID with respect to CV death and all-cause mortality, I do not recommend a mortality claim," Dr. Hicks said.

Significant Increases in Bleeding

On the safety side, rivaroxaban significantly increased the risk of all bleeding events, compared with placebo.

Across all strata, the 2.5-mg dose significantly increased the risk of the following TIMI classifications of bleeding: major, major or minor, life-threatening, intracranial hemorrhage, minor, clinically significant, and warranting medical attention. In stratum 2, the 2.5-mg dose significantly increased all TIMI major or minor bleeding, major bleeding, life-threatening bleeding, clinically significant bleeding, and medical attention bleeding. The 2.5-mg dose did not significantly increase the risk of TIMI major fatal bleeding or fatal intracranial hemorrhage.

In stratum 2, the 2.5-mg dose reduced the rate of the primary end point by 15% while increasing the rate of bleeding not related to coronary artery bypass graft surgery, Dr. Hicks said. "There was a twofold increase in TIMI major fatal bleeding and threefold increases in TIMI major bleeding, intracranial hemorrhage, hemorrhagic stroke, TIMI life-threatening bleeding, and TIMI major or minor bleeding. There was also an 18% increase in the risk of fatal stroke. Although the hazard ratios were increased, the absolute incidence of these events was low."

Subjects aged 75 years and older, and individuals weighing less than 60 kg, had an increased risk of bleeding events.

ACS subjects appeared to have a more pronounced tendency for liver injury than did populations studied in the atrial fibrillation and deep vein thrombosis prophylaxis studies. "Therefore, rivaroxaban, even in lower doses than what is recommended for other uses, appears possibly to cause mild liver injury in some patients. This finding likely reflects some increased susceptibility to drug-induced liver injury in patients with ACS," Dr. Hicks said.

Data Quality as a Counterargument to Approval

Dr. Hicks said that in arriving at her approval recommendation, she considered the argument that the amount of missing data from the ATLAS study weighed against approval.

Across all strata, 2,402 subjects (15.5%) discontinued the study prematurely, including 1,294 subjects (8%) who withdrew consent. "There were [more than] 1,000 subjects at the end of the trial with unknown vital status," Dr. Hicks said. Additionally, there were incomplete follow-up and uncounted deaths. "The quantity of missing data in ATLAS could affect the overall interpretability of the trial."

Nevertheless, Dr. Hicks suggested she was satisfied with the sponsors’ attempt to obtain vital status information on missing subjects and its responses to the FDA’s information requests on the issue. She also pointed to the broader problem of missing data in the setting of CV outcomes studies.

Shades of Ticagrelor

However, Dr. Thomas Marciniak, the review division’s medical team leader on the rivaroxaban application, takes a tougher stand on the issue of missing data and its ramifications for approval. In an April 26 memo, Dr. Marciniak suggests that the data quality may not support the favorable statistical results reported with the 2.5-mg dose.

The percentage of patients with incomplete follow-up in the study was high, averaging about 12%, he noted. "This percentage is far higher than the differences between the placebo and rivaroxaban arms in end point rates, which typically are about 1%-1.5%. The difference between placebo and rivaroxaban for bad follow-up rates matches these differences in end point rates. By [Johnson & Johnson’s] patient status statistics, there appears to be plenty of opportunity for incomplete data to obscure or magnify any differences in end points."

Furthermore, the rates of patients with unknown vital status exceed the reported differences in mortality rates, Dr. Marciniak said, asserting, "We cannot have confidence that the claimed mortality benefits are real."

He also challenged the sponsors’ approach to censoring patients and their classification of deaths that occurred after withdrawal of consent, saying this may have led to an overstatement of rivaroxaban’s efficacy.

"Because of the extent of missing follow-up in ATLAS, we cannot have confidence in either the calculated mortality or CV endpoint benefits," he said.

Marciniak’s criticisms about ATLAS are reminiscent of his attacks on the pivotal efficacy study for AstraZeneca PLC’s ticagrelor (Brilinta). During a July 2010 advisory committee review of the antiplatelet agent, Dr. Marciniak criticized the sponsor for inadequate end point and vital status follow-up in the 18,624-patient PLATO trial.

Dr. Marciniak’s criticisms were even more strenuous in his written reviews, in which he cited inadequate data collection and analyses, poor follow-up, faulty adverse event reporting, failure to adjudicate potential end points, an inappropriate primary end point, and censoring problems. The review division approved ticagrelor in July 2011 despite Dr. Marciniak’s recommendation against approval.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Merck and development partner Ariad Pharmaceuticals face a seemingly formidable task at the March 20 review of their investigational sarcoma therapy ridaforolimus by a Food and Drug Administration advisory panel.

The companies will have to persuade the Oncologic Drugs Advisory Committee (ODAC) that a statistically significant 26% improvement in progression-free survival (PFS), with a median benefit of just 2 weeks, is clinically meaningful in the maintenance setting for metastatic soft-tissue sarcoma (STS) or bone sarcoma.

They also will have to convince the panel that this benefit outweighs the risk of serious adverse events – including pneumonitis, renal failure, and hypersensitivity reactions – in the pivotal study of ridaforolimus (Taltorvic), a mammalian target of rapamycin (mTOR) inhibitor.

And they have to do all this after ODAC considers whether a soft-tissue sarcoma treatment indication should be added to the label of GlaxoSmithKline’s pazopanib (Votrient). Pazopanib demonstrated a statistically significant 65% improvement in progression-free survival, with a median benefit of 3 months, in a pivotal trial in patients who progressed following prior chemotherapy.

One efficacy parameter the two drugs share is that they both failed to demonstrate a statistically significant improvement in overall survival.

Ridaforolimus: Short PFS Benefit

Doxorubicin is the only FDA-approved drug for most adult sarcomas, Merck noted in its briefing document. The company is seeking to make ridaforolimus the first product approved as a maintenance therapy in sarcoma. The proposed indication is treatment of patients with metastatic STS or bone sarcoma whose disease has not progressed after at least four cycles of chemotherapy.

The New Drug Application rests on the results of a phase III trial presented at the American Society of Clinical Oncology (ASCO) meeting in June 2011. In the study, 711 patients were randomized to ridaforolimus or placebo; scans were performed every 8 weeks, and read by an independent review committee (IRC).

The data presented at ASCO showed ridaforolimus significantly reduced the risk of progression or death by 28%, according to IRC assessment. Median PFS was 17.7 weeks in the ridaforolimus arm and 14.6 weeks with placebo.

In discussing the study results, Ariad management asserted it was more important to look at the PFS hazard ratio than the 3-week median PFS benefit. Nevertheless, the small gain in median PFS was expected to raise the same types of questions about clinically meaningful improvement that led to FDA’s withdrawal of the metastatic breast cancer indication for Genentech’s bevacizumab (Avastin).

Such concerns about clinical significance are further heightened by the FDA’s analysis of the pivotal trial data – ridaforolimus fared even worse under the agency’s assessment.

While the drug was still associated with a statistically significant improvement in PFS, the hazard ratio increased to 0.74 (compared with 0.72 in the sponsor’s analysis), and the median PFS advantage shrank from 3 weeks to 2 weeks. Median PFS in the ridaforolimus arm was 16.1 weeks, compared with 14 weeks in the placebo arm, according to the agency’s analysis.

The FDA explained why its analysis differed from that of the sponsor, even though both relied on IRC-determined progression: "The difference between these involves the handling of scans read as new lesion/no progression by the IRC," the agency said. "The applicant analysis did not consider these new lesions as disease progression, while the FDA analysis, consistent with the RECIST [Response Evaluation Criteria in Solid Tumors] criteria, considered this to be progressive disease."

Investigator-assessed PFS suggested a more dramatic benefit with ridaforolimus, with a statistically significant 31% improvement and a 7-week advantage in median PFS over placebo. However, the FDA found considerable disagreement between investigator-assessed progression and the IRC’s evaluation. "Discordance occurred in 299 (42%) of patients. A difference in event (progression event vs. censoring) was seen in 107 patients and a difference in the time of progression in 228 patients," the agency wrote.

In its background briefing document, Merck, like Ariad, suggests that median PFS values underestimate ridaforolimus’ true treatment effect.

"Due to the shape of the Kaplan-Meier curves, the median when assessed by IRC is an underestimate of the effect of ridaforolimus on PFS compared to placebo, with an improvement of approximately 6 weeks in the median estimated by the hazard ratio or parametric modeling," the company said.

"These findings indicate that maintenance treatment of metastatic sarcoma patients with ridaforolimus significantly reduced the risk of disease progression or death."

In the final analysis, ridaforolimus was associated with a 7% improvement in overall survival (OS), but this did not reach the level of statistical significance. Median OS with ridaforolimus was 20.8 months, versus 19.6 months in the placebo group.

Toxicities in a Maintenance Setting

The FDA’s briefing document suggests strong consideration should be given to ridaforolimus’ toxicities. In the phase III trial, 70% of patients in the ridaforolimus arm had dose reductions; in total, there were 3,027 dose reductions in 239 patients. Dose delays were reported in 56% of patients on the drug.

"The number of patients who discontinued due to an adverse event (14% ridaforolimus, 2% placebo) is a particular concern in a drug intended for use as maintenance therapy," the FDA said. The most common adverse events reported were stomatitis, infections, fatigue, and rash.

Although the drug’s safety profile was similar to that of other mTOR inhibitors, adverse events of particular concern included pneumonitis, infection, and renal failure/impairment, the FDA said. Possible hypersensitivity reactions were reported in 10% of ridaforolimus-treated patients.

Pazopanib: Still No Survival Benefit

ODAC’s review of ridaforolimus will take place on the afternoon of March 20. During the panel’s morning session, the committee will consider a sarcoma indication for pazopanib.

GlaxoSmithKline is seeking to add a second use for its tyrosine kinase inhibitor, which was approved for renal cell carcinoma in 2009. In the pivotal 369-patient trial, pazopanib was associated with a statistically significant 65% improvement in PFS compared with placebo, according to the FDA’s analysis. Median PFS was 4.6 months in the pazopanib arm and 1.6 months in the placebo group.

There also was improvement in median PFS in the three prespecified histological subgroups of leiomyosarcoma, synovial sarcoma, and "other" STS, findings that suggest consistency of results in an otherwise heterogeneous population.

The phase III trial excluded patients with adipocytic STS or gastrointestinal stromal tumors, and this is reflected in the proposed indication as "Important Limitations of Use."

Although pazopanib was associated with a 13% reduced risk of death, this survival advantage did not reach statistical significance in the final analysis. Median overall survival with pazopanib was 12.6 months, versus 10.7 months with placebo.

The FDA’s briefing document raises several concerns about imbalances in the treatment arms.

"Based on the results of the central pathology review, a higher proportion of patients on the pazopanib arm had a diagnosis of leiomyosarcoma while the proportion of patients with a diagnosis of ‘other’ STS was higher in the placebo arm," the agency said. "Considering the variable chemosensitivity of different histological subtypes of STS, this imbalance can potentially confound the results of the efficacy analysis."

The agency also noted that a higher proportion of patients in the placebo group had high-grade disease. "The higher enrollment of patients with high-grade disease in the placebo arm may confound the results of this study as these patients have biologically more aggressive disease."

More patients in the placebo arm received follow-up anticancer therapy after withdrawal of study treatment than in the pazopanib arm. "It is unclear whether this imbalance in post-treatment anticancer therapies can affect the final OS results of this trial, as the magnitude of survival benefit achieved from these therapies, if any at all, is unknown."

Another possible explanation for the "inconsistency" between PFS and OS is that "a larger PFS effect would be necessary to achieve a parallel OS benefit," the FDA said.

In the pivotal study, 58% of pazopanib patients had a dose interruption and 39% had a dose reduction. An additional 14% of patients discontinued pazopanib therapy due to toxicity.

"The four adverse events most commonly contributing to a dose reduction and/or a dose interruption were fatigue, diarrhea, hypertension, and nausea," the FDA said. "Other important [adverse events] leading to dose modifications included skin disorder (hand and foot syndrome) and exfoliative rash, elevated liver transaminases, and left ventricular dysfunction."

The FDA found that pazopanib’s adverse event profile in STS patients was generally consistent with the current safety profile in renal cancer, albeit with some differences. As in the renal cell population, there were reported adverse events of fatal hepatotoxicity, fatal GI perforation, life-threatening hemorrhage, and severe hypertension. Additional adverse events with increased frequency in the STS population included myocardial dysfunction, thromboembolism, and pneumothorax.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Merck and development partner Ariad Pharmaceuticals face a seemingly formidable task at the March 20 review of their investigational sarcoma therapy ridaforolimus by a Food and Drug Administration advisory panel.

The companies will have to persuade the Oncologic Drugs Advisory Committee (ODAC) that a statistically significant 26% improvement in progression-free survival (PFS), with a median benefit of just 2 weeks, is clinically meaningful in the maintenance setting for metastatic soft-tissue sarcoma (STS) or bone sarcoma.

They also will have to convince the panel that this benefit outweighs the risk of serious adverse events – including pneumonitis, renal failure, and hypersensitivity reactions – in the pivotal study of ridaforolimus (Taltorvic), a mammalian target of rapamycin (mTOR) inhibitor.

And they have to do all this after ODAC considers whether a soft-tissue sarcoma treatment indication should be added to the label of GlaxoSmithKline’s pazopanib (Votrient). Pazopanib demonstrated a statistically significant 65% improvement in progression-free survival, with a median benefit of 3 months, in a pivotal trial in patients who progressed following prior chemotherapy.

One efficacy parameter the two drugs share is that they both failed to demonstrate a statistically significant improvement in overall survival.

Ridaforolimus: Short PFS Benefit

Doxorubicin is the only FDA-approved drug for most adult sarcomas, Merck noted in its briefing document. The company is seeking to make ridaforolimus the first product approved as a maintenance therapy in sarcoma. The proposed indication is treatment of patients with metastatic STS or bone sarcoma whose disease has not progressed after at least four cycles of chemotherapy.

The New Drug Application rests on the results of a phase III trial presented at the American Society of Clinical Oncology (ASCO) meeting in June 2011. In the study, 711 patients were randomized to ridaforolimus or placebo; scans were performed every 8 weeks, and read by an independent review committee (IRC).

The data presented at ASCO showed ridaforolimus significantly reduced the risk of progression or death by 28%, according to IRC assessment. Median PFS was 17.7 weeks in the ridaforolimus arm and 14.6 weeks with placebo.

In discussing the study results, Ariad management asserted it was more important to look at the PFS hazard ratio than the 3-week median PFS benefit. Nevertheless, the small gain in median PFS was expected to raise the same types of questions about clinically meaningful improvement that led to FDA’s withdrawal of the metastatic breast cancer indication for Genentech’s bevacizumab (Avastin).

Such concerns about clinical significance are further heightened by the FDA’s analysis of the pivotal trial data – ridaforolimus fared even worse under the agency’s assessment.

While the drug was still associated with a statistically significant improvement in PFS, the hazard ratio increased to 0.74 (compared with 0.72 in the sponsor’s analysis), and the median PFS advantage shrank from 3 weeks to 2 weeks. Median PFS in the ridaforolimus arm was 16.1 weeks, compared with 14 weeks in the placebo arm, according to the agency’s analysis.

The FDA explained why its analysis differed from that of the sponsor, even though both relied on IRC-determined progression: "The difference between these involves the handling of scans read as new lesion/no progression by the IRC," the agency said. "The applicant analysis did not consider these new lesions as disease progression, while the FDA analysis, consistent with the RECIST [Response Evaluation Criteria in Solid Tumors] criteria, considered this to be progressive disease."

Investigator-assessed PFS suggested a more dramatic benefit with ridaforolimus, with a statistically significant 31% improvement and a 7-week advantage in median PFS over placebo. However, the FDA found considerable disagreement between investigator-assessed progression and the IRC’s evaluation. "Discordance occurred in 299 (42%) of patients. A difference in event (progression event vs. censoring) was seen in 107 patients and a difference in the time of progression in 228 patients," the agency wrote.

In its background briefing document, Merck, like Ariad, suggests that median PFS values underestimate ridaforolimus’ true treatment effect.

"Due to the shape of the Kaplan-Meier curves, the median when assessed by IRC is an underestimate of the effect of ridaforolimus on PFS compared to placebo, with an improvement of approximately 6 weeks in the median estimated by the hazard ratio or parametric modeling," the company said.

"These findings indicate that maintenance treatment of metastatic sarcoma patients with ridaforolimus significantly reduced the risk of disease progression or death."

In the final analysis, ridaforolimus was associated with a 7% improvement in overall survival (OS), but this did not reach the level of statistical significance. Median OS with ridaforolimus was 20.8 months, versus 19.6 months in the placebo group.

Toxicities in a Maintenance Setting

The FDA’s briefing document suggests strong consideration should be given to ridaforolimus’ toxicities. In the phase III trial, 70% of patients in the ridaforolimus arm had dose reductions; in total, there were 3,027 dose reductions in 239 patients. Dose delays were reported in 56% of patients on the drug.

"The number of patients who discontinued due to an adverse event (14% ridaforolimus, 2% placebo) is a particular concern in a drug intended for use as maintenance therapy," the FDA said. The most common adverse events reported were stomatitis, infections, fatigue, and rash.

Although the drug’s safety profile was similar to that of other mTOR inhibitors, adverse events of particular concern included pneumonitis, infection, and renal failure/impairment, the FDA said. Possible hypersensitivity reactions were reported in 10% of ridaforolimus-treated patients.

Pazopanib: Still No Survival Benefit

ODAC’s review of ridaforolimus will take place on the afternoon of March 20. During the panel’s morning session, the committee will consider a sarcoma indication for pazopanib.

GlaxoSmithKline is seeking to add a second use for its tyrosine kinase inhibitor, which was approved for renal cell carcinoma in 2009. In the pivotal 369-patient trial, pazopanib was associated with a statistically significant 65% improvement in PFS compared with placebo, according to the FDA’s analysis. Median PFS was 4.6 months in the pazopanib arm and 1.6 months in the placebo group.

There also was improvement in median PFS in the three prespecified histological subgroups of leiomyosarcoma, synovial sarcoma, and "other" STS, findings that suggest consistency of results in an otherwise heterogeneous population.

The phase III trial excluded patients with adipocytic STS or gastrointestinal stromal tumors, and this is reflected in the proposed indication as "Important Limitations of Use."

Although pazopanib was associated with a 13% reduced risk of death, this survival advantage did not reach statistical significance in the final analysis. Median overall survival with pazopanib was 12.6 months, versus 10.7 months with placebo.

The FDA’s briefing document raises several concerns about imbalances in the treatment arms.

"Based on the results of the central pathology review, a higher proportion of patients on the pazopanib arm had a diagnosis of leiomyosarcoma while the proportion of patients with a diagnosis of ‘other’ STS was higher in the placebo arm," the agency said. "Considering the variable chemosensitivity of different histological subtypes of STS, this imbalance can potentially confound the results of the efficacy analysis."

The agency also noted that a higher proportion of patients in the placebo group had high-grade disease. "The higher enrollment of patients with high-grade disease in the placebo arm may confound the results of this study as these patients have biologically more aggressive disease."

More patients in the placebo arm received follow-up anticancer therapy after withdrawal of study treatment than in the pazopanib arm. "It is unclear whether this imbalance in post-treatment anticancer therapies can affect the final OS results of this trial, as the magnitude of survival benefit achieved from these therapies, if any at all, is unknown."

Another possible explanation for the "inconsistency" between PFS and OS is that "a larger PFS effect would be necessary to achieve a parallel OS benefit," the FDA said.

In the pivotal study, 58% of pazopanib patients had a dose interruption and 39% had a dose reduction. An additional 14% of patients discontinued pazopanib therapy due to toxicity.

"The four adverse events most commonly contributing to a dose reduction and/or a dose interruption were fatigue, diarrhea, hypertension, and nausea," the FDA said. "Other important [adverse events] leading to dose modifications included skin disorder (hand and foot syndrome) and exfoliative rash, elevated liver transaminases, and left ventricular dysfunction."

The FDA found that pazopanib’s adverse event profile in STS patients was generally consistent with the current safety profile in renal cancer, albeit with some differences. As in the renal cell population, there were reported adverse events of fatal hepatotoxicity, fatal GI perforation, life-threatening hemorrhage, and severe hypertension. Additional adverse events with increased frequency in the STS population included myocardial dysfunction, thromboembolism, and pneumothorax.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Merck and development partner Ariad Pharmaceuticals face a seemingly formidable task at the March 20 review of their investigational sarcoma therapy ridaforolimus by a Food and Drug Administration advisory panel.

The companies will have to persuade the Oncologic Drugs Advisory Committee (ODAC) that a statistically significant 26% improvement in progression-free survival (PFS), with a median benefit of just 2 weeks, is clinically meaningful in the maintenance setting for metastatic soft-tissue sarcoma (STS) or bone sarcoma.

They also will have to convince the panel that this benefit outweighs the risk of serious adverse events – including pneumonitis, renal failure, and hypersensitivity reactions – in the pivotal study of ridaforolimus (Taltorvic), a mammalian target of rapamycin (mTOR) inhibitor.

And they have to do all this after ODAC considers whether a soft-tissue sarcoma treatment indication should be added to the label of GlaxoSmithKline’s pazopanib (Votrient). Pazopanib demonstrated a statistically significant 65% improvement in progression-free survival, with a median benefit of 3 months, in a pivotal trial in patients who progressed following prior chemotherapy.

One efficacy parameter the two drugs share is that they both failed to demonstrate a statistically significant improvement in overall survival.

Ridaforolimus: Short PFS Benefit

Doxorubicin is the only FDA-approved drug for most adult sarcomas, Merck noted in its briefing document. The company is seeking to make ridaforolimus the first product approved as a maintenance therapy in sarcoma. The proposed indication is treatment of patients with metastatic STS or bone sarcoma whose disease has not progressed after at least four cycles of chemotherapy.

The New Drug Application rests on the results of a phase III trial presented at the American Society of Clinical Oncology (ASCO) meeting in June 2011. In the study, 711 patients were randomized to ridaforolimus or placebo; scans were performed every 8 weeks, and read by an independent review committee (IRC).

The data presented at ASCO showed ridaforolimus significantly reduced the risk of progression or death by 28%, according to IRC assessment. Median PFS was 17.7 weeks in the ridaforolimus arm and 14.6 weeks with placebo.

In discussing the study results, Ariad management asserted it was more important to look at the PFS hazard ratio than the 3-week median PFS benefit. Nevertheless, the small gain in median PFS was expected to raise the same types of questions about clinically meaningful improvement that led to FDA’s withdrawal of the metastatic breast cancer indication for Genentech’s bevacizumab (Avastin).

Such concerns about clinical significance are further heightened by the FDA’s analysis of the pivotal trial data – ridaforolimus fared even worse under the agency’s assessment.

While the drug was still associated with a statistically significant improvement in PFS, the hazard ratio increased to 0.74 (compared with 0.72 in the sponsor’s analysis), and the median PFS advantage shrank from 3 weeks to 2 weeks. Median PFS in the ridaforolimus arm was 16.1 weeks, compared with 14 weeks in the placebo arm, according to the agency’s analysis.

The FDA explained why its analysis differed from that of the sponsor, even though both relied on IRC-determined progression: "The difference between these involves the handling of scans read as new lesion/no progression by the IRC," the agency said. "The applicant analysis did not consider these new lesions as disease progression, while the FDA analysis, consistent with the RECIST [Response Evaluation Criteria in Solid Tumors] criteria, considered this to be progressive disease."

Investigator-assessed PFS suggested a more dramatic benefit with ridaforolimus, with a statistically significant 31% improvement and a 7-week advantage in median PFS over placebo. However, the FDA found considerable disagreement between investigator-assessed progression and the IRC’s evaluation. "Discordance occurred in 299 (42%) of patients. A difference in event (progression event vs. censoring) was seen in 107 patients and a difference in the time of progression in 228 patients," the agency wrote.

In its background briefing document, Merck, like Ariad, suggests that median PFS values underestimate ridaforolimus’ true treatment effect.

"Due to the shape of the Kaplan-Meier curves, the median when assessed by IRC is an underestimate of the effect of ridaforolimus on PFS compared to placebo, with an improvement of approximately 6 weeks in the median estimated by the hazard ratio or parametric modeling," the company said.

"These findings indicate that maintenance treatment of metastatic sarcoma patients with ridaforolimus significantly reduced the risk of disease progression or death."

In the final analysis, ridaforolimus was associated with a 7% improvement in overall survival (OS), but this did not reach the level of statistical significance. Median OS with ridaforolimus was 20.8 months, versus 19.6 months in the placebo group.

Toxicities in a Maintenance Setting

The FDA’s briefing document suggests strong consideration should be given to ridaforolimus’ toxicities. In the phase III trial, 70% of patients in the ridaforolimus arm had dose reductions; in total, there were 3,027 dose reductions in 239 patients. Dose delays were reported in 56% of patients on the drug.

"The number of patients who discontinued due to an adverse event (14% ridaforolimus, 2% placebo) is a particular concern in a drug intended for use as maintenance therapy," the FDA said. The most common adverse events reported were stomatitis, infections, fatigue, and rash.

Although the drug’s safety profile was similar to that of other mTOR inhibitors, adverse events of particular concern included pneumonitis, infection, and renal failure/impairment, the FDA said. Possible hypersensitivity reactions were reported in 10% of ridaforolimus-treated patients.

Pazopanib: Still No Survival Benefit

ODAC’s review of ridaforolimus will take place on the afternoon of March 20. During the panel’s morning session, the committee will consider a sarcoma indication for pazopanib.

GlaxoSmithKline is seeking to add a second use for its tyrosine kinase inhibitor, which was approved for renal cell carcinoma in 2009. In the pivotal 369-patient trial, pazopanib was associated with a statistically significant 65% improvement in PFS compared with placebo, according to the FDA’s analysis. Median PFS was 4.6 months in the pazopanib arm and 1.6 months in the placebo group.

There also was improvement in median PFS in the three prespecified histological subgroups of leiomyosarcoma, synovial sarcoma, and "other" STS, findings that suggest consistency of results in an otherwise heterogeneous population.

The phase III trial excluded patients with adipocytic STS or gastrointestinal stromal tumors, and this is reflected in the proposed indication as "Important Limitations of Use."

Although pazopanib was associated with a 13% reduced risk of death, this survival advantage did not reach statistical significance in the final analysis. Median overall survival with pazopanib was 12.6 months, versus 10.7 months with placebo.

The FDA’s briefing document raises several concerns about imbalances in the treatment arms.

"Based on the results of the central pathology review, a higher proportion of patients on the pazopanib arm had a diagnosis of leiomyosarcoma while the proportion of patients with a diagnosis of ‘other’ STS was higher in the placebo arm," the agency said. "Considering the variable chemosensitivity of different histological subtypes of STS, this imbalance can potentially confound the results of the efficacy analysis."

The agency also noted that a higher proportion of patients in the placebo group had high-grade disease. "The higher enrollment of patients with high-grade disease in the placebo arm may confound the results of this study as these patients have biologically more aggressive disease."

More patients in the placebo arm received follow-up anticancer therapy after withdrawal of study treatment than in the pazopanib arm. "It is unclear whether this imbalance in post-treatment anticancer therapies can affect the final OS results of this trial, as the magnitude of survival benefit achieved from these therapies, if any at all, is unknown."

Another possible explanation for the "inconsistency" between PFS and OS is that "a larger PFS effect would be necessary to achieve a parallel OS benefit," the FDA said.

In the pivotal study, 58% of pazopanib patients had a dose interruption and 39% had a dose reduction. An additional 14% of patients discontinued pazopanib therapy due to toxicity.

"The four adverse events most commonly contributing to a dose reduction and/or a dose interruption were fatigue, diarrhea, hypertension, and nausea," the FDA said. "Other important [adverse events] leading to dose modifications included skin disorder (hand and foot syndrome) and exfoliative rash, elevated liver transaminases, and left ventricular dysfunction."

The FDA found that pazopanib’s adverse event profile in STS patients was generally consistent with the current safety profile in renal cancer, albeit with some differences. As in the renal cell population, there were reported adverse events of fatal hepatotoxicity, fatal GI perforation, life-threatening hemorrhage, and severe hypertension. Additional adverse events with increased frequency in the STS population included myocardial dysfunction, thromboembolism, and pneumothorax.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The devastating nature of neurogenic orthostatic hypotension, coupled with the lack of good treatment options, tipped a Food and Drug Administration panel vote in favor of approval for droxidopa for the orphan condition Feb. 23.

Seven of 13 members of the Cardiovascular and Renal Drugs Advisory Committee supported approval for treatment of symptomatic NOH in patients with primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

Panelists in the majority said droxidopa (Northera), a prodrug of norepinephrine, appears effective in at least some patients who experience devastating and debilitating symptoms that limit their ability to stand, walk, and function.

"I voted ‘yes’ for my patients with a horrible disease that really there isn’t any effective therapy right now," said temporary voting member Dr. Jeffrey Cohen, of Dartmouth Hitchcock Medical Center, the lone neurologist on the committee. The adverse events potentially associated with the drug are "none the worse of what we presently have, at least as I can see."

However, the vote in favor of approval was far from a wholehearted endorsement. Four panel members dissented, citing the need for another randomized trial with longer-term efficacy and safety data before approval. One panel member who abstained and one panel member who did not vote also generally took negative views of the drug.

Given the advisory committee’s mixed verdict, coupled with the FDA review team’s own negative evaluation of the drug’s risk/benefit profile and criticisms of the patient-reported outcomes instrument used in the pivotal trials, droxidopa would appear to face a high hurdle to approval by its March 28 user fee deadline.

NOH is an orphan indication with few good therapeutic alternatives. The only drug approved for the indication is midodrine (Shire’s ProAmatine and generics), for which confirmatory trials have failed to verify clinical benefit. Shire and the Center for Drug Evaluation and Research recently reached an agreement pursuant to which midodrine will remain on the market while Shire conducts another study.

Midodrine carries a "black box" warning about supine hypertension; other drugs used off-label in treating NOH also are associated with serious safety concerns.

In briefing documents and at the advisory committee meeting, clinical reviewer Dr. Melanie Blank recommended against approving droxidopa at this time due to the lack of evidence of a durable treatment effect and questions about the drug’s long-term safety. The New Drug Application was supported by only one trial, Study 301, that met its primary efficacy end point based upon improvement in the composite Orthostatic Hypotension Questionnaire (OHQ), which comprises two subscales that rate the presence and severity of symptoms and their impact on daily activities that require standing or walking.

However, the randomized, double-blind portion of Study 301 lasted only 1 week. Two other studies, 302 and 303, failed to achieve their primary end points and had randomized, double-blind periods that lasted only 2 weeks.

This short duration of the studies’ randomized, double-blind phases created questions about the duration of benefit in a chronic condition and made it difficult to characterize the agent’s long-term safety, Dr. Blank said. Safety issues of concern included 19 deaths in phase III studies, hypertensive events, worsening of underlying neurological disease, and reports of neuroleptic malignant syndrome from Japan, where the drug has been available since 1989.

The committee also heard from Study Endpoints and Labeling Development clinical reviewer Dr. Elektra Papadopoulos, who said the OHQ instrument was not well validated and did not adequately measure NOH symptoms or the impact of those symptoms, although the component measuring dizziness/lightheadedness could be enough to support a labeling claim.

Most committee members believed that Studies 302 and 303 could not serve as confirmatory evidence of efficacy. Nevertheless, those voting in favor of approval believed that Study 301 showed that droxidopa can be effective for some patients. They also found persuasive the testimony of more than a half dozen NOH patients and caregivers during the open public portion of the meeting. The patients and their family members testified to dramatic quality-of-life improvements with droxidopa use.

"In the end, this is an effective agent for a very difficult disease," said committee chairman Dr. Michael Lincoff, of the Cleveland Clinic, adding that the drug’s risks are not unpredictable and are related to the known effects of norepinephrine.

"It appears there is a subset of patients that have marked improvement," said committee member Dr. Judith Hochman, of New York University. "The degree of impairment in terms of quality of life of these patients is severe, and quality of life is an extremely important outcome. I think the uncertainty regarding the safety profile can be dealt with in terms of labeling and also in terms of postmarketing studies."

However, committee members who did not support approval said they were troubled by the lack of evidence on durability of effect and the limited safety data.

Committee member Dr. Darren McGuire, of the University of Texas Southwestern Medical Center, said he was encouraged by the data but did not think they were "sufficiently persuasive for a single trial to bring approval, even factoring in the orphan nature of the disease.

"These are vulnerable patients and they have lots of disability, and they present clinical challenges that we all struggle with when we treat them. That vulnerability makes us want to rush new drugs to market," but care must be taken that "the drugs we’re rushing to market are going to do more good than harm." Dr. McGuire suggested that the sponsor, Chelsea Therapeutics International, conduct another randomized trial lasting 3 to 6 months.

"I think I can forgive almost an entire absence of safety data if I’m very convinced of the efficacy data," said committee member Dr. Mori Krantz, of Denver Health Medical Center, who abstained. "But I just felt with the 1-week duration for a chronic condition ... I was contorting myself and doing a backbend. I think this drug has promise, but at this point I was just uncomfortable without further data."

This coverage is provided courtesy of "The Pink Sheet." Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The devastating nature of neurogenic orthostatic hypotension, coupled with the lack of good treatment options, tipped a Food and Drug Administration panel vote in favor of approval for droxidopa for the orphan condition Feb. 23.

Seven of 13 members of the Cardiovascular and Renal Drugs Advisory Committee supported approval for treatment of symptomatic NOH in patients with primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

Panelists in the majority said droxidopa (Northera), a prodrug of norepinephrine, appears effective in at least some patients who experience devastating and debilitating symptoms that limit their ability to stand, walk, and function.

"I voted ‘yes’ for my patients with a horrible disease that really there isn’t any effective therapy right now," said temporary voting member Dr. Jeffrey Cohen, of Dartmouth Hitchcock Medical Center, the lone neurologist on the committee. The adverse events potentially associated with the drug are "none the worse of what we presently have, at least as I can see."

However, the vote in favor of approval was far from a wholehearted endorsement. Four panel members dissented, citing the need for another randomized trial with longer-term efficacy and safety data before approval. One panel member who abstained and one panel member who did not vote also generally took negative views of the drug.

Given the advisory committee’s mixed verdict, coupled with the FDA review team’s own negative evaluation of the drug’s risk/benefit profile and criticisms of the patient-reported outcomes instrument used in the pivotal trials, droxidopa would appear to face a high hurdle to approval by its March 28 user fee deadline.

NOH is an orphan indication with few good therapeutic alternatives. The only drug approved for the indication is midodrine (Shire’s ProAmatine and generics), for which confirmatory trials have failed to verify clinical benefit. Shire and the Center for Drug Evaluation and Research recently reached an agreement pursuant to which midodrine will remain on the market while Shire conducts another study.

Midodrine carries a "black box" warning about supine hypertension; other drugs used off-label in treating NOH also are associated with serious safety concerns.

In briefing documents and at the advisory committee meeting, clinical reviewer Dr. Melanie Blank recommended against approving droxidopa at this time due to the lack of evidence of a durable treatment effect and questions about the drug’s long-term safety. The New Drug Application was supported by only one trial, Study 301, that met its primary efficacy end point based upon improvement in the composite Orthostatic Hypotension Questionnaire (OHQ), which comprises two subscales that rate the presence and severity of symptoms and their impact on daily activities that require standing or walking.

However, the randomized, double-blind portion of Study 301 lasted only 1 week. Two other studies, 302 and 303, failed to achieve their primary end points and had randomized, double-blind periods that lasted only 2 weeks.

This short duration of the studies’ randomized, double-blind phases created questions about the duration of benefit in a chronic condition and made it difficult to characterize the agent’s long-term safety, Dr. Blank said. Safety issues of concern included 19 deaths in phase III studies, hypertensive events, worsening of underlying neurological disease, and reports of neuroleptic malignant syndrome from Japan, where the drug has been available since 1989.

The committee also heard from Study Endpoints and Labeling Development clinical reviewer Dr. Elektra Papadopoulos, who said the OHQ instrument was not well validated and did not adequately measure NOH symptoms or the impact of those symptoms, although the component measuring dizziness/lightheadedness could be enough to support a labeling claim.

Most committee members believed that Studies 302 and 303 could not serve as confirmatory evidence of efficacy. Nevertheless, those voting in favor of approval believed that Study 301 showed that droxidopa can be effective for some patients. They also found persuasive the testimony of more than a half dozen NOH patients and caregivers during the open public portion of the meeting. The patients and their family members testified to dramatic quality-of-life improvements with droxidopa use.

"In the end, this is an effective agent for a very difficult disease," said committee chairman Dr. Michael Lincoff, of the Cleveland Clinic, adding that the drug’s risks are not unpredictable and are related to the known effects of norepinephrine.

"It appears there is a subset of patients that have marked improvement," said committee member Dr. Judith Hochman, of New York University. "The degree of impairment in terms of quality of life of these patients is severe, and quality of life is an extremely important outcome. I think the uncertainty regarding the safety profile can be dealt with in terms of labeling and also in terms of postmarketing studies."

However, committee members who did not support approval said they were troubled by the lack of evidence on durability of effect and the limited safety data.

Committee member Dr. Darren McGuire, of the University of Texas Southwestern Medical Center, said he was encouraged by the data but did not think they were "sufficiently persuasive for a single trial to bring approval, even factoring in the orphan nature of the disease.

"These are vulnerable patients and they have lots of disability, and they present clinical challenges that we all struggle with when we treat them. That vulnerability makes us want to rush new drugs to market," but care must be taken that "the drugs we’re rushing to market are going to do more good than harm." Dr. McGuire suggested that the sponsor, Chelsea Therapeutics International, conduct another randomized trial lasting 3 to 6 months.

"I think I can forgive almost an entire absence of safety data if I’m very convinced of the efficacy data," said committee member Dr. Mori Krantz, of Denver Health Medical Center, who abstained. "But I just felt with the 1-week duration for a chronic condition ... I was contorting myself and doing a backbend. I think this drug has promise, but at this point I was just uncomfortable without further data."

This coverage is provided courtesy of "The Pink Sheet." Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

The devastating nature of neurogenic orthostatic hypotension, coupled with the lack of good treatment options, tipped a Food and Drug Administration panel vote in favor of approval for droxidopa for the orphan condition Feb. 23.

Seven of 13 members of the Cardiovascular and Renal Drugs Advisory Committee supported approval for treatment of symptomatic NOH in patients with primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

Panelists in the majority said droxidopa (Northera), a prodrug of norepinephrine, appears effective in at least some patients who experience devastating and debilitating symptoms that limit their ability to stand, walk, and function.

"I voted ‘yes’ for my patients with a horrible disease that really there isn’t any effective therapy right now," said temporary voting member Dr. Jeffrey Cohen, of Dartmouth Hitchcock Medical Center, the lone neurologist on the committee. The adverse events potentially associated with the drug are "none the worse of what we presently have, at least as I can see."

However, the vote in favor of approval was far from a wholehearted endorsement. Four panel members dissented, citing the need for another randomized trial with longer-term efficacy and safety data before approval. One panel member who abstained and one panel member who did not vote also generally took negative views of the drug.

Given the advisory committee’s mixed verdict, coupled with the FDA review team’s own negative evaluation of the drug’s risk/benefit profile and criticisms of the patient-reported outcomes instrument used in the pivotal trials, droxidopa would appear to face a high hurdle to approval by its March 28 user fee deadline.

NOH is an orphan indication with few good therapeutic alternatives. The only drug approved for the indication is midodrine (Shire’s ProAmatine and generics), for which confirmatory trials have failed to verify clinical benefit. Shire and the Center for Drug Evaluation and Research recently reached an agreement pursuant to which midodrine will remain on the market while Shire conducts another study.

Midodrine carries a "black box" warning about supine hypertension; other drugs used off-label in treating NOH also are associated with serious safety concerns.

In briefing documents and at the advisory committee meeting, clinical reviewer Dr. Melanie Blank recommended against approving droxidopa at this time due to the lack of evidence of a durable treatment effect and questions about the drug’s long-term safety. The New Drug Application was supported by only one trial, Study 301, that met its primary efficacy end point based upon improvement in the composite Orthostatic Hypotension Questionnaire (OHQ), which comprises two subscales that rate the presence and severity of symptoms and their impact on daily activities that require standing or walking.

However, the randomized, double-blind portion of Study 301 lasted only 1 week. Two other studies, 302 and 303, failed to achieve their primary end points and had randomized, double-blind periods that lasted only 2 weeks.

This short duration of the studies’ randomized, double-blind phases created questions about the duration of benefit in a chronic condition and made it difficult to characterize the agent’s long-term safety, Dr. Blank said. Safety issues of concern included 19 deaths in phase III studies, hypertensive events, worsening of underlying neurological disease, and reports of neuroleptic malignant syndrome from Japan, where the drug has been available since 1989.

The committee also heard from Study Endpoints and Labeling Development clinical reviewer Dr. Elektra Papadopoulos, who said the OHQ instrument was not well validated and did not adequately measure NOH symptoms or the impact of those symptoms, although the component measuring dizziness/lightheadedness could be enough to support a labeling claim.

Most committee members believed that Studies 302 and 303 could not serve as confirmatory evidence of efficacy. Nevertheless, those voting in favor of approval believed that Study 301 showed that droxidopa can be effective for some patients. They also found persuasive the testimony of more than a half dozen NOH patients and caregivers during the open public portion of the meeting. The patients and their family members testified to dramatic quality-of-life improvements with droxidopa use.

"In the end, this is an effective agent for a very difficult disease," said committee chairman Dr. Michael Lincoff, of the Cleveland Clinic, adding that the drug’s risks are not unpredictable and are related to the known effects of norepinephrine.

"It appears there is a subset of patients that have marked improvement," said committee member Dr. Judith Hochman, of New York University. "The degree of impairment in terms of quality of life of these patients is severe, and quality of life is an extremely important outcome. I think the uncertainty regarding the safety profile can be dealt with in terms of labeling and also in terms of postmarketing studies."

However, committee members who did not support approval said they were troubled by the lack of evidence on durability of effect and the limited safety data.

Committee member Dr. Darren McGuire, of the University of Texas Southwestern Medical Center, said he was encouraged by the data but did not think they were "sufficiently persuasive for a single trial to bring approval, even factoring in the orphan nature of the disease.

"These are vulnerable patients and they have lots of disability, and they present clinical challenges that we all struggle with when we treat them. That vulnerability makes us want to rush new drugs to market," but care must be taken that "the drugs we’re rushing to market are going to do more good than harm." Dr. McGuire suggested that the sponsor, Chelsea Therapeutics International, conduct another randomized trial lasting 3 to 6 months.

"I think I can forgive almost an entire absence of safety data if I’m very convinced of the efficacy data," said committee member Dr. Mori Krantz, of Denver Health Medical Center, who abstained. "But I just felt with the 1-week duration for a chronic condition ... I was contorting myself and doing a backbend. I think this drug has promise, but at this point I was just uncomfortable without further data."

This coverage is provided courtesy of "The Pink Sheet." Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

A Food and Drug Administration advisory committee review of Alexza Pharmaceuticals’ inhalable schizophrenia treatment Adasuve (loxapine) will focus on the drug’s pulmonary safety and the adequacy of a proposed Risk Evaluation and Mitigation Strategy to address this concern.

The Psychopharmacologic Drugs Advisory Committee will meet on Dec. 12 to discuss safety and efficacy issues for Adasuve, which is being proposed for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. The FDA’s meeting notice, published in the Federal Register on Oct. 24, cites pulmonary safety concerns as a particular issue for discussion.

Loxapine is an antipsychotic approved in oral and injectable forms. Adasuve uses Alexza’s Staccato system to vaporize the drug for deep lung inhalation and rapid treatment of agitation in schizophrenic and bipolar patients. Alexza is proposing the drug be used only in medically supervised settings, such as hospitals or psychiatric facilities.

Adasuve’s novel delivery form for an antipsychotic has posed some regulatory problems.

The new drug application was the subject of an October 2010 "complete response" letter that raised pulmonary safety concerns due to data from three phase I pulmonary safety studies. In those studies, healthy subjects and subjects with asthma or chronic obstructive pulmonary disease experienced dose-related, post-dose decreases in lung function, as measured by forced expiratory volume in 1 second. Lung function decreases also were recorded in subjects given the device-only placebo control.

The letter also cited issues with stability data. The Center for Devices and Radiological Health, which is providing input on the NDA review because of the inhalation device, requested a human factors study be conducted to provide assurance that the drug can be used effectively in the proposed clinical setting.

Following a December 2010 end-of-review meeting with the agency, Alexza said it would submit a proposed Risk Evaluation and Mitigation Strategy (REMS) aimed at ensuring that the drug is not prescribed to schizophrenics who may be susceptible to pulmonary adverse events.

The NDA was resubmitted in August with a REMS that includes a communication plan and various voluntary measures, such as an information checklist for screening patients with active airway disease who are at increased risk for bronchospasm. However, the REMS lacks elements to assure safe use.

Alexza CEO and President Tom King told "The Pink Sheet" that the REMS is aimed at screening patients to ensure those with active airway disease are not prescribed the drug. However, it also contains two "safety nets" in the event that patients with preexisting pulmonary problems are inappropriately given inhalable loxapine.

The REMS calls for patients to be observed for occurrence of respiratory adverse events for 1 hour after dosing and for inhaled albuterol to be readily accessible as a rescue medication to treat adverse reactions.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

A Food and Drug Administration advisory committee review of Alexza Pharmaceuticals’ inhalable schizophrenia treatment Adasuve (loxapine) will focus on the drug’s pulmonary safety and the adequacy of a proposed Risk Evaluation and Mitigation Strategy to address this concern.

The Psychopharmacologic Drugs Advisory Committee will meet on Dec. 12 to discuss safety and efficacy issues for Adasuve, which is being proposed for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. The FDA’s meeting notice, published in the Federal Register on Oct. 24, cites pulmonary safety concerns as a particular issue for discussion.

Loxapine is an antipsychotic approved in oral and injectable forms. Adasuve uses Alexza’s Staccato system to vaporize the drug for deep lung inhalation and rapid treatment of agitation in schizophrenic and bipolar patients. Alexza is proposing the drug be used only in medically supervised settings, such as hospitals or psychiatric facilities.

Adasuve’s novel delivery form for an antipsychotic has posed some regulatory problems.

The new drug application was the subject of an October 2010 "complete response" letter that raised pulmonary safety concerns due to data from three phase I pulmonary safety studies. In those studies, healthy subjects and subjects with asthma or chronic obstructive pulmonary disease experienced dose-related, post-dose decreases in lung function, as measured by forced expiratory volume in 1 second. Lung function decreases also were recorded in subjects given the device-only placebo control.

The letter also cited issues with stability data. The Center for Devices and Radiological Health, which is providing input on the NDA review because of the inhalation device, requested a human factors study be conducted to provide assurance that the drug can be used effectively in the proposed clinical setting.

Following a December 2010 end-of-review meeting with the agency, Alexza said it would submit a proposed Risk Evaluation and Mitigation Strategy (REMS) aimed at ensuring that the drug is not prescribed to schizophrenics who may be susceptible to pulmonary adverse events.

The NDA was resubmitted in August with a REMS that includes a communication plan and various voluntary measures, such as an information checklist for screening patients with active airway disease who are at increased risk for bronchospasm. However, the REMS lacks elements to assure safe use.

Alexza CEO and President Tom King told "The Pink Sheet" that the REMS is aimed at screening patients to ensure those with active airway disease are not prescribed the drug. However, it also contains two "safety nets" in the event that patients with preexisting pulmonary problems are inappropriately given inhalable loxapine.

The REMS calls for patients to be observed for occurrence of respiratory adverse events for 1 hour after dosing and for inhaled albuterol to be readily accessible as a rescue medication to treat adverse reactions.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

A Food and Drug Administration advisory committee review of Alexza Pharmaceuticals’ inhalable schizophrenia treatment Adasuve (loxapine) will focus on the drug’s pulmonary safety and the adequacy of a proposed Risk Evaluation and Mitigation Strategy to address this concern.

The Psychopharmacologic Drugs Advisory Committee will meet on Dec. 12 to discuss safety and efficacy issues for Adasuve, which is being proposed for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. The FDA’s meeting notice, published in the Federal Register on Oct. 24, cites pulmonary safety concerns as a particular issue for discussion.

Loxapine is an antipsychotic approved in oral and injectable forms. Adasuve uses Alexza’s Staccato system to vaporize the drug for deep lung inhalation and rapid treatment of agitation in schizophrenic and bipolar patients. Alexza is proposing the drug be used only in medically supervised settings, such as hospitals or psychiatric facilities.

Adasuve’s novel delivery form for an antipsychotic has posed some regulatory problems.

The new drug application was the subject of an October 2010 "complete response" letter that raised pulmonary safety concerns due to data from three phase I pulmonary safety studies. In those studies, healthy subjects and subjects with asthma or chronic obstructive pulmonary disease experienced dose-related, post-dose decreases in lung function, as measured by forced expiratory volume in 1 second. Lung function decreases also were recorded in subjects given the device-only placebo control.

The letter also cited issues with stability data. The Center for Devices and Radiological Health, which is providing input on the NDA review because of the inhalation device, requested a human factors study be conducted to provide assurance that the drug can be used effectively in the proposed clinical setting.

Following a December 2010 end-of-review meeting with the agency, Alexza said it would submit a proposed Risk Evaluation and Mitigation Strategy (REMS) aimed at ensuring that the drug is not prescribed to schizophrenics who may be susceptible to pulmonary adverse events.

The NDA was resubmitted in August with a REMS that includes a communication plan and various voluntary measures, such as an information checklist for screening patients with active airway disease who are at increased risk for bronchospasm. However, the REMS lacks elements to assure safe use.

Alexza CEO and President Tom King told "The Pink Sheet" that the REMS is aimed at screening patients to ensure those with active airway disease are not prescribed the drug. However, it also contains two "safety nets" in the event that patients with preexisting pulmonary problems are inappropriately given inhalable loxapine.

The REMS calls for patients to be observed for occurrence of respiratory adverse events for 1 hour after dosing and for inhaled albuterol to be readily accessible as a rescue medication to treat adverse reactions.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration’s policy requiring new drugs for serious conditions to be "as effective" as approved agents will take center stage at the Cardiovascular and Renal Drugs Advisory Committee’s Sept. 8 review of Bayer/Johnson & Johnson’s anticoagulant Xarelto (rivaroxaban) for atrial fibrillation.

The agency will ask the panel whether the oral Factor Xa inhibitor must be shown to be "as effective" as warfarin and/or Boehringer Ingelheim GmbH’s oral direct thrombin inhibitor Pradaxa (dabigatran) for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, according to FDA review documents released Sept. 6.

If the committee concludes that rivaroxaban must show similar efficacy to existing treatments and has demonstrated such efficacy, the agency asks whether a superiority claim over warfarin is warranted. Alternatively, the agency asks whether rivaroxaban should be used only in those patients who fail other anticoagulant therapy.

The committee also will be asked to comment on the adequacy of the ROCKET AF trial design and how the suboptimal use of warfarin in the 14,000-patient study impacted the interpretation of rivaroxaban’s efficacy results.

Concerns outlined in the FDA’s review documents about the suboptimal use of warfarin as a control in the clinical trial, coupled with an increase in strokes associated with transitioning patients to warfarin, suggest rivaroxaban faces a difficult regulatory path forward even if it manages to get a positive recommendation from the cardio-renal panel.

Commercial, Regulatory Challenges Ahead

The FDA approved rivaroxaban on July 1 for the prophylaxis of deep vein thrombosis in patients undergoing knee and hip replacement surgery. However, those acute indications carry limited durations of use, whereas chronic use in the atrial fibrillation population presents a far more lucrative market.

Yet, even ahead of the release of FDA’s advisory committee review documents, there were strong signs that development partners J&J and Bayer faced regulatory challenges with the atrial fibrillation claim, not the least of which was the agency’s decision to take a new drug application for a secondary indication to a panel.

Publication of results from the pivotal ROCKET AF study in August also suggested a number of areas of likely concern for the FDA and the committee. Among these were rivaroxaban’s showing of superiority over warfarin in the as-treated safety population, but not in the intention-to-treat analysis. The published data also spurred questions about how well warfarin was dosed in the comparator arm.

Even if the atrial fibrillation claim can pass regulatory muster, rivaroxaban seems poised to face commercial challenges from Pradaxa and Bristol-Myers Squibb/Pfizer’s investigational Factor Xa inhibitor Eliquis (apixaban).

Pradaxa has the first-mover advantage among the new oral anticoagulants, having entered the market in October 2010. It carries a "back-door" claim for superior efficacy over warfarin; the FDA determined that an overt claim was not warranted because dabigatran’s effect was driven by patients in the RE-LY trial’s warfarin arm whose clotting time, as measured by the International Normalized Ratio, was not well controlled.

According to the recently published results of the ARISTOTLE pivotal study, apixaban demonstrated both superior efficacy and bleeding safety over warfarin, along with a statistically significant, albeit slim, all-cause mortality benefit.

Agency Reviewers Urge "Complete Response"

These challenges notwithstanding, the FDA’s medical review released ahead of the Sept. 8 advisory committee meeting was highly negative. Reviewers Nhi Beasley, Preston Dunnmon, and Martin Rose recommended a "complete response" letter due to the need for additional efficacy and safety data.

The reviewers cited two main reasons for their recommendation that the NDA not be approved.

First, they said the ROCKET AF data were not adequate to determine whether rivaroxaban is as effective as warfarin when the latter is used skillfully. Interpretation of ROCKET AF results is complicated by the relatively poor degree of INR control in the study, the reviewers said.

The mean time in therapeutic range (TTR) in the warfarin arm was 55%, well below the TTR in other recent warfarin-controlled studies, which ranged from 63% to 73%.

TTRs in ROCKET AF varied widely by region and country, ranging from 36% in India to 75% in Sweden. The mean TTR of U.S. study sites was 63%.

"At global centers in ROCKET where warfarin was used skillfully, e.g., centers with mean TTR above [about] 68%, the study data suggest that patients had a numerically greater rate of primary end point events (stroke and systemic emboli, but most events were strokes) in the rivaroxaban arm," the reviewers said. "Such centers constituted about a quarter of the total in ROCKET, but the number of subjects at those centers was only about 15% of the total. The confidence interval around the point estimate for the hazard ratio in this subset of patients is quite wide, so there is a substantial measure of uncertainty about these data. Such uncertainty about comparability to approved therapy for stroke prevention argues strongly for the need for additional data to support approval."

Interpreting the FDA’s "As Effective" Requirement

The FDA reviewers seek to put the data into the context of FDA policy that requires new therapies be as effective as approved treatments when the disease at issue is life-threatening or capable of causing irreversible morbidity.

"The policy is broadly written and lacks a discussion of operational details," the reviewers said.

"For example, it does not state whether comparable effectiveness to an approved therapy used in an unskilled manner would be adequate for approval. However, if it is essential for a therapy to be as effective as an approved therapy to protect public health, it is logical that the new therapy should be as effective as the approved therapy when the approved therapy drug is used skillfully."

The reviewers said rivaroxaban should not be approved "unless the sponsor submits convincing information that it is as safe and effective for its target indication as warfarin when it is used skillfully (e.g. in the subgroup of patients at centers where TTR [is greater than or equal to about] 67%), or that it is as safe and effective as another approved agent, such as dabigatran."

The reviewers left a door open for rivaroxaban’s approval for those patients whose INR cannot be well controlled on warfarin or who are unwilling to take the vitamin K antagonist.

"However, such patients have an alternative, dabigatran, which is approved for rivaroxaban’s proposed indication," the reviewers pointed out. "Dabigatran was shown to be superior to warfarin in preventing stroke and systemic emboli in the overall results of the large global RE-LY trial (with a median TTR of about 67%), and it was robustly noninferior to warfarin at RE-LY centers with TTR above the median."

Given the availability of dabigatran, "it seems advisable to make rivaroxaban a third-line agent, behind both warfarin and dabigatran," the reviewers said.

In the draft questions to the advisory committee, the FDA notes its "as effective" policy explicitly does not apply if the new therapy is studied in a new population. The agency asks whether this exclusion applies to rivaroxaban based upon differences in the populations of the ROCKET AF and RE-LY trials.

Key among these differences was the enrollment in ROCKET of patients at higher risk for stroke, based upon CHADS scores, than those studied in RE-LY. ROCKET also enrolled more patients who had a prior stroke or systemic embolism.

A Firm "No" On Superiority

If the committee votes in favor of approval, the panel is asked to discuss whether a claim for superiority over warfarin is merited.

FDA reviewers said the sponsors’ request for superiority language should be rejected for several reasons. Among these, only the on-treatment analyses of the safety and per-protocol populations support superiority. "All analyses that include follow-up of patients for at least seven days after the last dose of study, and all ITT analyses do not support superiority. We generally prefer an ITT analyses as the basis of a superiority claim."

More Data Needed on Transition Strategy

In explaining their second reason why the NDA should not be approved, the reviewers pointed to a statistically significant increase in the rate of strokes in the rivaroxaban arm compared with warfarin while subjects were being transitioned from blinded study drug to open-label warfarin at the end of study.

Unlike in the RE-LY and ARISTOTLE trials, no provisions were made for a short period of dual therapy for patients in the rivaroxaban arm to continue anticoagulation during the lag period of INR control at the start of open-label warfarin.

"To ameliorate the risk of events after discontinuation of rivaroxaban, the sponsor has submitted proposed labeling with instructions for the transition from rivaroxaban to warfarin therapy. These instructions call for a period of concomitant treatment with both drugs under INR control (with INR measured at the end of the rivaroxaban dosing interval)," the reviewers said.

However, these instructions were developed after the ROCKET trial was completed and are based on pharmacokinetic/pharmacodynamic modeling; they have not been evaluated in a clinical trial. Given the serious risk of stroke associated with this transition period, "it seems prudent to require the sponsor to demonstrate in a clinical study in A Fib patients receiving rivaroxaban therapy that the proposed transition regimen is safe and effective."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration’s policy requiring new drugs for serious conditions to be "as effective" as approved agents will take center stage at the Cardiovascular and Renal Drugs Advisory Committee’s Sept. 8 review of Bayer/Johnson & Johnson’s anticoagulant Xarelto (rivaroxaban) for atrial fibrillation.

The agency will ask the panel whether the oral Factor Xa inhibitor must be shown to be "as effective" as warfarin and/or Boehringer Ingelheim GmbH’s oral direct thrombin inhibitor Pradaxa (dabigatran) for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, according to FDA review documents released Sept. 6.

If the committee concludes that rivaroxaban must show similar efficacy to existing treatments and has demonstrated such efficacy, the agency asks whether a superiority claim over warfarin is warranted. Alternatively, the agency asks whether rivaroxaban should be used only in those patients who fail other anticoagulant therapy.

The committee also will be asked to comment on the adequacy of the ROCKET AF trial design and how the suboptimal use of warfarin in the 14,000-patient study impacted the interpretation of rivaroxaban’s efficacy results.

Concerns outlined in the FDA’s review documents about the suboptimal use of warfarin as a control in the clinical trial, coupled with an increase in strokes associated with transitioning patients to warfarin, suggest rivaroxaban faces a difficult regulatory path forward even if it manages to get a positive recommendation from the cardio-renal panel.

Commercial, Regulatory Challenges Ahead

The FDA approved rivaroxaban on July 1 for the prophylaxis of deep vein thrombosis in patients undergoing knee and hip replacement surgery. However, those acute indications carry limited durations of use, whereas chronic use in the atrial fibrillation population presents a far more lucrative market.

Yet, even ahead of the release of FDA’s advisory committee review documents, there were strong signs that development partners J&J and Bayer faced regulatory challenges with the atrial fibrillation claim, not the least of which was the agency’s decision to take a new drug application for a secondary indication to a panel.

Publication of results from the pivotal ROCKET AF study in August also suggested a number of areas of likely concern for the FDA and the committee. Among these were rivaroxaban’s showing of superiority over warfarin in the as-treated safety population, but not in the intention-to-treat analysis. The published data also spurred questions about how well warfarin was dosed in the comparator arm.

Even if the atrial fibrillation claim can pass regulatory muster, rivaroxaban seems poised to face commercial challenges from Pradaxa and Bristol-Myers Squibb/Pfizer’s investigational Factor Xa inhibitor Eliquis (apixaban).

Pradaxa has the first-mover advantage among the new oral anticoagulants, having entered the market in October 2010. It carries a "back-door" claim for superior efficacy over warfarin; the FDA determined that an overt claim was not warranted because dabigatran’s effect was driven by patients in the RE-LY trial’s warfarin arm whose clotting time, as measured by the International Normalized Ratio, was not well controlled.

According to the recently published results of the ARISTOTLE pivotal study, apixaban demonstrated both superior efficacy and bleeding safety over warfarin, along with a statistically significant, albeit slim, all-cause mortality benefit.

Agency Reviewers Urge "Complete Response"

These challenges notwithstanding, the FDA’s medical review released ahead of the Sept. 8 advisory committee meeting was highly negative. Reviewers Nhi Beasley, Preston Dunnmon, and Martin Rose recommended a "complete response" letter due to the need for additional efficacy and safety data.

The reviewers cited two main reasons for their recommendation that the NDA not be approved.

First, they said the ROCKET AF data were not adequate to determine whether rivaroxaban is as effective as warfarin when the latter is used skillfully. Interpretation of ROCKET AF results is complicated by the relatively poor degree of INR control in the study, the reviewers said.

The mean time in therapeutic range (TTR) in the warfarin arm was 55%, well below the TTR in other recent warfarin-controlled studies, which ranged from 63% to 73%.

TTRs in ROCKET AF varied widely by region and country, ranging from 36% in India to 75% in Sweden. The mean TTR of U.S. study sites was 63%.

"At global centers in ROCKET where warfarin was used skillfully, e.g., centers with mean TTR above [about] 68%, the study data suggest that patients had a numerically greater rate of primary end point events (stroke and systemic emboli, but most events were strokes) in the rivaroxaban arm," the reviewers said. "Such centers constituted about a quarter of the total in ROCKET, but the number of subjects at those centers was only about 15% of the total. The confidence interval around the point estimate for the hazard ratio in this subset of patients is quite wide, so there is a substantial measure of uncertainty about these data. Such uncertainty about comparability to approved therapy for stroke prevention argues strongly for the need for additional data to support approval."

Interpreting the FDA’s "As Effective" Requirement

The FDA reviewers seek to put the data into the context of FDA policy that requires new therapies be as effective as approved treatments when the disease at issue is life-threatening or capable of causing irreversible morbidity.

"The policy is broadly written and lacks a discussion of operational details," the reviewers said.

"For example, it does not state whether comparable effectiveness to an approved therapy used in an unskilled manner would be adequate for approval. However, if it is essential for a therapy to be as effective as an approved therapy to protect public health, it is logical that the new therapy should be as effective as the approved therapy when the approved therapy drug is used skillfully."

The reviewers said rivaroxaban should not be approved "unless the sponsor submits convincing information that it is as safe and effective for its target indication as warfarin when it is used skillfully (e.g. in the subgroup of patients at centers where TTR [is greater than or equal to about] 67%), or that it is as safe and effective as another approved agent, such as dabigatran."

The reviewers left a door open for rivaroxaban’s approval for those patients whose INR cannot be well controlled on warfarin or who are unwilling to take the vitamin K antagonist.

"However, such patients have an alternative, dabigatran, which is approved for rivaroxaban’s proposed indication," the reviewers pointed out. "Dabigatran was shown to be superior to warfarin in preventing stroke and systemic emboli in the overall results of the large global RE-LY trial (with a median TTR of about 67%), and it was robustly noninferior to warfarin at RE-LY centers with TTR above the median."

Given the availability of dabigatran, "it seems advisable to make rivaroxaban a third-line agent, behind both warfarin and dabigatran," the reviewers said.

In the draft questions to the advisory committee, the FDA notes its "as effective" policy explicitly does not apply if the new therapy is studied in a new population. The agency asks whether this exclusion applies to rivaroxaban based upon differences in the populations of the ROCKET AF and RE-LY trials.

Key among these differences was the enrollment in ROCKET of patients at higher risk for stroke, based upon CHADS scores, than those studied in RE-LY. ROCKET also enrolled more patients who had a prior stroke or systemic embolism.

A Firm "No" On Superiority

If the committee votes in favor of approval, the panel is asked to discuss whether a claim for superiority over warfarin is merited.

FDA reviewers said the sponsors’ request for superiority language should be rejected for several reasons. Among these, only the on-treatment analyses of the safety and per-protocol populations support superiority. "All analyses that include follow-up of patients for at least seven days after the last dose of study, and all ITT analyses do not support superiority. We generally prefer an ITT analyses as the basis of a superiority claim."

More Data Needed on Transition Strategy

In explaining their second reason why the NDA should not be approved, the reviewers pointed to a statistically significant increase in the rate of strokes in the rivaroxaban arm compared with warfarin while subjects were being transitioned from blinded study drug to open-label warfarin at the end of study.

Unlike in the RE-LY and ARISTOTLE trials, no provisions were made for a short period of dual therapy for patients in the rivaroxaban arm to continue anticoagulation during the lag period of INR control at the start of open-label warfarin.

"To ameliorate the risk of events after discontinuation of rivaroxaban, the sponsor has submitted proposed labeling with instructions for the transition from rivaroxaban to warfarin therapy. These instructions call for a period of concomitant treatment with both drugs under INR control (with INR measured at the end of the rivaroxaban dosing interval)," the reviewers said.

However, these instructions were developed after the ROCKET trial was completed and are based on pharmacokinetic/pharmacodynamic modeling; they have not been evaluated in a clinical trial. Given the serious risk of stroke associated with this transition period, "it seems prudent to require the sponsor to demonstrate in a clinical study in A Fib patients receiving rivaroxaban therapy that the proposed transition regimen is safe and effective."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration’s policy requiring new drugs for serious conditions to be "as effective" as approved agents will take center stage at the Cardiovascular and Renal Drugs Advisory Committee’s Sept. 8 review of Bayer/Johnson & Johnson’s anticoagulant Xarelto (rivaroxaban) for atrial fibrillation.

The agency will ask the panel whether the oral Factor Xa inhibitor must be shown to be "as effective" as warfarin and/or Boehringer Ingelheim GmbH’s oral direct thrombin inhibitor Pradaxa (dabigatran) for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, according to FDA review documents released Sept. 6.

If the committee concludes that rivaroxaban must show similar efficacy to existing treatments and has demonstrated such efficacy, the agency asks whether a superiority claim over warfarin is warranted. Alternatively, the agency asks whether rivaroxaban should be used only in those patients who fail other anticoagulant therapy.

The committee also will be asked to comment on the adequacy of the ROCKET AF trial design and how the suboptimal use of warfarin in the 14,000-patient study impacted the interpretation of rivaroxaban’s efficacy results.

Concerns outlined in the FDA’s review documents about the suboptimal use of warfarin as a control in the clinical trial, coupled with an increase in strokes associated with transitioning patients to warfarin, suggest rivaroxaban faces a difficult regulatory path forward even if it manages to get a positive recommendation from the cardio-renal panel.

Commercial, Regulatory Challenges Ahead

The FDA approved rivaroxaban on July 1 for the prophylaxis of deep vein thrombosis in patients undergoing knee and hip replacement surgery. However, those acute indications carry limited durations of use, whereas chronic use in the atrial fibrillation population presents a far more lucrative market.

Yet, even ahead of the release of FDA’s advisory committee review documents, there were strong signs that development partners J&J and Bayer faced regulatory challenges with the atrial fibrillation claim, not the least of which was the agency’s decision to take a new drug application for a secondary indication to a panel.

Publication of results from the pivotal ROCKET AF study in August also suggested a number of areas of likely concern for the FDA and the committee. Among these were rivaroxaban’s showing of superiority over warfarin in the as-treated safety population, but not in the intention-to-treat analysis. The published data also spurred questions about how well warfarin was dosed in the comparator arm.

Even if the atrial fibrillation claim can pass regulatory muster, rivaroxaban seems poised to face commercial challenges from Pradaxa and Bristol-Myers Squibb/Pfizer’s investigational Factor Xa inhibitor Eliquis (apixaban).

Pradaxa has the first-mover advantage among the new oral anticoagulants, having entered the market in October 2010. It carries a "back-door" claim for superior efficacy over warfarin; the FDA determined that an overt claim was not warranted because dabigatran’s effect was driven by patients in the RE-LY trial’s warfarin arm whose clotting time, as measured by the International Normalized Ratio, was not well controlled.

According to the recently published results of the ARISTOTLE pivotal study, apixaban demonstrated both superior efficacy and bleeding safety over warfarin, along with a statistically significant, albeit slim, all-cause mortality benefit.

Agency Reviewers Urge "Complete Response"

These challenges notwithstanding, the FDA’s medical review released ahead of the Sept. 8 advisory committee meeting was highly negative. Reviewers Nhi Beasley, Preston Dunnmon, and Martin Rose recommended a "complete response" letter due to the need for additional efficacy and safety data.

The reviewers cited two main reasons for their recommendation that the NDA not be approved.

First, they said the ROCKET AF data were not adequate to determine whether rivaroxaban is as effective as warfarin when the latter is used skillfully. Interpretation of ROCKET AF results is complicated by the relatively poor degree of INR control in the study, the reviewers said.

The mean time in therapeutic range (TTR) in the warfarin arm was 55%, well below the TTR in other recent warfarin-controlled studies, which ranged from 63% to 73%.

TTRs in ROCKET AF varied widely by region and country, ranging from 36% in India to 75% in Sweden. The mean TTR of U.S. study sites was 63%.

"At global centers in ROCKET where warfarin was used skillfully, e.g., centers with mean TTR above [about] 68%, the study data suggest that patients had a numerically greater rate of primary end point events (stroke and systemic emboli, but most events were strokes) in the rivaroxaban arm," the reviewers said. "Such centers constituted about a quarter of the total in ROCKET, but the number of subjects at those centers was only about 15% of the total. The confidence interval around the point estimate for the hazard ratio in this subset of patients is quite wide, so there is a substantial measure of uncertainty about these data. Such uncertainty about comparability to approved therapy for stroke prevention argues strongly for the need for additional data to support approval."

Interpreting the FDA’s "As Effective" Requirement

The FDA reviewers seek to put the data into the context of FDA policy that requires new therapies be as effective as approved treatments when the disease at issue is life-threatening or capable of causing irreversible morbidity.

"The policy is broadly written and lacks a discussion of operational details," the reviewers said.

"For example, it does not state whether comparable effectiveness to an approved therapy used in an unskilled manner would be adequate for approval. However, if it is essential for a therapy to be as effective as an approved therapy to protect public health, it is logical that the new therapy should be as effective as the approved therapy when the approved therapy drug is used skillfully."

The reviewers said rivaroxaban should not be approved "unless the sponsor submits convincing information that it is as safe and effective for its target indication as warfarin when it is used skillfully (e.g. in the subgroup of patients at centers where TTR [is greater than or equal to about] 67%), or that it is as safe and effective as another approved agent, such as dabigatran."

The reviewers left a door open for rivaroxaban’s approval for those patients whose INR cannot be well controlled on warfarin or who are unwilling to take the vitamin K antagonist.

"However, such patients have an alternative, dabigatran, which is approved for rivaroxaban’s proposed indication," the reviewers pointed out. "Dabigatran was shown to be superior to warfarin in preventing stroke and systemic emboli in the overall results of the large global RE-LY trial (with a median TTR of about 67%), and it was robustly noninferior to warfarin at RE-LY centers with TTR above the median."

Given the availability of dabigatran, "it seems advisable to make rivaroxaban a third-line agent, behind both warfarin and dabigatran," the reviewers said.

In the draft questions to the advisory committee, the FDA notes its "as effective" policy explicitly does not apply if the new therapy is studied in a new population. The agency asks whether this exclusion applies to rivaroxaban based upon differences in the populations of the ROCKET AF and RE-LY trials.

Key among these differences was the enrollment in ROCKET of patients at higher risk for stroke, based upon CHADS scores, than those studied in RE-LY. ROCKET also enrolled more patients who had a prior stroke or systemic embolism.

A Firm "No" On Superiority

If the committee votes in favor of approval, the panel is asked to discuss whether a claim for superiority over warfarin is merited.

FDA reviewers said the sponsors’ request for superiority language should be rejected for several reasons. Among these, only the on-treatment analyses of the safety and per-protocol populations support superiority. "All analyses that include follow-up of patients for at least seven days after the last dose of study, and all ITT analyses do not support superiority. We generally prefer an ITT analyses as the basis of a superiority claim."

More Data Needed on Transition Strategy

In explaining their second reason why the NDA should not be approved, the reviewers pointed to a statistically significant increase in the rate of strokes in the rivaroxaban arm compared with warfarin while subjects were being transitioned from blinded study drug to open-label warfarin at the end of study.

Unlike in the RE-LY and ARISTOTLE trials, no provisions were made for a short period of dual therapy for patients in the rivaroxaban arm to continue anticoagulation during the lag period of INR control at the start of open-label warfarin.

"To ameliorate the risk of events after discontinuation of rivaroxaban, the sponsor has submitted proposed labeling with instructions for the transition from rivaroxaban to warfarin therapy. These instructions call for a period of concomitant treatment with both drugs under INR control (with INR measured at the end of the rivaroxaban dosing interval)," the reviewers said.

However, these instructions were developed after the ROCKET trial was completed and are based on pharmacokinetic/pharmacodynamic modeling; they have not been evaluated in a clinical trial. Given the serious risk of stroke associated with this transition period, "it seems prudent to require the sponsor to demonstrate in a clinical study in A Fib patients receiving rivaroxaban therapy that the proposed transition regimen is safe and effective."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Dapagliflozin seems to have skirted the cardiovascular safety concerns surrounding other agents intended for treating type 2 diabetes, but the Food and Drug Administration is nevertheless seeking advisory committee input on a handful of “unexpected” safety issues for the first-in-class sodium glucose cotransporter–2 inhibitor, including potential hepatic and cancer risks.

At a July 19 meeting, the agency will ask its Endocrinologic and Metabolic Drugs Advisory Committee whether sufficient evaluation has been conducted preapproval to determine if dapagliflozin is associated with a risk of hepatotoxicity, according to agency briefing documents released July 15.

The FDA also seeks panel discussion on numeric imbalances in cases of breast and bladder cancer observed in the clinical program, and it asks the committee to weigh the clinical significance of other safety findings, including the increased risk of genitourinary infections.

The agency has little quibble with dapagliflozin’s efficacy, other than to say it is limited to patients with normal renal function or only mild impairment. However, the FDA asks whether additional studies in special populations should be conducted to better characterize efficacy or whether renal function monitoring should be performed before and during treatment.

Novel Mechanism of Action

Dapagliflozin is the most advanced member of the new class of oral sodium glucose cotransporter–2 (SGLT2) inhibitors that cause renal elimination of glucose. The mechanism of action, which offers a way to lower blood glucose apart from insulin, has spurred predictions that the class would find its niche as add-on therapy at different stages of the disease.

Bristol-Myers Squibb and AstraZeneca are seeking a broad indication for dapagliflozin: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

The new drug application submission included data from three phase IIb and 11 phase III studies evaluating dapagliflozin as monotherapy, add-on therapy to metformin, sulfonylureas, pioglitazone (Actos), or insulin, as well as initial combination therapy with metformin. Efficacy results were comparable to those for existing agents, the FDA says.

“The magnitude of glycemic reduction in the clinical trials has been consistent and in line with recently approved antidiabetic drugs, such as dipeptidyl peptidase inhibitors,” the division of metabolism and endocrinology products says in its clinical briefing document. “In active-controlled trials, dapagliflozin demonstrated equivalent effects on HbA_1c as near maximally effective doses of metformin and glipizide at 1 year.”

However, the agency found efficacy to be limited in those patients with compromised renal function. The sponsors have proposed that the drug not be used in patients with moderate renal impairment, with a glomerular filtration rate (GFR) less than 45 mL/min per 1.73 m². But the agency cited a loss of statistically significant efficacy in patients with more mild impairment, with a GFR less than 45-59 mL/min per 1.73 m².

The loss of efficacy that accompanies an increase in renal impairment is particularly important for type 2 diabetics, FDA reviewers say.

“It is important to note that patients with [type 2 diabetes mellitus] are at risk for worsening renal function over the course of their disease. Unlike treatment with other classes of antidiabetic medications that rely on either insulin secretion or sensitivity, dapagliflozin’s effect is dependent on GFR and independent of beta-cell function. Therefore, secondary failure of glycemic control with dapagliflozin may represent deterioration of renal function, rather than beta-cell function, and discontinuation of dapagliflozin (in contrast to the practice of adding drugs of complementary effects) may be recommended.”

Cardiovascular Profile Looks Good

Concerns about the postmarketing cardiovascular (CV) safety of another diabetes drug, GlaxoSmithKline’s Avandia (rosiglitazone), spurred new FDA guidelines in December 2008 requiring sponsors to rule out an unacceptable level of increased cardiovascular risk before and after approval for type 2 treatments.

Sponsors must rule out an 80% increased risk of major adverse CV events preapproval. If preapproval clinical data show that the upper bound of the two-sided 95% confidence interval for the estimated risk lies between 1.3 and 1.8, companies generally will need to conduct a postmarketing trial to demonstrate that the upper bound is less than 1.3. If the preapproval data demonstrate an upper bound below 1.3, a postmarketing cardiovascular trial generally may not be necessary.

The guidance’s provisions applied to all drugs pending FDA review and in clinical development at the time it was issued. The new CV requirements tripped up at least one antidiabetic agent that had already been submitted for FDA review, Takeda’s DPP-4 inhibitor alogliptin.

However, it appears that dapagliflozin has easily overcome the preapproval CV hurdle laid out in the guidance.

Based on a meta-analysis of the phase II/III trials, the drug “does not appear to be associated with excess CV risk with an overall HR of 0.67 … relative to comparators for the primary composite of CV deaths, myocardial infarctions, stroke, and hospitalization for unstable angina,” Dr. Mary Parks, director of the division of metabolism and endocrinology products, writes in her memo to the advisory committee.

Although the upper bound of the 95% confidence interval was below 1.3, falling shy of the cut point for a mandatory postapproval CV outcomes trial, the FDA nevertheless has decided such a study will be required.

“The applicant has proposed to conduct a CV outcomes trial whose primary objective is to demonstrate a cardioprotective effect of dapagliflozin,” Dr. Parks writes. “FDA concurs with the applicant that a CV outcomes trial is necessary to better characterize the CV safety of this drug and to evaluate safety issues that have arisen in the course of this [new drug application] review. If approved, this CV outcomes trial will be a required postmarketing trial.”

But Hepatic, Cancer Concerns Worry

Although dapagliflozin’s premarketing CV profile looks clean, “several unexpected safety issues identified in this clinical development program were of sufficient concern to FDA to merit discussion of their impact on the overall benefit-risk consideration,” Dr. Parks writes.

Among these are the drug’s hepatic effects. There were a total of five dapagliflozin-treated patients in the phase IIb/III trials who met the laboratory criteria for Hy’s Law (AST or ALT levels greater than three times the upper limit of normal and elevation of total bilirubin level greater than two times the upper limit of normal). One of these was classified as a “probable” case of drug-induced liver injury.

In their review, Office of Surveillance and Epidemiology hepatologists Leonard Seeff and John Senior noted that in many cases the data were too limited to make a linkage between dapagliflozin and liver damage. Given the importance of recognizing sentinel cases of drug-induced liver injury in registrational trials, “it is prudent to gather more information on all relevant cases as part of an in-depth review of the dapagliflozin [new drug application] in order to assess whether this agent may be hepatotoxic,” they say, adding that careful hepatic monitoring should be performed in any future studies.

The FDA also calls the committee’s attention to numerical imbalances in cases of breast and bladder cancer among dapagliflozin-treated patients.

There were seven bladder cancer cases in dapagliflozin-treated patients at the time of the 4-month safety update, compared with none in the control group. Subsequently, two more cases were reported with dapagliflozin and one with controls. “This can be extrapolated to 207 cases per 100,000 person-year exposure in dapagliflozin-treated patients versus 53 cases per 100,000 person-year exposure in control[s],” the clinical review states.

The findings suggest dapagliflozin could be in for the same type of bladder cancer cloud currently hanging over Actos.

The FDA questions whether detection bias resulting from dapagliflozin’s mechanism of action and related genitourinary adverse effects could have contributed to the imbalance observed.

“More frequent assessments of urinalysis in the dapagliflozin group might result in postbaseline detection of hematuria requiring further work-up and higher rate of cancer diagnosis than control group, which might not have received as extensive monitoring,” the FDA reviewers state.

“In this regard, it is interesting to note that concerns of bladder cancer associated with pioglitazone use arose during premarketing development due to nonclinical findings of bladder cancer in male rodents. This led to a prospective assessment of urine cytology in approximately 1,800 patients in clinical trials up to 1 year [in] duration. Despite similar active surveillance for bladder cancer in pioglitazone and control groups, no clinical cases were detected premarketing. Imbalance of clinical bladder cancer risk with pioglitazone was not observed until after approval.”

There also was an imbalance in the number of breast cancer cases, with nine reported in the dapagliflozin-treated group and none in the control group.

For both types of cancer, the FDA concludes that the numbers observed exceeded the expected number of cases in the type 2 diabetic population. It asks the advisory committee whether any imbalance in baseline factors may have contributed to the findings and whether detection bias was a factor.

The FDA also wants the committee to consider the increase in genital and urinary infections associated with dapagliflozin. Such infections have become a well-known side effect of this class of drugs, given their mechanism of action.

This coverage is provided by “The Pink Sheet.” This news organization and “The Pink Sheet” are owned by Elsevier.

Dapagliflozin seems to have skirted the cardiovascular safety concerns surrounding other agents intended for treating type 2 diabetes, but the Food and Drug Administration is nevertheless seeking advisory committee input on a handful of “unexpected” safety issues for the first-in-class sodium glucose cotransporter–2 inhibitor, including potential hepatic and cancer risks.

At a July 19 meeting, the agency will ask its Endocrinologic and Metabolic Drugs Advisory Committee whether sufficient evaluation has been conducted preapproval to determine if dapagliflozin is associated with a risk of hepatotoxicity, according to agency briefing documents released July 15.

The FDA also seeks panel discussion on numeric imbalances in cases of breast and bladder cancer observed in the clinical program, and it asks the committee to weigh the clinical significance of other safety findings, including the increased risk of genitourinary infections.

The agency has little quibble with dapagliflozin’s efficacy, other than to say it is limited to patients with normal renal function or only mild impairment. However, the FDA asks whether additional studies in special populations should be conducted to better characterize efficacy or whether renal function monitoring should be performed before and during treatment.

Novel Mechanism of Action

Dapagliflozin is the most advanced member of the new class of oral sodium glucose cotransporter–2 (SGLT2) inhibitors that cause renal elimination of glucose. The mechanism of action, which offers a way to lower blood glucose apart from insulin, has spurred predictions that the class would find its niche as add-on therapy at different stages of the disease.

Bristol-Myers Squibb and AstraZeneca are seeking a broad indication for dapagliflozin: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

The new drug application submission included data from three phase IIb and 11 phase III studies evaluating dapagliflozin as monotherapy, add-on therapy to metformin, sulfonylureas, pioglitazone (Actos), or insulin, as well as initial combination therapy with metformin. Efficacy results were comparable to those for existing agents, the FDA says.

“The magnitude of glycemic reduction in the clinical trials has been consistent and in line with recently approved antidiabetic drugs, such as dipeptidyl peptidase inhibitors,” the division of metabolism and endocrinology products says in its clinical briefing document. “In active-controlled trials, dapagliflozin demonstrated equivalent effects on HbA_1c as near maximally effective doses of metformin and glipizide at 1 year.”

However, the agency found efficacy to be limited in those patients with compromised renal function. The sponsors have proposed that the drug not be used in patients with moderate renal impairment, with a glomerular filtration rate (GFR) less than 45 mL/min per 1.73 m². But the agency cited a loss of statistically significant efficacy in patients with more mild impairment, with a GFR less than 45-59 mL/min per 1.73 m².

The loss of efficacy that accompanies an increase in renal impairment is particularly important for type 2 diabetics, FDA reviewers say.

“It is important to note that patients with [type 2 diabetes mellitus] are at risk for worsening renal function over the course of their disease. Unlike treatment with other classes of antidiabetic medications that rely on either insulin secretion or sensitivity, dapagliflozin’s effect is dependent on GFR and independent of beta-cell function. Therefore, secondary failure of glycemic control with dapagliflozin may represent deterioration of renal function, rather than beta-cell function, and discontinuation of dapagliflozin (in contrast to the practice of adding drugs of complementary effects) may be recommended.”

Cardiovascular Profile Looks Good

Concerns about the postmarketing cardiovascular (CV) safety of another diabetes drug, GlaxoSmithKline’s Avandia (rosiglitazone), spurred new FDA guidelines in December 2008 requiring sponsors to rule out an unacceptable level of increased cardiovascular risk before and after approval for type 2 treatments.

Sponsors must rule out an 80% increased risk of major adverse CV events preapproval. If preapproval clinical data show that the upper bound of the two-sided 95% confidence interval for the estimated risk lies between 1.3 and 1.8, companies generally will need to conduct a postmarketing trial to demonstrate that the upper bound is less than 1.3. If the preapproval data demonstrate an upper bound below 1.3, a postmarketing cardiovascular trial generally may not be necessary.

The guidance’s provisions applied to all drugs pending FDA review and in clinical development at the time it was issued. The new CV requirements tripped up at least one antidiabetic agent that had already been submitted for FDA review, Takeda’s DPP-4 inhibitor alogliptin.

However, it appears that dapagliflozin has easily overcome the preapproval CV hurdle laid out in the guidance.

Based on a meta-analysis of the phase II/III trials, the drug “does not appear to be associated with excess CV risk with an overall HR of 0.67 … relative to comparators for the primary composite of CV deaths, myocardial infarctions, stroke, and hospitalization for unstable angina,” Dr. Mary Parks, director of the division of metabolism and endocrinology products, writes in her memo to the advisory committee.

Although the upper bound of the 95% confidence interval was below 1.3, falling shy of the cut point for a mandatory postapproval CV outcomes trial, the FDA nevertheless has decided such a study will be required.

“The applicant has proposed to conduct a CV outcomes trial whose primary objective is to demonstrate a cardioprotective effect of dapagliflozin,” Dr. Parks writes. “FDA concurs with the applicant that a CV outcomes trial is necessary to better characterize the CV safety of this drug and to evaluate safety issues that have arisen in the course of this [new drug application] review. If approved, this CV outcomes trial will be a required postmarketing trial.”

But Hepatic, Cancer Concerns Worry

Although dapagliflozin’s premarketing CV profile looks clean, “several unexpected safety issues identified in this clinical development program were of sufficient concern to FDA to merit discussion of their impact on the overall benefit-risk consideration,” Dr. Parks writes.

Among these are the drug’s hepatic effects. There were a total of five dapagliflozin-treated patients in the phase IIb/III trials who met the laboratory criteria for Hy’s Law (AST or ALT levels greater than three times the upper limit of normal and elevation of total bilirubin level greater than two times the upper limit of normal). One of these was classified as a “probable” case of drug-induced liver injury.

In their review, Office of Surveillance and Epidemiology hepatologists Leonard Seeff and John Senior noted that in many cases the data were too limited to make a linkage between dapagliflozin and liver damage. Given the importance of recognizing sentinel cases of drug-induced liver injury in registrational trials, “it is prudent to gather more information on all relevant cases as part of an in-depth review of the dapagliflozin [new drug application] in order to assess whether this agent may be hepatotoxic,” they say, adding that careful hepatic monitoring should be performed in any future studies.

The FDA also calls the committee’s attention to numerical imbalances in cases of breast and bladder cancer among dapagliflozin-treated patients.

There were seven bladder cancer cases in dapagliflozin-treated patients at the time of the 4-month safety update, compared with none in the control group. Subsequently, two more cases were reported with dapagliflozin and one with controls. “This can be extrapolated to 207 cases per 100,000 person-year exposure in dapagliflozin-treated patients versus 53 cases per 100,000 person-year exposure in control[s],” the clinical review states.

The findings suggest dapagliflozin could be in for the same type of bladder cancer cloud currently hanging over Actos.

The FDA questions whether detection bias resulting from dapagliflozin’s mechanism of action and related genitourinary adverse effects could have contributed to the imbalance observed.

“More frequent assessments of urinalysis in the dapagliflozin group might result in postbaseline detection of hematuria requiring further work-up and higher rate of cancer diagnosis than control group, which might not have received as extensive monitoring,” the FDA reviewers state.

“In this regard, it is interesting to note that concerns of bladder cancer associated with pioglitazone use arose during premarketing development due to nonclinical findings of bladder cancer in male rodents. This led to a prospective assessment of urine cytology in approximately 1,800 patients in clinical trials up to 1 year [in] duration. Despite similar active surveillance for bladder cancer in pioglitazone and control groups, no clinical cases were detected premarketing. Imbalance of clinical bladder cancer risk with pioglitazone was not observed until after approval.”

There also was an imbalance in the number of breast cancer cases, with nine reported in the dapagliflozin-treated group and none in the control group.

For both types of cancer, the FDA concludes that the numbers observed exceeded the expected number of cases in the type 2 diabetic population. It asks the advisory committee whether any imbalance in baseline factors may have contributed to the findings and whether detection bias was a factor.

The FDA also wants the committee to consider the increase in genital and urinary infections associated with dapagliflozin. Such infections have become a well-known side effect of this class of drugs, given their mechanism of action.

This coverage is provided by “The Pink Sheet.” This news organization and “The Pink Sheet” are owned by Elsevier.

Dapagliflozin seems to have skirted the cardiovascular safety concerns surrounding other agents intended for treating type 2 diabetes, but the Food and Drug Administration is nevertheless seeking advisory committee input on a handful of “unexpected” safety issues for the first-in-class sodium glucose cotransporter–2 inhibitor, including potential hepatic and cancer risks.

At a July 19 meeting, the agency will ask its Endocrinologic and Metabolic Drugs Advisory Committee whether sufficient evaluation has been conducted preapproval to determine if dapagliflozin is associated with a risk of hepatotoxicity, according to agency briefing documents released July 15.

The FDA also seeks panel discussion on numeric imbalances in cases of breast and bladder cancer observed in the clinical program, and it asks the committee to weigh the clinical significance of other safety findings, including the increased risk of genitourinary infections.

The agency has little quibble with dapagliflozin’s efficacy, other than to say it is limited to patients with normal renal function or only mild impairment. However, the FDA asks whether additional studies in special populations should be conducted to better characterize efficacy or whether renal function monitoring should be performed before and during treatment.

Novel Mechanism of Action

Dapagliflozin is the most advanced member of the new class of oral sodium glucose cotransporter–2 (SGLT2) inhibitors that cause renal elimination of glucose. The mechanism of action, which offers a way to lower blood glucose apart from insulin, has spurred predictions that the class would find its niche as add-on therapy at different stages of the disease.

Bristol-Myers Squibb and AstraZeneca are seeking a broad indication for dapagliflozin: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

The new drug application submission included data from three phase IIb and 11 phase III studies evaluating dapagliflozin as monotherapy, add-on therapy to metformin, sulfonylureas, pioglitazone (Actos), or insulin, as well as initial combination therapy with metformin. Efficacy results were comparable to those for existing agents, the FDA says.

“The magnitude of glycemic reduction in the clinical trials has been consistent and in line with recently approved antidiabetic drugs, such as dipeptidyl peptidase inhibitors,” the division of metabolism and endocrinology products says in its clinical briefing document. “In active-controlled trials, dapagliflozin demonstrated equivalent effects on HbA_1c as near maximally effective doses of metformin and glipizide at 1 year.”

However, the agency found efficacy to be limited in those patients with compromised renal function. The sponsors have proposed that the drug not be used in patients with moderate renal impairment, with a glomerular filtration rate (GFR) less than 45 mL/min per 1.73 m². But the agency cited a loss of statistically significant efficacy in patients with more mild impairment, with a GFR less than 45-59 mL/min per 1.73 m².

The loss of efficacy that accompanies an increase in renal impairment is particularly important for type 2 diabetics, FDA reviewers say.

“It is important to note that patients with [type 2 diabetes mellitus] are at risk for worsening renal function over the course of their disease. Unlike treatment with other classes of antidiabetic medications that rely on either insulin secretion or sensitivity, dapagliflozin’s effect is dependent on GFR and independent of beta-cell function. Therefore, secondary failure of glycemic control with dapagliflozin may represent deterioration of renal function, rather than beta-cell function, and discontinuation of dapagliflozin (in contrast to the practice of adding drugs of complementary effects) may be recommended.”

Cardiovascular Profile Looks Good

Concerns about the postmarketing cardiovascular (CV) safety of another diabetes drug, GlaxoSmithKline’s Avandia (rosiglitazone), spurred new FDA guidelines in December 2008 requiring sponsors to rule out an unacceptable level of increased cardiovascular risk before and after approval for type 2 treatments.

Sponsors must rule out an 80% increased risk of major adverse CV events preapproval. If preapproval clinical data show that the upper bound of the two-sided 95% confidence interval for the estimated risk lies between 1.3 and 1.8, companies generally will need to conduct a postmarketing trial to demonstrate that the upper bound is less than 1.3. If the preapproval data demonstrate an upper bound below 1.3, a postmarketing cardiovascular trial generally may not be necessary.

The guidance’s provisions applied to all drugs pending FDA review and in clinical development at the time it was issued. The new CV requirements tripped up at least one antidiabetic agent that had already been submitted for FDA review, Takeda’s DPP-4 inhibitor alogliptin.

However, it appears that dapagliflozin has easily overcome the preapproval CV hurdle laid out in the guidance.

Based on a meta-analysis of the phase II/III trials, the drug “does not appear to be associated with excess CV risk with an overall HR of 0.67 … relative to comparators for the primary composite of CV deaths, myocardial infarctions, stroke, and hospitalization for unstable angina,” Dr. Mary Parks, director of the division of metabolism and endocrinology products, writes in her memo to the advisory committee.

Although the upper bound of the 95% confidence interval was below 1.3, falling shy of the cut point for a mandatory postapproval CV outcomes trial, the FDA nevertheless has decided such a study will be required.

“The applicant has proposed to conduct a CV outcomes trial whose primary objective is to demonstrate a cardioprotective effect of dapagliflozin,” Dr. Parks writes. “FDA concurs with the applicant that a CV outcomes trial is necessary to better characterize the CV safety of this drug and to evaluate safety issues that have arisen in the course of this [new drug application] review. If approved, this CV outcomes trial will be a required postmarketing trial.”

But Hepatic, Cancer Concerns Worry

Although dapagliflozin’s premarketing CV profile looks clean, “several unexpected safety issues identified in this clinical development program were of sufficient concern to FDA to merit discussion of their impact on the overall benefit-risk consideration,” Dr. Parks writes.

Among these are the drug’s hepatic effects. There were a total of five dapagliflozin-treated patients in the phase IIb/III trials who met the laboratory criteria for Hy’s Law (AST or ALT levels greater than three times the upper limit of normal and elevation of total bilirubin level greater than two times the upper limit of normal). One of these was classified as a “probable” case of drug-induced liver injury.

In their review, Office of Surveillance and Epidemiology hepatologists Leonard Seeff and John Senior noted that in many cases the data were too limited to make a linkage between dapagliflozin and liver damage. Given the importance of recognizing sentinel cases of drug-induced liver injury in registrational trials, “it is prudent to gather more information on all relevant cases as part of an in-depth review of the dapagliflozin [new drug application] in order to assess whether this agent may be hepatotoxic,” they say, adding that careful hepatic monitoring should be performed in any future studies.

The FDA also calls the committee’s attention to numerical imbalances in cases of breast and bladder cancer among dapagliflozin-treated patients.

There were seven bladder cancer cases in dapagliflozin-treated patients at the time of the 4-month safety update, compared with none in the control group. Subsequently, two more cases were reported with dapagliflozin and one with controls. “This can be extrapolated to 207 cases per 100,000 person-year exposure in dapagliflozin-treated patients versus 53 cases per 100,000 person-year exposure in control[s],” the clinical review states.

The findings suggest dapagliflozin could be in for the same type of bladder cancer cloud currently hanging over Actos.

The FDA questions whether detection bias resulting from dapagliflozin’s mechanism of action and related genitourinary adverse effects could have contributed to the imbalance observed.

“More frequent assessments of urinalysis in the dapagliflozin group might result in postbaseline detection of hematuria requiring further work-up and higher rate of cancer diagnosis than control group, which might not have received as extensive monitoring,” the FDA reviewers state.

“In this regard, it is interesting to note that concerns of bladder cancer associated with pioglitazone use arose during premarketing development due to nonclinical findings of bladder cancer in male rodents. This led to a prospective assessment of urine cytology in approximately 1,800 patients in clinical trials up to 1 year [in] duration. Despite similar active surveillance for bladder cancer in pioglitazone and control groups, no clinical cases were detected premarketing. Imbalance of clinical bladder cancer risk with pioglitazone was not observed until after approval.”

There also was an imbalance in the number of breast cancer cases, with nine reported in the dapagliflozin-treated group and none in the control group.

For both types of cancer, the FDA concludes that the numbers observed exceeded the expected number of cases in the type 2 diabetic population. It asks the advisory committee whether any imbalance in baseline factors may have contributed to the findings and whether detection bias was a factor.

The FDA also wants the committee to consider the increase in genital and urinary infections associated with dapagliflozin. Such infections have become a well-known side effect of this class of drugs, given their mechanism of action.

This coverage is provided by “The Pink Sheet.” This news organization and “The Pink Sheet” are owned by Elsevier.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Association’s public hearing on Avastin’s metastatic breast cancer claim opened June 28 with an attack by officials from the agency’s Center for Drug Evaluation and Research on Genentech’s plan for a new confirmatory study.

Genentech’s proposed study of Avastin (bevacizumab) in combination with paclitaxel in first-line metastatic breast cancer (MBC) does not justify continued approval of the indication because the trial is unlikely to substantiate the magnitude of progression-free survival benefit seen in the E2100 trial and there are multiple factors that could delay the new study’s completion, said Dr. Patricia Keegan, director of the division of biologic oncology products.

Although Genentech may conduct further studies to establish that Avastin provides a clinical benefit for a subset of patients, it is not appropriate for the vascular endothelial growth factor (VEGF) inhibitor to continue to bear a label suggesting it is safe and effective for first-line MBC when the totality of currently available data suggests otherwise, she said.

Dr. Keegan was one of five CDER representatives who gave affirmative presentations during the first day of an unprecedented 2-day hearing on the drug center’s proposal to withdraw Avastin’s accelerated approval in MBC.

Genentech will make its affirmative presentation to hearing officer Dr. Karen Midthun and members of the Oncologic Drugs Advisory Committee on the morning of June 29. The ODAC members will discuss and vote on four questions later in the day.

Looking to Replicate E2100’s Benefit

CDER’s 2008 approval of the MBC claim was based on results from the E2100 trial, in which Avastin combined with paclitaxel demonstrated a median progression-free survival (PFS) benefit of 5.5 months, compared with paclitaxel alone.

Two confirmatory trials in the first-line setting, AVADO and RIBBON1, studied bevacizumab in combination with other chemotherapeutic agents and failed to show the same magnitude of PFS impact as that seen in E2100, instead demonstrating PFS benefit ranging from less than a month to about 3 months. No studies have demonstrated an improvement in overall survival or health-related quality of life, CDER said.

In December, CDER announced plans to withdraw the MBC indication, asserting that the biologic’s toxicities outweighed the minimal PFS benefit seen in all trials except E2100.

Genentech has suggested that Avastin’s effect may be predicated upon the chemotherapy partner with which it is paired as well as the duration of combination therapy. The company is fighting to retain Avastin’s MBC indication while it designs and conducts a new confirmatory trial of bevacizumab in combination with paclitaxel.

The proposed study would include a prospective biomarker analysis premised upon data gathered in AVADO, as well as in other settings, that suggest plasma VEGF-A levels may be predictive of bevacizumab’s efficacy.

CDER Turns New Phase II Data in its Favor

Dr. Keegan, however, maintained that the E2100 trial’s PFS results are an outlier and that this conclusion is supported by new data from a phase II study.

Study CIRG/TORI-010 was a three-arm, randomized, placebo- and active-controlled trial of 282 patients with HER2-negative metastatic breast cancer. There were three study arms: paclitaxel and placebo; paclitaxel in combination with Takeda/Amgen’s investigational VEGF inhibitor motesanib; and paclitaxel plus Avastin. The latter arm employed the same dose and dosing schedule as used in E2100.

Genentech originally cited the study’s results, in abstract form, in its January request for a hearing on the MBC indication. Avastin in combination with paclitaxel demonstrated a median PFS of 11.5 months, which was consistent with the median PFS of 11.3 months observed in E2100, the company said.

CDER takes a decidedly different view of the data. Based upon its review of results published in the Lancet in April 2011 but not the underlying raw data, the agency said the trial failed to replicate the PFS benefit seen in E2100.

The Avastin/paclitaxel arm was associated with a 2.5-month improvement in median PFS, compared with paclitaxel alone. These results are in line with the more modest benefits seen in AVADO and RIBBON1, Dr. Keegan noted.

"The results of Study 10 suggest that an additional study using the same dose and schedule of Avastin and paclitaxel in E2100 is unlikely to substantiate the magnitude of the PFS treatment effect seen in the E2100 study," she said.

Genentech’s proposed new study would be double-blinded, in comparison with the open-label nature of E2100, and would stratify patients by high versus low VEGF-A levels. Despite these differences, however, the proposed treatment arms and patient population are similar to those in the E2100 trial, Dr. Keegan said.

Delaying Factors

She also cited several factors that may delay completion of the new confirmatory trial and argue against keeping the breast cancer indication on the label in the interim.

The trial’s protocol remains under development, and the study would require a validated biomarker assay for measuring serum VEGF-A levels, which also is under development.

Finally, based upon recently conducted studies, submission of the results would not be expected until at least 3 years after enrollment begins, she said.

Genentech is expected to defend its study proposal and offer more details about it during the hearing’s second day.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.