Pharmacy

Micrograph showing MF

Credit: Peter Anderson

The US Food and Drug Administration (FDA) is expediting its review of pacritinib, a tyrosine kinase inhibitor with activity against JAK2 and FLT3, by granting the drug fast track designation.

Pacritinib is under review as a treatment for patients with intermediate- and high-risk myelofibrosis (MF), including those with disease-related or treatment-induced thrombocytopenia and those who cannot tolerate or do not respond well to other JAK2 therapy.

The FDA’s fast track process is designed to expedite the review of drugs to treat serious conditions and fill an unmet medical need.

The program enables a company—in this case, CTI BioPharma—to submit sections of a new drug application on a rolling basis as data becomes available.

That way, the FDA can review sections of the application as they are received, rather than waiting until every section of the application is completed before the entire application can be reviewed. This often leads to faster approval.

Pacritinib is currently under investigation in two phase 3 clinical trials, known as the PERSIST program, for patients with MF.

One of these trials, known as PERSIST-1, includes a broad set of patients without limitations on platelet counts. The other, PERSIST-2, includes patients with low platelet counts.

PERSIST-1

In July 2014, CTI Biopharma completed enrollment in the PERSIST-1 trial, which was designed to enroll approximately 320 patients.

This randomized trial was designed to compared the efficacy and safety of pacritinib with that of best available therapy, other than JAK inhibitors, in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, without exclusion for low platelet counts.

The primary endpoint is the percentage of patients achieving at least a 35% reduction in spleen volume, measured by MRI or CT from baseline to 24 weeks of treatment.

PERSIST-2

In March 2014, CTI announced the initiation of the PERSIST-2 trial, a comparison of pacritinib and best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with MF whose platelet counts are 100,000/uL or lower.

The trial is designed to enroll up to 300 patients in North America, Europe, Australia, and New Zealand. In October 2013, CTI reached agreement with the FDA on a special protocol assessment for the trial, a written agreement between CTI and the FDA regarding the planned design, endpoints, and statistical analysis approach of the trial to be used in support of a potential new drug application.

Under the special protocol assessment, the trial will have two primary endpoints. The first is the percentage of patients achieving a 35% or greater reduction in spleen volume, measured by MRI or CT scan from baseline to 24 weeks of treatment.

The second primary endpoint is the percentage of patients achieving a total symptom score reduction of 50% or greater using 6 key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.

More details on the PERSIST-1 and PERSIST-2 trials can be found at www.clinicaltrials.gov.

Micrograph showing MF

Credit: Peter Anderson

The US Food and Drug Administration (FDA) is expediting its review of pacritinib, a tyrosine kinase inhibitor with activity against JAK2 and FLT3, by granting the drug fast track designation.

Pacritinib is under review as a treatment for patients with intermediate- and high-risk myelofibrosis (MF), including those with disease-related or treatment-induced thrombocytopenia and those who cannot tolerate or do not respond well to other JAK2 therapy.

The FDA’s fast track process is designed to expedite the review of drugs to treat serious conditions and fill an unmet medical need.

The program enables a company—in this case, CTI BioPharma—to submit sections of a new drug application on a rolling basis as data becomes available.

That way, the FDA can review sections of the application as they are received, rather than waiting until every section of the application is completed before the entire application can be reviewed. This often leads to faster approval.

Pacritinib is currently under investigation in two phase 3 clinical trials, known as the PERSIST program, for patients with MF.

One of these trials, known as PERSIST-1, includes a broad set of patients without limitations on platelet counts. The other, PERSIST-2, includes patients with low platelet counts.

PERSIST-1

In July 2014, CTI Biopharma completed enrollment in the PERSIST-1 trial, which was designed to enroll approximately 320 patients.

This randomized trial was designed to compared the efficacy and safety of pacritinib with that of best available therapy, other than JAK inhibitors, in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, without exclusion for low platelet counts.

The primary endpoint is the percentage of patients achieving at least a 35% reduction in spleen volume, measured by MRI or CT from baseline to 24 weeks of treatment.

PERSIST-2

In March 2014, CTI announced the initiation of the PERSIST-2 trial, a comparison of pacritinib and best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with MF whose platelet counts are 100,000/uL or lower.

The trial is designed to enroll up to 300 patients in North America, Europe, Australia, and New Zealand. In October 2013, CTI reached agreement with the FDA on a special protocol assessment for the trial, a written agreement between CTI and the FDA regarding the planned design, endpoints, and statistical analysis approach of the trial to be used in support of a potential new drug application.

Under the special protocol assessment, the trial will have two primary endpoints. The first is the percentage of patients achieving a 35% or greater reduction in spleen volume, measured by MRI or CT scan from baseline to 24 weeks of treatment.

The second primary endpoint is the percentage of patients achieving a total symptom score reduction of 50% or greater using 6 key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.

More details on the PERSIST-1 and PERSIST-2 trials can be found at www.clinicaltrials.gov.

Micrograph showing MF

Credit: Peter Anderson

The US Food and Drug Administration (FDA) is expediting its review of pacritinib, a tyrosine kinase inhibitor with activity against JAK2 and FLT3, by granting the drug fast track designation.

Pacritinib is under review as a treatment for patients with intermediate- and high-risk myelofibrosis (MF), including those with disease-related or treatment-induced thrombocytopenia and those who cannot tolerate or do not respond well to other JAK2 therapy.

The FDA’s fast track process is designed to expedite the review of drugs to treat serious conditions and fill an unmet medical need.

The program enables a company—in this case, CTI BioPharma—to submit sections of a new drug application on a rolling basis as data becomes available.

That way, the FDA can review sections of the application as they are received, rather than waiting until every section of the application is completed before the entire application can be reviewed. This often leads to faster approval.

Pacritinib is currently under investigation in two phase 3 clinical trials, known as the PERSIST program, for patients with MF.

One of these trials, known as PERSIST-1, includes a broad set of patients without limitations on platelet counts. The other, PERSIST-2, includes patients with low platelet counts.

PERSIST-1

In July 2014, CTI Biopharma completed enrollment in the PERSIST-1 trial, which was designed to enroll approximately 320 patients.

This randomized trial was designed to compared the efficacy and safety of pacritinib with that of best available therapy, other than JAK inhibitors, in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, without exclusion for low platelet counts.

The primary endpoint is the percentage of patients achieving at least a 35% reduction in spleen volume, measured by MRI or CT from baseline to 24 weeks of treatment.

PERSIST-2

In March 2014, CTI announced the initiation of the PERSIST-2 trial, a comparison of pacritinib and best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with MF whose platelet counts are 100,000/uL or lower.

The trial is designed to enroll up to 300 patients in North America, Europe, Australia, and New Zealand. In October 2013, CTI reached agreement with the FDA on a special protocol assessment for the trial, a written agreement between CTI and the FDA regarding the planned design, endpoints, and statistical analysis approach of the trial to be used in support of a potential new drug application.

Under the special protocol assessment, the trial will have two primary endpoints. The first is the percentage of patients achieving a 35% or greater reduction in spleen volume, measured by MRI or CT scan from baseline to 24 weeks of treatment.

The second primary endpoint is the percentage of patients achieving a total symptom score reduction of 50% or greater using 6 key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.

More details on the PERSIST-1 and PERSIST-2 trials can be found at www.clinicaltrials.gov.

Vials of drug

Credit: Bill Branson

Health Canada and GlaxoSmithKline (GSK) have reported a fatal infusion reaction in a patient receiving the monoclonal antibody ofatumumab (Arzerra) to treat

chronic lymphocytic leukemia (CLL).

The patient had no known history of cardiac disease.

Ofatumumab’s product monograph is being updated to include a warning about the potential for fatal infusion reactions.

In Canada, ofatumumab is approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab.

The drug received this marketing authorization with conditions, pending the results of trials to verify its clinical benefit.

In light of the fatal infusion reaction, GSK and Health Canada are reminding healthcare professionals that ofatumumab should be administered under the supervision of a physician experienced in the use of cancer therapy. The drug should be given in an environment where facilities to adequately monitor and treat infusion reactions are available.

Prior to infusion, patients should always receive the appropriate premedication, as outlined in the product label. However, serious infusion reactions may occur despite premedication.

If you suspect a severe infusion reaction, stop the infusion immediately and provide symptomatic treatment. Signs and symptoms of an infusion reaction may include swelling of the face or mouth, fever, chills, difficulty breathing, tightness of the chest and/or throat, light headedness, nausea, diarrhea, and rash.

These symptoms can occur during or shortly after the infusion, predominantly with the first 2 infusions. So ensure patients are closely monitored, especially those with heart conditions. And inform patients about the risk of fatal infusion reactions associated with ofatumumab.

GSK has sent a letter to healthcare professionals detailing the risk of fatal infusion reactions. The information is also available on the Canadian website of GSK and the Health Canada website.

Any case of serious hypersensitivity, infusion reactions, or other serious or unexpected side effects in patients receiving ofatumumab should be reported to GSK or Health Canada.

Ofatumumab is also known to pose a risk of hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, serious and/or fatal cardiovascular events, and serious and/or fatal infections (bacterial, fungal, and viral).

Ofatumumab recently received approval in the European Union to be used in combination with chlorambucil or bendamustine for untreated CLL patients who are not eligible for fludarabine-based therapy. The drug previously received conditional approval in Europe as monotherapy to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab is approved for both of these indications in the US as well.

Vials of drug

Credit: Bill Branson

Health Canada and GlaxoSmithKline (GSK) have reported a fatal infusion reaction in a patient receiving the monoclonal antibody ofatumumab (Arzerra) to treat

chronic lymphocytic leukemia (CLL).

The patient had no known history of cardiac disease.

Ofatumumab’s product monograph is being updated to include a warning about the potential for fatal infusion reactions.

In Canada, ofatumumab is approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab.

The drug received this marketing authorization with conditions, pending the results of trials to verify its clinical benefit.

In light of the fatal infusion reaction, GSK and Health Canada are reminding healthcare professionals that ofatumumab should be administered under the supervision of a physician experienced in the use of cancer therapy. The drug should be given in an environment where facilities to adequately monitor and treat infusion reactions are available.

Prior to infusion, patients should always receive the appropriate premedication, as outlined in the product label. However, serious infusion reactions may occur despite premedication.

If you suspect a severe infusion reaction, stop the infusion immediately and provide symptomatic treatment. Signs and symptoms of an infusion reaction may include swelling of the face or mouth, fever, chills, difficulty breathing, tightness of the chest and/or throat, light headedness, nausea, diarrhea, and rash.

These symptoms can occur during or shortly after the infusion, predominantly with the first 2 infusions. So ensure patients are closely monitored, especially those with heart conditions. And inform patients about the risk of fatal infusion reactions associated with ofatumumab.

GSK has sent a letter to healthcare professionals detailing the risk of fatal infusion reactions. The information is also available on the Canadian website of GSK and the Health Canada website.

Any case of serious hypersensitivity, infusion reactions, or other serious or unexpected side effects in patients receiving ofatumumab should be reported to GSK or Health Canada.

Ofatumumab is also known to pose a risk of hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, serious and/or fatal cardiovascular events, and serious and/or fatal infections (bacterial, fungal, and viral).

Ofatumumab recently received approval in the European Union to be used in combination with chlorambucil or bendamustine for untreated CLL patients who are not eligible for fludarabine-based therapy. The drug previously received conditional approval in Europe as monotherapy to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab is approved for both of these indications in the US as well.

Vials of drug

Credit: Bill Branson

Health Canada and GlaxoSmithKline (GSK) have reported a fatal infusion reaction in a patient receiving the monoclonal antibody ofatumumab (Arzerra) to treat

chronic lymphocytic leukemia (CLL).

The patient had no known history of cardiac disease.

Ofatumumab’s product monograph is being updated to include a warning about the potential for fatal infusion reactions.

In Canada, ofatumumab is approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab.

The drug received this marketing authorization with conditions, pending the results of trials to verify its clinical benefit.

In light of the fatal infusion reaction, GSK and Health Canada are reminding healthcare professionals that ofatumumab should be administered under the supervision of a physician experienced in the use of cancer therapy. The drug should be given in an environment where facilities to adequately monitor and treat infusion reactions are available.

Prior to infusion, patients should always receive the appropriate premedication, as outlined in the product label. However, serious infusion reactions may occur despite premedication.

If you suspect a severe infusion reaction, stop the infusion immediately and provide symptomatic treatment. Signs and symptoms of an infusion reaction may include swelling of the face or mouth, fever, chills, difficulty breathing, tightness of the chest and/or throat, light headedness, nausea, diarrhea, and rash.

These symptoms can occur during or shortly after the infusion, predominantly with the first 2 infusions. So ensure patients are closely monitored, especially those with heart conditions. And inform patients about the risk of fatal infusion reactions associated with ofatumumab.

GSK has sent a letter to healthcare professionals detailing the risk of fatal infusion reactions. The information is also available on the Canadian website of GSK and the Health Canada website.

Any case of serious hypersensitivity, infusion reactions, or other serious or unexpected side effects in patients receiving ofatumumab should be reported to GSK or Health Canada.

Ofatumumab is also known to pose a risk of hepatitis B virus reactivation, progressive multifocal leukoencephalopathy, serious and/or fatal cardiovascular events, and serious and/or fatal infections (bacterial, fungal, and viral).

Ofatumumab recently received approval in the European Union to be used in combination with chlorambucil or bendamustine for untreated CLL patients who are not eligible for fludarabine-based therapy. The drug previously received conditional approval in Europe as monotherapy to treat CLL patients who are refractory to fludarabine and alemtuzumab.

Ofatumumab is approved for both of these indications in the US as well.

Candida albicans

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for intravenous (IV) posaconazole (Noxafil), an antifungal agent.

If the European Commission affirms the CHMP opinion, IV posaconazole will be authorized for use in the European Union, Iceland, Liechtenstein, and Norway.

The commission previously granted marketing authorization for posaconazole delayed-release tablets and oral suspension.

Posaconazole is used to prevent invasive fungal infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or patients with hematologic malignancies and prolonged neutropenia from chemotherapy.

The drug is also used to treat fungal diseases—invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis—when other antifungal agents—amphotericin B, itraconazole, or fluconazole—cannot be tolerated or have failed.

And posaconazole oral suspension is used as a first-line treatment for thrush, a fungal infection of the mouth and throat due to Candida.

Posaconazole injection is administered with a loading dose of 300 mg twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by IV infusion over approximately 90 minutes.

Once combined with a mixture of IV solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2°-8° C (36°-46° F).

The safety and effectiveness of IV posaconazole in patients younger than 18 years has not been established. IV posaconazole should not be used in pediatric patients because of non-clinical safety concerns.

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Patients with known hypersensitivity to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

Hepatic reactions have been reported as well. This includes mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis. Monitoring or discontinuation may be necessary in patients with hepatic reactions to posaconazole.

IV posaconazole should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole.

In clinical trials, the adverse events associated with IV posaconazole were generally similar to those in trials of posaconazole oral suspension. The most frequently reported events were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

IV posaconazole is under development by MSD (known as Merck in the US and Canada).

Candida albicans

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for intravenous (IV) posaconazole (Noxafil), an antifungal agent.

If the European Commission affirms the CHMP opinion, IV posaconazole will be authorized for use in the European Union, Iceland, Liechtenstein, and Norway.

The commission previously granted marketing authorization for posaconazole delayed-release tablets and oral suspension.

Posaconazole is used to prevent invasive fungal infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or patients with hematologic malignancies and prolonged neutropenia from chemotherapy.

The drug is also used to treat fungal diseases—invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis—when other antifungal agents—amphotericin B, itraconazole, or fluconazole—cannot be tolerated or have failed.

And posaconazole oral suspension is used as a first-line treatment for thrush, a fungal infection of the mouth and throat due to Candida.

Posaconazole injection is administered with a loading dose of 300 mg twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by IV infusion over approximately 90 minutes.

Once combined with a mixture of IV solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2°-8° C (36°-46° F).

The safety and effectiveness of IV posaconazole in patients younger than 18 years has not been established. IV posaconazole should not be used in pediatric patients because of non-clinical safety concerns.

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Patients with known hypersensitivity to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

Hepatic reactions have been reported as well. This includes mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis. Monitoring or discontinuation may be necessary in patients with hepatic reactions to posaconazole.

IV posaconazole should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole.

In clinical trials, the adverse events associated with IV posaconazole were generally similar to those in trials of posaconazole oral suspension. The most frequently reported events were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

IV posaconazole is under development by MSD (known as Merck in the US and Canada).

Candida albicans

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for intravenous (IV) posaconazole (Noxafil), an antifungal agent.

If the European Commission affirms the CHMP opinion, IV posaconazole will be authorized for use in the European Union, Iceland, Liechtenstein, and Norway.

The commission previously granted marketing authorization for posaconazole delayed-release tablets and oral suspension.

Posaconazole is used to prevent invasive fungal infections in severely immunocompromised patients, such as hematopoietic stem cell transplant recipients with graft-vs-host disease or patients with hematologic malignancies and prolonged neutropenia from chemotherapy.

The drug is also used to treat fungal diseases—invasive aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis—when other antifungal agents—amphotericin B, itraconazole, or fluconazole—cannot be tolerated or have failed.

And posaconazole oral suspension is used as a first-line treatment for thrush, a fungal infection of the mouth and throat due to Candida.

Posaconazole injection is administered with a loading dose of 300 mg twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by IV infusion over approximately 90 minutes.

Once combined with a mixture of IV solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2°-8° C (36°-46° F).

The safety and effectiveness of IV posaconazole in patients younger than 18 years has not been established. IV posaconazole should not be used in pediatric patients because of non-clinical safety concerns.

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Patients with known hypersensitivity to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

Hepatic reactions have been reported as well. This includes mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis. Monitoring or discontinuation may be necessary in patients with hepatic reactions to posaconazole.

IV posaconazole should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of posaconazole.

In clinical trials, the adverse events associated with IV posaconazole were generally similar to those in trials of posaconazole oral suspension. The most frequently reported events were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

IV posaconazole is under development by MSD (known as Merck in the US and Canada).

Prescription drugs

Credit: CDC

The introduction of expedited drug approvals in the US coincides with an increase in black box warnings and market withdrawals, a new study shows.

The researchers could not establish a causal link between the events, but they still believe physicians and patients should exercise caution when considering the use of drugs approved since 1992.

That’s when Congress passed a law allowing the Food and Drug Administration (FDA) to collect fees to expedite drug approvals.

The researchers found that drugs approved after the law—the Prescription Drug User Fee Act (PDUFA)—was enacted were significantly more likely than previously approved drugs to acquire a black box warning or be withdrawn for safety reasons.

“Our findings raise concern that the FDA is rushing its review of new drugs and allowing potentially unsafe medicines onto the market,” said Karen Lasser, MD, MPH, of Boston University School of Medicine and Boston Medical Center.

“As a primary care doctor, I’m wary of prescribing brand new drugs unless they’re really a breakthrough, since their full risks are often unknown. And patients should be wary too.”

Dr Lasser and her colleagues expressed this viewpoint and described the research supporting it in Health Affairs.

The researchers collected information on new molecular entities (active ingredients that have never before been marketed in the US in any form) approved by the FDA between 1975 and 2009.

Of these 748 drugs, 114 (15.2%) received one or more black box warnings, and 32 (4.3%) were withdrawn from the market for safety reasons.

Very few of the 32 withdrawn drugs had clearly unique benefits at the time of approval, but all had unique risks that eventually led to their withdrawal.

Half of all black box warnings appeared after a drug had been on the market for 12 years, and safety withdrawals have occurred as late as 30 years after a drug’s initial release.

Drugs approved after the enactment of PDUFA were significantly more likely to receive a black box warning or withdrawal than drugs approved before PDUFA’s enactment—26.7 out of 100 drugs vs 21.2 out of 100 drugs (P<0.05) at up to 16 years of follow-up.

Since the law was enacted, the average approval time for all drugs has fallen from 34 months to 16 months.

“Since PDUFA, the review times for the drugs that are eventually banned have decreased enormously,” said study author Sidney Wolfe, MD, founder of Public Citizen’s Health Research Group and author of Worst Pills, Best Pills.

“These shorter review times, combined with increased FDA authority to require further studies after approval—rather than settling safety issues before approval—possibly contributes to the increased rate of withdrawals and black box warnings.”

The researchers noted that they could not determine with certainty whether PDUFA caused the increase in drug withdrawals and black box warnings. It’s possible that other factors caused or contributed to the decrease in safety observed in recent years.

Prescription drugs

Credit: CDC

The introduction of expedited drug approvals in the US coincides with an increase in black box warnings and market withdrawals, a new study shows.

The researchers could not establish a causal link between the events, but they still believe physicians and patients should exercise caution when considering the use of drugs approved since 1992.

That’s when Congress passed a law allowing the Food and Drug Administration (FDA) to collect fees to expedite drug approvals.

The researchers found that drugs approved after the law—the Prescription Drug User Fee Act (PDUFA)—was enacted were significantly more likely than previously approved drugs to acquire a black box warning or be withdrawn for safety reasons.

“Our findings raise concern that the FDA is rushing its review of new drugs and allowing potentially unsafe medicines onto the market,” said Karen Lasser, MD, MPH, of Boston University School of Medicine and Boston Medical Center.

“As a primary care doctor, I’m wary of prescribing brand new drugs unless they’re really a breakthrough, since their full risks are often unknown. And patients should be wary too.”

Dr Lasser and her colleagues expressed this viewpoint and described the research supporting it in Health Affairs.

The researchers collected information on new molecular entities (active ingredients that have never before been marketed in the US in any form) approved by the FDA between 1975 and 2009.

Of these 748 drugs, 114 (15.2%) received one or more black box warnings, and 32 (4.3%) were withdrawn from the market for safety reasons.

Very few of the 32 withdrawn drugs had clearly unique benefits at the time of approval, but all had unique risks that eventually led to their withdrawal.

Half of all black box warnings appeared after a drug had been on the market for 12 years, and safety withdrawals have occurred as late as 30 years after a drug’s initial release.

Drugs approved after the enactment of PDUFA were significantly more likely to receive a black box warning or withdrawal than drugs approved before PDUFA’s enactment—26.7 out of 100 drugs vs 21.2 out of 100 drugs (P<0.05) at up to 16 years of follow-up.

Since the law was enacted, the average approval time for all drugs has fallen from 34 months to 16 months.

“Since PDUFA, the review times for the drugs that are eventually banned have decreased enormously,” said study author Sidney Wolfe, MD, founder of Public Citizen’s Health Research Group and author of Worst Pills, Best Pills.

“These shorter review times, combined with increased FDA authority to require further studies after approval—rather than settling safety issues before approval—possibly contributes to the increased rate of withdrawals and black box warnings.”

The researchers noted that they could not determine with certainty whether PDUFA caused the increase in drug withdrawals and black box warnings. It’s possible that other factors caused or contributed to the decrease in safety observed in recent years.

Prescription drugs

Credit: CDC

The introduction of expedited drug approvals in the US coincides with an increase in black box warnings and market withdrawals, a new study shows.

The researchers could not establish a causal link between the events, but they still believe physicians and patients should exercise caution when considering the use of drugs approved since 1992.

That’s when Congress passed a law allowing the Food and Drug Administration (FDA) to collect fees to expedite drug approvals.

The researchers found that drugs approved after the law—the Prescription Drug User Fee Act (PDUFA)—was enacted were significantly more likely than previously approved drugs to acquire a black box warning or be withdrawn for safety reasons.

“Our findings raise concern that the FDA is rushing its review of new drugs and allowing potentially unsafe medicines onto the market,” said Karen Lasser, MD, MPH, of Boston University School of Medicine and Boston Medical Center.

“As a primary care doctor, I’m wary of prescribing brand new drugs unless they’re really a breakthrough, since their full risks are often unknown. And patients should be wary too.”

Dr Lasser and her colleagues expressed this viewpoint and described the research supporting it in Health Affairs.

The researchers collected information on new molecular entities (active ingredients that have never before been marketed in the US in any form) approved by the FDA between 1975 and 2009.

Of these 748 drugs, 114 (15.2%) received one or more black box warnings, and 32 (4.3%) were withdrawn from the market for safety reasons.

Very few of the 32 withdrawn drugs had clearly unique benefits at the time of approval, but all had unique risks that eventually led to their withdrawal.

Half of all black box warnings appeared after a drug had been on the market for 12 years, and safety withdrawals have occurred as late as 30 years after a drug’s initial release.

Drugs approved after the enactment of PDUFA were significantly more likely to receive a black box warning or withdrawal than drugs approved before PDUFA’s enactment—26.7 out of 100 drugs vs 21.2 out of 100 drugs (P<0.05) at up to 16 years of follow-up.

Since the law was enacted, the average approval time for all drugs has fallen from 34 months to 16 months.

“Since PDUFA, the review times for the drugs that are eventually banned have decreased enormously,” said study author Sidney Wolfe, MD, founder of Public Citizen’s Health Research Group and author of Worst Pills, Best Pills.

“These shorter review times, combined with increased FDA authority to require further studies after approval—rather than settling safety issues before approval—possibly contributes to the increased rate of withdrawals and black box warnings.”

The researchers noted that they could not determine with certainty whether PDUFA caused the increase in drug withdrawals and black box warnings. It’s possible that other factors caused or contributed to the decrease in safety observed in recent years.

Blood samples

Credit: William Weinert

The US Food and Drug Administration (FDA) is taking steps to ensure better regulation of certain diagnostic tests.

The agency has issued a final guidance on the development, review, and approval of companion diagnostics.

The FDA has also notified Congress of its intention to publish a draft guidance outlining a plan for regulating laboratory-developed tests (LDTs).

The FDA is required to notify Congress before making the draft guidance public. This is mandated by the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA).

Companion diagnostics guidance

A companion diagnostic is a medical device that provides information essential for the safe and effective use of a corresponding drug or biological product. These tests are commonly used to detect certain types of gene-based cancers.

The FDA’s companion diagnostics guidance is intended to help companies identify the need for these tests during the earliest stages of drug development and to plan for the development of a drug and a companion test at the same time.

The ultimate goal of the final guidance is to stimulate early collaborations that will result in faster access to promising new treatments for patients living with serious and life-threatening diseases. This guidance finalizes and takes into consideration public comments on the draft guidance issued in 2011.

LDT oversight

An LDT is a type of in vitro diagnostic test that is designed, manufactured, and used within a single lab. LDTs include some genetic tests and tests used by healthcare professionals to guide patient treatment.

The FDA already oversees direct-to-consumer tests, regardless of whether they are LDTs or traditional diagnostics.

And while the FDA has historically exercised enforcement discretion over LDTs (generally not enforced applicable regulatory requirements), today, these tests may compete with FDA-approved tests without clinical studies to support their use.

The LDT notification to Congress provides the details of a draft guidance in which the FDA would propose to establish an LDT oversight framework. This would include pre-market review for higher-risk LDTs, such as those that have the same intended use as FDA-approved or cleared companion diagnostics currently on the market.

The draft guidance would also propose to phase in enforcement of pre-market review for other high-risk and moderate-risk LDTs over time.

In addition, the FDA intends to propose that it continue to exercise enforcement discretion for low-risk LDTs, LDTs for rare diseases and, under certain circumstances, LDTs for which there is no FDA-approved or cleared test.

“With today’s notification of the agency’s intent to issue the lab-developed test draft guidance, the FDA is seeking a better balanced approach for all diagnostics,” said Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health.

“The agency’s oversight would be based on a test’s level of risk to patients, not on whether it is made by a conventional manufacturer or in a single laboratory, while still providing flexibility to encourage innovation that addresses unmet medical needs.”

Finally, the FDA intends to publish a draft guidance outlining how labs can notify the FDA that they are manufacturing and using LDTs, how to provide information about their LDTs, and how they can comply with the medical device reporting requirements.

A provision in FDASIA requires the FDA to provide at least 60 days’ notice to Congress before the agency publishes for public comment any draft guidance on the regulation of LDTs.

As such, the comment period will open at a later date, when the draft guidances are published in the Federal Register and the public is alerted to the start of the comment period. The agency also intends to hold a public meeting during the comment period to collect additional input.

Blood samples

Credit: William Weinert

The US Food and Drug Administration (FDA) is taking steps to ensure better regulation of certain diagnostic tests.

The agency has issued a final guidance on the development, review, and approval of companion diagnostics.

The FDA has also notified Congress of its intention to publish a draft guidance outlining a plan for regulating laboratory-developed tests (LDTs).

The FDA is required to notify Congress before making the draft guidance public. This is mandated by the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA).

Companion diagnostics guidance

A companion diagnostic is a medical device that provides information essential for the safe and effective use of a corresponding drug or biological product. These tests are commonly used to detect certain types of gene-based cancers.

The FDA’s companion diagnostics guidance is intended to help companies identify the need for these tests during the earliest stages of drug development and to plan for the development of a drug and a companion test at the same time.

The ultimate goal of the final guidance is to stimulate early collaborations that will result in faster access to promising new treatments for patients living with serious and life-threatening diseases. This guidance finalizes and takes into consideration public comments on the draft guidance issued in 2011.

LDT oversight

An LDT is a type of in vitro diagnostic test that is designed, manufactured, and used within a single lab. LDTs include some genetic tests and tests used by healthcare professionals to guide patient treatment.

The FDA already oversees direct-to-consumer tests, regardless of whether they are LDTs or traditional diagnostics.

And while the FDA has historically exercised enforcement discretion over LDTs (generally not enforced applicable regulatory requirements), today, these tests may compete with FDA-approved tests without clinical studies to support their use.

The LDT notification to Congress provides the details of a draft guidance in which the FDA would propose to establish an LDT oversight framework. This would include pre-market review for higher-risk LDTs, such as those that have the same intended use as FDA-approved or cleared companion diagnostics currently on the market.

The draft guidance would also propose to phase in enforcement of pre-market review for other high-risk and moderate-risk LDTs over time.

In addition, the FDA intends to propose that it continue to exercise enforcement discretion for low-risk LDTs, LDTs for rare diseases and, under certain circumstances, LDTs for which there is no FDA-approved or cleared test.

“With today’s notification of the agency’s intent to issue the lab-developed test draft guidance, the FDA is seeking a better balanced approach for all diagnostics,” said Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health.

“The agency’s oversight would be based on a test’s level of risk to patients, not on whether it is made by a conventional manufacturer or in a single laboratory, while still providing flexibility to encourage innovation that addresses unmet medical needs.”

Finally, the FDA intends to publish a draft guidance outlining how labs can notify the FDA that they are manufacturing and using LDTs, how to provide information about their LDTs, and how they can comply with the medical device reporting requirements.

A provision in FDASIA requires the FDA to provide at least 60 days’ notice to Congress before the agency publishes for public comment any draft guidance on the regulation of LDTs.

As such, the comment period will open at a later date, when the draft guidances are published in the Federal Register and the public is alerted to the start of the comment period. The agency also intends to hold a public meeting during the comment period to collect additional input.

Blood samples

Credit: William Weinert

The US Food and Drug Administration (FDA) is taking steps to ensure better regulation of certain diagnostic tests.

The agency has issued a final guidance on the development, review, and approval of companion diagnostics.

The FDA has also notified Congress of its intention to publish a draft guidance outlining a plan for regulating laboratory-developed tests (LDTs).

The FDA is required to notify Congress before making the draft guidance public. This is mandated by the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA).

Companion diagnostics guidance

A companion diagnostic is a medical device that provides information essential for the safe and effective use of a corresponding drug or biological product. These tests are commonly used to detect certain types of gene-based cancers.

The FDA’s companion diagnostics guidance is intended to help companies identify the need for these tests during the earliest stages of drug development and to plan for the development of a drug and a companion test at the same time.

The ultimate goal of the final guidance is to stimulate early collaborations that will result in faster access to promising new treatments for patients living with serious and life-threatening diseases. This guidance finalizes and takes into consideration public comments on the draft guidance issued in 2011.

LDT oversight

An LDT is a type of in vitro diagnostic test that is designed, manufactured, and used within a single lab. LDTs include some genetic tests and tests used by healthcare professionals to guide patient treatment.

The FDA already oversees direct-to-consumer tests, regardless of whether they are LDTs or traditional diagnostics.

And while the FDA has historically exercised enforcement discretion over LDTs (generally not enforced applicable regulatory requirements), today, these tests may compete with FDA-approved tests without clinical studies to support their use.

The LDT notification to Congress provides the details of a draft guidance in which the FDA would propose to establish an LDT oversight framework. This would include pre-market review for higher-risk LDTs, such as those that have the same intended use as FDA-approved or cleared companion diagnostics currently on the market.

The draft guidance would also propose to phase in enforcement of pre-market review for other high-risk and moderate-risk LDTs over time.

In addition, the FDA intends to propose that it continue to exercise enforcement discretion for low-risk LDTs, LDTs for rare diseases and, under certain circumstances, LDTs for which there is no FDA-approved or cleared test.

“With today’s notification of the agency’s intent to issue the lab-developed test draft guidance, the FDA is seeking a better balanced approach for all diagnostics,” said Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health.

“The agency’s oversight would be based on a test’s level of risk to patients, not on whether it is made by a conventional manufacturer or in a single laboratory, while still providing flexibility to encourage innovation that addresses unmet medical needs.”

Finally, the FDA intends to publish a draft guidance outlining how labs can notify the FDA that they are manufacturing and using LDTs, how to provide information about their LDTs, and how they can comply with the medical device reporting requirements.

A provision in FDASIA requires the FDA to provide at least 60 days’ notice to Congress before the agency publishes for public comment any draft guidance on the regulation of LDTs.

As such, the comment period will open at a later date, when the draft guidances are published in the Federal Register and the public is alerted to the start of the comment period. The agency also intends to hold a public meeting during the comment period to collect additional input.

Thrombus

Credit: Kevin MacKenzie

The European Commission has approved apixaban (Eliquis) to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE).

The approval applies to all European Union (EU) member states, as well as Iceland and Norway.

Apixaban was already approved in the EU to prevent venous thromboembolism (VTE) in adults who have undergone total hip or knee replacement surgery, and to prevent stroke and systemic embolism in adults with nonvalvular atrial fibrillation.

The new marketing authorization for apixaban follows the positive opinion issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use in June and is supported by results of 2 phase 3 clinical trials, AMPLIFY and AMPLIFY-EXT.

Results of AMPLIFY

The AMPLIFY trial included 5395 patients with confirmed, symptomatic DVT or PE requiring treatment for 6 months. They had a mean age of 56.9 years, and 89.8% of randomized patients had unprovoked VTE.

About half of patients (n=2691) were randomized to receive apixaban at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.

The other half (n=2704) were randomized to the standard of care, which was enoxaparin at 1 mg/kg twice daily for at least 5 days until INR ≥ 2 and warfarin (target INR range 2.0-3.0) for 6 months.

Apixaban proved noninferior to standard therapy in the combined primary endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or PE) or VTE-related death.

This outcome occurred in 2.3% of patients in the apixaban arm and 2.7% of patients in the standard-therapy arm (P<0.0001 for noninferiority).

Apixaban also proved superior to standard therapy with regard to bleeding. The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).

Results of AMPLIFY-EXT

The AMPLIFY-EXT trial included 2486 patients who had completed 6 to 12 months of anticoagulation treatment for DVT or PE. The mean age was 56.7 years, and 91.7% of randomized patients had unprovoked VTE.

Patients were randomized to receive apixaban at 2.5 mg (n=842), apixaban at 5 mg (n=815), or placebo (n=829).

Both apixaban doses were significantly superior to placebo (P<0.001) with regard to the primary efficacy endpoint, which was recurrent VTE or all-cause death.

During the 12-month active study period, these events occurred in 3.8% of patients in the 2.5-mg arm, 4.2% of patients in the 5-mg arm, and 11.6% of patients in the placebo arm.

The primary safety endpoint was the incidence of major bleeding, and there was no significant difference among the treatment arms. Major bleeding occurred in 0.2% of patients in the 2.5-mg arm, 0.1% of patients in the 5-mg arm, and 0.5% of patients in the placebo arm.

About apixaban

Apixaban is approved to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation in the US, EU, Japan, and a number of other countries around the world.

The drug is approved to prevent VTE in adult patients who have undergone elective hip or knee replacement surgery in the US, EU, and a number of other countries.

And now, apixaban is approved for the treatment of DVT/PE and the prevention of recurrent DVT/PE in the EU. The drug is not approved for this indication in the US.

Apixaban is under joint development by Pfizer and Bristol-Myers Squibb.

Thrombus

Credit: Kevin MacKenzie

The European Commission has approved apixaban (Eliquis) to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE).

The approval applies to all European Union (EU) member states, as well as Iceland and Norway.

Apixaban was already approved in the EU to prevent venous thromboembolism (VTE) in adults who have undergone total hip or knee replacement surgery, and to prevent stroke and systemic embolism in adults with nonvalvular atrial fibrillation.

The new marketing authorization for apixaban follows the positive opinion issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use in June and is supported by results of 2 phase 3 clinical trials, AMPLIFY and AMPLIFY-EXT.

Results of AMPLIFY

The AMPLIFY trial included 5395 patients with confirmed, symptomatic DVT or PE requiring treatment for 6 months. They had a mean age of 56.9 years, and 89.8% of randomized patients had unprovoked VTE.

About half of patients (n=2691) were randomized to receive apixaban at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.

The other half (n=2704) were randomized to the standard of care, which was enoxaparin at 1 mg/kg twice daily for at least 5 days until INR ≥ 2 and warfarin (target INR range 2.0-3.0) for 6 months.

Apixaban proved noninferior to standard therapy in the combined primary endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or PE) or VTE-related death.

This outcome occurred in 2.3% of patients in the apixaban arm and 2.7% of patients in the standard-therapy arm (P<0.0001 for noninferiority).

Apixaban also proved superior to standard therapy with regard to bleeding. The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).

Results of AMPLIFY-EXT

The AMPLIFY-EXT trial included 2486 patients who had completed 6 to 12 months of anticoagulation treatment for DVT or PE. The mean age was 56.7 years, and 91.7% of randomized patients had unprovoked VTE.

Patients were randomized to receive apixaban at 2.5 mg (n=842), apixaban at 5 mg (n=815), or placebo (n=829).

Both apixaban doses were significantly superior to placebo (P<0.001) with regard to the primary efficacy endpoint, which was recurrent VTE or all-cause death.

During the 12-month active study period, these events occurred in 3.8% of patients in the 2.5-mg arm, 4.2% of patients in the 5-mg arm, and 11.6% of patients in the placebo arm.

The primary safety endpoint was the incidence of major bleeding, and there was no significant difference among the treatment arms. Major bleeding occurred in 0.2% of patients in the 2.5-mg arm, 0.1% of patients in the 5-mg arm, and 0.5% of patients in the placebo arm.

About apixaban

Apixaban is approved to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation in the US, EU, Japan, and a number of other countries around the world.

The drug is approved to prevent VTE in adult patients who have undergone elective hip or knee replacement surgery in the US, EU, and a number of other countries.

And now, apixaban is approved for the treatment of DVT/PE and the prevention of recurrent DVT/PE in the EU. The drug is not approved for this indication in the US.

Apixaban is under joint development by Pfizer and Bristol-Myers Squibb.

Thrombus

Credit: Kevin MacKenzie

The European Commission has approved apixaban (Eliquis) to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE).

The approval applies to all European Union (EU) member states, as well as Iceland and Norway.

Apixaban was already approved in the EU to prevent venous thromboembolism (VTE) in adults who have undergone total hip or knee replacement surgery, and to prevent stroke and systemic embolism in adults with nonvalvular atrial fibrillation.

The new marketing authorization for apixaban follows the positive opinion issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use in June and is supported by results of 2 phase 3 clinical trials, AMPLIFY and AMPLIFY-EXT.

Results of AMPLIFY

The AMPLIFY trial included 5395 patients with confirmed, symptomatic DVT or PE requiring treatment for 6 months. They had a mean age of 56.9 years, and 89.8% of randomized patients had unprovoked VTE.

About half of patients (n=2691) were randomized to receive apixaban at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.

The other half (n=2704) were randomized to the standard of care, which was enoxaparin at 1 mg/kg twice daily for at least 5 days until INR ≥ 2 and warfarin (target INR range 2.0-3.0) for 6 months.

Apixaban proved noninferior to standard therapy in the combined primary endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or PE) or VTE-related death.

This outcome occurred in 2.3% of patients in the apixaban arm and 2.7% of patients in the standard-therapy arm (P<0.0001 for noninferiority).

Apixaban also proved superior to standard therapy with regard to bleeding. The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).

Results of AMPLIFY-EXT

The AMPLIFY-EXT trial included 2486 patients who had completed 6 to 12 months of anticoagulation treatment for DVT or PE. The mean age was 56.7 years, and 91.7% of randomized patients had unprovoked VTE.

Patients were randomized to receive apixaban at 2.5 mg (n=842), apixaban at 5 mg (n=815), or placebo (n=829).

Both apixaban doses were significantly superior to placebo (P<0.001) with regard to the primary efficacy endpoint, which was recurrent VTE or all-cause death.

During the 12-month active study period, these events occurred in 3.8% of patients in the 2.5-mg arm, 4.2% of patients in the 5-mg arm, and 11.6% of patients in the placebo arm.

The primary safety endpoint was the incidence of major bleeding, and there was no significant difference among the treatment arms. Major bleeding occurred in 0.2% of patients in the 2.5-mg arm, 0.1% of patients in the 5-mg arm, and 0.5% of patients in the placebo arm.

About apixaban

Apixaban is approved to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation in the US, EU, Japan, and a number of other countries around the world.

The drug is approved to prevent VTE in adult patients who have undergone elective hip or knee replacement surgery in the US, EU, and a number of other countries.

And now, apixaban is approved for the treatment of DVT/PE and the prevention of recurrent DVT/PE in the EU. The drug is not approved for this indication in the US.

Apixaban is under joint development by Pfizer and Bristol-Myers Squibb.

The European Commission has approved the anti-CD20 monoclonal antibody obinutuzumab for use in the European Union (EU).

Obinutuzumab can now be used in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL) who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab is already approved for this indication in the US.

Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland but as Gazyva in the US and the rest of the world.

The European Commission’s approval follows a positive opinion granted by The European Medicine Agency’s Committee for Medicinal Products for Human Use in May.

The approval is based on results of the phase 3 CLL11 study, which showed that obinutuzumab plus chlorambucil improved progression-free survival (PFS), when compared to chlorambucil alone or in combination with rituximab.

This 2-stage study included 781 previously untreated CLL patients with comorbidities. In stage 1 (n=589), researchers compared obinutuzumab plus chlorambucil to chlorambucil alone and rituximab plus chlorambucil to chlorambucil alone.

Stage 2 (n=663) was a direct comparison of obinutuzumab plus chlorambucil and rituximab plus chlorambucil.

Stage 1 results were presented at ASCO 2013, stage 2 results were presented at ASH 2013, and the complete results were published in NEJM last March.

Obinutuzumab plus chlorambucil improved PFS when compared to chlorambucil alone. The median PFS was 26.7 months and 11.1 months, respectively (P<0.001).

Obinutuzumab plus chlorambucil also improved PFS when compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 16.3 months, respectively (P<0.001).

Infusion-related reactions and neutropenia were more common in the obinutuzumab arm than in the rituximab arm. But obinutuzumab-treated patients did not have an increased risk of infection.

Obinutuzumab is being developed by Roche. The company said it expects to begin launching the drug in a number of European countries this year.

The European Commission has approved the anti-CD20 monoclonal antibody obinutuzumab for use in the European Union (EU).

Obinutuzumab can now be used in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL) who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab is already approved for this indication in the US.

Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland but as Gazyva in the US and the rest of the world.

The European Commission’s approval follows a positive opinion granted by The European Medicine Agency’s Committee for Medicinal Products for Human Use in May.

The approval is based on results of the phase 3 CLL11 study, which showed that obinutuzumab plus chlorambucil improved progression-free survival (PFS), when compared to chlorambucil alone or in combination with rituximab.

This 2-stage study included 781 previously untreated CLL patients with comorbidities. In stage 1 (n=589), researchers compared obinutuzumab plus chlorambucil to chlorambucil alone and rituximab plus chlorambucil to chlorambucil alone.

Stage 2 (n=663) was a direct comparison of obinutuzumab plus chlorambucil and rituximab plus chlorambucil.

Stage 1 results were presented at ASCO 2013, stage 2 results were presented at ASH 2013, and the complete results were published in NEJM last March.

Obinutuzumab plus chlorambucil improved PFS when compared to chlorambucil alone. The median PFS was 26.7 months and 11.1 months, respectively (P<0.001).

Obinutuzumab plus chlorambucil also improved PFS when compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 16.3 months, respectively (P<0.001).

Infusion-related reactions and neutropenia were more common in the obinutuzumab arm than in the rituximab arm. But obinutuzumab-treated patients did not have an increased risk of infection.

Obinutuzumab is being developed by Roche. The company said it expects to begin launching the drug in a number of European countries this year.

The European Commission has approved the anti-CD20 monoclonal antibody obinutuzumab for use in the European Union (EU).

Obinutuzumab can now be used in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL) who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab is already approved for this indication in the US.

Obinutuzumab is marketed as Gazyvaro in the EU and Switzerland but as Gazyva in the US and the rest of the world.

The European Commission’s approval follows a positive opinion granted by The European Medicine Agency’s Committee for Medicinal Products for Human Use in May.

The approval is based on results of the phase 3 CLL11 study, which showed that obinutuzumab plus chlorambucil improved progression-free survival (PFS), when compared to chlorambucil alone or in combination with rituximab.

This 2-stage study included 781 previously untreated CLL patients with comorbidities. In stage 1 (n=589), researchers compared obinutuzumab plus chlorambucil to chlorambucil alone and rituximab plus chlorambucil to chlorambucil alone.

Stage 2 (n=663) was a direct comparison of obinutuzumab plus chlorambucil and rituximab plus chlorambucil.

Stage 1 results were presented at ASCO 2013, stage 2 results were presented at ASH 2013, and the complete results were published in NEJM last March.

Obinutuzumab plus chlorambucil improved PFS when compared to chlorambucil alone. The median PFS was 26.7 months and 11.1 months, respectively (P<0.001).

Obinutuzumab plus chlorambucil also improved PFS when compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 16.3 months, respectively (P<0.001).

Infusion-related reactions and neutropenia were more common in the obinutuzumab arm than in the rituximab arm. But obinutuzumab-treated patients did not have an increased risk of infection.

Obinutuzumab is being developed by Roche. The company said it expects to begin launching the drug in a number of European countries this year.

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has expanded the approved use of ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL).

The agency previously granted the drug accelerated approval to treat CLL patients who had received at least 1 prior therapy.

Now, the FDA has granted ibrutinib full approval for that indication and expanded the drug’s approved use to include previously treated and untreated CLL patients with 17p deletion.

The FDA’s decision to grant ibrutinib accelerated approval in CLL was based on the drug’s ability to elicit responses in previously treated patients.

Recent trial results have shown the drug can improve survival rates in CLL, which signifies a clinical benefit and allows the FDA to grant ibrutinib full approval.

Ibrutinib in CLL: Trial results

The expanded approval for ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib in development

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Before the FDA granted ibrutinib accelerated approval in CLL, the agency granted the drug accelerated approval for use in previously treated MCL patients. Studies to verify ibrutinib’s clinical benefit in MCL are ongoing.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended marketing authorization for ibrutinib to treat adults with relapsed or refractory MCL.

The committee has also recommended the drug for adults with CLL who have received at least 1 prior therapy and CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy.

Ibrutinib is already approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen Biotech and Pharmacyclics, Inc. The companies co-market ibrutinib in the US, but Janssen markets (or will market) ibrutinib in the rest of the world.

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has expanded the approved use of ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL).

The agency previously granted the drug accelerated approval to treat CLL patients who had received at least 1 prior therapy.

Now, the FDA has granted ibrutinib full approval for that indication and expanded the drug’s approved use to include previously treated and untreated CLL patients with 17p deletion.

The FDA’s decision to grant ibrutinib accelerated approval in CLL was based on the drug’s ability to elicit responses in previously treated patients.

Recent trial results have shown the drug can improve survival rates in CLL, which signifies a clinical benefit and allows the FDA to grant ibrutinib full approval.

Ibrutinib in CLL: Trial results

The expanded approval for ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib in development

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Before the FDA granted ibrutinib accelerated approval in CLL, the agency granted the drug accelerated approval for use in previously treated MCL patients. Studies to verify ibrutinib’s clinical benefit in MCL are ongoing.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended marketing authorization for ibrutinib to treat adults with relapsed or refractory MCL.

The committee has also recommended the drug for adults with CLL who have received at least 1 prior therapy and CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy.

Ibrutinib is already approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen Biotech and Pharmacyclics, Inc. The companies co-market ibrutinib in the US, but Janssen markets (or will market) ibrutinib in the rest of the world.

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has expanded the approved use of ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL).

The agency previously granted the drug accelerated approval to treat CLL patients who had received at least 1 prior therapy.

Now, the FDA has granted ibrutinib full approval for that indication and expanded the drug’s approved use to include previously treated and untreated CLL patients with 17p deletion.

The FDA’s decision to grant ibrutinib accelerated approval in CLL was based on the drug’s ability to elicit responses in previously treated patients.

Recent trial results have shown the drug can improve survival rates in CLL, which signifies a clinical benefit and allows the FDA to grant ibrutinib full approval.

Ibrutinib in CLL: Trial results

The expanded approval for ibrutinib is based on results of the phase 3 RESONATE trial, which were presented at this year’s ASCO and EHA meetings.

The trial included 391 previously treated patients, 127 of whom had 17p deletion. Patients were randomized to receive ibrutinib or the anti-CD20 monoclonal antibody ofatumumab until disease progression or unacceptable toxicity.

The trial was stopped early after a pre-planned interim analysis showed that ibrutinib-treated patients experienced a 78% reduction in the risk of disease progression or death.

At the time of interim analysis, the patients’ median time on study was 9.4 months. The best overall response among evaluable patients was 78% in the ibrutinib arm and 11% in the ofatumumab arm.

Ibrutinib significantly prolonged progression-free and overall survival. The median progression-free survival was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001). The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Of the 127 patients with 17p deletion, those treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death.

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

Ibrutinib in development

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Before the FDA granted ibrutinib accelerated approval in CLL, the agency granted the drug accelerated approval for use in previously treated MCL patients. Studies to verify ibrutinib’s clinical benefit in MCL are ongoing.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended marketing authorization for ibrutinib to treat adults with relapsed or refractory MCL.

The committee has also recommended the drug for adults with CLL who have received at least 1 prior therapy and CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy.

Ibrutinib is already approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen Biotech and Pharmacyclics, Inc. The companies co-market ibrutinib in the US, but Janssen markets (or will market) ibrutinib in the rest of the world.

 

 

Micrograph showing MCL

 

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending marketing authorization for ibrutinib (Imbruvica).

The committee is endorsing the Bruton’s tyrosine kinase (BTK) inhibitor for use in adults with relapsed or refractory mantle cell lymphoma (MCL) and certain adults with chronic lymphocytic leukemia (CLL).

This includes untreated CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy and patients who have received at least 1 prior therapy.

The European Commission will take the CHMP’s opinion into account when deciding whether to authorize the commercialization of ibrutinib in the European Union.

The CHMP based its recommendations on data from 2 CLL studies—the phase 3 RESONATE trial (PCYC-1112) and a phase 1b/2 trial (PCYC-1102)—as well as a phase 2 trial (PCYC-1104) in MCL.

RESONATE trial

Results of RESONATE were recently presented at the 2014 EHA Congress. The trial included 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL).

Patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57). The median time on study was 9.4 months.

The best overall response rate was higher in the ibrutinib arm than the ofatumumab arm, at 78% and 11%, respectively. And ibrutinib significantly prolonged progression-free survival. The median was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001).

Ibrutinib significantly prolonged overall survival as well. The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

PCYC-1102: Ibrutinib in CLL/SLL

Results of this phase 1b/2 trial were published in The Lancet Oncology in January. The trial enrolled 29 patients with previously untreated CLL and 2 with SLL.

They received 28-day cycles of once-daily ibrutinib at 420 mg or 840 mg. The 840 mg dose was discontinued after enrollment had begun because the doses showed comparable activity.

After a median follow-up of 22.1 months, 71% of patients achieved an objective response. Four patients (13%) had a complete response. The median time to response was 1.9 months.

Study investigators did not establish whether ibrutinib confers improvements in survival or disease-related symptoms.

Common adverse events included diarrhea (68%), nausea (48%), fatigue (32%), peripheral edema (29%), hypertension (29%), dizziness (26%), dyspepsia (26%), upper respiratory tract infection (26%), arthralgia (23%), constipation (23%), urinary tract infection (23%), and vomiting (23%).

Grade 3 adverse events included diarrhea (13%), fatigue (3%), hypertension (6%), dizziness (3%), urinary tract infection (3%), headache (3%), back pain (3%), and neutropenia (3%). One patient (3%) had grade 4 thrombocytopenia.

PCYC-1104 trial: Ibrutinib in MCL

Results of this trial were presented at ASH 2012 and published in NEJM in 2013. The NEJM data included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.

The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months.

The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).

Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.

About ibrutinib

Ibrutinib works by inhibiting BTK, a protein involved in mediating the cellular signaling pathways that control B-cell maturation and survival. In malignant B cells, there is excessive signaling through the B-cell receptor signaling pathway, which includes BTK.

Ibrutinib forms a strong covalent bond with BTK, which inhibits the excessive transmission of cell survival signals within the malignant B cells and stops their excessive build-up in protected environmental areas such as the lymph nodes.

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, MCL, Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Ibrutinib received accelerated approval from the US Food and Drug Administration in November 2013 to treat MCL. The drug received accelerated approval in February 2014 to treat CLL patients who have received at least 1 prior therapy.

Ibrutinib is also approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen and Pharmacyclics. The companies co-market ibrutinib in the US, but, pending the drug’s approval, Janssen will market ibrutinib in the rest of the world.

 

 

Micrograph showing MCL

 

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending marketing authorization for ibrutinib (Imbruvica).

The committee is endorsing the Bruton’s tyrosine kinase (BTK) inhibitor for use in adults with relapsed or refractory mantle cell lymphoma (MCL) and certain adults with chronic lymphocytic leukemia (CLL).

This includes untreated CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy and patients who have received at least 1 prior therapy.

The European Commission will take the CHMP’s opinion into account when deciding whether to authorize the commercialization of ibrutinib in the European Union.

The CHMP based its recommendations on data from 2 CLL studies—the phase 3 RESONATE trial (PCYC-1112) and a phase 1b/2 trial (PCYC-1102)—as well as a phase 2 trial (PCYC-1104) in MCL.

RESONATE trial

Results of RESONATE were recently presented at the 2014 EHA Congress. The trial included 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL).

Patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57). The median time on study was 9.4 months.

The best overall response rate was higher in the ibrutinib arm than the ofatumumab arm, at 78% and 11%, respectively. And ibrutinib significantly prolonged progression-free survival. The median was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001).

Ibrutinib significantly prolonged overall survival as well. The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

PCYC-1102: Ibrutinib in CLL/SLL

Results of this phase 1b/2 trial were published in The Lancet Oncology in January. The trial enrolled 29 patients with previously untreated CLL and 2 with SLL.

They received 28-day cycles of once-daily ibrutinib at 420 mg or 840 mg. The 840 mg dose was discontinued after enrollment had begun because the doses showed comparable activity.

After a median follow-up of 22.1 months, 71% of patients achieved an objective response. Four patients (13%) had a complete response. The median time to response was 1.9 months.

Study investigators did not establish whether ibrutinib confers improvements in survival or disease-related symptoms.

Common adverse events included diarrhea (68%), nausea (48%), fatigue (32%), peripheral edema (29%), hypertension (29%), dizziness (26%), dyspepsia (26%), upper respiratory tract infection (26%), arthralgia (23%), constipation (23%), urinary tract infection (23%), and vomiting (23%).

Grade 3 adverse events included diarrhea (13%), fatigue (3%), hypertension (6%), dizziness (3%), urinary tract infection (3%), headache (3%), back pain (3%), and neutropenia (3%). One patient (3%) had grade 4 thrombocytopenia.

PCYC-1104 trial: Ibrutinib in MCL

Results of this trial were presented at ASH 2012 and published in NEJM in 2013. The NEJM data included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.

The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months.

The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).

Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.

About ibrutinib

Ibrutinib works by inhibiting BTK, a protein involved in mediating the cellular signaling pathways that control B-cell maturation and survival. In malignant B cells, there is excessive signaling through the B-cell receptor signaling pathway, which includes BTK.

Ibrutinib forms a strong covalent bond with BTK, which inhibits the excessive transmission of cell survival signals within the malignant B cells and stops their excessive build-up in protected environmental areas such as the lymph nodes.

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, MCL, Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Ibrutinib received accelerated approval from the US Food and Drug Administration in November 2013 to treat MCL. The drug received accelerated approval in February 2014 to treat CLL patients who have received at least 1 prior therapy.

Ibrutinib is also approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen and Pharmacyclics. The companies co-market ibrutinib in the US, but, pending the drug’s approval, Janssen will market ibrutinib in the rest of the world.

 

 

Micrograph showing MCL

 

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is recommending marketing authorization for ibrutinib (Imbruvica).

The committee is endorsing the Bruton’s tyrosine kinase (BTK) inhibitor for use in adults with relapsed or refractory mantle cell lymphoma (MCL) and certain adults with chronic lymphocytic leukemia (CLL).

This includes untreated CLL patients with 17p deletion or TP53 mutation who cannot receive chemo-immunotherapy and patients who have received at least 1 prior therapy.

The European Commission will take the CHMP’s opinion into account when deciding whether to authorize the commercialization of ibrutinib in the European Union.

The CHMP based its recommendations on data from 2 CLL studies—the phase 3 RESONATE trial (PCYC-1112) and a phase 1b/2 trial (PCYC-1102)—as well as a phase 2 trial (PCYC-1104) in MCL.

RESONATE trial

Results of RESONATE were recently presented at the 2014 EHA Congress. The trial included 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL).

Patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). Patients in the ofatumumab arm were allowed to cross over to ibrutinib if they progressed (n=57). The median time on study was 9.4 months.

The best overall response rate was higher in the ibrutinib arm than the ofatumumab arm, at 78% and 11%, respectively. And ibrutinib significantly prolonged progression-free survival. The median was 8.1 months in the ofatumumab arm and was not reached in the ibrutinib arm (P<0.0001).

Ibrutinib significantly prolonged overall survival as well. The median overall survival was not reached in either arm, but the hazard ratio was 0.434 (P=0.0049).

Adverse events occurred in 99% of patients in the ibrutinib arm and 98% of those in the ofatumumab arm. Grade 3/4 events occurred in 51% and 39%, respectively.

Atrial fibrillation, bleeding-related events, diarrhea, and arthralgia were more common in the ibrutinib arm. Infusion-related reactions, peripheral sensory neuropathy, urticaria, night sweats, and pruritus were more common in the ofatumumab arm.

PCYC-1102: Ibrutinib in CLL/SLL

Results of this phase 1b/2 trial were published in The Lancet Oncology in January. The trial enrolled 29 patients with previously untreated CLL and 2 with SLL.

They received 28-day cycles of once-daily ibrutinib at 420 mg or 840 mg. The 840 mg dose was discontinued after enrollment had begun because the doses showed comparable activity.

After a median follow-up of 22.1 months, 71% of patients achieved an objective response. Four patients (13%) had a complete response. The median time to response was 1.9 months.

Study investigators did not establish whether ibrutinib confers improvements in survival or disease-related symptoms.

Common adverse events included diarrhea (68%), nausea (48%), fatigue (32%), peripheral edema (29%), hypertension (29%), dizziness (26%), dyspepsia (26%), upper respiratory tract infection (26%), arthralgia (23%), constipation (23%), urinary tract infection (23%), and vomiting (23%).

Grade 3 adverse events included diarrhea (13%), fatigue (3%), hypertension (6%), dizziness (3%), urinary tract infection (3%), headache (3%), back pain (3%), and neutropenia (3%). One patient (3%) had grade 4 thrombocytopenia.

PCYC-1104 trial: Ibrutinib in MCL

Results of this trial were presented at ASH 2012 and published in NEJM in 2013. The NEJM data included 111 patients who received ibrutinib at 560 mg daily in continuous, 28-day cycles until disease progression.

The overall response rate was 68%, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months.

The estimated progression-free survival was 13.9 months, and the overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

Common nonhematologic adverse events included diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), dyspnea (27%), constipation (25%), upper respiratory tract infection (23%), vomiting (23%), and decreased appetite (21%). The most common grade 3, 4, or 5 infection was pneumonia (6%).

Grade 3 and 4 hematologic adverse events included neutropenia (16%), thrombocytopenia (11%), and anemia (10%). Grade 3 bleeding events occurred in 5 patients.

About ibrutinib

Ibrutinib works by inhibiting BTK, a protein involved in mediating the cellular signaling pathways that control B-cell maturation and survival. In malignant B cells, there is excessive signaling through the B-cell receptor signaling pathway, which includes BTK.

Ibrutinib forms a strong covalent bond with BTK, which inhibits the excessive transmission of cell survival signals within the malignant B cells and stops their excessive build-up in protected environmental areas such as the lymph nodes.

Ibrutinib is being studied alone and in combination with other treatments in several hematologic malignancies, including CLL, MCL, Waldenstrom’s macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.

Ibrutinib received accelerated approval from the US Food and Drug Administration in November 2013 to treat MCL. The drug received accelerated approval in February 2014 to treat CLL patients who have received at least 1 prior therapy.

Ibrutinib is also approved in Israel for the treatment of adults with MCL who have received at least 1 prior therapy.

Ibrutinib is under development by Janssen and Pharmacyclics. The companies co-market ibrutinib in the US, but, pending the drug’s approval, Janssen will market ibrutinib in the rest of the world.

 

 

Micrograph showing FL

 

Days after gaining approval for 3 indications in the US, idelalisib (Zydelig) has earned a positive opinion from the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP).

The CHMP is recommending the PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

If approved, the drug would be used as monotherapy for adults with FL that is refractory to 2 prior lines of treatment.

Idelalisib would also be used in combination with rituximab for adults with CLL who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and cannot receive chemo-immunotherapy.

The CHMP’s recommendation for idelalisib (150 mg film-coated tablets) will be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union.

The CHMP’s positive opinion of idelalisib is based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

In this phase 2 trial, idelalisib was given as a single agent to patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent.

In the 72 patients with FL, the overall response rate was 54%, and the complete response rate was 8%. The median duration of response was not reached (range, 0-14.8 months).

Improvements in patient survival or disease-related symptoms have not been established.

The most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

About idelalisib 

Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.

Idelalisib is being developed by Gilead Sciences. On July 23, the drug received US Food and Drug Administration approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone. The agency also granted idelalisib accelerated approval to treat patients with relapsed FL or small lymphocytic lymphoma who have received at least 2 prior systemic therapies.

 

 

Micrograph showing FL

 

Days after gaining approval for 3 indications in the US, idelalisib (Zydelig) has earned a positive opinion from the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP).

The CHMP is recommending the PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

If approved, the drug would be used as monotherapy for adults with FL that is refractory to 2 prior lines of treatment.

Idelalisib would also be used in combination with rituximab for adults with CLL who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and cannot receive chemo-immunotherapy.

The CHMP’s recommendation for idelalisib (150 mg film-coated tablets) will be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union.

The CHMP’s positive opinion of idelalisib is based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

In this phase 2 trial, idelalisib was given as a single agent to patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent.

In the 72 patients with FL, the overall response rate was 54%, and the complete response rate was 8%. The median duration of response was not reached (range, 0-14.8 months).

Improvements in patient survival or disease-related symptoms have not been established.

The most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

About idelalisib 

Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.

Idelalisib is being developed by Gilead Sciences. On July 23, the drug received US Food and Drug Administration approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone. The agency also granted idelalisib accelerated approval to treat patients with relapsed FL or small lymphocytic lymphoma who have received at least 2 prior systemic therapies.

 

 

Micrograph showing FL

 

Days after gaining approval for 3 indications in the US, idelalisib (Zydelig) has earned a positive opinion from the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP).

The CHMP is recommending the PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

If approved, the drug would be used as monotherapy for adults with FL that is refractory to 2 prior lines of treatment.

Idelalisib would also be used in combination with rituximab for adults with CLL who have received at least 1 prior therapy or as first-line treatment in CLL patients who have 17p deletion or TP53 mutation and cannot receive chemo-immunotherapy.

The CHMP’s recommendation for idelalisib (150 mg film-coated tablets) will be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 countries of the European Union.

The CHMP’s positive opinion of idelalisib is based on data from 2 clinical trials—Study 116 and Study 101-09.

Study 116: Idelalisib in CLL

This phase 3 trial was stopped early because idelalisib had a significant impact on progression-free survival.

The study included 220 CLL patients who could not receive chemotherapy. Half were randomized to receive idelalisib plus rituximab, and the other half were randomized to rituximab plus placebo.

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

At 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

Most adverse events, in either treatment arm, were grade 2 or lower. The most common events in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common events were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious adverse events in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious events were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Study 101-09: Idelalisib in FL

In this phase 2 trial, idelalisib was given as a single agent to patients with indolent non-Hodgkin lymphoma who were refractory to rituximab and chemotherapy containing an alkylating agent.

In the 72 patients with FL, the overall response rate was 54%, and the complete response rate was 8%. The median duration of response was not reached (range, 0-14.8 months).

Improvements in patient survival or disease-related symptoms have not been established.

The most common grade 3 or higher adverse events were neutropenia (27%), elevations in aminotransferase levels (13%), diarrhea (13%), and pneumonia (7%).

About idelalisib 

Idelalisib is an oral inhibitor of PI3K delta, a protein that plays a role in the activation, proliferation, and viability of B cells. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and, by inhibiting the protein, idelalisib blocks several cellular signaling pathways that drive B-cell viability.

Idelalisib is being developed by Gilead Sciences. On July 23, the drug received US Food and Drug Administration approval for use in combination with rituximab to treat patients with relapsed CLL who cannot receive rituximab alone. The agency also granted idelalisib accelerated approval to treat patients with relapsed FL or small lymphocytic lymphoma who have received at least 2 prior systemic therapies.