HT Staff

Vials of chemotherapy drugs

Credit: Bill Branson

Counter to its previous recommendations, the UK’s National Institute for Health and Care Excellence (NICE) is now supporting the use of pixantrone for certain patients with non-Hodgkin lymphoma (NHL).

In prior draft guidance documents, NICE said it could not recommend the antineoplastic agent for patients with relapsed or refractory NHL, due to concerns about efficacy and cost.

But now, in its final draft guidance, the agency has said pixantrone should be funded by the National Health Service to treat certain patients with B-cell NHL.

NICE is recommending pixantrone for patients with relapsed or refractory disease who have already received rituximab and are receiving their third- or fourth-line treatment.

The NICE guidance also says pixantrone can only be funded if the manufacturer, Cell Therapeutics, provides the drug at a discounted rate, as agreed between the manufacturer and the Department of Health.

“We are pleased that the manufacturer was able to provide a patient access scheme,” said Carole Longson, NICE Health Technology Evaluation Centre Director. “Pixantrone will be a useful addition to the treatment options available.”

Consultees now have until January 23, 2014, to appeal the draft recommendation. If no appeals are lodged, the final guidance should be published in February.

Clinical effectiveness

NICE’s current recommendations are based on the opinion of an independent appraisal committee. The committee considered data from the EXTEND PIX301 clinical trial. The committee said there are a number of uncertainties associated with this trial.

However, the group also said there was limited evidence suggesting that pixantrone works better than other available treatments for patients who had previously received rituximab and patients receiving third- or fourth-line treatment.

The EXTEND PIX301 trial enrolled 140 patients with aggressive B-cell lymphoma. Half of the patients were randomized to receive pixantrone and the other half to their physicians’ choice of treatment.

At the end of treatment, confirmed and unconfirmed response rates for the intent-to-treat population  were significantly higher in the pixantrone arm than the comparator arm—20% and 5.7%, respectively (P=0.021). The same was true after 18 months of follow-up—24.3% and 7.1%, respectively (P=0.009).

The median progression-free survival was significantly longer in the pixantrone arm than the comparator arm—5.3 months and 2.6 months, respectively (P=0.005). But there was no significant difference in median overall survival—10.2 months and 7.6 months, respectively (P=0.251).

Cell Therapeutics also submitted results observed in 4 subgroups of patients with aggressive disease and in patients who had previously received rituximab. For detailed data from the trial, see pages 3 through 13 of the final draft guidance.

Cost-effectiveness

The appraisal committee said the manufacturer’s patient access scheme (the details of which are commercial-in-confidence) improved the cost-effectiveness of pixantrone.

The treatment would be cost-effective for patients who had previously received rituximab and patients receiving their third- or fourth-line treatment. The drug’s incremental cost-effectiveness ratio was estimated to be under £22,000 per quality adjusted life year gained for both groups.

According to the manufacturer, pixantrone costs £553.50 per 20 mL vial, excluding tax. The estimated cost of a course of treatment is £19,926.

The costs were calculated over 4 cycles using an average of 3 vials per dose and were based on the median length of treatment in the EXTEND PIX301 trial. Costs may vary in different settings because of negotiated discounts.

Marketing authorization

Pixantrone has conditional marketing authorization in the European Union as monotherapy for adults with relapsed or refractory NHL who have received at least 2 previous lines of treatment. However, the European Medicine’s Agency has noted that it is unclear whether pixantrone is effective as fifth-line or greater treatment in refractory patients.

The drug’s marketing authorization is linked to results of the phase 3 PIX306 trial, which is investigating pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed or refractory B-cell NHL who have previously received a rituximab-containing regimen.

Vials of chemotherapy drugs

Credit: Bill Branson

Counter to its previous recommendations, the UK’s National Institute for Health and Care Excellence (NICE) is now supporting the use of pixantrone for certain patients with non-Hodgkin lymphoma (NHL).

In prior draft guidance documents, NICE said it could not recommend the antineoplastic agent for patients with relapsed or refractory NHL, due to concerns about efficacy and cost.

But now, in its final draft guidance, the agency has said pixantrone should be funded by the National Health Service to treat certain patients with B-cell NHL.

NICE is recommending pixantrone for patients with relapsed or refractory disease who have already received rituximab and are receiving their third- or fourth-line treatment.

The NICE guidance also says pixantrone can only be funded if the manufacturer, Cell Therapeutics, provides the drug at a discounted rate, as agreed between the manufacturer and the Department of Health.

“We are pleased that the manufacturer was able to provide a patient access scheme,” said Carole Longson, NICE Health Technology Evaluation Centre Director. “Pixantrone will be a useful addition to the treatment options available.”

Consultees now have until January 23, 2014, to appeal the draft recommendation. If no appeals are lodged, the final guidance should be published in February.

Clinical effectiveness

NICE’s current recommendations are based on the opinion of an independent appraisal committee. The committee considered data from the EXTEND PIX301 clinical trial. The committee said there are a number of uncertainties associated with this trial.

However, the group also said there was limited evidence suggesting that pixantrone works better than other available treatments for patients who had previously received rituximab and patients receiving third- or fourth-line treatment.

The EXTEND PIX301 trial enrolled 140 patients with aggressive B-cell lymphoma. Half of the patients were randomized to receive pixantrone and the other half to their physicians’ choice of treatment.

At the end of treatment, confirmed and unconfirmed response rates for the intent-to-treat population  were significantly higher in the pixantrone arm than the comparator arm—20% and 5.7%, respectively (P=0.021). The same was true after 18 months of follow-up—24.3% and 7.1%, respectively (P=0.009).

The median progression-free survival was significantly longer in the pixantrone arm than the comparator arm—5.3 months and 2.6 months, respectively (P=0.005). But there was no significant difference in median overall survival—10.2 months and 7.6 months, respectively (P=0.251).

Cell Therapeutics also submitted results observed in 4 subgroups of patients with aggressive disease and in patients who had previously received rituximab. For detailed data from the trial, see pages 3 through 13 of the final draft guidance.

Cost-effectiveness

The appraisal committee said the manufacturer’s patient access scheme (the details of which are commercial-in-confidence) improved the cost-effectiveness of pixantrone.

The treatment would be cost-effective for patients who had previously received rituximab and patients receiving their third- or fourth-line treatment. The drug’s incremental cost-effectiveness ratio was estimated to be under £22,000 per quality adjusted life year gained for both groups.

According to the manufacturer, pixantrone costs £553.50 per 20 mL vial, excluding tax. The estimated cost of a course of treatment is £19,926.

The costs were calculated over 4 cycles using an average of 3 vials per dose and were based on the median length of treatment in the EXTEND PIX301 trial. Costs may vary in different settings because of negotiated discounts.

Marketing authorization

Pixantrone has conditional marketing authorization in the European Union as monotherapy for adults with relapsed or refractory NHL who have received at least 2 previous lines of treatment. However, the European Medicine’s Agency has noted that it is unclear whether pixantrone is effective as fifth-line or greater treatment in refractory patients.

The drug’s marketing authorization is linked to results of the phase 3 PIX306 trial, which is investigating pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed or refractory B-cell NHL who have previously received a rituximab-containing regimen.

Vials of chemotherapy drugs

Credit: Bill Branson

Counter to its previous recommendations, the UK’s National Institute for Health and Care Excellence (NICE) is now supporting the use of pixantrone for certain patients with non-Hodgkin lymphoma (NHL).

In prior draft guidance documents, NICE said it could not recommend the antineoplastic agent for patients with relapsed or refractory NHL, due to concerns about efficacy and cost.

But now, in its final draft guidance, the agency has said pixantrone should be funded by the National Health Service to treat certain patients with B-cell NHL.

NICE is recommending pixantrone for patients with relapsed or refractory disease who have already received rituximab and are receiving their third- or fourth-line treatment.

The NICE guidance also says pixantrone can only be funded if the manufacturer, Cell Therapeutics, provides the drug at a discounted rate, as agreed between the manufacturer and the Department of Health.

“We are pleased that the manufacturer was able to provide a patient access scheme,” said Carole Longson, NICE Health Technology Evaluation Centre Director. “Pixantrone will be a useful addition to the treatment options available.”

Consultees now have until January 23, 2014, to appeal the draft recommendation. If no appeals are lodged, the final guidance should be published in February.

Clinical effectiveness

NICE’s current recommendations are based on the opinion of an independent appraisal committee. The committee considered data from the EXTEND PIX301 clinical trial. The committee said there are a number of uncertainties associated with this trial.

However, the group also said there was limited evidence suggesting that pixantrone works better than other available treatments for patients who had previously received rituximab and patients receiving third- or fourth-line treatment.

The EXTEND PIX301 trial enrolled 140 patients with aggressive B-cell lymphoma. Half of the patients were randomized to receive pixantrone and the other half to their physicians’ choice of treatment.

At the end of treatment, confirmed and unconfirmed response rates for the intent-to-treat population  were significantly higher in the pixantrone arm than the comparator arm—20% and 5.7%, respectively (P=0.021). The same was true after 18 months of follow-up—24.3% and 7.1%, respectively (P=0.009).

The median progression-free survival was significantly longer in the pixantrone arm than the comparator arm—5.3 months and 2.6 months, respectively (P=0.005). But there was no significant difference in median overall survival—10.2 months and 7.6 months, respectively (P=0.251).

Cell Therapeutics also submitted results observed in 4 subgroups of patients with aggressive disease and in patients who had previously received rituximab. For detailed data from the trial, see pages 3 through 13 of the final draft guidance.

Cost-effectiveness

The appraisal committee said the manufacturer’s patient access scheme (the details of which are commercial-in-confidence) improved the cost-effectiveness of pixantrone.

The treatment would be cost-effective for patients who had previously received rituximab and patients receiving their third- or fourth-line treatment. The drug’s incremental cost-effectiveness ratio was estimated to be under £22,000 per quality adjusted life year gained for both groups.

According to the manufacturer, pixantrone costs £553.50 per 20 mL vial, excluding tax. The estimated cost of a course of treatment is £19,926.

The costs were calculated over 4 cycles using an average of 3 vials per dose and were based on the median length of treatment in the EXTEND PIX301 trial. Costs may vary in different settings because of negotiated discounts.

Marketing authorization

Pixantrone has conditional marketing authorization in the European Union as monotherapy for adults with relapsed or refractory NHL who have received at least 2 previous lines of treatment. However, the European Medicine’s Agency has noted that it is unclear whether pixantrone is effective as fifth-line or greater treatment in refractory patients.

The drug’s marketing authorization is linked to results of the phase 3 PIX306 trial, which is investigating pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed or refractory B-cell NHL who have previously received a rituximab-containing regimen.

Monoclonal antibodies
Credit: Linda Bartlett

NEW ORLEANS—Brentuximab vedotin has demonstrated “compelling” antitumor activity in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to researchers.

The investigators were also surprised

to find that the activity of this anti-CD30 monoclonal antibody

conjugate did not seem to

correlate with a patient’s level of CD30 expression.

In fact, some of

the patients with the weakest CD30 expression had the best responses to

the drug.

Eric Jacobsen, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues presented these results at the 2013 ASH Annual Meeting as abstract 848.

Thus far, the researchers have enrolled 62 patients with B-cell lymphomas, including 44 with DLBCL, on this phase 2 study.

Sixty-five percent of patients had primary refractory disease, 76% were refractory to their most recent prior therapy, and 23% had never responded to any treatment.

However, 40% of the 43 evaluable DLBCL patients had an objective response to brentuximab vedotin. The median response duration was 36 weeks, and some responses lasted more than 8 months.

Seven patients had complete remissions, and 10 had partial remissions. In the other B-cell lymphoma patients, 22 had an objective response.

The researchers called this compelling antitumor activity in a highly refractory population.

“[Brentuximab vedotin] was more active than many expected,” Dr Jacobsen said. “In my opinion, these results are encouraging enough to take the drug forward in diffuse large B-cell lymphoma.”

The researchers said the drug’s safety profile was consistent with previous results. Six patients stopped treatment due to adverse events, including 2 who developed peripheral neuropathy. 

Treatment-emergent adverse events included fatigue (40%), nausea (37%), neutropenia (37%), fever (32%), diarrhea (31%), peripheral sensory neuropathy (26%), vomiting (23%), anemia (21%), and constipation (21%).

Role of CD30

Brentuximab vedotin is a monoclonal antibody that binds to CD30. This molecule’s expression varies, but researchers have estimated that CD30 is present in a quarter to a third of B-cell non-Hodgkin lymphoma cells.

In this study, some of the patients’ lymphoma cells strongly expressed CD30. But, in other patients, the investigators were unable to detect any CD30 expression at all. And the patients’ level of CD30 expression bore no relationship to how they responded to the drug.

“In fact, although the trend was not statistically significant, there was almost an inverse correlation,” Dr Jacobsen said. “Some patients with the weakest CD30 expression had the most positive responses.”

One possible explanation for this is that the drug bound to another target, but preclinical tests suggested this was not the case. Other possibilities are that brentuximab vedotin binds more effectively to CD30 than the antibody used to detect CD30 in the lab or that different cells have differing abilities to ingest brentuximab once the antibody binds to the cell.

There is no clear answer from the study, Dr Jacobsen said, but lab tests are ongoing. He and his colleagues are beginning to evaluate the drug’s activity in a cohort of patients whose lymphomas have no measurable CD30 expression.

This study was supported by Seattle Genetics.

Monoclonal antibodies
Credit: Linda Bartlett

NEW ORLEANS—Brentuximab vedotin has demonstrated “compelling” antitumor activity in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to researchers.

The investigators were also surprised

to find that the activity of this anti-CD30 monoclonal antibody

conjugate did not seem to

correlate with a patient’s level of CD30 expression.

In fact, some of

the patients with the weakest CD30 expression had the best responses to

the drug.

Eric Jacobsen, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues presented these results at the 2013 ASH Annual Meeting as abstract 848.

Thus far, the researchers have enrolled 62 patients with B-cell lymphomas, including 44 with DLBCL, on this phase 2 study.

Sixty-five percent of patients had primary refractory disease, 76% were refractory to their most recent prior therapy, and 23% had never responded to any treatment.

However, 40% of the 43 evaluable DLBCL patients had an objective response to brentuximab vedotin. The median response duration was 36 weeks, and some responses lasted more than 8 months.

Seven patients had complete remissions, and 10 had partial remissions. In the other B-cell lymphoma patients, 22 had an objective response.

The researchers called this compelling antitumor activity in a highly refractory population.

“[Brentuximab vedotin] was more active than many expected,” Dr Jacobsen said. “In my opinion, these results are encouraging enough to take the drug forward in diffuse large B-cell lymphoma.”

The researchers said the drug’s safety profile was consistent with previous results. Six patients stopped treatment due to adverse events, including 2 who developed peripheral neuropathy. 

Treatment-emergent adverse events included fatigue (40%), nausea (37%), neutropenia (37%), fever (32%), diarrhea (31%), peripheral sensory neuropathy (26%), vomiting (23%), anemia (21%), and constipation (21%).

Role of CD30

Brentuximab vedotin is a monoclonal antibody that binds to CD30. This molecule’s expression varies, but researchers have estimated that CD30 is present in a quarter to a third of B-cell non-Hodgkin lymphoma cells.

In this study, some of the patients’ lymphoma cells strongly expressed CD30. But, in other patients, the investigators were unable to detect any CD30 expression at all. And the patients’ level of CD30 expression bore no relationship to how they responded to the drug.

“In fact, although the trend was not statistically significant, there was almost an inverse correlation,” Dr Jacobsen said. “Some patients with the weakest CD30 expression had the most positive responses.”

One possible explanation for this is that the drug bound to another target, but preclinical tests suggested this was not the case. Other possibilities are that brentuximab vedotin binds more effectively to CD30 than the antibody used to detect CD30 in the lab or that different cells have differing abilities to ingest brentuximab once the antibody binds to the cell.

There is no clear answer from the study, Dr Jacobsen said, but lab tests are ongoing. He and his colleagues are beginning to evaluate the drug’s activity in a cohort of patients whose lymphomas have no measurable CD30 expression.

This study was supported by Seattle Genetics.

Monoclonal antibodies
Credit: Linda Bartlett

NEW ORLEANS—Brentuximab vedotin has demonstrated “compelling” antitumor activity in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to researchers.

The investigators were also surprised

to find that the activity of this anti-CD30 monoclonal antibody

conjugate did not seem to

correlate with a patient’s level of CD30 expression.

In fact, some of

the patients with the weakest CD30 expression had the best responses to

the drug.

Eric Jacobsen, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues presented these results at the 2013 ASH Annual Meeting as abstract 848.

Thus far, the researchers have enrolled 62 patients with B-cell lymphomas, including 44 with DLBCL, on this phase 2 study.

Sixty-five percent of patients had primary refractory disease, 76% were refractory to their most recent prior therapy, and 23% had never responded to any treatment.

However, 40% of the 43 evaluable DLBCL patients had an objective response to brentuximab vedotin. The median response duration was 36 weeks, and some responses lasted more than 8 months.

Seven patients had complete remissions, and 10 had partial remissions. In the other B-cell lymphoma patients, 22 had an objective response.

The researchers called this compelling antitumor activity in a highly refractory population.

“[Brentuximab vedotin] was more active than many expected,” Dr Jacobsen said. “In my opinion, these results are encouraging enough to take the drug forward in diffuse large B-cell lymphoma.”

The researchers said the drug’s safety profile was consistent with previous results. Six patients stopped treatment due to adverse events, including 2 who developed peripheral neuropathy. 

Treatment-emergent adverse events included fatigue (40%), nausea (37%), neutropenia (37%), fever (32%), diarrhea (31%), peripheral sensory neuropathy (26%), vomiting (23%), anemia (21%), and constipation (21%).

Role of CD30

Brentuximab vedotin is a monoclonal antibody that binds to CD30. This molecule’s expression varies, but researchers have estimated that CD30 is present in a quarter to a third of B-cell non-Hodgkin lymphoma cells.

In this study, some of the patients’ lymphoma cells strongly expressed CD30. But, in other patients, the investigators were unable to detect any CD30 expression at all. And the patients’ level of CD30 expression bore no relationship to how they responded to the drug.

“In fact, although the trend was not statistically significant, there was almost an inverse correlation,” Dr Jacobsen said. “Some patients with the weakest CD30 expression had the most positive responses.”

One possible explanation for this is that the drug bound to another target, but preclinical tests suggested this was not the case. Other possibilities are that brentuximab vedotin binds more effectively to CD30 than the antibody used to detect CD30 in the lab or that different cells have differing abilities to ingest brentuximab once the antibody binds to the cell.

There is no clear answer from the study, Dr Jacobsen said, but lab tests are ongoing. He and his colleagues are beginning to evaluate the drug’s activity in a cohort of patients whose lymphomas have no measurable CD30 expression.

This study was supported by Seattle Genetics.

The leukemia drug ponatinib is expected to return to market once the drug’s manufacturer has implemented measures to address the recently discovered safety risks.

The US Food and Drug Administration (FDA) is requiring that a number of safety measures be adopted, including changes to ponatinib’s label to narrow the drug’s indication and the addition of warnings about the increased risk of thrombosis and venous occlusion associated with ponatinib use.

In addition, dosing and administration recommendations must be revised, the patient medication guide must be updated, a risk evaluation and mitigation strategy (REMS) must be implemented, and postmarket investigations must be conducted to further characterize the drug’s safety and dosing.

Ponatinib was approved by the FDA in December 2012 to treat adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).

But in October 2013, follow-up results of the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.

Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. Now, the agency has decided ponatinib can return to the market if the new safety measures are implemented.

Safety measures in detail

The FDA is requiring that ponatinib use be restricted to:

• Adults with T315I-positive CML (chronic phase, accelerated phase, or blast phase)
• Adults with T315I-positive Ph+ ALL
• Adults with CML (chronic phase, accelerated phase, or blast phase) who cannot receive another TKI
• Adults with Ph+ ALL who cannot receive another TKI.

The Warnings and Precautions section of the drug’s label must be revised to include a description of the arterial and venous thrombosis and occlusions that have occurred in at least 27%—more than 1 in every 4—of patients treated with ponatinib.

The Dosage and Administration recommendations must be revised to state that the optimal dose of ponatinib has not been identified. The recommended starting dose remains 45 mg administered orally once daily, with or without food.

The patient Medication Guide must be revised to include additional safety information consistent with the safety information in the revised drug label.

The ponatinib REMS must inform prescribers about the approved indications for use and the serious risk of vascular occlusion and thromboembolism associated with the drug. The REMS must include the following:

• REMS letter to healthcare professionals who are known or likely to prescribe ponatinib
• REMS letter for professional societies to be distributed to their members
• REMS fact sheet for healthcare professionals
• Public statement to be published quarterly for 1 year in several professional journals
• Information to be prominently displayed at scientific meetings
• Ponatinib REMS website to provide access to all REMS materials for the duration of the REMS.

And postmarket investigations must further evaluate the dose selection, drug exposure, treatment response, and toxicity of ponatinib.

For more information, see the FDA’s safety communication.

The leukemia drug ponatinib is expected to return to market once the drug’s manufacturer has implemented measures to address the recently discovered safety risks.

The US Food and Drug Administration (FDA) is requiring that a number of safety measures be adopted, including changes to ponatinib’s label to narrow the drug’s indication and the addition of warnings about the increased risk of thrombosis and venous occlusion associated with ponatinib use.

In addition, dosing and administration recommendations must be revised, the patient medication guide must be updated, a risk evaluation and mitigation strategy (REMS) must be implemented, and postmarket investigations must be conducted to further characterize the drug’s safety and dosing.

Ponatinib was approved by the FDA in December 2012 to treat adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).

But in October 2013, follow-up results of the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.

Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. Now, the agency has decided ponatinib can return to the market if the new safety measures are implemented.

Safety measures in detail

The FDA is requiring that ponatinib use be restricted to:

• Adults with T315I-positive CML (chronic phase, accelerated phase, or blast phase)
• Adults with T315I-positive Ph+ ALL
• Adults with CML (chronic phase, accelerated phase, or blast phase) who cannot receive another TKI
• Adults with Ph+ ALL who cannot receive another TKI.

The Warnings and Precautions section of the drug’s label must be revised to include a description of the arterial and venous thrombosis and occlusions that have occurred in at least 27%—more than 1 in every 4—of patients treated with ponatinib.

The Dosage and Administration recommendations must be revised to state that the optimal dose of ponatinib has not been identified. The recommended starting dose remains 45 mg administered orally once daily, with or without food.

The patient Medication Guide must be revised to include additional safety information consistent with the safety information in the revised drug label.

The ponatinib REMS must inform prescribers about the approved indications for use and the serious risk of vascular occlusion and thromboembolism associated with the drug. The REMS must include the following:

• REMS letter to healthcare professionals who are known or likely to prescribe ponatinib
• REMS letter for professional societies to be distributed to their members
• REMS fact sheet for healthcare professionals
• Public statement to be published quarterly for 1 year in several professional journals
• Information to be prominently displayed at scientific meetings
• Ponatinib REMS website to provide access to all REMS materials for the duration of the REMS.

And postmarket investigations must further evaluate the dose selection, drug exposure, treatment response, and toxicity of ponatinib.

For more information, see the FDA’s safety communication.

The leukemia drug ponatinib is expected to return to market once the drug’s manufacturer has implemented measures to address the recently discovered safety risks.

The US Food and Drug Administration (FDA) is requiring that a number of safety measures be adopted, including changes to ponatinib’s label to narrow the drug’s indication and the addition of warnings about the increased risk of thrombosis and venous occlusion associated with ponatinib use.

In addition, dosing and administration recommendations must be revised, the patient medication guide must be updated, a risk evaluation and mitigation strategy (REMS) must be implemented, and postmarket investigations must be conducted to further characterize the drug’s safety and dosing.

Ponatinib was approved by the FDA in December 2012 to treat adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant to or intolerant of other tyrosine kinase inhibitors (TKIs).

But in October 2013, follow-up results of the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the phase 3 EPIC trial, which was discontinued.

Then, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. Now, the agency has decided ponatinib can return to the market if the new safety measures are implemented.

Safety measures in detail

The FDA is requiring that ponatinib use be restricted to:

• Adults with T315I-positive CML (chronic phase, accelerated phase, or blast phase)
• Adults with T315I-positive Ph+ ALL
• Adults with CML (chronic phase, accelerated phase, or blast phase) who cannot receive another TKI
• Adults with Ph+ ALL who cannot receive another TKI.

The Warnings and Precautions section of the drug’s label must be revised to include a description of the arterial and venous thrombosis and occlusions that have occurred in at least 27%—more than 1 in every 4—of patients treated with ponatinib.

The Dosage and Administration recommendations must be revised to state that the optimal dose of ponatinib has not been identified. The recommended starting dose remains 45 mg administered orally once daily, with or without food.

The patient Medication Guide must be revised to include additional safety information consistent with the safety information in the revised drug label.

The ponatinib REMS must inform prescribers about the approved indications for use and the serious risk of vascular occlusion and thromboembolism associated with the drug. The REMS must include the following:

• REMS letter to healthcare professionals who are known or likely to prescribe ponatinib
• REMS letter for professional societies to be distributed to their members
• REMS fact sheet for healthcare professionals
• Public statement to be published quarterly for 1 year in several professional journals
• Information to be prominently displayed at scientific meetings
• Ponatinib REMS website to provide access to all REMS materials for the duration of the REMS.

And postmarket investigations must further evaluate the dose selection, drug exposure, treatment response, and toxicity of ponatinib.

For more information, see the FDA’s safety communication.

Prescriptions
Credit: CDC

NEW ORLEANS—New data indicate a trend for longer overall survival and event-free survival in newly diagnosed chronic myeloid leukemia (CML) patients on nilotinib versus imatinib.

Five-year data from the phase 3 ENESTnd study demonstrate higher rates of early and deeper molecular response in newly diagnosed CML patients taking nilotinib, as well as a reduced risk of progression compared to imatinib.

These results were presented at the 2013 ASH Annual Meeting as abstract 92.

“These new, updated data reaffirm the superiority of nilotinib over imatinib at achieving deeper molecular responses and provide even more evidence supporting nilotinib as an appropriate treatment of choice in newly diagnosed patients,” said Giuseppe Saglio, MD, of the University of Turin in Italy.

“Now, we are looking at how deeper molecular responses may help guide our approach towards how we treat CML in the future.”

The 5-year ENESTnd data showed that nilotinib can produce superior responses across various Philadelphia chromosome-positive CML patient populations, including newly diagnosed patients. Results showed higher rates of early and deeper sustained molecular response, known as MR4.5.

The difference in the rates of MR4.5 continued to be higher when nilotinib was given at 300 mg or 400 mg twice daily, when compared to imatinib (MR4.5: 6%-10% difference by 1 year, 21%-23% difference by 5 years).

“The most important endpoint is cumulative incidence of MR4.5,” Dr Saglio said. “At 5 years, this is achieved by 54% of those in nilotinib-300-mg group, 52% in the nilotinib-400-mg group, and 31% in the imatinib group. And the curves are still diverging.” 

The data also indicate a trend for higher overall survival and event-free survival rates in patients treated with nilotinib.

Fifteen patients treated with imatinib had CML-related deaths, compared to 6 patients in the arm receiving nilotinib at 300 mg twice daily and 4 patients in the arm receiving nilotinib at 400 mg twice daily.

Few new adverse events and laboratory abnormalities were observed between year 4 and year 5. Rates of patients with adverse events leading to discontinuation were 11.1% in the 300-mg nilotinib group, 17.7% in the 400-mg nilotinib group, and 13.2% in the imatinib group.

Dr Saglio noted that select cardiac and vascular events are slightly more frequent on nilotinib versus imatinib. But there has been no increase in the annual incidence of these events over time.

Therefore, Dr Saglio concluded, “Nilotinib, a standard-of-care frontline therapy option for newly diagnosed, chronic-phase CML patients, affords superior efficacy compared with imatinib, including higher rates of early molecular response (which is associated with improved long-term outcomes), higher rates of deep molecular response, and a lower risk of disease progression. Nilotinib continues to show good tolerability with long-term follow-up.”

Prescriptions
Credit: CDC

NEW ORLEANS—New data indicate a trend for longer overall survival and event-free survival in newly diagnosed chronic myeloid leukemia (CML) patients on nilotinib versus imatinib.

Five-year data from the phase 3 ENESTnd study demonstrate higher rates of early and deeper molecular response in newly diagnosed CML patients taking nilotinib, as well as a reduced risk of progression compared to imatinib.

These results were presented at the 2013 ASH Annual Meeting as abstract 92.

“These new, updated data reaffirm the superiority of nilotinib over imatinib at achieving deeper molecular responses and provide even more evidence supporting nilotinib as an appropriate treatment of choice in newly diagnosed patients,” said Giuseppe Saglio, MD, of the University of Turin in Italy.

“Now, we are looking at how deeper molecular responses may help guide our approach towards how we treat CML in the future.”

The 5-year ENESTnd data showed that nilotinib can produce superior responses across various Philadelphia chromosome-positive CML patient populations, including newly diagnosed patients. Results showed higher rates of early and deeper sustained molecular response, known as MR4.5.

The difference in the rates of MR4.5 continued to be higher when nilotinib was given at 300 mg or 400 mg twice daily, when compared to imatinib (MR4.5: 6%-10% difference by 1 year, 21%-23% difference by 5 years).

“The most important endpoint is cumulative incidence of MR4.5,” Dr Saglio said. “At 5 years, this is achieved by 54% of those in nilotinib-300-mg group, 52% in the nilotinib-400-mg group, and 31% in the imatinib group. And the curves are still diverging.” 

The data also indicate a trend for higher overall survival and event-free survival rates in patients treated with nilotinib.

Fifteen patients treated with imatinib had CML-related deaths, compared to 6 patients in the arm receiving nilotinib at 300 mg twice daily and 4 patients in the arm receiving nilotinib at 400 mg twice daily.

Few new adverse events and laboratory abnormalities were observed between year 4 and year 5. Rates of patients with adverse events leading to discontinuation were 11.1% in the 300-mg nilotinib group, 17.7% in the 400-mg nilotinib group, and 13.2% in the imatinib group.

Dr Saglio noted that select cardiac and vascular events are slightly more frequent on nilotinib versus imatinib. But there has been no increase in the annual incidence of these events over time.

Therefore, Dr Saglio concluded, “Nilotinib, a standard-of-care frontline therapy option for newly diagnosed, chronic-phase CML patients, affords superior efficacy compared with imatinib, including higher rates of early molecular response (which is associated with improved long-term outcomes), higher rates of deep molecular response, and a lower risk of disease progression. Nilotinib continues to show good tolerability with long-term follow-up.”

Prescriptions
Credit: CDC

NEW ORLEANS—New data indicate a trend for longer overall survival and event-free survival in newly diagnosed chronic myeloid leukemia (CML) patients on nilotinib versus imatinib.

Five-year data from the phase 3 ENESTnd study demonstrate higher rates of early and deeper molecular response in newly diagnosed CML patients taking nilotinib, as well as a reduced risk of progression compared to imatinib.

These results were presented at the 2013 ASH Annual Meeting as abstract 92.

“These new, updated data reaffirm the superiority of nilotinib over imatinib at achieving deeper molecular responses and provide even more evidence supporting nilotinib as an appropriate treatment of choice in newly diagnosed patients,” said Giuseppe Saglio, MD, of the University of Turin in Italy.

“Now, we are looking at how deeper molecular responses may help guide our approach towards how we treat CML in the future.”

The 5-year ENESTnd data showed that nilotinib can produce superior responses across various Philadelphia chromosome-positive CML patient populations, including newly diagnosed patients. Results showed higher rates of early and deeper sustained molecular response, known as MR4.5.

The difference in the rates of MR4.5 continued to be higher when nilotinib was given at 300 mg or 400 mg twice daily, when compared to imatinib (MR4.5: 6%-10% difference by 1 year, 21%-23% difference by 5 years).

“The most important endpoint is cumulative incidence of MR4.5,” Dr Saglio said. “At 5 years, this is achieved by 54% of those in nilotinib-300-mg group, 52% in the nilotinib-400-mg group, and 31% in the imatinib group. And the curves are still diverging.” 

The data also indicate a trend for higher overall survival and event-free survival rates in patients treated with nilotinib.

Fifteen patients treated with imatinib had CML-related deaths, compared to 6 patients in the arm receiving nilotinib at 300 mg twice daily and 4 patients in the arm receiving nilotinib at 400 mg twice daily.

Few new adverse events and laboratory abnormalities were observed between year 4 and year 5. Rates of patients with adverse events leading to discontinuation were 11.1% in the 300-mg nilotinib group, 17.7% in the 400-mg nilotinib group, and 13.2% in the imatinib group.

Dr Saglio noted that select cardiac and vascular events are slightly more frequent on nilotinib versus imatinib. But there has been no increase in the annual incidence of these events over time.

Therefore, Dr Saglio concluded, “Nilotinib, a standard-of-care frontline therapy option for newly diagnosed, chronic-phase CML patients, affords superior efficacy compared with imatinib, including higher rates of early molecular response (which is associated with improved long-term outcomes), higher rates of deep molecular response, and a lower risk of disease progression. Nilotinib continues to show good tolerability with long-term follow-up.”

Inside the Ernest N. Morial
Convention Center, site of the
2013 ASH Annual Meeting

NEW ORLEANS—In a phase 3 study, patients with diffuse large B-cell lymphoma (DLBCL) who received post-induction therapy with enzastaurin saw no improvements in survival over patients who received placebo.

All patients were in their first remission after treatment with R-CHOP, but they were thought to have a high risk of relapse.

The patients who received 3 years of treatment with enzastaurin had similar rates of event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) as patients who received placebo.

Michael Crump, MD, of Princess Margaret Cancer Centre in Toronto, Canada, reported these results at the 2013 ASH Annual Meeting as abstract 371.

Dr Crump noted that enzastaurin is a potent and selective inhibitor of PKCβ, the major isoform expressed in normal and malignant B cells. The kinase is required for signaling through the B-cell receptor, is necessary for activation of NF-κB, and is involved in VEGF-mediated angiogenesis.   

“It was a little more than 10 years ago that Margaret Shipp and her colleagues demonstrated that overexpression of PKCβ mRNA and protein was associated with relapsed and fatal diffuse large B-cell lymphoma,” Dr Crump said.

“Since that time, other investigators have also shown that overexpression of either protein or mRNA is associated with a worse outcome in patients receiving CHOP chemotherapy as well as R-CHOP. So [PKCβ] seems to be a rational therapeutic target.” 

With this in mind, Dr Crump and his colleagues conducted the phase 3 PRELUDE trial, comparing enzastaurin to placebo in DLBCL patients.

Patient population

The researchers enrolled 866 patients who had a complete response, unconfirmed complete response, or negative FDG-PET scan following treatment with R-CHOP14 or R-CHOP21.

The team randomized 758 of the patients to receive placebo or oral enzastaurin at 500 mg once daily, with a 1125 mg loading dose on day 1. A total of 263 patients in the enzastaurin arm and 129 patients in the placebo arm completed 3 years of treatment.

The rates of discontinuation were similar between the arms—46.7% (n=230) in the enzastaurin arm and 48.2% (n=120) in the placebo arm. In both groups, the most common reason for discontinuation was disease progression (n=103 and 60, respectively). Adverse events were the second most common reason (n=72 and 28, respectively). 

Baseline characteristics were similar between the 2 groups. The median age was 64, most patients were Caucasian, most had an ECOG performance status of 0, most had stage IV disease, and more than half of the patients in each arm were PET-negative (although about 40% of patients in each arm did not have a PET scan).

Survival outcomes

The 2-year OS rate was 87% in the enzastaurin arm and 89% in the placebo arm. The 4-year OS rates were 81% and 82%, respectively. And the hazard ratio was 1.04 (P=0.807).

The 2-year EFS rate was 78% in the enzastaurin arm and 73% in the placebo arm. The 4-year EFS rates were 69% and 70%, respectively. And the hazard ratio was 0.90 (P=0.460).

The 2-year DFS rate was 79% in the enzastaurin arm and 75% in the placebo arm. The 4-year DFS rates were 70% and 71%, respectively. And the hazard ratio was 0.92 (P=0.541).

The researchers also assessed DFS according to cell of origin. And they found no difference between patients who had germinal center B-cell (GCB) DLBCL and patients who did not.

Overall, the hazard ratio for GCB vs non-GCB DLBCL was 0.92 (P=0.74). In the enzastaurin arm, the hazard ratio was 0.77 (P=0.40). And in the placebo arm, the hazard ratio was 1.31 (P=0.54).

“One would anticipate a drug that interferes with B-cell receptor signaling might have benefitted patients with tumors that are not of germinal center origin,” Dr Crump said. “Altogether, however . . ., there was actually no difference in GCB vs non-GCB, in terms of outcome.”

“Perhaps [the patients] being in a complete response is one of the reasons why we don’t actually see a difference in outcomes,” he added. “These are all patients who’ve had very good responses to their primary treatment.” 

Adverse events

Dr Crump said there were a number of adverse events that could be related to enzastaurin treatment.

Chromaturia occurred in 18.5% of patients in the enzastaurin arm and 0.4% of patients in the placebo arm (P<0.001). Prolonged QT interval was an issue in 10.8% and 3.6%, respectively; diarrhea occurred in 10.3% and 2.8%, respectively; and discolored feces arose in 7.7% and 0%, respectively (P<0.001 for all).

Other adverse events (occurring in 5% of patients or greater) included neutropenia, rash, fatigue, and nausea. But the rates of these events were similar between the treatment arms.

Dr Crump noted that these results are consistent with the established safety profile of enzastaurin when it’s used as a single agent in lymphoma and other cancers.

Inside the Ernest N. Morial
Convention Center, site of the
2013 ASH Annual Meeting

NEW ORLEANS—In a phase 3 study, patients with diffuse large B-cell lymphoma (DLBCL) who received post-induction therapy with enzastaurin saw no improvements in survival over patients who received placebo.

All patients were in their first remission after treatment with R-CHOP, but they were thought to have a high risk of relapse.

The patients who received 3 years of treatment with enzastaurin had similar rates of event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) as patients who received placebo.

Michael Crump, MD, of Princess Margaret Cancer Centre in Toronto, Canada, reported these results at the 2013 ASH Annual Meeting as abstract 371.

Dr Crump noted that enzastaurin is a potent and selective inhibitor of PKCβ, the major isoform expressed in normal and malignant B cells. The kinase is required for signaling through the B-cell receptor, is necessary for activation of NF-κB, and is involved in VEGF-mediated angiogenesis.   

“It was a little more than 10 years ago that Margaret Shipp and her colleagues demonstrated that overexpression of PKCβ mRNA and protein was associated with relapsed and fatal diffuse large B-cell lymphoma,” Dr Crump said.

“Since that time, other investigators have also shown that overexpression of either protein or mRNA is associated with a worse outcome in patients receiving CHOP chemotherapy as well as R-CHOP. So [PKCβ] seems to be a rational therapeutic target.” 

With this in mind, Dr Crump and his colleagues conducted the phase 3 PRELUDE trial, comparing enzastaurin to placebo in DLBCL patients.

Patient population

The researchers enrolled 866 patients who had a complete response, unconfirmed complete response, or negative FDG-PET scan following treatment with R-CHOP14 or R-CHOP21.

The team randomized 758 of the patients to receive placebo or oral enzastaurin at 500 mg once daily, with a 1125 mg loading dose on day 1. A total of 263 patients in the enzastaurin arm and 129 patients in the placebo arm completed 3 years of treatment.

The rates of discontinuation were similar between the arms—46.7% (n=230) in the enzastaurin arm and 48.2% (n=120) in the placebo arm. In both groups, the most common reason for discontinuation was disease progression (n=103 and 60, respectively). Adverse events were the second most common reason (n=72 and 28, respectively). 

Baseline characteristics were similar between the 2 groups. The median age was 64, most patients were Caucasian, most had an ECOG performance status of 0, most had stage IV disease, and more than half of the patients in each arm were PET-negative (although about 40% of patients in each arm did not have a PET scan).

Survival outcomes

The 2-year OS rate was 87% in the enzastaurin arm and 89% in the placebo arm. The 4-year OS rates were 81% and 82%, respectively. And the hazard ratio was 1.04 (P=0.807).

The 2-year EFS rate was 78% in the enzastaurin arm and 73% in the placebo arm. The 4-year EFS rates were 69% and 70%, respectively. And the hazard ratio was 0.90 (P=0.460).

The 2-year DFS rate was 79% in the enzastaurin arm and 75% in the placebo arm. The 4-year DFS rates were 70% and 71%, respectively. And the hazard ratio was 0.92 (P=0.541).

The researchers also assessed DFS according to cell of origin. And they found no difference between patients who had germinal center B-cell (GCB) DLBCL and patients who did not.

Overall, the hazard ratio for GCB vs non-GCB DLBCL was 0.92 (P=0.74). In the enzastaurin arm, the hazard ratio was 0.77 (P=0.40). And in the placebo arm, the hazard ratio was 1.31 (P=0.54).

“One would anticipate a drug that interferes with B-cell receptor signaling might have benefitted patients with tumors that are not of germinal center origin,” Dr Crump said. “Altogether, however . . ., there was actually no difference in GCB vs non-GCB, in terms of outcome.”

“Perhaps [the patients] being in a complete response is one of the reasons why we don’t actually see a difference in outcomes,” he added. “These are all patients who’ve had very good responses to their primary treatment.” 

Adverse events

Dr Crump said there were a number of adverse events that could be related to enzastaurin treatment.

Chromaturia occurred in 18.5% of patients in the enzastaurin arm and 0.4% of patients in the placebo arm (P<0.001). Prolonged QT interval was an issue in 10.8% and 3.6%, respectively; diarrhea occurred in 10.3% and 2.8%, respectively; and discolored feces arose in 7.7% and 0%, respectively (P<0.001 for all).

Other adverse events (occurring in 5% of patients or greater) included neutropenia, rash, fatigue, and nausea. But the rates of these events were similar between the treatment arms.

Dr Crump noted that these results are consistent with the established safety profile of enzastaurin when it’s used as a single agent in lymphoma and other cancers.

Inside the Ernest N. Morial
Convention Center, site of the
2013 ASH Annual Meeting

NEW ORLEANS—In a phase 3 study, patients with diffuse large B-cell lymphoma (DLBCL) who received post-induction therapy with enzastaurin saw no improvements in survival over patients who received placebo.

All patients were in their first remission after treatment with R-CHOP, but they were thought to have a high risk of relapse.

The patients who received 3 years of treatment with enzastaurin had similar rates of event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) as patients who received placebo.

Michael Crump, MD, of Princess Margaret Cancer Centre in Toronto, Canada, reported these results at the 2013 ASH Annual Meeting as abstract 371.

Dr Crump noted that enzastaurin is a potent and selective inhibitor of PKCβ, the major isoform expressed in normal and malignant B cells. The kinase is required for signaling through the B-cell receptor, is necessary for activation of NF-κB, and is involved in VEGF-mediated angiogenesis.   

“It was a little more than 10 years ago that Margaret Shipp and her colleagues demonstrated that overexpression of PKCβ mRNA and protein was associated with relapsed and fatal diffuse large B-cell lymphoma,” Dr Crump said.

“Since that time, other investigators have also shown that overexpression of either protein or mRNA is associated with a worse outcome in patients receiving CHOP chemotherapy as well as R-CHOP. So [PKCβ] seems to be a rational therapeutic target.” 

With this in mind, Dr Crump and his colleagues conducted the phase 3 PRELUDE trial, comparing enzastaurin to placebo in DLBCL patients.

Patient population

The researchers enrolled 866 patients who had a complete response, unconfirmed complete response, or negative FDG-PET scan following treatment with R-CHOP14 or R-CHOP21.

The team randomized 758 of the patients to receive placebo or oral enzastaurin at 500 mg once daily, with a 1125 mg loading dose on day 1. A total of 263 patients in the enzastaurin arm and 129 patients in the placebo arm completed 3 years of treatment.

The rates of discontinuation were similar between the arms—46.7% (n=230) in the enzastaurin arm and 48.2% (n=120) in the placebo arm. In both groups, the most common reason for discontinuation was disease progression (n=103 and 60, respectively). Adverse events were the second most common reason (n=72 and 28, respectively). 

Baseline characteristics were similar between the 2 groups. The median age was 64, most patients were Caucasian, most had an ECOG performance status of 0, most had stage IV disease, and more than half of the patients in each arm were PET-negative (although about 40% of patients in each arm did not have a PET scan).

Survival outcomes

The 2-year OS rate was 87% in the enzastaurin arm and 89% in the placebo arm. The 4-year OS rates were 81% and 82%, respectively. And the hazard ratio was 1.04 (P=0.807).

The 2-year EFS rate was 78% in the enzastaurin arm and 73% in the placebo arm. The 4-year EFS rates were 69% and 70%, respectively. And the hazard ratio was 0.90 (P=0.460).

The 2-year DFS rate was 79% in the enzastaurin arm and 75% in the placebo arm. The 4-year DFS rates were 70% and 71%, respectively. And the hazard ratio was 0.92 (P=0.541).

The researchers also assessed DFS according to cell of origin. And they found no difference between patients who had germinal center B-cell (GCB) DLBCL and patients who did not.

Overall, the hazard ratio for GCB vs non-GCB DLBCL was 0.92 (P=0.74). In the enzastaurin arm, the hazard ratio was 0.77 (P=0.40). And in the placebo arm, the hazard ratio was 1.31 (P=0.54).

“One would anticipate a drug that interferes with B-cell receptor signaling might have benefitted patients with tumors that are not of germinal center origin,” Dr Crump said. “Altogether, however . . ., there was actually no difference in GCB vs non-GCB, in terms of outcome.”

“Perhaps [the patients] being in a complete response is one of the reasons why we don’t actually see a difference in outcomes,” he added. “These are all patients who’ve had very good responses to their primary treatment.” 

Adverse events

Dr Crump said there were a number of adverse events that could be related to enzastaurin treatment.

Chromaturia occurred in 18.5% of patients in the enzastaurin arm and 0.4% of patients in the placebo arm (P<0.001). Prolonged QT interval was an issue in 10.8% and 3.6%, respectively; diarrhea occurred in 10.3% and 2.8%, respectively; and discolored feces arose in 7.7% and 0%, respectively (P<0.001 for all).

Other adverse events (occurring in 5% of patients or greater) included neutropenia, rash, fatigue, and nausea. But the rates of these events were similar between the treatment arms.

Dr Crump noted that these results are consistent with the established safety profile of enzastaurin when it’s used as a single agent in lymphoma and other cancers.

Red blood cell culture showing
Staphylococcus infection
Credit: Bill Branson

Researchers have identified a receptor that may be instrumental in the body’s response to sepsis. And they believe this discovery could be the key to unlocking new treatments for the disease.

The nociceptin receptor activates the chemical nociceptin. Previous research revealed that nociceptin is involved in inflammation; it is known to affect white blood cell function.

This suggests nociceptin has an important role in the body’s response to inflammation and sepsis, according to David Lambert, PhD, of the University of Leicester in the UK, and his colleagues.

The group’s theory, which they have explored in 2 papers published in PLOS ONE, is that nociceptin makes inflammation or sepsis worse. And by blocking the nociceptin system, the symptoms of sepsis could be reduced, which could lead to new treatments.

“We have found that nociceptin, a chemical similar to endorphins produced in the body, is increased in inflammation and sepsis,” said study author Jonathan Thompson, MD, MB ChB, also of the University of Leicester.

“This suggests that drugs which block the nociceptin receptor could dampen the widespread inflammation that occurs in sepsis, and improve outcome. More work is needed, but these drugs are being developed. If they are effective, then we could potentially save many lives.”

In their first paper, the researchers described how they used fluorescent chemistry to find nociceptin receptors on blood vessels with no nerve supply. The team also showed, in a lab model of sepsis, that blocking these receptors has a protective effect.

In the second paper, the researchers recounted their discovery that bloodstream nociceptin levels are elevated in sepsis patients in intensive care. This suggests nociceptin activation might be important in critically ill patients suffering from sepsis.

Dr Lambert and his colleagues noted that sepsis remains a leading cause of admission to intensive care units, with high mortality, costs, and long-term morbidity in those who survive. The incidence of severe sepsis has increased in the last decade, making the discovery of new treatments highly desirable.

“Sepsis is a major health problem . . . that has often been under-recognized,” Dr Thompson said. “It can be rapidly fatal, especially if not diagnosed and treated early, because inflammation can spread and affect many different organs in the body.”

Dr Lambert added, “I am particularly excited by these findings, as they translate many years of laboratory work into a possible target for this disease.”

Red blood cell culture showing
Staphylococcus infection
Credit: Bill Branson

Researchers have identified a receptor that may be instrumental in the body’s response to sepsis. And they believe this discovery could be the key to unlocking new treatments for the disease.

The nociceptin receptor activates the chemical nociceptin. Previous research revealed that nociceptin is involved in inflammation; it is known to affect white blood cell function.

This suggests nociceptin has an important role in the body’s response to inflammation and sepsis, according to David Lambert, PhD, of the University of Leicester in the UK, and his colleagues.

The group’s theory, which they have explored in 2 papers published in PLOS ONE, is that nociceptin makes inflammation or sepsis worse. And by blocking the nociceptin system, the symptoms of sepsis could be reduced, which could lead to new treatments.

“We have found that nociceptin, a chemical similar to endorphins produced in the body, is increased in inflammation and sepsis,” said study author Jonathan Thompson, MD, MB ChB, also of the University of Leicester.

“This suggests that drugs which block the nociceptin receptor could dampen the widespread inflammation that occurs in sepsis, and improve outcome. More work is needed, but these drugs are being developed. If they are effective, then we could potentially save many lives.”

In their first paper, the researchers described how they used fluorescent chemistry to find nociceptin receptors on blood vessels with no nerve supply. The team also showed, in a lab model of sepsis, that blocking these receptors has a protective effect.

In the second paper, the researchers recounted their discovery that bloodstream nociceptin levels are elevated in sepsis patients in intensive care. This suggests nociceptin activation might be important in critically ill patients suffering from sepsis.

Dr Lambert and his colleagues noted that sepsis remains a leading cause of admission to intensive care units, with high mortality, costs, and long-term morbidity in those who survive. The incidence of severe sepsis has increased in the last decade, making the discovery of new treatments highly desirable.

“Sepsis is a major health problem . . . that has often been under-recognized,” Dr Thompson said. “It can be rapidly fatal, especially if not diagnosed and treated early, because inflammation can spread and affect many different organs in the body.”

Dr Lambert added, “I am particularly excited by these findings, as they translate many years of laboratory work into a possible target for this disease.”

Red blood cell culture showing
Staphylococcus infection
Credit: Bill Branson

Researchers have identified a receptor that may be instrumental in the body’s response to sepsis. And they believe this discovery could be the key to unlocking new treatments for the disease.

The nociceptin receptor activates the chemical nociceptin. Previous research revealed that nociceptin is involved in inflammation; it is known to affect white blood cell function.

This suggests nociceptin has an important role in the body’s response to inflammation and sepsis, according to David Lambert, PhD, of the University of Leicester in the UK, and his colleagues.

The group’s theory, which they have explored in 2 papers published in PLOS ONE, is that nociceptin makes inflammation or sepsis worse. And by blocking the nociceptin system, the symptoms of sepsis could be reduced, which could lead to new treatments.

“We have found that nociceptin, a chemical similar to endorphins produced in the body, is increased in inflammation and sepsis,” said study author Jonathan Thompson, MD, MB ChB, also of the University of Leicester.

“This suggests that drugs which block the nociceptin receptor could dampen the widespread inflammation that occurs in sepsis, and improve outcome. More work is needed, but these drugs are being developed. If they are effective, then we could potentially save many lives.”

In their first paper, the researchers described how they used fluorescent chemistry to find nociceptin receptors on blood vessels with no nerve supply. The team also showed, in a lab model of sepsis, that blocking these receptors has a protective effect.

In the second paper, the researchers recounted their discovery that bloodstream nociceptin levels are elevated in sepsis patients in intensive care. This suggests nociceptin activation might be important in critically ill patients suffering from sepsis.

Dr Lambert and his colleagues noted that sepsis remains a leading cause of admission to intensive care units, with high mortality, costs, and long-term morbidity in those who survive. The incidence of severe sepsis has increased in the last decade, making the discovery of new treatments highly desirable.

“Sepsis is a major health problem . . . that has often been under-recognized,” Dr Thompson said. “It can be rapidly fatal, especially if not diagnosed and treated early, because inflammation can spread and affect many different organs in the body.”

Dr Lambert added, “I am particularly excited by these findings, as they translate many years of laboratory work into a possible target for this disease.”

Red blood cells positive
for Staphylococcus infection
Credit: Bill Branson

A new technique could cut hours off the time it takes to diagnose blood infections, according to a report  published in mBio.

The

method combines a selective lysis step in which blood cells are destroyed, a centrifugation step to collect any bacteria or

fungi, and a fluorescence step that reveals the “fingerprint” of any

pathogens present in the blood sample.

In tests, this method identified

the species of bacteria or fungi in 96.5% of positive blood culture

samples.

“The primary benefit of getting a rapid identification is making sure the patient is on the right [antibiotic] therapy and to quickly make any needed adjustments to the initial therapy,” said study author John Walsh, of bioMérieux, Inc. in Durham, North Carolina.

Walsh added that the current standard approach to diagnosing bloodstream infections—Gram staining and overnight sub-culture followed by phenotypic ID tests—has limitations that can prevent timely treatment.

Gram staining provides early, low-level information about the type of microorganism present, but it sometimes takes hours to deliver a result, and technicians can make mistakes in the process that provide misleading results.

Other, more specific identification methods are also available for diagnosis, but they can take at least a day or two to produce results, and many require expensive equipment.

So Walsh and his colleagues developed a new technique. With this method, a sample of positive blood culture is treated with lysis buffer, to “pop” the blood cells, then transferred to a specialized optical tube.

Next, the tube is centrifuged, which drives bacteria or fungi down through a liquid density cushion to form a pellet at the bottom of the tube.

Then comes the intrinsic fluorescence spectroscopy. The microbial pellet is irradiated with light ranging from the deep ultraviolet to infrared. This excites certain organic molecules in the microorganisms—tryptophan, NADH, FAD, porphyrins, and others—and causes them to fluoresce in a characteristic way depending on the identity of the microbe.

The exact pattern of fluorescence is then compared with a database of 37 common pathogens to identify the organism present.

“We’re using intrinsic fluorescence to identify the microorganisms,” Walsh noted. “It’s an innate property of most living organisms. Because it’s intrinsic, no reagents are needed for the identification step.”

This removes many of the opportunities for mistakes and lowers test costs, he added.

In tests, this method correctly identified the species in 96.5% of all samples. In the 2.7% of samples for which no species identity was provided, the system was able to correctly identify 67% to the family level, which is often enough information to select an effective therapy.

More than 1000 samples were tested, and the method never gave an incorrect result as to the family level or the Gram type.

Walsh and his colleagues are now working on automating this system with robotics to make it a fully hands-off process. He noted that blood cultures grow in their own time, often producing a positive result at an inconvenient time of the day for clinical labs, so automation could speed up diagnosis significantly.

“Our vision is to have a system that will automatically identify the blood culture isolate within 15 minutes of the culture being called positive,” Walsh said.

If a culture is positive at 2 am, automating this method could make it possible to identify the organism by 2:15 am and send an electronic report to a patient’s physician.

The researchers hope to begin testing and evaluating the feasibility of an automated form of the system in a clinical environment within months.

Red blood cells positive
for Staphylococcus infection
Credit: Bill Branson

A new technique could cut hours off the time it takes to diagnose blood infections, according to a report  published in mBio.

The

method combines a selective lysis step in which blood cells are destroyed, a centrifugation step to collect any bacteria or

fungi, and a fluorescence step that reveals the “fingerprint” of any

pathogens present in the blood sample.

In tests, this method identified

the species of bacteria or fungi in 96.5% of positive blood culture

samples.

“The primary benefit of getting a rapid identification is making sure the patient is on the right [antibiotic] therapy and to quickly make any needed adjustments to the initial therapy,” said study author John Walsh, of bioMérieux, Inc. in Durham, North Carolina.

Walsh added that the current standard approach to diagnosing bloodstream infections—Gram staining and overnight sub-culture followed by phenotypic ID tests—has limitations that can prevent timely treatment.

Gram staining provides early, low-level information about the type of microorganism present, but it sometimes takes hours to deliver a result, and technicians can make mistakes in the process that provide misleading results.

Other, more specific identification methods are also available for diagnosis, but they can take at least a day or two to produce results, and many require expensive equipment.

So Walsh and his colleagues developed a new technique. With this method, a sample of positive blood culture is treated with lysis buffer, to “pop” the blood cells, then transferred to a specialized optical tube.

Next, the tube is centrifuged, which drives bacteria or fungi down through a liquid density cushion to form a pellet at the bottom of the tube.

Then comes the intrinsic fluorescence spectroscopy. The microbial pellet is irradiated with light ranging from the deep ultraviolet to infrared. This excites certain organic molecules in the microorganisms—tryptophan, NADH, FAD, porphyrins, and others—and causes them to fluoresce in a characteristic way depending on the identity of the microbe.

The exact pattern of fluorescence is then compared with a database of 37 common pathogens to identify the organism present.

“We’re using intrinsic fluorescence to identify the microorganisms,” Walsh noted. “It’s an innate property of most living organisms. Because it’s intrinsic, no reagents are needed for the identification step.”

This removes many of the opportunities for mistakes and lowers test costs, he added.

In tests, this method correctly identified the species in 96.5% of all samples. In the 2.7% of samples for which no species identity was provided, the system was able to correctly identify 67% to the family level, which is often enough information to select an effective therapy.

More than 1000 samples were tested, and the method never gave an incorrect result as to the family level or the Gram type.

Walsh and his colleagues are now working on automating this system with robotics to make it a fully hands-off process. He noted that blood cultures grow in their own time, often producing a positive result at an inconvenient time of the day for clinical labs, so automation could speed up diagnosis significantly.

“Our vision is to have a system that will automatically identify the blood culture isolate within 15 minutes of the culture being called positive,” Walsh said.

If a culture is positive at 2 am, automating this method could make it possible to identify the organism by 2:15 am and send an electronic report to a patient’s physician.

The researchers hope to begin testing and evaluating the feasibility of an automated form of the system in a clinical environment within months.

Red blood cells positive
for Staphylococcus infection
Credit: Bill Branson

A new technique could cut hours off the time it takes to diagnose blood infections, according to a report  published in mBio.

The

method combines a selective lysis step in which blood cells are destroyed, a centrifugation step to collect any bacteria or

fungi, and a fluorescence step that reveals the “fingerprint” of any

pathogens present in the blood sample.

In tests, this method identified

the species of bacteria or fungi in 96.5% of positive blood culture

samples.

“The primary benefit of getting a rapid identification is making sure the patient is on the right [antibiotic] therapy and to quickly make any needed adjustments to the initial therapy,” said study author John Walsh, of bioMérieux, Inc. in Durham, North Carolina.

Walsh added that the current standard approach to diagnosing bloodstream infections—Gram staining and overnight sub-culture followed by phenotypic ID tests—has limitations that can prevent timely treatment.

Gram staining provides early, low-level information about the type of microorganism present, but it sometimes takes hours to deliver a result, and technicians can make mistakes in the process that provide misleading results.

Other, more specific identification methods are also available for diagnosis, but they can take at least a day or two to produce results, and many require expensive equipment.

So Walsh and his colleagues developed a new technique. With this method, a sample of positive blood culture is treated with lysis buffer, to “pop” the blood cells, then transferred to a specialized optical tube.

Next, the tube is centrifuged, which drives bacteria or fungi down through a liquid density cushion to form a pellet at the bottom of the tube.

Then comes the intrinsic fluorescence spectroscopy. The microbial pellet is irradiated with light ranging from the deep ultraviolet to infrared. This excites certain organic molecules in the microorganisms—tryptophan, NADH, FAD, porphyrins, and others—and causes them to fluoresce in a characteristic way depending on the identity of the microbe.

The exact pattern of fluorescence is then compared with a database of 37 common pathogens to identify the organism present.

“We’re using intrinsic fluorescence to identify the microorganisms,” Walsh noted. “It’s an innate property of most living organisms. Because it’s intrinsic, no reagents are needed for the identification step.”

This removes many of the opportunities for mistakes and lowers test costs, he added.

In tests, this method correctly identified the species in 96.5% of all samples. In the 2.7% of samples for which no species identity was provided, the system was able to correctly identify 67% to the family level, which is often enough information to select an effective therapy.

More than 1000 samples were tested, and the method never gave an incorrect result as to the family level or the Gram type.

Walsh and his colleagues are now working on automating this system with robotics to make it a fully hands-off process. He noted that blood cultures grow in their own time, often producing a positive result at an inconvenient time of the day for clinical labs, so automation could speed up diagnosis significantly.

“Our vision is to have a system that will automatically identify the blood culture isolate within 15 minutes of the culture being called positive,” Walsh said.

If a culture is positive at 2 am, automating this method could make it possible to identify the organism by 2:15 am and send an electronic report to a patient’s physician.

The researchers hope to begin testing and evaluating the feasibility of an automated form of the system in a clinical environment within months.

Sleeping newborn
Photo by Bertrand Devouard

The Centers for Disease Control and Prevention (CDC) has identified a

small group of newborns in Tennessee with late vitamin K deficiency

bleeding (VKDB).

The agency reported 4 cases of late VKDB, a

serious but preventable bleeding disorder that can cause intracranial

hemorrhage, neurological deficits, and death.

In each case, the newborn’s parents

declined a vitamin K injection at birth, mainly because they were

uninformed about the risk of late VKBD.

Preliminary findings of the CDC’s investigation, in collaboration with the Tennessee Department of Health, appear in the current issue of the Morbidity and Mortality Weekly Report.

“Not giving vitamin K at birth is an emerging trend that can have devastating outcomes for infants and their families,” said CDC Director Tom Frieden, MD. “Ensuring that every newborn receives a vitamin K injection at birth is critical to protect infants.”

Between February and September of this year, 4 cases of late VKDB were diagnosed at a hospital in Nashville, Tennessee.

Three of the infants experienced intracranial hemorrhage, and the fourth had gastrointestinal bleeding. None of the patients had received a vitamin K injection at birth.

Fortunately, all of the infants survived. The patient with gastrointestinal bleeding has made a full recovery. And the 3 infants with intracranial hemorrhage are being followed by neurologists.

One patient has an apparent gross motor deficit, but it seems the others do not. However, all of the patients are still less than 1 year of age, so the full impact of VKDB might only become apparent with time.

The infants’ parents said they declined vitamin K prophylaxis for a number of reasons, including concern about an increased risk of leukemia, the belief that the injection was unnecessary, and a desire to minimize the newborn’s exposure to “toxins.”

Concern about the increased risk of leukemia associated with vitamin K prophylaxis was initially generated by a report published in 1992, but the finding has not been replicated in subsequent studies.

In all cases, parents were uninformed or insufficiently informed about the risk of late VKDB. Most parents only learned about the possibility of late VKDB after their infants developed the condition.

These findings illustrate the importance of educating parents about vitamin K prophylaxis, said Lauren Marcewicz, MD, of the CDC’s National Center on Birth Defects and Developmental Disabilities. 

A vitamin K injection at birth has been standard practice in the US since it was first recommended as prophylaxis for late VKDB by the American Academy of Pediatrics in 1961.

The late form of VKDB can develop in infants 2 weeks to 6 months of age who did not receive a vitamin K injection and do not have enough vitamin K-dependent proteins in their bodies to allow normal blood clotting. If untreated, this can cause intracranial hemorrhage, which may lead to neurological problems and can be fatal.

The risk for developing late VKDB has been estimated at 81 times greater among infants who do not receive a vitamin K injection at birth than in infants who do receive it.

The CDC said it is currently working with the Tennessee Department of Health to determine if other cases of late VKDB occurred in the state in recent years.

In addition, a case-control study is underway to assess whether any additional risk factors might contribute to the development of late VKDB in children who do not receive vitamin K prophylaxis.

Sleeping newborn
Photo by Bertrand Devouard

The Centers for Disease Control and Prevention (CDC) has identified a

small group of newborns in Tennessee with late vitamin K deficiency

bleeding (VKDB).

The agency reported 4 cases of late VKDB, a

serious but preventable bleeding disorder that can cause intracranial

hemorrhage, neurological deficits, and death.

In each case, the newborn’s parents

declined a vitamin K injection at birth, mainly because they were

uninformed about the risk of late VKBD.

Preliminary findings of the CDC’s investigation, in collaboration with the Tennessee Department of Health, appear in the current issue of the Morbidity and Mortality Weekly Report.

“Not giving vitamin K at birth is an emerging trend that can have devastating outcomes for infants and their families,” said CDC Director Tom Frieden, MD. “Ensuring that every newborn receives a vitamin K injection at birth is critical to protect infants.”

Between February and September of this year, 4 cases of late VKDB were diagnosed at a hospital in Nashville, Tennessee.

Three of the infants experienced intracranial hemorrhage, and the fourth had gastrointestinal bleeding. None of the patients had received a vitamin K injection at birth.

Fortunately, all of the infants survived. The patient with gastrointestinal bleeding has made a full recovery. And the 3 infants with intracranial hemorrhage are being followed by neurologists.

One patient has an apparent gross motor deficit, but it seems the others do not. However, all of the patients are still less than 1 year of age, so the full impact of VKDB might only become apparent with time.

The infants’ parents said they declined vitamin K prophylaxis for a number of reasons, including concern about an increased risk of leukemia, the belief that the injection was unnecessary, and a desire to minimize the newborn’s exposure to “toxins.”

Concern about the increased risk of leukemia associated with vitamin K prophylaxis was initially generated by a report published in 1992, but the finding has not been replicated in subsequent studies.

In all cases, parents were uninformed or insufficiently informed about the risk of late VKDB. Most parents only learned about the possibility of late VKDB after their infants developed the condition.

These findings illustrate the importance of educating parents about vitamin K prophylaxis, said Lauren Marcewicz, MD, of the CDC’s National Center on Birth Defects and Developmental Disabilities. 

A vitamin K injection at birth has been standard practice in the US since it was first recommended as prophylaxis for late VKDB by the American Academy of Pediatrics in 1961.

The late form of VKDB can develop in infants 2 weeks to 6 months of age who did not receive a vitamin K injection and do not have enough vitamin K-dependent proteins in their bodies to allow normal blood clotting. If untreated, this can cause intracranial hemorrhage, which may lead to neurological problems and can be fatal.

The risk for developing late VKDB has been estimated at 81 times greater among infants who do not receive a vitamin K injection at birth than in infants who do receive it.

The CDC said it is currently working with the Tennessee Department of Health to determine if other cases of late VKDB occurred in the state in recent years.

In addition, a case-control study is underway to assess whether any additional risk factors might contribute to the development of late VKDB in children who do not receive vitamin K prophylaxis.

Sleeping newborn
Photo by Bertrand Devouard

The Centers for Disease Control and Prevention (CDC) has identified a

small group of newborns in Tennessee with late vitamin K deficiency

bleeding (VKDB).

The agency reported 4 cases of late VKDB, a

serious but preventable bleeding disorder that can cause intracranial

hemorrhage, neurological deficits, and death.

In each case, the newborn’s parents

declined a vitamin K injection at birth, mainly because they were

uninformed about the risk of late VKBD.

Preliminary findings of the CDC’s investigation, in collaboration with the Tennessee Department of Health, appear in the current issue of the Morbidity and Mortality Weekly Report.

“Not giving vitamin K at birth is an emerging trend that can have devastating outcomes for infants and their families,” said CDC Director Tom Frieden, MD. “Ensuring that every newborn receives a vitamin K injection at birth is critical to protect infants.”

Between February and September of this year, 4 cases of late VKDB were diagnosed at a hospital in Nashville, Tennessee.

Three of the infants experienced intracranial hemorrhage, and the fourth had gastrointestinal bleeding. None of the patients had received a vitamin K injection at birth.

Fortunately, all of the infants survived. The patient with gastrointestinal bleeding has made a full recovery. And the 3 infants with intracranial hemorrhage are being followed by neurologists.

One patient has an apparent gross motor deficit, but it seems the others do not. However, all of the patients are still less than 1 year of age, so the full impact of VKDB might only become apparent with time.

The infants’ parents said they declined vitamin K prophylaxis for a number of reasons, including concern about an increased risk of leukemia, the belief that the injection was unnecessary, and a desire to minimize the newborn’s exposure to “toxins.”

Concern about the increased risk of leukemia associated with vitamin K prophylaxis was initially generated by a report published in 1992, but the finding has not been replicated in subsequent studies.

In all cases, parents were uninformed or insufficiently informed about the risk of late VKDB. Most parents only learned about the possibility of late VKDB after their infants developed the condition.

These findings illustrate the importance of educating parents about vitamin K prophylaxis, said Lauren Marcewicz, MD, of the CDC’s National Center on Birth Defects and Developmental Disabilities. 

A vitamin K injection at birth has been standard practice in the US since it was first recommended as prophylaxis for late VKDB by the American Academy of Pediatrics in 1961.

The late form of VKDB can develop in infants 2 weeks to 6 months of age who did not receive a vitamin K injection and do not have enough vitamin K-dependent proteins in their bodies to allow normal blood clotting. If untreated, this can cause intracranial hemorrhage, which may lead to neurological problems and can be fatal.

The risk for developing late VKDB has been estimated at 81 times greater among infants who do not receive a vitamin K injection at birth than in infants who do receive it.

The CDC said it is currently working with the Tennessee Department of Health to determine if other cases of late VKDB occurred in the state in recent years.

In addition, a case-control study is underway to assess whether any additional risk factors might contribute to the development of late VKDB in children who do not receive vitamin K prophylaxis.

Results of a phase 3 trial suggest a recombinant factor VIII Fc fusion protein (rFVIIIFc/efmoroctocog alfa, Eloctate/Elocta) can be used to prevent or reduce bleeding episodes in patients with severe hemophilia A.

Researchers found that prophylaxis with rFVIIIFc resulted in low annualized bleeding rates, and patients did not develop neutralizing antibodies.

Furthermore, the product was generally well-tolerated and had a prolonged half-life when compared with recombinant factor VIII.

Data from this study, called A-LONG, have been published in Blood.

Researchers tested rFVIIIFc in 165 male patients with severe hemophilia A who were 12 years of age and older.

Patients were divided into 3 treatment arms. Arm 1 received individualized prophylaxis, or 25 to 65 IU/kg every 3 to 5 days (n=118). Patients in arm 2 received a weekly prophylactic dose of 65 IU/kg (n=24). And patients in arm 3 received episodic treatment at doses of 10 to 50 IU/kg (n=23).

A total of 153 patients completed the study, and 757 bleeding episodes were treated with rFVIIIFc. Across the treatment arms, 87.3% of bleeding episodes were resolved with 1 injection of rFVIIIFc.

The annualized bleeding rate was significantly reduced with prophylaxis—by 92% for patients in arm 1 and 76% for those in arm 2—when compared with episodic treatment.

This was based on annualized bleeding rate estimates from a negative binomial regression model—2.91 for arm 1, 8.92 for arm 2, and 37.25 for arm 3.

The median annualized bleeding rates were 1.6 in arm 1, 3.6 in arm 2, and 33.6 in arm 3.

In arm 3, there were 9 patients who received rFVIIIFc to control bleeding during major surgery. In these cases, physicians rated the hemostatic response as “excellent” (n=8) or “good” (n=1).

There were no serious adverse events related to rFVIIIFc, and none of the patients developed neutralizing antibodies.

The most common adverse events (with an incidence of 5% or more) that occurred outside the perioperative period included nasopharyngitis, arthralgia, headache, and upper respiratory infection.

The researchers also compared the pharmacokinetics of rFVIIIFc and recombinant factor VIII. And they found the terminal half-life of rFVIIIFc was extended 1.5-fold compared to recombinant factor VIII—19.0 hours and 12.4 hours, respectively.

rFVIIIFc was developed using Fc fusion technology, which takes advantage of a naturally occurring pathway that delays the breakdown of IgG1 protein in the body by recycling it back into the bloodstream. This technology prolongs the time rFVIIIFc circulates in the body.

“There is an unmet medical need in the hemophilia community for longer intervals between prophylactic infusions while maintaining good control of bleeding episodes,” said study author Johnny Mahlangu, MD, director of the Haemophilia Comprehensive Care Centre at the University of the Witwatersrand and National Health Laboratory Service in Johannesburg, South Africa.

“A-LONG is the first clinical study to show that effective control over breakthrough bleeding may be achieved with once- or twice-weekly prophylactic infusions in people with severe hemophilia A.”

This study was funded by Biogen Idec, makers of rFVIIIFc.

Results of a phase 3 trial suggest a recombinant factor VIII Fc fusion protein (rFVIIIFc/efmoroctocog alfa, Eloctate/Elocta) can be used to prevent or reduce bleeding episodes in patients with severe hemophilia A.

Researchers found that prophylaxis with rFVIIIFc resulted in low annualized bleeding rates, and patients did not develop neutralizing antibodies.

Furthermore, the product was generally well-tolerated and had a prolonged half-life when compared with recombinant factor VIII.

Data from this study, called A-LONG, have been published in Blood.

Researchers tested rFVIIIFc in 165 male patients with severe hemophilia A who were 12 years of age and older.

Patients were divided into 3 treatment arms. Arm 1 received individualized prophylaxis, or 25 to 65 IU/kg every 3 to 5 days (n=118). Patients in arm 2 received a weekly prophylactic dose of 65 IU/kg (n=24). And patients in arm 3 received episodic treatment at doses of 10 to 50 IU/kg (n=23).

A total of 153 patients completed the study, and 757 bleeding episodes were treated with rFVIIIFc. Across the treatment arms, 87.3% of bleeding episodes were resolved with 1 injection of rFVIIIFc.

The annualized bleeding rate was significantly reduced with prophylaxis—by 92% for patients in arm 1 and 76% for those in arm 2—when compared with episodic treatment.

This was based on annualized bleeding rate estimates from a negative binomial regression model—2.91 for arm 1, 8.92 for arm 2, and 37.25 for arm 3.

The median annualized bleeding rates were 1.6 in arm 1, 3.6 in arm 2, and 33.6 in arm 3.

In arm 3, there were 9 patients who received rFVIIIFc to control bleeding during major surgery. In these cases, physicians rated the hemostatic response as “excellent” (n=8) or “good” (n=1).

There were no serious adverse events related to rFVIIIFc, and none of the patients developed neutralizing antibodies.

The most common adverse events (with an incidence of 5% or more) that occurred outside the perioperative period included nasopharyngitis, arthralgia, headache, and upper respiratory infection.

The researchers also compared the pharmacokinetics of rFVIIIFc and recombinant factor VIII. And they found the terminal half-life of rFVIIIFc was extended 1.5-fold compared to recombinant factor VIII—19.0 hours and 12.4 hours, respectively.

rFVIIIFc was developed using Fc fusion technology, which takes advantage of a naturally occurring pathway that delays the breakdown of IgG1 protein in the body by recycling it back into the bloodstream. This technology prolongs the time rFVIIIFc circulates in the body.

“There is an unmet medical need in the hemophilia community for longer intervals between prophylactic infusions while maintaining good control of bleeding episodes,” said study author Johnny Mahlangu, MD, director of the Haemophilia Comprehensive Care Centre at the University of the Witwatersrand and National Health Laboratory Service in Johannesburg, South Africa.

“A-LONG is the first clinical study to show that effective control over breakthrough bleeding may be achieved with once- or twice-weekly prophylactic infusions in people with severe hemophilia A.”

This study was funded by Biogen Idec, makers of rFVIIIFc.

Results of a phase 3 trial suggest a recombinant factor VIII Fc fusion protein (rFVIIIFc/efmoroctocog alfa, Eloctate/Elocta) can be used to prevent or reduce bleeding episodes in patients with severe hemophilia A.

Researchers found that prophylaxis with rFVIIIFc resulted in low annualized bleeding rates, and patients did not develop neutralizing antibodies.

Furthermore, the product was generally well-tolerated and had a prolonged half-life when compared with recombinant factor VIII.

Data from this study, called A-LONG, have been published in Blood.

Researchers tested rFVIIIFc in 165 male patients with severe hemophilia A who were 12 years of age and older.

Patients were divided into 3 treatment arms. Arm 1 received individualized prophylaxis, or 25 to 65 IU/kg every 3 to 5 days (n=118). Patients in arm 2 received a weekly prophylactic dose of 65 IU/kg (n=24). And patients in arm 3 received episodic treatment at doses of 10 to 50 IU/kg (n=23).

A total of 153 patients completed the study, and 757 bleeding episodes were treated with rFVIIIFc. Across the treatment arms, 87.3% of bleeding episodes were resolved with 1 injection of rFVIIIFc.

The annualized bleeding rate was significantly reduced with prophylaxis—by 92% for patients in arm 1 and 76% for those in arm 2—when compared with episodic treatment.

This was based on annualized bleeding rate estimates from a negative binomial regression model—2.91 for arm 1, 8.92 for arm 2, and 37.25 for arm 3.

The median annualized bleeding rates were 1.6 in arm 1, 3.6 in arm 2, and 33.6 in arm 3.

In arm 3, there were 9 patients who received rFVIIIFc to control bleeding during major surgery. In these cases, physicians rated the hemostatic response as “excellent” (n=8) or “good” (n=1).

There were no serious adverse events related to rFVIIIFc, and none of the patients developed neutralizing antibodies.

The most common adverse events (with an incidence of 5% or more) that occurred outside the perioperative period included nasopharyngitis, arthralgia, headache, and upper respiratory infection.

The researchers also compared the pharmacokinetics of rFVIIIFc and recombinant factor VIII. And they found the terminal half-life of rFVIIIFc was extended 1.5-fold compared to recombinant factor VIII—19.0 hours and 12.4 hours, respectively.

rFVIIIFc was developed using Fc fusion technology, which takes advantage of a naturally occurring pathway that delays the breakdown of IgG1 protein in the body by recycling it back into the bloodstream. This technology prolongs the time rFVIIIFc circulates in the body.

“There is an unmet medical need in the hemophilia community for longer intervals between prophylactic infusions while maintaining good control of bleeding episodes,” said study author Johnny Mahlangu, MD, director of the Haemophilia Comprehensive Care Centre at the University of the Witwatersrand and National Health Laboratory Service in Johannesburg, South Africa.

“A-LONG is the first clinical study to show that effective control over breakthrough bleeding may be achieved with once- or twice-weekly prophylactic infusions in people with severe hemophilia A.”

This study was funded by Biogen Idec, makers of rFVIIIFc.

Micrograph showing MCL

The US Food and Drug Administration (FDA) has has granted accelerated approval for

ibrutinib (Imbruvica) to treat patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.

Ibrutinib works by inhibiting the function of Bruton’s tyrosine kinase, a molecule that plays an important role in the survival of malignant B cells.

The drug showed promising results in the phase 2 PCYC-1104 trial, which was presented at ASH 2012 and published in NEJM in August.

The FDA granted ibrutinib breakthrough therapy designation because of these results and the life-threatening nature of MCL. Ibrutinib is the second drug with breakthrough therapy designation to receive FDA approval.

The FDA granted ibrutinib accelerated approval, rather than traditional approval, because the drug has not yet shown a clinical benefit. Accelerated approval of a drug is based

on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to

predict clinical benefit.

PCYC-1104 trial

The data published in NEJM 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.

The “Warnings and Precautions” section of ibrutinib’s prescribing information notes that patients taking ibrutinib have experienced hemorrhage, fatal and non-fatal infections, myelosuppression, renal toxicity, second primary malignancies, and embryo-fetal toxicity.

For the full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Ibrutinib is now commercially available. It is co-marketed by Pharmacyclics (based in Sunnyvale, California) and Janssen Biotech, Inc. (based in Raritan, New Jersey).

Micrograph showing MCL

The US Food and Drug Administration (FDA) has has granted accelerated approval for

ibrutinib (Imbruvica) to treat patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.

Ibrutinib works by inhibiting the function of Bruton’s tyrosine kinase, a molecule that plays an important role in the survival of malignant B cells.

The drug showed promising results in the phase 2 PCYC-1104 trial, which was presented at ASH 2012 and published in NEJM in August.

The FDA granted ibrutinib breakthrough therapy designation because of these results and the life-threatening nature of MCL. Ibrutinib is the second drug with breakthrough therapy designation to receive FDA approval.

The FDA granted ibrutinib accelerated approval, rather than traditional approval, because the drug has not yet shown a clinical benefit. Accelerated approval of a drug is based

on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to

predict clinical benefit.

PCYC-1104 trial

The data published in NEJM 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.

The “Warnings and Precautions” section of ibrutinib’s prescribing information notes that patients taking ibrutinib have experienced hemorrhage, fatal and non-fatal infections, myelosuppression, renal toxicity, second primary malignancies, and embryo-fetal toxicity.

For the full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Ibrutinib is now commercially available. It is co-marketed by Pharmacyclics (based in Sunnyvale, California) and Janssen Biotech, Inc. (based in Raritan, New Jersey).

Micrograph showing MCL

The US Food and Drug Administration (FDA) has has granted accelerated approval for

ibrutinib (Imbruvica) to treat patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.

Ibrutinib works by inhibiting the function of Bruton’s tyrosine kinase, a molecule that plays an important role in the survival of malignant B cells.

The drug showed promising results in the phase 2 PCYC-1104 trial, which was presented at ASH 2012 and published in NEJM in August.

The FDA granted ibrutinib breakthrough therapy designation because of these results and the life-threatening nature of MCL. Ibrutinib is the second drug with breakthrough therapy designation to receive FDA approval.

The FDA granted ibrutinib accelerated approval, rather than traditional approval, because the drug has not yet shown a clinical benefit. Accelerated approval of a drug is based

on a surrogate or intermediate endpoint—in this case, overall response rate—that is reasonably likely to

predict clinical benefit.

PCYC-1104 trial

The data published in NEJM 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.

The “Warnings and Precautions” section of ibrutinib’s prescribing information notes that patients taking ibrutinib have experienced hemorrhage, fatal and non-fatal infections, myelosuppression, renal toxicity, second primary malignancies, and embryo-fetal toxicity.

For the full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Ibrutinib is now commercially available. It is co-marketed by Pharmacyclics (based in Sunnyvale, California) and Janssen Biotech, Inc. (based in Raritan, New Jersey).