Pharmacy

Vials and a syringe

The US Food and Drug Administration (FDA) has approved a factor X product derived from human plasma (Coagadex) to treat patients with hereditary factor X deficiency who are 12 years of age and older.

Coagadex is approved for on-demand treatment and control of bleeding episodes in these patients as well as for perioperative management of bleeding in patients with mild hereditary factor X deficiency.

Prior to this approval, there was no specific coagulation factor replacement therapy available for patients with hereditary factor X deficiency in the US. The FDA previously granted Coagadex orphan product designation, fast track designation, and priority review.

The FDA based its approval of Coagadex on results from 2 phase 3 trials of patients age 12 and older.

The first trial included 16 patients who received Coagadex for pharmacokinetic evaluation, on-demand treatment and control of bleeding episodes, and/or perioperative management of minor surgical or dental procedures.

Coagadex was used to treat 208 bleeding episodes, and 187 of these episodes (in 15 patients) were evaluated for efficacy. Ninety-eight episodes were major bleeds, 88 were minor bleeds, and 1 was not assessed.

One hundred and fifty-five bleeds (83%) were treated with a single infusion of Coagadex, 28 (15%) were treated with 2 infusions, 3 bleeds (2%) required 3 infusions, and 1 bleed (0.5%) required 4 infusions. Four bleeding episodes in 2 patients were considered treatment failures.

The mean dose of Coagadex per infusion was 25.4 IU/kg, and the mean total dose was 30.4 IU/kg. The recommended dose of 25 IU/kg to treat a bleed was maintained for 14 of the 16 patients. The other 2 patients used doses of up to 30 IU/kg and 33 IU/kg.

There were 176 adverse events in this trial, but only 6 events in 2 patients were considered possibly related to Coagadex. This included 2 reports of infusion site erythema in 1 patient, 2 reports of fatigue in 1 patient, 1 report of back pain, and 1 report of infusion site pain.

The second trial included patients who received Coagadex for perioperative management. Five patients received Coagadex for 7 surgical procedures.

For major surgeries, a median of 13 infusions (range, 2-15) and a median cumulative dose of 181 IU/kg (range, 45-210 IU/kg) were required to maintain hemostasis. For minor surgeries, a median of 2.5 infusions (range, 1-4) and a median cumulative dose of 89 IU/kg (range, 51-127 IU/kg) were required to maintain hemostasis.

There were no adverse events related to Coagadex in this trial.

For more details on these trials, see the Coagadex package insert. Coagadex is manufactured by Bio Products Laboratory Limited in Elstree, Hertfordshire, UK.

Vials and a syringe

The US Food and Drug Administration (FDA) has approved a factor X product derived from human plasma (Coagadex) to treat patients with hereditary factor X deficiency who are 12 years of age and older.

Coagadex is approved for on-demand treatment and control of bleeding episodes in these patients as well as for perioperative management of bleeding in patients with mild hereditary factor X deficiency.

Prior to this approval, there was no specific coagulation factor replacement therapy available for patients with hereditary factor X deficiency in the US. The FDA previously granted Coagadex orphan product designation, fast track designation, and priority review.

The FDA based its approval of Coagadex on results from 2 phase 3 trials of patients age 12 and older.

The first trial included 16 patients who received Coagadex for pharmacokinetic evaluation, on-demand treatment and control of bleeding episodes, and/or perioperative management of minor surgical or dental procedures.

Coagadex was used to treat 208 bleeding episodes, and 187 of these episodes (in 15 patients) were evaluated for efficacy. Ninety-eight episodes were major bleeds, 88 were minor bleeds, and 1 was not assessed.

One hundred and fifty-five bleeds (83%) were treated with a single infusion of Coagadex, 28 (15%) were treated with 2 infusions, 3 bleeds (2%) required 3 infusions, and 1 bleed (0.5%) required 4 infusions. Four bleeding episodes in 2 patients were considered treatment failures.

The mean dose of Coagadex per infusion was 25.4 IU/kg, and the mean total dose was 30.4 IU/kg. The recommended dose of 25 IU/kg to treat a bleed was maintained for 14 of the 16 patients. The other 2 patients used doses of up to 30 IU/kg and 33 IU/kg.

There were 176 adverse events in this trial, but only 6 events in 2 patients were considered possibly related to Coagadex. This included 2 reports of infusion site erythema in 1 patient, 2 reports of fatigue in 1 patient, 1 report of back pain, and 1 report of infusion site pain.

The second trial included patients who received Coagadex for perioperative management. Five patients received Coagadex for 7 surgical procedures.

For major surgeries, a median of 13 infusions (range, 2-15) and a median cumulative dose of 181 IU/kg (range, 45-210 IU/kg) were required to maintain hemostasis. For minor surgeries, a median of 2.5 infusions (range, 1-4) and a median cumulative dose of 89 IU/kg (range, 51-127 IU/kg) were required to maintain hemostasis.

There were no adverse events related to Coagadex in this trial.

For more details on these trials, see the Coagadex package insert. Coagadex is manufactured by Bio Products Laboratory Limited in Elstree, Hertfordshire, UK.

Vials and a syringe

The US Food and Drug Administration (FDA) has approved a factor X product derived from human plasma (Coagadex) to treat patients with hereditary factor X deficiency who are 12 years of age and older.

Coagadex is approved for on-demand treatment and control of bleeding episodes in these patients as well as for perioperative management of bleeding in patients with mild hereditary factor X deficiency.

Prior to this approval, there was no specific coagulation factor replacement therapy available for patients with hereditary factor X deficiency in the US. The FDA previously granted Coagadex orphan product designation, fast track designation, and priority review.

The FDA based its approval of Coagadex on results from 2 phase 3 trials of patients age 12 and older.

The first trial included 16 patients who received Coagadex for pharmacokinetic evaluation, on-demand treatment and control of bleeding episodes, and/or perioperative management of minor surgical or dental procedures.

Coagadex was used to treat 208 bleeding episodes, and 187 of these episodes (in 15 patients) were evaluated for efficacy. Ninety-eight episodes were major bleeds, 88 were minor bleeds, and 1 was not assessed.

One hundred and fifty-five bleeds (83%) were treated with a single infusion of Coagadex, 28 (15%) were treated with 2 infusions, 3 bleeds (2%) required 3 infusions, and 1 bleed (0.5%) required 4 infusions. Four bleeding episodes in 2 patients were considered treatment failures.

The mean dose of Coagadex per infusion was 25.4 IU/kg, and the mean total dose was 30.4 IU/kg. The recommended dose of 25 IU/kg to treat a bleed was maintained for 14 of the 16 patients. The other 2 patients used doses of up to 30 IU/kg and 33 IU/kg.

There were 176 adverse events in this trial, but only 6 events in 2 patients were considered possibly related to Coagadex. This included 2 reports of infusion site erythema in 1 patient, 2 reports of fatigue in 1 patient, 1 report of back pain, and 1 report of infusion site pain.

The second trial included patients who received Coagadex for perioperative management. Five patients received Coagadex for 7 surgical procedures.

For major surgeries, a median of 13 infusions (range, 2-15) and a median cumulative dose of 181 IU/kg (range, 45-210 IU/kg) were required to maintain hemostasis. For minor surgeries, a median of 2.5 infusions (range, 1-4) and a median cumulative dose of 89 IU/kg (range, 51-127 IU/kg) were required to maintain hemostasis.

There were no adverse events related to Coagadex in this trial.

For more details on these trials, see the Coagadex package insert. Coagadex is manufactured by Bio Products Laboratory Limited in Elstree, Hertfordshire, UK.

B-cell ALL

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for inotuzumab ozogamicin to treat adults with acute lymphoblastic leukemia (ALL).

Inotuzumab ozogamicin consists of a monoclonal antibody targeting CD22 and the cytotoxic agent calicheamicin.

When this antibody-drug conjugate binds to the CD22 antigen on malignant B cells, it is internalized, and calicheamicin is released to destroy the cell.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

The FDA’s decision to grant inotuzumab ozogamicin breakthrough designation was based on results of the phase 3 INO-VATE ALL trial.

Results from this trial were presented at the 20th Congress of the European Hematology Association (EHA) last June (abstract LB2073*). The study is sponsored by Pfizer, the company developing inotuzumab ozogamicin.

This ongoing trial has enrolled 326 adult patients with relapsed or refractory, CD22-positive ALL. At EHA, Daniel DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presented efficacy results in 205 patients and safety results in 259 patients.

Patients were assigned to receive inotuzumab ozogamicin (InO) or a defined set of chemotherapy choices (chemo). The InO schedule was once weekly for 3 weeks on a 3- to 4-week cycle for up to 6 cycles. Chemotherapy options included fludarabine, cytarabine, and G-CSF (FLAG); high-dose cytarabine (HIDAC); or cytarabine and mitoxantrone.

The primary endpoints of the study are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Survival data are not yet mature.

However, Dr DeAngelo reported that CR/CRi was significantly higher in the InO arm than the chemo arm—80.7% and 33.3%, respectively (P<0.0001). CR occurred in 35.8% and 19.8% of patients, respectively (P=0.0056), and CRi occurred in 45% and 13.5%, respectively (P<0.0001).

In both arms, most patients achieved CR/CRi during the first cycle of treatment—73% in the InO arm and 91% in the chemo arm.

The median duration of remission was 4.6 months in the InO arm and 3.1 months in the chemo arm (P=0.0169).

Overall, treatment-emergent adverse events (AEs) were similar between the arms. The incidence of any treatment-emergent AE was 98% in the InO arm and 99% in the chemo arm. The incidence of grade 3 or higher AEs was 91% and 95%, respectively. And the incidence of serious AEs was 48% and 46%, respectively.

Several AEs were more common in the chemo arm than the InO arm, including thrombocytopenia (61% vs 45%), anemia (53% vs 30%), febrile neutropenia (52% vs 27%), nausea (47% vs 32%), and pyrexia (42% vs 27%). The only AE that was more common in the InO arm than the chemo arm was AST increase (20% vs 10%).

There were 17 deaths in InO arm and 11 in the chemo arm. Four deaths in the InO arm and 2 in the chemo arm were considered treatment-related.

Causes of treatment-related deaths in the InO arm were acute respiratory distress syndrome as a terminal event of pneumonia (n=1), intestinal ischemia/septic shock (n=1), and veno-occlusive disease/ sinusoidal obstruction syndrome (n=2, both after post-study stem cell transplant).

*Information in the abstract differs from the presentation.

B-cell ALL

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for inotuzumab ozogamicin to treat adults with acute lymphoblastic leukemia (ALL).

Inotuzumab ozogamicin consists of a monoclonal antibody targeting CD22 and the cytotoxic agent calicheamicin.

When this antibody-drug conjugate binds to the CD22 antigen on malignant B cells, it is internalized, and calicheamicin is released to destroy the cell.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

The FDA’s decision to grant inotuzumab ozogamicin breakthrough designation was based on results of the phase 3 INO-VATE ALL trial.

Results from this trial were presented at the 20th Congress of the European Hematology Association (EHA) last June (abstract LB2073*). The study is sponsored by Pfizer, the company developing inotuzumab ozogamicin.

This ongoing trial has enrolled 326 adult patients with relapsed or refractory, CD22-positive ALL. At EHA, Daniel DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presented efficacy results in 205 patients and safety results in 259 patients.

Patients were assigned to receive inotuzumab ozogamicin (InO) or a defined set of chemotherapy choices (chemo). The InO schedule was once weekly for 3 weeks on a 3- to 4-week cycle for up to 6 cycles. Chemotherapy options included fludarabine, cytarabine, and G-CSF (FLAG); high-dose cytarabine (HIDAC); or cytarabine and mitoxantrone.

The primary endpoints of the study are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Survival data are not yet mature.

However, Dr DeAngelo reported that CR/CRi was significantly higher in the InO arm than the chemo arm—80.7% and 33.3%, respectively (P<0.0001). CR occurred in 35.8% and 19.8% of patients, respectively (P=0.0056), and CRi occurred in 45% and 13.5%, respectively (P<0.0001).

In both arms, most patients achieved CR/CRi during the first cycle of treatment—73% in the InO arm and 91% in the chemo arm.

The median duration of remission was 4.6 months in the InO arm and 3.1 months in the chemo arm (P=0.0169).

Overall, treatment-emergent adverse events (AEs) were similar between the arms. The incidence of any treatment-emergent AE was 98% in the InO arm and 99% in the chemo arm. The incidence of grade 3 or higher AEs was 91% and 95%, respectively. And the incidence of serious AEs was 48% and 46%, respectively.

Several AEs were more common in the chemo arm than the InO arm, including thrombocytopenia (61% vs 45%), anemia (53% vs 30%), febrile neutropenia (52% vs 27%), nausea (47% vs 32%), and pyrexia (42% vs 27%). The only AE that was more common in the InO arm than the chemo arm was AST increase (20% vs 10%).

There were 17 deaths in InO arm and 11 in the chemo arm. Four deaths in the InO arm and 2 in the chemo arm were considered treatment-related.

Causes of treatment-related deaths in the InO arm were acute respiratory distress syndrome as a terminal event of pneumonia (n=1), intestinal ischemia/septic shock (n=1), and veno-occlusive disease/ sinusoidal obstruction syndrome (n=2, both after post-study stem cell transplant).

*Information in the abstract differs from the presentation.

B-cell ALL

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for inotuzumab ozogamicin to treat adults with acute lymphoblastic leukemia (ALL).

Inotuzumab ozogamicin consists of a monoclonal antibody targeting CD22 and the cytotoxic agent calicheamicin.

When this antibody-drug conjugate binds to the CD22 antigen on malignant B cells, it is internalized, and calicheamicin is released to destroy the cell.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

The FDA’s decision to grant inotuzumab ozogamicin breakthrough designation was based on results of the phase 3 INO-VATE ALL trial.

Results from this trial were presented at the 20th Congress of the European Hematology Association (EHA) last June (abstract LB2073*). The study is sponsored by Pfizer, the company developing inotuzumab ozogamicin.

This ongoing trial has enrolled 326 adult patients with relapsed or refractory, CD22-positive ALL. At EHA, Daniel DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, presented efficacy results in 205 patients and safety results in 259 patients.

Patients were assigned to receive inotuzumab ozogamicin (InO) or a defined set of chemotherapy choices (chemo). The InO schedule was once weekly for 3 weeks on a 3- to 4-week cycle for up to 6 cycles. Chemotherapy options included fludarabine, cytarabine, and G-CSF (FLAG); high-dose cytarabine (HIDAC); or cytarabine and mitoxantrone.

The primary endpoints of the study are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Survival data are not yet mature.

However, Dr DeAngelo reported that CR/CRi was significantly higher in the InO arm than the chemo arm—80.7% and 33.3%, respectively (P<0.0001). CR occurred in 35.8% and 19.8% of patients, respectively (P=0.0056), and CRi occurred in 45% and 13.5%, respectively (P<0.0001).

In both arms, most patients achieved CR/CRi during the first cycle of treatment—73% in the InO arm and 91% in the chemo arm.

The median duration of remission was 4.6 months in the InO arm and 3.1 months in the chemo arm (P=0.0169).

Overall, treatment-emergent adverse events (AEs) were similar between the arms. The incidence of any treatment-emergent AE was 98% in the InO arm and 99% in the chemo arm. The incidence of grade 3 or higher AEs was 91% and 95%, respectively. And the incidence of serious AEs was 48% and 46%, respectively.

Several AEs were more common in the chemo arm than the InO arm, including thrombocytopenia (61% vs 45%), anemia (53% vs 30%), febrile neutropenia (52% vs 27%), nausea (47% vs 32%), and pyrexia (42% vs 27%). The only AE that was more common in the InO arm than the chemo arm was AST increase (20% vs 10%).

There were 17 deaths in InO arm and 11 in the chemo arm. Four deaths in the InO arm and 2 in the chemo arm were considered treatment-related.

Causes of treatment-related deaths in the InO arm were acute respiratory distress syndrome as a terminal event of pneumonia (n=1), intestinal ischemia/septic shock (n=1), and veno-occlusive disease/ sinusoidal obstruction syndrome (n=2, both after post-study stem cell transplant).

*Information in the abstract differs from the presentation.

Emergency medical team

treating a patient

Photo by Tom Watanabe

The US Food and Drug Administration (FDA) has granted accelerated approval for idarucizumab (Praxbind), the first reversal agent for the direct thrombin inhibitor dabigatran (Pradaxa).

Idarucizumab is now approved for use in emergency situations when there is a need to reverse the anticoagulant effect of dabigatran.

The FDA’s accelerated approval program allows the agency to approve drugs for serious conditions that fill an unmet medical need.

Accelerated approval is based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict a clinical benefit to patients. So the company developing the drug is required to submit additional information after approval to confirm the drug’s clinical benefit.

About dabigatran and idarucizumab

Dabigatran is FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, as well as for the treatment and prevention of deep vein thrombosis and pulmonary embolism.

Idarucizumab is the first reversal agent approved specifically for dabigatran and works by binding to the drug compound to neutralize its effect. Idarucizumab is administered via intravenous injection.

Both idarucizumab and dabigatran are under development by Boehringer Ingelheim.

Idarucizumab has been studied in 3 randomized, double-blind, phase 1 trials of subjects who were not previously taking dabigatran and a phase 3 trial (RE-VERSE AD) of patients who were taking dabigatran and required reversal in an emergency setting.

Phase 1 trials

One phase 1 study (NCT01688830) enrolled 157 healthy male volunteers and consisted of 3 parts. Part 1 included 110 subjects who received placebo or idarucizumab at doses ranging from 20 mg to 8 g.

Idarucizumab (in the absence of dabigatran) was deemed safe and well tolerated. These results were published in Thrombosis and Haemostasis.

Parts 2 and 3 of the study included 47 subjects (part 2, n=35; part 3, n=12), and researchers investigated how well various doses of idarucizumab reversed the anticoagulant effect of dabigatran.

Results from parts 2 and 3 were published in The Lancet. The researchers said idarucizumab (given at 2 g or greater) provided immediate, complete, and sustained reversal of the anticoagulant effect of dabigatran, without producing serious adverse events.

In a second phase 1 study (NCT01955720), researchers evaluated idarucizumab in 46 subjects (males and females). This included healthy volunteers, elderly subjects, and participants with pre-existing mild or moderate kidney impairment.

Idarucizumab immediately and completely reversed dabigatran’s anticoagulant effect in these subjects, and they were able to restart dabigatran within 24 hours of receiving idarucizumab.

In addition, the researchers said there were no clinically relevant adverse events related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. These results were presented at the 2014 ASH Annual Meeting.

A third phase 1 study (NCT02028780) enrolled 80 healthy Japanese subjects. Researchers assessed the safety, tolerability, and pharmacokinetics of single, increasing doses of idarucizumab, administered both alone and after dabigatran.

Phase 3 trial

In the ongoing phase 3 trial, RE-VERSE AD, researchers are evaluating idarucizumab in emergency settings. The team reported interim results in 90 patients in NEJM and at the 2015 ISTH Congress.

Idarucizumab normalized diluted thrombin time and ecarin clotting time in a majority of patients who had uncontrolled or life-threatening bleeding complications while on dabigatran and in most patients who had to reverse dabigatran’s effects because they required emergency surgery or an invasive procedure.

The researchers said there were no safety concerns related to idarucizumab. However, 23% of patients experienced serious adverse events, 20% died, and several patients had thrombotic or bleeding events after receiving idarucizumab.

Emergency medical team

treating a patient

Photo by Tom Watanabe

The US Food and Drug Administration (FDA) has granted accelerated approval for idarucizumab (Praxbind), the first reversal agent for the direct thrombin inhibitor dabigatran (Pradaxa).

Idarucizumab is now approved for use in emergency situations when there is a need to reverse the anticoagulant effect of dabigatran.

The FDA’s accelerated approval program allows the agency to approve drugs for serious conditions that fill an unmet medical need.

Accelerated approval is based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict a clinical benefit to patients. So the company developing the drug is required to submit additional information after approval to confirm the drug’s clinical benefit.

About dabigatran and idarucizumab

Dabigatran is FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, as well as for the treatment and prevention of deep vein thrombosis and pulmonary embolism.

Idarucizumab is the first reversal agent approved specifically for dabigatran and works by binding to the drug compound to neutralize its effect. Idarucizumab is administered via intravenous injection.

Both idarucizumab and dabigatran are under development by Boehringer Ingelheim.

Idarucizumab has been studied in 3 randomized, double-blind, phase 1 trials of subjects who were not previously taking dabigatran and a phase 3 trial (RE-VERSE AD) of patients who were taking dabigatran and required reversal in an emergency setting.

Phase 1 trials

One phase 1 study (NCT01688830) enrolled 157 healthy male volunteers and consisted of 3 parts. Part 1 included 110 subjects who received placebo or idarucizumab at doses ranging from 20 mg to 8 g.

Idarucizumab (in the absence of dabigatran) was deemed safe and well tolerated. These results were published in Thrombosis and Haemostasis.

Parts 2 and 3 of the study included 47 subjects (part 2, n=35; part 3, n=12), and researchers investigated how well various doses of idarucizumab reversed the anticoagulant effect of dabigatran.

Results from parts 2 and 3 were published in The Lancet. The researchers said idarucizumab (given at 2 g or greater) provided immediate, complete, and sustained reversal of the anticoagulant effect of dabigatran, without producing serious adverse events.

In a second phase 1 study (NCT01955720), researchers evaluated idarucizumab in 46 subjects (males and females). This included healthy volunteers, elderly subjects, and participants with pre-existing mild or moderate kidney impairment.

Idarucizumab immediately and completely reversed dabigatran’s anticoagulant effect in these subjects, and they were able to restart dabigatran within 24 hours of receiving idarucizumab.

In addition, the researchers said there were no clinically relevant adverse events related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. These results were presented at the 2014 ASH Annual Meeting.

A third phase 1 study (NCT02028780) enrolled 80 healthy Japanese subjects. Researchers assessed the safety, tolerability, and pharmacokinetics of single, increasing doses of idarucizumab, administered both alone and after dabigatran.

Phase 3 trial

In the ongoing phase 3 trial, RE-VERSE AD, researchers are evaluating idarucizumab in emergency settings. The team reported interim results in 90 patients in NEJM and at the 2015 ISTH Congress.

Idarucizumab normalized diluted thrombin time and ecarin clotting time in a majority of patients who had uncontrolled or life-threatening bleeding complications while on dabigatran and in most patients who had to reverse dabigatran’s effects because they required emergency surgery or an invasive procedure.

The researchers said there were no safety concerns related to idarucizumab. However, 23% of patients experienced serious adverse events, 20% died, and several patients had thrombotic or bleeding events after receiving idarucizumab.

Emergency medical team

treating a patient

Photo by Tom Watanabe

The US Food and Drug Administration (FDA) has granted accelerated approval for idarucizumab (Praxbind), the first reversal agent for the direct thrombin inhibitor dabigatran (Pradaxa).

Idarucizumab is now approved for use in emergency situations when there is a need to reverse the anticoagulant effect of dabigatran.

The FDA’s accelerated approval program allows the agency to approve drugs for serious conditions that fill an unmet medical need.

Accelerated approval is based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict a clinical benefit to patients. So the company developing the drug is required to submit additional information after approval to confirm the drug’s clinical benefit.

About dabigatran and idarucizumab

Dabigatran is FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, as well as for the treatment and prevention of deep vein thrombosis and pulmonary embolism.

Idarucizumab is the first reversal agent approved specifically for dabigatran and works by binding to the drug compound to neutralize its effect. Idarucizumab is administered via intravenous injection.

Both idarucizumab and dabigatran are under development by Boehringer Ingelheim.

Idarucizumab has been studied in 3 randomized, double-blind, phase 1 trials of subjects who were not previously taking dabigatran and a phase 3 trial (RE-VERSE AD) of patients who were taking dabigatran and required reversal in an emergency setting.

Phase 1 trials

One phase 1 study (NCT01688830) enrolled 157 healthy male volunteers and consisted of 3 parts. Part 1 included 110 subjects who received placebo or idarucizumab at doses ranging from 20 mg to 8 g.

Idarucizumab (in the absence of dabigatran) was deemed safe and well tolerated. These results were published in Thrombosis and Haemostasis.

Parts 2 and 3 of the study included 47 subjects (part 2, n=35; part 3, n=12), and researchers investigated how well various doses of idarucizumab reversed the anticoagulant effect of dabigatran.

Results from parts 2 and 3 were published in The Lancet. The researchers said idarucizumab (given at 2 g or greater) provided immediate, complete, and sustained reversal of the anticoagulant effect of dabigatran, without producing serious adverse events.

In a second phase 1 study (NCT01955720), researchers evaluated idarucizumab in 46 subjects (males and females). This included healthy volunteers, elderly subjects, and participants with pre-existing mild or moderate kidney impairment.

Idarucizumab immediately and completely reversed dabigatran’s anticoagulant effect in these subjects, and they were able to restart dabigatran within 24 hours of receiving idarucizumab.

In addition, the researchers said there were no clinically relevant adverse events related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. These results were presented at the 2014 ASH Annual Meeting.

A third phase 1 study (NCT02028780) enrolled 80 healthy Japanese subjects. Researchers assessed the safety, tolerability, and pharmacokinetics of single, increasing doses of idarucizumab, administered both alone and after dabigatran.

Phase 3 trial

In the ongoing phase 3 trial, RE-VERSE AD, researchers are evaluating idarucizumab in emergency settings. The team reported interim results in 90 patients in NEJM and at the 2015 ISTH Congress.

Idarucizumab normalized diluted thrombin time and ecarin clotting time in a majority of patients who had uncontrolled or life-threatening bleeding complications while on dabigatran and in most patients who had to reverse dabigatran’s effects because they required emergency surgery or an invasive procedure.

The researchers said there were no safety concerns related to idarucizumab. However, 23% of patients experienced serious adverse events, 20% died, and several patients had thrombotic or bleeding events after receiving idarucizumab.

Vial of Obizur

Photo courtesy of

Baxter International Inc.

Health Canada has approved a recombinant porcine factor VIII (FVIII) product (Obizur) to treat bleeding episodes in patients with acquired hemophilia A caused by autoantibodies to FVIII.

Obizur is the first recombinant porcine treatment to be made available for acquired hemophilia A in Canada.

It is specifically designed so physicians can monitor treatment response by measuring FVIII activity levels in addition to making clinical assessments.

Health Canada’s approval is based on a phase 2/3 trial in which patients with acquired hemophilia A received Obizur as treatment for serious bleeding episodes.

Twenty-nine patients were enrolled in this trial and evaluated for safety. Researchers determined that one of the patients did not actually have acquired hemophilia A, so this patient could not be evaluated for efficacy.

At 24 hours after the initial infusion, all 28 patients in the efficacy analysis had a positive response to Obizur. This meant that bleeding stopped or decreased, the patients experienced clinical stabilization or improvement, and FVIII levels were 20% or higher.

Eighty-six percent of patients (24/28) had successful treatment of their initial bleeding episode. The overall treatment success was determined by the investigator based on the ability to discontinue or reduce the dose and/or dosing frequency of Obizur.

The adverse event most frequently reported in the 29 patients in the safety analysis was the development of inhibitors to porcine FVIII.

Nineteen patients were negative for anti-porcine FVIII antibodies at baseline, and 5 of these patients (26%) developed anti-porcine FVIII antibodies following exposure to Obizur.

Of the 10 patients with detectable anti-porcine FVIII antibodies at baseline, 2 (20%) experienced an increase in titer, and 8 (80%) decreased to a non-detectable titer.

Obizur is under development by Baxalta Incorporated. The drug is currently approved for use in the US and is under regulatory review in the European Union, Switzerland, Australia, and Colombia.

Vial of Obizur

Photo courtesy of

Baxter International Inc.

Health Canada has approved a recombinant porcine factor VIII (FVIII) product (Obizur) to treat bleeding episodes in patients with acquired hemophilia A caused by autoantibodies to FVIII.

Obizur is the first recombinant porcine treatment to be made available for acquired hemophilia A in Canada.

It is specifically designed so physicians can monitor treatment response by measuring FVIII activity levels in addition to making clinical assessments.

Health Canada’s approval is based on a phase 2/3 trial in which patients with acquired hemophilia A received Obizur as treatment for serious bleeding episodes.

Twenty-nine patients were enrolled in this trial and evaluated for safety. Researchers determined that one of the patients did not actually have acquired hemophilia A, so this patient could not be evaluated for efficacy.

At 24 hours after the initial infusion, all 28 patients in the efficacy analysis had a positive response to Obizur. This meant that bleeding stopped or decreased, the patients experienced clinical stabilization or improvement, and FVIII levels were 20% or higher.

Eighty-six percent of patients (24/28) had successful treatment of their initial bleeding episode. The overall treatment success was determined by the investigator based on the ability to discontinue or reduce the dose and/or dosing frequency of Obizur.

The adverse event most frequently reported in the 29 patients in the safety analysis was the development of inhibitors to porcine FVIII.

Nineteen patients were negative for anti-porcine FVIII antibodies at baseline, and 5 of these patients (26%) developed anti-porcine FVIII antibodies following exposure to Obizur.

Of the 10 patients with detectable anti-porcine FVIII antibodies at baseline, 2 (20%) experienced an increase in titer, and 8 (80%) decreased to a non-detectable titer.

Obizur is under development by Baxalta Incorporated. The drug is currently approved for use in the US and is under regulatory review in the European Union, Switzerland, Australia, and Colombia.

Vial of Obizur

Photo courtesy of

Baxter International Inc.

Health Canada has approved a recombinant porcine factor VIII (FVIII) product (Obizur) to treat bleeding episodes in patients with acquired hemophilia A caused by autoantibodies to FVIII.

Obizur is the first recombinant porcine treatment to be made available for acquired hemophilia A in Canada.

It is specifically designed so physicians can monitor treatment response by measuring FVIII activity levels in addition to making clinical assessments.

Health Canada’s approval is based on a phase 2/3 trial in which patients with acquired hemophilia A received Obizur as treatment for serious bleeding episodes.

Twenty-nine patients were enrolled in this trial and evaluated for safety. Researchers determined that one of the patients did not actually have acquired hemophilia A, so this patient could not be evaluated for efficacy.

At 24 hours after the initial infusion, all 28 patients in the efficacy analysis had a positive response to Obizur. This meant that bleeding stopped or decreased, the patients experienced clinical stabilization or improvement, and FVIII levels were 20% or higher.

Eighty-six percent of patients (24/28) had successful treatment of their initial bleeding episode. The overall treatment success was determined by the investigator based on the ability to discontinue or reduce the dose and/or dosing frequency of Obizur.

The adverse event most frequently reported in the 29 patients in the safety analysis was the development of inhibitors to porcine FVIII.

Nineteen patients were negative for anti-porcine FVIII antibodies at baseline, and 5 of these patients (26%) developed anti-porcine FVIII antibodies following exposure to Obizur.

Of the 10 patients with detectable anti-porcine FVIII antibodies at baseline, 2 (20%) experienced an increase in titer, and 8 (80%) decreased to a non-detectable titer.

Obizur is under development by Baxalta Incorporated. The drug is currently approved for use in the US and is under regulatory review in the European Union, Switzerland, Australia, and Colombia.

Follicular lymphoma

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has adopted positive opinions recommending orphan designation for KTE-C19 to treat acute lymphoblastic leukemia, chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma.

KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the surface of B cells.

The CAR T-cell therapy already has orphan designation for the treatment of diffuse large B-cell lymphoma in the US and the European Union (EU).

KTE-C19 also has COMP positive opinions for orphan designation in the EU for primary mediastinal B-cell lymphoma and mantle cell lymphoma.

About orphan designation

The COMP adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

KTE-C19 research

Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of the CAR T-cell therapy. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.

KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.

KTE-C19 is currently under investigation in a phase 1/2 trial (ZUMA-1) of patients with refractory, aggressive non-Hodgkin lymphomas. Kite Pharma, Inc., the company developing KTE-C19, plans to present top-line phase 1 data at the 2015 ASH Annual Meeting.

Follicular lymphoma

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has adopted positive opinions recommending orphan designation for KTE-C19 to treat acute lymphoblastic leukemia, chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma.

KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the surface of B cells.

The CAR T-cell therapy already has orphan designation for the treatment of diffuse large B-cell lymphoma in the US and the European Union (EU).

KTE-C19 also has COMP positive opinions for orphan designation in the EU for primary mediastinal B-cell lymphoma and mantle cell lymphoma.

About orphan designation

The COMP adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

KTE-C19 research

Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of the CAR T-cell therapy. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.

KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.

KTE-C19 is currently under investigation in a phase 1/2 trial (ZUMA-1) of patients with refractory, aggressive non-Hodgkin lymphomas. Kite Pharma, Inc., the company developing KTE-C19, plans to present top-line phase 1 data at the 2015 ASH Annual Meeting.

Follicular lymphoma

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has adopted positive opinions recommending orphan designation for KTE-C19 to treat acute lymphoblastic leukemia, chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma.

KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the surface of B cells.

The CAR T-cell therapy already has orphan designation for the treatment of diffuse large B-cell lymphoma in the US and the European Union (EU).

KTE-C19 also has COMP positive opinions for orphan designation in the EU for primary mediastinal B-cell lymphoma and mantle cell lymphoma.

About orphan designation

The COMP adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

KTE-C19 research

Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of the CAR T-cell therapy. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory diffuse large B-cell lymphoma, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.

KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.

KTE-C19 is currently under investigation in a phase 1/2 trial (ZUMA-1) of patients with refractory, aggressive non-Hodgkin lymphomas. Kite Pharma, Inc., the company developing KTE-C19, plans to present top-line phase 1 data at the 2015 ASH Annual Meeting.

Dabigatran (Pradaxa) capsules

Photo by ec-jpr

The US Food and Drug Administration’s (FDA’s) oversight of the oral anticoagulant dabigatran (Pradaxa) raises questions about the agency’s reliability, according to a report by the Project On Government Oversight (POGO).

POGO’s report describes a series of “questionable” calls the FDA has made in its oversight of dabigatran.

The report calls attention to issues with the clinical trial used to support dabigatran’s approval.

It also details concerns regarding FDA advisory committee members, the distribution of potentially misleading information about dabigatran, the possibility that patients receiving dabigatran may actually need to be monitored, and other issues.

“The deeply disturbing part is that the public has to trust the FDA to keep it safe, and the way the agency handled Pradaxa doesn’t inspire confidence,” said Daniel Brian, POGO’s executive director.

This is not the first time the safety of dabigatran and results of dabigatran trials have been called into question.

Following post-marketing reports of adverse events and deaths related to dabigatran, the FDA conducted its own studies investigating the drug’s safety. The agency ultimately concluded that dabigatran’s benefits outweigh any detriments.

Still, a paper published in JAMA in 2012 suggested the FDA may have approved dabigatran too soon.

And several papers published in The BMJ last year indicated that Boehringer Ingelheim, the company developing dabigatran, underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.

The company has denied these allegations, but POGO’s report appears to support these claims, in addition to raising other concerns.

Trial issues

Dabigatran was initially approved by the FDA in 2010 on the basis of the RE-LY trial, in which researchers compared dabigatran and warfarin.

POGO’s report notes that this was an unblinded trial and suggests that investigators treated patients in the dabigatran arm differently than those in the warfarin arm. An FDA review showed that, when study subjects showed “signs of trouble,” those in the dabigatran arm were more likely to stop receiving treatment. This may have prevented adverse events such as hemorrhagic strokes.

FDA inspections also revealed that RE-LY investigators mismanaged parts of the trial. For example, they enrolled patients who were supposed to be excluded and failed to promptly inform Boehringer Ingelheim about possible adverse effects of dabigatran, among other infractions.

POGO’s report also cites FDA documents showing that the agency allowed Boehringer Ingelheim to finalize the scoring system for the RE-LY trial after it was over and the data had been gathered. A subsequent FDA review suggested that this allowance worked in dabigatran’s favor.

Advisory committee concerns

POGO’s report points out that members of the committee that advised the FDA on dabigatran’s approval have financial ties to the drug’s maker.

According to public databases, 2 of the advisory committee members who voted to approve dabigatran went on to receive tens of thousands of dollars from Boehringer Ingelheim.

POGO also found that when Boehringer Ingelheim held a practice session to prepare for questioning by the FDA advisory committee, a former member and a former chairman of that committee were paid to play roles in the rehearsal.

‘Misleading’ information

Another of POGO’s concerns is that the FDA redacted information from a public memo announcing and explaining its decision to approve dabigatran. The deleted section said that patients who were well-treated using warfarin had no reason to switch to dabigatran.

POGO’s report also points out that the FDA initially refused to allow Boehringer Ingelheim to claim that dabigatran was superior to warfarin but later changed its mind without providing much explanation.

In addition, the FDA allowed Boehringer Ingelheim to advertise that, in a clinical trial, dabigatran “reduced stroke risk 35% more than warfarin.” But after dabigatran had been on the market for more than 2.5 years, the FDA decided this claim was misleading.

The agency told Boehringer Ingelheim to add the following clarification: “That means that, in a large clinical study, 3.4% of patients taking warfarin had a stroke, compared to 2.2% of patients taking Pradaxa.” So, in absolute terms, the difference between the drugs was 1.2%.

Potential need for monitoring

According to POGO, Boehringer Ingelheim has been the target of thousands of lawsuits regarding adverse events and deaths thought to be related to dabigatran. In 2013, Boehringer Ingelheim was fined by a federal judge for withholding or failing to preserve records.

Some of these documents suggested that patients taking dabigatran may require monitoring to ensure they remain within a therapeutic range. A scientist at Boehringer Ingelheim, Thorsten Lehr, drafted a paper concluding that there is a therapeutic range for dabigatran.

But company emails indicated that other employees were against publishing this paper. An email from Boehringer Ingelheim’s Jutta Heinrich-Nols said publishing the paper would “make any defense of no monitoring . . . extremely difficult . . . and undermine our efforts to compete” with other new anticoagulants.

For more details, see POGO’s full report. POGO is a nonpartisan, independent watchdog that champions government reform.

Dabigatran (Pradaxa) capsules

Photo by ec-jpr

The US Food and Drug Administration’s (FDA’s) oversight of the oral anticoagulant dabigatran (Pradaxa) raises questions about the agency’s reliability, according to a report by the Project On Government Oversight (POGO).

POGO’s report describes a series of “questionable” calls the FDA has made in its oversight of dabigatran.

The report calls attention to issues with the clinical trial used to support dabigatran’s approval.

It also details concerns regarding FDA advisory committee members, the distribution of potentially misleading information about dabigatran, the possibility that patients receiving dabigatran may actually need to be monitored, and other issues.

“The deeply disturbing part is that the public has to trust the FDA to keep it safe, and the way the agency handled Pradaxa doesn’t inspire confidence,” said Daniel Brian, POGO’s executive director.

This is not the first time the safety of dabigatran and results of dabigatran trials have been called into question.

Following post-marketing reports of adverse events and deaths related to dabigatran, the FDA conducted its own studies investigating the drug’s safety. The agency ultimately concluded that dabigatran’s benefits outweigh any detriments.

Still, a paper published in JAMA in 2012 suggested the FDA may have approved dabigatran too soon.

And several papers published in The BMJ last year indicated that Boehringer Ingelheim, the company developing dabigatran, underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.

The company has denied these allegations, but POGO’s report appears to support these claims, in addition to raising other concerns.

Trial issues

Dabigatran was initially approved by the FDA in 2010 on the basis of the RE-LY trial, in which researchers compared dabigatran and warfarin.

POGO’s report notes that this was an unblinded trial and suggests that investigators treated patients in the dabigatran arm differently than those in the warfarin arm. An FDA review showed that, when study subjects showed “signs of trouble,” those in the dabigatran arm were more likely to stop receiving treatment. This may have prevented adverse events such as hemorrhagic strokes.

FDA inspections also revealed that RE-LY investigators mismanaged parts of the trial. For example, they enrolled patients who were supposed to be excluded and failed to promptly inform Boehringer Ingelheim about possible adverse effects of dabigatran, among other infractions.

POGO’s report also cites FDA documents showing that the agency allowed Boehringer Ingelheim to finalize the scoring system for the RE-LY trial after it was over and the data had been gathered. A subsequent FDA review suggested that this allowance worked in dabigatran’s favor.

Advisory committee concerns

POGO’s report points out that members of the committee that advised the FDA on dabigatran’s approval have financial ties to the drug’s maker.

According to public databases, 2 of the advisory committee members who voted to approve dabigatran went on to receive tens of thousands of dollars from Boehringer Ingelheim.

POGO also found that when Boehringer Ingelheim held a practice session to prepare for questioning by the FDA advisory committee, a former member and a former chairman of that committee were paid to play roles in the rehearsal.

‘Misleading’ information

Another of POGO’s concerns is that the FDA redacted information from a public memo announcing and explaining its decision to approve dabigatran. The deleted section said that patients who were well-treated using warfarin had no reason to switch to dabigatran.

POGO’s report also points out that the FDA initially refused to allow Boehringer Ingelheim to claim that dabigatran was superior to warfarin but later changed its mind without providing much explanation.

In addition, the FDA allowed Boehringer Ingelheim to advertise that, in a clinical trial, dabigatran “reduced stroke risk 35% more than warfarin.” But after dabigatran had been on the market for more than 2.5 years, the FDA decided this claim was misleading.

The agency told Boehringer Ingelheim to add the following clarification: “That means that, in a large clinical study, 3.4% of patients taking warfarin had a stroke, compared to 2.2% of patients taking Pradaxa.” So, in absolute terms, the difference between the drugs was 1.2%.

Potential need for monitoring

According to POGO, Boehringer Ingelheim has been the target of thousands of lawsuits regarding adverse events and deaths thought to be related to dabigatran. In 2013, Boehringer Ingelheim was fined by a federal judge for withholding or failing to preserve records.

Some of these documents suggested that patients taking dabigatran may require monitoring to ensure they remain within a therapeutic range. A scientist at Boehringer Ingelheim, Thorsten Lehr, drafted a paper concluding that there is a therapeutic range for dabigatran.

But company emails indicated that other employees were against publishing this paper. An email from Boehringer Ingelheim’s Jutta Heinrich-Nols said publishing the paper would “make any defense of no monitoring . . . extremely difficult . . . and undermine our efforts to compete” with other new anticoagulants.

For more details, see POGO’s full report. POGO is a nonpartisan, independent watchdog that champions government reform.

Dabigatran (Pradaxa) capsules

Photo by ec-jpr

The US Food and Drug Administration’s (FDA’s) oversight of the oral anticoagulant dabigatran (Pradaxa) raises questions about the agency’s reliability, according to a report by the Project On Government Oversight (POGO).

POGO’s report describes a series of “questionable” calls the FDA has made in its oversight of dabigatran.

The report calls attention to issues with the clinical trial used to support dabigatran’s approval.

It also details concerns regarding FDA advisory committee members, the distribution of potentially misleading information about dabigatran, the possibility that patients receiving dabigatran may actually need to be monitored, and other issues.

“The deeply disturbing part is that the public has to trust the FDA to keep it safe, and the way the agency handled Pradaxa doesn’t inspire confidence,” said Daniel Brian, POGO’s executive director.

This is not the first time the safety of dabigatran and results of dabigatran trials have been called into question.

Following post-marketing reports of adverse events and deaths related to dabigatran, the FDA conducted its own studies investigating the drug’s safety. The agency ultimately concluded that dabigatran’s benefits outweigh any detriments.

Still, a paper published in JAMA in 2012 suggested the FDA may have approved dabigatran too soon.

And several papers published in The BMJ last year indicated that Boehringer Ingelheim, the company developing dabigatran, underreported events associated with the drug and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy.

The company has denied these allegations, but POGO’s report appears to support these claims, in addition to raising other concerns.

Trial issues

Dabigatran was initially approved by the FDA in 2010 on the basis of the RE-LY trial, in which researchers compared dabigatran and warfarin.

POGO’s report notes that this was an unblinded trial and suggests that investigators treated patients in the dabigatran arm differently than those in the warfarin arm. An FDA review showed that, when study subjects showed “signs of trouble,” those in the dabigatran arm were more likely to stop receiving treatment. This may have prevented adverse events such as hemorrhagic strokes.

FDA inspections also revealed that RE-LY investigators mismanaged parts of the trial. For example, they enrolled patients who were supposed to be excluded and failed to promptly inform Boehringer Ingelheim about possible adverse effects of dabigatran, among other infractions.

POGO’s report also cites FDA documents showing that the agency allowed Boehringer Ingelheim to finalize the scoring system for the RE-LY trial after it was over and the data had been gathered. A subsequent FDA review suggested that this allowance worked in dabigatran’s favor.

Advisory committee concerns

POGO’s report points out that members of the committee that advised the FDA on dabigatran’s approval have financial ties to the drug’s maker.

According to public databases, 2 of the advisory committee members who voted to approve dabigatran went on to receive tens of thousands of dollars from Boehringer Ingelheim.

POGO also found that when Boehringer Ingelheim held a practice session to prepare for questioning by the FDA advisory committee, a former member and a former chairman of that committee were paid to play roles in the rehearsal.

‘Misleading’ information

Another of POGO’s concerns is that the FDA redacted information from a public memo announcing and explaining its decision to approve dabigatran. The deleted section said that patients who were well-treated using warfarin had no reason to switch to dabigatran.

POGO’s report also points out that the FDA initially refused to allow Boehringer Ingelheim to claim that dabigatran was superior to warfarin but later changed its mind without providing much explanation.

In addition, the FDA allowed Boehringer Ingelheim to advertise that, in a clinical trial, dabigatran “reduced stroke risk 35% more than warfarin.” But after dabigatran had been on the market for more than 2.5 years, the FDA decided this claim was misleading.

The agency told Boehringer Ingelheim to add the following clarification: “That means that, in a large clinical study, 3.4% of patients taking warfarin had a stroke, compared to 2.2% of patients taking Pradaxa.” So, in absolute terms, the difference between the drugs was 1.2%.

Potential need for monitoring

According to POGO, Boehringer Ingelheim has been the target of thousands of lawsuits regarding adverse events and deaths thought to be related to dabigatran. In 2013, Boehringer Ingelheim was fined by a federal judge for withholding or failing to preserve records.

Some of these documents suggested that patients taking dabigatran may require monitoring to ensure they remain within a therapeutic range. A scientist at Boehringer Ingelheim, Thorsten Lehr, drafted a paper concluding that there is a therapeutic range for dabigatran.

But company emails indicated that other employees were against publishing this paper. An email from Boehringer Ingelheim’s Jutta Heinrich-Nols said publishing the paper would “make any defense of no monitoring . . . extremely difficult . . . and undermine our efforts to compete” with other new anticoagulants.

For more details, see POGO’s full report. POGO is a nonpartisan, independent watchdog that champions government reform.

Thrombus

Image by Kevin MacKenzie

The US Food and Drug Administration (FDA) has granted fast track designation to betrixaban as extended-duration venous thromboembolism (VTE) prophylaxis for acute medically ill patients.

This includes patients who are hospitalized for serious medical conditions such as heart failure, stroke, infection, and pulmonary disease.

Betrixaban is an investigational oral anticoagulant that directly inhibits the activity of factor Xa.

According to Portola Pharmaceuticals, the company developing betrixaban, the drug has distinct properties that may allow it to demonstrate clinical benefit without significantly increasing the risk of fatal bleeding and certain other serious side effects.

These benefits include a 19- to 25-hour half-life for once-daily dosing, a low peak-to-trough drug concentration ratio that minimizes anticoagulant variability, low renal clearance, and no significant CYP3A4 metabolism, which may reduce the risk of drug-drug interactions.

Betrixaban trials

In the phase 2 Explore-Xa trial, researchers compared betrixaban and warfarin in patients with atrial fibrillation. The team randomized 508 patients to 1 of 3 blinded doses of betrixaban (40 mg, 60 mg, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0.

The primary outcome was major or clinically relevant non-major bleeding. At a mean follow-up of 147 days, the primary outcome had been met by 1 patient in the 40 mg betrixaban arm, 5 each in the 60 mg and 80 mg betrixaban arms, and 7 in the warfarin arm.

One patient each in the 60 mg and 80 mg arms experienced an ischemic stroke. And there were 2 vascular deaths, 1 each in the 40 mg arm and the warfarin arm.

In the phase 2 EXPERT trial, researchers compared betrixaban and enoxaparin as VTE prophylaxis in patients who underwent total knee replacement.

The team enrolled 215 patients and assigned them to 1 of 3 post-operative prophylaxis regimens: betrixaban at 15 mg twice daily, betrixaban at 40 mg twice daily, or enoxaparin at 30 mg every 12 hours—all for 10 to 14 days.

The primary efficacy outcome was the incidence of VTE during the dosing period, and 175 patients were evaluable for this outcome. VTE occurred in 20% of patients in the 15 mg betrixaban arm (14/70), 15% in the 40 mg betrixaban arm (10/65), and 10% (4/40) in the enoxaparin arm.

Safety outcomes included major and clinically significant non-major bleeds through 48 hours after treatment. There were no bleeds in the 15 mg betrixaban arm, 2 (2.4%) clinically significant non-major bleeds in the 40 mg betrixaban arm, and 1 (2.3%) major bleed and 2 (4.6%) clinically significant non-major bleeds in the enoxaparin arm.

Betrixaban is currently being tested in the phase 3 APEX trial for the prevention of VTE in acute medically ill patients. Portola said it expects to complete enrollment in APEX by the end of this year and report top-line data in the first quarter of 2016.

If the trial is successful, the company plans to submit a new drug application to the FDA later in 2016 under the fast track designation.

About fast track designation

The FDA’s fast track program is designed to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the drug may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings with the FDA to discuss the drug’s development plan and ensure collection of the appropriate data needed to support drug approval. And the designation allows for more frequent written communication from the FDA about things such as the design of proposed clinical trials and the use of biomarkers.

Thrombus

Image by Kevin MacKenzie

The US Food and Drug Administration (FDA) has granted fast track designation to betrixaban as extended-duration venous thromboembolism (VTE) prophylaxis for acute medically ill patients.

This includes patients who are hospitalized for serious medical conditions such as heart failure, stroke, infection, and pulmonary disease.

Betrixaban is an investigational oral anticoagulant that directly inhibits the activity of factor Xa.

According to Portola Pharmaceuticals, the company developing betrixaban, the drug has distinct properties that may allow it to demonstrate clinical benefit without significantly increasing the risk of fatal bleeding and certain other serious side effects.

These benefits include a 19- to 25-hour half-life for once-daily dosing, a low peak-to-trough drug concentration ratio that minimizes anticoagulant variability, low renal clearance, and no significant CYP3A4 metabolism, which may reduce the risk of drug-drug interactions.

Betrixaban trials

In the phase 2 Explore-Xa trial, researchers compared betrixaban and warfarin in patients with atrial fibrillation. The team randomized 508 patients to 1 of 3 blinded doses of betrixaban (40 mg, 60 mg, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0.

The primary outcome was major or clinically relevant non-major bleeding. At a mean follow-up of 147 days, the primary outcome had been met by 1 patient in the 40 mg betrixaban arm, 5 each in the 60 mg and 80 mg betrixaban arms, and 7 in the warfarin arm.

One patient each in the 60 mg and 80 mg arms experienced an ischemic stroke. And there were 2 vascular deaths, 1 each in the 40 mg arm and the warfarin arm.

In the phase 2 EXPERT trial, researchers compared betrixaban and enoxaparin as VTE prophylaxis in patients who underwent total knee replacement.

The team enrolled 215 patients and assigned them to 1 of 3 post-operative prophylaxis regimens: betrixaban at 15 mg twice daily, betrixaban at 40 mg twice daily, or enoxaparin at 30 mg every 12 hours—all for 10 to 14 days.

The primary efficacy outcome was the incidence of VTE during the dosing period, and 175 patients were evaluable for this outcome. VTE occurred in 20% of patients in the 15 mg betrixaban arm (14/70), 15% in the 40 mg betrixaban arm (10/65), and 10% (4/40) in the enoxaparin arm.

Safety outcomes included major and clinically significant non-major bleeds through 48 hours after treatment. There were no bleeds in the 15 mg betrixaban arm, 2 (2.4%) clinically significant non-major bleeds in the 40 mg betrixaban arm, and 1 (2.3%) major bleed and 2 (4.6%) clinically significant non-major bleeds in the enoxaparin arm.

Betrixaban is currently being tested in the phase 3 APEX trial for the prevention of VTE in acute medically ill patients. Portola said it expects to complete enrollment in APEX by the end of this year and report top-line data in the first quarter of 2016.

If the trial is successful, the company plans to submit a new drug application to the FDA later in 2016 under the fast track designation.

About fast track designation

The FDA’s fast track program is designed to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the drug may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings with the FDA to discuss the drug’s development plan and ensure collection of the appropriate data needed to support drug approval. And the designation allows for more frequent written communication from the FDA about things such as the design of proposed clinical trials and the use of biomarkers.

Thrombus

Image by Kevin MacKenzie

The US Food and Drug Administration (FDA) has granted fast track designation to betrixaban as extended-duration venous thromboembolism (VTE) prophylaxis for acute medically ill patients.

This includes patients who are hospitalized for serious medical conditions such as heart failure, stroke, infection, and pulmonary disease.

Betrixaban is an investigational oral anticoagulant that directly inhibits the activity of factor Xa.

According to Portola Pharmaceuticals, the company developing betrixaban, the drug has distinct properties that may allow it to demonstrate clinical benefit without significantly increasing the risk of fatal bleeding and certain other serious side effects.

These benefits include a 19- to 25-hour half-life for once-daily dosing, a low peak-to-trough drug concentration ratio that minimizes anticoagulant variability, low renal clearance, and no significant CYP3A4 metabolism, which may reduce the risk of drug-drug interactions.

Betrixaban trials

In the phase 2 Explore-Xa trial, researchers compared betrixaban and warfarin in patients with atrial fibrillation. The team randomized 508 patients to 1 of 3 blinded doses of betrixaban (40 mg, 60 mg, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0.

The primary outcome was major or clinically relevant non-major bleeding. At a mean follow-up of 147 days, the primary outcome had been met by 1 patient in the 40 mg betrixaban arm, 5 each in the 60 mg and 80 mg betrixaban arms, and 7 in the warfarin arm.

One patient each in the 60 mg and 80 mg arms experienced an ischemic stroke. And there were 2 vascular deaths, 1 each in the 40 mg arm and the warfarin arm.

In the phase 2 EXPERT trial, researchers compared betrixaban and enoxaparin as VTE prophylaxis in patients who underwent total knee replacement.

The team enrolled 215 patients and assigned them to 1 of 3 post-operative prophylaxis regimens: betrixaban at 15 mg twice daily, betrixaban at 40 mg twice daily, or enoxaparin at 30 mg every 12 hours—all for 10 to 14 days.

The primary efficacy outcome was the incidence of VTE during the dosing period, and 175 patients were evaluable for this outcome. VTE occurred in 20% of patients in the 15 mg betrixaban arm (14/70), 15% in the 40 mg betrixaban arm (10/65), and 10% (4/40) in the enoxaparin arm.

Safety outcomes included major and clinically significant non-major bleeds through 48 hours after treatment. There were no bleeds in the 15 mg betrixaban arm, 2 (2.4%) clinically significant non-major bleeds in the 40 mg betrixaban arm, and 1 (2.3%) major bleed and 2 (4.6%) clinically significant non-major bleeds in the enoxaparin arm.

Betrixaban is currently being tested in the phase 3 APEX trial for the prevention of VTE in acute medically ill patients. Portola said it expects to complete enrollment in APEX by the end of this year and report top-line data in the first quarter of 2016.

If the trial is successful, the company plans to submit a new drug application to the FDA later in 2016 under the fast track designation.

About fast track designation

The FDA’s fast track program is designed to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the drug may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings with the FDA to discuss the drug’s development plan and ensure collection of the appropriate data needed to support drug approval. And the designation allows for more frequent written communication from the FDA about things such as the design of proposed clinical trials and the use of biomarkers.

Monoclonal antibodies

Photo by Linda Bartlett

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has agreed to provide accelerated assessment for daratumumab.

The drug is under review as monotherapy for patients with relapsed and refractory multiple myeloma (MM).

The CHMP grants accelerated assessment when a product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

Accelerated assessment shortens the review period from 210 days to 150 days.

About daratumumab

Daratumumab is an investigational monoclonal antibody that works by binding to CD38 on the surface of MM cells. In doing so, daratumumab triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.

In July 2013, daratumumab was granted orphan drug status by the European Medicines Agency for the treatment of plasma cell myeloma.

The drug has been accepted for priority review in the US as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an immunomodulatory agent or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.

In August 2012, Janssen Biotech, Inc. and Genmab entered an agreement that granted Janssen an exclusive worldwide license to develop, manufacture, and commercialize daratumumab.

Daratumumab trials

The marketing authorization application for daratumumab includes data from the phase 2 MMY2002 (SIRIUS) study, the phase 1/2 GEN501 study, and 3 additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.

Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Monoclonal antibodies

Photo by Linda Bartlett

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has agreed to provide accelerated assessment for daratumumab.

The drug is under review as monotherapy for patients with relapsed and refractory multiple myeloma (MM).

The CHMP grants accelerated assessment when a product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

Accelerated assessment shortens the review period from 210 days to 150 days.

About daratumumab

Daratumumab is an investigational monoclonal antibody that works by binding to CD38 on the surface of MM cells. In doing so, daratumumab triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.

In July 2013, daratumumab was granted orphan drug status by the European Medicines Agency for the treatment of plasma cell myeloma.

The drug has been accepted for priority review in the US as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an immunomodulatory agent or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.

In August 2012, Janssen Biotech, Inc. and Genmab entered an agreement that granted Janssen an exclusive worldwide license to develop, manufacture, and commercialize daratumumab.

Daratumumab trials

The marketing authorization application for daratumumab includes data from the phase 2 MMY2002 (SIRIUS) study, the phase 1/2 GEN501 study, and 3 additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.

Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Monoclonal antibodies

Photo by Linda Bartlett

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has agreed to provide accelerated assessment for daratumumab.

The drug is under review as monotherapy for patients with relapsed and refractory multiple myeloma (MM).

The CHMP grants accelerated assessment when a product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

Accelerated assessment shortens the review period from 210 days to 150 days.

About daratumumab

Daratumumab is an investigational monoclonal antibody that works by binding to CD38 on the surface of MM cells. In doing so, daratumumab triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.

In July 2013, daratumumab was granted orphan drug status by the European Medicines Agency for the treatment of plasma cell myeloma.

The drug has been accepted for priority review in the US as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an immunomodulatory agent or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.

In August 2012, Janssen Biotech, Inc. and Genmab entered an agreement that granted Janssen an exclusive worldwide license to develop, manufacture, and commercialize daratumumab.

Daratumumab trials

The marketing authorization application for daratumumab includes data from the phase 2 MMY2002 (SIRIUS) study, the phase 1/2 GEN501 study, and 3 additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.

Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Antihemophilic factor

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the recombinant factor VIII Fc fusion protein efmoroctocog alfa (Elocta) to treat patients with hemophilia A.

The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to

deliver its final decision within 3 months.

If approved by the EC, efmoroctocog alfa would be the first hemophilia A treatment with prolonged circulation available in the European Union (plus Iceland, Lichtenstein, and Norway).

The CHMP’s positive opinion of efmoroctocog alfa was based on results from 2 phase 3 studies—A-LONG and Kids A-LONG.

A-LONG

The A-LONG study included 165 previously treated males 12 years of age and older with severe hemophilia A. Researchers evaluated individualized and weekly prophylaxis to reduce or prevent bleeding episodes and on-demand dosing to treat bleeding episodes.

Prophylaxis with efmoroctocog alfa resulted in low annualized bleeding rates, and a majority of bleeding episodes were controlled with a single injection of efmoroctocog alfa.

None of the patients developed neutralizing antibodies, efmoroctocog alfa was considered well-tolerated, and the product had a prolonged half-life when compared with rFVIII.

Kids A-LONG

The Kids A-LONG study included 71 boys (younger than 12) with severe hemophilia A who had at least 50 prior exposure days to FVIII therapies.

The children saw their median annualized bleeding rate decrease with efmoroctocog alfa, and close to half of the children did not have any bleeding episodes while they were receiving efmoroctocog alfa.

None of the patients developed inhibitors, and researchers said adverse events were typical of a pediatric hemophilia population.

ASPIRE

Participants in both the A-LONG and Kids A-LONG trials were able to enroll in ASPIRE, a phase 3 extension study evaluating the long-term safety and efficacy of efmoroctocog alfa.

Interim results of ASPIRE suggested that extended treatment with efmoroctocog alfa was largely safe and effective.

Efmoroctocog alfa development

Elocta is the European trade name for efmoroctocog alfa, which is known as Eloctate in the US, Canada, Australia, New Zealand, and Japan, where it is approved for the treatment of hemophilia A.

Biogen and Sobi are collaboration partners in the development and commercialization of efmoroctocog alfa for hemophilia A.

Last year, Sobi exercised its opt-in right to assume final development and commercialization of efmoroctocog alfa in the Sobi territories (essentially, Europe, North Africa, Russia, and certain countries in the Middle East). Biogen leads development for efmoroctocog alfa, has manufacturing rights, and has commercialization rights in North America and all other regions in the world excluding the Sobi territories.

Antihemophilic factor

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the recombinant factor VIII Fc fusion protein efmoroctocog alfa (Elocta) to treat patients with hemophilia A.

The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to

deliver its final decision within 3 months.

If approved by the EC, efmoroctocog alfa would be the first hemophilia A treatment with prolonged circulation available in the European Union (plus Iceland, Lichtenstein, and Norway).

The CHMP’s positive opinion of efmoroctocog alfa was based on results from 2 phase 3 studies—A-LONG and Kids A-LONG.

A-LONG

The A-LONG study included 165 previously treated males 12 years of age and older with severe hemophilia A. Researchers evaluated individualized and weekly prophylaxis to reduce or prevent bleeding episodes and on-demand dosing to treat bleeding episodes.

Prophylaxis with efmoroctocog alfa resulted in low annualized bleeding rates, and a majority of bleeding episodes were controlled with a single injection of efmoroctocog alfa.

None of the patients developed neutralizing antibodies, efmoroctocog alfa was considered well-tolerated, and the product had a prolonged half-life when compared with rFVIII.

Kids A-LONG

The Kids A-LONG study included 71 boys (younger than 12) with severe hemophilia A who had at least 50 prior exposure days to FVIII therapies.

The children saw their median annualized bleeding rate decrease with efmoroctocog alfa, and close to half of the children did not have any bleeding episodes while they were receiving efmoroctocog alfa.

None of the patients developed inhibitors, and researchers said adverse events were typical of a pediatric hemophilia population.

ASPIRE

Participants in both the A-LONG and Kids A-LONG trials were able to enroll in ASPIRE, a phase 3 extension study evaluating the long-term safety and efficacy of efmoroctocog alfa.

Interim results of ASPIRE suggested that extended treatment with efmoroctocog alfa was largely safe and effective.

Efmoroctocog alfa development

Elocta is the European trade name for efmoroctocog alfa, which is known as Eloctate in the US, Canada, Australia, New Zealand, and Japan, where it is approved for the treatment of hemophilia A.

Biogen and Sobi are collaboration partners in the development and commercialization of efmoroctocog alfa for hemophilia A.

Last year, Sobi exercised its opt-in right to assume final development and commercialization of efmoroctocog alfa in the Sobi territories (essentially, Europe, North Africa, Russia, and certain countries in the Middle East). Biogen leads development for efmoroctocog alfa, has manufacturing rights, and has commercialization rights in North America and all other regions in the world excluding the Sobi territories.

Antihemophilic factor

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the recombinant factor VIII Fc fusion protein efmoroctocog alfa (Elocta) to treat patients with hemophilia A.

The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to

deliver its final decision within 3 months.

If approved by the EC, efmoroctocog alfa would be the first hemophilia A treatment with prolonged circulation available in the European Union (plus Iceland, Lichtenstein, and Norway).

The CHMP’s positive opinion of efmoroctocog alfa was based on results from 2 phase 3 studies—A-LONG and Kids A-LONG.

A-LONG

The A-LONG study included 165 previously treated males 12 years of age and older with severe hemophilia A. Researchers evaluated individualized and weekly prophylaxis to reduce or prevent bleeding episodes and on-demand dosing to treat bleeding episodes.

Prophylaxis with efmoroctocog alfa resulted in low annualized bleeding rates, and a majority of bleeding episodes were controlled with a single injection of efmoroctocog alfa.

None of the patients developed neutralizing antibodies, efmoroctocog alfa was considered well-tolerated, and the product had a prolonged half-life when compared with rFVIII.

Kids A-LONG

The Kids A-LONG study included 71 boys (younger than 12) with severe hemophilia A who had at least 50 prior exposure days to FVIII therapies.

The children saw their median annualized bleeding rate decrease with efmoroctocog alfa, and close to half of the children did not have any bleeding episodes while they were receiving efmoroctocog alfa.

None of the patients developed inhibitors, and researchers said adverse events were typical of a pediatric hemophilia population.

ASPIRE

Participants in both the A-LONG and Kids A-LONG trials were able to enroll in ASPIRE, a phase 3 extension study evaluating the long-term safety and efficacy of efmoroctocog alfa.

Interim results of ASPIRE suggested that extended treatment with efmoroctocog alfa was largely safe and effective.

Efmoroctocog alfa development

Elocta is the European trade name for efmoroctocog alfa, which is known as Eloctate in the US, Canada, Australia, New Zealand, and Japan, where it is approved for the treatment of hemophilia A.

Biogen and Sobi are collaboration partners in the development and commercialization of efmoroctocog alfa for hemophilia A.

Last year, Sobi exercised its opt-in right to assume final development and commercialization of efmoroctocog alfa in the Sobi territories (essentially, Europe, North Africa, Russia, and certain countries in the Middle East). Biogen leads development for efmoroctocog alfa, has manufacturing rights, and has commercialization rights in North America and all other regions in the world excluding the Sobi territories.

Micrograph showing AML

Image by Lance Liotta

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for azacitidine for injection (Vidaza).

The CHMP is recommending that azacitidine be approved to treat adults age 65 and older with acute myeloid leukemia (AML) who are not eligible for hematopoietic stem cell transplant (HSCT) and have more than 30% blasts according to the WHO classification.

The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision in 2 months.

The CHMP said this new indication for azacitidine would bring significant clinical benefit in comparison with existing therapies. If the EC follows the CHMP’s recommendation, azacitidine will receive extended market protection in all its indications for an additional year throughout the European Economic Area.

Azacitidine is already approved in the European Economic Area for the treatment of HSCT-ineligible adults diagnosed with intermediate-2- and high-risk myelodysplastic syndromes; chronic myelomonocytic leukemia with 10%-29% marrow blasts without myeloproliferative disorder; or AML with 20%-30% blasts and multi-lineage dysplasia.

AML-001 trial

The CHMP’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.

Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle) or best supportive care only.

Patients were then randomized to receive either azacitidine (75 mg/m²/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).

Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).

One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.

Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.

Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33%, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively. 

Micrograph showing AML

Image by Lance Liotta

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for azacitidine for injection (Vidaza).

The CHMP is recommending that azacitidine be approved to treat adults age 65 and older with acute myeloid leukemia (AML) who are not eligible for hematopoietic stem cell transplant (HSCT) and have more than 30% blasts according to the WHO classification.

The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision in 2 months.

The CHMP said this new indication for azacitidine would bring significant clinical benefit in comparison with existing therapies. If the EC follows the CHMP’s recommendation, azacitidine will receive extended market protection in all its indications for an additional year throughout the European Economic Area.

Azacitidine is already approved in the European Economic Area for the treatment of HSCT-ineligible adults diagnosed with intermediate-2- and high-risk myelodysplastic syndromes; chronic myelomonocytic leukemia with 10%-29% marrow blasts without myeloproliferative disorder; or AML with 20%-30% blasts and multi-lineage dysplasia.

AML-001 trial

The CHMP’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.

Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle) or best supportive care only.

Patients were then randomized to receive either azacitidine (75 mg/m²/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).

Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).

One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.

Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.

Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33%, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively. 

Micrograph showing AML

Image by Lance Liotta

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for azacitidine for injection (Vidaza).

The CHMP is recommending that azacitidine be approved to treat adults age 65 and older with acute myeloid leukemia (AML) who are not eligible for hematopoietic stem cell transplant (HSCT) and have more than 30% blasts according to the WHO classification.

The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision in 2 months.

The CHMP said this new indication for azacitidine would bring significant clinical benefit in comparison with existing therapies. If the EC follows the CHMP’s recommendation, azacitidine will receive extended market protection in all its indications for an additional year throughout the European Economic Area.

Azacitidine is already approved in the European Economic Area for the treatment of HSCT-ineligible adults diagnosed with intermediate-2- and high-risk myelodysplastic syndromes; chronic myelomonocytic leukemia with 10%-29% marrow blasts without myeloproliferative disorder; or AML with 20%-30% blasts and multi-lineage dysplasia.

AML-001 trial

The CHMP’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.

Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle) or best supportive care only.

Patients were then randomized to receive either azacitidine (75 mg/m²/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).

Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).

One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.

Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.

Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33%, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively.