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Idarucizumab reversed dabigatran completely and rapidly in study
One IV 5-g dose of idarucizumab completely, rapidly, and safely reversed the anticoagulant effect of dabigatran, according to final results for 503 patients in the multicenter, prospective, open-label, uncontrolled RE-VERSE AD study.
Uncontrolled bleeding stopped a median of 2.5 hours after 134 patients received idarucizumab. In a separate group of 202 patients, 197 were able to undergo urgent procedures after a median of 1.6 hours, Charles V. Pollack Jr., MD, and his associates reported at the International Society on Thrombosis and Haemostasis congress. The report was simultaneously published in the New England Journal of Medicine.
Idarucizumab was specifically developed to reverse the anticoagulant effect of dabigatran. Many countries have already licensed the humanized monoclonal antibody fragment based on interim results for the first 90 patients enrolled in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study (NCT02104947), noted Dr. Pollack, of Thomas Jefferson University, Philadelphia.
The final RE-VERSE AD cohort included 301 patients with uncontrolled gastrointestinal, intracranial, or trauma-related bleeding and 202 patients who needed urgent procedures. Participants from both groups typically were white, in their late 70s (age range, 21-96 years), and receiving 110 mg (75-150 mg) dabigatran twice daily. The primary endpoint was maximum percentage reversal within 4 hours after patients received idarucizumab, based on diluted thrombin time and ecarin clotting time.
The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100% to 100%) in more than 98% of patients, and the effect usually lasted 24 hours. Among patients who underwent procedures, intraprocedural hemostasis was considered normal in 93% of cases, mildly abnormal in 5% of cases, and moderately abnormal in 2% of cases, the researchers noted. Seven patients received another dose of idarucizumab after developing recurrent or postoperative bleeding.
A total of 24 patients had an adjudicated thrombotic event within 30 days after receiving idarucizumab. These events included pulmonary embolism, systemic embolism, ischemic stroke, deep vein thrombosis, and myocardial infarction. The fact that many patients did not restart anticoagulation could have contributed to these thrombotic events, the researchers asserted. They noted that idarucizumab had no procoagulant activity in studies of animals and healthy human volunteers.
About 19% of patients in both groups died within 90 days. “Patients enrolled in this study were elderly, had numerous coexisting conditions, and presented with serious index events, such as intracranial hemorrhage, multiple trauma, sepsis, acute abdomen, or open fracture,” the investigators wrote. “Most of the deaths that occurred within 5 days after enrollment appeared to be related to the severity of the index event or to coexisting conditions, such as respiratory failure or multiple organ failure, whereas deaths that occurred after 30 days were more likely to be independent events or related to coexisting conditions.”
Boehringer Ingelheim Pharmaceuticals provided funding. Dr. Pollack disclosed grant support from Boehringer Ingelheim during the course of the study and ties to Daiichi Sankyo, Portola, CSL Behring, Bristol-Myers Squibb/Pfizer, Janssen Pharma, and AstraZeneca. Eighteen coinvestigators also disclosed ties to Boehringer Ingelheim and a number of other pharmaceutical companies. Two coinvestigators had no relevant financial disclosures.
One IV 5-g dose of idarucizumab completely, rapidly, and safely reversed the anticoagulant effect of dabigatran, according to final results for 503 patients in the multicenter, prospective, open-label, uncontrolled RE-VERSE AD study.
Uncontrolled bleeding stopped a median of 2.5 hours after 134 patients received idarucizumab. In a separate group of 202 patients, 197 were able to undergo urgent procedures after a median of 1.6 hours, Charles V. Pollack Jr., MD, and his associates reported at the International Society on Thrombosis and Haemostasis congress. The report was simultaneously published in the New England Journal of Medicine.
Idarucizumab was specifically developed to reverse the anticoagulant effect of dabigatran. Many countries have already licensed the humanized monoclonal antibody fragment based on interim results for the first 90 patients enrolled in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study (NCT02104947), noted Dr. Pollack, of Thomas Jefferson University, Philadelphia.
The final RE-VERSE AD cohort included 301 patients with uncontrolled gastrointestinal, intracranial, or trauma-related bleeding and 202 patients who needed urgent procedures. Participants from both groups typically were white, in their late 70s (age range, 21-96 years), and receiving 110 mg (75-150 mg) dabigatran twice daily. The primary endpoint was maximum percentage reversal within 4 hours after patients received idarucizumab, based on diluted thrombin time and ecarin clotting time.
The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100% to 100%) in more than 98% of patients, and the effect usually lasted 24 hours. Among patients who underwent procedures, intraprocedural hemostasis was considered normal in 93% of cases, mildly abnormal in 5% of cases, and moderately abnormal in 2% of cases, the researchers noted. Seven patients received another dose of idarucizumab after developing recurrent or postoperative bleeding.
A total of 24 patients had an adjudicated thrombotic event within 30 days after receiving idarucizumab. These events included pulmonary embolism, systemic embolism, ischemic stroke, deep vein thrombosis, and myocardial infarction. The fact that many patients did not restart anticoagulation could have contributed to these thrombotic events, the researchers asserted. They noted that idarucizumab had no procoagulant activity in studies of animals and healthy human volunteers.
About 19% of patients in both groups died within 90 days. “Patients enrolled in this study were elderly, had numerous coexisting conditions, and presented with serious index events, such as intracranial hemorrhage, multiple trauma, sepsis, acute abdomen, or open fracture,” the investigators wrote. “Most of the deaths that occurred within 5 days after enrollment appeared to be related to the severity of the index event or to coexisting conditions, such as respiratory failure or multiple organ failure, whereas deaths that occurred after 30 days were more likely to be independent events or related to coexisting conditions.”
Boehringer Ingelheim Pharmaceuticals provided funding. Dr. Pollack disclosed grant support from Boehringer Ingelheim during the course of the study and ties to Daiichi Sankyo, Portola, CSL Behring, Bristol-Myers Squibb/Pfizer, Janssen Pharma, and AstraZeneca. Eighteen coinvestigators also disclosed ties to Boehringer Ingelheim and a number of other pharmaceutical companies. Two coinvestigators had no relevant financial disclosures.
One IV 5-g dose of idarucizumab completely, rapidly, and safely reversed the anticoagulant effect of dabigatran, according to final results for 503 patients in the multicenter, prospective, open-label, uncontrolled RE-VERSE AD study.
Uncontrolled bleeding stopped a median of 2.5 hours after 134 patients received idarucizumab. In a separate group of 202 patients, 197 were able to undergo urgent procedures after a median of 1.6 hours, Charles V. Pollack Jr., MD, and his associates reported at the International Society on Thrombosis and Haemostasis congress. The report was simultaneously published in the New England Journal of Medicine.
Idarucizumab was specifically developed to reverse the anticoagulant effect of dabigatran. Many countries have already licensed the humanized monoclonal antibody fragment based on interim results for the first 90 patients enrolled in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study (NCT02104947), noted Dr. Pollack, of Thomas Jefferson University, Philadelphia.
The final RE-VERSE AD cohort included 301 patients with uncontrolled gastrointestinal, intracranial, or trauma-related bleeding and 202 patients who needed urgent procedures. Participants from both groups typically were white, in their late 70s (age range, 21-96 years), and receiving 110 mg (75-150 mg) dabigatran twice daily. The primary endpoint was maximum percentage reversal within 4 hours after patients received idarucizumab, based on diluted thrombin time and ecarin clotting time.
The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100% to 100%) in more than 98% of patients, and the effect usually lasted 24 hours. Among patients who underwent procedures, intraprocedural hemostasis was considered normal in 93% of cases, mildly abnormal in 5% of cases, and moderately abnormal in 2% of cases, the researchers noted. Seven patients received another dose of idarucizumab after developing recurrent or postoperative bleeding.
A total of 24 patients had an adjudicated thrombotic event within 30 days after receiving idarucizumab. These events included pulmonary embolism, systemic embolism, ischemic stroke, deep vein thrombosis, and myocardial infarction. The fact that many patients did not restart anticoagulation could have contributed to these thrombotic events, the researchers asserted. They noted that idarucizumab had no procoagulant activity in studies of animals and healthy human volunteers.
About 19% of patients in both groups died within 90 days. “Patients enrolled in this study were elderly, had numerous coexisting conditions, and presented with serious index events, such as intracranial hemorrhage, multiple trauma, sepsis, acute abdomen, or open fracture,” the investigators wrote. “Most of the deaths that occurred within 5 days after enrollment appeared to be related to the severity of the index event or to coexisting conditions, such as respiratory failure or multiple organ failure, whereas deaths that occurred after 30 days were more likely to be independent events or related to coexisting conditions.”
Boehringer Ingelheim Pharmaceuticals provided funding. Dr. Pollack disclosed grant support from Boehringer Ingelheim during the course of the study and ties to Daiichi Sankyo, Portola, CSL Behring, Bristol-Myers Squibb/Pfizer, Janssen Pharma, and AstraZeneca. Eighteen coinvestigators also disclosed ties to Boehringer Ingelheim and a number of other pharmaceutical companies. Two coinvestigators had no relevant financial disclosures.
FROM 2017 ISTH CONGRESS
Key clinical point:
Major finding: Uncontrolled bleeding stopped a median of 2.5 hours after 134 patients received idarucizumab. In a separate group, 197 patients were able to undergo urgent procedures after a median of 1.6 hours.
Data source: A multicenter, prospective, open-label study of 503 patients (RE-VERSE AD).
Disclosures: Boehringer Ingelheim Pharmaceuticals provided funding. Dr. Pollack disclosed grant support from Boehringer Ingelheim during the course of the study and ties to Daiichi Sankyo, Portola, CSL Behring, BMS/Pfizer, Janssen Pharma, and AstraZeneca. Eighteen coinvestigators disclosed ties to Boehringer Ingelheim and a number of other pharmaceutical companies. Two coinvestigators had no relevant financial disclosures.
Monthly fitusiran showed promise in small phase I hemophilia trial
and increased thrombin production, according to the results of a small phase I dose-escalation study.
Compared with baseline, levels of antithrombin dropped by 70%-89%, K. John Pasi, MB, ChB, PhD, of the Royal London Haemophilia Centre and the London School of Medicine and Dentistry and his associates reported at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine. There were no thromboembolic events during the study, and the most common adverse events were mild injection-site reactions, they added.
Patients with hemophilia typically need frequent infusions of clotting factors, creating an urgent need for new therapies. Fitusiran is an investigational RNA interference (RNAi) therapy that targets antithrombin. This multicenter, open-label, phase I study included four healthy volunteers and 25 patients with moderate or severe hemophilia A or B without inhibitors. The healthy participants received a single subcutaneous injection of fitusiran (0.03 mg/kg) or placebo. The hemophilia patients received three injections of fitusiran either once weekly (0.015, 0.045, or 0.075 mg/kg) or once monthly (0.225, 0.45, 0.9, or 1.8 mg/kg, or a fixed dose of 80 mg (N Engl J Med. 2017 July 10. doi: 10.1056/NEJMoa1616569).
The single fitusiran dose and the weekly treatment regimens both produced consistent, sustained drops in plasma antithrombin levels, which supported a longer interval between doses, the researchers said. A monthly dose of 0.225 mg/kg cut antithrombin levels by about 70%, compared with baseline (standard deviation, ±9%), while a monthly dose of 1.8 mg/kg produced about an 89% (standard deviation, ±1%) drop in antithrombin levels. The fixed 80-mg dose consistently lowered antithrombin levels by about 87%, compared with baseline. The decreases in antithrombin varied little during the weeks between doses and were associated with increased thrombin generation, regardless of whether patients had hemophilia A or B, Dr. Pasi and his associates said.
One patient stopped treatment because of severe chest pain, but the investigators ruled out thrombosis as a cause. Fitusiran targets the liver, and 36% of patients developed transient increases in liver aminotransferase levels, they noted. Most of these patients had a history of hepatitis C virus infection. An extension study (NCT02554773) is ongoing to assess longer-term safety and efficacy findings. The investigators also are studying fitusiran in patients with inhibitory alloantibodies.
Alnylam Pharmaceuticals provided funding. Dr. Pasi disclosed research funding, advisory board fees, and travel grants from Alnylam and Genzyme. Four coinvestigators also disclosed receiving support from Alnylam during the conduct of the study.
and increased thrombin production, according to the results of a small phase I dose-escalation study.
Compared with baseline, levels of antithrombin dropped by 70%-89%, K. John Pasi, MB, ChB, PhD, of the Royal London Haemophilia Centre and the London School of Medicine and Dentistry and his associates reported at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine. There were no thromboembolic events during the study, and the most common adverse events were mild injection-site reactions, they added.
Patients with hemophilia typically need frequent infusions of clotting factors, creating an urgent need for new therapies. Fitusiran is an investigational RNA interference (RNAi) therapy that targets antithrombin. This multicenter, open-label, phase I study included four healthy volunteers and 25 patients with moderate or severe hemophilia A or B without inhibitors. The healthy participants received a single subcutaneous injection of fitusiran (0.03 mg/kg) or placebo. The hemophilia patients received three injections of fitusiran either once weekly (0.015, 0.045, or 0.075 mg/kg) or once monthly (0.225, 0.45, 0.9, or 1.8 mg/kg, or a fixed dose of 80 mg (N Engl J Med. 2017 July 10. doi: 10.1056/NEJMoa1616569).
The single fitusiran dose and the weekly treatment regimens both produced consistent, sustained drops in plasma antithrombin levels, which supported a longer interval between doses, the researchers said. A monthly dose of 0.225 mg/kg cut antithrombin levels by about 70%, compared with baseline (standard deviation, ±9%), while a monthly dose of 1.8 mg/kg produced about an 89% (standard deviation, ±1%) drop in antithrombin levels. The fixed 80-mg dose consistently lowered antithrombin levels by about 87%, compared with baseline. The decreases in antithrombin varied little during the weeks between doses and were associated with increased thrombin generation, regardless of whether patients had hemophilia A or B, Dr. Pasi and his associates said.
One patient stopped treatment because of severe chest pain, but the investigators ruled out thrombosis as a cause. Fitusiran targets the liver, and 36% of patients developed transient increases in liver aminotransferase levels, they noted. Most of these patients had a history of hepatitis C virus infection. An extension study (NCT02554773) is ongoing to assess longer-term safety and efficacy findings. The investigators also are studying fitusiran in patients with inhibitory alloantibodies.
Alnylam Pharmaceuticals provided funding. Dr. Pasi disclosed research funding, advisory board fees, and travel grants from Alnylam and Genzyme. Four coinvestigators also disclosed receiving support from Alnylam during the conduct of the study.
and increased thrombin production, according to the results of a small phase I dose-escalation study.
Compared with baseline, levels of antithrombin dropped by 70%-89%, K. John Pasi, MB, ChB, PhD, of the Royal London Haemophilia Centre and the London School of Medicine and Dentistry and his associates reported at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine. There were no thromboembolic events during the study, and the most common adverse events were mild injection-site reactions, they added.
Patients with hemophilia typically need frequent infusions of clotting factors, creating an urgent need for new therapies. Fitusiran is an investigational RNA interference (RNAi) therapy that targets antithrombin. This multicenter, open-label, phase I study included four healthy volunteers and 25 patients with moderate or severe hemophilia A or B without inhibitors. The healthy participants received a single subcutaneous injection of fitusiran (0.03 mg/kg) or placebo. The hemophilia patients received three injections of fitusiran either once weekly (0.015, 0.045, or 0.075 mg/kg) or once monthly (0.225, 0.45, 0.9, or 1.8 mg/kg, or a fixed dose of 80 mg (N Engl J Med. 2017 July 10. doi: 10.1056/NEJMoa1616569).
The single fitusiran dose and the weekly treatment regimens both produced consistent, sustained drops in plasma antithrombin levels, which supported a longer interval between doses, the researchers said. A monthly dose of 0.225 mg/kg cut antithrombin levels by about 70%, compared with baseline (standard deviation, ±9%), while a monthly dose of 1.8 mg/kg produced about an 89% (standard deviation, ±1%) drop in antithrombin levels. The fixed 80-mg dose consistently lowered antithrombin levels by about 87%, compared with baseline. The decreases in antithrombin varied little during the weeks between doses and were associated with increased thrombin generation, regardless of whether patients had hemophilia A or B, Dr. Pasi and his associates said.
One patient stopped treatment because of severe chest pain, but the investigators ruled out thrombosis as a cause. Fitusiran targets the liver, and 36% of patients developed transient increases in liver aminotransferase levels, they noted. Most of these patients had a history of hepatitis C virus infection. An extension study (NCT02554773) is ongoing to assess longer-term safety and efficacy findings. The investigators also are studying fitusiran in patients with inhibitory alloantibodies.
Alnylam Pharmaceuticals provided funding. Dr. Pasi disclosed research funding, advisory board fees, and travel grants from Alnylam and Genzyme. Four coinvestigators also disclosed receiving support from Alnylam during the conduct of the study.
FROM THE 2017 ISTH CONGRESS
Key clinical point: Once-monthly subcutaneous treatment with fitusiran led to dose-dependent lowering of antithrombin levels and increased thrombin production among patients with hemophilia A or B without inhibitors.
Major finding: Compared with baseline, levels of antithrombin dropped by 70%-89%. There were no episodes of thrombosis, and the most common adverse events were injection-site reactions.
Data source: A phase I dose-escalation study.
Disclosures: Alnylam Pharmaceuticals provided funding. Dr. Pasi disclosed research funding, advisory board fees, and travel grants from Alnylam and Genzyme. Four coinvestigators also disclosed receiving support from Alnylam during the conduct of the study.
Prophylactic emicizumab cut bleeds by 87% in hemophilia A with inhibitors
Once-weekly prophylactic therapy with emicizumab (ACE910) was associated an 87% lower rate of treated bleeding than no prophylaxis among patients with hemophilia A with inhibitors in the open-label, phase III HAVEN 1 trial.
After a median 24 weeks of treatment (range, 3-48 weeks), the 35 patients who were randomly assigned to prophylactic emicizumab (3.0 mg per kg for 4 weeks, followed by 1.5 mg per kg) had an annualized bleeding rate of 2.9 events, compared with an annualized rate of 23.3 events among the 18 patients who received no prophylaxis. The difference was statistically significant, reported Johannes Oldenburg, MD, PhD, and his associates at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jul 10. doi: 10.1056/NEJMoa1703068).
In addition, 63% of patients who received prophylactic emicizumab had no bleeding events, compared with only 6% of the comparison group, said Dr. Oldenburg of Universitaetsklinikum Bonn, Germany. Emicizumab also was associated with a 79% lower rate of treated bleeds, compared with the historic rate among 24 patients who previously had been on prophylactic bypassing agents (P less than .001). No patient developed detectable antidrug antibodies.
The most common adverse events were injection site reactions (15% of patients), followed by headache, upper respiratory tract infection, arthralgia, and fatigue. Four patients developed thrombotic microangiopathy or cavernous sinus thrombosis and skin necrosis, all of whom had experienced breakthrough bleeding for which they had received multiple infusions of activated prothrombin complex concentrate at doses averaging more than 100 U per kg per day.
Patients with severe hemophilia A typically require prophylactic factor VIII infusions two to three times a week, but 30% develop neutralizing antibodies against factor VIII (inhibitors), which increases care burden, costs, and complication rates.
Emicizumab is a recombinant humanized bispecific monoclonal antibody that restores the function of missing active factor VIII by bridging activated factor IX and factor X, the investigators noted. A phase I study linked once-weekly emicizumab prophylaxis to markedly lower bleeding rates without dose-limiting toxicities (N Engl J Med 2016;374:2044-53). Subsequently, the phase III HAVEN 1 study (NCT02622321) compared once-weekly subcutaneous prophylactic emicizumab with on-demand (episodic) and prophylactic use of bypassing agents (BPAs) in 109 adults and adolescents (12 years and older) with hemophilia A with inhibitors. The primary endpoint was the difference in rates of treated bleeds between the groups. Patients had a median age of 28 years, all were male, and most had severe hemophilia at baseline. They typically had more than nine bleeding events in the 6 months before enrollment, with bleeding in more than one target joint and factor VIII titers of 180 Bethesda units per mL.
HAVEN 1 was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. Dr. Oldenburg and 13 coinvestigators disclosed ties to Chugai, Roche, and other pharmaceutical companies. The remaining coinvestigator had no disclosures.
The results of this phase III trial are of great importance to patients with for hemophilia A, offering “an elegant new solution for treatment.” Although it is not clear how best to treat the infrequent events of breakthrough bleeding when administering emicizumab, it is evident that repeated high doses of activated prothrombin complex concentrate should be avoided. Also, how to integrate emicizumab prophylaxis with current schedules for the induction of immune tolerance to factor VIII remains to be seen.
Meanwhile, weekly subcutaneous emicizumab prophylaxis offer great reductions in bleeding rates and improve quality of life “for this very challenging patient group.” Additional studies already are underway to ascertain the benefit of emicizumab prophylaxis in children with hemophilia with inhibitors, and a study for patients with hemophilia A without inhibitors is planned.
“These are extraordinary times for innovation in hemophilia therapy, and the introduction of emicizumab represents a major contribution toward achieving an enhanced standard of care for this lifelong bleeding disorder.”
David Lillicrap, MD, is with the department of pathology and molecular medicine at Queen’s University, Kingston, Ontario. He reported having no relevant conflicts of interest. These comments are from his accompanying editorial (N Engl J Med. 2017 June 10. doi: 10.1056/NEJMe1707802).
The results of this phase III trial are of great importance to patients with for hemophilia A, offering “an elegant new solution for treatment.” Although it is not clear how best to treat the infrequent events of breakthrough bleeding when administering emicizumab, it is evident that repeated high doses of activated prothrombin complex concentrate should be avoided. Also, how to integrate emicizumab prophylaxis with current schedules for the induction of immune tolerance to factor VIII remains to be seen.
Meanwhile, weekly subcutaneous emicizumab prophylaxis offer great reductions in bleeding rates and improve quality of life “for this very challenging patient group.” Additional studies already are underway to ascertain the benefit of emicizumab prophylaxis in children with hemophilia with inhibitors, and a study for patients with hemophilia A without inhibitors is planned.
“These are extraordinary times for innovation in hemophilia therapy, and the introduction of emicizumab represents a major contribution toward achieving an enhanced standard of care for this lifelong bleeding disorder.”
David Lillicrap, MD, is with the department of pathology and molecular medicine at Queen’s University, Kingston, Ontario. He reported having no relevant conflicts of interest. These comments are from his accompanying editorial (N Engl J Med. 2017 June 10. doi: 10.1056/NEJMe1707802).
The results of this phase III trial are of great importance to patients with for hemophilia A, offering “an elegant new solution for treatment.” Although it is not clear how best to treat the infrequent events of breakthrough bleeding when administering emicizumab, it is evident that repeated high doses of activated prothrombin complex concentrate should be avoided. Also, how to integrate emicizumab prophylaxis with current schedules for the induction of immune tolerance to factor VIII remains to be seen.
Meanwhile, weekly subcutaneous emicizumab prophylaxis offer great reductions in bleeding rates and improve quality of life “for this very challenging patient group.” Additional studies already are underway to ascertain the benefit of emicizumab prophylaxis in children with hemophilia with inhibitors, and a study for patients with hemophilia A without inhibitors is planned.
“These are extraordinary times for innovation in hemophilia therapy, and the introduction of emicizumab represents a major contribution toward achieving an enhanced standard of care for this lifelong bleeding disorder.”
David Lillicrap, MD, is with the department of pathology and molecular medicine at Queen’s University, Kingston, Ontario. He reported having no relevant conflicts of interest. These comments are from his accompanying editorial (N Engl J Med. 2017 June 10. doi: 10.1056/NEJMe1707802).
Once-weekly prophylactic therapy with emicizumab (ACE910) was associated an 87% lower rate of treated bleeding than no prophylaxis among patients with hemophilia A with inhibitors in the open-label, phase III HAVEN 1 trial.
After a median 24 weeks of treatment (range, 3-48 weeks), the 35 patients who were randomly assigned to prophylactic emicizumab (3.0 mg per kg for 4 weeks, followed by 1.5 mg per kg) had an annualized bleeding rate of 2.9 events, compared with an annualized rate of 23.3 events among the 18 patients who received no prophylaxis. The difference was statistically significant, reported Johannes Oldenburg, MD, PhD, and his associates at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jul 10. doi: 10.1056/NEJMoa1703068).
In addition, 63% of patients who received prophylactic emicizumab had no bleeding events, compared with only 6% of the comparison group, said Dr. Oldenburg of Universitaetsklinikum Bonn, Germany. Emicizumab also was associated with a 79% lower rate of treated bleeds, compared with the historic rate among 24 patients who previously had been on prophylactic bypassing agents (P less than .001). No patient developed detectable antidrug antibodies.
The most common adverse events were injection site reactions (15% of patients), followed by headache, upper respiratory tract infection, arthralgia, and fatigue. Four patients developed thrombotic microangiopathy or cavernous sinus thrombosis and skin necrosis, all of whom had experienced breakthrough bleeding for which they had received multiple infusions of activated prothrombin complex concentrate at doses averaging more than 100 U per kg per day.
Patients with severe hemophilia A typically require prophylactic factor VIII infusions two to three times a week, but 30% develop neutralizing antibodies against factor VIII (inhibitors), which increases care burden, costs, and complication rates.
Emicizumab is a recombinant humanized bispecific monoclonal antibody that restores the function of missing active factor VIII by bridging activated factor IX and factor X, the investigators noted. A phase I study linked once-weekly emicizumab prophylaxis to markedly lower bleeding rates without dose-limiting toxicities (N Engl J Med 2016;374:2044-53). Subsequently, the phase III HAVEN 1 study (NCT02622321) compared once-weekly subcutaneous prophylactic emicizumab with on-demand (episodic) and prophylactic use of bypassing agents (BPAs) in 109 adults and adolescents (12 years and older) with hemophilia A with inhibitors. The primary endpoint was the difference in rates of treated bleeds between the groups. Patients had a median age of 28 years, all were male, and most had severe hemophilia at baseline. They typically had more than nine bleeding events in the 6 months before enrollment, with bleeding in more than one target joint and factor VIII titers of 180 Bethesda units per mL.
HAVEN 1 was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. Dr. Oldenburg and 13 coinvestigators disclosed ties to Chugai, Roche, and other pharmaceutical companies. The remaining coinvestigator had no disclosures.
Once-weekly prophylactic therapy with emicizumab (ACE910) was associated an 87% lower rate of treated bleeding than no prophylaxis among patients with hemophilia A with inhibitors in the open-label, phase III HAVEN 1 trial.
After a median 24 weeks of treatment (range, 3-48 weeks), the 35 patients who were randomly assigned to prophylactic emicizumab (3.0 mg per kg for 4 weeks, followed by 1.5 mg per kg) had an annualized bleeding rate of 2.9 events, compared with an annualized rate of 23.3 events among the 18 patients who received no prophylaxis. The difference was statistically significant, reported Johannes Oldenburg, MD, PhD, and his associates at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jul 10. doi: 10.1056/NEJMoa1703068).
In addition, 63% of patients who received prophylactic emicizumab had no bleeding events, compared with only 6% of the comparison group, said Dr. Oldenburg of Universitaetsklinikum Bonn, Germany. Emicizumab also was associated with a 79% lower rate of treated bleeds, compared with the historic rate among 24 patients who previously had been on prophylactic bypassing agents (P less than .001). No patient developed detectable antidrug antibodies.
The most common adverse events were injection site reactions (15% of patients), followed by headache, upper respiratory tract infection, arthralgia, and fatigue. Four patients developed thrombotic microangiopathy or cavernous sinus thrombosis and skin necrosis, all of whom had experienced breakthrough bleeding for which they had received multiple infusions of activated prothrombin complex concentrate at doses averaging more than 100 U per kg per day.
Patients with severe hemophilia A typically require prophylactic factor VIII infusions two to three times a week, but 30% develop neutralizing antibodies against factor VIII (inhibitors), which increases care burden, costs, and complication rates.
Emicizumab is a recombinant humanized bispecific monoclonal antibody that restores the function of missing active factor VIII by bridging activated factor IX and factor X, the investigators noted. A phase I study linked once-weekly emicizumab prophylaxis to markedly lower bleeding rates without dose-limiting toxicities (N Engl J Med 2016;374:2044-53). Subsequently, the phase III HAVEN 1 study (NCT02622321) compared once-weekly subcutaneous prophylactic emicizumab with on-demand (episodic) and prophylactic use of bypassing agents (BPAs) in 109 adults and adolescents (12 years and older) with hemophilia A with inhibitors. The primary endpoint was the difference in rates of treated bleeds between the groups. Patients had a median age of 28 years, all were male, and most had severe hemophilia at baseline. They typically had more than nine bleeding events in the 6 months before enrollment, with bleeding in more than one target joint and factor VIII titers of 180 Bethesda units per mL.
HAVEN 1 was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. Dr. Oldenburg and 13 coinvestigators disclosed ties to Chugai, Roche, and other pharmaceutical companies. The remaining coinvestigator had no disclosures.
From 2017 ISTH CONGRESS
Key clinical point: .
Major finding: After a median 24 weeks of treatment, the intervention group averaged 2.9 bleeds per year vs. 23.3 events in the control group.
Data source: A phase III randomized multicenter open-label trial of 109 male adolescents and adults with hemophilia A and factor VIII inhibitors.
Disclosures: HAVEN 1 was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. Dr. Oldenburg and 13 coinvestigators disclosed ties to Chugai, Roche, and other pharmaceutical companies. The remaining coinvestigator had no disclosures.