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The bispecific factor VIII–mimetic antibody ACE910 has a longer half-life than current hemophilia A treatments, potentially offering a more convenient once-weekly, subcutaneous injection, based on a study published in Blood.
In a phase I study, ACE910 was well tolerated at doses up to 1 mg/kg, with an average half life of 28 to 34 days. Based on tests in FVIII-depleted plasma, ACE910 shortened activated partial thromboplastin time (APTT) and increased peak height of thrombin generation, and exhibited a long-lasting response throughout the 24-week study period. ACE910 at 1 mg/kg resulted in APTT similar to that seen in normal plasma, although the peak height of thrombin generation did not reach normal levels.
The findings suggest “that ACE910 has the potential to reduce bleeding frequency in patients with severe hemophilia A to that of patients with mild hemophilia A, even at less frequent dosing, compared with existing FVIII and bypassing drugs. Furthermore, ACE910 may change the treatment paradigm from the current approach of maintaining trough levels of FVIII:C greater than 1% to a new approach of maintaining a constant hemostatic activity corresponding to a mild hemophilia A level,” wrote Dr. Naoki Uchida of Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, Tokyo, and colleagues (Blood. 2016 Apr 7. doi: 10.1182/blood-2015-06-650226).
Adverse events were comparable with those of placebo; 13 of 48 subjects who received ACE910 reported 15 adverse events, compared with 6 adverse events reported by 4 of 16 subjects who received placebo. Except for moderate nasopharyngitis reported in one subject, all adverse events were mild, were not dose dependent, and were similar for Japanese and white subjects. Clinical and laboratory findings showed normal coagulability with ACE910 administered at any dose.
An anti-drug antibody response was observed in 2 of 48 patients (1 Japanese, 1 white) both at 0.1 mg/kg ACE910. The anti-drug antibody responses were not IgE mediated, and no allergic symptoms were observed.
This new nonsubstitutive therapy for hemophilia A has potential to become a disruptive technology that displaces the current therapeutic approach.
By binding to factor IXa and factor X, ACE910 bypasses factor VIII in the generation of factor Xa. Since ACE910 is a distinct entity from factor VIII, anti-FVIII antibodies do not neutralize the agent.
Infusion of recombinant factor VIII has an average half-life of 8 to 12 hours, or 1.5 to 1.7 hours longer with the recent introduction of extended half-life products. Patients who develop factor VIII allo- or autoantibodies require frequent, less effective intravenous therapies. ACE910 switches up the paradigm, with repeat doses given subcutaneously once per week.
Of concern is the potential for thrombosis and anti-drug antibodies (ADAs). Despite the long half-life of ACE910 and that the phase I study was conducted on healthy volunteers with normal coagulation systems, investigators observed no rise in D-dimer formation. Similarly, no rise in thrombin-antithrombin complex was observed.
Two of 48 subjects had anti-ACE910 antibodies, and in one of these subjects ACE910 half-life was reduced, as was APTT correction and thrombin generation. These findings suggest a functional ADA. A key issue for future studies will be the number of individuals who develop ADAs after repeated exposure to ACE910.
Dr. Michael Makris is professor of haemostasis and thrombosis at the University of Sheffield (England). These remarks were part of an editorial accompanying a report in Blood (2016 Apr 7. doi: 10.1182/blood-2016-01-691469).
This new nonsubstitutive therapy for hemophilia A has potential to become a disruptive technology that displaces the current therapeutic approach.
By binding to factor IXa and factor X, ACE910 bypasses factor VIII in the generation of factor Xa. Since ACE910 is a distinct entity from factor VIII, anti-FVIII antibodies do not neutralize the agent.
Infusion of recombinant factor VIII has an average half-life of 8 to 12 hours, or 1.5 to 1.7 hours longer with the recent introduction of extended half-life products. Patients who develop factor VIII allo- or autoantibodies require frequent, less effective intravenous therapies. ACE910 switches up the paradigm, with repeat doses given subcutaneously once per week.
Of concern is the potential for thrombosis and anti-drug antibodies (ADAs). Despite the long half-life of ACE910 and that the phase I study was conducted on healthy volunteers with normal coagulation systems, investigators observed no rise in D-dimer formation. Similarly, no rise in thrombin-antithrombin complex was observed.
Two of 48 subjects had anti-ACE910 antibodies, and in one of these subjects ACE910 half-life was reduced, as was APTT correction and thrombin generation. These findings suggest a functional ADA. A key issue for future studies will be the number of individuals who develop ADAs after repeated exposure to ACE910.
Dr. Michael Makris is professor of haemostasis and thrombosis at the University of Sheffield (England). These remarks were part of an editorial accompanying a report in Blood (2016 Apr 7. doi: 10.1182/blood-2016-01-691469).
This new nonsubstitutive therapy for hemophilia A has potential to become a disruptive technology that displaces the current therapeutic approach.
By binding to factor IXa and factor X, ACE910 bypasses factor VIII in the generation of factor Xa. Since ACE910 is a distinct entity from factor VIII, anti-FVIII antibodies do not neutralize the agent.
Infusion of recombinant factor VIII has an average half-life of 8 to 12 hours, or 1.5 to 1.7 hours longer with the recent introduction of extended half-life products. Patients who develop factor VIII allo- or autoantibodies require frequent, less effective intravenous therapies. ACE910 switches up the paradigm, with repeat doses given subcutaneously once per week.
Of concern is the potential for thrombosis and anti-drug antibodies (ADAs). Despite the long half-life of ACE910 and that the phase I study was conducted on healthy volunteers with normal coagulation systems, investigators observed no rise in D-dimer formation. Similarly, no rise in thrombin-antithrombin complex was observed.
Two of 48 subjects had anti-ACE910 antibodies, and in one of these subjects ACE910 half-life was reduced, as was APTT correction and thrombin generation. These findings suggest a functional ADA. A key issue for future studies will be the number of individuals who develop ADAs after repeated exposure to ACE910.
Dr. Michael Makris is professor of haemostasis and thrombosis at the University of Sheffield (England). These remarks were part of an editorial accompanying a report in Blood (2016 Apr 7. doi: 10.1182/blood-2016-01-691469).
The bispecific factor VIII–mimetic antibody ACE910 has a longer half-life than current hemophilia A treatments, potentially offering a more convenient once-weekly, subcutaneous injection, based on a study published in Blood.
In a phase I study, ACE910 was well tolerated at doses up to 1 mg/kg, with an average half life of 28 to 34 days. Based on tests in FVIII-depleted plasma, ACE910 shortened activated partial thromboplastin time (APTT) and increased peak height of thrombin generation, and exhibited a long-lasting response throughout the 24-week study period. ACE910 at 1 mg/kg resulted in APTT similar to that seen in normal plasma, although the peak height of thrombin generation did not reach normal levels.
The findings suggest “that ACE910 has the potential to reduce bleeding frequency in patients with severe hemophilia A to that of patients with mild hemophilia A, even at less frequent dosing, compared with existing FVIII and bypassing drugs. Furthermore, ACE910 may change the treatment paradigm from the current approach of maintaining trough levels of FVIII:C greater than 1% to a new approach of maintaining a constant hemostatic activity corresponding to a mild hemophilia A level,” wrote Dr. Naoki Uchida of Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, Tokyo, and colleagues (Blood. 2016 Apr 7. doi: 10.1182/blood-2015-06-650226).
Adverse events were comparable with those of placebo; 13 of 48 subjects who received ACE910 reported 15 adverse events, compared with 6 adverse events reported by 4 of 16 subjects who received placebo. Except for moderate nasopharyngitis reported in one subject, all adverse events were mild, were not dose dependent, and were similar for Japanese and white subjects. Clinical and laboratory findings showed normal coagulability with ACE910 administered at any dose.
An anti-drug antibody response was observed in 2 of 48 patients (1 Japanese, 1 white) both at 0.1 mg/kg ACE910. The anti-drug antibody responses were not IgE mediated, and no allergic symptoms were observed.
The bispecific factor VIII–mimetic antibody ACE910 has a longer half-life than current hemophilia A treatments, potentially offering a more convenient once-weekly, subcutaneous injection, based on a study published in Blood.
In a phase I study, ACE910 was well tolerated at doses up to 1 mg/kg, with an average half life of 28 to 34 days. Based on tests in FVIII-depleted plasma, ACE910 shortened activated partial thromboplastin time (APTT) and increased peak height of thrombin generation, and exhibited a long-lasting response throughout the 24-week study period. ACE910 at 1 mg/kg resulted in APTT similar to that seen in normal plasma, although the peak height of thrombin generation did not reach normal levels.
The findings suggest “that ACE910 has the potential to reduce bleeding frequency in patients with severe hemophilia A to that of patients with mild hemophilia A, even at less frequent dosing, compared with existing FVIII and bypassing drugs. Furthermore, ACE910 may change the treatment paradigm from the current approach of maintaining trough levels of FVIII:C greater than 1% to a new approach of maintaining a constant hemostatic activity corresponding to a mild hemophilia A level,” wrote Dr. Naoki Uchida of Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, Tokyo, and colleagues (Blood. 2016 Apr 7. doi: 10.1182/blood-2015-06-650226).
Adverse events were comparable with those of placebo; 13 of 48 subjects who received ACE910 reported 15 adverse events, compared with 6 adverse events reported by 4 of 16 subjects who received placebo. Except for moderate nasopharyngitis reported in one subject, all adverse events were mild, were not dose dependent, and were similar for Japanese and white subjects. Clinical and laboratory findings showed normal coagulability with ACE910 administered at any dose.
An anti-drug antibody response was observed in 2 of 48 patients (1 Japanese, 1 white) both at 0.1 mg/kg ACE910. The anti-drug antibody responses were not IgE mediated, and no allergic symptoms were observed.
FROM BLOOD
Key clinical point: The bispecific antibody ACE910 was safe and effective as a long-acting hemostatic drug for hemophilia A in a phase I trial of healthy subjects.
Major finding: ACE910 was well tolerated up to 1 mg/kg with an average half-life of 28 to 34 days; in factor VIII–depleted plasma, ACE910 at 1 mg/kg resulted in an APTT similar to normal plasma.
Data sources: The first-in-human, double-blind, randomized, placebo-controlled dose-escalation study included 40 Japanese men and 24 white men.
Disclosures: The study was sponsored by Chugai Pharmaceutical. Dr. Uchida reported having no disclosures. His coauthors reported ties to Chugai Pharmaceutical and F. Hoffmann-La Roche, as well as holding patents related to anti-FIXa/X bispecific antibodies.
