Alphanate in Immune Tolerance Induction Therapy

A Multicenter Phase 2 Open-Label, Single-Arm, Prospective, Interventional Study of Plasma-Derived Factor VIII/VWF (Alphanate®) in Immune Tolerance Induction Therapy in Subjects With Congenital Hemophilia A

This is a multicenter, multinational, prospective, single-arm, nonrandomized, open-label study, planned in of approximately 25 male participants with congenital hemophilia A who will receive their first (primary) immune tolerance induction (ITI) treatment with alphanate.

The study consists of 2 phases:

• An ITI Treatment Phase in which all eligible participants will receive ITI treatment with alphanate for a period of up to 33 months. Upon confirmation of complete immune tolerization, participants will then enter a 12-month Prophylactic Phase. If, after 33 months of ITI, a participants has achieved partial immune tolerance, the participants will enter a 12-month Prophylactic Phase.
• A 12-month Prophylactic Phase for all participants who meet the criteria for complete or partial success to continue on a prophylactic dosing regimen of alphanate. Due to limited enrollment, this study was early terminated.

Male participants <12 years of age with an inhibitor titer >0.6 to <10 Bethesda Units (BU) will be screened before the planned start of ITI treatment. Participants continuing to meet the entrance criteria will enter the ITI Treatment Phase and receive daily doses of alphanate 100 IU/kg/day for up to 33 months, with a one-time option to increase to a dosing regimen of 200 IU/kg/day at any time after 90 days of ITI treatment.

Participants will continue to receive their daily alphanate dose for up to 33 months until the titer is negative (<0.6 BU) on 2 consecutive assessments and treatment success is confirmed by FVIII:C pharmacokinetic assessments, at which time they will enter the 12-month Prophylactic Phase.

In addition, participants who have achieved partial immune tolerance at the completion of 33 months of ITI treatment will enter the 12-month Prophylactic Phase. Participants who do not achieve partial immune tolerance at the completion of 33 months of ITI treatment will be discontinued as treatment failures.

The Prophylactic Phase begins with an 8-week taper period for participants tolerized with 100 IU/kg/day or with a 12-week taper period for participants tolerized with 200 IU/kg/day to bring the dose down in a step-wise manner to a prophylactic dose of alphanate 50 IU/kg every other day or 3 times per week, at the investigator's discretion. During the Prophylactic Phase, participants will be monitored monthly for the first 4 months and then every 2 months for the remaining 8 months to assess sustainability of immune tolerance. Due to limited enrollment, this study was early terminated.

Inclusion Criteria:

• The subject has a documented diagnosis of severe congenital hemophilia A with FVIII:C <1% of normal.
• The subject is a male <12 years (and at least 2 years of age if in India) at the Baseline Visit.
• The subject's documented historical peak inhibitor titer is ≥5 BU and ≤200 BU.
• The subject has an inhibitor titer >0.6 BU and <10 BU at Screening.
• The subject has had a delay ≤24 months from the date of diagnosis of the inhibitor to the start of the subject's ITI treatment.

Exclusion Criteria:

• The subject has acquired factor VIII (FVIII) deficiency.
• The subject has previously received ITI treatment.
• The subject has a recent (within 1 month) history of central line infection at the time of Screening.
• The subject has a high risk of cardiovascular, cerebrovascular, or thromboembolic event as judged by the investigator.
• The subject is currently undergoing treatment with immunosuppressive drugs (eg, systemic corticosteroids), azathioprine, cyclophosphamide, high dose immunoglobulin, interferon, or the use of a protein A column or plasmapheresis and is unwilling to discontinue these treatments starting at the screening visit.
• The subject has a known infection with human immunodeficiency virus (HIV) or has clinical signs and symptoms consistent with current HIV infection.
• The subject has a known previous infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) or has clinical signs and symptoms consistent with current HBV or HCV infection.
• The subject has significant proteinuria, has a history of acute renal failure or severe renal impairment (blood urea nitrogen or creatinine >2 times the upper limit of normal), or is receiving dialysis at Screening.
• The subject has a value of aspartate transaminase or alanine aminotransferase >2 times the upper limit of normal at Screening.
• The subject has clinical evidence of any significant acute or chronic disease that, in the opinion of the investigator, may interfere with successful completion of the trial or place the subject at undue medical risk.
• The subject has a history of anaphylaxis or severe systemic reaction to any plasma derived or other blood products.