The Crimson 1 Study: A Phase 3 Study to Evaluate the Efficacy and Safety of Subcutaneous Marzeptocog Alfa (activated) for on-Demand Treatment and Control of Bleeding Episodes in Subjects with Hemophilia A or Hemophilia B, with Inhibitors

Background

Hemophilia A (HA) and HB are X-linked bleeding disorders caused by a deficiency of Factor VIII (HA) or Factor IX (HB). A significant number of individuals with HA and HB develop inhibitors against the wild-type FVIII or FIX, respectively, and thereby become refractory to factor replacement treatment. Treatment of episodic bleeding in these individuals requires technical expertise to gain the requisite intravenous (IV) access and is often associated with pain. This causes delays in administration, which results in prolonged bleeding and accumulation of blood in the joint or other bleeding site. Currently approved FVIIa containing products take 6-24 hours to achieve hemostasis and maintain efficacy. Marzeptacog alfa (activated) (MarzAA), a novel variant activated recombinant Factor VII (rFVIIa), is being developed for subcutaneous (SQ) administration to address this important unmet need. Data from the Phase 1 study, MAA-102, demonstrated that SQ MarzAA is quickly absorbed and has the potential to achieve and maintain plasma levels in the desired range with an acceptable safety profile.

This open-label, global, multi-center, randomized, cross-over Phase 3 study will evaluate the efficacy and safety of MarzAA for on demand treatment of spontaneous or traumatic bleeding episodes in adolescents and adults with congenital HA or HB with inhibitors. MarzAA will be compared to the Standard of Care (SOC). Approximately 60 subjects will be enrolled at 54 sites in 19 countries.

Study Design and Methods

Key inclusion criteria: Eligible male or female subjects ≥ 12 years of age must have: confirmed diagnosis of HA or HB unresponsive to or intolerant of standard replacement therapy; history of bleeding with annualized bleeding rate of ≥ 8; investigator-confirmed subject’s ability to identify bleeding episodes and administer MarzAA SQ and infuse SOC IV at home.

Key exclusion criteria: Subjects should not have had previous exposure to SQ administration of rFVIIa or exposure to any other variant rFVIIa; known positive antibody or hypersensitivity to MarzAA, FVIIa, or variants thereof; history of other coagulation disorder(s); platelet count <50,000/µL; CD4 T cell count <200 cells/mm³.

Treatment: Subjects >17 years of age will be randomized in blocks to target treatment of approximately 5 bleeds with MarzAA and an additional 5 bleeds with SOC in either order, Sequence A or Sequence B, with a washout period to assess anti-drug antibodies (ADA) status between treatments. A total of 488 eligible bleeds will be treated, ~244 bleeds with each treatment, until ≥80% of patients have ≥3 bleeds treated with MarzAA and SOC. Pharmacokinetic samples will be collected during the MarzAA treatment period. Subjects 12-17 years of age will be enrolled after a positive DSMB assessment of 30 eligible bleeds treated with MarzAA. Subjects will administer 60 µg/kg SQ dose of MarzAA, at 3-hour intervals, for up to 3 doses as required to achieve hemostasis.

Endpoints: Primary endpoint includes percentage of treated bleeds resulting in effective hemostasis (excellent or good) at 24 hours after the initial dose. Key secondary endpoints include time to cessation of bleeding after the initial dose; percentage of treated bleeds resulting in effective hemostasis at fixed timepoints; percentage of those that maintain hemostasis at 48 hours after the initial dose; use and amount of rescue therapy. Key safety endpoints include the incidence of adverse events; occurrence of thrombotic events and binding and/or neutralizing anti-drug antibodies. Key exploratory endpoints include assess patient satisfaction with the Treatment Satisfaction Questionnaire for Medicine- 9; assessment of pain using the Visual Analogue Scale; time required to administer treatment.

Statistics: The goal is to demonstrate the true proportion of bleeds effectively treated with MarzAA is not inferior to SOC. Using a baseline efficacy of 85% for SOC, with a -12% margin of non-inferiority, treatment of 244 bleeds in each group provides 90% power with a one-sided 2.5% significance level to substantiate this result.