Study of Coagulation Factor VIIa Variant Marzeptacog Alfa (Activated) in Adult Subjects With Hemophilia A and B

Multi-center, open-label Phase 2 study to evaluate the PK, bioavailability, PD, efficacy and safety of a daily SC treatment regimen with MarzAA for bleeding prophylaxis in adult subjects with hemophilia A or B with an inhibitor. The study will enroll and dose, both intravenously and subcutaneously, a total of 12 adult male subjects with severe congenital hemophilia A or B with an inhibitor, and history of frequent bleeding episodes during the 6 months prior to enrollment, as per the individual's bleeding and treatment records.

Once a subject is enrolled into the trial, the study will be conducted in three parts (occurring consecutively):

Part 1a (24 hours): Single IV administration of MarzAA; Part 1b (48 hours): Single SC administration of MarzAA; Part 2: Daily SC administration. Dose escalation in Part 2 will occur if breakthrough bleeding occurs. Subjects are treated for 50 days at the final dose level required.

• Coagulation Factor VIIa variant (Biological): Single intravenous injection of MarzAA, followed by single subcutaneous injection of MarzAA, followed by daily subcutaneous injection of MarzAA for 50 days at final dose level required.

Primary outcomes

• Bleeding Episode Prevention Success [Day 1 of final MarzAA dose level - Day 50]: Annualized bleed rate (ABR; spontaneous and total) during Part 2 when on final MarzAA dose level versus recorded historical ABR. The analysis of the primary endpoint (annualized bleeding rate ABR for spontaneous and traumatic bleeds) of the final dose of MarzAA each subject was treated was based on the 1-sample test compared to a predefined rate assumed for the on-demand therapy. The latter was assumed to be 12 (or 1 bleed per month), which was the minimum ABR for each subject according to inclusion criterion 2 (defined as the H0), with no maximum value. A higher score indicated a worse outcome. ABR is on a scale of 0 to 365, with a lower score reflective of a lower number of bleeding events in a year.

Secondary outcomes

• Occurrence of Breakthrough Bleeding [From Day 5 of dose level until occurrence of event]: Occurrence of breakthrough bleeds requiring escalation to higher dose level
• Occurrence of Clinical Thrombotic Event [From date of first dose until date of first occurrence of clinical event, assessed up to treatment Day 50]: Occurrence of clinical thrombotic event not attributable to another cause
• Coagulation Assessment - Prothrombin Time [From date of pre-dose to 24 hours (Part 1a), pre-dose to 48 hours (Part 1b), and pre-dose to Day 50 (Part 2)]: Change in coagulation parameter (prothrombin time \[PT\]) from pre-dose. Min-max values are reflective of the highest and lowest values for all measured timepoints.
• Coagulation Assessment - Activated Partial Thromboplastin Time [From date of pre-dose to 24 hours (Part 1a), 48 hours (Part 1b), to Day 50/end of study (Part 2)]: Change in coagulation parameter (activated partial thromboplastin time \[aPTT\]) from pre-dose. Min-max values are reflective of the highest and lowest values for all measured timepoints.
• Coagulation Assessment - Fibrinogen [From date of pre-dose to 24 hours (Part 1a), 48 hours (Part 1b), or Day 50 (Part 2).]: Change in coagulation parameter (fibrinogen) from pre-dose. Min-max values are reflective of the highest and lowest values for all measured timepoints.
• Number of Events of Antibody Formation [From time of first dose of MarzAA until date of first occurrence of clinical event, assessed up to treatment Day 50]: Occurrence of antibody formation resulting in a decreased endogenous level of coagulation Factor VII (FVII) or Factor VII activated (FVIIa)
• Number of Events of an Antibody Response [From time of first dose of MarzAA until date of first occurrence of clinical event, assessed up to treatment Day 50.]: Occurrence of an antibody response to MarzAA and whether it is inhibitory and cross-reactive to wild-type recombinant coagulation FVII (wt-rFVII) or wt-FVIIa.
• Thrombogenicity Assessment [From time of pre-dose of MarzAA at Day 1 until date of first occurrence of thrombotic event, assessed up to treatment Day 50.]: Number of participants with clinically significant levels of thrombogenicity markers (D-dimer, Prothrombin fragment 1+2 (F1+2), and thrombin-antithrombin complex \[TAT\]), based on standard laboratory tests and clinical examination with a specific search for any signs of thrombosis

Sex: Male, ages: 18 Years to any

Inclusion Criteria:

* Severe congenital hemophilia A or B with an inhibitor.
* History of frequent spontaneous bleeding episodes.
* Male, age 18 or older.
* Affirmation of informed consent with signature confirmation before any trial-related activities.

Exclusion Criteria:

* Receiving prophylaxis treatment.
* Previous participation in a clinical trial evaluating a modified rFVIIa agent.
* Known positive antibody to FVII or FVIIa detected by central laboratory at screening.
* Have a coagulation disorder other than hemophilia A or B.
* Significant contraindication to participation.

Participant flow

Outcome results

• Bleeding Episode Prevention Success (Primary), Mean, score on a scale: Part 2 1.4640 +/- 3.08638
• Occurrence of Breakthrough Bleeding (Secondary), Number, number of breakthrough bleeds: Part 1a, MarzAA IV 18 µg/kg 0; Part 1b, MarzAA SC 30 µg/kg 0; Part 2, MarzAA 30 µg/kg 5; Part 2, MarzAA 60 µg/kg 0
• Occurrence of Clinical Thrombotic Event (Secondary), Number, number of events: Part 1, MarzAA IV 18 µg/kg 0; Part 1, MarzAA SC 30 µg/kg 0; Part 2, MarzAA 30 µg/kg 0; Part 2, MarzAA 60 µg/kg 0
• Coagulation Assessment - Prothrombin Time (Secondary), Median, seconds: Part 1a, MarzAA IV 18 µg/kg -3.70 (-5.30 to 1.50); Part 1b, MarzAA SC 30 µg/kg -2.80 (-4.8 to -0.3); Part 2, MarzAA 30 µg/kg -3.0 (-6.5 to 1.2); Part 2, MarzAA 60 µg/kg -4.80 (-4.8 to 3.8)
• Coagulation Assessment - Activated Partial Thromboplastin Time (Secondary), Median, seconds: Part 1a, MarzAA IV 18 µg/kg -10.60 (-57.4 to 140.8); Part 1b, MarzAA SC 30 µg/kg 1.30 (-30.65 to 50.1); Part 2, MarzAA 30 µg/kg -8.30 (-47.3 to 30.3); Part 2, MarzAA 60 µg/kg -15.00 (-20.15 to 2.0)
• Coagulation Assessment - Fibrinogen (Secondary), Median, mg/dL: Part 1a -10.0 (-173 to 51); Part 1b -15.00 (-133 to 108); Part 2, MarzAA 30 µg/kg -4.0 (-112 to 146); Part 2, MarzAA 60 ug/kg -4.0 (-84.0 to 116)
• Number of Events of Antibody Formation (Secondary), Number, number of events of antibody formation: Part 1a 0; Part 1b 0; Part 2, MarzAA 30 µg/kg 0; Part 2, MarzAA 60 µg/kg 0
• Number of Events of an Antibody Response (Secondary), Number, number of events of antibody response: Part 1a 0; Part 1b 0; Part 2, MarzAA 30 µg/kg 0; Part 2, MarzAA 60 µg/kg 0
• Thrombogenicity Assessment (Secondary), Number, participants: Part 1a, MarzAA IV 18 µg/kg 0; Part 1b, MarzAA SC 30 µg/kg 0

Adverse events

Time frame: Members of the study team recorded all reportable events with start dates occurring any time after informed consent was obtained until study completion, or discharge, for non-serious AEs and until 30 days after the last day of study participation for SAEs. The duration of the study was 52 days.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: A planned outcome measure (coagulation assessment via MarzAA activity levels) of the protocol was not calculated as as a satisfactory assay could not be developed. Data is not reported for two allowed dose groups in Part 2, MarzAA 90 μg and 120 μg, as no subjects were treated at these dose levels

• Study Protocol (PDF, 2018-08-25)
• Statistical Analysis Plan (PDF, 2018-11-05)

• Howard Levy, MD, PhD, MMM, Study director, Catalyst Biosciences