Serpinpc in Persons with Severe Hemophilia (PwH): Updated Results from a Multi-Center, Multi-Part, First-in-Human Study

Introduction SerpinPC is a recombinant serine protease inhibitor (SERPIN), whose specificity and kinetics aim to rebalance hemostasis for PwH. SerpinPC is designed to increase the amount of thrombin at sites of tissue damage by reducing the activity level of circulating activated protein C (APC) and thereby prolong the activity of prothrombinase. The normal levels and activity of the zymogen precursor protein C are likely maintained due to SerpinPC's specificity for the active form.

Methods AP-0101 is an ongoing first in human open label multicenter study utilizing an adaptive design to investigate the safety, tolerability and pharmacokinetics of subcutaneous doses of SerpinPC in male participants with severe hemophilia A or B (HemA, HemB). Reduction in the annualized bleeding rates (ABRs) was also assessed. AP-0101 consists of 5 parts: Part 1 was a Single Ascending Dose Study completed in 15 healthy male subjects and in 12 male PwH (Part 1b: 0.1 to 1.2 mg/kg, 4 cohorts). All 12 PwH in Part 1b chose to participate in Part 2. Part 2 enrolled 23 male PwH (19 HemA and 4 HemB) who were not on replacement factor prophylaxis to receive SerpinPC at 0.3, 0.6 or 1.2 mg/kg, administered as a subcutaneous injection every 4 weeks over a 24-week period (6 total doses). In Part 3, subjects who completed Part 2 receive a flat dose of 60mg of SerpinPC every 4 weeks for 48 weeks. Part 4 is a further extension in which subjects who completed Part 3 receive 1.2mg/kg of SerpinPC every 2 weeks for 24 weeks. Part 5 is an additional extension in which subjects who complete Part 4 receive 1.2mg/kg of SerpinPC every 2 weeks for a further 52 weeks.

ResultsUpdated results from Part 3 and 4 - with an estimated follow-up of 48 and 24 weeks respectively - are expected for presentation at the meeting. In Part 2, one subject with a history of a skin disorder discontinued treatment due to an injection site reaction. No other treatment-related adverse events were observed. There was no reported sustained elevation in D-dimer throughout the 24-week study. Two subjects had anti-drug antibodies and remained on treatment without apparent impact on ABRs. In the highest dose cohort, SerpinPC reduced the self-reported 'all bleeds ABR' by 88% during the pre-specified assessment period as compared with the 'all bleeds ABR' prospectively measured during the pre-exposure observation period. The self-reported spontaneous joint bleeds ABR was reduced by 94%. ABR reductions appeared to be similar between the HemA and HemB subgroups.

Conclusions The results from Parts 1 and 2 suggest that SerpinPC was well-tolerated in subjects. Reduction in ABR in Part 2 provides preliminary evidence of activity for SerpinPC as a prophylactic agent in preventing bleeding in PwH. The effects of length of treatment and exposure will be further examined in Parts 3-5. More clinical trials are planned to evaluate the benefit and risk profile of SerpinPC in PwH.

Baglin:Centessa Pharmaceuticals Ltd: Current Employment, Current equity holder in publicly-traded company. Koch:ApcinteX: Other: contracted to run Part A of the study on behalf of the sponsor. Huntington:SDS Therapeutics Ltd: Current equity holder in private company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Centessa: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Cambridge Protein Works Ltd: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; University of Cambridge: Current Employment; SDS Therapeutics: Current Employment; ApcinteX Ltd: Consultancy, Ended employment in the past 24 months; Z Factor Ltd: Consultancy, Ended employment in the past 24 months.