A Fixed (Weight-independent) Subcutaneous Once-Weekly Dose for Marstacimab, an Anti-TFPI Monoclonal Antibody for the Prophylactic Treatment of Hemophilia Α and B

Introduction: Marstacimab is a human anti-TFPI monoclonal antibody currently in phase 3 development, intended for routine prophylaxis treatment to prevent or reduce the frequency of bleeding episodes in hemophilia A or B patients (with or without inhibitors). Marstacimab demonstrated superiority over routine prophylaxis treatment and superiority over on-demand treatment as measured by Annualized Bleed Rate (ABR) of treated bleeds in the phase 3 study (EAHAD 2024 abstract # 285). A once-weekly weight independent (i.e. flat/fixed), subcutaneous dosing regimen for marstacimab is expected to provide significant advantages of patient convenience, compliance, less risk of dosing errors and cost-effectiveness over current standard of care.

Methods: Data from hemophilia participants receiving once weekly (QW) marstacimab at doses of 150 mg subcutaneous (SC) QW (with a loading dose of 300 mg SC), 300 mg SC QW and 450 mg SC QW in Phase 2 (NCT03363321, NCT02974855) and phase 3 (NCT03938792) studies were included in the analysis. To understand the effect of weight on marstacimab PK and PD ie. peak thrombin (biomarker closely related to clinical bleed endpoint; Verhagen et al, 2023), 5000 PK and PD simulations were performed for a uniform weight distribution in the range of 30 to 120 kg (~500 subjects in each 10-kg weight category). Simulations were performed using R (ver. 4.2.1) and were based on a population PK model using Target Mediated Drug Disposition (for PK) and an E_max model (for PD) model with model parameters estimated in NONMEM (v 7.5.0). Steady-state average, maximum and minimum drug concentration and peak thrombin values were calculated for each participant.

Results: PK: Simulated marstacimab concentrations were seen to decrease with increasing weights (weight range: 35 – 74 kg for adolescents and 43 – 120 kg for adults). Marstacimab exposures (C_avg,ss, C_max,ss and C_min,ss) were calculated to be approximately 2 to 2.5-fold higher in adolescents compared to adults. In general, an overlap was seen for the observed concentration range across the 40 – 50 kg to 80 - 90 kg weight categories. PK simulations showed that median C_avg,ss exposures are predicted to be ~ 4X higher for the 30 - 50 kg group and ~ 6X lower for the 100 - 130 kg group in comparison to predicted exposures for a standard weight of 70 - 80 kg. At lower weights, the higher concentrations are predicted to be below the maximum concentrations seen in clinical studies (Maximum Tolerated Dose i.e MTD not reached). At higher weights, concentrations are predicted to be above the marstacimab plasma EC₅₀ based on animal and phase 1/2 clinical data. PD: No trends in peak thrombin are seen based on weight; median and range of peak thrombin values are comparable across all weight categories. Furthermore, peak thrombin values are generally within the normal physiological range without evidence of any excessive pharmacology (ISTH 2024 poster # PB0518). This trend is likely explained by marstacimab concentrations being in the maximal effect range of the exposure-response relationship. ABR: No apparent trends are seen in the median ABR values across the weight categories. To date, no thromboembolic events have been observed in hemophilia patients at any of the clinical doses (EAHAD 2024 poster # P0186).

Conclusions: A flat (fixed) dosing regimen for marstacimab, supported by comparable PD and ABRs across weight ranges, lack of safety concerns to date and an absence of a narrow therapeutic window profile, provides significant advantages of patient convenience, compliance, less risk of dosing errors as well as cost-effectiveness.