Characterization of participants with elevated bleeding rates responding to prophylactic marstacimab treatment in the phase 3 BASIS trial

Abstract Background Marstacimab, a monoclonal antibody targeting tissue factor pathway inhibitor to reduce inhibition of the extrinsic coagulation pathway and rebalance hemostasis, is approved for prophylaxis in patients with hemophilia A (HA) or B (HB) without inhibitors. The phase 3 BASIS study (NCT03938792) demonstrated marstacimab was effective in reducing treated annualized bleeding rate (ABR) vs prior on-demand (OD) or routine prophylaxis (RP) therapy in participants (pts) with severe HA (FVIII <1%) or moderately severe to severe HB (FIX ≤2%) without inhibitors. Marstacimab was generally well tolerated with no unanticipated side effects. However, some pts had high ABRs during marstacimab treatment that deviated from the overall study population. Understanding factors that influence responder outcomes is crucial for personalized treatment and effective management of hemophilia. We aimed to identify prognostic factors for pts with elevated ABRs in BASIS. Methods Eligible pts were male, aged ≥12 to <75 years with severe HA or moderately severe to severe HB with or without inhibitors. Results are reported for the noninhibitor cohort. Pts entered a 6-month observational phase (OP) and received prescribed factor replacement therapy (OD or RP) before receiving a single subcutaneous (SC) dose of 300 mg marstacimab (2×150 mg) followed by 150 mg SC once weekly (QW) in the 12-month active treatment phase (ATP). Dose escalation to 300 mg was allowed per investigator's discretion after Day 180 for pts who met protocol-specified criteria based on breakthrough bleeding. After completing the ATP, pts could enroll in the open-label extension (OLE) study (NCT05145127). Pts with elevated ABRs were identified based on the data distribution of ABR in the ATP from all pts (OD+RP); pts with an ABR in the ATP greater than the mean ABR+1.5× interquartile range (ie, ABR >12) were assessed. Prognostic factors evaluated for an elevated ABR were age, region, hemophilic arthropathy, baseline hemophilia joint health score (HJHS) total score and number of target joints at baseline. Descriptive data are presented. Results In all, 116 pts received marstacimab in the ATP. Model-based mean ABR (95% CI) decreased from the OP to the ATP in OD and RP groups (OD: 39.9 [33.1-48.1] vs 3.2 [2.1-4.9]; RP: 7.9 [5.1-10.7] vs 5.1 [3.4-6.8]). Overall, 12 pts (OD: n=1; RP: n=11; HA: n=10; HB: n=2) with an ABR >12 in the ATP were identified. At baseline, most (n=11; 92%) pts were aged >18 y (5 [42%] ≥45 y), 6 (50%) pts were Asian and 6 (50%) were White. Most (n=11; 92%) had ≥1 target joint (≥3 target joints: n=5, 42%) and 8 (67%) had hemophilic arthropathy. Compared with the lower ABR group (ABR ≤12), the group with elevated ABRs (ABR >12) was comprised of a higher percentage of adults (OD: 100% vs 93.8%; RP: 90.9% vs 77.8%), a higher percentage with hemophilic arthropathy (OD: 100% vs 50%; RP: 63.6% vs 54.2%), a higher mean HJHS total score indicative of worse joint health (OD: 29.0 vs 21.0; RP: 22.7 vs 16.8), more target joints at baseline (pts with ≥3 target joints: OD: 100.0 vs 34.4; RP: 36.4 vs 12.5) and a greater proportion of RP pts from Asia (OD: 0% vs 65.6%; RP: 54.5% vs 33.3%). Although these pts had a higher ABR during the ATP (range 13.8-35.5) vs the lower ABR group (range 0.0-11.2), 41.7% (n=5/12) had a mean decrease in ABR of 55.4% (SD 28.1) vs the OP. Of the pts with an elevated ABR, 5 (42%) dose-escalated to marstacimab 300 mg SC QW; ABR decreased in all pts after dose escalation (range 0.0-10.1). Neutralizing antibodies were detected in 1 pt at Day 60; titers were transient and resolved by Day 180. Eight (67%) pts with an elevated ABR continued into the OLE (3 discontinued early, 1 chose not to enroll) and continued ABR improvements were observed in 7 (88%) pts. Conclusions Twelve pts had an ABR >12 during the ATP. The sample size precludes definitive conclusions on prognostic factors but variables associated with an elevated ABR included older age, residence in Asia, hemophilic arthropathy, higher baseline HJHS total score and baseline target joints. Worse joint disease correlated with a higher ABR. However, most pts with an elevated ABR showed ABR reductions during the ATP or OLE, suggesting these pts still responded to marstacimab. Dose escalation to marstacimab 300 mg SC QW led to reduced ABR in all pts with an elevated ABR who escalated, suggesting this may be an option for select pts.