Management of breakthrough bleeds in participants with hemophilia Α or Β without inhibitors receiving marstacimab prophylaxis in the phase 3 BASIS study

Abstract Background Marstacimab is a monoclonal antibody that targets the tissue factor pathway inhibitor to rebalance hemostasis. It is approved for prophylaxis in patients with hemophilia A (HA) or B (HB) without inhibitors. The pivotal phase 3 BASIS study (NCT03938792) demonstrated marstacimab was effective in reducing treated bleeds 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. We aimed to assess the management of breakthrough bleeding episodes in pts who received concomitant factor replacement therapy (FRT) and weekly (QW) marstacimab in BASIS. Methods BASIS enrolled male pts aged ≥12 to <75 years. Results are reported for the noninhibitor cohort. Pts entered a 6-month observational phase (OP) and received prescribed FRT (OD or RP) before entering the 12-month active treatment phase (ATP) to receive a single dose of 300 mg marstacimab (2×150 mg subcutaneous [SC]) followed by 150 mg SC QW. To manage breakthrough bleeds, pts could take their prescribed FRT at the lowest effective dose, determined by each investigator per the approved product label. FRT dose, date, and time of infusions and FRT product were recorded in an electronic diary; the type of product (plasma-derived [pd], recombinant standard half-life [SHL], or recombinant extended half-life [EHL]) was determined. An acute treated bleed was defined as a bleeding event treated with episodic FRT within 48 hours of the bleed starting. Results Of 128 pts (HA: n=101; 78.9%; HB: n=27; 21.1%) who entered the OP, 116 received marstacimab prophylaxis in the 12-month ATP. At baseline, median age was 30.0 (range 13-66) years, and most were White (50.8%) or Asian (47.7%); 36 (97.3%) and 53 (58.2%) pts in the OD and RP groups, respectively, had ≥1 target joint. The median (range) marstacimab treatment duration was 12.1 months for both the OD (11.5-13.1 months) and RP (0.9-12.8 months) groups. In all, 75 (64.6%) pts experienced 453 acute bleeding events in the ATP, which were treated with 555 FRT infusions (OD: 125; RP: 430). Most acute breakthrough bleeds (OD: 83.7%; RP: 83.1%) were treated with a single infusion of FRT; 18.3% and 12.3% of bleeds in the OD and RP group, respectively, were treated with 2 infusions; in the RP group, 2.9% of bleeds were treated with 3 infusions and 1.7% of bleeds were treated with ≥4 infusions (5/6 were spontaneous joint bleeds). For both OD and RP pts with HA or HB, the most frequently used FRT to treat acute breakthrough bleeds was pd or SHL product; 401/453 (88.5%) bleeds were treated with pd or SHL product (HA: 351/375 [93.6%]; HB: 50/78 [64.1%] bleeds). For OD pts with HA during ATP, the mean (SD) pd/SHL FVIII dose/infusion was 24.19 (7.98) IU/kg (n=19) (OP: 21.63 [10.72] IU/kg [n=26]) and mean (SD) EHL FVIII dose/infusion was 19.93 (5.67) IU/kg (n=4) (OP: 16.46 [5.05] IU/kg [n=8]). For RP pts with HA during ATP, the mean (SD) pd/SHL FVIII dose/infusion was 24.61 (8.09) IU/kg (n=40) (OP: 28.06 [8.83] IU/kg [n=37]) and mean (SD) EHL FVIII dose/infusion was 30.57 (9.83) IU/kg (n=4) (OP: 43.44 [8.59] IU/kg [n=5]). In all OD and RP pts with HA, 80.4% and 82.4% of acute bleeds were treated with a single infusion of FRT, respectively. For OD pts with HB during ATP, the mean (SD) pd/SHL FIX dose/infusion was 23.70 (7.15) IU/kg (n=3) (OP: 23.76 [10.77] IU/kg [n=5]) and mean (SD) EHL FIX dose/infusion was 12.60 (5.06) IU/kg (n=2) (OP: 13.16 [5.65] IU/kg [n=4]). For RP pts with HB during ATP, the mean (SD) pd/SHL FIX dose/infusion was 49.51 (26.40) IU/kg (n=5) (OP: 47.28 [17.10] IU/kg [n=6]) and mean (SD) EHL FIX dose/infusion was 47.04 (11.53) IU/kg (n=6) (OP: 74.36 [21.47] IU/kg [n=4]). In OD and RP pts with HB, 100.0% and 85.7% of acute bleeds were treated with a single infusion of FRT, respectively. For RP pts with HB, FIX consumption was influenced by 2 marstacimab-treated adolescents with several traumatic bleeds that required FRT. No thromboembolic events were reported in association with concomitant FRT use. Conclusions In the BASIS study, for pts with HA or HB without inhibitors, acute breakthrough bleeding episodes were successfully managed with episodic FRT during concurrent QW marstacimab prophylaxis and marstacimab was generally safe. Most acute breakthrough bleeds were managed with a single infusion of FRT, and the most common treatment agents were SHL FVIII products (recombinant or pd).