Safety Biomarkers in Participants With Severe Hemophilia A or Moderately Severe to Severe Hemophilia B Without Inhibitors Receiving Prophylactic Marstacimab Treatment: Results From the Phase 3 BASIS Trial

Background

Marstacimab is a human monoclonal antibody targeted to the K2 domain of tissue factor pathway inhibitor (TFPI) to improve hemostasis through the extrinsic coagulation pathway. BASIS (NCT03938792) is an ongoing one-way, cross-over, open-label, multicenter, pivotal phase 3 study of marstacimab in participants with severe (factor VIII [FVIII] <1%) hemophilia A (HA) or moderately severe to severe (factor IX [FIX] ≤2%) hemophilia B (HB) with or without inhibitors. The efficacy and safety of marstacimab administration up to 450 mg once-weekly (QW) has been previously demonstrated in BASIS and previous phase 1/2 studies. Here, we present safety biomarker data from the BASIS study.

Methods

BASIS enrolled males aged ≥12–˂75 years with severe HA or moderately severe to severe HB. Here, we report results for the non-inhibitor cohort (the inhibitor cohort is ongoing). Participants entered a 6-month observational phase (OP) wherein they received their prescribed factor replacement therapy: on-demand (OD) or routine prophylaxis (RP). Participants then crossed over to the 12-month active treatment phase (ATP) and received a single loading dose of 300 mg marstacimab (2×150 mg subcutaneous [SC] injections) followed by 150 mg SC QW. Safety assessments included monitoring changes from baseline (CFB) during the OP (to day 60) and ATP (to day 360) in biomarker profiles for: red blood cell count (hemoglobin and hematocrit), coagulation (activated partial thromboplastin time [aPTT], prothrombin time, fibrinogen, and platelet count), hepatic function (liver function tests [LFTs]), renal function (serum creatinine), cardiac function (troponin I), and inflammation (leukocyte count). Blood samples were collected at OP baseline (day 1), and day 0 (baseline, pre-dose), 60, 180, 300 and 360 of the ATP to generate data on safety biomarkers and were analyzed descriptively.

Results

A total of 128 participants (median age, 30 [range 13–66] years) entered the OP (n: OD: HA 29, HB 8; RP: HA 72, HB 19) and 116 (n: OD 33, RP 83) were treated with marstacimab in the ATP. The mean (range) treatment duration with marstacimab was 12.1 (11.5–13.1) months for the OD group and 11.6 (0.9–12.8) months for RP group in the ATP. For both groups, mean hemoglobin and hematocrit either remained stable or improved during the ATP compared with the OP. Marstacimab did not result in CFBs in mean (SD; range) prothrombin time for the OD (0.1 seconds [0.6; -1.1–1.6]) and RP groups (0.2 seconds [0.6; -0.9–1.4]). The mean (SD; range) aPTT increased for the OD group from ATP day 0 (56.9 sec [9.5]; 36.0–81.7) to ATP day 360 (62.5 sec [18.19; 39.7–151.0]) with a change of 6.5 sec (14.6; -22.5–69.9), and increased for the RP group from ATP day 0 (50.9 sec [9.35; 33.8–65.3] to ATP day 360 (59.4 sec [13.74; 30.4–116.8]) with a CFB of 7.8 sec (13.3; -17.0–69.9). For most participants, fibrinogen values were normal in the OP and a small mean (SD; range) decrease from baseline was observed in both the OD (-0.2 g/L [0.48; -0.8–0.7]) and RP groups (-0.2g/L [0.64; -1.6–1.0] during the ATP. A decrease in mean (SD; range) platelet count from baseline was observed for the OD group (-15.6 [47.9 -132.0–91.0]) and maintained for the RP group (-0.7 [45.0; -96.0–177.0]) with values remaining within the normal range for most participants throughout the OP and ATP. Most LFT values were similar between the OP and ATP, with minimal CFB in both groups. Hyperbilirubinemia was observed for 2 participants (OD n=1, RP n=1). Troponin I levels were within the normal range during the OP and no participants developed elevated levels above normal with marstacimab. Leukocyte count values were normal in most participants over the OP and ATP. Across all parameters, none of the laboratory test abnormalities were considered clinically significant or reported as adverse events by the investigator.

Conclusions

Overall, evaluation of CFB for safety biomarkers showed no clinically important findings in participants with severe HA or moderately severe to severe HB. Parameters indicative of red blood cell count (hemoglobin and hematocrit) either remained stable or improved with marstacimab, and small decreases in fibrinogen were consistent with the mode of action of marstacimab. There was no clinically meaningful impact on aPTT. There were no reported adverse events related to CFB in safety biomarkers in any participants.