Safety, tolerability, pharmacokinetics and pharmacodynamics of a single dose of marstacimab in Chinese participants with severe haemophilia.

For severe haemophilia A or B (factor VIII [FVIII] or IX [FIX] activity levels <1% of normal [<1 IU/dL]), the main prophylaxis treatment is standard clotting factor concentrates (CFCs). Limitations of CFCs include short half-life, frequent intravenous infusions and poor compliance.1 A low-dose prophylaxis regimen in China requires infusion of FVIII 10 IU/kg two to three times per week for haemophilia A and FIX 20 IU/kg once weekly for haemophilia B.2 Marstacimab is an anti-tissue factor pathway inhibitor (anti-TFPI) monoclonal antibody (immunoglobulin G1) that targets the Kunitz-2 domain of TFPI to neutralize its inhibitory activity, increasing free activated factor X and enabling coagulation.3 It is in development to prevent or reduce bleeding episode frequency in those with haemophilia A or B, with or without inhibitors, via a once-weekly fixed subcutaneous (SC) dose. Compared to CFCs and other nonfactor replacement therapies,4 marstacimab has the advantage of fixed instead of body weight-based dosing, easier dose preparation, and reduced cost and possibility of dosing errors.5 A first-in-human phase 1 study (NCT02531815) evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of marstacimab or placebo in 41 healthy participants, including four Japanese participants who received a single 300 mg SC dose. The results demonstrated marstacimab was generally safe and well tolerated.6 The favourable benefit–risk profile of marstacimab was also demonstrated in the phase 1b/2 study (NCT02974855) to evaluate the safety, efficacy, PK and PD of multiple ascending doses in participants with haemophilia7 and its phase 2 extension study (NCT03363321)8 and supported further evaluation in an ongoing phase 3 study (NCT03938792). Here, we describe the results of the first phase 1 study (NCT04878731) for marstacimab in Chinese patients with severe haemophilia. The primary objective of this single-arm, open-label, non-randomised, non-controlled study was to determine the safety and tolerability of marstacimab in Chinese participants following a single 300 mg dose. Secondary objectives were to characterise PK, PD and immunogenicity. To explore ethnic sensitivity, we used the same 300 mg dose used in healthy Japanese and White participants in the previous phase 1 study.6 This study was approved by the institutional ethics committee and complied with all relevant guidelines. Eligible participants were Chinese men aged 18–˂75 years with severe haemophilia A or B, with or without inhibitors, and body weight ≥30 kg. All participants provided written informed consent. Participants were admitted to the clinical research unit on Day −1. Marstacimab 300 mg was administered as two 150 mg/mL SC injections in a prefilled syringe on Day 1. Participants remained in the clinical research unit for 7 days and returned for clinic visits on Days 14, 21 and 28. Blood samples for PK and PD analyses were taken pre-dose and 1, 4, 12, 24, 48 and 72 h post-dose and then at Days 7, 14, 21 and 28. Blood samples for antidrug antibody (ADA) and neutralising antibody (NAb) against marstacimab were collected pre-dose and at Days 14, 21 and 28. Day 42 follow-up was conducted either face-to-face or by telephone, at the discretion of the investigator. Safety assessments included treatment-emergent adverse events (TEAEs) and withdrawals due to TEAEs, abnormal laboratory findings, change in vital signs, electrocardiogram parameters, physical examinations and injection site reactions. Total marstacimab concentrations were analysed. PK parameters were calculated using noncompartmental analysis: area under the plasma concentration–time (AUC) profile from time zero extrapolated to infinity (AUCinf), AUC from time zero to the last quantifiable concentration (AUClast), maximum plasma concentration (Cmax), time for Cmax (Tmax), terminal half-life (t1/2), apparent volume of distribution (Vz/F) and apparent clearance (CL/F). Target binding by marstacimab was assessed by measuring total TFPI concentrations. PD endpoints included maximum PD change from baseline (maximum increase from baseline for total TFPI, prothrombin fragment 1 and 2 [PF1 + 2], D-dimer, thrombin generation assay [TGA] peak, and TGA endogenous thrombin generation potential [EGTP] and maximum decrease from baseline for dilute prothrombin time [dPT] and TGA lag time). Immunogenicity endpoints included frequency of ADA and NAb against marstacimab. Treatment for bleeding episodes was provided. See Supplementary methods. Of the nine male Chinese participants screened, six (haemophilia A, n = 5; haemophilia B, n = 1) were enrolled and completed the study. Median (range) age was 31.5 (27−34) years and median body mass index was 20.08 (15.6−25.9) kg/m2. No participants had inhibitors; all had haemophilic arthropathy. There were no TEAEs, serious adverse events (AEs), severe AEs (grade ≥3), thrombotic events or deaths. One participant experienced an all-causality grade 2 AE (upper respiratory tract infection). All participants had laboratory test abnormalities not reported as AEs by the investigator. One participant had an increase from baseline of ≥20 mm Hg in their supine diastolic blood pressure (determined to be white coat hypertension and not clinically significant). Spontaneous bleeding events occurred in all six participants (first occurrences on Days 22, 13, 14, 29, 22 and 13); one participant had a traumatic bleeding event (Day 47). Bleeding was mostly at joints, rather than soft tissue or muscle, and occurred unilaterally. Clotting factor replacement was administered to treat all but two bleeding events. There were no clinically significant abnormalities for prothrombin, fibrinogen, antithrombin III, or troponin I, nor evidence of excessive procoagulant activity. Marstacimab treatment was not associated with any thrombotic events. No new important risks or safety signals were identified in Chinese participants with severe haemophilia compared with non-Chinese participants in previous studies.6, 7 Plasma marstacimab PK parameters and concentration–time profiles are presented in Table 1 and Figure 1A, respectively. Marstacimab median Tmax was 73.15 h and the arithmetic mean t½ was 90.48 h. The geometric mean values for marstacimab CL/F and Vz/F were 0.06595 L/h and 8.305 L, respectively. Following a single 300 mg SC dose, marstacimab exposures in Chinese participants with severe haemophilia (Cmax: 15.61 μg/mL; AUClast: 2917 μg h/mL) were similar to values seen in healthy Japanese (n = 4) and White (n = 6) participants (Cmax: 18.50 and 16.49 μg/mL, respectively; AUClast: 3551 and 3120 μg h/mL, respectively) in the previous phase 1 study,6 which used intensive PK sampling (with similar nominal collection timepoints as this study). Further, marstacimab geometric mean Cmax in Chinese participants was also similar to Cmax values (range: 14.88−19.68 μg/mL) seen in non-Asian (White, Black/African American) adult male participants with severe haemophilia that received a single 300 mg dose in the first week in the previous phase 1b/2 study, which used sparsely sampled PK data.7 Overall, inter-individual variability for marstacimab exposure, based on the percent geometric coefficient of variation (%CV), was 35% for Cmax and 60% for AUClast. These values were comparable with those seen in healthy Japanese and White participants.6 Cmax %CV was also comparable with that seen in non-Asian participants with severe haemophilia.7 Treatment-related changes were observed for all PD endpoints. The pharmacologic effects of marstacimab lasted more than 7 days on PD markers, and maximum or near-maximum effects occurred most often within the first week. Following a single 300 mg dose, compared with baseline, increases were observed in plasma total TFPI (Figure 1B), PF1 + 2, D-dimer, TGA peak and TGA EGTP, and a shortening of dPT and TGA lag time (Figure S1) were observed. Descriptive summaries of maximum change from baseline for all PD parameters are presented in Table S1. The observed increases in plasma total TFPI were consistent with marstacimab binding free TFPI to delay elimination of TFPI due to the longer half-life of marstacimab compared with the target TFPI.9 For Chinese participants with severe haemophilia, median (range) baseline total TFPI (i.e., total target) levels of 131.50 (110.0−143.0) ng/mL were similar to those seen in healthy non-Chinese participants (n = 41)6 and non-Asian patients with haemophilia (n = 26).7 A previous phase 1 study suggested marstacimab undergoes target-mediated drug disposition,6 and a related model was developed.10 No clinically relevant racial difference was observed for baseline total TFPI, the target of marstacimab. Median (range) baseline TGA peak level (a key coagulation-related clinical biomarker) of 9.20 (4.9−45.3) nmol in Chinese participants with severe haemophilia was similar to that seen in non-Asian patients with haemophilia (n = 26).7 The treatment-related trends in all PD endpoints were similar to those seen in healthy White participants6 and non-Asian participants with severe haemophilia following administration of a single 300 mg dose of marstacimab.7 No participants had positive ADAs at baseline. Two participants had positive ADA titres (≥1.54) post-dose (Day 21, 1.99 [n = 1]; Day 28, 1.63 [n = 1]); however, their corresponding NAb samples were negative (˂1.08). No impact to safety, PK or PD was reported in participants with positive ADA titres. The small sample size, with one participant with haemophilia B and none with inhibitors, is a potential limitation; however, it was acceptable for the study objectives. Overall, marstacimab demonstrated an adequate safety profile following a single 300 mg SC dose in Chinese participants with severe haemophilia without inhibitors. Marstacimab exposures were similar to those seen in healthy Japanese and White participants6 and in non-Asian participants with severe haemophilia.7 Treatment-related trends in PD were similar to those observed in non-Asian participants with severe haemophilia.7 These findings support a conclusion of ethnic similarity and justify the dose for further drug development in China. Xiaohong Sun, Wei Liu, Binyu Luo, Dongwei Ma, Hindu Kalluru, Yangmei Zhou, Ao Peng, Yuwang Liu, John Teeter, Sangeeta Raje and Renchi Yang were involved in the study design, data analyses and data interpretation. Renchi Yang was the principal investigator and Wei Liu was sub-investigator that provided patients, conducted the study and reported data. Jin Li, Xin Tong and Lei Sun contributed to data collection. All authors had full access to the data, and all authors contributed to the critical review and revision of the manuscript. All authors granted approval of the final manuscript for submission. Editorial support was provided by Marion James, PhD, CMPP, of Engage Scientific Solutions (Horsham, UK) and Courtney M. Cameron, PhD, of Engage Scientific Solutions (Fairfield, CT) and was funded by Pfizer. The authors thank all participants and related site staff for their contributions to the study. The authors also thank Wenru Luo from Pfizer for support of bioanalysis of pharmacokinetics, total TFPI and ADA/NAb measurements; Richard P. Giovanelli from Pfizer for support with TGA measurements; and Xiaoduo Guan from Pfizer for support with pharmacokinetic parameter comparisons between studies. Wei Liu has no conflicts of interest to declare. Renchi Yang has received speaker/consultancy fees from Novo Nordisk, Pfizer, Roche, Sanofi and Takeda. Xiaohong Sun, Binyu Luo, Dongwei Ma, Hindu Kalluru, Jin Li, Ao Peng, Yuwang Liu, Xin Tong, Lei Sun, John Teeter and Sangeeta Raje are employees and shareholders of Pfizer Inc. Yangmei Zhou is an employee of Pfizer Inc. This study (NCT04878731) was approved by the ethics committee of the institution and was conducted in compliance with the Declaration of Helsinki Council, Council for International Organisations of Medical Sciences International Ethics Guidelines, International Council for Harmonisation Good Clinical Practice guidelines, applicable International Organization for Standardization 14155 guidelines, medical device guidelines, and other applicable laws and regulations. All participants provided written informed consent prior to enrolment. Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.