Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Pharmacotherapeutic group: antihemorrhagics, other systemic hemostatics
ATC code: B02BX11
Marstacimab is a human monoclonal IgG1 antibody directed against the Kunitz domain 2 (K2) of tissue factor pathway inhibitor (TFPI), the primary inhibitor of the extrinsic coagulation cascade. TFPI initially binds to and inhibits the factor Xa active site via its second Kunitz inhibitor domain (K2). The action of marstacimab to neutralise the inhibitory activity of TFPI may serve to enhance the extrinsic pathway and bypass deficiencies in the intrinsic pathway of coagulation by increasing free factor Xa available to increase thrombin generation and promote haemostasis.
Consistent with its anti-TFPI mechanism, marstacimab administration to haemophilia patients causes an increase in total TFPI and downstream biomarkers of thrombin generation such as prothrombin fragments 1+2, peak thrombin, and D-Dimer. These changes were reversible after treatment discontinuation. Sporadic or transient increases in D-Dimer and prothrombin fragments 1+2 above physiological values were reported in the Phase 3 study with no associated safety concerns.
The pivotal Phase 3 study was a one-way, cross-over, open-label, multi-centre study in 116 adult and adolescent males (aged 12 years and older and ≥35 kg) with severe haemophilia A without FVIII inhibitors or severe haemophilia B without FIX inhibitors who previously received “on-demand” (N=33) or prophylactic (N=83) treatment with FVIII or FIX. Patients with previous or current treatment for or history of coronary artery disease, venous or arterial thrombosis or ischaemic disease were excluded from the study.
The study population was characterised by a severe bleeding phenotype. The mean annualised bleeding rates (ABRs) were 38.00 and 7.85 in a 6-month Observational Phase for the on-demand and prophylaxis cohorts, respectively, prior to crossing over to weekly marstacimab prophylaxis. All (100%) patients in the on-demand cohort had one or more target joints at study entry and 36% had 3 or more target joints at study entry. In the routine prophylaxis cohort, 56.6% of the patients had one or more target joints at study entry and 15.7% had 3 or more target joints at study entry.
After the 6-month Observational Phase in which patients received either on-demand or routine prophylactic factor-based replacement therapy, patients received an initial 300 mg loading dose of marstacimab followed by maintenance doses of 150 mg of marstacimab once weekly for 12 months. Dose escalation to 300 mg of marstacimab once weekly was allowed after 6 months for patients weighing ≥50 kg experiencing 2 or more breakthrough bleeds. Fourteen (12.1%) out of 116 patients who received marstacimab for at least 6 months underwent dose escalation of their maintenance dose.
The mean age across the treatment groups was 32.4 years (min 13, max 66); 16.4% of patients were 12 to <18 years, and 83.6% were ≥18 years, 100% were male. In this study 48.3% of patients were White, 50.0% were Asian, 0.9% were Black or African American, and 0.9% race information missing; 10.3% of patients identified as Hispanic or Latino. All patients were non-inhibitors (78.4% haemophilia A, 21.6% haemophilia B).
The primary efficacy objective of the study was to compare marstacimab prophylaxis during the Active Treatment Phase versus routine prophylactic factor-based therapy in the Observational Phase as measured by the ABR of treated bleeds. Other key efficacy objectives of the study included evaluation of marstacimab prophylaxis in comparison with routine prophylactic factor-based therapy as measured by the incidences of spontaneous bleeds, joint bleeds, target joint bleeds and total bleeds, as well as assessing patients' health-related quality of life (HRQoL).
Table 2 shows the efficacy results of marstacimab prophylaxis compared with routine prophylactic factor-based therapy. Marstacimab showed non-inferiority and statistical superiority over routine prophylactic factor-based therapy as measured by ABR of treated bleeds.
Table 2. Comparison of ABR with Hympavzi prophylaxis versus previous routine factor-based prophylaxis in patients ≥12 years of age without factor VIII or factor IX inhibitors:
| Endpoints in the order of testing hierarchy | Routine factor-based prophylaxis during 6-month OP (N=83) | Hympavzi prophylaxis during 12-month ATP (N=83) |
|---|---|---|
| Treated bleeds (Primary) | ||
| ABR, model-based (95% CI) | 7.85 (5.09, 10.61) | 5.08 (3.40, 6.77) |
| Difference vs. RP (95% CI) | -2.77 (-5.37, -0.16) p-value = 0.0376* | |
| Participants with 0 bleeds, n (%) | 33 (39.8) | 29 (34.9) |
| Spontaneous bleeds, treated | ||
| ABR, model-based (95% CI) | 5.86 (3.54, 8.19) | 3.78 (2.25, 5.31) |
| Difference vs. RP (95% CI) | -2.09 (-4.23, 0.06) Non-inferiority* | |
| Joint bleeds, treated | ||
| ABR, model-based (95% CI) | 5.66 (3.33, 7.98) | 4.13 (2.59, 5.67) |
| Difference vs. RP (95% CI) | -1.53 (-3.70, 0.64) Non-inferiority* | |
| Total bleeds, treated and untreated | ||
| ABR, model-based (95% CI) | 8.84 (5.97, 11.72) | 5.97 (4.13, 7.81) |
| Difference vs. RP (95% CI) | -2.87 (-5.61, -0.12) Non-inferiority* | |
| Target joint bleeds, treated | ||
| ABR, model-based (95% CI) | 3.36 (1.59, 5.14) | 2.51 (1.25, 3.76) |
| Difference vs. RP (95% CI) | -0.86 (-2.41, 0.70) Non-inferiority* | |
* Criterion Met (Non-inferiority/p-value if met superiority)
In the OLE of the pivotal Phase 3 study, 87 patients received marstacimab at the doses established during participation in the B7841005 study (i.e. 150 mg or 300 mg subcutaneously once weekly) for up to an additional 16 months (mean 7 months) where marstacimab was shown to maintain long-term (>12 months) efficacy with no new safety signals identified.
Descriptive analyses were conducted to assess marstacimab prophylaxis over time. The model-based mean and other descriptive summaries for the ABR of treated bleeds are shown in Table 3.
Table 3. ABR with Hympavzi prophylaxis over time in patients ≥ 12 years of age without factor VIII or factor IX inhibitors:
| Endpoint | Time interval | ||
|---|---|---|---|
| First 6 months of ATP (N=116) | Second 6 months of ATP (N=112) | B7841007* (N=87) | |
| Treated Bleeds | |||
| Mean ABR (95% CI) | 4.95 (3.67, 6.68) | 3.25 (2.38, 4.42) | 2.79 (1.90, 4.09) |
| Median ABR (IQR) | 2.00 (0.00, 5.99) | 1.91 (0.00, 4.09) | 0.00 (0.00, 4.10) |
* Patients received marstacimab for up to an additional 16 months (mean 7 months) during B7841007.
During the 12-month treatment period in the pivotal Phase 3 Study B7841005, 23 of the 116 (19.8%) ADA-evaluable marstacimab-treated patients developed ADAs. ADAs were transient in 61% (14/23) and persistent in 39% (9/23) of the ADA-positive patients, indicative of a transient ADA profile in the majority of the patients. ADA titres resolved in 22/23 (95.7%) patients by the end of the study. Neutralising antibodies (NAbs) developed in 6/116 (5.2%) ADA-evaluable marstacimab-treated patients during the study. The NAbs were transient in all patients and no patients were NAb positive at the end of the study. Although slightly lower mean marstacimab concentrations (approximately 24%-32% lower) were reported in ADA-positive patients compared to ADA-negative patients, concentrations largely overlapped between these 2 groups and there was no identified clinically significant effect of ADAs, including NAbs, on safety or efficacy of marstacimab over the treatment duration of 12 months. Overall, the safety profile of marstacimab was similar between those patients with ADAs (including NAbs) and those without.
In the Phase 3 OLE study, only one of the 44 ADA-evaluable patients continuing to receive marstacimab for at least 6 months was persistently positive for ADAs.
The European Medicines Agency has deferred the obligation to submit the results of studies with Hympavzi in one or more subsets of the paediatric population in the treatment of congenital haemophilia A and congenital haemophilia B.
The pharmacokinetics of marstacimab were determined via non-compartmental analysis in healthy participants and haemophilia A and B patients as well as using a population pharmacokinetic analysis on a database composed of 213 participants (150 haemophilia patients and 63 healthy participants) who received once weekly subcutaneous (30 mg to 450 mg) or intravenous (150 and 440 mg) doses of marstacimab.
Marstacimab exhibited non-linear pharmacokinetics with systemic exposure to marstacimab, as measured by AUC and Cmax, increasing in a greater than dose-proportional manner. This non-linear pharmacokinetic behaviour is caused by target-mediated drug disposition (TMDD) and concentration dependent non-linear elimination of marstacimab which occurs when marstacimab binds to endothelial TFPI.
Mean steady-state accumulation ratio for marstacimab was approximately 3 to 4, relative to the first dose exposure following weekly subcutaneous dosing of 150 mg and 300 mg. Steady-state concentrations of marstacimab are expected to be achieved by approximately 60 days, i.e. by the 8th or 9th subcutaneous dose when administered once weekly. For marstacimab 150 mg subcutaneous once weekly, population estimates of mean Cmax,ss, Cmin,ss, and Cavg,ss for adults and adolescents are shown in Table 4.
Table 4. Steady-state marstacimab plasma concentrations following once-weekly subcutaneous administration of 150 mg (with a loading dose of 300 mg subcutaneous):
| Parameter | Adults | Adolescents |
|---|---|---|
| Cmin,ss (ng/mL) | 13 700 (90.4%) | 27 300 (53.2%) |
| Cmax,ss (ng/mL) | 17 900 (77.5%) | 34 700 (48.5%) |
| Cavg,ss (ng/mL) | 16 500 (81.2%) | 32 100 (49.5%) |
Following multiple subcutaneous administrations of marstacimab to haemophilia patients, median Tmax ranged from 23 to 59 hours. Bioavailability of marstacimab following subcutaneous administration was estimated to be about 71% by population pharmacokinetic modeling. No relevant differences were seen in marstacimab bioavailability between arm, thigh and abdomen.
Marstacimab steady-state volume of distribution in haemophilia patients was 8.6 L based on a population pharmacokinetic analysis. This limited extravascular distribution suggests that marstacimab is restricted to the intravascular space.
Metabolism studies were not conducted with marstacimab. Similar to other therapeutic proteins with molecular weights above the glomerular filtration cut-off, marstacimab is expected to undergo proteolytic catabolism and receptor-mediated clearance. In addition, based on the TMDD, marstacimab is expected to be also cleared by target-mediated clearance as formation of marstacimab/TFPI complex.
Excretion studies were not conducted with marstacimab. Based on the molecular weight, marstacimab is expected to undergo catabolic degradation and is not expected to be renally cleared. Marstacimab is cleared via linear and non-linear mechanisms. Following multiple subcutaneous doses and based on a population PK analysis, marstacimab linear clearance was approximately 0.019 L/hr. Mean effective steady-state half-life of marstacimab was estimated to be approximately 16 to 18 days for both adults and adolescents and across dose groups.
Although weight was an important covariate to describe the pharmacokinetics of marstacimab, no alteration in dosing is required based on weight in patients weighing ≥35 kg. Marstacimab clearance (CL) was 29% lower in adolescents (12 to <18 years of age) compared to adults (18 years and older). After adjusting for weight, CL (L/hr/kg) in adolescents was estimated to be approximately 3% lower compared to that in adults, indicating that weight accounts for most of the differences in CL. This difference in PK did not translate to a clinically relevant difference in levels of the downstream pharmacodynamic marker peak thrombin between the 2 groups.
The impact of haemophilia type on the pharmacokinetics of marstacimab was not found to be clinically relevant in the patient population.
Race (Asian vs. non-Asian) was not identified as a covariate influencing marstacimab pharmacokinetics. Marstacimab weight-adjusted clearance was 32% higher in Asian patients as compared to non-Asian patients. This difference is not considered clinically relevant. There are insufficient data to evaluate potential differences in the exposure of marstacimab in other races or ethnicity.
Clinical studies of marstacimab did not include a sufficient number of patients aged 65 years and older to determine whether there are differences in exposure compared with younger patients.
Renal clearance is not considered important for elimination of mAbs due to their large size and inefficient filtration through the glomerulus. Clinical studies have not been conducted to evaluate the effect of renal impairment on the PK of marstacimab.
All patients with haemophilia A and B in the population pharmacokinetic analysis had normal renal function (N=129; eGFR ≥90 mL/min/1.73 m²) or mild renal impairment (N=21; eGFR of 60 to 89 mL/min/1.73 m²). Mild renal impairment did not affect the pharmacokinetics of marstacimab. There are no data available on the use of marstacimab in patients with moderate or severe renal impairment.
Marstacimab is a monoclonal antibody and is cleared via catabolism rather than renal excretion and a change in dose is not expected to be required for patients with renal impairment.
Clinical studies have not been conducted to evaluate the effect of hepatic impairment on the PK of marstacimab, as it is generally not considered clinically relevant for mAbs.
All patients with haemophilia A and B in the clinical studies had normal hepatic function (N=135; total bilirubin and AST ≤ ULN) or mild hepatic impairment (N=15; total bilirubin >1× to ≤1.5× ULN). Mild hepatic impairment did not affect the pharmacokinetics of marstacimab. No data are available on the use of marstacimab in patients with moderate or severe hepatic impairment.
Marstacimab is a monoclonal antibody and is cleared via catabolism rather than hepatic metabolism and a change in dose is not expected to be required for patients with hepatic impairment.
Nonclinical data reveal no special hazard for humans based on repeat-dose toxicity, including safety pharmacology endpoints, and local tolerance. Reversible mixed cell infiltration, haemorrhage, and necrosis were observed at the injection sites in rats following subcutaneous injection. No studies have been conducted to assess the potential for carcinogenicity, mutagenicity, or effects on embryo-foetal development.
Marstacimab did not affect fertility or early embryonic development when administered as a repeat dose to male rats at doses up to 1 000 mg/kg/dose and an exposure margin of 212× the AUC exposure at a clinical dose of 300 mg subcutaneous weekly.
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