Long‐term safety and efficacy of the anti‐tissue factor pathway inhibitor marstacimab in participants with severe haemophilia: Phase II study results

Mahlangu, Johnny; Lamas, José Luis; Morales, Juan Cristobal; Malan, Daniel Rudolf; Teeter, John G.; Charnigo, Robert J; Hwang, Eunhee; Arkin, Steven

doi:10.1111/bjh.18495

Cited by 32 publications

(14 citation statements)

References 22 publications

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“…54 The Phase 2 long-term study of marstacimab in participants with haemophilia A and B, with and without inhibitors, reported that marstacimab was generally well-tolerated with no thrombotic events or treatment-related serious adverse events reported. 55 Furthermore, mean overall ABR was 1.5 for the cohort receiving 300 mg cohort weekly, and 2.7 for the cohort receiving 150 mg once weekly after a loading dose of 300 mg. 55 These non-factor therapies have different mechanisms of action than FVIII replacement therapies, aiming to partially restore haemostasis by acting on different points of the coagulation process. As such, monitoring the pharmacodynamics of these non-factor therapies, when they do not directly increase FVIII activity levels, is challenging; alternative assays may be needed to evaluate the haemostatic efficacy of these therapies.…”

Section: Investigational Non-factor Replacement Therapiesmentioning

confidence: 88%

“…Included 63 patients with severe haemophilia A (median [range] age, 28 7–59 years) receiving tertiary prophylaxis.…”

Section: Rationale For Aiming For Higher Fviii Activity Levelsmentioning

confidence: 99%

“…However, non‐inferiority of concizumab to previous prophylaxis was not confirmed and the median (IQR) ABR for participants with haemophilia A on prior prophylaxis was 2.2 (0.8–6.2) versus 2.3 (0.0–4.7) for concizumab prophylaxis 54 . The Phase 2 long‐term study of marstacimab in participants with haemophilia A and B, with and without inhibitors, reported that marstacimab was generally well‐tolerated with no thrombotic events or treatment‐related serious adverse events reported 55 . Furthermore, mean overall ABR was 1.5 for the cohort receiving 300 mg cohort weekly, and 2.7 for the cohort receiving 150 mg once weekly after a loading dose of 300 mg 55 …”

Section: Non‐factor Replacement Therapies and Fviii Equivalencementioning

confidence: 99%

“…The Phase 2 long‐term study of marstacimab in participants with haemophilia A and B, with and without inhibitors, reported that marstacimab was generally well‐tolerated with no thrombotic events or treatment‐related serious adverse events reported 55 . Furthermore, mean overall ABR was 1.5 for the cohort receiving 300 mg cohort weekly, and 2.7 for the cohort receiving 150 mg once weekly after a loading dose of 300 mg 55 …”

Section: Non‐factor Replacement Therapies and Fviii Equivalencementioning

confidence: 99%

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Targeting higher factor VIII levels for prophylaxis in haemophilia A: a narrative review

Malec,

Matino

2023

Haemophilia

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IntroductionThe standard of care in severe haemophilia A is prophylaxis, which has historically aimed for a factor VIII (FVIII) trough level of ≥1%. However, despite prophylactic treatment, people with haemophilia remain at risk of bleeds that have physical and quality of life implications, and that impact everyday life.AimThe aim of this review was to evaluate evidence supporting the relationship between targeting higher FVIII activity levels with prophylaxis and improved outcomes in people with haemophilia A.MethodsWe conducted a narrative review that defined the unmet needs and treatment goals in people with haemophilia A, evaluated evidence to support targeting higher FVIII activity levels, and highlighted therapies that may support higher and sustained FVIII activity levels and improved outcomes for people with haemophilia A.ResultsDespite recent advances in treatment, unmet needs remain, and people with haemophilia continue to experience joint and functional impairment, acute and chronic pain, and poor mental health. All these negatively impact their health‐related quality of life. Evidence suggests that FVIII activity levels of up to 50% may be needed to achieve a near‐zero joint bleed rate. However, achieving high FVIII activity levels with current standard and extended half‐life (EHL) FVIII replacement therapies is associated with a high treatment burden. Innovative treatment options may provide high sustained FVIII activity levels and improved patient outcomes.ConclusionEvidence suggests that FVIII activity levels in people with haemophilia A should be sustained at higher levels to improve joint and patient outcomes and enable progression towards health equity.

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Section: Investigational Non-factor Replacement Therapiesmentioning

confidence: 88%

“…Included 63 patients with severe haemophilia A (median [range] age, 28 7–59 years) receiving tertiary prophylaxis.…”

Section: Rationale For Aiming For Higher Fviii Activity Levelsmentioning

confidence: 99%

Section: Non‐factor Replacement Therapies and Fviii Equivalencementioning

confidence: 99%

Section: Non‐factor Replacement Therapies and Fviii Equivalencementioning

confidence: 99%

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Targeting higher factor VIII levels for prophylaxis in haemophilia A: a narrative review

Malec,

Matino

2023

Haemophilia

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“…4 Another therapeutic option, recombinant porcine FVIII, although not technically a BPA, is currently approved for use in patients with acquired (autoimmune) HA 5 ; case reports have shown successful use in congenital HA and either low titer or absent cross-reacting porcine FVIII inhibitors. 6,7 A novel approach to managing hemophilia with or without inhibitors is the use of nonfactor agents that are either approved for clinical use (emicizumab, Hemlibra) or in clinical trials including fitusiran, 8 concizumab, 9 marstacimab, 10 and SerpinPC 11,12 (see ►Table 1).…”

mentioning

confidence: 99%

The Use of Bypassing Treatment Strategies in Hemophilia and Their Effect on Laboratory Testing

Pruthi

Chen

2023

Semin Thromb Hemost

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Factor VIII and IX inhibitors in congenital hemophilia A and B, respectively, neutralize the infused coagulation factor concentrate rendering them ineffective. Bypassing agents (BPAs) that circumvent the block imposed by the inhibitors are used for the prevention and management of bleeding. Activated prothrombin complex concentrate was the original BPA, recombinant activated factor VII was then introduced, and more recently nonfactor agents that target the procoagulant and anticoagulant systems have been developed and are in clinical use (e.g., emicizumab, a bispecific antibody for hemophilia A). Other BPAs are in clinical trials (e.g., fitusiran targets antithrombin, concizumab and marstacimab target tissue factor pathway inhibitor, and SerpinPC targets activated protein C). The BPAs have a varied effect on coagulation assays, and as more patients are exposed to these agents, it is important to be aware of the effects. Herein, we present an overview of the effect of BPAs on routine and specialized coagulation assays including thrombin generation and viscoelastic assays.

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Evaluating Gene Therapy as a Potential Paradigm Shift in Treating Severe Hemophilia

Thornburg,

Simmons,

von Drygalski

2023

BioDrugs

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Hemophilia is characterized by a deficiency in coagulation factors VIII or IX. The general standard of care for severe hemophilia is frequent intravenous recombinant or plasma-derived factor replacement to prevent bleeding. While this treatment is effective in preventing bleeding, frequent infusions are burdensome for patients. Nonadherence to the therapeutic regimen leaves people with hemophilia at risk for spontaneous and traumatic bleeds into joints as well as life-threatening bleeds such as intracranial hemorrhage. The chronicity of the disorder often leads to the formation of target joints, causing long-term pain and impairing mobility. As a monogenic disorder with well-understood genetics, hemophilia is an ideal disorder for implementing innovations in gene therapies. Indeed, recent approvals of two gene therapy products have the potential to shift the hemophilia treatment paradigm. Valoctocogene roxaparvovec and etranacogene dezaparvovec-drlb are gene therapies for hemophilia A and B, respectively. These therapies, given as a single intravenous infusion, may improve patients’ quality of life, decreasing treatment burden and resulting in factor expression that virtually eliminates the need for factor replacement. Since both treatments involve viral vectors targeted to the liver, short- and long-term safety and efficacy monitoring involves monitoring liver enzymes to track liver health. Long-term monitoring of efficacy, durability of gene expression, and safety are ongoing. Gene therapy presents a promising new therapeutic option for patients with hemophilia and warrants continued innovation and investigation.

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Long‐term safety and efficacy of the anti‐tissue factor pathway inhibitor marstacimab in participants with severe haemophilia: Phase II study results

Cited by 32 publications

References 22 publications

Targeting higher factor VIII levels for prophylaxis in haemophilia A: a narrative review

Targeting higher factor VIII levels for prophylaxis in haemophilia A: a narrative review

The Use of Bypassing Treatment Strategies in Hemophilia and Their Effect on Laboratory Testing

Evaluating Gene Therapy as a Potential Paradigm Shift in Treating Severe Hemophilia

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