Denecimig Wins Broad EC Approval But Faces Payer Squeeze Without Head-to-Head Superiority

EU Approves Novo Nordisk's FREHEMGO® for Haemophilia A

Novo Nordisk announced that the European Commission has granted marketing authorisation for FREHEMGO® (denecimig) for routine prophylaxis in adults and children with haemophilia A, with or without inhibitors. This FVIIIa mimetic bispecific antibody offers flexible dosing options: once-monthly, once-every-two-weeks, or once-weekly, administered via a single-use pre-filled pen. The approval is supported by the FRONTIER clinical trial program, including the pivotal FRONTIER2 trial, which demonstrated a significant reduction in annualised bleeding rates compared to prior treatments. Results from FRONTIER3 in children and FRONTIER5 on switching from emicizumab also showed consistent efficacy and no new safety signals.

• Flexible Dosing and Administration: FREHEMGO® (denecimig) is the first FVIIIa mimetic to provide patients and healthcare teams with a choice of once-monthly, once-every-two-weeks, or once-weekly subcutaneous prophylaxis using a convenient single-use pre-filled pen. This flexibility aims to better integrate treatment into patients' daily lives, enhancing adherence and quality of life for individuals with haemophilia A.
• Robust Clinical Efficacy: The approval is underpinned by the comprehensive FRONTIER clinical program, particularly the pivotal FRONTIER2 trial, which showed denecimig significantly reduced annualised bleeding rates in adults and adolescents with haemophilia A, irrespective of inhibitor status. Consistent efficacy was also observed in children in the FRONTIER3 trial, with a substantial proportion of participants across the program achieving zero treated bleeds.
• Safety and Switching Profile: Data from the FRONTIER5 trial demonstrated that directly switching patients from emicizumab to denecimig prophylaxis was safe, with no new safety signals identified. This trial also highlighted a clear preference for the denecimig pen and showed a sustained increase in thrombin generation into the normal range without posing a thrombotic risk, offering a viable transition option for patients.

Addressing Unmet Needs in Haemophilia A with FREHEMGO®

Hemophilia A management reflects a delicate balance between procoagulant and anticoagulant mechanisms, where bleeding prophylaxis must be weighed against paradoxical thrombotic risks. Current factor and non-factor approaches have improved outcomes, yet inhibitor development, pharmacokinetic variability, and aging-related comorbidities continue to limit long-term control.

• Inhibitor development renders FVIII replacement ineffective: Inhibitors are alloantibodies that neutralize the procoagulant activity of exogenous FVIII and represent the most severe complication of haemophilia A. Treatment requires administration of FVIII-containing products either on demand or as prophylaxis, which can induce inhibitor development in 20%-35% of patients. Patients with inhibitors present with bleeding episodes that are difficult to control, and they have reduced response to FVIII replacement.

• Immune tolerance induction is lengthy, costly and incompletely effective: Immune tolerance induction (ITI) is the treatment of choice for inhibitor eradication and the strategy for achieving antigen-specific tolerance to FVIII. ITI success rate ranges commonly between 60% and 80%, with one registry reporting ITI was successful in 91/137 patients (66.4%), while in nonsevere haemophilia A most inhibitors disappear spontaneously but an anamnestic response still can occur when rechallenged in 35% (25/72) of these patients.

• Bypassing and rebalancing agents carry thromboembolic risk with unestablished monitoring: For treatment of patients with high-titre, high-responding inhibitors, 'by-pass' therapy with activated prothrombin complex concentrates or recombinant factor VIIa is generally recommended. Incidence rates were 15.4 events (95% CI: 6.7–30.3) per 1,000 aPCC-exposed py; 18.2 events (95% CI: 8.3–34.6) per 1,000 rFVIIa-exposed py; and 29.7 events (95% CI: 6.1–86.7) per 1,000 py of concomitant exposure to both agents. The treatment with emicizumab showed tolerable safety both in clinical trials and long-term real-world observations with few thrombotic events, while in some clinical trials with rebalancing therapies (fitusiran and concizumab) thrombotic events occurred, and monitoring of the haemostatic function of novel therapies especially with concomitant haemostatic treatment is not yet established.

• Pharmacokinetic variability limits protection on extended prophylaxis: During 1 year of pharmacokinetic-guided prophylaxis every third day, 131 bleeding episodes occurred in 24/34 patients. Average peak FVIII levels ranged from 24 to 168 IU dL(-1), with higher values associated with a decreased risk for all bleeding and joint bleeding, while median percent of time spent with FVIII levels >20 IU dL(-1) was 22% and median AUC was 1363, supporting the need for high peak levels and AUC in some patients treated every third day.

• Aging, comorbidities and gene therapy durability complicate long-term care: Aging-related comorbidities, including cardiovascular disease, atrial fibrillation, HIV-associated complications, and acute coronary syndromes, impact thrombotic risk, with acute coronary syndromes occurring even among relatively younger persons with haemophilia typically in association with multiple cardiovascular risk factors. For adeno-associated virus vector expression of FVIII, long-term follow-up showed a continuous decline in the FVIII transgene levels starting 1 year after vector injection through year 5, vector readministration is not feasible at this time, and hepatocyte health including chronic hepatitis C virus infection and metabolic dysfunction-associated steatosis or steatohepatitis may compromise efficacy and safety.

FRONTIER Program: Demonstrating FREHEMGO®'s Efficacy and Safety

Recent studies in congenital haemophilia A have evaluated factor-based and non-factor strategies in patients with and without inhibitors. The data span immune tolerance induction dosing, porcine-sequence FVIII replacement for inhibitor bleeds, and every-4-week emicizumab prophylaxis.