Novo’s Denecimig Shows Tolerability After Direct Switch from Emicizumab in Phase 3b FRONTIER5

Novo Nordisk reported 26-week results from the phase 3b FRONTIER5 study evaluating a direct switch from emicizumab to investigational denecimig in adolescents and adults with haemophilia A, with or without inhibitors. The study found no unforeseen safety concerns after the switch, while exploratory data showed sustained increases in thrombin generation. Most participants also preferred the denecimig prefilled pen injector over their previous emicizumab vial-and-syringe administration method.

Direct Switch Avoided a Washout Period

FRONTIER5 was an open-label phase 3b safety study in 61 patients aged 12 years and older with haemophilia A. All participants completed the 26-week treatment period after switching directly from emicizumab to denecimig.

The primary safety analysis recorded 107 treatment-emergent adverse events (TEAEs) in 43 patients (70.5%). Most events were mild to moderate, accounting for 98.1% of TEAEs. Twenty-four events were considered possibly or probably related to denecimig. No thromboembolic events, hypersensitivity reactions, treatment discontinuations because of TEAEs, or clinical evidence of neutralizing anti-denecimig antibodies were observed.

The direct transition is clinically relevant because switching haemophilia therapies can require treatment spacing to avoid overlapping effects on thrombin generation and potential gaps in bleeding protection. FRONTIER5 evaluated the transition without waiting for emicizumab clearance and without an initial denecimig loading dose.

 Thrombin Generation Increased into the Normal Range

Denecimig is a bispecific antibody that mimics activated factor VIII (FVIIIa). It bridges factor IXa and factor X, reproducing an important function of FVIIIa in the coagulation cascade and supporting thrombin generation. The investigational therapy is being developed as subcutaneous prophylaxis for people with haemophilia A, including those with inhibitors.

An exploratory endpoint showed mean peak thrombin generation increasing from 25.5 nmol/L at week 0 to 39.8 nmol/L at week 26 across dosing groups. The mean within-patient percentage increase was 78.8%. The increase remained sustained across once-weekly, once-every-two-weeks and once-monthly dosing, without clinical evidence of excessive clotting. Denecimig reached steady-state plasma concentrations by week 16 without a loading dose.

Patients Reported Lower Administration Burden

Among 59 participants completing the device assessment, 98.3% rated the denecimig pen as easy or very easy to use. 94.9% said it was easier to use than their previous administration method, while 96.6% preferred the pen.

Treatment burden also declined. Among 55 assessed patients, the mean Hemo-TEM score fell by 4.7 points from baseline to week 26, with reductions reported across all three dosing frequencies.

FDA Review Underway

A Biologics License Application (BLA) for denecimig is currently under review by the U.S. Food and Drug Administration for routine prophylaxis in adults and pediatric patients with haemophilia A, with or without inhibitors. The proposed regimen includes once-weekly, once-every-two-weeks or once-monthly dosing.

The broader FRONTIER program includes studies evaluating denecimig across age groups and dosing schedules. FRONTIER4 is continuing long-term safety and efficacy follow-up, while FRONTIER5 specifically addresses the transition from emicizumab.

Reference

Novo’s denecimig demonstrates tolerability after switch from emicizumab in FRONTIER5 study of people with haemophilia A as published in the Journal of Thrombosis and Haemostasis, Novo Nordisk, 17 September 2026

A Research Study Looking at How Safe it is to Switch from Emicizumab to Mim8 in People With Haemophilia A (FRONTIER 5), ClinicalTrials.gov ID NCT05878938