Denecimig excels at reducing bleeds in hemophilia A patients: Study

Denecimig (Mim8) was significantly better than on-demand or standard preventive treatments at reducing bleeding episodes in people with hemophilia A, regardless of inhibitor status.

That’s according to published data from the FRONTIER2 trial (NCT05053139), which evaluated the efficacy and safety of once-monthly and once-weekly denecimig treatment in adults and adolescents ages 12 years and older with hemophilia A.

The results, “Mim8 Bispecific Antibody Prophylaxis in Hemophilia A with or without Inhibitors,” were published in The New England Journal of Medicine.

“The prevention and reduction of bleeding episodes is the ultimate goal for people living with hemophilia A. These results from the FRONTIER2 study provide important data on the potential of denecimig as a preventive treatment option regardless of hemophilia A severity or inhibitor status,” Maria Elisa Mancuso, MD, PhD, professor at Humanitas University in Italy and lead investigator of the trial, said in a press release from Novo Nordisk, the treatment’s developer.

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Hemophilia A is caused by mutations in the F8 gene that lead to missing or defective factor VIII (FVIII), a protein needed for the blood to clot. Standard treatment includes factor replacement therapies, although some patients develop inhibitors, or neutralizing antibodies against the administered clotting factor, which may limit the therapy’s efficacy.

Denecimig is designed to prevent or reduce the frequency of bleeding episodes in people with hemophilia A. Its active ingredient is a bispecific antibody that mimics FVIII function and stimulates production of thrombin, an enzyme involved in blood clotting. The treatment is administered via subcutaneous (under-the-skin) injections and can be given to patients with or without inhibitors.

The FRONTIER2 study enrolled 254 adults and adolescents with hemophilia A, with or without inhibitors, who were receiving on-demand treatment or preventive treatment before the trial. Participants were then randomly assigned to continue on-demand treatment or to receive denecimig once weekly or once monthly, for 26 weeks (about six months).

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Annualized rate of treated bleeding events fell by more than 90%

In the pretrial on-demand group, the annualized rate of treated bleeding events — the number of bleeding episodes a patient is expected to have in one year that require treatment — was reduced by nearly 96% with denecimig taken once weekly and by nearly 99% with it taken once monthly compared to on-demand treatment.

Among patients previously receiving preventive treatment, denecimig reduced annualized treated bleeding events by 54% when administered once weekly and by about 43% when administered once monthly.

Additionally, among patients who had previously received on-demand treatment, most who switched to denecimig had no bleeding events requiring treatment, including 81% of those receiving once-weekly dosing and 95% of those receiving once-monthly dosing. In contrast, none of the patients who remained on their prior on-demand treatment were free of treated bleeding events.

Among patients who had received prior preventive treatment, 66% of those who switched to denecimig once weekly and 64% of those who received denecimig once monthly had no treated bleeding events.

According to the researchers, these results show that “[denecimig] prophylaxis was superior to on-demand treatment” and “to clotting factor concentrate prophylaxis.”

With denecimig recently submitted to the FDA … these NEJM data further underscore its potential as a preventive treatment option that may help address the persistent unmet needs of people living with hemophilia A, with or without inhibitors.

Overall, 486 adverse events, mostly mild to moderate in severity, were reported. About 10% of the patients reported injection site reactions, usually including redness and itching. No patient was reported to have a thromboembolic event (blood clot formation) or clinical evidence of anti-denecimig antibodies.

Three patients discontinued denecimig due to adverse events, including nerve paralysis in one patient and sleep disorder and indigestion in another, possibly related to denecimig. Another patient had coronary artery disease, in which the arteries that supply the heart are blocked, reducing blood flow to the heart muscle, which was considered unrelated to the treatment.

Based on the results from this trial, the FRONTIER 3 Phase 3 trial (NCT05306418), and the open-label extension study FRONTIER 4 (NCT05685238), the company has submitted an application to the U.S. Food and Drug Administration (FDA) seeking denecimig’s approval to prevent bleeds in people with hemophilia A with or without inhibitors.

“With denecimig recently submitted to the FDA … these NEJM data further underscore its potential as a preventive treatment option that may help address the persistent unmet needs of people living with hemophilia A, with or without inhibitors,” said Anna Windle, PhD, head of clinical development, medical and regulatory affairs at Novo Nordisk US Operations.

The FRONTIER 3 study demonstrated that the treatment was safe and effective at controlling bleeds in children with hemophilia A. Participants who completed the FRONTIER studies had the option to continue long-term treatment in FRONTIER 4, which is evaluating denecimig’s efficacy when given once every two weeks and the long-term safety across all dosing regimens.