Concizumab Prophylaxis Reduced Bleeding Rates in Hemophilia

— Phase III trial shows 86% reduction in treated bleeds in hemophilia A and B with inhibitors

A computer rendering of red blood cells and platelets healing a wound.

Compared with on-demand treatment, prophylaxis with concizumab -- designed to achieve hemostasis in all hemophilia types -- reduced annualized bleeding rates among patients who have hemophilia A or B with inhibitors, the phase III explorer7 trial showed.

Patients who received the anti-tissue factor pathway inhibitor monoclonal antibody for at least 32 weeks had an estimated mean annualized bleeding rate of 1.7 episodes compared with 11.8 episodes among those who had no prophylaxis for at least 24 weeks -- representing an 86% reduction in treated bleeds (rate ratio [RR] 0.14, 95% CI 0.07-0.29, P<0.001), reported Tadashi Matsushita, MD, PhD, of Nagoya University Hospital in Japan, and colleagues.

"Concizumab represents a novel, subcutaneous treatment option in patients with hemophilia A or B with inhibitors that can potentially improve long-term outcomes," the authors wrote in the New England Journal of Medicine.

The annualized rates of other bleeding episodes were also lower in the concizumab prophylaxis group compared with the on-demand group:

  • Spontaneous bleeding episodes: 1.3 vs 9.4 (RR 0.14, 95% 0.06-0.30)
  • Joint bleeding episodes: 1.4 vs 9.1 (RR 0.15, 95% CI 0.07-0.32)
  • Target joint bleeding episodes: 0.1 vs 1.1 (RR 0.12, 95% CI 0.02-0.84)
  • All treated and untreated bleeding episodes: 4.4 vs 13.3 (RR 0.33, 95% CI 0.17-0.64)

"It is reassuring that this first-in-class drug is effective in treating hemophilia A or B with inhibitors," commented H. Marijke van den Berg, MD, PhD, of the PedNet Hemophilia Research Foundation in Baarn, the Netherlands, and Alok Srivastava, MD, of the Christian Medical College Vellore in India, in an accompanying "Science Behind the Study" editorial. "Given its reported efficacy in both types of hemophilia without inhibitors, concizumab is evolving as an attractive therapeutic for all patients with hemophilia."

While the results of the study "represent an advance in the management of hemophilia, the ramifications of rebalancing hemostasis, particularly during stress or inflammatory conditions, are not well understood and warrant further investigation," the editorialists wrote. Furthermore, more data are needed on the safety and efficacy of the therapy in early childhood, they added.

Moreover, new treatment options like concizumab must be weighed against the potential of cure offered by gene therapy, they said. However, the durability of gene therapy factor product is still being defined and the "abundance of therapeutic options such as concizumab, other non-factor-replacement products, and a multitude of clotting factor products will play a large role in prevention of bleeding in hemophilia for the foreseeable future," they wrote.

While concizumab was recently approved in Canada (marketed as Alhemo), the FDA recently issued a complete response letter, requesting that developer Novo Nordisk provide additional information about its manufacturing process and more details on dose monitoring to ensure the therapy is administered as intended. The agency in 2020 had forced the drugmaker to pause the trial over clotting events.

The explorer7 study enrolled 133 patients, 80 with hemophilia A and 53 with hemophilia B, both with inhibitors. Anywhere from one in three to one in five people with hemophilia A have inhibitors, while just 1% to 4% of those with hemophilia B have inhibitors.

The patients were randomized 1:2 to receive no prophylaxis for at least 24 weeks (19 patients in group 1) or concizumab prophylaxis for at least 32 weeks (33 in group 2). The remaining 81 patients were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4).

The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes compared with 9.8 episodes in group 1.

In the study (as well as the explorer8 trial), concizumab was paused by the safety committee in March 2020, due to nonfatal thromboembolic events in three patients receiving concizumab, including a patient from the explorer7 trial who had a renal infarct. The FDA subsequently issued a clinical hold.

On-demand treatment in group 1 continued during the pause, while patients in the concizumab prophylaxis groups switched to alternative therapies at the investigator's discretion. The trials were restarted 6 months later with participants given a loading dose of 1.0 mg/kg, followed by 0.2 mg/kg daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4).

No thromboembolic events were reported after concizumab therapy was restarted.

The most frequently reported adverse events in patients who received concizumab during the period when patients were considered to be exposed to concizumab included arthralgia (10%), injection-site erythema (7%), and upper respiratory tract infection (6%).

A total of five serious adverse events occurred in three patients who received no prophylaxis in group 1, while 18 serious adverse events occurred in 14 patients who received concizumab in groups 1-4. Three patients had serious adverse events related to bleeding, and four patients had serious adverse events related to infections.

  • author['full_name']

    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.


The trial was supported by Novo Nordisk.

Matsushita reported relationships with Novo Nordisk.

Co-authors reported multiple relationships with industry.

Srivastava reported relationships with Roche, Novo Nordisk, Sanofi, Pfizer, Takeda, Bayer, and Biomarin.

van den Berg disclosed no relationships.

Primary Source

New England Journal of Medicine

Source Reference: Matsushita T, et al "Phase 3 trial of concizumab in hemophilia with inhibitors" N Engl J Med 2023; DOI: 10.1056/NEJMoa2216455.

Secondary Source

New England Journal of Medicine

Source Reference: van den Berg HM, Srivastava A "Hemostasis -- A balancing act" N Engl J Med 2023; DOI: 10.1056/NEJMe2304535.