Concizumab Reduces Bleeding in Hem A and B Patients: Phase 3 Trial
Once-daily preventive treatment with Novo Nordisk’s experimental therapy concizumab significantly reduced bleeding rates in people with both hemophilia A and B with inhibitors, according to new data from the Phase 3 explorer7 trial.
In fact, bleeding rates in patients receiving concizumab in trial decreased by more than 85%.
Based on these data, Novo Nordisk is expecting to submit applications later this year in the U.S. and Japan seeking the approval of concizumab as a prophylactic, or preventive, treatment for hemophilia A or B with inhibitors. The company said it plans to submit similar applications in the EU and the U.K. next year.
“For people living with haemophilia and the medical community, it is important to allow for fully individualised care, which includes offering different treatment options that directly address each changing and individual need. This ensures all people living with haemophilia receive appropriate care throughout their life,” Stephanie Seremetis, the chief medical officer of rare blood disorders at Novo Nordisk, said in an emailed statement to Hemophilia News Today.
The new trial findings were presented at the International Society of Thrombosis and Haemostasis Annual Congress (ISTH 2022), held July 9–13 in London. The late-breaking presentation, titled “Concizumab Prophylaxis in Patients With Haemophilia A or B With Inhibitors: Efficacy and Safety Results From the Primary Analysis of the Phase 3 explorer7 Trial,” was given by Victor Jiménez-Yuste, MD, PhD, lead investigator of explorer7.
Inhibitors can lessen therapy effectiveness
Hemophilia is caused by genetic mutations that impair the function of clotting proteins — factor IX (FIX) in the case of hemophilia B, and factor VIII (FVIII) in the case of hemophilia A. Replacement therapy is a standard hemophilia treatment that involves administering a version of the missing protein.
However, in some patients, the immune system can mistake replacement therapies for an infectious threat, and make antibodies against the supplied clotting factors. These neutralizing antibodies, called inhibitors, may lower the therapy’s effectiveness, and potentially render it useless.
“One of the most critical complications in the treatment of haemophilia is the development of inhibitors, as they render standard replacement therapy ineffective and severely limit treatment options for haemophilia B,” Jiménez-Yuste, also a professor at La Paz University Hospital in Madrid, said in a press release.
“Based on the results of the explorer7 study, there is a potential for concizumab to become a new treatment option for people living with haemophilia A or B with inhibitors,” Jiménez-Yuste said.
Concizumab is an experimental antibody-based therapy designed to block a protein called tissue factor pathway inhibitor (TFPI) that normally halts blood clotting. By doing so, concizumab promotes the production of thrombin, a protein that enhances blood clotting and helps prevent bleeds.
“The treatment of haemophilia is complex and no one treatment fits all,” said Martin Lange, executive vice president and head of development at Novo Nordisk. “Concizumab offers the potential for everyday protection for people living with haemophilia and provides an important potential addition to our haemophilia offering, especially in the haemophilia B with inhibitor population who currently have limited treatment options.”
Novo Nordisk’s explorer7 trial
In explorer7 (NCT04083781), 33 hemophilia patients with inhibitors were given prophylactic treatment with concizumab, administered once daily via subcutaneous (under-the-skin) injection. Another 19 participants received no prophylaxis. Both groups were followed for at least six months, with 28 patients in the concizumab group and 14 in the no-prophylaxis group completing the study.
Trials of concizumab were paused in 2020 amid safety concerns related to blood clotting events reported in some patients. After the studies were restarted later that year, participants in explorer7 on concizumab were initially given a loading dose of 1 mg/kg, followed by daily doses of 0.20 mg/kg, with potential adjustments to 0.15 or 0.25 mg/kg, based on the medication’s levels in the bloodstream measured after four weeks of treatment.
Results showed that, over about six months, the mean estimated bleeding rate in the no-prophylaxis group was 11.8 bleeds per year. In the concizumab group, the mean rate was 1.7 bleeds per year — an 86% decrease.
The median annualized bleeding rate for patients on concizumab was zero; in other words, most patients receiving prophylactic therapy did not have any reported bleeds. Consistently, more than half (63.6%) of the patients on concizumab experienced no bleeds that required treatment, while two (10.5%) in the no-prophylaxis group did.
Researchers also noted “positive trends” in life quality scores — measured via the 36-Item Short-Form Health Survey — for patients on concizumab. No blood clotting-related events were reported following the study’s restart.
“The results of the explorer7 study are encouraging for people living with haemophilia A or B with inhibitors and the medical community,” Seremetis said. “They demonstrate the potential of concizumab to prevent bleeds in a population with complex treatment needs, and potentially help to address the significant challenge of inhibitors in haemophilia A and B.”
For hemophilia patients, developing inhibitors is “one of the most critical complications in the treatment of haemophilia today,” according to Seremetis, who added that such inhibitors especially limit potential therapy options for those with haemophilia B.
“If approved by the regulatory authorities, concizumab is planned to be supplied in a pen device. The ready-to-use pen would be room-temperature stable for up to 28 days, enable administration of low volumes of the treatment, with an ultra-small needle designed to reduce pain, sensitivity or reactions at the injection sites which potentially can lead to improved adherence,” Seremetis said.
The researchers noted that concizumab was shown in the trial to be safe and well-tolerated.