Top 10 Hemophilia Stories of 2020

Hemophilia News Today brought you daily coverage in 2020 of important discoveries, treatment advancements, clinical trial findings, and other important events related to hemophilia.

As we look forward to bringing you more news this year, we present here the 10 most-read stories of 2020, along with a summary of what made each story relevant to the patient community.

No. 10 – “Novo Nordisk Pauses 3 Clinical Trials of Concizumab Amid Safety Concerns”

Novo Nordisk announced in March its decision to halt three clinical trials — the Phase 2 Explorer 5 (NCT03196297), and the Phase 3 Explorer 7 (NCT04083781) and Explorer 8 (NCT04082429) — assessing the safety and efficacy of concizumab, when given to prevent bleeds in patients with hemophilia A and B. The company’s decision to suspend enrollment and dosing in all Explorer trials was motivated by safety concerns arising from the fact that three patients participating in concizumab’s clinical program had experienced non-fatal thrombotic (blood clotting) events.

Concizumab is an antibody-based therapy designed to block the anticoagulant protein known as tissue factor pathway inhibitor, and promote the production of thrombin, a blood clotting protein. Through this mechanism, the investigational therapy is designed to help prevent spontaneous bleeding episodes associated with both forms of hemophilia. The therapy had previously been named an orphan drug for hemophilia B treatment in Europe.

No. 9 – “Novo Nordisk Resumes Phase 3 Trials of Concizumab in Hemophilia A and B”

Novo Nordisk announced in August that it had resumed its Phase 3 trials, Explorer 7 and Explorer 8, evaluating concizumab in hemophilia A and B. After reviewing all available data, the company established, in collaboration with relevant authorities, a series of safety guidelines to minimize the risk of thrombotic events associated with treatment. The U.S. Food and Drug Administration (FDA) agreed to these changes and decided to lift the clinical hold it had placed on both studies.

Together, Explorer 7 and 8 aim to enroll nearly 300 patients with hemophilia A or B, including those with and without inhibitors (neutralizing antibodies that render replacement therapies useless), from several countries worldwide. Recruitment is still underway in both studies. Explorer 5, a Phase 2 trial of concizumab that had also been suspended in March, concluded in the meantime.

No. 8 – “Infection by New Coronavirus Can Induce AHA, Case Report Says”

In May, physicians in Italy described the case of a 66-year-old man who saw his acquired hemophilia A (AHA) return after contracting COVID-19. AHA is an autoimmune disease that causes the body’s immune system to destroy a blood clotting protein, called factor VIII (FVIII), leading to spontaneous bleeds that resemble those seen in people with hemophilia A.

The patient had experienced his first AHA episode nine years prior, after being admitted to the hospital in November 2011 for severe spontaneous bleeds in his skin and muscles. He entered into remission after receiving a combination of blood clotting factors to stop bleeding and medications to reduce his overactive immune system.

However, he was re-admitted to the hospital in March 2020 with shortness of breath, fever, and pneumonia associated with COVID-19. Further tests showed his FVIII levels were abnormally low, indicating an AHA relapse. He was then treated for both COVID-19 and AHA, and fully recovered in the following weeks. According to the researchers, this case highlights the importance of constantly monitoring blood coagulation in patients admitted to the hospital for COVID-19.

No. 7 – “Fitusiran Continues to Prevent Bleeds in Hemophilia A or B, Trial Shows”

We reported interim data in June from a Phase 1/2 extension study (NCT02554773) showing that fitusiran, an investigational treatment for hemophilia, safely lowered bleed frequency in people with moderate to severe hemophilia A or B, when given prophylactically once monthly for nearly five years.

Jointly developed by Alnylam Pharmaceuticals and Sanofi Genzyme, fitusiran (ALN-AT3) is an experimental RNA interference agent that blocks the activity of antithrombin, a protein that normally inhibits thrombin and blood coagulation. Earlier data from a Phase 1 trial (NCT02035605) showed that when given once monthly, fitusiran was able to lower the levels of antithrombin and restore the balance of clotting factors in patients with hemophilia A or B. New data from an extension study, which enrolled those who completed this trial, showed safe lowering of antithrombin levels and bleed frequency over nearly five years. This was observed across all patient subgroups, including those with and without inhibitors.

No. 6 – “ ‘Huge Step Back’ for Hemophilia Gene Therapy, Expert Says of FDA Delay on Roctavian”

In August, Hemophilia News Today interviewed Guy Young, MD, a professor of pediatrics at the Keck School of Medicine at the University of Southern California, to discuss the delay in the FDA’s decision to approve Roctavian (valoctocogene roxaparvovec), BioMarin’s investigational gene therapy for hemophilia A.

The agency explained that its decision was due to the lack of long-term data to support the therapy’s durability, adding that additional two-year data from the Phase 3 GENEr8-1 study (NCT03370913), one of the trials that supported Roctavian’s original approval request, would be needed before a final decision could be made. The FDA also expressed concerns about the differences between GENEr8-1 and a previous Phase 1/2 study (NCT02576795), whose three-year data were also used to support BioMarin’s approval request.

Young, who is also the director of the Hemostasis and Thrombosis Program at the Children’s Hospital of Los Angeles, was surprised and disappointed to hear the FDA’s verdict, especially considering none of the trials evaluating the therapy had reported major safety issues associated with its use. Young acknowledged that the FDA’s concerns about the therapy’s long-term durability were legitimate, but failed to see how complete data from GENEr8-1 would fully address that concern. He added that this setback with Roctavian’s approval might extend to other gene therapies currently being developed to treat hemophilia.

No. 5 – “BioMarin’s Valrox, Possible 1st Gene Therapy for Hemophilia A, Under FDA Priority Review”

BioMarin announced in February that the FDA had accepted to review — under priority review — its application requesting Roctavian be approved to treat those with hemophilia A in the U.S., and set Aug. 21 as a deadline for its final decision.

Formerly known as Valrox and BMN 270, Roctavin uses a harmless adeno-associated virus (AAV), called AAV5, to deliver a smaller working version of F8 — the gene that encodes FVIII and is faulty in people with hemophilia A — to liver cells. Through this mechanism, Roctavian is thought to increase FVIII production, lowering the frequency of spontaneous bleeds and the need for repeated infusions of artificial FVIII.

The company’s approval request was supported by six-month interim data from GENEr8-1 and three-year data from an earlier Phase 1/2 study, which demonstrated that a single infusion of Roctavian was able to increase FVIII activity levels and reduce bleed frequency in men with severe hemophilia A.

In addition to the therapy’s application, the FDA also accepted a premarket approval request for an AAV5 antibody test, produced by ARUP Laboratories, that is meant as a diagnostic companion to identify people more likely to respond to Roctavian.

No. 4 – “Pfizer Taking over Development of Potential Gene Therapy SB-525, Advancing into Phase 3 Trials”

In January, we covered the clinical development transfer of SB-525 — an investigational gene therapy for hemophilia A originally co-developed by Sangamo Therapeutics and Pfizer — to Pfizer. The company had already launched a six-month lead-in Phase 3 study (NCT03587116) that will evaluate the safety and effectiveness of replacement therapies in patients with hemophilia A or B, and is expected to pave the way for a future Phase 3 registrational trial of SB-525.

The launch of the therapy’s Phase 3 clinical program was supported by data from an earlier Phase 1/2 trial (NCT03061201) showing that a single infusion of SB-525 was able to safely restore FVIII activity and prevent bleeds in men with severe hemophilia A. Patients enrolled in the trial also ceased to require replacement therapies after completing a short preventive treatment course following SB-525 administration.

No. 3 – “FDA Delays Decision on Roctavian, Potential Hemophilia A Gene Therapy, for a Year or More”

In a lead-in story to our interview with Young, we reported the FDA had decided to postpone by more than a year its decision on whether to approve Roctavian. In a complete response letter, the agency stated it was unable to clear BioMarin’s approval request in its present state, and that more time and additional trial data would be needed before a final decision could be made.

No. 2 – “BioMarin’s Gene Therapy for Hemophilia A Remains on Track for US Approval”

BioMarin announced in May that the COVID-19 pandemic did not affect the review timeline of its application to the FDA a few months earlier requesting Roctavian’s approval in the U.S. to treat those with hemophilia A. However, the company was anticipating that the therapy’s review process in Europe would be delayed by at least three months. The company received feedback from the European Medicines Agency (EMA) in September. Like the FDA, EMA also decided to push back its decision on Roctavian’s approval and requested additional trial data be provided.

No. 1 – “Valrox, Potential Hemophilia A Gene Therapy, May Cost Up to $3 Million, BioMarin Says”

Our most-read story of 2020 covered the news that, if approved, Roctavian — still known as Valrox at the time — might cost up to $3 million, placing it as the world’s most expensive one-time therapy ever commercialized. The topic of the therapy’s list price was discussed by Jean-Jacques Bienaimé, chairman and CEO of BioMarin, at the J.P. Morgan Healthcare Conference. Bienaimé argued that even if Roctavian is marketed at $3 million, “society is better off,” since the treatment could save healthcare systems more than $20 million over standard hemophilia treatments in a patient’s lifetime.

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At Hemophilia News Today, we hope our continuous coverage in 2020 contributed to informing and improving the lives of those with hemophilia, their caregivers, and loved ones.

We wish all our readers a happy 2021.