Top 10 Hemophilia Stories of 2021

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by Marta Figueiredo PhD |

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Hemophilia News Today brought you daily coverage throughout 2021 of the latest scientific findings, treatment developments, and clinical trials related to hemophilia.

As a reminder of what mattered most to you during this year, here are the top 10 most-read articles of 2021, with brief descriptions of what made them interesting and relevant to the hemophilia community.

We look forward to reporting more of this relevant news to patients, family members, and caregivers dealing with hemophilia during 2022.

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For Too Long, I Thought My Bleeding Was Normal

No. 10 – “Breakthrough Bleeds Likely for Hem A Patients on Hemlibra, Study Finds

A small real-life study in Israel suggested that most people with hemophilia A on preventive treatment with Hemlibra (emicizumab) will still experience spontaneous or traumatic bleeds at some point. Given in an under-the-skin injection, Hemlibra works by mimicking the activity of factor VIII (FVIII), the clotting protein that is missing or faulty in hemophilia A. The treatment is approved to prevent or reduce bleeds in hemophilia A patients with and without inhibitors, or neutralizing antibodies that can block the activity of conventional FVIII replacement therapies. The study followed 70 hemophilia A patients who received preventive treatment with Hemlibra for at least 18 months. Data showed that more than half of the patients experienced at least one bleeding event, with joint bleeds being the most common. Notably, older age was found to be a significant risk factor for bleeds.

No. 9 – “Phase 3 Trial of Gene Therapy SB-525 for Hemophilia A on FDA Hold

In November, the U.S. Food and Drug Administration (FDA) put a hold on Pfizer‘s Phase 3 AFFINE trial (NCT04370054), for hemophilia A, to review protocol changes, the company announced. The trial was testing the experimental gene therapy SB-525 (giroctocogene fitelparvovec) in 63 men with moderate to severe hemophilia A. SB-525 is designed to increase the levels of FVIII by providing patients with a working version of F8, the gene that contains the instructions for making FVIII and that is mutated in hemophilia A patients. A modified and harmless adeno-associated virus (AAV) is used to carry and deliver the gene specifically to liver cells, the main producers of clotting factors. Developed in collaboration with Sangamo Therapeutics, the gene therapy is given through a single infusion directly into the bloodstream. The clinical hold was established to give the FDA time to review trial protocol changes implemented by Pfizer after unusually high FVIII levels were reported in some treated participants. Given that these levels — greater than 150% of normal, or the top threshold for the normal range — raise the risk of blood clots, implemented protocol changes are meant to provide guidance for managing participants with such high FVIII levels.

No. 8 – “Data Show Potential of Roctavian Gene Therapy for Hemophilia A

Positive preclinical data on Roctavian (valoctocogene roxaparvovec), a gene therapy candidate for hemophilia A, was presented in May by its developer, BioMarin Pharmaceutical. Given through a single into-the-vein (intravenous) infusion, Roctavian is designed to use a modified, harmless AAV to deliver a working copy of the F8 gene to liver cells. That working F8 gene is expected to restore FVIII levels and prevent bleeds. Of note, genes delivered by gene therapies such as Roctavian are not meant to be inserted into a person’s DNA, remaining outside the nucleus, where all genetic information is stored. Using non-human primates, researchers found that F8 gene integration into liver cells’ DNA was a rare event, at a frequency in line with expectations for AAV-based gene therapies and much lower than the annual rate of natural mutations in humans. Also, integration sites were distributed across the whole genome, and no signs of precancerous lesions, tumors or malignancy were detected. These findings showed the potential of Roctavian for treating hemophilia A, the researchers said.

No. 7 — “Roctavian’s Benefits Sustained for Up to 5 Years in Trial Patients

Updated results from a Phase 1/2 trial (NCT02576795) showed that a single dose of Roctavian sustainably reduced the bleeding frequency and the use of FVIII replacement therapies in men with severe hemophilia A for up to five years. The trial is evaluating the therapy’s seven-year safety and effectiveness in 15 men with severe disease. The new data concerned seven participants treated with a high dose of Roctavian (6e13 vector genomes per kilogram, or vg/kg) and who were followed for up to five years, and six who received a lower dose (4e13 vg/kg) and were followed for four years. Results showed the gene therapy led to a reduction in annualized bleeding rates by more than 90% and in the use of replacement therapies by more than 94%. In addition, Roctavian was associated with stable or improved quality of life after four to five years. In both groups, FVIII levels increased to a peak at one-year post-treatment, then slowly declined. These findings support the therapy’s long-term benefits in this patient population.

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Gene Therapy SB-525 Controls Bleedings in Men for at Least 2 Years

No. 6 — “Efanesoctocog Alfa on Fast Track for Hemophilia A

The FDA’s fast track designation was granted in February to efanesoctocog alfa, an investigational FVIII replacement therapy for hemophilia. Co-developed by Sanofi subsidiary Bioverativ and Sobi, the therapy had previously received orphan drug designation in the U.S. and Europe. These designations are meant to expedite efanesoctocog alfa’s clinical development and regulatory review. Efanesoctocog alfa comprises a unique formulation of lab-made FVIII that is designed to prolong its half-life — the time it takes for its levels in the blood to drop by half — allowing for less frequent prophylactic (preventive) dosing relative to current replacement therapies. Data from a previous Phase 1/2 trial, called EXTEN-A (NCT03205163), showed that a single dose of efanesoctocog alfa safely and effectively increased FVIII activity in men with severe hemophilia A. The therapy also had a three to four times longer half-life than Takeda’s Advate, an approved FVIII replacement therapy. Efanesoctocog alfa is now being tested in 150 severe hemophilia A patients, ages 12 and older, in the Phase 3 XTEND-1 trial (NCT04161495), expected to conclude later this month.

No. 5 — “Nasal Desmopressin Recall Affects Availability Through 2023

In February, Ferring Pharmaceuticals announced that measures to overcome the manufacturing issue that led to the recall of its intranasal desmopressin compounds — used to treat mild to moderate hemophilia A and von Willebrand disease type 1 — were expected to affect product availability through at least 2023. This followed the identification of a bottle seal tightness issue as the cause of the lower volumes of solution and subsequent higher-than-specified desmopressin concentrations observed in several of the company’s formulations, including Stimate. Desmopressin works by boosting the levels of FVIII and von Willebrand factor, another clotting protein. The product recall was due to problems caused by excess desmopressin. In mild cases, it can cause water retention, low blood pressure, and low blood sodium levels. In extreme cases, it can lead to seizure, coma, and death. Production of desmopressin products is expected to resume in the first half of 2023, with market availability expected by the end of next year, if approved by health authorities.

No. 4 — “COVID-19 May Trigger Acquired Hemophilia A, Case Study Says

Researchers in the U.S. reported the case of a 65-year-old man who developed acquired hemophilia A (AHA) following an asymptomatic infection by SARS-CoV-2, the virus that causes COVID-19. AHA is a very rare, non-inherited condition in which the body’s immune system wrongly produces antibodies that target and destroy FVIII. It can be caused by autoimmune disorders and infections, and SARS-CoV-2 has been reported to induce autoimmune conditions. This marked the fourth published case suggesting an association between COVID-19 infection and AHA. This patient had a clinical history of Hashimoto’s disease, an autoimmune disorder in which the body produces antibodies that attack the thyroid gland. While it was impossible to guarantee that SARS-CoV-2 was the absolute cause of AHA since the man did not have any COVID-19 symptoms, the investigators hypothesized that his underlying predisposition for autoimmunity might have contributed to the development of abnormal antibodies targeting FVIII following SARS-CoV-2 infection. This case suggests that COVID-19 infection should be considered when looking for potential causes of AHA.

No. 3 — “Fitusiran Dosing in Trials Reduced to Lower Blood-clot Risk

Early in 2021, as reported in this top 10 most-read story, Sanofi announced that it was reducing the dosing of fitusiran, an investigational treatment for hemophilia A and B, in ongoing Phase 1 and Phase 3 trials. That move was designed to minimize the risk of blood clots, the company said. It followed the voluntary dosing hold placed on fitusiran’s clinical development program in October 2020 after reports of non-fatal blood clot-related events in five trial participants. Evaluation of these reports suggested that the risk of such events may be greater when levels of antithrombin — a protein that normally helps prevent clotting and the target of fitusiran — have dropped below 10% of normal. As such, fitusiran’s dose was reduced to 50 mg every other month to maintain antithrombin levels between 15% and 35%, and thereby improve the therapy’s benefit-risk profile. Developed by Alnylam Pharmaceuticals and Sanofi Genzyme, the therapy is given through an under-the-skin (subcutaneous) injection. Previous trial data had shown that fitusiran effectively reduced the frequency of bleeding episodes in people with moderate to severe hemophilia A or B.

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No. 2 — “Roctavian, Hem A Gene Therapy, Sustains Drop in Bleeding Rates, Phase 3 Data Show

Top-line data from the Phase 3 GENEr8-1 trial (NCT03370913) showed that a single infusion of Roctavian significantly reduced bleeding rates and the need for replacement therapies in men with severe hemophilia A over at least one year. A total of 134 participants received a single 6e13 vg/kg dose of the gene therapy and were followed for nearly 18 months. The results also showed a slower decline in FVIII levels over time in a subgroup of 17 patients treated for at least two years ago relative to what was observed in an earlier Phase 1/2 trial. The durability of the therapy’s benefits had been called into question by previous findings showing that, following a sharp increase, FVIII levels dropped by 63% between one and four years post-treatment. These GENEr8-1 findings supported Roctavian’s durable effects.

No. 1 — “Roctavian, Potential Hemophilia A Gene Therapy, Gets Fresh FDA Support

Our most-read article of 2021 covered the news, announced in March, that Roctavian had received a regenerative medicine advanced therapy designation from the FDA for the treatment of severe hemophilia A. The therapy had been designated an orphan drug in both the U.S. and Europe for the same indication, and also had received breakthrough therapy status in the U.S. and priority medicine designation in Europe. All these designations are meant to speed Roctavian’s development and review. An application seeking the therapy’s approval is currently being reviewed for a second time in Europe, with a decision expected by June 2022. In 2020, Roctavian’s regulatory applications — comprising six-month, interim results from the GENEr8-1 trial — were rejected both in Europe and in the U.S., with health authorities requesting one-year follow-up data in Europe, and two years’ worth in the U.S. BioMarin plans to resubmit a similar application to the FDA, with the requested two-year data, between April and June 2022. A decision may be expected after a six-month review period.

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At Hemophilia News Today we hope these stories and our reporting throughout 2021 helped to better inform and improve the lives of everyone affected by hemophilia.

We wish all our readers a happy 2022.