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Gene Therapy for Hemophilia B Found Safe and Effective in First Phase III Trial

Study in ASH Late-Breaking Abstracts session shows most patients were able to stop intensive intravenous regimens, results may open doors for patients previously not included in gene therapy trials

(WASHINGTON, Dec. 8, 2020) – The gene therapy etranacogene dezaparvovec substantially increased production of the blood clotting protein factor IX among 52 patients in the largest and most inclusive hemophilia B gene therapy trial to date. The trial is also the first to include patients with certain immune system markers and found that they did not appear to confer any increased risks, a finding that could significantly broaden the number of patients who may be eligible for gene therapy.

A majority of trial participants (96%) successfully discontinued factor IX replacement therapy after receiving the gene therapy and have been producing their own factor IX for six months. The findings suggest gene therapy could, with a single treatment, give patients the ability to maintain factor IX levels and reduce or eliminate the need for additional factor IX replacement therapy, according to researchers.

“Most patients with hemophilia B are bound to a prophylactic factor regimen of one to two intravenous infusions per week from birth through the rest of their life,” said senior study author Steven W. Pipe, MD, of the University of Michigan, Ann Arbor. “Gene therapy offers the chance to liberate patients from the burden of their prior treatments, allowing for spontaneity and the freedom to do more in day-to-day life.”

Hemophilia B, which accounts for about one-fifth of hemophilia cases, is caused by an inherited mutation of the gene for factor IX. Lacking the ability to produce the blood clotting factor IX, patients with hemophilia B can suffer uncontrolled bleeding, including internal and joint bleeding that leads to joint deterioration and chronic pain.

Factor IX replacement therapy can reduce bleeding associated with hemophilia B, but it requires weekly or biweekly infusions to maintain factor IX levels, a burdensome regimen that costs several hundred thousand dollars per year. In gene therapy, viral particles are used to shuttle engineered genes to cells in the liver. These genes replace the patient’s faulty factor IX gene, allowing the patient’s own body to produce factor IX on an ongoing basis. While several gene therapies for hemophilia have shown promise in early phase trials, the study is the first phase III trial to test the approach in a large and diverse array of patients, said Dr. Pipe.

Fifty-four patients enrolled in the study; all were dependent on factor IX replacement therapy, and 70% had bleeding episodes in the six months prior to the study despite this prophylactic treatment. After receiving the etranacogene dezaparvovec gene therapy via a single infusion lasting roughly one hour, factor IX activity increased rapidly from a baseline of up to 2% (moderate to severe hemophilia) to a mean of 37% (very mild hemophilia) at 26 weeks, meeting the trial’s primary endpoint. At that level, a patient’s bleeding risk is essentially the same as someone without hemophilia, Dr. Pipe noted.

Seventy-two percent of patients reported no bleeding events in the 26 weeks after receiving the gene therapy. “This tells us that the bleeding phenotype can be corrected through this treatment, which is a remarkable achievement,” said Dr. Pipe. Fifteen patients experienced some bleeding, which the researchers indicate is not unexpected given that many of the patients had severely affected joints entering the trial.

“What we’ve seen from patients in the study is that they really don’t have to think about their hemophilia anymore,” said Dr. Pipe. “The transformative nature that we hear from the patient stories is, to me, the most important outcome from this study.”

The trial is also the first to attempt gene therapy in patients with neutralizing antibodies, a component of the immune system that helps the body fight pathogens. About 40% of trial participants had antibodies to adeno-associated virus serotype 5, or AAV5, the viral vector used in etranacogene dezaparvovec. “In any other trial protocol, these patients would not have been eligible to participate,” Dr. Pipe noted.

Previous trials have excluded such patients from gene therapies that use viral vectors under the assumption that antibodies could either block the uptake of the viral vectors in the liver or trigger a dangerous immune response to the therapy. The trial found no evidence of either problem, suggesting neutralizing antibodies do not preclude successful gene therapy.

Two patients did not respond to the gene therapy. One did not receive a full dose because the infusion was stopped after the patient showed signs of a reaction to the infusion. The other had a level of neutralizing antibodies about five times higher than any other patient. Since other patients with neutralizing antibodies responded well to the therapy regardless of their level of antibodies, this finding suggests antibodies may pose a problem only at extremely high levels.

No treatment-related serious adverse events were reported. Adverse events were relatively common, occurring in 68% of patients, but most were mild and related to the infusion itself. Nine patients showed evidence of an immune response to the therapy, which was resolved in all cases with a course of corticosteroids.

The researchers will continue to follow patients for five years. Patients will be assessed for sustained factor IX production and effective bleed control over 52 weeks, as well as patient-reported outcome measures to assess impact on quality of life.

Steven W. Pipe, MD, University of Michigan, Ann Arbor, will present this study during the Late-Breaking Abstracts session on Tuesday, December 8 at 7:00 a.m. Pacific time on the ASH annual meeting virtual platform.

For the complete annual meeting program and abstracts, visit www.hematology.org/annual-meeting. Follow ASH and #ASH20 on Twitter, Instagram, LinkedIn, and Facebook for the most up-to-date information about the 2020 ASH Annual Meeting.

The American Society of Hematology (ASH) (www.hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. ASH publishes Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, and Blood Advances (www.bloodadvances.org), an online, peer-reviewed open-access journal.

Leah Enser, ASH, [email protected]
Brianne Cannon, FleishmanHillard, [email protected]