Gene Therapy for Hemophilia B Shows Promise


A small study finds that an adeno-associated virus gene therapy eliminated both spontaneous bleeding and the need for factor IX prophylaxis in patients with hemophilia B.

A gene therapy being tested in a phase 1/2 study for hemophilia B achieved normal levels of factor IX at low doses, but required immunosuppression, according to findings of a study recently published in the New England Journal of Medicine.

In the small study, 9 of the 10 patients with hemophilia B treated with the gene therapy, verbrinacogene setparvovec (FLT180a), had durable factor IX expression. The gene therapy eliminated both spontaneous bleeding and the need for factor IX prophylaxis. Hemophilia B is a genetic disorder caused by missing or defective factor IX, a clotting protein.

Amit Nathwani, M.D., Ph.D.

Amit Nathwani, M.D., Ph.D.

“Gene therapy is still a young field that pushes the boundaries of science for people with severe genetic diseases,” Amit Nathwani, M.D., Ph.D., professor of hematology at the University College London Cancer Institute, one of the study authors and co-founder and board member of Freeline, said in a press release. “The B-AMAZE long-term data add to the growing body of evidence that gene therapy has the potential to free patients from the challenges of having to adhere to lifelong therapy or could provide treatment where none exists today.”

Nathwani is also a founder and clinical and scientific advisor and director at Freeline.

But developing a gene therapy for hemophilia B has been challenging. Previous studies didn’t prevent bleeding, and high doses of the vector used to carry the gene to the liver led to inflammation and hepatoxicity.

The developer of verbrinacogene setparvovec, London-based Freeline Therapeutics, has developed a proprietary technology that directs the gene therapy to the liver. The therapy contains several components. The first is an adeno-associated virus that is used as a delivery mechanism, or vector. In the case of verbrinacogene setparvovec, the vector AAVS3 has a protein shell, or capsid. Within this is a cassette that encodes the Padua variant of human factor IX. (The Padua variant was identified by researchers at the University of Padua in Italy and has a single point mutation, which can lead to more efficient thrombin generation.)

The capsid is responsible for directing the gene into the correct cells and the expression cassette guides tissue-specific synthesis of the therapeutic protein. Company researchers believe this technology allows higher gene activity and lower viral load from the vector.

The B-AMAZE dose-finding study was an open-label, single-dose phase 1/2 trial in 10 adult men. Patients had received one of four doses of verbrinacogene setparvovec, as well as glucocorticoids with or without tacrolimus (an immunosuppressant) to decrease the risk of vector-related immune responses. After 26 weeks, patients were enrolled in a long-term follow-up study. The primary end points were safety and efficacy, assessed by factor IX levels at week 26.

At the data-cutoff date of Sept. 20, 2021, five patients had normal factor IX levels, three patients had levels from 23% to 43%, and one had a level of 260%. Normal plasma levels range from 50% to 150%. A level below 50% is considered half of what is needed to form a clot and when patients begin to experience symptoms.

One patient in the study resumed factor IX prophylaxis treatment, which occurred after the failure of his immunosuppression regimen. The other nine patients had steady factor IX activity starting at month 12.

The mean annualized bleeding rate across all patients in the study decreased from 2.93 events per year at baseline to 0.71 events per year after treatment with verbrinacogene setparvovec. No patients withdrew from the trial because of toxic effects, and no deaths were reported. Additionally there were no infusion reactions. Of the reported adverse events, about 10% were related to the therapy and 24% to immunosuppression.

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