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Gene Therapy: A ‘One and Done’ Hemophilia B Treatment?

Nearly all patients treated with a one-time gene therapy shot for hemophilia B (HB) were able to discontinue full-dose bleeding prophylaxis, a new industry-funded phase 3 study finds, and annual bleed rates (ABR) fell by 64% after the lead-in period.

The report on the gene therapy treatment, known as etranacogene dezaparvovec (EtranaDez), was released at the Feb. 2-4, 2022, annual meeting of the European Association of Hemophilia and Allied Disorders.

In an interview, study lead author Wolfgang Miesbach, MD, PhD, of University Hospital Frankfurt in Germany, touted the decline in ABR. “This statistically significant reduction not only met the primary endpoint for non-inferiority but also demonstrates clear superiority of etranacogene dezaparvovec to prophylaxis in the lead-in period,” he said. “In addition to that, the quality of life improved significantly, [and] there was an overall favorable safety profile.”

Hemophilia B is much rarer than hemophilia A. In a 2020 report, the CDC estimated that type A accounted for less than a quarter of the 29,761-32,985 cases of U.S. males who had hemophilia from 2012-2018. The rest had type B. Most of the males with hemophilia were white (81.2%) and fairly young (just 20.6% were older than 39).

High Adherence and High Prices

Factor IX (FIX) replacement therapy aims to boost levels of the blood-clotting protein in patients with severe hepatitis B. However, the intravenous prophylactic treatment requires a “high level of adherence” due to the need for self-administration several times a week, Miesbach said, adding that the treatment does not reliably prevent bleeding and joint destruction.

Also, the price of FIX replacement therapy in the United States is exorbitant, costing an average of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.

The gene therapy treatment, formerly known as AMT-061, “consists of a functional FIX gene with higher activity than the wild-type FIX (Padua variant), together with an AAV (AAV5),” Miesbach said. “AAV 5 is a vector with high liver tropism to transduce the liver cells and lead to the production of the functional FIX gene there.”

For the new open-label, single-dose, single-arm HOPE-B study, researchers treated 54 adult men with severe or moderately severe HB (FIX ≤2%), 31 with and 23 without preexisting AAV5 neutralizing antibodies. The average age was 41.5, 81.5% had severe cases (FIX<1%), and 25.9% had no bleeds at lead-in.

The participants began 12 months of treatment with gene therapy following a 6-month lead-in period of FIX prophylaxis. All but one completed follow-up.

“Mean FIX activity was 39.0 IU/dL (±18.7; 8.2, 97.1) (standard deviation; min, max) at month 6 and 36.9 IU/dL (±21.4; 4.5, 122.9) at month 18,” the researchers reported. ABR dropped by 64% from the lead-in period to the 12-month treatment period (4.19 vs. 1.51, P = .0002), and FIX-treated bleeds fell by 77% (ABR=3.65 vs. 0.83, P < .0001).

Fifty-two of 54 patients stopped full-dose prophylaxis and didn’t return to it. Mean unadjusted annualized FIX use dropped by 97% overall from the lead-in period to months 13-18 (257,338.8 vs. 8,486.6 IU/year/participant).

Thirty-seven participants experienced 92 treatment-related adverse events such as abnormal alanine aminotransferase (16.7%), headache (14.8%), influenza-like illness (13.0%), infusion-related infection (13.0%), and abnormal aspartate aminotransferase (9.3). Researchers determined 74 (80.4%) of the adverse effects were mild.

“Transaminase increases were reported, and corticosteroids were required in nine participants, but the mean duration of corticosteroids, including taper, was only 79 days,” Miesbach said.

“There was no prophylactic use of steroids in this study. FIX expression was maintained. One death was found to be unrelated to study treatment. One case of hepatocellular carcinoma, which has been reported in detail previously, was reported. But after detailed molecular analysis, this was found to be unrelated to study treatment,” he noted.

Quality of life scores improved by 21.5%-28.78%. The P values, ranging from < .0001 to .0036, were considered to be “nominally significant” due to analysis limitations.

A ‘One and Done’ Treatment

While the trial is expected to continue until 2025, no further treatment with etranacogene dezaparvovec was given. “Gene therapy is a ‘one and done’ treatment,” Miesbach said. “According to our current knowledge, it cannot be repeated.”

No information about the expected cost of the treatment is available. CSL Behring, which licensed global rights for the gene therapy from developer uniQure, is expected to seek Food and Drug Administration approval this year.

The trial was funded by CSL Behring. Miesbach and other study authors report various disclosures including support from CSL Behring and uniQure. Some authors are employees of CSL Behring and uniQure.

This article originally appeared on, part of the Medscape Professional Network.

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