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Durable factor IX levels in the normal range were observed with a single dose of an experimental gene therapy, eliminating the need for factor IX prophylaxis, in men with severe or moderately severe hemophilia B, according to results from a small phase I/II study.

Among 10 patients who received one of four doses of FLT180a (verbrinacogene setparvovec), all had a dose-dependent increase in factor IX levels, with sustained activity observed in nine patients at a median follow-up of 27.2 months, reported Amit Nathwani, MB, ChB, PhD, of Katharine Dormandy Haemophilia and Thrombosis Centre at Royal Free Hospital in London, and colleagues.

As of data cutoff (Sept. 21, 2021), five patients had normal factor IX levels (50-150%), ranging from 51% to 78%, while three patients had levels below the normal range (23-43%). One patient who was given the highest dose had higher than normal levels (260%), they noted in the .

People with hemophilia are looking for a "safe, effective, predictable, and durable gene therapy," Leonard Valentino, MD, president and CEO of the National Hemophilia Foundation, told 名媛直播. The results of this trial "check some of these boxes, but not all."

"Normal factor IX levels were achieved in only half of the participants in the clinical trial, and an additional three out of 10 achieved levels in the mild range," noted Valentino, who was not involved in the study. "A dose response was observed but the predictability of the response remains to be established in a larger number of people in a phase III trial."

Among the 10 patients, the mean annualized bleeding rate at baseline was 2.93 events per year compared with a mean of 0.71 events per year after gene therapy, while annualized factor IX consumption per patient decreased from a baseline mean of 226,026 IU per year to a mean of 9,723 IU per year after gene therapy.

"Our trial results support further evaluation of FLT180a in clinical trials to confirm the dose and immunosuppressive regimen that are necessary for the maintenance of adequate hemostasis in patients with hemophilia B," the authors wrote.

FLT180a is a liver-directed adeno-associated virus gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B.

"We found that normal factor IX levels can be achieved in patients with severe or moderately severe hemophilia B with the use of relatively low vector doses of FLT180a," the authors noted.

For this multicenter, open-label study, Nathwani and colleagues included 10 adult men with severe or moderately severe hemophilia B. All 10 completed the 26-week trial and enrolled in the long-term follow-up study.

All patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses.

As for safety, approximately 10% of reported adverse events were related to FLT180a, and 24% were related to immunosuppression. Increases in liver aminotransferase levels were the most common FLT180a-related adverse events, with late increases occurring in patients who had received prolonged tacrolimus beyond the glucocorticoid taper.

"Safety remains a major concern," Valentino pointed out. "Elevated liver enzymes were observed in all the participants and prophylactic steroids were given to all participants and most required additional immunosuppressive medications."

He also noted that the patient who developed very high factor IX levels above the normal range developed thrombosis and required anticoagulant medications.

The one patient who did not achieve sustained factor IX activity resumed prophylaxis during month 13 after factor IX levels fell to less than 2% at month 11. According to the authors, this occurred after failure of the patient's immunosuppression regimen, due to delayed recognition of an immune response occurring about 22 weeks after treatment.

The researchers should conduct "a phase III trial that will examine the long-term safety, efficacy, and durability of the gene therapy," Valentino noted.

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