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Over the past year, momentum for gene therapy in hemophilia has continued to build -- a trend suggesting it will be available in the clinic sooner rather than later.

After three decades of talking about gene therapy and two decades of clinical trials in hemophilia, "we've now been able to move towards a safety benefit ratio that I think is going to lead to commercial availability of a gene therapy product for both hemophilia A and hemophilia B in the next probably 12 to 18 months," Steven Pipe, MD, pediatric medical director of the Hemophilia and Coagulation Disorders Clinic at the University of Michigan in Ann Arbor, told 名媛直播 last December. "This is the most excited I've been about a truly transformative medicine to come to this field."

Gene Therapy and Hemophilia A

In March, results from the phase III GENEr8-1 trial showed that a single infusion of the investigational gene therapy valoctocogene roxaparvovec -- marketed as Roctavian in Europe -- significantly increased factor VIII activity and reduced annualized rates of factor VIII concentrate use and bleeding in men with severe hemophilia A.

Among 132 HIV-negative men who had been receiving standard factor VIII prophylaxis, mean factor VIII activity level at weeks 49 through 52 after infusion increased by 41.9 IU/dL from baseline (95% CI 34.1-49.7, P<0.001), with a median change of 22.9 IU/dL.

Additionally, in a subgroup of 112 patients, the mean annualized rates of factor VIII concentrate use and bleeding after week 4 decreased by 98.6% and 83.8%, respectively (P<0.001 for both).

In this cohort of patients, mean and median annualized factor VIII infusion rates of 135.9 and 128.6 per year at baseline fell to 2 and 0 infusions per year after week 4. For treated bleeding episodes, the mean and median annualized rates were 4.8 and 2.8 bleeds per year at baseline, which declined to 0.8 and 0 bleeds per year after week 4.

"If approved, this first-generation gene therapy would offer a new choice for care that could be truly transformative and liberating for eligible men with hemophilia," authors of an editorial accompanying the GENEr8-1 study wrote.

In August, BioMarin announced that the for the treatment of severe hemophilia A. Last month, the company said that the for the gene therapy, with a Prescription Drug User Fee Act target action date of March 31, 2023.

Progress in Hemophilia B

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

Among 10 patients who received one of four doses of verbrinacogene setparvovec (FLT180a), 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.

As of data cutoff, 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%).

The 10 patients in the study had a mean annualized bleeding rate of 0.71 events per year after gene therapy compared with 2.93 events per year at baseline, 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.

Fitusiran Prophylaxis Effective in Hemophilia A and B

In non-gene therapy developments, two phase III studies presented last December at the American Society of Hematology (ASH) annual meeting showed that fitusiran prophylaxis was able to cut bleeding events in hemophilia patients -- with and without inhibitors -- by about 90% compared with on-demand bypassing agents (BPAs).

In ATLAS-INH, which included 57 patients ages 12 and older with severe hemophilia A or B with inhibitors, the mean estimated annualized bleeding rate for all bleeding events was 1.67 (95% CI 1.01-2.74) in the fitusiran arm and 18.07 (95% CI 10.60-30.81) in the BPA arm, for a rate ratio of 0.09 (95% CI 0.04-0.19, P<0.0001).

"This is just not a statistically significant endpoint, but it's definitely a clinically meaningful and important endpoint as well," said Guy Young, MD, of Children's Hospital Los Angeles at the University of Southern California, who presented the data at ASH.

ATLAS-A/B, which included 119 patients with severe hemophilia A or B without inhibitors, the median observed annualized bleeding rate for all bleeding events was 0.0 (interquartile range [IQR] 0.0-3.4) in the fitusiran arm and 21.8 (IQR 8.4-41.0) in the BPA arm, with an estimated reduction in the fitusiran arm versus the BPA arm of 89.9% (95% CI 84.1-93.6, P<0.0001).

"What we are able to achieve with fitusiran is that steady state hemostatic re-balancing, which means 24-7, 365 days a year, the patient has the same hemostatic balance restoration, which I think liberates them for more spontaneity in their day-to-day activities, [and not be] wedded to the timing of their infusions," said Pipe, who co-authored the ATLAS-A/B study. "I think it has the opportunity to really transform the day-to-day lives of patients going forward."

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