Conference Coverage

Early phase trial shows durable responses to gene therapy for hemophilia A



MELBOURNE – A gene therapy treatment for hemophilia A has shown sustained reductions in bleeding rates 3 years after treatment, with no major safety issues, according to findings presented at the International Society on Thrombosis and Haemostasis congress.

Valoctocogene roxaparvovec is an investigational gene therapy that involves using an adenovirus-associated virus to deliver the gene for clotting factor VIII.

Dr. John Pasi, Royal London Haemophilia Centre, Barts Health NHS Trust Bianca Nogrady/MDedge News

Dr. John Pasi

John Pasi, MBChB, PhD, of the Royal London Haemophilia Centre, Barts Health NHS Trust, presented the 3-year efficacy and safety results from the phase 1/2 trial of the therapy, involving 15 men with hemophilia A without inhibitors who received a single intravenous dose – either 4 x 1013 vector genomes (vg) per kg or 6 x 1013 vg/kg – of the therapy.

Participants’ mean annualized bleeding rate at baseline ranged from 6.5 among men who had been receiving prophylactic therapy to 25 among those who had been historically been treated on demand.

The treatment was associated with a substantial, significant reduction in mean annualized bleed rates; a 96% reduction in the 6 x 1013 vg/kg group by year 3, and 92% reduction in the 4 x 1013 vg/kg group by year 2.

By year 3, 86% of patients in the higher dose group had not experienced a bleed in the prior 12 months, all patients were off prophylaxis, and all had experienced resolution of target joints.

Mean factor VIII usage also decreased significantly, with a 96% reduction by year 3 in the higher dose cohort, and a 97% reduction by year 2 in the lower dose cohort.

The study also showed significant improvements in quality of life across all domains, Dr. Pasi reported.

There were no significant safety concerns raised during the study. Several patients experienced mild to moderate, transient rises in alanine aminotransferase levels at around 8-16 weeks after treatment, but there was no significant impact on liver function or on corticosteroid use. Two patients reported mild infusion reactions, which resolved within 48 hours with altering treatment.

The researchers also examined durability of factor VIII activity levels following the gene therapy, which was monitored using chromogenic assays. This revealed that after the initial increase following therapy, the factor VIII levels plateaued between years 2 and 3.

“We’ve got what we feel is really good clinical evidence of a persistent effect and we think this is dramatic,” Dr. Pasi said. A phase 3 trial is now underway.

A commenter from the audience, who remarked that the data were incredible and would make a huge difference for patients, asked about whether this represented a possible cure for the disease.

It’s premature to talk about a cure, Dr. Pasi said.

“It’s like watching paint dry; it’s going to take years before we know where we are,” he said in an interview.

However, this could represent massive and transformational change in the management of hemophilia A, he added.

On the question of whether this approach might also work in patients with inhibitors, Dr. Pasi said there were animal data suggesting that gene therapy could work in individuals with inhibitors, but the focus for the moment was on patients without inhibitors.

“But for patients that previously had a history of inhibitors and are now tolerant, that’s quite a significant group of patients that we were going to have to think about how we deal with that in due course,” he said.

The study was sponsored by manufacturer BioMarin Pharmaceutical. Dr. Pasi reported financial relationships with the study sponsor and other companies.

SOURCE: Pasi KJ et al. 2019 ISTH Congress, Abstract LB 01.2.

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