Benefits of Roctavian, Hem A Gene Therapy, Holding for 2 or More Years

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A single dose of the experimental gene therapy Roctavian (valoctocogene roxaparvovec) continues to prevent bleeds and the need for preventive treatment, or prophylaxis, over at least two years in men with severe hemophilia A, according to updated data from the Phase 3 GENEr8-1 trial.

Notably, the activity of factor VIII (FVIII), the missing clotting protein in hemophilia A, remained in the therapeutic range through two years post-dosing.

“A potential single treatment that provides a durable response for years could be a game-changer by offering a transformative treatment choice beyond existing therapies and addressing an unmet medical need for people with hemophilia A,” Steven W. Pipe, MD, the trial’s principal investigator at the University of Michigan, said in a press release.

“I have witnessed the transformative liberating potential of [Roctavian] for hemophilia A in my own clinical trial participants” and am “delighted to see these results broadly confirmed in the largest study of its kind,” added Pipe, a professor of pediatrics and pathology at the university.

Hank Fuchs, MD, the president of worldwide research and development at BioMarin Pharmaceutical, Roctavian’s developer, said data show that the therapy “could profoundly change the way hemophilia A is treated.”

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The company plans to present additional trial data at upcoming medical meetings.

A regulatory application seeking Roctavian’s approval to treat severe hemophilia A is currently being reviewed in the European Union (EU) for the second time, with a decision expected before the close of June.

BioMarin plans to meet with the U.S. Food and Drug Administration (FDA) to discuss resubmitting a similar application, anticipated between April and June, and if accepted is expecting a six-month review period.

“We are looking forward to continuing to work with health authorities to bring this therapy to patients,” Fuchs said.

Roctavian’s initial regulatory applications — filed in 2020 and covering six-month, interim results from the Phase 3 GENEr8-1 trial (NCT03370913) — were rejected both in the EU and the U.S., with health authorities requesting one-year follow-up data in the EU, and two years’ worth in the U.S.

Given as a single infusion directly into the bloodstream, Roctavian is designed to raise FVIII levels by providing patients with a working version of F8, the gene that contains the instructions for making FVIII and that is mutated in hemophilia A patients.

A modified and harmless version of an adeno-associated virus is used to carry and deliver the gene specifically to liver cells, the body’s main producers of clotting factors.

The therapy is expected to promote a sustained production of FVIII that reaches levels at least within the mild, therapeutic range (between 5% and 40% of normal), thereby lowering or eliminating spontaneous bleeds and the need for preventive FVIII replacement therapies.

GENEr8-1 is evaluating the five-year safety and effectiveness of a single dose of Roctavian (6×10e13 vector genomes per kilogram) in 134 men with severe hemophilia A.

Top-line, one-year results showed the therapy was generally safe and significantly increased FVIII activity levels, while reducing bleeding rates and the need for replacement therapy — meeting both main and secondary trial goals.

Newly announced, two-year data showed that patients’ FVIII activity remained within the mild, therapeutic range at the end of the second year, with levels between 23% and 36.1% of normal, depending on the test used.

In addition, the mean annualized bleeding rate (ABR) was significantly reduced by 85% in the 112 patients whose ABRs were assessed for at least six months in a non-treatment study prior to GENEr8-1. Specifically, their mean ABR dropped from 4.8 at the GENEr8-1’s start to 0.8 after treatment (0.9 in the first year and 0.7 during the second year).

In this patient group, Roctavian also led to a 98% reduction in the need for FVIII replacement therapy — from a mean of 135.9 annual infusions at study’s start to 2.6 infusions per year through the two-year period (1.5 infusions during year one, and 3.4 during year two).

In 17 men dosed at least three years ago, mean FVIII activity levels were 16.8% or 27%, depending on the test used, by the end of year three. Patients experienced less than one bleed per year (ABR of 0.7 over the three-year period and 0.6 in the third year).

These reductions in bleeding rates and replacement therapy use were consistent with those observed in the second and third year post-dosing in men with severe hemophilia A given the same Roctavian dose in a Phase 1/2 trial called Study 270–201 (NCT02576795).

In GENEr8-1, Roctavian continued to be generally well-tolerated, with no new safety concerns identified and no additional treatment-related serious adverse events reported. No patient experienced blood clot-related events or developed FVIII inhibitors (neutralizing antibodies) and liver masses.

The most common treatment-related side effects occurred early, were mild to moderate, and included an increase in the levels of a liver enzyme called alanine aminotransferase (89%) — a common event with virus-based gene therapies that suggests liver damage due to immune reactions against the viral carrier. This rise was transient, the company reported.

Most patients discontinued immunosuppressive treatment (corticosteroids), which is recommended to suppress such immune reactions, in the first year after dosing. No corticosteroid-related serious adverse events were reported among patients being tapered off the immunosuppressive therapy in year two.

Other common side effects included headache (41%), joint pain (40%), nausea (38%), higher-than-normal levels of another liver enzyme (35%), and fatigue (30%).

“We are grateful for the support of the bleeding disorders community to conduct this clinical program,” Fuchs said.

Roctavian was given orphan drug, breakthrough therapy, and regenerative medicine advanced therapy status in the U.S., and orphan drug and priority medicine status in Europe for severe hemophilia A. All of these designations are meant to expedite its development and regulatory review.