BioMarin’s Gene Therapy for Severe Hemophilia Yields Sustained Benefit, Data Show

BioMarin Pharmaceutical’s investigative gene therapy, called valoctocogene roxaparvovec, is capable of sustained control of bleeding rate requiring factor VIII infusions by at least 92% in adults with severe hemophilia A, three-year data from a Phase 1/2 trial show.

Moreover, a model predicts that the gene therapy, administered via a single injection, will maintain its efficacy for at least eight years.

“With three years of data, it’s clear that valoctocogene roxaparvovec has the potential to change the way we treat this debilitating disease, which can improve the quality of life for people with severe hemophilia A,” John Pasi, MB, ChB, PhD, from Barts and the London School of Medicine and Dentistry and the trial’s lead investigator, said in a press release.

“For people who have had to inject themselves with factor VIII every other day to prevent bleeding, this treatment has the potential to be transformational,” Pasi said.

Valoctocogene roxaparvovec, formerly known as BMN 270, is a gene therapy designed to deliver the active form of the blood clotting factor VIII to overcome the effects of severe hemophilia A. This strategy will potentially allow the normal production of the missing clotting factor VIII, representing a possible cure.

The Phase 1/2 trial (NCT02576795), still ongoing, is evaluating valoctocogene roxaparvovec’s safety and efficacy in restoring levels of factor VIII, which plays a crucial role in blood clotting and prevents bleeding events in patients with severe hemophilia A.

Six patients received intravenously a single 4e13 vg/kg (vector genomes per kilogram) dose of BMN 270, and seven patients received a 6e13 vg/kg dose.

Earlier clinical results around seven months after treatment showed that five patients treated with the 4e13 vg/kg dose achieved levels of factor VIII that meet the low range of normal. The sixth patient reached the mild range for factor VIII levels. Four weeks after treatment, the annual factor VIII administration rates and median annualized bleeding rates were zero.

Patients treated with the highest dose (6e13 vg/kg) presented mean levels of factor VIII within normal range upon 20 weeks post-treatment follow-up. After one year, these patients still presented mean factor VIII levels of more than 50 percent.

Now, data after three years of follow-up show that factor VIII levels in the 6e13 vg/kg cohort have reached a plateau — at year one, mean factor VIII levels were 64.3 international units per deciliter (IU/dL) per year, falling to 36.4 at the end of year two and maintaining the level of 32.7 IU/dL at the end of year three (data measured using a chromogenic substrate, or CS, assay).

In the 4e13 vg/kg cohort, at the end of the first and second years, mean levels of factor VIII were 21.0 and 14.7 IU/dL, respectively, as measured by the CS assay.

Overall, these data show that in the 6e13 vg/kg dose cohort, factor VIII levels declined at a rate of 5.72 IU/dL per year, and by 1.56 IU/dL per year in the 4e13 vg/kg cohort.

The three-year data suggest that factor VIII levels decline more slowly as time and expression level decline.

The annualized bleed rate (ABR) and the need for factor VIII infusions showed a marked reduction in the 6e13 vg/kg cohort. Before joining the trial, patients (who were on preventive treatment before the trial) had a mean ABR of 16.3 and a mean 136.7 factor VIII infusions a year.

After three years, the ABR and the number of annual factor VIII infusions declined to a mean of 0.7 and 5.5, respectively. This represents a 96% reduction in mean ABR and of 96% in the mean factor VIII usage over the three years.

Additionally, while in the year prior to study entry, only 14% of the participants had zero bleeds requiring factor VIII infusions, this increased to 71%, 86%, and 86% in the study’s first, second, and third years, respectively.

In the 4e13 vg/kg cohort, the mean ABR was reduced from 12.2 in the year prior to study entry to 1.2 at the end of the second year, a 92% decrease.

At the end of the first and second year after treatment with valoctocogene roxaparvovec, 83% and 67% of the participants had zero bleeds requiring factor VIII infusions, in clear contrast to only 17% of the patients in the year before joining the trial — a reduction of 97% in mean  factor VIII usage over two years.

“These data confirm that valoctocogene roxaparvovec has the potential to profoundly impact the lives of people with severe hemophilia A through a sustained reduction in bleeds and factor VIII usage,” said Hank Fuchs, MD, president of global research and development at BioMarin. “Importantly, we’ve now observed that maintenance of factor expression is a function of expression level and time. Therefore, by three years post a one-time infusion of valoctocogene roxaparvovec, we anticipate we are nearing the plateau of expression.”

BioMarin’s statistical model to predict the durability of the bleed control — up until factor VII levels reach 5 IU/dl — estimates that the gene therapy will maintain its efficacy for at least eight years. “This is fantastic news for the hemophilia community,” Fuchs said.

The results will be submitted for presentation at the International Society on Thrombosis and Haemostasis, taking place in Melbourne, Australia, July 6-10.

BioMarin has launched a global Phase 3 program for valoctocogene roxaparvovec, which includes the GENEr8-1 (NCT03370913) and the GENEr8-2 (NCT03392974) studies.

The trials, currently looking to recruit around 70 and 130 participants, respectively, will take place at more than 70 clinical sites around the world. In GENEr8-1 and GENEr8-2, researchers will continue to evaluate the safety and superiority of valoctocogene roxaparvovec relative to the current standard-of-care preventive therapy, administered as a single injection at 6e13 vg/kg and 4e13 vg/kg, respectively.