- One year after receiving an experimental gene therapy, adults with severe hemophilia A enrolled in a study run by BioMarin Pharmaceutical were producing blood clotting protein at levels associated with mild disease, according to data released by the Californian biotech on Sunday.
- Treatment with the gene therapy, called Roctavian, dramatically reduced the average rate of bleeding events per year among participants in the Phase 3 study, as well as almost entirely eliminated the need for preventive infusions of blood-clotting proteins, also known as factor replacement therapy.
- As in an earlier trial, data appeared to show the effects of treatment on clotting protein levels waned over time, a trend that raises questions about the durability of Roctavian's benefit. BioMarin expects a single Roctavian infusion will work for many years, however, and the Phase 3 results are the strongest evidence yet the gene therapy can better control hemophilia than standard factor treatment.
The full one-year results from the study are an important milestone for Roctavian, which was unexpectedly rejected last August by the Food and Drug Administration after BioMarin had applied for an accelerated approval. The regulator, apparently concerned early findings weren't holding up in the larger study, asked BioMarin for two years of follow-up data.
The trial results released Sunday get the company closer to that goal. Executives plan to discuss the data with the FDA, though they emphasized that they still expect to need the longer follow-up before being able to resubmit Roctavian for approval.
"We're starting to accumulate data that are addressing the concerns they have," said Hank Fuchs, BioMarin's head of research and development, on a conference call with analysts Sunday evening. "It's moving into the zone of: when is this data strong enough, rather than whether."
BioMarin's rejected application included results from a small Phase 1/2 study of 13 adults with severe hemophilia A as well as data from the first 20 participants enrolled into the Phase 3 trial.
Sunday's data, by comparison, cover all 132 Phase 3 study participants, 112 of whom were followed for six months before treatment with Roctavian to assess their bleeding frequency and use of factor replacement therapy.
Prior to receiving the gene therapy, participants experienced, on average, five bleeding episodes per year and reported using about 136 factor infusions per year. Treatment with Roctavian cut those average annualized numbers by 84% and 99%, respectively, to just under 1 and to 2.
Observed side effects were common, typically liver enzyme elevations, headache and nausea. But no participant experienced any thromboembolic events or developed an immune response to Roctavian. About 15% of people in the study experienced a side effect classified as serious, but all resolved
The results are a convincing display of Roctavian's impact, at least initially. Delivered via a modified virus, Roctavian replaces the Factor VIII gene that's damaged in hemophilia A patients with a functional copy. Once in the body's cells, the functional gene instructs for the production of the blood-clotting Factor VIII protein.
Typically, an adult with severe hemophilia A will produce less than 1% the normal amount of Factor VIII protein. If untreated with factor replacement therapy, the low protein levels lead to excessive and spontaneous bleeding. Even with treatment, people with severe disease can still experience "breakthrough" bleeds.
Those with milder disease usually produce between 5% and 40% of normal factor levels. Data from BioMarin has shown Roctavian treatment can raise levels to this range and keep them there for years. The Phase 3 trial, however, was the biggest test yet of how well Roctavian performs over a much larger group of people.
After one year, average protein levels among the group of 112 participants were 43.6 international units per deciliter, a lower number than what was observed in the smaller Phase 1/2 trial but still considered mild. Among 17 participants who were enrolled into the study without a six-month run-in period and followed for two years, average protein levels fell to 24.4 IU/dL.
By comparison, average protein levels were 63.6 IU/dL and 36.4 IU/dL after one and two years, respectively, among the 7 patients given the same Roctavian dose in the earlier study.
Differences in the rate of decline for protein activity between the Phase 1/2 trial and the first cohort of the Phase 3 trial appeared to factor into the FDA's decision to reject BioMarin's bid for a speedy Roctavian approval.
On Sunday, BioMarin executives noted a slower rate of decline in protein activity for the 17 Phase 3 study participants followed for two years, and expressed confidence the numbers had stabilized. Durability is a key question for gene therapy as treatment is meant to be given only once.
BioMarin's success in Phase 3, even if currently insufficient to ask again for approval, are positive news for the gene therapy field, which recently hit several notable setbacks. Just last week, Sarepta Therapeutics announced disappointing data for a closely-watched experimental treatment for Duchenne muscular dystrophy. And back in December, UniQure reported a case of liver cancer in a trial of its gene therapy for hemophilia B. (The biotech is now investigating whether there's any link between its therapy and the cancer case.)
While BioMarin will wait for two-year results in the U.S., the company this year plans to resubmit Roctavian for approval in the European Union after initially withdrawing its application there.