BioMarin Pharmaceutical plans to return to the Food and Drug Administration later this year with clinical trial results it says prove its gene therapy for hemophilia can prevent bleeding for years after treatment.
The data from BioMarin's study, disclosed Sunday ahead of the J.P. Morgan Healthcare Conference, are meant to meet requirements laid out by the agency when it rejected the company's previous approval application a year and a half ago.
They show the gene therapy restored blood clotting protein levels to a range consistent with mild hemophilia and, while those levels waned over time, that trial participants experienced very few, if any, bleeds across the two years most were studied. A handful of volunteers in the Phase 3 trial, the largest to date of a hemophilia gene therapy, were followed for three years and had similar results.
"I believe that these results will answer, quantitatively, quite a lot of the questions that agencies have had," said Hank Fuchs, BioMarin's head of research and development, on a conference call Sunday.
Regulators in Europe have already begun evaluating an application from BioMarin and are expected to make a decision in the first half of this year. In the U.S., BioMarin aims to quickly review the results with the FDA and, should the agency agree, potentially resubmit the therapy in the second quarter.
BioMarin's gene therapy, called Roctavian, is the product of years of research by the California biotech and builds on more than a decade of work by other scientists to develop a treatment for hemophilia's genetic cause. It is designed to deliver into the body a functional copy of the gene that's mutated in people with the "A" form of hemophilia, who are left with little or no clotting protein to stem bleeding.
People with severe hemophilia A, who make up about half of all those with disease, must take regular, preventive infusions of "replacement" clotting protein, also known as Factor VIII. Roctavian, which is meant for these individuals, would in theory allow them to stop, freeing them from chronic treatment while more effectively preventing bleeding.
Results from an earlier, much smaller trial showed such promise and, by mid-2020, BioMarin had come close to replicating those findings in the first group of volunteers enrolled in its Phase 3 study. But the FDA — unexpectedly, according to the company — sought more information to prove that benefit could last two years.
Last January, BioMarin revealed one-year results from all participants in the trial and, on Sunday, disclosed data from its two-year analysis. Treatment decreased the number of bleeds per year by 85%, from an average of nearly five among the 112 volunteers who were studied for at least six months before infusion to less than one at year two.
Among 17 participants who were given Roctavian three years before the analysis was conducted, the average annual bleeding rate remained below one as well.
"Our clinical outcome here is unassailably great," said Fuchs in a separate interview. "It almost makes the application, honestly, bulletproof."
But levels of Factor VIII activity, which had risen sharply to an average of 43 international units per deciliter of blood at one year, declined to 23 IU/dL by year two and, for those 17 participants, 17 IU/dL by year three. BioMarin reported these values using a lab test known as a chromogenic assay, which it says is more conservative than another one also used.
People with severe hemophilia typically have less than one IU/dL of Factor VIII in their blood, while mild hemophilia is typically considered to be between 5 IU/dL and 40 IU/dL.
The decline has been a source of doubt, causing concerns that Roctavian's ability to prevent bleeds might wane over time as well. At least for the first few years, Sunday's results show that isn't happening yet. BioMarin also points to data from an earlier study, in which annualized bleeding rates remained below one through five years, despite reduced Factor VIII activity.
"A small amount of Factor VIII is going to go a long way towards hemostatic efficacy," said Fuchs on Sunday's call, "and it gives us confidence that what we've seen so far in the Phase 2 study is gonna read through to the Phase 3 study when we get there."
Extrapolating efficacy puts BioMarin on somewhat uncertain ground, however, as it is the first company to advance this far with a gene therapy for hemophilia A. Jean-Jacques Bienaime, BioMarin's CEO, argues the data so far for Roctavian indicate treatment should result in at least five years of bleeding control and perhaps even eight or longer.
"With the Phase 2, we have demonstrated at least five years already. Predicting eight years, I don't think, is a big stretch," he said in an interview.
How the FDA will view BioMarin's data is unclear, although analysts on Wall Street predicted the latest results would be enough to merit an approval. The agency could convene a panel of outside experts to review a resubmitted application from the company, a possibility Fuchs acknowledged on the conference call.
Also uncertain is how Roctavian would be perceived by hemophilia patients and by insurers, should it eventually secure an approval. BioMarin has previously suggested a price as high as between $2 million and $3 million, but that might be viewed as high if Roctavian's benefit isn't lifelong. (ICER, a looked-to drug cost watchdog, previously found Roctavian could be cost effective at a price of even $2.5 million.)
Fuchs said the company plans to present more data at a medical meeting, likely this year, that should help clarify the relationship between Factor VIII activity and expected durability of benefit.
Importantly for Roctavian's future, Sunday's data, while relatively sparse, indicated no new safety issues had emerged in testing. There were no cases of "inhibitors," or antibodies that work against clotting protein, developing following treatment, nor were there any cases of cancer or blood clot blockages.
The former two are both newly of interest following reports of cancers developing in other gene therapy trials, and data showing higher-than-normal levels of clotting factor in a trial of another hemophilia gene therapy being developed by Pfizer and Sangamo Therapeutics.
Note: This story has been updated to include mention of the assay used by BioMarin to measure Factor VIII activity, and of ICER's analysis.