BioMarin Plans To Return To FDA With Updated Data On Hemophilia Gene Therapy


BioMarin Pharmaceutical plans to return to the Food and Drug Administration later this year with clinical trial results that prove its gene therapy for hemophilia can prevent bleeding for years after treatment.

Data from the BioMarin study, disclosed sunday ahead of the JP Morgan Healthcare Conference, are expected to meet the requirements set out by the agency when it rejected the company’s previous request for approval a year and a half ago.

They show that gene therapy restored blood clotting protein levels to a range compatible with mild hemophilia and, while these levels declined over time, trial participants experienced very little, if any, , bleeding during the two most studied years. A handful of volunteers in the Phase 3 trial, the largest to date in gene therapy for hemophilia, were followed for three years and had similar results.

“I think these results will answer, quantitatively, a lot of the questions the agencies have asked themselves,” Hank Fuchs, head of research and development at BioMarin, said in a conference call Sunday.

European regulators have already started to assess an application for BioMarin and are expected to make a decision in the first half of this year. In the United States, BioMarin aims to quickly review the results with the FDA and, if the agency agrees, possibly resubmit treatment in the second trimester.

BioMarin’s gene therapy, called Roctavian, is the product of years of research by Californian biotechnology and builds on more than a decade of work by other scientists to develop a treatment for the genetic cause of the disease. haemophilia. It is designed to deliver a working copy of the mutated gene into the body in people with form “A” hemophilia, who have little or no clotting protein to stop the bleeding.

People with severe hemophilia A, who make up about half of all people with the disease, need regular preventative infusions of the “replacement” clotting protein, also known as factor VIII. Roctavian, which is aimed at these people, would in theory allow them to stop, freeing them from chronic treatments while more effectively preventing bleeding.

Results from a much smaller earlier trial showed such promise, and by mid-2020 BioMarin was set to replicate those results in the first group of volunteers enrolled in its Phase 3 study. But the FDA – unexpectedly, according to the company – asked for more information to prove that the benefit could last for two years.

Last January, BioMarin revealed one-year results for all trial participants and on Sunday disclosed data from its two-year analysis. The treatment reduced 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 the infusion to less than one in the second year.

Among the 17 participants who received Roctavian three years before the test was performed, the average annual bleeding rate also remained below one.

“Our clinical outcome here is unquestionably excellent,” Fuchs said in a separate interview. “It almost makes the app, honestly, bulletproof.”

But factor VIII activity levels, which had risen sharply to an average of 43 international units per deciliter of blood at one year, declined to 23 IU / dL in the second year, and for those 17 participants, 17 IU / dL the third year. BioMarin reported these values ​​using a lab test known as a chromogenic test, which it says is more conservative than one that is also used.

People with severe hemophilia usually have less than one IU / dL of factor VIII in their blood, while mild hemophilia is generally considered to be between 5 IU / dL and 40 IU / dL.

The decline has been a source of doubt, raising concerns that Roctavian’s ability to prevent bleeding may also wane over time. At least for the first few years, Sunday’s results show that is not yet the case. BioMarin also highlights data from an earlier study, in which annualized bleeding rates remained below one to five years, despite reduced factor VIII activity.

“A small amount of factor VIII will greatly contribute to hemostatic efficiency,” Fuchs said on Sunday’s call, “and this gives us reassurance that what we’ve seen so far in the study of Phase 2 will read through the Phase 3 Study when we get there. “

Extrapolation of efficacy puts BioMarin on somewhat uncertain ground, however, as it is the first company to go this far with gene therapy for hemophilia A. Jean-Jacques Bienaime, CEO of BioMarin, supports that data to date for Roctavian indicates that treatment should result in at least five years of bleeding control and maybe even eight or more.

“With phase 2 we have already demonstrated at least five years. Planning eight years, I don’t think, is a big effort,” he said in an interview.

How the FDA will view BioMarin’s data is unclear, although Wall Street analysts have predicted that the latest results would be enough to warrant approval. The agency could convene a panel of outside experts to consider a new application from the company, a possibility Fuchs acknowledged during the conference call.

It is also uncertain how Roctavian would be viewed by hemophilia patients and by insurers, if it were to ultimately get approval. BioMarin has already suggested a price as high as between $ 2-3 million, but that could be considered high if the benefits of Roctavian do not last a lifetime. (ICER, a drug cost watchdog, has already found that Roctavian could pay off at a price of $ 2.5 million.)

Fuchs said the company plans to present more data at a medical meeting, possibly this year, that should help clarify the relationship between factor VIII activity and the expected sustainability of the benefits.

Importantly for Roctavian’s future, Sunday’s data, although relatively sparse, indicated that no new security issues emerged during testing. There have been no cases of “inhibitors” or antibodies that work against the clotting protein, developing after treatment, nor cases of cancer or blockage of blood clots.

The first two are both of new interest following reports of cancer development in other gene therapy trials and data showing higher than normal clotting factor levels in a trial of another gene therapy. hemophilia developed by Pfizer and Sangamo Therapeutics.

Note: This story has been updated to include mention of the test used by BioMarin to measure factor VIII activity and the ICER assay.


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