Investment banks didn't need many words to summarize the news. RBC Capital Markets called it a "massive surprise," while Piper Sandler preferred "major surprise." Stifel and Cantor Fitzgerald left it at just "surprising."
Indeed, the Food and Drug Administration's decision not to approve a hemophilia gene therapy from BioMarin Pharmaceutical came as a shock to investors, who had expected the opposite based on months of company feedback. Shares of the Californian biotech fell 35% between Tuesday and Wednesday, wiping more than $7.5 billion from its market value.
BioMarin said it, too, was confused. The company submitted its therapy, called Roctavian, to the FDA for review in December, supported by a year's worth of data from some patients enrolled in a large clinical trial. CEO Jean-Jacques Bienaime said the agency had agreed that this data, combined with results from an earlier study, would be enough to evaluate the drug.
But on Tuesday, BioMarin received a rejection letter that asked for two years of data on every patient in the larger study, a request which bumps Roctavian's possible approval date back to at least mid-2022.
"They never, ever discussed that with us in any meetings we had with them," Bienaime said in an interview.
Yet, there are doctors who say the FDA's rejection wasn't the first, or perhaps even the biggest, unexpected development in Roctavian's journey.
"A lot of us were surprised, to be honest, that the FDA was allowing them to proceed in the first place," said Robert Sidonio, a pediatric hematologist at Children's Healthcare of Atlanta who has consulted for BioMarin and Spark Therapeutics, another gene therapy developer.
The clinical trials of Roctavian enrolled patients with a severe form of hemophilia A, the more common type of the rare bleeding disorder. After receiving a higher dose of the therapy just once, patients experienced steep rises in blood clotting protein and sharp reductions in bleeding rates.
The results were impressive, but not without some shortcomings. Longer follow-up showed Roctavian's effects seem to wane over time. The larger study also showed less clotting protein activity than what was seen in earlier testing.
Doctors like Sidonio therefore expected BioMarin would need to sort out these discrepancies before filing its drug for approval. The fact that, after multiple meetings between BioMarin and the FDA, Roctavian was filed and later rejected raises questions around the data requirements necessary to get a gene therapy approved.
Until this week, the two gene therapies that had successfully come to market did so with relatively small amounts of supportive data. If the requirements for Roctavian extend to other one-time hemophilia treatments, as BioMarin and others suspect, it could be years before patients get access to them.
"It's very clear to the community that this is the threshold you have to clear to be considered, and I wish that was just set up from the beginning," Sidonio said.
Valder Arruda, a researcher in the hematology division of The Children's Hospital of Philadelphia, expects that any gene therapy that doesn't show a sustained plateau in clotting protein levels will face a similar level of scrutiny as Roctavian. That's not a bad thing, he argues, as it shows the FDA is both prioritizing safety and looking to better understand the variability seen thus far.
"This delay is a small price to pay from a physician, scientist perspective," he said.
From the patient viewpoint, the FDA's rejection lengthens the timeline before another treatment option becomes available.
Roctavian, though, wouldn't have been a cure-all for many patients due to the various biological and commercial barriers that stood in its way. Hemophilia patients also benefit from having many effective treatment options and relatively long life expectancy, unlike some of the other rare diseases that have been a target for gene therapy, such as spinal muscular atrophy, or SMA.
"This is not SMA," said Len Valentino, CEO of the National Hemophilia Foundation. "This is not a life-threatening disease for which there is no current therapy."
As such, doctors and patient advocacy groups say the rejection, though disappointing, shouldn't diminish patients' optimism in gene therapy.
The rejection "will also give us a real opportunity as a scientific community to understand the issues around the immune response and the potential for re-dosing," Valentino added.
"It gives our scientists more time to sort of figure out what the barriers are for success."