For some years now, BioMarin (NASDAQ:BMRN) has been working on a gene therapy for hemophilia A. That’s the form of the disease caused by a deficiency in Factor VIII, which is a necessary part of the blood-clotting cascade. Like many such conditions, it comes in a wide range of phenotypes. One group of patients (around 10%) makes a nonfunctional version of the protein, while the majority just make insufficient amounts of the functional one (all the way down to making none of it at all). The majority of cases can be traced back to inheritance within a family, but about 30% of new cases seem to be truly new idiopathic mutations.
If the disease is not too severe, it can be treated with the vasopressin analog desmopressin, which releases stored Factor VIII and can take patients back into a more normal clotting time. Otherwise, the main thing to do is to provide Factor VIII protein itself, either recombinant or isolated from human plasma, with the amounts and dose schedule tailored to the patient’s level of remaining function. Biochemically this works fine, but the practical difficulties are (as you would figure) around the repeated i.v. administration. A permanent venous port can make this easier, but these can be prone to infection. So although this is not an untreatable disease, better options would be welcome.
In 2017, a trial funded by BioMarin reported results of a AAV5 viral-vector gene therapy approach to splice in a functional Factor VIII gene into nine volunteers. Two lower-dose patients did not appear to respond, but 6 out of the 7 higher-dose patients showed definitely improved Factor VIII levels that persisted out to at least a year, with a corresponding sharp drop in bleeding incidents. All of the responding patients were able to discontinue dosing with extra Factor VIII itself. These results were certainly encouraging, and got a good amount of press at the time.
The company has continued to monitor these patients, and the most recent data on them has good news and bad news. The good news is that six of the seven patients still showed no bleeding incidents in the fourth year after the single dose, and all of them remained off prophylactic doses of Factor VIII. The bad news was that the effects of the gene therapy seemed to be wearing off: the amount of circulating Factor VIII had already gone down by year 3 from what was seen in the first year, and the drop in year 4 was even greater. So while the patients were (mostly) still at useful levels, it seemed likely that they would soon be dropping back into some level of hemophilia.
And that is what the FDA now seems to be worried about. Wednesday morning, the company announced that they had received a Complete Response Letter from the agency, which many readers will know means, roughly, “We Are Completely Not Approving Your Drug Right Now”. The FDA wants to see two more years of data to see how far the Factor VIII levels drop, a primary endpoint of “annualized bleeding rate,” and safety monitoring as well. You can tell from the BioMarin announcement of this that they’re pretty upset with the news: “The Agency first informed the Company of this recommendation in the CRL having not raised this at any time during development or review.”
Well, yeah – but the agency found out at the same time as BioMarin that the levels had dropped even more in year 4, so it’s not like they were going to recommend this based on the earlier data. And the company must have (should have) been thinking about the possibility that they would ask for further monitoring. BioMarin’s investors don’t seem to have been thinking about it, though – BMRN stock is down about 36% as I write.
This decision can be argued about, although the FDA is going to win that argument in the end. Their point is that they’d like to know what they’re approving: is this a cure, a four-or-five-year abatement in hemophilia, or what? It would seem that the theoretical option of getting re-gene-therapied is a long shot, since you would expect these patients to have primed an immune response to the AAV5 vector. More realistically, how do these patients do once they have to go back to taking extraneous Factor VIII – are they back to status quo ante, or does what might be a fairly brief excursion into health end up hurting them more in the long run? We really don’t know until we see the data, and the FDA is saying that they want to see it. The belief seems to be that the disease already has direct treatment options without gene therapy, so a completely new mode of therapy like this one needs to prove its worth before it gets approved. Not everyone is going to be happy about this, but the agency does have a case.
In the end, it might still be worth it for people to have a few years off of Factor VIII treatment (although that’s going to be a call for insurance companies to make, for the most part, isn’t it?). Or it might turn out to be a bad idea. We’ll revisit the topic in two years, by which time everyone involved will really be ready to argue.
Editor’s Note: The summary bullets for this article were chosen by Seeking Alpha editors.