Lately, there has been heightened attention to briefing documents in the CNS space, a notoriously tricky area to get drugs approved, which can affect company stock prices.
Typically, a few days before a U.S. Food and Drug Administration advisory committee meets to discuss a drug application, the agency publishes submission details and analysis of the data. This is designed to give the advisory committee — and potentially the public — access to a review of the data.
For the most part, the public doesn’t pay much attention unless it’s a particularly newsworthy event. For example, some public attention was paid ahead of the FDA’s decision on Biogen’s Aduhelm (aducanumab) for Alzheimer’s disease. And there was plenty of attention paid to early data on the various COVID-19 vaccinations.
Otherwise, it’s a bit of “inside baseball” for the industry and for investors. And in some cases, for investors, it gives analysts a shot at predicting how the advisory committee will land on their recommendation, which is typically - but not always - an indicator of how the agency will decide on the drug application. In the central nervous system (CNS) space, such as with Biogen’s Aduhelm, a notoriously tricky area to get drugs approved in, there has lately been heightened attention to briefing documents, with resultant effects on company stock prices.
Amylyx’ ALS Drug
As reported yesterday, the FDA released briefing documents ahead of today’s Peripheral and Central Nervous System Drugs Advisory Committee meeting to discuss Amylyx Pharmaceuticals’ New Drug Application (NDA) for sodium phenylbutyrate/taurursodiol powder for oral suspension for the treatment of amyotrophic lateral sclerosis (ALS). The drug has been granted Priority Review.
Company shares took a serious hit after the news and after analysts wrote about their concerns about the data and the FDA’s position on it. Shares cratered 41.3%, although they’ve bounced back a bit today.
In its documents, the FDA argued that there was insufficient data for approval, that Amylyx reported a “positive result on a prespecified but non-preferred analysis of a functional endpoint in ALS, which did not appropriately account for deaths that occurred during the study. The prespecified statistical result was not exceptionally persuasive and there were analytical and interpretative issues associated with its consideration.”
Umer Raffat, an analyst with Evercore ISI, wrote to investors, “Does the briefing document read materially worse than expectation? Absolutely. Does it mean FDA won’t approve it? That’s a loaded question … and we will go on a limb to say it still has a very realistic shot.”
Potentially it might be approved under an Accelerated Review pathway, with further clinical efficacy to be determined with future clinical trials. ALS is a CNS disorder with no cure. Death typically occurs within three to five years from the onset of symptoms. The advisory committee and the agency might decide that even modest benefits in a limited trial are worth the potential of giving these patients a few extra months.
The company recently initiated a Phase III trial in 600 patients worldwide, but the data isn’t expected to read out until 2024. It is also evaluating data from an open-label extension study, whose findings have already been reported and published but are not necessarily part of the data package the FDA received.
Reata Pharma Catches Fallout
Reata Pharmaceuticals’ stock plunged 31.4%, and some analysts think it’s because of the FDA’s briefing documents on Amylyx. Reata started a rolling New Drug Application submission for omaveloxolone for Friedreich’s ataxia in late February. It hopes to complete the NDA by the end of the first quarter of this year — in other words, this week.
Friedreich’s ataxia is a rare, genetic degenerative neuromuscular disease. It is caused by a trinucleotide repeat expansion in the first intron of the frataxin gene. This is a sort of genetic stutter, where three nucleotides get repeated over and over again.
The gene encodes the mitochondrial protein frataxin, and the repeats lead to impaired transcription and decreased frataxin expression. This in turn can cause mitochondrial iron overload and poor cellular iron regulation, increased sensitivity to oxidative stress, and impaired ATP production by the mitochondria, the energy-producing organs of the cells. The disease leads to progressive loss of coordination, muscle weakness, and fatigue.
So why would Amylyx’s neurodegenerative drug affect Reata’s neuromuscular drug application? This is most likely because investors are suddenly jittery about drug approvals in the CNS space. Another reason is that Reata has submitted limited data for omaveloxolone, but some investors are applying the FDA’s criticism of Amylyx’s lack of morbidity analysis to Reata’s data.
Citi, on its part, thinks the Reata selloff was overblown. “ALS is a fast-progressing disease where deaths would be expected to occur (and did occur) over the course of the 24-week Centaur trail,” wrote Citi analyst Yigal Nochomovitz. FA, on the other hand, is a “more-slowly progressing neuromuscular disorder.”
Bloomberg quoted Nochomovitz, saying, “We confirmed with Reata management today that FDA has not recommended any type of mortality analysis in the key efficacy analyses.”
It’s also likely that investors in the life sciences are jittery from news on Monday that Biogen and Ionis Pharmaceuticals were killing off an ALS drug program after the failure of their Phase I trial of BIIB078. The study failed to meet clinical endpoints. And in October 2021, Ionis and Biogen reported another antisense drug failure in ALS. In that case, it was the Phase III VALOR trial of tofersen.
Biogen may be pivotal as well for all the investor nerves. Although its Aduhelm was the first Alzheimer’s drug to be approved in about twenty years, it’s controversial and Medicare and insurers are reluctant to pay for it. And in mid-March, Biogen’s development partner Eisai modified their deal on the drug, with Eisai shifting to royalties-only and taking control of another Alzheimer’s program with Biogen for lecanemab.
And the latest Centers for Medicare & Medicaid Services proposed draft national coverage proposal for Aduhelm intends to place limits on reimbursements for an entire class of Alzheimer’s and other CNS drugs that are designed to clear amyloid. Although it’s not yet finalized, several drug companies have delayed or put their CNS drugs on the back burner.
