The FDA posted briefing documents related to the Nov. 6 meeting of the Peripheral and Central Nervous System Drugs Advisory Committee, and Wall Street’s opinion turned out decidedly mixed regarding the odds for aducanumab, the anti-amyloid beta monoclonal antibody for Alzheimer’s disease (AD) from Cambridge, Mass.-based Biogen Inc. and Eisai Co. Ltd., of Tokyo.

Aducanumab will face four voting questions, focused mainly on two positive studies, 103 (called Prime) and 302 (Emerge) and not on the negative 301 (Engage) experiment, with 302 considered primary and 103 supportive, noted Guggenheim analyst Yatin Suneja, who found the ultimate approval of the compound “more likely than not.” Study 302 results are seen by regulators as robust, he said in a report, with 79 of 80 prespecified subgroups showing a good outcome. Biomarker data were seen as supportive of clinical outcomes, and gatekeepers in their conclusion agreed with Biogen’s thesis linking drug exposure to benefit.

“We think aducanumab has the potential to generate about $5-10 billion in peak sales,” Suneja said, and “a successful launch of aducanumab has the potential to completely change the profile of the company.” Echoing him was H.C. Wainwright’s Andrew Fein, who said in a report that “the totality of the data supports aducanumab being effective in removing a core pathology of AD and slowing of clinical decline [in the realms of] memory, language, executive and visuospatial function, personality, and behavior.”

Not on board, however, was Baird’s Brian Skorney. “We totally underestimated the FDA willingness to be flexible,” he said in a report. “Color us shocked” since the documents “endorse each of Biogen's claims of the efficacy of aducanumab. After reading through the major points, it looks pretty clear that the responsible parties at the FDA have written up an endorsement in the hopes of swaying panelists on Friday to vote for an approval,” he said, deeming the documents “extraordinary,” as they go “above and beyond traditional data mining to support claims of efficacy.”

This summer, the FDA accepted the BLA related for aducanumab in AD and assigned it priority review. Biogen and Eisai about a year ago restarted the clinical program with aducanumab, which had failed a futility analysis, after ransacking a larger dataset to discover that the drug may have important activity in AD, the most frequently occurring type of amyloidosis in humans and the commonest form of dementia. Skorney is far from convinced, citing “more than enough evidence” that aducanumab is “unlikely to provide clinical benefit to AD patients” and will become a cost drain, “either on Biogen, in the form of additional clinical development, or society at large, if regulatory bodies were to grant commercial approval.”

‘A stake in the sand’

Bolstering Skorney’s case is the FDA’s own biostatistical review, which used language such as “no replication, highly conflicting results in two studies, [and] conflicting subgroup results.” Mizuho analyst Salim Syed also zeroed in on the review, flagging its findings as an “underappreciated risk” ahead of the adcom, since it runs almost “completely counter to the adcom briefing docs. This is this type of stuff that starts small, seems benign, but has [the] potential to snowball,” he said in a report. Piper Sandler analyst Christopher Raymond said he was “surprised at the degree to which FDA’s clinical reviewer appears to walk away from well-established scientific and evidentiary standards in recommending approval of this drug.” He nodded to the unmet need in AD, but said in a report that “protests from the neurology community are likely to only increase in volume, given the limited efficacy, offset by substantial healthcare system burden and meaningful impairment to future AD drug development efforts.” His firm, he said, “prefer[s] to watch this drama from the sidelines.”

Evercore ISI’s Umer Raffat plucked what he said were key lines from the statistical review: “It’s not like we have one strong study in isolation,” in the case of aducanumab. “If you have two [studies] and you take the best and pretend like it’s the only one, your estimate is likely biased.” Raffat also noticed that the main FDA reviewer, Kevin Krudys, “is actually from the [agency’s] Office of Clinical Pharmacology. I find this to be really puzzling, especially given how high profile this review is for the FDA.” Along with the favorable briefing docs, Biogen may have scored another break when Mayo Clinic neurologist – and aducanumab skeptic – David Knopman was recused from the adcom panel because of potential conflict of interest, since he was involved in some of the trials. Knopman and others recently published a paper in Alzheimer’s & Dementia. The adcom panelists include four epidemiologists/statisticians expected to “take a very close look at this presentation,” said Baird’s Skorney.

Shares of Biogen (NASDAQ:BIIB) closed at $355.63, up $108.62, or 44%. Riding the news were AD players including Lausanne, Switzerland-based AC Immune SA (NASDAQ:ACIU), which rose 80 cents, or 17% to close at $5.56; Athira Pharma Inc., of Seattle, which saw its shares (NASDAQ:ATHA) reach $24.69, up $4.80, or 24%; New York-based Intra-Cellular Therapies Inc. (NASDAQ:ITCI), which ended at $26.47, up $2.55, or 10.6%; and Prothena Corp. plc (NASDAQ:PRTA), finishing at $13.94, up $2.58, or 23%. Gene Kinney, CEO of Dublin-based Prothena, told BioWorld that the FDA’s regard for aducanumab as concluded in the briefing documents is “not all that discordant from what we believe” about the drug, which he said merits approval. “From a purely statistical perspective, the comments that are being made are on the mark, but at the same time, I think one needs to look at the totality of the data,” he said. “That’s obviously within the discretion of regulatory authorities to do.”

At the Clinical Trials on Alzheimer’s Disease conference this week, Prothena is offering details about next-generation anti-amyloid beta antibodies in the works for subcutaneous administration to improve access for patients with AD as well as a multi-immunogen amyloid beta-tau vaccine for prevention and treatment of AD. In amyloid beta, “when there were failures – and there were a number of failures – folks jumped right to the biological hypothesis,” placing blame on the target, Kinney said. But a closer look at each case revealed problems with the molecule, the patient population or clinical endpoint. “We don’t think amyloid beta is the end of the story” in AD, although it’s an important component, he said. Once researchers “put a stake in the sand with an aducanumab-like molecule and start talking about disease-modifying agents,” he added, the next step is to create a drug with an even better profile.