Aducanumab, the Alzheimer’s disease candidate Biogen has co-developed with Eisai, has run into an unexpected pothole on the road to FDA approval after an advisory panel on Friday issued a surprise recommendation not to approve the drug.

The FDA usually follows—but does not have to abide by—the recommendations of advisory committees like the one that considered aducanumab in a closely-anticipated virtual meeting that ran longer than seven hours.

If approved by the FDA, aducanumab would be the first therapy indicated for reducing clinical decline in people with Alzheimer’s disease, and would also be the first therapy to tie improved clinical outcomes to removing amyloid beta. Aducanumab would be marketed under the name Aduhelm.

Aducanumab is being evaluated by the FDA under Priority Review, with a target action date of March 7, 2021, despite U.S. sponsor Biogen not using its Priority Review voucher for the aducanumab BLA. The FDA accepted Biogen’s BLA for aducanumab in August.

Biogen surprised analysts in October 2019 by planning to file for FDA approval of aducanumab despite halting two failed Phase III studies of the drug seven months earlier. Biogen and Eisai asserted that one of those trials, Study 301 or ENGAGE (NCT02484547) met its primary endpoint showing a significant reduction in clinical decline—a result the companies later said was supported by results from a subset of patients in the other halted Phase III trial, Study 302 or EMERGE (NCT02477800).

The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee agreed that aducanumab’s U.S. sponsor Biogen presented strong evidence of a pharmacodynamic effect on Alzheimer’s disease pathophysiology in the Phase I proof of concept trial known as Study 103 or PRIME (NCT01677572), in a 5–0 vote with six members uncertain.

But in three other votes, the advisory committee balked at endorsing aducanumab. By an 8-1 vote (two members uncertain), the panel agreed that EMERGE, viewed independently from ENGAGE, did not provide strong evidence supporting the effectiveness of aducanumab for the treatment of Alzheimer’s disease.

Not “reasonable”

Worse for aducanumab, the committee voted 10–0 (one member uncertain) that it was not “reasonable to consider EMERGE as primary evidence of effectiveness of aducanumab for Alzheimer’s.”

The panel also concurred that the Phase I PRIME trial (NCT01677572), also known as Study 103, failed to provide evidence supporting the effectiveness of aducanumab as an Alzheimer’s treatment, in a 7–0 vote (four uncertain).

“We think approving aducanumab, in the face of such an overwhelmingly negative vote and commentary, is virtually impossible and would destroy the agency’s reputation at a very tenuous time for the regulator, ahead of potential actions on COVID vaccines,” Brian P. Skorney, CFA Sr. Research Analyst with Baird, wrote today in a research note that urged investors to position themselves to profit from a declining price for Biogen stock: “Press the short,” Skorney advised.

“The agency cannot afford to come to a conclusion that goes against the most scientific interpretation of the data supported by their own advisory committee and allow one Office Director to exercise such dominance over a decision that has so much meaning for the future of drug regulation, particularly with the pending data from the myriad of SARS-CoV2 vaccines,” Skorney added. “Maybe we are just being too optimistic about the state of scientific integrity at FDA, but we are sticking with our view that this is getting rejected.”

The advisory committee votes followed an apparent split within the FDA over aducanumab, with Billy Dunn, MD, Director of the FDA’s Office of Neuroscience, siding with Biogen in urging the panel to recommend approval of aducanumab: “The evidence supporting its approval appears strong.”

However, Tristan Massie, PhD, a statistician with the agency, concluded that “there is no compelling substantial evidence of treatment effect,” and questioned the difference in results between ENGAGE (Study 301) and EMERGE (Study 302): “In this case we do not have a single strong study in isolation [EMERGE]. On the contrary, we actually have a second trial [ENGAGE]  in which the purported effective dose was in the wrong direction compared to placebo, i.e., numerically worse than placebo.”

The accompanying slide stated: “We have an equally-sized and identically-designed study, 301, that directly contradicts 302.”

Massie asserted: “If we select only the better study our estimate is very likely biased, and we already know not consistently repeatable in our experience. Thus excluding data from a large trial without sufficient justification is unscientific, statistically inappropriate, and misleading. At best, the evidence in this application is from Study 302 only, and there exists compellingly conflicting Phase III evidence.”

Not so, countered Samantha Budd Haeberlein, PhD, senior vice president, head of neurodegeneration development unit, Biogen.

“Study 301 high dose arm clinical outcome was substantially impacted by lower exposures to the target dose of 10 mg/kg and an imbalance in a very small number of rapidly progressing subjects. However, subjects in Study 301 who were randomized to dose regimens allowing the full 14 doses of 10mg/kg had pharmacological activity and clinical efficacy consistent with Study 302,” Haeberlein told the panel.

“Simply put, an imbalance in rapid progressors and less exposure to 10mg/kg dosing drove the difference between studies. When these factors were not present, results from 301 were similar to 302,” Haeberlein added before acknowledging: “Nevertheless, 301 is a failed study. These findings do not add to the substantial evidence of efficacy from Studies 302 and 103 – but neither do they detract from that evidence.”

Canaccord Genuity analyst Sumant Kulkarni maintained the firm’s “buy” rating on Biogen this morning, writing in a research note that the FDA could bridge the divide on aducanumab: “We do think there is a potential path forward. Specifically, we view a fallback on biomarkers/surrogate endpoints to support adu [aducanumab] approval with commitments to conduct post-approval trials as an option to bring adu to the market.”

“A reminder”

In a statement issued Friday evening after the advisory panel meeting, Howard Fillit, MD, founding executive director and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), observed: “Although today’s non-binding committee vote is not the final say, it is a reminder about the challenges of finding effective treatments for Alzheimer’s disease.”

Trading in Biogen shares was halted Friday pending the outcome of the advisory committee meeting, after shares closed Thursday at $328.90, down 7.5% from Wednesday’s close of $355.63. When shares resumed trading this morning, their value plunged 31%, to $227.77 as of 10:32 a.m.

Biogen’s shares surged 44% on Wednesday from the previous day’s close of $247.01 after the FDA released materials for the advisory committee meeting that included positive comments about aducanumab and the clinical trials that support its BLA.

“The results of Study 302 are highly persuasive and the study is capable of providing the primary contribution to a demonstration of substantial evidence of effectiveness of aducanumab,” FDA staff researchers concluded in a 343-page briefing document prepared for the advisory committee.

“In fact, the effects observed for the primary and secondary endpoints encompass two acceptable approaches to establish effectiveness: (1) primary endpoint of CDR-SB [Clinical Dementia Rating-Sum of Boxes ] and (2) co-primary endpoints of ADAS-Cog 13 [Alzheimer’s Disease Assessment Scale – Cognitive 13-Item Scale] and ADCS-ADL-MCI [Alzheimer’s Disease Cooperative Study – Activities of Daily Living – Mild Cognitive Impairment].

“Substantial evidence”

The EMERGE trial, according to the staff researchers, “appeared to be a strongly positive study on many distinct clinical measures, robust to numerous sensitivity analyses, and supported by well-characterized biomarker data.”

“The applicant has provided substantial evidence of effectiveness to support approval,” the FDA staff researchers added.

If the FDA hoped to persuade advisory committee members by pushing hard for aducanumab, its hopes were dramatically dashed.

“In our view, it seems that the remarkably positive language of the FDA in the briefing docs backfired, as it upset the panelists who believed the FDA should have been less assertive with its opinion,” Marc Goodman, a senior research analyst at SVB Leerink covering Neuroscience and Ophthalmology, wrote last night in a research note.

“However, while it would be so easy to bail on this positive call and change our view given that very negative AdCom, we still believe there is a good chance that the FDA will approve this product anyway,” Goodman added. “While we have never seen a drug get approved with such a negative panel, we also have never seen FDA briefing documents that were so blatantly obvious about the FDA’s positive view.”

Another reason Goodman sees an eventual FDA approval for aducanumab: “For Billy Dunn to have been as passive as he was during the combative discussions and not having tried to sway the panel, in our view it seemed like he was not as concerned about the panel agreeing with the FDA’s positive view.”

Eisai joined Biogen in partnering on aducanumab in 2017—10 years after Biogen (then called Biogen Idec) began developing the drug under license from its original developer, Zurich-based Neurimmune.

Biogen and Eisai hope to succeed where numerous other drug developers have failed in the long struggle to create successful new drugs for Alzheimer’s disease. Only a handful of drug successes have ever reached the market, and even they have merely slowed progression of symptoms by 6 to 12 months.

2014 Cleveland Clinic study found a 99.6% failure rate of clinical trials for Alzheimer’s disease drug candidates between 2002 and 2012. That study found high attrition rates for Alzheimer’s disease treatments, with 72% of agents failing in Phase I, 92% failing in Phase II, and 98% failing in Phase III.

However, according to ADDF, more than 100 drugs against Alzheimer’s are under study in clinical trials, with the foundation currently supporting about 20% of these drugs.

“Drug trials are complex and do not always deliver the unequivocal answers we would like,” ADDF’s Fillit added. “But one clinical trial builds on another and gives us clues to help the next.”

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