After much anticipation, Biogen Inc.'s Alzheimer's disease drug candidate aducanumab landed with a thud on the desks of the independent expert advisers reviewing it for the U.S. Food and Drug Administration.
The Peripheral and Central Nervous System Drugs Advisory Committee voted against approval of aducanumab during a Nov. 6 meeting based on two late-stage clinical trials that were split between success and failure. In one study, the drug was found to be ineffective at altering the underlying pathologies of Alzheimer's disease, a type of dementia that causes memory loss and other problems with thinking and behavior. In the other study, Biogen determined that the drug did indeed benefit patients. The company is developing aducanumab with Eisai Co. Ltd.
Committee members expressed concern that the data was not strong enough to support approval while acknowledging that a clinically meaningful treatment for Alzheimer's is desperately needed. The FDA does not have to heed the advice of the panel and had earlier indicated in briefing documents that the agency was supportive of approval.
"The outcome of this [meeting] has clearly placed BIIB and the FDA between a rock and a hard place" on meeting the March 7, 2021, decision deadline, said Canaccord Genuity analyst Sumant Kulkarni in a statement. "The ball is now firmly in the FDA's court on approval, and we do think there is a potential path forward."
Kulkarni is not alone in this view, suggesting that the agency could require follow-up studies to prove effectiveness or that the approval could be based not on the main goal of the trial but on secondary goals that still could provide meaningful improvements for patients. Cantor Fitzgerald called the panel's vote "a very chaotic turn of events" for Biogen's candidate and did not rule out approval.
"There is also a scenario where the FDA offered benign feedback and also allowed the panel to 'lay the hammer down,'" Cantor Fitzgerald's analysts said. "We can't really assess which scenario is the case but would hope the FDA's opinions were motivated on the data itself rather than anything else."
The FDA panel did somewhat agree that Biogen's therapy demonstrated an ability to clear tau and amyloid beta plaques in the brain, which are known hallmarks of the disease. A number of high-profile failures of drugs have attempted to do just that, and Cantor Fitzgerald analysts posited in another note whether the committee's decision could read as a positive for Eli Lilly and Co., which has developed several Alzheimer's candidates, including at least three that deploy the same mechanism of action as aducanumab.
"The FDA clearly wants more [Alzheimer's disease] drugs given the high unmet need, keeping the door wide open for [Alzheimer's disease] drug development," the analysts said.
The analyst chatter underscored a broader debate in Alzheimer's drug development: if not aducanumab, then what? The FDA meeting took place as leaders in the disease area met virtually at the annual Clinical Trials on Alzheimer's Disease conference to discuss other promising drug candidates.
As many as six clinical trials in Alzheimer's are expected to have readouts in the first half of 2021, according to Cowen analyst Steve Scalia. Two of those focus on the anti-amyloid theory, and four involve novel mechanisms of action. Three of the readouts are expected from Lilly, two from AbbVie Inc. and another from Roche Holding AG.
Many of these therapies have had high profile failures in the clinic, and the FDA committee's vote is another setback for Alzheimer's disease, according to Cowen.
Some other prospects from smaller biotechs include ACADIA Pharmaceuticals Inc.'s Nuplazid, already approved for treating hallucinations and delusions associated with Parkinson's disease psychosis and has shown positive data in reducing the risk of psychosis in dementia patients.
Research into different approaches to Alzheimer's has picked up in recent years, which could point to a "rapidly evolving ... treatment paradigm" in the near future, according to Cantor. Aducanumab, despite the rocky road it is taking toward an FDA decision, has contributed to "re-invigorated interest" in treatments that can alter the course of Alzheimer's.
Other promising drugs include Prothena Corp. PLC's prasinezumab for treating Parkinson's disease, Anavex Life Sciences Corp.'s ANAVEX 2-73, Axsome Therapeutics Inc.'s AXS-05 and Cassava Sciences Inc.'s sumifilam.
Cantor counted 121 unique agents in clinical trials for Alzheimer's disease as of early 2020.
"We believe that these neuro-innovators may benefit from growing clinical investigator/regulatory/investor interest in the space should a therapeutic, with even incremental benefit, get over the goal line and 'light the way,'" Cantor said Nov. 2 before the aducanumab vote.