Biogen's long and winding road in Alzheimer's hits wall

Yesterday's negative FDA advisory committee vote may be the final nail in the coffin in the up-and-down registration path of Biogen (NASDAQ:BIIB) and collaboration partner Eisai's (OTCPK:ESALY) aducanumab (formerly BIIB037) for the treatment of patients with mild Alzheimer's disease (AD). This is the latest setback for therapies targeting the underlying pathology of AD, a notoriously treatment-resistant neurodegenerative disorder. The advisory committee voted 8-1 (2 uncertain) that the Phase 3 EMERGE study, in which the highest dose achieved the primary endpoint, was insufficient to demonstrate efficacy. A recap of the asset's history:

• Aducanumab was derived from human B cells collected from healthy elderly people with no symptoms of cognitive impairment and from cognitively impaired seniors with unusually slow clinical decline. Screening the libraries of human memory B cells for reactivity against beta-amyloid led to aducanumab, a monoclonal antibody that binds to beta-amyloid aggregates.
• Ridding the brain of these aggregates, commonly called amyloid plaques, has been an AD drug target for many years. All efforts to date, including those by members of Big Biopharma including Eli Lilly (NYSE:LLY) and Johnson & Johnson (NYSE:JNJ), have come up empty, fueling the debate on whether amyloid plaques are a product of AD rather than the cause.

Aducanumab was discovered at Swiss biotech Neurimmune which out-licensed the asset to Biogen in November 2007. Biogen took over development and assumed responsibility for commercialization. In May 2018, Biogen exercised its option to reduce its royalty exposure by 5% paying Neurimmune $50M. The deal followed a 15% royalty reduction in October 2017. The resultant royalty rate was high single-digit to low teens.

• In March 2014, Biogen inked an agreement with Eisai to develop and commercialize aducanumab, an anti-tau monoclonal antibody and two Eisai candidates, E2609, a β-site amyloid precursor protein cleaving enzyme (BACE) inhibitor, and BAN2401, another anti-beta-amyloid monoclonal antibody. In October 2017, Eisai exercised its option to co-develop and co-promote aducanumab in the U.S., Europe and Asia (exclusive of China and South Korea).
• On the clinical trial front, the first encouraging signs of efficacy were announced in late 2014 based on interim data generated in a Phase 1 trial called PRIME. In October 2018, the company announced sustained reductions in amyloid plaque levels at months 36 and 48 from the long-term extension portion of the trial.

The attention, predictably, was on results from larger pivotal studies. Two Phase 3s, ENGAGE and EMERGE, launched in September 2015. This is where the turbulence began. Investors were temporarily unnerved in February 2018 when the company announced enrollment increases in both studies, typically a signal that efficacy was less than clearcut. In March 2019, the companies announced the termination of both trials after a futility analysis showed that neither was likely to be successful. Biogen, though, didn't give up. In stealth mode, it worked with scientists, regulators and statisticians combing through the results for any light at the end of the tunnel.

• In December 2019, Biogen announced that the high dose arm in EMERGE met the primary endpoint and several key secondary endpoints while the low-dose arm missed all endpoints. Both dose groups missed all endpoints in ENGAGE. It also disclosed that it planned to file a U.S. marketing application based on the totality of the data. The FDA accepted the application four months ago with an action date of March 7, 2021.
• Critics accuse the company of shooting first, then drawing a bullseye reflecting their lack of enthusiasm for Biogen's post hoc analyses, an opinion confirmed by the one-sided negative vote.
• The key date is, of course, March 7. May be a play with deep out-of-the-money calls? Who knows.

https://seekingalpha.com/news/3633230-biogens-long-and-winding-road-in-alzheimers-hits-wall