In his latest piece on Alzheimer’s Disease (AD) drug Aducanumab’s winding journey to market, Dr Neil Cashman looks forward to the US FDA Advisory Committee’s meeting on November 6 2020, what it means for that Aducanumab, and the impact on next-generation AD treatments.

November 6 could prove to be a milestone day for the millions of Americans living with Alzheimer’s disease. An FDA Advisory Committee (AC) will convene and potentially recommend approval for Biogen’s aducanumab as the first disease-modifying treatment for Alzheimer’s. Despite a tortuous road to approval and modest demonstrated treatment benefit, aducanumab’s remarkable regulatory progress is galvanizing the development of safe and effective therapies for Alzheimer’s disease.

Aducanumab snapshot: how did we get here

After cancelling its two global phase 3 studies in March 2019, Biogen shocked the AD community in October 2019 when it said re-analyses of data from their late-stage phase 3 studies show that aducanumab, given at higher doses over a long duration, did indeed reduce the rate of patients’ cognitive decline. The demonstrated 23 percent reduction in cognitive decline is modest but statistically significant. Biogen’s biomarker analyses also support the interpretation that aducanumab beneficially impacts the underlying AD neuropathology.

At the time of their October 2019 reversal, Biogen stated they had met with the FDA at least twice to review the new analyses and that “after consultation with the FDA, we believe that the totality of these data support a regulatory filing.” Since then, Biogen has provided additional phase 3 data as well as details of their FDA interactions. In August, the FDA accepted Biogen’s Biologics License Application (BLA) for aducanumab and granted it Priority Review. On November 6 the Advisory Committee (“AdCom”)will provide “advice and recommendations” on the BLA. The FDA, in granting its fastest possible review for a treatment, recognizes the tremendous need for the first disease-modifying therapy for Alzheimer’s disease.

Likely AdCom deliberations

There are various statistical issues and subset analyses one must grapple with before accepting Biogen’s position, and the AdCom will undoubtedly debate them. The committee will acknowledge that aducanumab’s treatment benefit is modest, and there are safety considerations. At the effective higher therapeutic level, the incidence of adverse ARIA-E (brain swelling) affected 35 percent of study participants despite attempts to minimize it with drug titration. Clinical investigators believe the side effect can be managed, but the safety concerns limit the maximum dose that can be administered to a group of AD patients.

Aducanumab’s most meaningful limitation, however, is that it does not target the real culprit of AD. The drug was originally designed to target amyloid-beta plaque, now believed to be an ineffective drug target for AD. An accumulating body of data has shifted drug development focus to a different species of amyloid-beta called the toxic oligomer which has since been shown to be the true culprit in driving disease progression. Aducanumab’s ability to cross-react and partially neutralize toxic oligomers results in its modest treatment benefit.

Aducanumab shows substantial evidence of effectiveness

I anticipate that the AC is likely to agree aducanumab’s treatment benefit is clinically meaningful. Though there may be several strong dissents, I expect a majority of the AdCom members will vote YES as to whether the aducanumab BLA demonstrates substantial evidence of effectiveness. Alzheimer’s disease is one of the highest unmet medical need indications in medicine and FDA is committed to approving a drug for this indication. FDA neuroscientists and team leaders have been active in promoting the development of new cognitive endpoints and biomarkers to demonstrate drug impact on the underlying neurobiology of AD. Also in Biogen’s favor is the FDA’s demonstrated sensitivity to medical need in the past—notably for the ALS treatment edaravone in 2017 and again in 2019 for the Duchenne muscular dystrophy treatment golodirsen, both approved with limited clinical data.

Next-generation therapies needed

Aducanumab should, and I believe will be, approved. The drug’s modest efficacy and safety concerns, however, justify the need for a next-generation therapeutic that selectively targets toxic oligomers. Such drugs in development provide a high degree of binding to toxic oligomers without binding to non-toxic forms of amyloid-beta plaque. These highly targeted therapeutics hold great potential to avoid ARIA-E and allow for higher dosing and efficacy. The preclinical data for these drugs are promising compared with therapies like aducanumab that target only amyloid beta plaques. These new drug candidates will benefit from novel blood and cerebrospinal fluid (CSF) biomarkers that measure disease progression, enabling dramatic improvements to the speed and cost-effectiveness of clinical development.

A positive recommendation at the November 6th AdCom meeting will both provide support to the FDA in its decision making and catalyze investor interest in the next generation of therapies targeting amyloid-beta oligomers. A green light from the AdCom will and should be hailed as an important milestone in Alzheimer’s treatment. Aducanumab’s most powerful impact, however, will be on future therapy development, specifically second-generation therapies that demonstrate more precise targeting for amyloid-beta toxicity with greater efficacy and safety.