2021-06-25| R&DTrials & Approvals

FDA Grants Breakthrough Status to Two Experimental Alzheimer’s Drugs While Pushback Over Aduhelm’s Approval Still Rages On

by Rajaneesh K. Gopinath
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Just a couple of weeks have passed since the historic FDA okay of Biogen and Eisai’s Aduhelm (aducanumab) for treating Alzheimer’s disease (AD) patients, but the controversy surrounding the approval is still raging on. Although the drug approval was welcomed by clinicians and members of the Alzheimer’s community, the headlines were rife with the pushback the amyloid beta targeting antibody received from some experts.

Dr. G. Caleb Alexander, a member of the FDA advisory committee, said the drug registered no solid evidence to suggest it works. Soon after, three members, namely David S. Knopman from the Mayo Clinic, Joel S. Perlmutter from the Washington University, and Aaron Kesselheim from Harvard Medical School, resigned from the panel. Many were critical of the drug’s $56,000 price tag, but the apprehension was more towards setting a bad precedent for subsequent drug approvals.

Several analysts agreed that the aduhelm approval would open the floodgates for similar Alzheimer’s drug candidates in development. The recent conferral of breakthrough therapy status to two experimental Alzheimer’s drugs has substantiated those concerns. In the past two days, Biogen and Eisai’s lecanemab and Eli Lilly’s donanemab have received the FDA’s Breakthrough Therapy designation (BTD).


Biogen, Eisai’s Second Alzheimer’s Drug Candidate Reduces Clinical Decline

On June 23rd, Biogen and Eisai announced that lecanemab, their second experimental Alzheimer’s drug that targets soluble, toxic amyloid beta aggregates (protofibril), received the FDA’s BTD based on the recently published Phase 2b trial results.

The proof-of-concept Study 201 conducted with 856 Alzheimer’s patients evaluated lecanemab’s capability of slowing clinical decline and reducing amyloid beta aggregation in the brain. The enrolled patients displayed mild cognitive impairment (MCI) due to AD and mild AD with confirmed presence of amyloid pathology. Data analysis revealed that at its highest doses, the investigational antibody showed a consistent reduction of clinical decline across several clinical and biomarker endpoints.

In March, the companies announced completing the enrollment of around 1,795 patients with early AD in a Phase 3 Clarity AD study. The study’s primary endpoint would be completed by the end of September 2022, according to a statement.

Results presented in the recently concluded Alzheimer’s Disease and Parkinson’s Disease Conference showed that patients treated with lecanemab showed a time-dependent reduction of amyloid beta in the brain. The drug is also currently investigated in Phase 3, AHEAD 3-45 study in clinically normal patients who have intermediate or elevated levels of amyloid in their brains (preclinical AD).


Lilly’s Donanemab Slows Clinical Decline by 32 Percent

The very next day to granting BTD to lecanemab,  the FDA has also conferred the status to Lilly’s donanemab, an investigational antibody that targets a modified form of amyloid beta called N3pG. The decision is based on the impressive data that the antibody registered in the Phase 2 trial, TRAILBLAZER-ALZ which evaluated donanemab in patients with early, symptomatic AD.

Updated results show that donanemab has met its primary endpoint and demonstrated significant slowing of cognitive and functional decline. As measured by the integrated Alzheimer’s Disease Rating Scale (iADRS), at 76 weeks compared to baseline, donanemab slowed decline by 32 percent versus the placebo. The data were presented at the 15th International Conference on Alzheimer’s & Parkinson’s Diseases 2021 and published simultaneously in the New England Journal of Medicine journal.

Based on these Phase 2 results, Lilly intends to submit a BLA for donanemab under the accelerated approval pathway later this year. In addition, it is also evaluating the safety, tolerability, and efficacy of the drug in an ongoing randomized Phase 3, TRAILBLAZER-ALZ 2 (NCT04437511) trial.

Related Article: Biogen’s Controversial Alzheimer’s Drug Wins Historic FDA Approval


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