Two die in Ei Lilly Phase 3 study of Alzheimer's drug

Photo: Jeff Lagasse/Healthcare Finance News

Donanemab, an Alzheimer's drug candidate produced by Eli Lilly, showed that it can slow cognitive decline by 35% in the company's new Phase 3 study, but there are some safety risks – exemplified by two deaths that occurred during the trial that were attributed to brain swelling, according to the drug company.

In addition to the risk of brain swelling, the trial showed that close to one in four participants experienced abnormalities related to amyloid-related imaging.

Still, Eli Lilly is touting the results, saying that donanemab met the primary endpoint of change from baseline until 18 months on the integrated Alzheimer's Disease Rating Scale (iADRS). The primary endpoint of iADRS measures cognition and activities of daily living such as managing finances, driving, engaging in hobbies and conversing about current events.

Based on the results, Eli Lilly will proceed with global regulatory submissions as quickly as possible, and anticipates making a submission to the U.S. Food and Drug Administration this quarter.

WHAT'S THE IMPACT?

Donanemab is a type of beta-amyloid targeted antibody. It works slightly differently than other drug candidates in that it's designed to bind to beta-amyloid proteins that have already aggregated into plaques. It works by stimulating the immune system to attack beta-amyloid plaques and clear them from the brain.

The FDA submission for accelerated approval for donanemab was based on TRAILBLAZER-ALZ, a Phase 2, randomized, double-blind, placebo-controlled study in 257 patients with early symptomatic Alzheimer's disease. Donanemab met its primary study objective, slowing the clinical decline of Alzheimer's disease by 32% relative to placebo on the iADRS at 76 weeks.

Also, there was a "substantial reduction" of amyloid plaque, with 68% of patients who received donanemab achieving complete amyloid clearance.

In the new trial, 47% of participants showed no decline in terms of dementia; 52% of participants completed their course of treatment by one year, and 72% completed it by 18 months as a result of achieving plaque clearance.

Also, those taking donanemab had 40% less decline in their ability to perform daily living tasks after 18 months, and a 39% lower risk of progressing to the next stage of the disease compared to the placebo group.

Two deaths were attributed to amyloid-related imaging abnormalities (ARIA), while a third died "after an incident of serious ARIA," according to the drugmaker.

THE LARGER TREND

According to Optum, there's a high unmet need for treatments for Alzheimer's disease, since it's a leading cause of illness and death among the elderly. Existing treatment options have been ineffective. 

In June 2021, the FDA approved Aduhelm (aducanumab), the first amyloid beta-directed antibody, via the accelerated approval pathway based on reductions in amyloid beta plaques. Subsequently, a Centers for Medicare and Medicaid Services National Coverage Determination limited Medicare coverage for Aduhelm and other beta-amyloid targeted therapies to patients enrolled in clinical trials because of unknown clinical benefit.

A December 2022 staff report by two House committees pointed to alleged irregularities in the FDA's approval of Aduhelm.

In January, CMS released a proposed National Coverage Determination decision memorandum that said the NCD would cover FDA-approved monoclonal antibodies that target amyloid for the treatment of Alzheimer's disease through coverage with evidence development, meaning for Medicare recipients enrolled in qualifying clinical trials.

Twitter: @JELagasse
Email the writer: Jeff.Lagasse@himssmedia.com