Eli Lilly Hopes to Clear Runway for AD Drug with New Amyloid Data

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Eli Lilly and Company presented data analysis from the Phase II TRAILBLAZER-ALZ study at the Alzheimer’s Association International Conference (AAIC) that supports the argument that decreases in beta-amyloid in Alzheimer’s disease slows cognitive decline.

One of the reasons this is so significant has to do with the controversial approval of Biogen’s Aduhelm for Alzheimer’s. Aduhelm is a monoclonal antibody that targets beta-amyloid. The U.S. Food and Drug Administration granted accelerated approval on the basis of a reduction of beta-amyloid, not the slowing of cognitive decline although some of the data in the submission did suggest that. Part of Biogen and the FDA’s defense against criticism has been that although the approval used the surrogate endpoint of beta-amyloid reduction instead of cognitive decline, decreased beta-amyloid does lead to the slowing of the decline. Many experts argue that there is no real proof of that.

For example, on July 28, seven members of the FDA’s advisory committee that voted against Aduhelm published an article in the New England Journal of Medicine, arguing that the FDA had not offered a persuasive scientific basis for using beta-amyloid as a reasonable surrogate for accelerated approval.

Lilly’s data is two exploratory analyses from the TrailBLAZER-ALZ trial of their own monoclonal antibody, donanemab. It targets a modified form of beta-amyloid plaque known as N3pG. In one analysis, they found that larger changes to amyloid plaques after treatment with donanemab was “highly associated with less cognitive decline.” In addition, the patients with the most plaque clearance at 24 weeks also had less progression of yet another abnormal protein found in Alzheimer’s patients, tau. The second analysis demonstrated that donanemab resulted in a rapid decrease of a biomarker that is associated with Alzheimer’s pathology, plasma P-tau217, which was observed within 12 weeks.

Although Alzheimer’s is not well understood, beta-amyloid has long been hypothesized to be a trigger for the disease. These abnormal proteins accumulate in the brains of Alzheimer’s patients early in the disease. They also appear to trigger or feed neuroinflammation, which may cause the actual damage to the brain. Tau is also another abnormal protein associated with Alzheimer’s which typically appears later in the disease. The Amyloid theory has been that if you cleared amyloid, you would improve the symptoms of the disease. Over the years, numerous drugs have been able to decrease or clear amyloid, but have not demonstrated improvement in disease symptoms. This resulted in the abandonment of many of those programs.

Aduhelm’s approval convinced many drug companies to re-evaluate those drugs.

“We are excited by these promising results, which provide further evidence on the potential for donanemab to slow disease progression for people with early symptomatic Alzheimer’s disease,” said Mark Mintun, vice president of Pain and Neurodegeneration Research at Lilly. “Importantly, these data link the mechanism of action of donanemab, plaque clearance, with positive effects on both clinical outcomes and brain tau pathology.”

Greater amyloid plaque clearance at 24 weeks was associated with an improved Integrated Alzheimer’s Disease Rating Scale (iADRS) score, which is a validated, composite measurement that combines two well-established approaches to evaluating cognition and daily function in Alzheimer’s clinical trials. Lilly also said that pharmacokinetic/pharmacodynamic modeling indicated greater relative amyloid plaque clearance was associated with more clinical benefit.

The TRAILBLAZER-ALZ Phase II study involved dosing patients with 800 mg of donanemab every four weeks for the first three doses, then 1400 mg every four weeks, for up to 76 weeks. They then had scheduled blinded dose reduction tests at 24 and 52 weeks.

The drug is also being evaluated in the ongoing Phase III TRAILBLAZER-ALZ 2 trial in early symptomatic Alzheimer’s disease patients. It is a prevention study to determine if the drug can prevent clinical progression of the disease before clinical impairments start.

John Sims, M.D., senior medical director of neurodegeneration and co-author of the analysis, stated, “Notably, these data support the amyloid cascade hypothesis and suggest that amyloid-related tauopathy can be altered with donanemab’s impact on plaque clearance. Furthermore, the data support that early and profound amyloid clearance may translate into clinical benefit for patients.”

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