FDA to hold Advisory Committee on Donanemab in Alzheimer’s Disease

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Regulators want to discuss safety issues, as well as the phase 3 trial’s design where patients were treated based on an assessment of amyloid plaque and the inclusion of patients based on tau protein levels.

The FDA plans to hold a meeting of the Peripheral and Central Nervous System Drugs Advisory Committee to discuss the phase 3 trial of Lilly’s donanemab in early symptomatic Alzheimer's disease.

Regulators said they want to discuss the safety results in donanemab-treated patients and the efficacy implications of the unique trial design of the TRAILBLAZER-ALZ 2 study. Specifically they want to discuss the trial’s use of limited-duration dosing regimen that allowed patients to complete treatment based on an assessment of amyloid plaque and the inclusion of participants based on tau levels.

Anne E. White

Anne E. White

“We will work with the FDA and the stakeholders in the community to make that presentation and answer all questions,” Anne E. White, executive vice president of Eli Lilly and Company, and president of Lilly Neuroscience, said in a press release.

The announcement of an advisory committee meeting, however, does not take away from the breakthroughs the first class of disease modifying treatments, officials from the Alzheimer's Drug Discovery Foundation (ADDF) said in a statement. “As the first class of Alzheimer's drugs come to market — with the promise of more novel therapies to follow — the field is working together to build the path forward for future drug approvals,” said Howard Fillit, M.D., co-founder and chief science officer, of ADDF.

Donanemab was under review for full approval to treat patients with early Alzheimer’s disease. A decision had been expected by the end of 2023. The FDA had previously said it wouldn’t grant accelerated approval of donanemab to treat patients with early Alzheimer’s disease. In a complete response letter in January 2023, the agency indicated that there too few patients with at least 12 months of data provided in Lilly’s submission. Lilly had resubmitted the application in July 2023 for full approval

Full results from the trial show that donanemab slowed cognitive and functional decline in people with early symptomatic Alzheimer’s disease. Almost half of participants at earlier stage of disease on donanemab had no clinical progression at one year. Additionally, analyses of patients at earliest stage of the disease had even greater benefit, with 60% slowing of decline compared with placebo.

The data were shared at the 2023 Alzheimer’s Association International Conference and also published in the Journal of the American Medical Association.

The TRAILBLAZER-ALZ 2 enrolled 1,736 patients with a broad range of cognitive scores and amyloid levels. Patients were stratified by their level of tau, a predictive biomarker for disease progression. The trial used the Amyvid and Tauvid PET scans to enroll patients with confirmed amyloid plaques, allowing investigators to confirm clearance or reduction of the pathology in later scans.

Among all patients treatment with donanemab, the therapy reduced amyloid plaque on average by 84% at 18 months, compared with a 1% decrease for patients taking placebo.

Patients were able to stop taking donanemab once they achieved pre-defined criteria of amyloid plaque clearance. About half of patients met this threshold at 12 months and about seven of every 10 participants reached it at 18 months.

Among patients with low-to-medium levels of tau, donanemab-treatment patients slowed cognitive decline by 35% on integrated Alzheimer’s Disease Rating Scale, which measures cognitive ability and activities of daily living. Donanemab slowed decline by 36% on the Clinical Dementia Rating-Sum of Boxes, a widely used scale for dementia staging.

Among all amyloid-positive early symptomatic patients, treatment with donanemab slowed decline by 22% on the integrated Alzheimer’s Disease Rating Scale and 29% on Clinical Dementia Rating-Sum of Boxes.

In terms of safety, 17.4% of patients in the donanemab the group experienced any serious adverse event compared with 15.8% in the placebo group. Infusion-related reactions were experienced by 8.7% of patients in the donanemab group.

The incidence of amyloid-related imaging abnormalities (ARIA) was consistent with the previous TRAILBLAZER-ALZ study. ARIA occurs across the class of amyloid plaque clearing antibody therapies. It is most commonly observed as temporary swelling in an area or areas of the brain (ARIA-E) or as microhemorrhages or superficial siderosis (ARIA-H).

Other commonly reported adverse events includes infusion-related reactions, headache and nausea.

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