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FDA Advisors Support Eli Lilly’s Alzheimer’s Drug

FDA Advisors Support Eli Lilly’s Alzheimer’s Drug

On Monday, an independent advisory panel to the Food and Drug Administration (FDA) endorsed Eli Lilly’s Alzheimer’s treatment, donanemab, potentially leading to its full approval in the U.S. later this year.

The FDA generally follows the advice of its advisory panels, though it is not obligated to do so. Should the drug receive approval, donanemab will join Leqembi, another Alzheimer’s treatment from Biogen and its Japanese partner Eisai, on the U.S. market.

Approval would broaden the currently limited treatment options for over 6 million Americans affected by Alzheimer’s, the fifth-leading cause of death for adults over 65.

In their first vote, the committee unanimously agreed that available data demonstrates donanemab’s effectiveness in treating early-stage Alzheimer’s. However, several advisors pointed out the need for more data on the drug’s effects in Black and Hispanic patients, among other groups.

In a subsequent vote, the advisors unanimously concluded that the benefits of donanemab outweigh its risks. “There’s a huge unmet medical need here that hopefully can be addressed,” commented temporary committee member Sarah Dolan, a consultant for the non-profit organization Critical Path Institute, during Monday’s meeting.

Eli Lilly expressed satisfaction with the panel’s recommendation, with Mark Mintun, group vice president of neuroscience research and development, stating, “We are pleased with the panel’s recommendation and look forward to bringing the treatment to patients.”

The recommendation comes after a series of challenges Eli Lilly faced in bringing the treatment to market. In March, the FDA convened a last-minute advisory panel meeting to reassess the safety and efficacy of donanemab in a late-stage trial, just weeks before the agency’s decision deadline. This was another setback for Eli Lilly, which had anticipated approval by the end of last year. The FDA had previously rejected the drug in January of the previous year, citing insufficient data.

The FDA appears to be exercising greater caution in its review of donanemab following the controversial approval of Aduhelm, an Alzheimer’s drug from Biogen and Eisai. Despite a negative recommendation from an advisory panel, the FDA granted accelerated approval to Aduhelm. Biogen and Eisai have since discontinued the drug.

Leqembi and donanemab represent significant milestones in Alzheimer’s treatment. Both are monoclonal antibodies that target amyloid plaque in the brain, a hallmark of Alzheimer’s, aiming to slow disease progression in early-stage patients. However, neither treatment offers a cure.

Drugs that target amyloid plaque can cause brain swelling and bleeding, potentially severe and fatal. In a late-stage trial, three patients on donanemab died from such side effects, known as amyloid-related imaging abnormalities (ARIA).

Leqembi’s rollout has been hindered since its approval in July, due to the complexities of diagnosing Alzheimer’s, monitoring, and managing the required weekly infusions. Despite these challenges, Biogen and Eisai indicated in April that adoption is increasing.

In a note on Sunday, Leerink Partners analyst David Risinger predicted limited commercial uptake of donanemab compared to Leqembi, citing “more safety liabilities” and less convenience, as donanemab requires monthly intravenous infusions. Leqembi is currently administered bi-weekly, but Biogen plans to introduce an injectable version next year. Risinger expects donanemab to generate $500 million in sales by the end of the decade.

Eli Lilly’s phase three trial, involving over 1,700 patients, revealed that donanemab slowed Alzheimer’s progression by 29% compared to a placebo after 18 months, using a traditional dementia severity measure. These results are comparable to Leqembi’s.

Patients in the trial had to test positive for amyloid plaque and tau, another brain protein linked to Alzheimer’s severity. The primary analysis excluded individuals with low or no tau levels, as their condition was less likely to progress. The trial mainly targeted patients with low to medium tau levels, who showed greater benefit from the treatment.

Eli Lilly advocated for amyloid plaque testing for drug eligibility, but not tau testing, arguing it would likely limit the eligible patient population. Most advisors agreed, stating that tau testing should not be a barrier to accessing donanemab.

During the trial, patients whose brain amyloid levels dropped below a certain threshold could switch to a placebo. By the trial’s end, 60% of participants on donanemab were able to discontinue treatment. Dolan highlighted that this discontinuation option could motivate patients to adhere to their treatment regimen.

Approximately 24% of trial participants experienced brain swelling and 31% experienced brain bleeding. Most ARIA cases were mild to moderate, with serious cases occurring in 1.5% of patients with brain swelling and less than 1% with brain bleeding.

If approved, the FDA expects donanemab’s label to include a strong warning about the risks of brain swelling and bleeding, particularly for individuals with two copies of the ApoE4 gene. Recommendations for MRIs to monitor these side effects are anticipated.

There were 19 deaths among donanemab participants, including three attributed to the drug, during the 18-month trial, compared to 16 deaths in the placebo group, reflecting a slight imbalance.