Lilly looks for fast approval for experimental Alzheimer’s drug

Changing Course

In April, a top company executive at Eli Lilly told investors that Lilly did not anticipate submitting its experimental Alzheimer’s medicine donanemab for an accelerated approval based on the clinical trial evidence it had accrued. Then, the FDA “controversially cleared Biogen’s Alzheimer’s drug Aduhelm on a conditional basis, citing the therapy’s effect on brain plaques associated with the disease. Donanemab works similarly,” reported Ned Pagliarulo, lead editor of?BioPharma Dive.

Now Lilly, in a reversal, is?seeking accelerated Food and Drug Administration approval for donanemab, announcing on June 24 plans to file an application with the agency later this year. The FDA has granted Breakthrough Therapy designation for donanemab, which means closer collaboration between the agency and the company and expedited review. Lilly shares went up by nearly 8 percent in pre-market trading after the news.

According Pagliarulo, “The FDA’s accelerated approval of Aduhelm appears to have set a precedent that Lilly is now following. In clearing Aduhelm, the agency based its decision on how well the drug removed the sticky clumps of amyloid, a key protein in Alzheimer’s, from the brain. This reduction in amyloid, the FDA said, was ‘reasonably likely’ to translate to slower cognitive decline in patients with the disease.”

As previously reported, the approval is very controversial. The link between amyloid clearance and clinical benefit is highly debated. In addition, evidence from two big clinical trials of Aduhelm was contradictory with one study showing treatment with a high dose leading to an approximately 20 percent slower decline in cognition and function than did placebo and the other not showing those results. Many experts feared that the alleged effectiveness in the first trial could be a “false positive” result.

Other than the team doing a statistical review of the Biogen results, FDA officials appear to be convinced that the Biogen decision was right and have strongly defended their position. The announcement from Lilly leads to speculation that the FDA may consider similar approvals, a scenario that caused Lilly shares to rise even before the company’s intentions were made clear.

A Phase 2 study, published in?The New England Journal of Medicine, shows that Lilly’s drug drastically reduced amyloid plaque in the brains of clinical trial participants. By 76 weeks, the end of the study, roughly 68 percent of the 131 patients who had gotten donanemab were negative for brain amyloid. The researchers said that there was slower cognitive and functional decline, as measured by a rating scale, among donanemab-treated patients. While the results were encouraging, some experts questioned the degree of benefit. The article also showed treatment with donanemab did not meet several secondary goals of the study, but the clinical trial’s small size made that harder to accomplish.

According to David Knopman, a neurologist and Alzheimer’s specialist at the Mayo Clinic, “[Donanemab] actually did move the needle a tiny bit in the context of dramatically clearing amyloid, but the effect size in the donanemab trial was very small. Is that the best we can do?”

If Lilly has accelerated approval, it will not need conclusive proof that donanemab results in significant clinical benefit, only that its effects are likely to predict an eventual improvement. “The drug’s clear impact on amyloid, following the FDA’s acceptance of amyloid reduction as a surrogate marker for Aduhelm’s efficacy, could be enough for the agency to agree to review the drug,” Pagliarulo said.

“We think it would make zero sense for FDA to approve Aduhelm, but not donanemab,” said Brian Skorney, an analyst at Baird who has been critical of the data supporting Aduhelm.

Lilly has already started a Phase 3 study of donanemab that could yield results by mid-2023. If the drug were to be approved, it could serve as a confirmatory study. Biogen has not begun a required confirmatory trial of Aduhelm. Skorney said that Aduhelm’s accelerated approval and Lilly’s decision to ask for the same could “be the beginning of a broader trend” that might see other amyloid-targeting drugs submitted to the agency. Roche is still developing a treatment that had previously failed in late-stage studies.