Eli Lilly's Alzheimer's drug to face safety, dosing scrutiny from FDA advisers

By Eleanor Laise

Approval would trigger new competition for Biogen and Eisai's Leqembi

When a Food and Drug Administration advisory panel meets Monday to size up Eli Lilly & Co.'s experimental Alzheimer's drug donanemab, questions about safety, selection of patients for treatment, and dosing will be at the fore, documents released Thursday show.

In a briefing document prepared for the advisory committee, the FDA raised questions about a unique aspect of the donanemab clinical trial: Patients taking the drug were eligible to be switched over to a placebo if their levels of amyloid, a hallmark of Alzheimer's disease, fell below a certain threshold. There was no comparison group to show outcomes in similar patients if they had continued treatment, so "there remains uncertainty regarding the optimal treatment regimen" for patients whose amyloid falls to low levels, the FDA said in the document.

Among the key safety considerations, the FDA said in its report, are amyloid-related imaging abnormalities, which often appear as temporary brain swelling but can also lead to brain bleeding and may be severe. That side effect has also been a concern for patients taking Biogen Inc. (BIIB) and Eisai Co. Ltd.'s (ESALF) Leqembi, a similar treatment that was approved last year.

Monday's meeting will be closely watched by investors who are wondering how well donanemab might compete against Leqembi, which has had a relatively sluggish launch, as well as patients and doctors looking for new treatment options. Nearly 7 million people in the U.S. are living with Alzheimer's, according to the Alzheimer's Association, which projects that figure will rise to nearly 13 million by 2050. After a long dry spell for pharmaceutical companies trying to develop new Alzheimer's treatments, decades of scientific research are "just starting to pay off," Howard Fillit, a geriatrician and co-founder and chief science officer of the Alzheimer's Drug Discovery Foundation, told MarketWatch.

Overall, documents released in advance of the meeting "appear bullish on approval," William Blair analysts said in a research note Thursday. Lilly's stock (LLY) hit a new all-time closing high after the FDA briefing documents were posted Thursday, and the shares have gained 43% in the year to date.

The gathering of expert advisers was set after the FDA surprised Lilly earlier this year with the news that it would convene a panel meeting to review the phase 3 study of donanemab. That move delayed the FDA decision on donanemab's approval beyond the expected time frame of the first quarter and temporarily weighed on Lilly's stock.

"Lilly recognizes the societal importance of ensuring that this emerging class of amyloid-targeting disease-modifying therapies for Alzheimer's disease are well characterized, with favorable benefit-risk profiles," the company said in a statement Thursday. "We look forward to the opportunity to share the clinically meaningful data demonstrated in clinical trials of donanemab."

Despite the multiple questions raised, the FDA document broadly "does not question the efficacy of donanemab in the treatment population," BMO Capital Markets analyst Evan David Seigerman said in a report Thursday.

The advisory committee is set to discuss whether donanemab is effective for the overall patient population studied or only certain subgroups, factors that might guide decisions on stopping or continuing donanemab dosing, and whether the treatment's benefits outweigh its risks.

A quarter of patients treated with donanemab in the Lilly study had microhemorrhages linked with amyloid-related imaging abnormalities, the FDA noted in its briefing document, compared with 11% of those on placebo.

Examining the rate of deaths among patients treated with donanemab versus a placebo, the FDA said it had asked Lilly for additional details on patients who dropped out of the trial early. Although Lilly got some of that data, it doesn't reveal the cause of death, the agency said. After factoring in the newly collected data, 2% of donanemab-treated patients died within 76 weeks of starting treatment, compared with 1.7% of patients on placebo, Lilly said in its report.

Given that Lilly's trial stopped donanemab treatment for patients whose amyloid fell below certain levels, "there remains no effective true comparison to assess the merits of treating and stopping treatment," Seigerman said in the research note. That may not be a concern for the drug's approval but could be a practical consideration for doctors, Seigerman said.

If donanemab treatment is halted, "the question becomes, what do we do about restarting the drug as amyloid starts to reaccumulate?" Fillit said.

Pausing donanemab treatment when amyloid falls below certain levels, however, could ultimately save a lot of money, Fillit said, by cutting down infusion costs. "The stopping rules are economically a big advantage for society and for individuals," he said.

The FDA also noted that patients with very low levels of tau, a protein that has been linked with Alzheimer's disease severity, were excluded from Lilly's trial, and that the company focused its analysis on patients with low to medium tau levels. Lilly did not propose that confirmation of tau levels be required before prescribing donanemab, the FDA said.

Lilly said in its briefing document that the trial's efficacy results support treatment of patients regardless of tau level. The company also conducted a separate study that included patients with no or very low tau and found positive treatment responses.

Ultimately, drugs like donanemab are likely to be used in combination with other novel treatments for Alzheimer's disease, Fillit said. Many novel Alzheimer's drugs now in development are designed to combat inflammation, he said, which has also been recognized as a factor contributing to the disease.

-Eleanor Laise

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06-07-24 0845ET

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