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In unanimous votes, FDA advisory committee favors approval of Lilly’s donanemab

Jun 17, 2024

Eli Lilly gained serious momentum last week in its quest for FDA approval of donanemab, an investigational treatment for early Alzheimer’s disease.

Lilly had hoped to receive accelerated approval of donanemab earlier this year, but the FDA declined to grant it.

The regulatory agency was scheduled to decide on the drug’s fate in March but extended the decision deadline to allow time for input from a panel of independent experts. The Peripheral and Central Nervous System Drugs Advisory Committee met last Monday to discuss specific topics pertaining to the design of the drug’s pivotal trial and the outcomes.

In the Phase III TRAILBLAZER-ALZ 2 trial, enrollees underwent PET imaging to evaluate the presence and level of tau in their brains. Tau, a protein that forms after amyloid accumulates, appears to correlate with the severity of cognitive impairment. Those with no or very low tau were excluded, and Lilly focused primarily on participants with low to medium levels of tau (indicating an earlier stage of the disease).

While those with higher tau levels (indicating more advanced disease) were included in the overall study population, Lilly said it would likely be more difficult to determine a treatment effect in these participants. Slightly more than two-thirds of the 1,736 participants were in the low/medium tau group and the remaining participants were in the high tau group.

The FDA asked the panel of experts to weigh in on Lilly’s use of tau imaging in the trial, the exclusion of enrollees with no or low tau, and the fact that Lilly did not request that tau imaging be used to screen potential patients before starting treatment with donanemab in routine clinical practice.

The committee’s chairperson, Dr. Thomas Montine, said most of the panel members believed that requiring tau imaging would present an unnecessary barrier that would restrict access to the drug.

The trial results demonstrated that participants with intermediate tau levels experienced a significantly slower decline during treatment — measured using two different scales — as compared with those having higher levels of tau (and compared with placebo).

In separate votes, the committee voted 11-0 that 1) the available data supports the effectiveness of donanemab in individuals with mild cognitive impairment and mild dementia, and 2) the drug’s benefits outweigh its risks in these same individuals.

Dr. Kathleen Poston, also a member of the panel, said the biomarker data “were convincing of the effect,” adding, “the benefits outweigh the risks, as long as the risks are being monitored.”

Like other drugs in its class, donanemab appears to increase the risk for amyloid-related imaging abnormalities (ARIA), particularly ARIA with edema or effusion (ARIA-E; brain swelling) and ARIA with microhemorrhages and hemosiderin deposits (ARIA-H; brain bleeding). In most cases, ARIA is asymptomatic and resolves with time, though it can be severe and sometimes fatal. Individuals with a certain genetic form of Alzheimer’s are at higher risk of developing ARIA.

In the TRAILBLAZER-ALZ 2 trial, 24% of the participants in the donanemab group experienced ARIA-E and 31.4% experienced ARIA-H. Three ARIA-related deaths were attributed to treatment with donanemab.

In documents Lilly provided ahead of the committee meeting, the company wrote, “Beyond the known class-risk of ARIA with a low frequency of fatal events (0.03%), there is no evidence of an increase in risk of mortality or excess death related to donanemab.”

Dr. Cynthia Carlsson, another panel member, said steps to manage ARIA could be implemented, and risks could be “safely clarified with a proposed MRI program and training.”

Advocates for patients with Alzheimer’s had the opportunity to provide comments during the committee meeting. Several noted that people living with the disease face certain decline and death, and that even modest benefits are worth the risks associated with treatment.

The FDA also asked the panel members for their opinions on a unique aspect of TRAILBLAZER-ALZ 2: Trial participants stopped taking donanemab when scans showed they had achieved clearance of amyloid.

Overall, the committee members thought that stopping treatment would be beneficial for patients who no longer need to be on the drug, but they questioned how clinicians would be able to determine when patients should undergo additional PET scans to assess the absence of amyloid.

Dr. Montine, the committee chair, said the trial design prompts questions about the duration of the drug’s benefit, how to monitor patients between the time they stop and resume treatment, and what kind of side effects patients might experience during the cessation period or when they restart treatment.

“We just don’t know the answer to any of these things,” he said, noting that his feeling after listening to comments during the hearing “is the committee feels that this is an innovative and positive outcome of the way the trial was designed.”

The panel suggested that additional testing might provide answers to some of the questions. Some committee members also urged Lilly to study the drug in a more diverse population, including more Black patients, Hispanic patients, and patients with Down syndrome or autosomal dominance Alzheimer’s disease.

However, the committee members did not think a lack of evidence for these subgroups of the population should delay making the drug available to the public.

The FDA has not set a date for deciding whether to approve donanemab. The agency usually follows the recommendations of its advisory committees.

Our Take: If the FDA approves donanemab, which we expect to happen fairly quickly now, then Eisai and Biogen will have a rival for their approved Alzheimer’s treatment, Leqembi (lecanemab-irmb), which, like donanemab, is an anti amyloid antibody.

Leqembi was approved in January 2023 on an accelerated basis, and the drug received traditional approval last July.

No head-to-head trials have been conducted to compare Leqembi and donanemab, but the results of trials that have been conducted seem to suggest that Leqembi may have a preferable safety profile.

Paul Matteis, an analyst with Stifel, wrote in a client note that Leqembi’s “clear safety advantage is a huge deal for risk-averse neurologists, especially for a drug class where the magnitude of efficacy continues to be debated,” Biopharma Dive reported.

But some physicians may choose to initiate treatment with donanemab because of its dosing schedule. It requires infusions once every four weeks, whereas Leqembi is infused every two weeks.

Although additional studies may reveal more distinctive differences between the two drugs, in the interim, some industry analysts believe donanemab’s approval could increase sales of Leqembi.

“A rising tide lifts all boats, in our view,” wrote Myles Minter, an analyst as William Blair, according to Biopharma Dive.

Marc Goodman, an analyst at Leerink Partners, wrote that donanemab’s approval could “accelerate the uptake of this class by helping build the commercial infrastructure” the drugs need.

And Michael Yee, with Jefferies, noted that having a choice of two drugs would serve to raise awareness among physicians and patients.

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