Impact of Donanemab Approval on Leqembi

Earlier this month, an FDA advisory committee concluded that Eli Lilly’s anti-amyloid antibody, donanemab, is an effective treatment for Alzheimer’s disease, with its benefits outweighing the risks. Experts are optimistic about the therapy and suggest that donanemab's approval could also boost the market for Biogen and Eisai’s Leqembi, another anti-amyloid antibody approved last year.

Myles Minter, a research analyst at William Blair, stated that donanemab could be part of the first disease-modifying drug class for Alzheimer’s disease. “The more options available, the more companies in that market, getting people in for amyloid scans, and getting people into infusion centers. I think a rising tide lifts all boats,” Minter noted. Many experts anticipate that donanemab will eventually receive approval.

“The FDA clearly holds a positive stance regarding donanemab’s potential approval,” Minter added, mentioning that the briefing documents released before the advisory committee meeting were highly favorable for approval with a comprehensive label.

The advisory committee’s discussion on donanemab focused on issues of trial design and safety. The FDA scrutinized Lilly’s use of its integrated Alzheimer’s Disease Rating Scale (iADRS) as the primary endpoint for Phase III trials and its criteria for enrolling patients based on tau protein levels. Patients with no or very low levels of tau were excluded from the study.

Despite the lack of clinical data for the low- and no-tau population, biomarker data showing similar amyloid reduction swayed the advisory committee members. This was reported by Evan Seigerman, managing director and senior research analyst at Bank of Montreal Capital Markets.

In terms of safety, experts expected more debate around amyloid-related imaging abnormalities (ARIA), which was a significant concern during the approval process for Leqembi. Lilly reported that ARIA was observed in donanemab trials, manifesting as temporary swelling in brain areas (ARIA-E) or as microhemorrhages (ARIA-H).

“I was surprised by the general lack of discussion about ARIA” in the donanemab advisory committee meeting, Minter commented, noting the potential risks of strokes and interactions with anticoagulants. He pointed out that donanemab showed a higher incidence of ARIA compared to a placebo.

In the Phase III TRAILBLAZER-ALZ 2 study, ARIA-E occurred in 24% of patients, with 6.1% experiencing symptomatic ARIA-E, while ARIA-H occurred in 31.4% of donanemab-treated patients compared to 13.6% on placebo.

Paul Matteis, managing director and head of therapeutics research and biotechnology at Stifel, remarked that the ARIA discussion could have been more nuanced and possibly less favorable for donanemab. Minter concurred, indicating that Leqembi might present a lower risk of ARIA.

The ARIA monitoring protocol for donanemab remains undetermined and may become a labeling issue. Leqembi’s label recommends enhanced clinical vigilance for ARIA during the first 14 weeks of treatment.

Other experts were struck by the advisory committee’s focus not on whether to approve donanemab, but on its prescribing requirements. Rajesh Kumar, head of life sciences and healthcare equity research at HSBC, highlighted that the committee debated diagnostic needs to minimize the burden on doctors, ensuring broader patient access.

If approved, donanemab will compete directly with Leqembi, which received full FDA approval last July. Kumar forecasts that donanemab could achieve peak sales of $8 billion, with a conservative estimate of $4 billion. Analysts project Leqembi’s peak sales to range between $3 billion and $12.9 billion.

The committee noted a logistical advantage for donanemab, which is administered once a month compared to Leqembi’s bi-weekly dosing. Donanemab requires around 30 minutes of treatment followed by a 30-minute monitoring period, whereas Leqembi’s regimen involves 30 minutes to an hour of treatment followed by three hours of monitoring. However, Leqembi’s potentially lower ARIA risk could be advantageous.

The increased ARIA rate with donanemab may diminish some of its convenience benefits if more MRI scans are needed to monitor the condition, Matteis added. He believes that while there is a place for both drugs, safer treatments like Leqembi might gain more market share, as seen in other neurology fields.