Lilly's Alzheimer's win looks like a runaway, but data are more comparable to Leqembi on a deeper dive, analysts say

The headline number from Eli Lilly’s Alzheimer’s data showing donanemab slowed cognitive decline by 36% may have grabbed eyes, but analysts see a more even comparison with Biogen and Eisai’s Leqembi when you dig a little deeper.

Plus, Lilly’s triumph is good for the amyloid-beta theory in Alzheimer’s as a whole, and it appears, the companies involved. Both Lilly and Biogen were trading higher Wednesday as the markets opened. Lilly gained nearly $18 in value to hit $422.06 per share as of 10:13 a.m. ET, while Biogen had a smaller $5 bump to $314.96 apiece.

“We believe the results seem more comparable on efficacy (than the headline suggests), safety looks better with Biogen's Leqembi (and that can matter in an elderly population with a new drug class),” Mizuho Securities wrote in a note to clients Wednesday morning.

Mizuho and SVB Securities pushed aside the headline number of a 36% slowing of decline, which Lilly calculated from a group of 1,182 patients within the trial who had intermediate tau. When the entire trial population of 1,736 is considered, donanemab demonstrated a 29% slowing of cognitive decline at 18 months—just 2% higher than what Leqembi clocked in the phase 3 CLARITY-AD trial back in September 2022.

Lilly’s announcement from the late-stage TRAILBLAZER-ALZ 2 trial did not include results in lower tau patients, which is a key difference with Eisai’s CLARITY study that focused on early Alzheimer’s.

Both analysts zeroed in on the safety data, too, which showed that donanemab had a higher rate of ARIA, including two patient deaths plus one that occurred after an ARIA event. Amyloid-related imaging abnormalities, or ARIA, has been seen with the class of amyloid-clearing monoclonal antibodies like donanemab, Leqembi and Biogen and Eisai’s earlier offering Aduhelm.

“Leqembi continues to look better here,” Mizuho said. SVB Securities agreed, noting the rate of ARIA-E (brain swelling) of 24% and ARIA-H (small brain bleeds) of 31.4%, compared to Leqembi’s 12.6% and 17.3%, respectively. Eisai also reported combined ARIA data at a rate of 21.5%, which was missing from Lilly’s release.

The rate of ARIA-E was two times that of what was seen in the Leqembi trial, Mizuho said. Symptomatic ARIA was also higher for donanemab at 6.1% vs. 2.8% for Leqembi.

An “issue to watch,” according to Mizuho, is how the deaths are handled. This “has potential to slow down donanemab uptake potentially and may be an underappreciated headwind; this will be debated, it seems,” the firm wrote.

Lilly did not flag blood thinners as a cause, and executives told Fierce Biotech that they do not believe these commonly used meds contributed to the deaths. Mizuho said the absence of that data suggests that “the blame seems to be placed entirely on drug-induced ARIA.”

"These deaths aren't related to those at all and they're small numbers, so it'd be hard to talk about any kind of correlations even if there were blood thinners involved with these patients but that does not seem to be the case here," Lilly's John Sims, M.D., head of medical, Alzheimer’s disease development, said in an interview. Sims does suspect that there will be a class-wide warning of ARIA on the label required by the FDA. 

Eisai has claimed that ARIA was not to blame for any deaths that occurred in the CLARITY study and pointed to anti-coagulant usage instead—although outside scientists have protested that and linked several deaths to the drug.

“In an elderly population, where people care so deeply for their parents and grandparents, in a new drug class, safety can become a big underline in the conversation when reality is met with having to make a decision; pick your drug,” Mizuho said.

Lilly for its part acknowledged the risk but said—similar to what Eisai has—that patients will need to understand the risks and benefits. The Indianapolis Big Pharma hopes that the efficacy will outweigh any concerns.

Another thing Lilly touted is that patients took the drug for a year or 18 months, stopping when plaque clearance was achieved. But Mizuho notes that the plaque clearance levels were similar between donanemab’s phase 2 trial and Leqembi at 18 months.

“So while, the street mantra may be a bit stronger that donanemab may get used finitely, and Leqembi would be chronic, I struggle here—the PET scans show amyloid negativity at 18 months is very similar between the compounds (and we're talking about the same disease here),” Mizuho said.

Lilly may have the edge on dosing, as donanemab only needs to be infused once monthly, compared to Leqembi’s twice a month. That could help commercially, Mizuho said. But donanemab treatment requires two PET scans, one each for amyloid and another for tau, which could further complicate reimbursement discussions with the Centers for Medicare and Medicaid Services. Lilly could also receive a label restriction to only patients with intermediate tau, which was the target of this study analysis.

SVB Securities, meanwhile, was hoping for more answers on a few items, including data on carriers of the ApoE4 gene, which is one of the strongest risk factors for Alzheimer’s. A post-hoc analysis of previous research suggested that donanemab could be particularly effective in these patients, but Lilly has not yet released that information. Leqembi has shown a higher treatment effect in patients who do not carry the gene, SVB Securities noted. The firm would also like to see data on the time at which separation of clinical decline began in relation to placebo, discontinuation rate, the all-ARIA rate and more information on ARIA vs. placebo.

Lilly promised to present more data at the Alzheimer's Association International Conference in July.

While analysts parsed the nitty gritty details, the Alzheimer’s Association heralded the study as the “strongest to date,” and used the opportunity to urge CMS to reconsider its coverage determination limiting reimbursement to only patients participating in clinical trials.

"These are the strongest phase 3 data for an Alzheimer's treatment to date. This further underscores the inflection point we are at for the Alzheimer's field. The progress we've seen in this class of treatments, as well as the diversification of potential new therapies over the past few years, provides hope to those impacted by this devastating disease," said Maria Carrillo, Ph.D., chief science officer of the Alzheimer's Association. "Yet, Medicare stubbornly continues to block access for the people who could benefit."

Mizuho, for its part, thinks that Lilly’s data could boost the overall class.

“If anything, today's news is good for the beta-amyloid class as a whole, continues to validate the beta-amyloid hypothesis, and should help commercial/reimbursement overall,” the firm wrote.

Mizuho expects sales of $10 billion for Leqembi, which could move higher thanks to Lilly’s news today, but did not provide an estimate yet for donanemab.