Eli Lilly’s Donanemab: The Anti-Amyloid Saga Continues (NYSE:LLY)

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Eli Lilly’s (NYSE:LLY) data for its anti-amyloid drug candidate donanemab continues a pattern of less than stellar results for this class of drugs (although one would not suspect this from their press release). 47 percent of patients with mild to moderate Alzheimer’s disease who took the drug and 29 percent of those on placebo showed no decline in disease severity on the Clinical Dementia Rating Scale – Sum of Boxes. These patients did not remain cognitively stable, they simply did not advance to a more severe stage.

The specific cognition numbers for donanemab are quite similar to other anti-amyloid drugs. Eli Lilly divided its results between a group with intermediate tau levels and a combined intermediate and high tau level group (high tau levels may represent further disease progression):

Intermediate Tau Group

• 36% slower decline in CDR-SB scores
• 40% slower decline in integrated-Alzheimer’s Disease Rating Scale (iADRS combines cognitive and activities of daily living measures).

Combined Intermediate and High Tau Group

• 29% slower decline in CDR-SB scores
• 23% slower decline in iADRS scores

Eli Lilly could have just compared the results between those with mild Alzheimer’s disease and moderate Alzheimer’s disease or at least between the intermediate tau group and the high tau group but chose to make the numbers look better by combining the intermediate and high tau groups. But in essence, Eli Lilly is still acknowledging what is already known: the further advanced one is in Alzheimer’s Disease the less effective anti-amyloid drugs become. Or as Eli Lilly put it:

The study also enrolled a small number of people with high levels of tau at baseline (n=552), representing a later stage of disease progression… suggesting they would be less likely to respond to treatment.

That is a safe disclaimer for Eli Lilly to make as the FDA would not approve donanemab for moderate to severe Alzheimer’s disease any way (although it once considered doing so for Aduhelm without any clinical trial evidence to do so).

But what Eli Lilly left out this time is that the drug has no significant effect on non-APOE4 carriers. Eli Lilly acknowledged such last year:

Relationships between amyloid reduction and iADRS scores were significant in APOE4 carriers, but not in participants without APOE4 which may be due to relatively few noncarriers in TRAILBLAZER-ALZ or pharmacogenomics difference in treatment response, the researchers noted (source of quote).

The answer is that only APOE4 carriers have enough amyloid in their brain for it to contribute to the early progression of Alzheimer’s disease (study).

The FDA [Food and Drug Administration] did approve Aduhelm/aducanumab even though it knew the drug had no significant effect on non-carriers and the agency may well do so again for both Eli Lilly’s donanemab and Biogen (BIIB) and Eisai’s (OTCPK:ESALF) Leqembi/lecanemab (FDA statistician report, p. 12/58). However, even if the FDA were to look the other way again, Medicare would be unlikely to extend coverage to non-carriers if the real data was known. This may be why Eli Lilly and Biogen and Eisai have taken pains to obscure past results in this regard (previous article).

Added to this is the spectre of deaths from amyloid removing drugs due to brain bleeds and brain swelling. With varying degrees of certainty, three deaths have been attributed to donanemab and three deaths to Leqembi/lecanemab. These numbers will surely increase if either drug is widely prescribed. One has to ask the following question: is the risk of severe complications that can result in death worth it for drugs whose effects on disease progression might not even be clinically significant (analysis)?

By far the safest anti-amyloid drug for Alzheimer’s disease is Alzheon’s ALZ-801 (valiltrampirosate). Rather than removing amyloid, ALZ-801 prevents amyloid monomers from aggregating into oligomers and plaques. An earlier version of the drug – trampirosate produced the following results:

Highest efficacy was observed in APOE4/4 homozygotes receiving 150 mg BID [twice daily] of trampirosate showing statistically significant effects on ADAS-cog and positive trends on CDR-SB (respectively, 40-66% and 25-45% benefit compared to placebo). APOE4 heterozygotes showed intermediate efficacy, and non-carriers showed no benefit. In 426 patients with MRI scans, no cases of treatment-emergent vascogenic endema were observed. In the three subgroups, the most common adverse events were nausea, vomiting, and decreased weight (source of quote).

Alzheon’s goal is to submit an application for approval of ALZ-801 to the FDA in two years. That is not on the radar of investors in Eli Lilly, Biogen, and Eisai but it should be. ALZ-801 is just as effective as donanemab and Leqembi (formerly lecanemab), but far safer.

The Alzheimer’s Association and other advocacy groups, along with several high profile politicians are putting pressure on Medicare to provide full coverage for Leqembi and donanemab (article). This campaign borders on unseemly considering that the drugs have no significant impact on non-carriers, very modestly slow down disease progression in APOE4 carriers, and can lead to severe side effects and even death in APOE4 carriers. Medicare has pledged to expand coverage for lecanemab and donanemab upon FDA approval (which now seems quite probable), but may do so only where data is being collected (policy).

I predicted a few months ago that Biogen was unlikely to go under 200 points and Eli Lilly was unlikely to go over 300 points. Bad prediction. Biogen is now over 300 points and Eli Lilly is over 400 points. Eli Lilly is currently slightly above the level Biogen was after the approval of Aduhelm. Both companies, of course, have other important approved drugs and other drugs in their pipeline, but Alzheimer’s disease to a large extent is still driving the price action. The short-term prospects for both companies are good. But future Medicare actions, additional deaths, and the possible approval of ALZ-801 are all wildcards that could significantly lower the stock values of Eli Lilly and Biogen.

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