Donanemab delivers for Lilly

Pivotal data on the Alzheimer’s project beat expectations, raising hopes for a swift reimbursement U-turn.

Hopes were already high for success in Trailblazer-Alz 2, Lilly’s confirmatory pivotal donanemab trial, and topline data do not fail to impress. Efficacy measures beat expectations, and on the surface seemed to surpass the results generated by Eisai's rival, Leqembi.

Still, with three patient deaths linked to the brain swelling disorder Aria-E, donanemab continues to look like a more toxic option. Full study details remain crucial to know, but the headline hit was enough for investors to send Lilly shares up 4% in early trade, boosted by an assumption that this strong showing will swiftly open the doors to more lenient reimbursement in the all-important US market.

A second hit with an anti-amyloid beta MAb will certainly ramp up the pressure on the US Centers for Medicare & Medicaid Services (CMS) to change its stance; last year the agency introduced stringent reimbursement criteria for this class of drug. Until this shifts sales of neither Leqembi nor donanemab – assuming they both win full approval – can take off in the US.

Eisai and its marketing partner Biogen expect to receive full approval for Leqembi by July. Lilly today said it would file donanemab with the FDA this quarter; the company was knocked back on accelerated approval in January.

Stacking them up

As both agents now look likely to reach the market, attention turns to donanemab and Leqembi’s relative advantages. Making any rigorous comparison before full Trailblazer-Alz 2 data is tricky, however, and of course the usual caveats of cross-trial comparisons apply here.

One important difference between Clarity-AD and Trailblazer-Alz 2 is Lilly’s use of patient stratification via Tau expression levels, which was measured by PET scan. High Tau is associated with rapid disease progression, and these patients were excluded from the primary endpoint, which was run only on the intermediate Tau cohort.

The relevance of such a measure when it comes to real-world use is an open question, as many doubt that Tau imaging will be used in clinical practice to guide the use of these drugs – unless the FDA makes this a requirement of donanemab’s approval.

That future consideration aside, donanemab’s result in the combined intermediate and high Tau group arguably makes for a better comparison against Leqembi; Eisai used an all-comers approach regarding Tau in its trial. And on the CDR-SB endpoint the agents look pretty similar when this broader patient group is considered.

Stacking up the Alzheimer's Mabs
  Donanemab (Trailblazer-Alz 2) Leqembi (Clarity-AD)
Tau level Intermediate tau (primary endpoint) Combined intermediate and high tau N/A
CDR-SB (relative slowing vs placebo) 36% 29% 27%
iADRS (relative slowing vs placebo) 40% 23%
ADCS-iADL (relative slowing vs placebo) 43% 28% 37%*
Adas-Cog (relative slowing vs placebo) 35%** 19%** 26%**
Aria-E 24% 13% 
Symptomatic Aria-E 6% 3%
Aria-H (microhaemorrhages) 31%  17%
Notes: all mixed model for repeated measures (MMRM) statistical analysis; CDR-SB = Clinical Dementia Rating-Sum of Boxes; iADRS = integrated Alzheimer's Disease Rating Scale; ADCS-iADL= Alzheimer's Disease Cooperative Study – instrumental Activities of Daily Living Inventory; Adas-Cog = Alzheimer's Disease Assessment Scale – Cognitive. *Clarity-AD used ADCS ADL-MCI, adapted for mild cognitive impairment subjects. **Trailblazer Alz 2 used Adas-Cog13 and Clarity-AD used Adas-Cog14. Sources: company releases & CTAD presentation.

Throw in donanemab’s more serious toxicity, with around double the rate of Aria-E, and any decision to use the Lilly MAb over Eisai’s offering becomes even harder to make.

Perhaps the answer to these considerations will become more obvious on full presentation of Lilly’s data, which is slated for the Alzheimer's Association International Conference in July. Other issues that need further clarity include the three Aria-E deaths that occurred in Trailblazer-Alz 2, while a closer look at certain subgroups will be of interest, for example those with a genetic predisposition to developing Alzheimer’s.

The performance of the high-Tau cohort is also likely to come into focus. Analysts at Evercore ISI calculated a relative -13% efficacy versus placebo on the iADRS endpoint for this group. 

With Biogen shares opening 1% higher this morning, after earlier trading down around 4% in the premarket, it is clear that there are more nuances to this result than the impressive topline hit suggests.

These results and those of Leqembi leave much room for improvement, on both efficacy and safety. But it hard not to see this as a step forward for the Alzheimer’s space, from which Biogen, Eisai and Lilly will all benefit.

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