Lecanemab can; now the wait for details begins

 There will be plenty of devil in the detail of lecanemab’s Clarity AD trial – whose shock success was revealed last night – but it surely represents the biggest win seen so far for Alzheimer’s disease in general, and for the amyloid-beta hypothesis in particular.

Of course, the bar was low, and the details remain under wraps until the CTAD congress on November 29. Among the unknowns are what the effect means in terms of real clinical benefit, and to what extent unblinding compromised Clarity AD. But the fact that the trial seems to have hit traditional cognitive and functional endpoints, as well as the more questionable CDR-SB measure, could be its biggest success.

Clarity AD had a sole primary endpoint of an effect on CDR-SB versus placebo. CDR-SB is a subjective tool used by doctors to make an initial assessment of a patient’s condition, but became an acceptable endpoint when in 2013 the FDA relaxed guidelines, conceding that co-primary cognitive/functional measures might prove impractical in early Alzheimer’s.

27%, p=0.00005

The headline result of Clarity AD is a 27% improvement versus placebo on 18-month CDR-SB, with Eisai boasting a p value of 0.00005, and calling the -0.45 numerical effect size clinically meaningful. By how much this actually delays the cognitive decline of a patient with early Alzheimer’s is a key unknown but, since analysts had set 20-25% as the threshold to beat, the result is a clear success.

Given the unreliability of CDR-SB the fact that Eisai said Clarity AD met “all secondary endpoints”, among which it listed the 18-month cognitive Adas-Cog14 and functional ADCS MCI-ADL scales, is highly relevant. However, while p values are said to be below 0.01, the effect sizes here have not been disclosed.

On the safety side, the brain swelling side effect Aria-E, which some think closed off the therapeutic window for other amyloid-beta MAbs, came in at a manageable rate of 12.5%. This echoes the 10% seen in the phase 2 Study 201 with lecanemab 10mg/kg biweekly (the dose tested in Clarity AD), and well below the 35% seen with Biogen’s controversially approved Aduhelm.

The comparison against Study 201 is important, as Clarity AD appears largely to exonerate that earlier trial’s debatable Bayesian analysis. While Study 201 failed its primary endpoint, 12-month change in Adcoms score across several doses, a benefit was teased out for the 10mg/kg biweekly dose at 18 months, and this drove the design of Clarity AD.

The Clarity AD result also justifies Eisai’s move to double down on lecanemab and hand the Aduhelm hot potato back to Biogen. Eisai’s lecanemab interest flowed from a 2005 deal with Sweden’s Bioarctic, while Biogen had licensed Aduhelm from Neurimmune; Eisai and Biogen had been collaborating on the two projects since 2014.

As it stands now lecanemab profits are shared 50/50 between Eisai, which closed up 17% in Japan yesterday, and Biogen, whose stock surged 40% today. Though Biogen added an amazing $11bn to its valuation, percentage-wise Bioartic was the biggest winner, climbing 160% in Stockholm.

Source: Eisai.

On an investor call Eisai directly attributed lecanemab’s success to the “arctic mutation” theory, published in 2001 in a paper by a team including Professor Lars Lannfelt, Bioarctic’s founder.

This mutation, specifically at amyloid-beta’s amino acid position 22, was found to be associated with Alzheimer’s in a Swedish family, and was further found to increase the formation of large soluble oligomers called protofibrils. Eisai says lecanemab normally targets amyloid-beta 1-16 but, when the peptide aggregates, positions 21-29 are recognised too, giving the MAb high selectivity for protofibrils.

While this might offer a neat explanation for lecanemab succeeding where all others failed, numerous questions remain. One concerns the extent to which Aria-E occurrence disclosed which patients were on lecanemab and called Clarity AD’s result into question.

Promisingly, however, Eisai said the rate of symptomatic Aria-E was just 2.8%, so there might not have been much actual unblinding. Another question is whether carriers of the ApoE4 genotype drove the benefit, and whether these were, as has been seen before, especially prone to Aria-E.

Either way, an apparent stumbling block is that patients enrolled into Clarity AD had to have brain amyloid pathology. This is typically confirmed with positron emission tomography, and a requirement for such scanning could limit lecanemab's real-world uptake.

Approvable?

That said, it is hard not to see lecanemab as eminently approvable on the available data. Eisai’s accelerated US filing, based largely on Study 201, has a January 6 action date, and the group says it is pursuing full approval, including the Clarity AD data, planning to file for this by the end of March.

But reimbursement could still be problematic. The final nail in Aduhelm’s coffin was the CMS’s extremely restrictive national coverage determination, and as it stands this relates also to other amyloid-beta drugs, even those that secure full approval backed by a cognition benefit. Eisai now urgently needs to engage with the CMS to reverse this stance.

As for a second barrier to reimbursement, lecanemab’s biweekly IV delivery, a subcutaneous formulation is in an open-label extension phase of Clarity AD.

Attention will now turn to the full Clarity AD results at CTAD, as well as to those from the phase 3 Graduate I and II trials of Roche’s gantenerumab, set to be presented at a CTAD late-breaker on November 30. After that it will be Lilly’s turn, with its latest amyloid-beta offering, donanemab, set to yield pivotal data in 2023.

Intriguingly, gantenerumab is also said to recognise amyloid-beta’s position 22, where the “arctic mutation” occurs. Roche was up 4% today.

https://www.evaluate.com/vantage/articles/news/trial-results/lecanemab-can-now-wait-details-begins