Biogen primes investors for a lecanemab data dredge

Clarity AD could yield a range of scenarios, and Biogen isn’t ruling out dredging secondary endpoints if the primary fails.

With Aduhelm confirmed as a disaster, the effectively rudderless Biogen today primed investors for its next big Alzheimer’s readout, the Clarity AD trial of lecanemab, and many might be rolling their eyes at the prospect of yet another failed amyloid-beta MAb study being data dredged.

Clarity AD has CDR-SB as its primary endpoint, and Biogen stressed that it was gunning for a positive win here for lecanemab against placebo. But Priya Singhal, interim R&D head, said the group was considering a range of scenarios for the readout, due in the third quarter, adding: “The totality of the data will be very important.”

This statement came in response to a question about what the company would do if Clarity AD failed on CDR-SB yet showed numerical improvement in one or more secondaries. Clarity AD enrolled 1,795 early Alzheimer’s patients, and secondary measures include changes in PET and measures on the Adas-Cog14, Adcoms and ADCS-ADL scales.

Consider a spectrum

Ms Singhal said there was a spectrum of Clarity AD outcomes, with a positive primary hit at one end and outright failure at the other. “There could be several mixed scenarios, there could be several permutations or combinations. We are considering all of this.”

Biogen insists that a statistically significant effect in Clarity AD on CDR-SB would be clinically meaningful. How the FDA would consider anything else, especially after the storm whipped up by its controversial approval of Aduhelm, is another story.

And the same goes for reimbursement. The US Centers for Medicare & Medicaid Services famously slammed Aduhelm, denying broad coverage to any amyloid-beta drug that had not demonstrated a meaningful benefit on cognition and function in a controlled trial. Ms Singhal said if Clarity-AD was positive it “could meet the bar for full CMS coverage”.

The lecanemab timeline
Phase 2 Study 201 final 18-month analysis Jul 5 2018
Aduhelm approved on accelerated basis Jun 7 2021
Rolling lecanemab filing for US accelerated approval Sep 27 2021
FDA acceptance of lecanemab AA filing Jul 5 2022
Readout of confirmatory Clarity AD trial Due Q3 2022
Pdufa date for lecanemab accelerated approval Due Jan 6 2023
Filing for full lecanemab approval based on Clarity AD Possible in Q1 2023
Source: company statements.

In theory lecanemab could be approved in the absence of any Clarity-AD data. Its filing, handled by Eisai, is on an accelerated basis and has been set a January 6, 2023 Pdufa date. But no one realistically expects the FDA to issue a green light in the absence of confirmatory data.

Biogen today confirmed that Clarity AD could serve as the necessary confirmatory trial, and should it be positive the data would be incorporated into an application for full approval by the end of the first quarter. “At this moment we do not have the indication than an adcom will be necessary,” said Ms Singhal.

Still, the likeliest outcome given the track record of amyloid-beta MAbs is that Clarity-AD is a bust. Tellingly, Biogen has moved to dismantle its commercial infrastructure around Aduhelm; should lecanemab somehow succeed this would need to be rebuilt.

Sales of $0.1m

Second-quarter numbers laid bare the Aduhelm disaster. Biogen took a $71m restructuring charge to cover the effective winding up of a drug that sold $0.1m in the quarter; this brought Aduhelm cumulative revenues since it was approved in June 2021 to a measly $5.9m. After Eisai disentangled itself from Aduhelm it reimbursed $46m of costs incurred by Biogen.

Though Biogen today threw investors the crumb of increased full-year earnings guidance, on the R&D front there was further disappointment: it quietly slipped out the failure and discontinuation of BIIB104, an AMPA agonist, in the phase 2 Tally study of cognitive impairment associated with schizophrenia.

Biogen has also discontinued an anti-Tau antibody, BIIB076, in Alzheimer's and the exportin 1 inhibitor BIIB100 for ALS.

These are no longer realistic concerns for the group’s chief executive, Michel Vounatsos, who is paying the price for Aduhelm and staying on only until a successor is found. On this front Biogen would only say an executive search was proceeding as planned.

It would be naïve to expect an appointment, or indeed any major strategic decisions, before Clarity AD reads out.

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