UPDATE: Roche, Biogen temper Alzheimer's expectations in Q2 calls. Will Lilly follow suit in August?

A year ago, the Alzheimer’s drug development scene exploded with excitement after the approval of Biogen and Eisai’s Aduhelm. Major pharmaceutical companies were in a moment where they saw the possibility of their experimental therapies getting approved and gaining a foothold in the market.

But now, executives from two of the three major players that have reported second quarter earnings so far—Roche and Biogen—seem to be tempering expectations for success.

The third leading Alzheimer’s developer, Eli Lilly, will report its second quarter updates on Aug. 4, leaving an important question on how the Alzheimer's drug development field will shape up this year.

Roche CEO Severin Schwan called the company’s Alzheimer’s therapy gantenerumab “a high-risk project” Thursday during an investor call. The Swiss pharma is awaiting a crucial readout from the phase 3 Graduate 1 and 2 studies later this year. 

“I’d say we plan for a situation where it doesn’t come through,” he said of the expected late-stage results. He stressed that the company does not have any new information that would hint at a failure for the upcoming readout, but he’s simply being cautious and realistic. Roche has always been a bit more restrained in its commentary and clinical development surrounding gantenerumab, opting to finish the late-stage trials rather than seek accelerated approval like its peers Biogen and Lilly. 

“Of course, if it is positive that would be transformative,” said Schwan, who announced he will soon step away from the CEO role and diagnostics division chief Thomas Schinecker, Ph.D., will take his place. “I say let’s hope for the best but not plan on that basis.”

Schwan’s comments came a little more than a month after Roche unit Genentech announced the disappointing phase 2 failure of crenezumab in early Alzheimer’s. The setback was a sobering reminder of the brutal drug development scene that has always plagued the neurodegenerative disease, despite a year of intense interest in the wake of Aduhelm's accelerated approval.

The day before the crenezumab news, Biogen executives took a similar stance when discussing the company’s therapy, lecanemab, which is also being developed with Eisai. Priya Singhal, head of Global Safety & Regulatory Sciences and interim head of Research & Development, said that the upcoming results from the phase 3 Clarity trial should tell the company—and the world—more about the effects of removing amyloid from the brain in patients with Alzheimer’s.

But, after touting the upcoming results, Singhal later tempered expectations when asked by an analyst what would happen if Clarity is not a clear success on the primary goal.

“We believe that the totality of the data will be really important,” Singhal said. “It's possible that the study is negative,” she acknowledged, before pointing to Lilly’s upcoming late-stage read out for donanemab and Genentech’s gantenerumab as two other anti-amyloid therapies that can help speak to the larger theory of amyloid in Alzheimer’s.

“So really this is a bigger question about these readouts and what they mean for the anti-amyloid hypothesis in early Alzheimer's disease,” Singhal said.

Clarity is also designed as a confirmatory study, which if positive could switch the Biogen and Eisai's requested accelerated approval into a full, regular approval next year.

This is crucial, because—in a precedent set by Biogen’s own Aduhelm—the Centers for Medicaid & Medicare Services will only provide coverage for patients involved in an approved clinical trial for monoclonal antibodies approved under the accelerated pathway for Alzheimer’s disease.

There could be several scenarios if the Clarity results are mixed, such as a miss on the main goal but encouraging results on some secondary endpoints. Singhal declined to speculate on the different scenarios or what Biogen might do but said the company is considering “all of this.”

“Currently, our focus is on ensuring that we collect the data, close the study, have a very clear readout, and then we will be engaging, of course, with the FDA,” Singhal said. Lecanemab has breakthrough and fast-track designation from the agency, giving Biogen closer contact with regulators as the therapy moves through the clinic.

Singhal said the Clarity trial is well designed to show that lecanemab can produce clinically meaningful results such as improvement on a scale that rates Alzheimer’s severity. The FDA has indicated that it will accept a measure like this to support a regulatory approval, according to Singhal. This is also key, because as occurred with Aduhelm, the company never presented results that showed true efficacy beyond biomarker data that suggested the treatment could remove amyloid from the brain. That biomarker-based approval set off a torrent of criticism against the FDA and Biogen.

“We feel quite good about the fact that it's well powered,” Singhal said of the lecanemab trial, which is being led by Eisai. In April 2021, when Eisai announced that the trial had completed enrollment, the company stated that the study had signed on 1,795 patients. The study's clinicaltrials.gov page, last updated on June 13 of this year, shows a target enrollment of 1,906. 

Later, Biogen’s executives were asked about their commitment to neuroscience in the wake of the challenges with Aduhelm, which has failed to gain a foothold in the market and led to layoffs and other troubles at the company. Singhal and CEO Michel Vounatsos pointed to the company’s clinical program, which they said boasts 29 products. Also in development and already before regulators is depression therapy, zuranolone, which is in a partnership with Sage Therapeutics.

“We've had a lot of success in the space … and potentially we could have success with Alzheimer's,” she said.

Singhal's statement stands in contrast to the triumphant stance that Vounatsos took when Aduhelm was granted accelerated approval in June 2021.

“This historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come,” he said.

All eyes now turn to what Lilly will say during its second-quarter update. Will CEO David Ricks and his R&D team take a similar step back from their previous enthusiasm for donanemab?

Lilly will of course be providing updates on its regulatory milestones during the Q2 call, spokeswoman Kristen Porter Basu confirmed in an email. She noted that Lilly has previously announced intentions to wrap up an accelerated approval request to the FDA for donanemab by the end of this quarter, so analysts will certainly be listening intently for news of that application's completion. 

The company also pointed to previous results from the phase 2 Trailblazer-Alz program, suggesting that the therapy has shown success on measures of reducing amyloid—"the FDA approved surrogate endpoint suggestive of potential clinical benefit"—and on decline in function and cognition. 

But another name cropped up in the Alzheimer's program update: remternetug, what Porter Basu called a "next-generation anti-amyloid antibody " that has shown the ability to clear amyloid plaques in the brain during a phase 1b study. Formerly known as LY3372993 or N3pG 4 on Lilly's pipeline, remternetug is another monoclonal antibody and a follow up to donanemab. 

The first trial in the phase 3 Trailrunner-Alz-1 program is expected to get underway soon, testing this next-gen therapy on safety and its plaque-lowering ability in early symptomatic Alzheimer's disease. A page for the study in the federal clinical trials database posted July 19 lists the primary outcome as the percentage of participants who reach amyloid plaque clearance as measured using PET imaging. Secondary outcomes are also related to plaque clearance. The placebo-controlled study is slated to enroll 400 patients.

So as confident as Lilly has been on donanemab, even the Indianapolis Big Pharma does not have all its eggs in one basket. 

Editor's note: This story was updated at 2:30 p.m. ET on July 22, 2022, to include an update from Eli Lilly.