The end of 2022 and early 2023 could prove a momentous period for Alzheimer’s disease (AD) drug development, with four key Phase III clinical trial readouts on the docket.

In the aftermath of a market debacle for Biogen’s Aduhelm (aducanumab), three major therapies targeting the same amyloid beta pathway have upcoming Phase III results. Roche’s gantenerumab and Eisai’s lecanemab have readouts expected by the end of 2022, and Eli Lilly’s donanemab has results expected in 2Q 2023.

Meanwhile, Anavex’s blarcamesine hydrochloride, also known as ANAVEX2-73, will look to jolt the AD field with a new therapeutic approach. Phase III results for Anavex’s small molecule targeting the Sigma-1 receptor are also expected by the end of 2022.

The Aduhelm effect

Though positive results for Anavex could shake-up the field, most eyes are focused on the anti-amyloid antibodies from Roche, Eisai, and Lilly. Like Aduhelm, these therapies can reduce amyloid plaque build-up in the brain—long thought to be a hallmark of AD. (Clinical Trials Arena recently covered brewing controversies over the amyloid target).

Overall, the AD field is mixed on what Aduhelm’s market flop means for the future of therapeutics targeting amyloid in AD. Though Aduhelm gained FDA accelerated approval in June 2021, the antibody has had almost no sales since Medicare severely restricted coverage.

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According to Dr Dennis Selkoe, co-director of the Center for Neurological Diseases and Brigham and Women’s Hospital, the controversy surrounding Aduhelm stems from questionable trial designs—not the amyloid target itself. The two Phase III trials used for Aduhelm’s approval included multiple protocol amendments and premature terminations, leading to mixed and unclear results, he says. However, there is still overwhelming evidence that the amyloid pathway is a principal driver of Alzheimer’s disease, he adds.

On the other hand, Dr George Perry, Chair of Neurobiology at University of Texas at San Antonio, says he is skeptical that targeting amyloid in clinical trials will ever yield a clinically meaningful result. Though these trials may achieve slight statistical significance, they are unlikely to ever provide meaningful benefit, he notes. “We have to test 1,000 patients in order to see a tiny signal; is that really clinically meaningful?” Perry explains.

Clinical trials for Roche’s gantenerumab and Eisai’s lecanemab

Both Roche and Eisai have large Phase III trials with readouts expected before the end of 2022. Roche is testing gantenerumab in two parallel studies—the 985-patient GRADUATE-I study (NCT03443973) and the 981-patient GRADUATE-2 study (NCT03444870)—both over 116 weeks. Meanwhile, Eisai’s Phase III trial tests 1,906 patients over 78 weeks (NCT03887455).

Each trial specifically targets patients with early AD and uses a primary endpoint of Clinical Dementia Rating–Sum of Boxes (CDR-SB), which combines cognitive and functional outcomes. Selkoe says CDR-SB is a good endpoint for measuring AD, though it is not as sensitive as the field had initially hoped.

Because both antibodies have the same target, the key differentiation in trial results could come down to safety rather than efficacy, Selkoe adds. In particular, both antibodies could show different rates of ARIA-E, a brain imaging abnormality common in these therapies, he notes.

Anavex’s blarcamesine hydrochloride takes new approach to Alzheimer’s

Anavex’s blarcamesine hydrochloride has Phase III results for a 509-patient Phase IIb/III trial (NCT03790709) expected this fall. The oral pill is an agonist of the Sigma-1 receptor, which could alter signaling functions to provide neuroprotective and antiapoptotic effects.

As coprimary endpoints, the Phase IIb/III trial of ANAVEX2-73 uses the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog) scale and the Activities of Daily Living (ADCS-ADL) scale. ADAS-Cog measures cognitive decline, while ADCS-ADL assesses ability to perform daily activities.

Because the Sigma-1 receptor is a drastically new target in AD, Perry says the upcoming results will be key to determining if this approach could work: “This new target is promising, but the proof is in the pudding.”

Eli Lilly’s donanemab joins amyloid antibodies with upcoming readout

Lilly’s donanemab rounds out the slate of amyloid-targeting antibodies with Phase III results for the 1,800 patient TRAILBLAZER-ALZ 2 study (NCT04437511) expected in Q2 of 2023. As a primary endpoint, TRAILBLAZER-ALZ 2 measures the integrated Alzheimer's Disease Rating Scale (iADRS). iADRS is a composite measure combining two validated endpoints measuring cognition and daily function in AD.

Meanwhile, Lilly is also comparing donanemab head-to-head with Biogen’s Aducanumab in a separate 200-patient Phase III trial (NCT05108922). This study measures the rate of amyloid plaque reduction, which is the surrogate marker used to approve Aduhelm in June 2021.

Looking ahead, the key question will be whether the FDA feels pressure to approve these new antibodies given the controversial Aduhelm accelerated approval, Perry says.

Correction: An earlier version of this article listed only one of Roche’s two Phase III trials of gantenerumab with readouts expected in 2022. The article has been updated to include both trials.