Expanding the Alzheimer Drug Development Pipeline

EP: 1.Donanemab Dosing and ARIA Risk in TRAILBLAZER-ALZ 6

EP: 2.Maintaining Efficacy in Safer Donanemab Dosing Regimen

EP: 3.Importance of Patient Selection and Future Therapies in Alzheimer Treatment

EP: 4.Eligibility and Safety Considerations for Antiamyloid Alzheimer Therapies

EP: 5.Monitoring and Managing ARIA in Antiamyloid Treatments

EP: 6.Setting Realistic Expectations for Antiamyloid Therapeutics

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EP: 7.Expanding the Alzheimer Drug Development Pipeline

At the 2025 Alzheimer’s Association International Conference, held July 27-30, in Toronto, Canada, Alzheimer disease (AD) expert Sharon Cohen, MD, FRCPC, spoke with NeurologyLive^® to discuss the use of emerging AD therapies, specifically focusing on approved antiamyloid antibodies lecanemab (Leqembi; Eisai) and donanemab (Kisulna; Eli Lilly). In this part of the video series, Cohen highlighted key differences between these AD treatments, such as eligibility requirements and safety protocols. She also highlighted amyloid related imaging abnormalities (ARIA) risks and the importance of aligning patient expectations with treatment goals.

In the seventh episode of this AAIC Special Report, Cohen discussed the diverse and evolving drug development pipeline for AD. She noted the promise of next-generation antiamyloid antibodies, genetic approaches to reducing amyloid production, and oral drugs that work by preventing toxic oligomer formation. Beyond amyloid, she emphasized emerging antitau therapies as well as the potential benefit of combining amyloid and tau treatments. Cohen also pointed to inflammation as an important target, with GLP-1 receptor agonists in phase 3 trials showing potential for neuroprotection in early AD.

Transcript below edited for clarity.

Sharon Cohen, MD, FRCPC: The drug development pipeline for AD is quite varied. So, we have antiamyloid drugs. We've talked about a couple of them that have regulatory approval now in many countries, but there are others under development that are antibodies that show very rapid clearance of amyloid with almost no ARIA. So, that's very exciting. That's the trontinemab phase 2 data—the ability to get an antibody into the brain using a brain shuttle approach. We'll see what phase 3 brings, but I think there's a lot of enthusiasm about that.

There are other approaches that are earlier in development, but they are genetically engineered to shut off production of amyloid. That would be the Alnylam Pharmaceuticals mivelsiran program, where intrathecal dosing every 6 months may really knock down the production of all daughter proteins of amyloid precursor proteins. So, that's exciting.

In between, we have valiltramiprosate, which is also working on the amyloid therapeutic target area, but it works differently. It's an oral drug, and particularly in APOE4 homozygotes who maybe don't have other treatment options with the same safety as nonAPOE4 homozygotes, we have a drug that stops monomers of amyloid from becoming oligomers. Oligomers are felt to be the most toxic. So, I've talked a lot about the antiamyloid approaches. It's not all antibodies, and we'll see what the field brings.

However, tau is also a bad actor in AD, and we have a new generation of antitau antibodies that are targeting the mid-domain of tau in the hope that we can shut off cell-to-cell spread of tau. There are several of these in phase 2. There's also an antisense oligonucleotide, again getting at the genetic knockdown approach. This is a Biogen BIIB080 drug that shuts off production of tau. So, that will be very interesting.

I think the combination of treating amyloid and tau—whether it's sequentially or immediately in a symptomatic patient, because both amyloid and tau are already acting in the brain in patients who have Alzheimer symptoms—will be important.

Then you have other approaches. Maybe I'll just mention briefly, because I could go on and on here—you can see I'm excited about it—but the role of inflammation is important in AD. It's also a bad actor, and maybe not just at the endpoint of disease, but even early on. So, there are a number of drugs acting differently in the drug development pipeline to target inflammation. But one of them that will be familiar to many clinicians is this class of drug, GLP-1 receptor agonists. Specifically, semaglutide, under development by Novo Nordisk, will read out its phase 3 program in AD—in early Alzheimer, MCI, and mild dementia because of Alzheimer—to see if we get a neuroprotective effect. We will have that data by the end of this year. I think it will be reported at CTAD.

So, very exciting to think that we'll have an oral drug that is repurposed from diabetes and obesity. This class of drugs is now expanding in its indications, but originally it was a diabetes drug, familiar to many practitioners who aren't Alzheimer specialists, and maybe an option for individuals with early AD.