NeuroVoices: Ronald C. Petersen, MD, PhD, on Redefining Clinically Meaningful Benefit in Alzheimer Drug Development


The director of the Alzheimer’s Disease Research Center at Mayo Clinic provided insight on new considerations for interpreting data from cognitive and functional measures in trials assessing agents for Alzheimer disease.

Ronald C. Peterson, MD, PhD

Ronald C. Petersen, MD, PhD

Following the approval of aducanumab (Aduhelm; Biogen) in June 2021, several in the Alzheimer disease (AD) field raised concerns pertaining to the concept of clinically meaningful change in outcome. Aducanumab was the first agent approved for the neurodegenerative disease since 2003, and was followed by lecanemab (Leqembi; Eisai), another antiamyloid agent, in January 2023. While the expansion in therapeutics is promising, it comes with caution.

In early February 2023, a group of experts convened by the Alzheimer’s Association published a paper specifically focusing on the true definition of clinically meaningful benefit or slowing. Led by Ronald C. Petersen, MD, PhD, the paper suggested introducing a treatment strategy early in the disease and assessing a meaningful change over the course of a relatively brief 18-month clinical trial to understand the value of an effective agent. Because of the complex pathophysiology of AD, the group noted that expectations on certain therapies may be tempered, and that a modest clinical impact from an agent is probably not reasonable.

The argument was not meant to “lower the bar” of expectations of AD randomized controlled trials; rather, it was meant to view them from a realistic perspective, the study authors concluded. As part of a new iteration of NeuroVoices, Peterson, director of the Alzheimer’s Disease Research Center at Mayo Clinic, provided perspective on the recently published paper. He discussed the complexities of identifying clinically meaningful benefit, potential for adaptive trials, and the lessons learned from antiamyloid therapies like aducanumab and lecanemab.

NeurologyLive®: What are some of the top line messages that the paper highlights? And how does it sort of apply to the Alzheimer's community in general?

Ronald C. Peterson, MD, PhD: With the recent accelerated approval of a couple of drugs for disease modification of Alzheimer disease, we thought we'd sort of address the issue of “What is a clinically meaningful response to these drugs?” For part of it, we had to take a step back and say, “What does the field expect from these drugs?” In other words, what kind of result? What kind of improvement? What kind of stabilization? What do we expect? It’s become apparent that these are disease modifying therapies. What they're meant to do is change the rate of progression of the disease. If the placebo group declines dramatically, we're trying to lessen that slope, if you will, and stabilize the functional nature of the patient. The clinical meaningfulness then translates to the patient, and his/hers family. What does this mean for that individual?

We're hoping that these drugs will maintain the level of function of the individual—whatever level it is, whatever the person does on a day-to-day basis—at that stage for 4, 6, 8 months, to be determined. Over an 18-month trial, you can only measure change to a certain degree. The metric that is commonly used in these trials is the Clinical Dementia Rating Scale, or CDR. A half of a point on this assessment means that the person is stabilized at a functional level for a period. In the paper, we used some examples in the paper of what that might mean for the individual. Essentially, we're trying to put the clinical change, the clinical response of these drugs, into a perspective that is reasonable for clinicians, patients, families, and public stakeholders to say, “Yeah, that makes sense. I see the point you're trying to make. And it makes sense.” Now, whether we get there or not, I guess remains to be determined. But that was the focus of it.

Do you envision more adaptive type of trials becoming more prevalent?

These would involve changes in the overall conduct of the study: depending on how patients perform, adjusting doses or length of follow up, things of that nature. Those are being considered. In fact, there's a trial that is being reviewed at the National Institutes of Health right now using a combination of amyloid and potentially some tau therapies that will use adaptive methodology, although it hasn't been approved yet. It's not up and running, but I think that it holds promise for the future as we learn more about the drugs, the biomarker responses of those drugs, and how we may adapt to somebody on an individual basis, depending upon how their biomarkers perform. You might change the dose, you might increase the therapy, or you might stop the therapy. If the person is a non-responder, you might say why risk side effects in this individual? That could be a situation. We're still not there yet in terms of adaptive trials for Alzheimer disease, but it certainly is on the horizon.

What has the antiamyloid class trials taught us thus far?

It's been encouraging in the field that intervening on the amyloid cascade process has a clinical impact. That was always a big question: is amyloid a primary player in this disease process? And, if we manipulate it pharmacologically, is it going to make any difference? These recent trials have demonstrated, yes, it does have an impact. What it really suggests is that if we can intervene on amyloid in the symptomatic stages of the disease, mild cognitive impairment, mild dementia, would it make sense to move back up the clinical continuum to people who are clinically asymptomatic, but biomarker positive? Would it make more sense to intervene at that stage to try to prevent the clinical symptoms from developing? Trials exploring this are underway now. There are some preclinical trials that are testing these drugs, testing solanuzumab, to see if in fact, we can intervene earlier in the process.

It has been a major success to show an ability to impact amyloid and its processing down the road. But amyloid does not exist in a vacuum, we know that the other part of the Alzheimer disease processes is the tau molecule. Tau, presumably downstream, is going to have an impact on clinical outcomes. But these two protein opothies often exist in a setting of perhaps an alpha synuclein opothy, Lewy Body component, TDP-43, vascular disease, and CSF dynamic issues. Taking a look at the bigger picture of all of these possible proteins operating in concert, if we impact one of them, let’s say amyloid, or any of the others in isolation, how much of a clinical impact are we likely to have? What we're seeing from the clinical trials right now is that degree of impact is clinically meaningful, it's important, but it's certainly not the whole picture. We have to look at the broader context of these proteins and how they may be interacting together.

Transcript edited for clarity. Click here for more iterations of NeuroVoices.

1. Peterson RC, Aisen PS, Andrews JC, et al. Expectations and clinical meaningfulness of randomized controlled trials. Alzheimers Dement. 2023;1-7. doi:10.1002/alz.12959
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