The Clinical Takeaways from Phase 2 Data on Donanemab in Alzheimer Disease

Howard Fillit, MD

Eli Lilly recently announced that new data on its investigational Alzheimer disease (AD) agent, donanemab, from the phase 2 TRAILBLAZER-ALZ study (NCT03367403). The data suggest that donanemab treatment results in better composite scores for cognition and ability to perform activities of daily living after 76 weeks compared to placebo in patients with early AD.^1,2

After 76 weeks, the treatment group’s scores on the Integrated Alzheimer’s Disease Rating Scale (iADRS) declined by 6.86 points, while the placebo group scores declined by 10.06 (difference, 3.20; 95% CI, 0.12-6.27; P = .04). This change was equivalent to a 32% difference in slowing decline for the donanemab group, a significant difference that was identifiable by month 9. At baseline, iADRS score was 106 in both the donanemab (n = 131) and placebo (n = 126; 1 participant was excluded from the modified intent-to-treat population) groups.

To find out more about the therapy’s potential in AD and what the clinical community should know about these data, NeurologyLive spoke with Howard Fillit, MD, founding executive director and chief science officer, Alzheimer's Drug Discovery Foundation (ADDF).³ Fillit shared his insight into the clinical implications of these findings for the AD community.

NeurologyLive: What was your main takeaway from these phase 2 data on donanemab?

Howard Fillit, MD: Well, I think normally if a study hits its end point on the primary outcome that's prespecified, then people would consider it a success. I wouldn't think any differently here. It's very clear that on the primary outcome—which I think is a reliable outcome, it measures cognition and function, the iADRS. It’s a composite of the ADAS-Cog-13 [AD Assessment Scale-Cognition] and the ADCS-ADL [AD Cooperative Study–Activities of Daily Living], so it's a cognition and function measure that seems to be more sensitive than the one that's historically used, which is the CDR-SB [Clinical Dementia Rating-Sum of Boxes], and Lily did a fair amount of research evaluating these assessment scales. The study hit its primary outcome, which is great.

Then, almost all the secondary outcomes had a signal in the right direction. That's important, too, because it's supporting evidence in a relatively small trial—there were only about 120 patients in each group. For a phase 2 study to hit its primary outcome on a clinical measure, and then have trends on basically all the other clinical measures that were studied as the secondary outcomes [is great]. Plus, the biomarkers of pharmacological efficacy, in terms of removing amyloid, were clearly hit in terms of target engagement. By the end of the study, most patients had completely negative amyloid scans, and then the whole tau story is fascinating.

They not only used the flortaucipir PET scan to enroll patients in this window, which makes a lot of sense as the people who might be most responsive. They weren't too early [in the disease], where they didn't have enough pathology to be responsive, and they weren't too late, where they had too much tau pathology to be responsive. But then, to be able to ask the question, if you treat with an anti-amyloid drug, what's the effect on the outcome of tangles in the brain or as measured by the PET tau scan? It was very clear that they had statistical improvement in the tau scan, particularly in the relevant parts of the brain: the frontal lobe, the parietal lobe, the medial temporal lobes. Taken together, if we pull all the evidence together, it's I think it's a pretty impressive study. Any study can be criticized, and we always say a good scientific study raises more questions than it answers, but I think this study as a clinical trial really gives us a lot of very interesting findings that in the composite gives me hope that this could be a drug that works. It certainly works in its pharmacology, in terms of doing what it's supposed to do, which is remove the amyloid from the brain. The way the study was designed, we can see the downstream effects of that on tau and on clinical outcomes, and I think the composite here for me is pretty positive.

What’re you looking forward to now with donanemab?

I think when you combine the results here with the results from the Biogen study [of aducanumab], which were also in the direction of efficacy—both pharmacologically in terms of removing amyloid and clinically in terms of slowing the rate of decline in patients—we have kind of a “proof of concept” in a way. Of course, the Biogen studies are very large studies that are in front of the FDA right now. Regardless of regulatory decisions at this point, we're really, I think, seeing 2 things.

One is that we're seeing tremendous advances in the rigor, efficiency, and creativity of how we're designing clinical trials for AD. That's really the result of decades of research on how we do clinical trials, not just the molecules that are being studied, but how we do the clinical trials. The effect sizes, the statistics around planning that, the refinement of a clinical assessment scales both for function and cognition, and, finally, we have biomarkers. Most fields, for example, diabetes, got hemoglobin a1c, hypertension has a blood pressure cuff, cancers got all kinds of biomarkers enabling precision medicine, but AD has been a delayed field just based on historical issues of when we started doing research in the 1980s, whereas cancer research started in the 1940s and diabetes research started in 1920s. We've had a time lag. But we're finally in an age, sort of what I call a modern era, of clinical trials for AD where we have the biomarkers—and there are many more biomarkers emerging.

I would be excited that both for patients and clinicians that we're definitely getting closer. We're seeing positive data now. The anti-amyloid antibodies, and maybe the anti-tau antibodies, they're just the first coming down into phase 3 of new drugs that have the potential to be the first drugs for the treatment of AD. We're going to, ultimately—because Alzheimer's is a disease of aging and old age—like cancer, be going into an era of combination therapy based on precision medicine that's enabled by new biomarkers.

Do you think that this says something positive about the AD pipeline?

Well, our Foundation does a survey every year of the clinical pipeline for AD, and there are other pipeline surveys out there as well, and they all pretty much agree. There are about 120 drugs in development now for AD, which is for our field, quite a lot. For other fields—again, we're doing catch-up—there might be 3000 drugs in the pipeline, but that's a different story. From a historical perspective, 120 drugs is a lot.

But what's interesting about the pipeline now is that for the first time, way more than half of those drugs, are non-amyloid and non-tau approaches. There's a real interest now in neuroinflammation, epigenetics, proteostasis, metabolism—all these other biological pathways of age that affect the brain and probably not only make whatever amyloid pathology is causing worse, but actually probably lead to amyloid pathology, and the tangles, and neuronal death. I think that we're going to find that there's a vicious cycle in amyloid pathology. We know that inflammation causes amyloid deposition, and we know that amyloid deposition causes inflammation. We also know that people that just have amyloid in their brain and no inflammation, for whatever reason they're not reactive, don't really progress. They don't have much cognitive impairment. Many people, a third of people maybe, at age 90, can die with amyloid in their brain and not have overt cognitive impairment. Taking these other biological pathways that are based on biogerontology, the study of aging, and understanding the general pathways by which we age, and then applying those principles in a translational science manner to the study of developing new drugs for AD is going to really pay off in a big way.

I've been doing research in AD and taking care of people for over 40 years. We've seen tremendous progress, and the donanemab studies are just the leading edge. I'm very excited about where we are and where we're going now and the momentum that we have in the field. I think that the basic research over the last 40 years in AD has really taught us and gave us tremendous insights into how the disease happens. This is a time that's very ripe for translating that basic science into new drugs, and I think we're going see just a continuing expansion of the pipeline.

Transcript edited for clarity.

REFERENCES
1. Mintun MA, Lo AC, Evans CD, et al. Donanemab in Early Alzheimer’s Disease. N J Med. Published online March 13, 2021. doi: 10.1056/NEJMoa2100708.
2. Lilly's donanemab slowed Alzheimer's disease progression in Phase 2 trial: full data presented at AD/PD™ 2021 and published in NEJM. News release. March 13, 2021. Accessed March 25, 2021. https://www.prnewswire.com/news-releases/lillys-donanemab-slowed-alzheimers-disease-progression-in-phase-2-trial-full-data-presented-at-adpd-2021-and-published-in-nejm-301246745.html
3. Alzheimer's Drug Discovery Foundation Comment On TRAILBLAZER-ALZ Results. News release. March 13, 2021. Accessed March 25, 2021. https://www.prnewswire.com/news-releases/alzheimers-drug-discovery-foundation-comment-on-trailblazer-alz-results-301246778.html