Mike Detke, MD, PhD, chief medical officer, Cortexyme, provided context on atuzaginstat’s high ceiling in Alzheimer disease, its regulatory path, and its unique dental substudy.
This is a 2-part interview. For part 1, click here.
Infection of porphyromonas gingivalis (Pg) in a preclinical mouse model resulted in classic Alzheimer disease (AD) pathology; however, this was blocked by atuzaginstat (Cortexyme), an irreversible lysine-gingipain inhibitor. The mechanism of action of the agent is based on the discover of gingipains, toxic protease virulence factors from Pg, which is found in more than 90% of brains with AD. The phase 2/3 GAIN trial, designed to be potentially pivotal, will evaluate the efficacy and safety of atuzaginstat in 642 randomized subjects with mild to moderate AD.
To date, the subjects enrolled have exhibited baseline characteristics consistent with AD and with Pg infection. If successful, the study could pave way for investigators to further examine more about the correlations between Pg and AD diagnosis, as well as potentially grow the treatment landscape for patients with AD. GAIN will also feature a dental substudy that includes 233 trial participants. While not selected for periodontal disease, approximately 90% of the population have moderate to severe periodontitis.
Mike Detke, MD, PhD, chief medical officer, Cortexyme, shared initial enrollment baseline data, along with a company update on the GAIN trial at the 2021 Alzheimer’s Association International Conference (AAIC), July 26-30. In the second half of this conversation with NeurologyLive, he discussed the current knowledge on the correlations between Pg and AD, specific outcomes being observed in the dental substudy, future decisions on the drug pending the study’s success, and takeaways from AAIC 2021.
Mike Detke, MD, PhD: The people who put this together were the cofounders of Cortexyme, Casey Lynch, who was a Alzheimer bench researcher before she became an entrepreneur, and Steve Dominy, MD, who’s a geriatric psychiatrist and also trained as a pharmacist. Steve treated a lot of HIV at his practice in the Bay Area, which is another infection that if ultimately untreated, can lead to dementia. Both saw that there was a lot going on in Alzheimer disease. Not just plaques and tangles, but all these other signs of an infectious process. There are these signs that the human body is responding with inflammatory markers, inflammatory activation—the compliment cascade activation.
There’s all of this going on that suggests it can be an infection, but no one had suggested this bacterium prior to Steve and Casey figuring it out. Most of what has been done has been done in the last 6 or 8 years by Cortexyme, but there’s a lot left. The GAIN trial results should give us some interesting answers. For example, for our patients that have higher levels of p-gingivalis in their blood, are they more likely to respond better to this drug? Does efficacy of the drug on clinical outcomes like cognition and function correlate with declining PG? With declining amyloid? With declining tau? We’ll be looking at all of those, which is why the results should be exciting.
The basics include the ADAS-Cog [Alzheimer's Disease Assessment Scale–Cognitive Subscale] and the ADCS-ADL [Alzheimer's Disease Cooperative Study - Activities of Daily Living], which are the standard accepted by the regulatory bodies and within the medical field. We’re using the standard clinical outcomes to measure periodontal disease. We have periodontal experts advising us like Dr. Mark Ryder, who’s the former chief of Periodontology at UCSF. Those outcomes are called pocket depth, which is the little pocket next to your tooth and gum. When you go to your dentist and they probe it, they count the millimeters of the pocket depth. That’s what pocket depth is. The other is called clinical attachment level, which is how well and how much the gum is attached to the tooth. The pocket depth gets bigger, and the clinical attachment level gets worse as periodontal disease proceeds. We’ll be looking to see if those are improving in the active treatment group more so than the placebo group. We’ll look at other things and correlate those clinical outcomes with biomarkers as well, but those are the key outcomes.
As a drug developer and a scientist, you need to design the trial around the hypothesis correctly. You do a substudy when it’s fit for purpose, which is sort of the British term. I’d love to see more of them. I’ve done some like this in the past, but for this particular mechanism of p-gingivalis and its known role in periodontal disease, it made perfect sense to do these 2 together.
The study is designed for 90% statistical power to show a 50% reduction or slowing of decline in patients with Alzheimer disease. If we see data like that, we will certainly go and speak. We have ongoing discussions with major regulatory agencies like the FDA and the EMA. Also note that this is in mild to moderate Alzheimer disease. Should we need more studies to file and get approval, we’ll do those in mild to moderate. The other obvious step in this treats upstream. If it works well in this population, which we strongly felt was the best population to test it in, it should work in earlier disease, or even preventatively. Clinical trials in that space in Alzheimer would be an obvious next step.
Taking this drug, or other drugs we have within our pipeline, forward for periodontal disease would be another possibility. We have a pipeline of molecules and a list of high unmet diseases that have been associated with p-gingivalis infection. Parkinson disease we’ve talked about before. P-gingivalis is in the saliva, it colonizes in your mouth and specifically in the GI tract. It has been associated with cancers in the GI tract, with ulcerative colitis and Crohn’s in the intestine, and so forth.
I’m looking forward to the innovation and people looking at different targets. There’s a lot of people working on inflammatory things. We think ours is upstream of that, and therefore can explain a lot, if not all of those. We’re looking forward to sharing our data and helping people understand what they can expect from the outcome of the GAIN trial next quarter as well.
Transcript was edited for clarity. For more coverage of AAIC 2021, click here.