NeuroVoices: Anthony Caggiano, MD, PhD, on Therapeutic Progress of Alzheimer Agent CT1812

Anthony Caggiano, MD, PhD

The therapeutic development for the treatment of Alzheimer disease (AD), one of the most rapidly growing neurodegenerative disorders, has been exponential in recent years. There are now 2 FDA-approved treatments—lecanemab (Leqembi; Eisai) and donanemab (Kisunla; Eli Lilly)—that act on removing amyloid plaques, otherwise considered a hallmark of the disease, located in patients’ brains. There are dozens of other investigational treatments making their way through the pipeline, including CT1812 (Cognition Therapeutics), a small molecule oligomer antagonist that penetrates the blood-brain barrier and binds selectively to the sigma-2 receptor complex.

At the recently concluded 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 1, in Philadelphia, Pennsylvania, investigators presented data from SHINE, a proof-of-concept, double-blind, placebo-controlled study (NCT03507790) assessing the safety and efficacy of CT1812. After a 6-month treatment period, patients on the investigational drug declined by an average of 1.66 points on the Alzheimer’s Disease Assessment Scale-Cognitive subscale 11 whereas those on placebo declined by 2.70 points, resulting in a 39% slowing in favor of the active drug.

The data, presented by Anthony Caggiano, MD, PhD, also showed that proteins dysregulated in AD were found to be normalized with CT1812 treatment. In addition, Brain network mapping and pathway analysis identified statistically significant biological processes altered by CT1812, including those related to synapses, lipoprotein, and amyloid-ß biology, and neuroinflammation.

As part of a new iteration of NeuroVoices, Caggiano, chief medical officer and head of Research & Development at Cognition Therapeutics, sat down to discuss the totality of the proof-of-concept data, and the promise behind CT1812. He spoke on the overall design and results of the study, the mechanism of action of the drug, and some of its notable impacts on AD biomarkers and neuroinflammation. Furthermore, he provided some updates on other ongoing studies of the agent in other neurodegenerative disorders like Lewy body dementia.

NeurologyLive: What did the phase 2 study look like?

Anthony Caggiano, MD, PhD: CT1812 is our lead product. It’s an antagonist of beta-amyloid oligomers, reducing their binding affinity to their targets. It acts as a ligand for the sigma-2 receptor. This study, SHINE, is our first proof-of-concept study where we looked at cognitive outcomes following six months of treatment in 153 randomized individuals. They were evenly randomized into three groups—two on the drug, one on placebo. Everyone had mild to moderate Alzheimer's, with an MMSE score of 18 to 26 going into the trial. Each person had a diagnosis of Alzheimer’s disease confirmed with amyloid pathology, either via PET scan or cerebrospinal fluid biomarkers. The primary objective of the study was safety and tolerability. However, we pre-specified the ADAS-Cog 11 scale as the first of our exploratory cognitive outcome measures to protect it statistically.

How would you assess the safety and efficacy observed from the study?

As I mentioned, the primary objective was safety and tolerability, and we saw a very nice safety profile. Our adverse events were well balanced between the active drug and placebo. There was one death in the study, and that was in a placebo participant. So overall, the safety profile was very nice.

When we looked at the exploratory cognitive outcome measures, we were very pleased to see a trend of improvement across all measures in individuals treated with CT1812. For example, the ADAS-Cog 11 scale was our primary cognitive outcome measure, and we pre-specified that the first analysis would be the pooled 100 mg and 300 mg doses versus placebo. Throughout the course of the study, those on placebo worsened by about 2.7 points on the scale, while those in the pooled drug group had about a one-point advantage, which amounts to approximately a 40% slowing of disease progression as measured by ADAS-Cog 11 over six months. We saw similar changes in MMSE and other cognitive composite measures, so overall, we were very pleased with the general trend.

We also measured biomarkers in the study. For about half of the individuals randomized, we collected cerebrospinal fluid samples before treatment and after six months. We analyzed changes in the canonical Alzheimer's biomarkers. Notably, we saw a significant reduction in neurofilament light chain (NFL) levels compared to placebo. NFL is generally a marker of neurodegeneration. In the placebo group, NFL levels steadily increased, while in the CT1812 groups—both 100 mg and 300 mg—there was a reduction in NFL levels after six months of treatment. In the 300 mg group, this reduction was statistically significant.

Why do we believe this drug can be successful in treating AD? Discuss its mechanism of action.

Absolutely. So, the drug was discovered in our own labs through a screening program aimed at finding molecules that could protect neurons from the toxicity of beta-amyloid oligomers. As we all know, amyloid is a big component of Alzheimer’s disease. We can debate whether it’s everything or not, but it doesn’t really matter. What the world has come to understand in the last decade or so is that the soluble forms of amyloid—the oligomers and protofibrils—are really the most toxic form. They interact with neurons at specific receptors and cause all the bad downstream effects.

When we pulled this drug out of our screen, we found that it was a ligand for what’s known as the sigma-2 receptor. Subsequent research has shown that the sigma-2 receptor interacts directly with the beta-amyloid oligomer receptor, and when bound to the drug, the affinity of oligomers for the receptor is reduced. So essentially, more oligomers are coming off, and fewer are binding. We believe that’s how we’re protecting neurons. Instead of removing all the amyloid with an antibody—which is a fine approach—we're taking a more traditional pharmaceutical approach by modulating the receptors. By doing so, we reduce the affinity of the oligomers and protect the neurons.

We’ve shown in earlier, smaller trials that we can displace oligomers in individuals with mild to moderate Alzheimer’s disease. We did this by taking cerebrospinal fluid samples before and after drug administration and measuring the change in free oligomers. We’ve also shown that we can normalize EEG patterns in individuals with mild to moderate disease. This was demonstrated in a study we conducted in Amsterdam with 16 individuals, where we observed changes in EEG patterns in a crossover design—on drug, during a washout period, and off drug. Finally, we’ve also seen a trend toward slowing brain atrophy in a study conducted at Yale with their Alzheimer’s and imaging group. We believe this trend matches very nicely with the reduction in NFL levels observed in the SHINE study that we’re discussing today.

Have you discussed what a future trial would look like?

We just now got the data, so we haven’t really planned the next phase of trials yet. What’s nice for us with this data is that we can now decide whether to do a six-month, 12-month, or 18-month trial, and determine how large that trial needs to be. Again, we haven’t designed it, and we haven’t talked about it in detail, but we know it’s not going to be a 10,000-participant cardiovascular risk trial. It’ll likely be similar to other phase 3 trials in the Alzheimer’s space. If we continue to operate in the mild to moderate space, we’ll probably use the ADAS-Cog scale, the ADCs Activities of Daily Living scale, and SGIC as outcomes, which the FDA has already said are appropriate for assessing cognition and function. So right now, I wouldn’t expect anything atypical.

We also have another trial ongoing, which is in early Alzheimer’s disease, called the START trial. It’s a 540-individual study, with two doses of the drug versus placebo. In that study, we’re using the CDR-Sum of Boxes as a primary outcome because it’s targeting earlier-stage individuals. Again, that’s not atypical, and I would anticipate that the next phase of study won’t have many surprises.

Can you provide an update on the other trials? Specifically, the SHIMMER and START studies?

Sure, I’ll go in reverse order. The SHIMMER study is our trial in individuals with Lewy body dementia. We’ve announced that we anticipate a readout towards the end of this year. We recently announced that the last patient has been randomized, which is great. It’s a six-month study, so it takes time to complete the dosing, safety follow-up, data cleaning, and so forth. We’re excited to see the results towards the end of the year.

As for the START study, which is our early Alzheimer’s trial, we haven’t provided updates on the progression, such as the number of randomized participants and so forth. However, one can go on clinicaltrials.gov to see the number of activated sites and other details. Right now, we’re looking at about 50 sites throughout the United States, and it’s actively enrolling.