AAIC Data Highlights Therapeutic Potential of CT1812 in Alzheimer Disease
CT1812, a sigma-2 receptor ligand, showed favorable changes in biomarkers like Aß40, Aß42, and neurofilament light (NfL), indicating its potential as a synaptoprotective agent.
Anthony Caggiano, MD, PhD
At the 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 1 in Philadelphia, Pennsylvania, several poster presentations demonstrated the impact of investigational CT1812 (Cognition Therapeutics) on cognition and relevant biomarkers of Alzheimer disease (AD) in treated patients. All told, the proof-of-concept SHINE study (NCT03507790) achieved its primary objective and demonstrated a favorable safety and tolerability profile, consistent with previous clinical experience.1
SHINE, a double-blind, placebo-controlled study, included 153 adults with mild-to-moderate AD who were randomly assigned to either placebo or 1 of 2 doses of CT1812 (100 mg or 300 mg) for a 6-month treatment period. Using the Alzheimer’s Disease Assessment Scale-Cognitive subscale 11 (ADAS-Cog11), patients on CT1812 declined by an average of 1.66 points in comparison with declines of 2.70 for those on placebo, resulting in a 39% slowing of decline favoring active drug. Similar results were seen on the Mini-Mental State Exam (MMSE) score on day 98, the midpoint of the study, for the pooled CT1812 arms.
Overall, CT1812 did not achieve statistical significance on the first of the ordered secondary efficacy end points in the pooled 100 mg and 300 mg dose group compared with placebo. It did however demonstrate an effect on several cerebrospinal fluid (CSF) biomarkers, further supporting its development as a potential treatment for AD. In the interim analysis of the first 24 patients (SHINE-A), differential expression analyses identified proteins altered (P ≤.01 and P ≤.05) in CT1812 vs placebo CSF, and hierarchical clustering demonstrated stratification of patients by treatment.
Comparisons to reference standards showed proteins disrupted in or genetically linked to AD that were impacted by CT1812. Proteins dysregulated in AD were found to be normalized with CT1812 treatment and biomarkers of pathway engagement were identified (APP, NPC1). 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.2
"What the world has come to understand over the last decade or so is that the soluble forms of amyloid, the oligomers and the protofibrils, are really the most toxic form, and they interact with neurons at specific receptors and cause all bad downstream effects," Anthony Caggiano, MD, PhD, chief medical officer and head of Research & Development at Cognition, told NeurologyLive® at the meeting. "What we've learned is that our drug is a ligand for what's known as the sigma-2 receptor. Subsequent research has shown that the sigma-2 receptor interacts directly with the amyloid-ß oligomer receptor, and when bound to drug, the affinity of oligomers for the receptor is reduced."
He added, "Essentially, more oligomers are coming off and fewer are coming on. We believe that's how we're protecting neurons. Rather than remove all the amyloid with an antibody, which is a fine approach, we're taking a little more of a traditional pharmacological approach of modulating the receptors. Through modulating the receptors, we reduce the affinity and protect those neurons. We've shown in earlier, smaller trials that we can displace oligomers in individuals with mild to moderate Alzheimer disease through spinal fluid."
Continued data from the first 24 participants showed a significant (P <.05) change from placebo for Aß40, Aß42, was observed with 300 mg of CT1812, along with trends of changes in other biomarkers. Treatment with the agent also resulted in favorable changes on neurofilament light (NfL), a biomarker of neuroaxonal damage. These changes were significant at the 300 mg dose, further supporting CT1812’s role as a synaptoprotective agent. Other CSF biomarkers that did not reach statistical significance included neurogranin, synaptotagmin, SNAP25, phosphorylated tau, total tau, and glial fibrillary acidic protein.3
These findings are expected to be used to design and power a future trial. Although the company has not begun to have conversations about what that would look like, Caggiano told NeurologyLive, "It'll [probably] be a study much like we've seen with other phase 3 drugs in the Alzheimer space. If we continue to operate in the mild-to-moderate area, we'll use the ADAS-Cog scale, we've used the ADSC-CGIC. These are outcomes that the FDA has already said in their guidance are appropriate for assessing cognition and function."
CT1812, a small molecule oligomer antagonist that penetrates the blood-brain barrier and binds selectively to the sigma-2 receptor complex, is also being studied in several other neurodegenerative disorders. Participants are currently being recruited in the SHIMMER study (NCT05225415) of CT1812 in adults with dementia with Lewy bodies; the START study (NCT05531656) of CT1812 in adults with early AD; and the MAGNIFY study (NCT05893537) in adults with geographic atrophy secondary to dry age-related macular degeneration.
"For the SHIMMER study, we've announced that we anticipate readout towards the end of this year," Caggiano said. "We put out an announcement and the last patient has been randomized, which is great. It's a 6-month study, so it will take at least 6 months to complete the dosing and safety follow-up, data clearing and so forth. We're excited to see the results towards the end of the year. In the START study, we're looking at about 50 sites throughout the United States, and we're actively enrolling now."
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