In this insightful discussion, we interview Anthony Caggiano, Chief Medical Officer and Lisa Ricciardi, CEO, of Cognition Therapeutics about their innovative work in Alzheimer’s disease and dementia with Lewy bodies. They delve into the outcomes of the SHINE Phase II study, the significance of biomarkers in Alzheimer’s pathology, and the unique approach of CT1812. They also explore the challenges and future directions in treating neurodegenerative diseases.
Moe Alsumidaie: Can you explain the cognitive outcomes of the SHINE Phase II study and their implications for CT1812 in Alzheimer’s treatment?
Anthony Caggiano: In the SHINE Phase II study, we focused on several cognitive outcomes to assess CT1812’s impact. We used the ADAS COG 11, a standard measure in Alzheimer’s research, to evaluate cognitive function. Additionally, we included the ADAS cognition, which expands on the ADAS COG 11 with two additional components. Other assessments included the MINI mental state exam and a cognitive composite that integrates various cognitive domains. We also looked at functional outcomes, such as the clinician’s global impression of change and activities of daily living, to
understand how patients manage their daily lives. This multi-faceted approach allows us to capture a broad spectrum of cognitive and functional changes, offering a detailed understanding of how CT1812 may benefit individuals with Alzheimer’s disease.
Moe Alsumidaie: How does the SHIMMER trial for DLB differ from SHINE in design and goals?
Anthony Caggiano: The SHIMMER trial is similar in size and duration to the SHINE trial, with the primary objective of demonstrating safety and tolerability. However, the outcome measures are more diverse due to the varied symptoms of DLB. We aim to show a positive impact on patients’ function, considering cognitive, movement, and sleep-related outcomes. While we don’t expect statistical significance due to the small sample size, we hope to gather valuable insights into CT1812’s potential benefits for DLB patients. The SHIMMER trial includes multiple endpoints, such as the UDPRS for movement, the Epworth Sleep Scale for sleep disturbances, and the CDR for cognitive assessment.
Moe Alsumidaie: How will findings on low plasma P Tau 217 affect participant selection and trial design?
Anthony Caggiano: The recent data presented at CTAD highlighted the significance of low plasma P Tau 217 in predicting cognitive stabilization. We observed that individuals with lower baseline plasma P Tau levels had a robust response to CT1812, indicating a dramatic effect on slowing cognitive decline. Moving forward, we are considering enriching our study population with individuals in this lower range of P Tau. Another approach, similar to Lilly’s, involves using a broader range initially and then focusing on a more restricted range in the primary analysis. We are currently analyzing our entire study population to identify specific inflection points that could guide participant selection in future trials. This strategic focus on P Tau levels aims to optimize the therapeutic impact of CT1812, ensuring that we target those most likely to benefit from the treatment.
Moe Alsumidaie: Why is P Tau 217 a crucial biomarker in Alzheimer’s pathology?
Anthony Caggiano: P Tau 217 is a crucial biomarker because it correlates well with total brain amyloid and Tau, providing a blood-based assessment of Alzheimer’s pathology. Our data, along with findings from Lilly and Eisai, suggest that individuals with lower P Tau levels are more responsive to treatment. This biomarker helps us understand the disease’s progression and identify patients who might benefit most from therapies like CT1812. It’s important to note that while low Tau levels might suggest less advanced disease, our study found that early-stage patients with both high and low MMSE scores can have varying Tau levels. This challenges the assumption that only patients with low Tau are suitable for treatment, highlighting the complexity of Alzheimer’s pathology. By focusing on P Tau 217, we can better tailor our therapeutic strategies to individual patient needs.
Moe Alsumidaie: How does CT1812’s mechanism differ from other Alzheimer’s therapies?
Lisa Ricciardi: CT1812 takes a unique approach by targeting synaptic integrity and amyloid beta toxicity. Unlike monoclonal antibodies that remove amyloid plaques, CT1812 modulates receptors to prevent soluble amyloid proteins from interacting with neurons. This pharmaceutical approach offers potential advantages, such as easier delivery as a pill and reduced risk of side effects like ARIA. By preventing new plaque formation, CT1812 aims to intervene earlier in the disease process, offering a promising alternative to traditional therapies.
This is crucial because people can have amyloid plaques in their brains for decades before symptoms appear. By targeting the underlying pathology, we hope to offer a more effective treatment option.
Moe Alsumidaie: What are the next stages for CT1812, and how will you target low plasma P Tau 217 patients?
Lisa Ricciardi: We are moving rapidly to advance CT1812 in Alzheimer’s disease and plan to request an end-of-Phase 2 meeting with the FDA where we will review CT1812’s safety and tolerability profile as well as the totality of results from SHINE. As we consider the next stages of clinical development, we plan to stick closely to the SHINE study population and design outcomes. Given the promising results, we will likely continue to focus on patients with low plasma P Tau 217 levels, and we will aim to recruit a similar population to ensure consistency and reliability in our findings. Our goal is to address Alzheimer’s disease from its earliest stages through to the most severe cases, adapting our approach based on emerging data. By maintaining a consistent study design, we can build on our existing knowledge and refine our strategies to maximize the therapeutic potential of CT1812.
Moe Alsumidaie: Can you describe DLB and why it’s challenging to treat?
Lisa Ricciardi: Dementia with Lewy bodies (DLB) is a complex neurodegenerative disease characterized by a range of symptoms, including cognitive decline, gastrointestinal issues, hallucinations, and sleep disorders. Patients often take 18 months to receive a proper diagnosis, visiting multiple specialists due to the diverse symptomology. Diagnosis is challenging, often requiring a punch biopsy for alpha-synuclein. The overlap with Parkinson’s disease symptoms further complicates diagnosis, as clinicians must determine whether cognitive or physical symptoms appeared first. This complexity makes DLB a particularly challenging condition to diagnose and treat, highlighting the need for more effective diagnostic tools and therapeutic options.
Moe Alsumidaie: Have you considered using digital endpoints or decentralized elements in your trials?
Anthony Caggiano: While digital outcomes like activity and linguistics are interesting, they haven’t been validated in large studies. We currently adhere to FDA-recommended measures, which have been proven effective in recent trials by companies like Lilly and Eisai. However, we recognize the potential of these technologies and may consider them in future studies as they become more established and validated. The SHIMMER trial was designed several years ago, and while digital technologies have advanced, we are committed to executing the trial as planned. However, we remain open to exploring new technologies in future phases, particularly as they become more integrated into clinical research.
Moe Alsumidaie is Chief Editor of The Clinical Trial Vanguard. Moe holds decades of experience in the clinical trials industry. Moe also serves as Head of Research at CliniBiz and Chief Data Scientist at Annex Clinical Corporation.
