Better Biomarkers Increase The Probability Of Success In Alzheimer's Drug Development

By Lisa Ricciardi, CEO, Cognition Therapeutics

As our understanding of the biology of Alzheimer’s disease (AD) has expanded, it has become clear that multiple processes are involved in disease progression. Age-related stressors including toxic proteins, oxidative stress, and neuroinflammation can all impact cellular health and interrupt regulatory processes, leading to synaptic dysfunction, neuroinflammation, and, eventually, neuronal degeneration. The drug development industry is exploring a vast array of therapeutic approaches to address these neuronal injury pathways in unique ways:

• Immunotherapies — antibodies targeting certain species of Aβ protein, tau, and TREM
• Small molecule inhibitors of oligomer formation and APP production
• Small molecule modulators of neurovascular repair, autophagy/trafficking, microglial activity, and HGF/MET signaling
• Vaccines designed to generate immune response against Aβ
• RNAi, antisense therapies

An equally important and complementary effort is ongoing to develop tools that can accurately assess the impact that therapies have on disease biology. For a complex disease that progresses over years or decades, improving cognition or reducing the loss of cognitive abilities can only be effectively measured over many months or years. So, finding tools to measure a drug’s impact — such as biomarkers — over much shorter time frames (weeks or months) is an enormous benefit to drug developers.

Identifying Better Biomarkers To Enable Drug Discovery, Secure Funding

Cognition Therapeutics is working on both efforts simultaneously, developing a novel potential treatment for AD in parallel with its investigation into better biomarkers. We are developing CT1812, an orally delivered small molecule modulator of the sigma-2 (σ-2) receptor complex, which has shown promise in protecting neurons by shielding them from toxic interactions with aggregated proteins, oxidative stress, and other disease drivers. The σ-2 receptor complex is involved in the regulation of key cellular processes such as membrane trafficking and autophagy that are damaged in age-related degenerative diseases such as AD, dementia with Lewy bodies (DLB), and dry age-related macular degeneration (dry AMD). This damage to sensitive cells can progress to a loss of function, which manifests as cognitive impairment in AD and loss of vision in dry AMD.

Since Cognition’s inception, we have relied on a growing understanding of biomarkers. Initially, we used biomarkers of synapse health to screen molecules that conferred protection from toxic Aβ oligomers to cultured neurons from Alzheimer’s patients. It was this screening method that led us to the selection of a family of potentially effective compounds. Preclinical studies in vitro and in vivo used biomarkers in go/no-go decisions as compounds were vetted for blood-brain barrier penetration, target engagement, and binding affinity, pointing to CT1812 to target sigma-2 receptors and specific biomarker pathways.

The use of biomarker studies gave us increasing confidence about CT1812 along its development path in Alzheimer’s disease and now into other indications. The biomarker evidence that we gathered supported grant approvals from the National Institute of Aging (NIA) that enabled studies ranging from early in vitro work to a 540-person, 18-month Phase 2 START study.

Identifying Biomarkers For Clinical Research

In our ongoing clinical trials, we are using biomarkers to identify early signals of biologic activity — changes in brain wave patterns, brain volume as measured by MRI, and in circulating levels of proteins known to be associated with neuronal function or loss. Our 16-patient randomized, double-blind Phase 2 SEQUEL trial is a case in point for examining less invasive methods of measuring brain activity in patients with mild-to-moderate Alzheimer’s disease at a low cost, both in terms of dollars and healthcare resources. The government-funded study uses quantitative electroencephalogram (qEEG) to measure theta waves that are most commonly associated with processing information and memory formation. The use of qEEG enables the observation of synaptic activity as a change in neural oscillation — the natural ebb and flow of electrical activity that is associated with normal communication between neurons. This study looks at patients after four weeks on or off treatment, and we believe this exploratory qEEG endpoint could point the way toward measuring response to therapeutic intervention. In our most recently concluded study in mild-to-moderate Alzheimer’s disease, CT1812 showed a reduction in hippocampal atrophy, which may be an important surrogate for neuronal survival. And in an interim analysis from our ongoing SHINE study in mild-to-moderate Alzheimer’s disease, CT1812 showed positive shifts in key proteins, which suggests that CT1812 may be having a favorable impact on synapse biology, neuroinflammation, and disease progression.

Leveraging Biomarkers In Patient Care

Stepping back to look more broadly at the fields of neurology and psychiatry, biomarkers may have an increasingly important role to help guide treatment — strengthening patient assessments for conditions that have traditionally relied on physical exams and talk therapy. Biomarker approaches like structural and functional imaging are helping researchers draw connections to circuitry in major depression, while imaging metabolic activity in specific regions, such as in the amygdala and the ventral tegmental area, may help researchers distinguish between anxiety and depression.¹ Similarly, DLB and AD can confound diagnosis as many DLB patients are initially misdiagnosed with Alzheimer’s disease.²  Medical professionals and family members alike can recognize the profound importance of improving diagnosis via better biomarkers; a clearer window into the most complex organ could remove a massive burden for patients who, sadly, often cannot adequately express themselves in a brief assessment with a doctor.

Considering The Patient Experience When Choosing Biomarkers

Going forward, as our collective understanding of neurocognitive diseases expands, we will continue to validate more decisive biomarkers, utilizing imaging techniques, protein levels, electrical patterns, or other emerging technologies to see into the brain. These various tools will offer clinicians the ability to monitor the progress of patients in their care and will give regulators new analytical benchmarks to assess novel therapeutic candidates.

Access to these novel tools will be important, as we drug developers must be mindful of the resources used for different tests. Resources impact the cost and convenience for patients and caretakers. As more biomarkers become more meaningful as diagnostic signposts, they must bring value to the landscape of treating aging and AD by being simpler to attain and more decisive in their diagnosis. Real-world factors like geography play a role: PET scans for Aβ diagnostic are an important part of the AD landscape, but frequent visits to an imaging center are untenable for many patients, excluding many from clinical research. Protein levels from cerebrospinal fluid (CSF) may offer other important metrics, but drawing a CSF sample entails a spinal tap, which may create anxiety or discomfort for patients. As the industry brings more biomarkers to the forefront, they must be clinically meaningful, but costs and convenience also will be crucial to a disease already having dire economic consequences for our healthcare system.

Biomarkers For Drug Development And For Patient Care

In the future, we envision multiple approved medications working through unique mechanisms; biomarkers have the potential to inform physicians when drugs or combinations are or are not having an effect, allowing them to hone treatment regimens for individual patients. And for the industry, validated biomarkers may improve the speed of drug development, allowing companies to detect efficacy signals faster than cognitive changes would be observed. Non-invasive biomarkers such as brain wave analysis and minimally invasive tests for biomarkers in blood or cerebrospinal fluid could also extend the medical community’s ability to diagnose patients where specialized imaging equipment is unavailable.

At Cognition, our immediate focus is on the execution of our ongoing clinical trials in which biomarkers increasingly play a vital role. But the impact of biomarkers extends well beyond the confines of our clinical programs by making care more personalized, with enormous potential for informing diagnosis, research, clinical development, and medical care.

Acknowledgements:

Lisa Ricciardi would like to thank the Alzheimer’s Drug Discovery Foundation for supporting not only new drug development but also enabling technologies such as novel biomarkers to accelerate the development process.

References:

1. Glannon, Walter, “Biomarkers in Psychiatric Disorders,” Cambridge Quarterly of Healthcare Ethics, Oct. 31, 2022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9672933/
2. National Institute on Aging, “Diagnosing Lewy Body Dementia for Professionals.” https://www.nia.nih.gov/health/diagnosing-lewy-body-dementia-professionals

About The Author:

Lisa Ricciardi has served as Cognition Therapeutics’ chief executive officer and president since March 2020 and as a member of the board of directors since March 2019. From July 2018 to October 2019, she served as CEO of Suono Bio, a biotech company based on Langer Labs (MIT) technology. Earlier in her career, Ricciardi served as the senior vice president of global corporate & business development of Foundation Medicine from  2014 and2015, and senior vice president of U.S. and international business development of Express Scripts from 2010 to 2012, and led the M&A teams to sell the two companies.

Ricciardi was in the commercial division of Pfizer Inc., taking three drugs to launch before being appointed to run global business development. Ricciardi previously served on the boards of Contrafect (Nasdaq: CFRX), Chimerix (Nasdaq: CMRX), United Drug Healthcare Group, PLC (LSE: UDG) and Sepracor (Nasdaq: SEPR). She was appointed as the executive in residence at Columbia Technology Ventures in January 2020.