THERAPEUTIC FOCUS - Perspectives on Sigma-2 Modulation as a Therapeutic Modality for Slowing Age-Related Degenerative Disease

INTRODUCTION

The senior population in the US is expected to grow from 46 million today to 95 million by 2060.¹ This unprecedented growth is expected to fuel an increase in the number of elderly individuals requiring skilled nursing care for dementia, vision loss, and other conditions that can rob a person of their ability to live independently. Looking forward at the impending impact on the US healthcare system, we feel a distinct sense of urgency to find new treatments for age-related degenerative diseases, which may allow people to live independently longer.

A defining trait of many age-related degenerative diseases is the build-up of toxic proteins, oxidative stress, and inflamma­tion. On a molecular level, these factors impair normal cellular function and ultimately lead to cell death. These cellular changes drive disease progression, translating to functional disability and loss of independence for people with Alzheimer’s disease and other dementias, Parkinson’s diseases, as well as neuro-oph­thalmic disorders like dry age-related macular degeneration (dry AMD). Disease-modifying treatments for these and related con­ditions have eluded researchers – until recently.

Last year, we witnessed very positive news with the FDA ap­proval of the first disease-modifying Alzheimer’s disease treat­ment, LEQEMBI^® (lecanemab-irmb injection for intravenous use) followed by FDA approval of the first complement inhibitor for dry AMD, SYFOVRE^® (pegcetacoplan injection). The recent progress against these diseases reinforces our understanding of the factors driving disease progression and helps elucidate po­tential pharmaceutical targets, one of which is the sigma-2 re­ceptor.

Cognition Therapeutics recently published a comprehensive review examining the sigma-2 receptor complex, which has been shown to have a role in Alzheimer’s disease, dry AMD, and in synucleinopathies, such as dementia with Lewy bodies (DLB).² There is evidence the sigma-2 receptor acts as a regulator of cel­lular processes, such as autophagy and protein trafficking, which are impaired in age-related degenerative diseases. We have demonstrated in preclinical models these critical functions can be rescued by administering a sigma-2 receptor modulator, which we believe may protect neurons from the damage inflicted by protein aggregates, oxidative stress, and inflammation.

For these reasons, we and others believe sigma-2 represents a compelling drug target. Currently, Cognition Therapeutics is conducting Phase 2 clinical trials in adults with Alzheimer’s dis­ease, DLB, and geographic atrophy (GA) secondary to dry AMD with CT1812, an investigational, oral, small-molecule sigma-2 receptor modulator. CT1812 represents a distinctly new approach to targeting these degenerative diseases.

SIGMA-2 RECEPTOR MODULATORS IN DISEASE

Interest in sigma-2 receptors as therapeutic targets is grow­ing given the high expression of these receptors in multiple cell types, including neurons in the brain and retina, which are sus­ceptible to damage by pathogenic proteins, oxidative stress, and inflammation. The sigma-2 receptor has been shown to regulate cell functions disrupted by these toxins, such as cholesterol biosyn­thesis/trafficking, membrane trafficking, breaking down faulty proteins, lipid membrane-bound protein trafficking, and receptor stabilization at the cell surface.²

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In vitro studies provide experimental evidence that small molecule sigma-2 modulators can rescue these biological processes. Experimental sigma-2 receptor modulators tested by several independent research groups have been shown to be neuroprotective.

ALZHEIMER’S DISEASE

Synaptic loss is a hallmark of Alzheimer’s disease and is characterized by a progressive reduction of synaptic den­sity in disease-related brain regions.¹⁴ The accumulation of Aβ is a hallmark of Alzheimer’s disease progression and is believed to be a primary cause of synaptic dysfunction, dysregulation and eventually neuronal death.¹⁵ Aggregated Aβ fibrils and plaque are now readily observable using PET imaging and are the targets of several approved and experimental im­munotherapies.

However, while fibrils and plaques may be prevalent, Aβ oligomers are widely recognized as the most toxic. To date, their low molecular weight and relative scarcity has made them difficult to target with monoclonal antibodies. However, results from preclinical Alzheimer’s models and from a small clinical study in adults with mild-to-moderate Alzheimer’s disease show that oligomers can be displaced from synapses by targeting the sigma-2 receptor. In cultured neurons, this dis­placement facilitates synaptic recovery, which we expect will have a beneficial ef­fect on cognitive decline.^6,16

The clinical benefit of recently ap­proved LEQEMBI, which targets soluble Aβ protofibrils, encourages the pursuit of ther­apies that target similar species of Aβ. There is potential for synergy between the sigma-2 receptor modulator, CT1812, which acts by displacing Aβ oligomers from synapses, and anti-Aβ antibody treatments that increase the clearance of these displaced Aβ oligomers. (Figure 2) Additionally, sigma-2 receptor modulators have been independently shown to rescue memory and cognitive deficits in an Alzheimer’s mouse model, suggesting one of the major debilitating symptoms of Alzheimer’s disease—the loss of ability to form new long-term memories—may be restored at a fundamental level by thera­peutics targeting sigma-2 receptors.

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ALPHA-SYNUCLEINOPATHIES: PARKINSON’S DISEASE & DEMENTIA WITH LEWY BODIES

Two primary alpha-synucleinopathies are Parkinson’s disease and DLB, both of which are associated with motor function and cognitive decline due to synaptic dys­function and loss.^17,18 There are currently no disease-modifying treatments for either condition. While the cell types and brain structures affected in Parkinson’s disease and DLB differ, a common feature is the accumulation of alpha-synuclein aggre­gates, a major constituent of the Lewy bodies found in brain neurons. Increasing evidence suggests that alpha-synuclein also forms soluble oligomers, which are more toxic than fibrils.^19-21

Based on our understanding of the role of sigma-2 receptors, we conducted preclinical research to determine the im­pact of alpha-synuclein oligomers on neu­rons with and without the addition of CT1812. As expected, we observed that alpha-synuclein oligomers are rapidly in­ternalized into neurons, where they impair key cellular functions, such as protein traf­ficking and autophagy. The addition of the of sigma-2 modulator, CT1812, blocks the internalization of alpha-synuclein, which reverses the trafficking disruption.¹²

DRY AGE-RELATED MACULAR DEGENERATION

Dry AMD, which affects approximately 2 million Americans, also involves a dys­regulation of cellular processes including autophagy. When impaired, the retinal pigment epithelial (RPE) cells are unable to process debris generated by photorecep­tors. As debris accumulates into deposits of lipid and protein, known as drusen, the architecture of the RPE is disrupted. Over time, damaged RPE cells die and are un­able to support the photoreceptors, which leads to visual impairment.

Several lines of evidence suggest modulation of sigma-2 receptors may pro­vide significant therapeutic utility for the treatment of dry AMD. First, several large-scale, independent genome-wide associa­tion studies identify a mutation in the gene encoding sigma-2 (TMEM-97) that confers decreased risk for dry AMD.^22,23 Second, proteomic analysis of cerebral spinal fluid (CSF) and plasma from the first cohort of a Phase 2 clinical trial of CT1812 in mild-to-moderate Alzheimer’s disease (SHINE-A), showed the expression of many proteins known to be disrupted in dry AMD were altered by treatment with CT1812 versus placebo.²⁴ Lastly, in vitro studies showed the sigma-2 modulator, CT1812, rescued autophagy in cultured RPE cells that were put under disease-like condi­tions.²⁵

Taken together, these data indicate CT1812 may slow disease progression and ultimately protect vision in people with dry AMD. The Phase 2 MAGNIFY study is currently testing CT1812 as treatment for people with dry AMD who have measura­ble geographic atrophy.

DEMANDING A RESPONSE

Alzheimer’s disease, alpha-synucle­inopathies, and dry AMD are important age-related degenerative diseases for which current therapeutics are unavail­able, offer limited benefit, or require bur­densome regimens. Yet the clinical and societal needs to address such diseases are profound. Alzheimer’s disease preva­lence is expected to more than double with related costs rising to an estimated $1 tril­lion by 2050 in the US.²⁶ According to the Parkinson’s Foundation and the Lewy Body Dementia Association, direct healthcare costs for individuals with Parkinson’s dis­ease and DLB are estimated to be more than $55 billion combined. AMD is the leading cause of blindness in people over 50 years of age in the US and afflicts ap­proximately 11 million people.

As we’ve previously discussed, the po­tential of sigma-2 receptor modulators to protect neurons in the CNS and retina and by doing so preserve their function is com­pelling. The rigorous preclinical and clini­cal testing we have conducted, much of which is summarized in our published re­view, has given us the support we and reg­ulators needed to advance CT1812 into Phase 2 clinical studies in adults with early as well as mild-to-moderate Alzheimer’s disease, DLB, and dry AMD. While the specialty pharmacology trials we have completed have given us valuable insights into the potential of CT1812, the top-line results from the first of our Phase 2 studies, which we anticipate in 2024, will offer us the most concrete evidence yet of its ther­apeutic potential. If its activity is confirmed, CT1812 and other sigma-2 receptor mod­ulators could represent a significant bene­fit for people with these devastating diseases and their families.

REFERENCES

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Dr. Anthony O. Caggiano is the Chief Medical Officer and Head of R&D at Cognition Therapeutics. He has broad experience in the development of new medicines for neurological conditions having worked 17 years of at Acorda Therapeutics; he also served as CMO and head of R&D at Neurotrauma Sciences and earlier as acting President and CMO at Constant Pharmaceuticals and Aeromics, Inc. He earned his BA from the University of Virginia in interdisciplinary studies, focusing on biology, chemistry and psychology. He earned his PhD from the University of Chicago, and his MD from the University of Chicago, Pritzker School of Medicine.