Evaluating Sigma-2 Receptor Modulators as Prospective DMTs for Parkinson Disease

Mary Hamby, PhD

Earlier this month, Cognition Therapeutics announced that it had received a Therapeutic Pipeline Program Grant from The Michael J. Fox Foundation for Parkinson’s Research (MJFF) to fund preclinical studies of 2 sigma-2 receptor modulators in animal models of Parkinson disease (PD).¹

Led by Mary Hamby, PhD, vice president of research, Cognition, the approach has the potential to have a disease-modifying effect in a condition that otherwise lacks any treatment of the sort. A study published in 2021, with investigators led by Colleen S. Limegrover, BS, PhD student at the University of Cambridge and former research scientist at Cognition, provided preclinical data on the sigma-2 modulators and the ability to block α-synuclein toxicity to neurons.²

To learn more about the MJFF award, as well as the development of the sigma-2 modulators, we sat down with Hamby and Lisa Ricciardi, CEO of Cognition. Hamby and Ricciardi outlined plans for the studies, beginning in the first quarter of 2022, with experts anticipating a better understanding of how the 2 chemically distinct sigma-2 modulators impact PD in disease models by the end of this year.

NeurologyLive^®: Can you provide some background and additional information on the two sigma-2 receptor modulators?

Mary Hamby, PhD: Susan Catalano, PhD, founded the company with a phenotypic assay, and what came out of looking at small molecules [was] that [they] could block the ability of amyloid-ß oligomers from binding to neuronal synapses. From that small molecule library screen, sigma‑2 receptor modulators were found to be the most efficacious in preventing Aß oligomers [binding] to neural synapses. So that's how we developed our first candidate. CT1812, our [lead] program, is in several clinical trials right now for Alzheimer disease, and also, is positioned to [be evaluated in] a dementia with Lewy bodies clinical trial this year.

Our other candidate, CT2168, was found a little bit later in time, and that was when we started an α-synuclein oligomer program at Cognition. What we learned was that our mechanism—that we elaborated in Alzheimer disease where sigma-2 receptor modulators could block the ability of Aß oligomers to bind—also transferred to an ability to block α-synuclein oligomers from binding to neuronal synapses. We published a paper in 2021, Limegrover et al, that elucidates and shows some of our preclinical rationale for how sigma-2 receptor modulators block α-synuclein toxicity to neurons.

If successful, what are the potential benefits for patients with Parkinson disease?

Mary Hamby, PhD: That is the subject of the Michael J. Fox Foundation award that we received. We're very excited about that work. So, the [Limegrover et al] data I previously mentioned was in vitro proof-of-concept. The Michael J. Fox Foundation is supporting our work to understand in more detail in a whole organism—a living organism—how we impact the disease, looking at key disease-relevant readouts, including motor function, as well as a variety of pathological endpoint measures: α-synuclein, the spread of the pathology. In short, we believe that sigma-2 receptor modulators may be disease modifying, and we're going to be testing that in two mechanistically distinct, α-synuclein-based preclinical animal models.

Lisa Ricciardi

Lisa Ricciardi: The exciting thing is to think we can move beyond formulations of a target that's worked, which is dopamine, for years and years and years, and there are many formulations of it; but our goal is to move beyond the movement disorders into the cognitive aspects of Parkinson disease. As Mary said, this could potentially be disease modifying and a significant breakthrough for patients and their caregivers. If the drug is demonstrated to work—that would be a big change.

How is the MJFF grant awarded? When are studies anticipated to begin?

Mary Hamby, PhD: It is milestone based, and we have a very ambitious program, where we're carrying out the two preclinical in vivo models I mentioned in parallel. So that will all begin in quarter 1 of this year, and different data endpoints will come out in several points in 2022. By the end of this year, we will understand fully how sigma-2 receptor modulators—2 chemically distinct sigma-2 modulators—impact [Parkinson] disease in these disease models.

The first study needed to be dose selection, so we did a lead-in PK [pharmacokinetics] study to select appropriate doses for testing efficacy. The lead in PK data is back, we are selecting doses; and the 2 animal models, like I said, we'll begin that work shortly for efficacy.

What do clinicians need to know regarding these research efforts?

Lisa Ricciardi: I'll put something out there—by targeting the sigma-2 receptor, we feel like we have, at least from the perspective of AD, and possibly PD—PD has a lot more oral agents—a very different approach. I know, certainly in the Alzheimer disease area, we think that we can be synergistic with a number of other drugs that are out there. I'll leave it to Mary to comment on whether we foresee synergistic activity with an oral agent demonstrated to impact both cognition as well as movement disorders.

Mary Hamby, PhD: We do believe that we have a disease-modifying approach; and that's important, because currently to-date, there are no disease-modifying therapies available for [patients with Parkinson disease]. There are only symptomatic [treatments], and most have really focused on providing the essential neurotransmitter dopamine, needed to maintain motor function and to remedy some other symptoms [patients with] Parkinson have. As Lisa pointed out, based off what we know from our Alzheimer disease program, we think that we can positively impact cognition and make an impact there. As I mentioned, we're also testing the ability to improve motor symptoms, but this would be a disease-modifying approach, not symptomatic.

Is there anything else you would like to add?

Lisa Ricciardi: I would communicate that most of the trial work we have done and are doing now is in Alzheimer disease, and we are kicking off a clinical phase 2 trial in dementia with Lewy bodies. Parkinson is a great area of focus and research, and we're delighted that Mary got these 2 grants because it allows us to take some of our scientists and put them to work on these programs to advance very quickly other molecules for other indications. We think it's a really relevant target—it's well within our wheelhouse as a company that's focused on age-related neurodegenerative disorders—and we hope we can bring something to the market that is truly value added and changes clinical outcome over what's available now. While it is an early program, [it is] an area of great interest to the company and focus, led by Mary and her team.

Transcript edited for clarity.

REFERENCES
1. Cognition Therapeutics receives grant from Michael J. Fox Foundation to support development of signma-2 receptor modulator for Parkinson’s disease. News release. Cognition Therapeutics, Inc. January 4, 2022. Accessed February 3, 2022. https://www.biospace.com/article/releases/cognition-therapeutics-receives-grant-from-michael-j-fox-foundation-to-support-development-of-sigma-2-receptor-modulator-for-parkinson-s-disease/
2. Limegrover CS, Yurko R, Izzo NJ, et al. Sigma‐2 receptor antagonists rescue neuronal dysfunction induced by Parkinson’s patient brain‐derived α‐synuclein. J Neurosci Res. 2021; 99(4):1161-1176. doi:10.1002/jnr.24782