Alzheimer Agent COYA 301 Halts Cognitive Decline, Restores Regulatory T Cell Dysfunction in Phase 1 Study

Stanley H. Appel, MD

Findings from a proof-of-concept phase 1 study assessing low-dose COYA 301 (Coya Therapeutics), an investigational interleukin-2 (IL-2) treatment, indicated sustained cognition among patients with Alzheimer disease (AD). The therapy also restored peripheral T cell regulatory (Treg) function and ameliorated systemic pro-inflammatory mediators.

These data were presented at the Keystone Symposium – Neurodegeneration: New Biology Guiding the Next Generation of Therapeutic Development, in Whistler, B.C. Canada. Comprised of 8 individuals with a confirmed presence of brain amyloid pathology, findings showed statistically significant improvement in mean Mini-Mental State Examination (MMSE) scores after 168 days of treatment (P = .015).

"Our study of low-dose IL-2 in patients with AD provided promising results," Stanley H. Appel, MD, director, Ann Kimball & John W. Johnson Center for Cellular Therapeutics, Houston Methodist, said in a statement.¹ "The therapy was well tolerated, and most significantly it demonstrated expansion in Treg population, and lowered pro-inflammatory cytokines and chemokines. These positive findings were further supported by lack of decline in cognitive function during the treatment phase, suggesting that low dose IL-2 may provide a potentially meaningful approach for the treatment of AD."

COYA 301 is a combination immunotherapy designed to lower activated T effector cells and activated macrophages/microglia, while increasing Treg function and numbers. In the study, enrolled individuals received monthly 5-day course of subcutaneous low-dose IL-2 for 4 cycles and were followed for an additional 2 months post-treatment. Treg immunophenotype and functional analysis were assessed at screening and day 1, and 3 days after the fifth dose of each treatment cycle during therapy, and then at weeks 17 and 24. Coming into the trial, patients had baseline MMSE Scores between 12 and 25.

During the 4-month treatment period, COYA 301 appeared to be well tolerated, with mild injection-site reactions (37.5%; n = 3) and mild leukopenia (37.5%; n = 3) as the most common adverse events (AEs) observed. All patients completed the 4-month treatment phase as well as 2-month post-treatment follow up phase. Of note, there were no serious AEs recorded throughout the trial.

On cognition, MMSE scores at day 120 and 168 of treatment were comparable to the baseline level. A trend toward improvement was observed in Clinical Dementia Rating-Sum of Boxes score on day 120 which was reverse toward baseline on day 168. On days 120 and 168, scores on Alzheimer’s Disease Assessment Scale-Cognitive Subscale were comparable to that observed at baseline.

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Findings also revealed that low-dose IL-2 immunotherapy suppressed pro-inflammatory cytokines and chemokines, demonstrated by attenuation in the plasma levels of IL-15, CCL2, CCL11. At the end of treatment, treated patients showed a nearly doubling in percentage of Tregs, from 4.55 (SD, 1.97) at baseline to 8.68 (SD, 2.99; P = .0004). Mean Treg suppressive function was 46.61% (SD, 7.74) at baseline, and significantly increased to 79.5% (SD, 20.55) at the end of treatment (P = .003).

"We believe the outcomes of this proof-of-concept study of COYA 301 in patients with AD are encouraging and we will continue to analyze the data to decide our next steps. These results and the recent positive data for COYA 302 in the treatment of ALS strengthen Coya’s approach for the development of immunotherapies for the treatment of neurodegenerative diseases," Adrian Hepner, MD, PhD, president and chief medical officer, Coya Therapeutics, said in a statement.¹

Coya has also conducted studies assessing its Treg treatment in patients with amyotrophic lateral sclerosis (ALS). A small-scale study published in Neurology in 2022 featured 7 individuals with ALS randomly assigned to receive Treg infusions (1 x 10⁶ cells/kg) intravenously every 4 weeks and IL-2 (2 x 10⁵ IU/m²) injections 3 times/week or matching placebo for a 24-week period, followed by a 24-week dose-escalation open-label extension.³

Compared with baseline, findings from that phase 1 study showed increased Treg suppressive function and numbers. Additonally, 6 of the 8 participants changed by an average of –2.7 points on ALS Functional Rating Scale-Revised, whereas the other 2 changed by an average of –10.5 points. Elevated levels of 2 markers of peripheral inflammation—IL-17C and IL-17F—and 2 markers of oxidative stress—oxidized low-density lipoprotein receptor 1 and oxidized LDL—were present in the 2 rapidly progressing participants but not in the slower progressing group.

REFERENCES
1. Coya Therapeutics’ COYA 301 increased Treg function and halted cognitive decline in an open-label study in patients with Alzheimer’s disease. News release. Coya Therapeutics. May 16, 2023. Accessed May 16, 2023. https://ir.coyatherapeutics.com/news/news-details/2023/Coya-Therapeutics-COYA-301-Increased-Treg-Function-and-Halted-Cognitive-Decline-in-an-Open-Label-Study-in-Patients-with-Alzheimers-Disease/default.aspx
2. Faridar A, Eid AM, Thome AD, et al. Regulatory T cell expansion strategy to target inflammation in AD: Phase 1 feasibility trial. Presented at: Keystone Symposium – Neurodegeneration: New Biology Guiding the Next Generation of Therapeutic Development.
3. Thonhoff JR, Berry JD, Macklin EA, et al. Combined regulatory T-lymphocyte and IL-2 treatment is safe, tolerable, and biologically active for 1 year in persons with amyotrophic lateral sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022;9(6):e20019. doi:10.1212/NXI.0000000200019.