Low-Dose Interleukin-2 Reduces Proinflammatory Biomarkers in Phase 2 Study of Alzheimer Disease

Fred Grossman, DO

Newly announced data from an investigator-initiated, double-blind, placebo-controlled, exploratory phase 2 study showed that treatment with low-dose interleukin-2 (LD IL-2), also known as COYA 301, resulted in significant reductions of several proinflammatory biomarkers among patients with early-stage Alzheimer disease (AD). Coya Therapeutics, the drug manufacturer of the agent, believes these data further support continued clinical development of COYA 301 as a potential treatment for the disease.¹

The trial comprised of participants aged 50 to 86 with Mini Mental State Examination (MMSE) scores ranging from 12 to 26 who were randomly assigned 1:1 to either 5 days of LD IL-2 (106 IU/day) (LD IL-2 q4wks) or placebo every four weeks for 21 weeks. A total of 22 participants made up this group while an additional 16 participants were randomized in a 2:1 ratio to receive 5-day cycles of LD IL-2 every 2 weeks (LD IL-2 q2wks) or placebo for the same 21-week duration. All participants were monitored for 9 weeks post-treatment, resulting in a total study duration period of 30 weeks.

Among those on a monthly cycle of LD IL-2, investigators observed lower blood levels of the proinflammatory chemokine (C-C motif) ligand 2 (CCL2; P <.05) and proinflammatory cytokine IL-15 (P <.001) were statistically significant in comparison with placebo. In addition, there was a statistically significant increase in the anti-inflammatory cytokine IL-4 (P <.01) in those on monthly cycles of LD IL-2. Notably, once patients stopped treatment at the end of the 5-month period, anti-inflammatory benefits revered back to placebo levels.

"We believe the reduction of proinflammatory factors within peripheral blood corresponding with significant improvement in beta amyloid 42 in the cerebrospinal fluid and cognitive stabilization during LD IL-2 therapy underscores the importance of targeting regulatory T cells in Alzheimer disease," Fred Grossman, DO, chief medical officer at Coya, said in a statement. "We believe LD IL-2 offers an immunomodulatory strategy that enhances Treg function for potentially treating Alzheimer disease and several other neurodegenerative disorders."

In the study, monthly LD IL-2 demonstrated statistically significant improvoements in serum inflammatory markers, aligning with earlier findings in patients with AD. This regimen also led to a 4.93-point improvement in the Alzheimer’s Disease Assessment Cognitive Scale (ADAS-Cog) score compared with placebo over a 21-week treatment period. Monthly LD IL-2 also increased amyloid-ß 42 levels in cerebrospinal fluid (CSF), suggesting enhanced amyloid-ß clearance, maintained stable neurofilament light chain (NfL) levels in CSF, and achieved significant regulatory T cell (Treg) expansion, highlighting its targeted biological activity. In contrast, biweekly LD IL-2 or placebo did not yield similar results.

READ MORE: Finding Happiness as a Trailblazer

COYA 301, designed to enhance the anti-inflammatory function of Tregs, was considered well tolerated, with no serious adverse events (SAEs) or deaths reported. Mild injection site reactions and a mild increase in eosinophil counts were among the most common AEs reported. Coya noted that a comprehensive data set will be presented and released throughout 2025 and in a peer reviewed publication.

"While monotherapy with LD IL-2 shows targeted improvement in biological activity in patients with AD, as demonstrated in this early Phase 2 academic study, we think that combining our proprietary LD IL-2 (COYA 301) with several other immunomodulatory modalities could deliver additive or even synergistic targeted effects," Arun Swaminathan, PhD, chief executive officer at Coya, said in a statement.

In a previously conducted phase 1 proof-of-concept study featuring 8 individuals with a confirmed presence of brain amyloid pathology, treatment with COYA 301 led to statistically significant improvement in MMSE scores after 168 days (P = .015). 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). Above all, the treatment was well tolerated, with mild injection-site reactions (37.5%; n = 3) and mild leukopenia (37.5%; n = 3) as the most common AEs observed. Similar to the phase 2 study, there were no serious AEs recorded throughout the trial.^2,3

REFERENCES
1. Coya Therapeutics Reports Statistically Significant Improvement of Inflammatory Blood Markers in Patients with Alzheimer’s Disease Following Monthly Dosing with Low-Dose IL-2, Further Supporting Clinical Development. Coya Therapeutics. News release. February 6, 2025. Accessed February 7, 2025. https://finance.yahoo.com/news/coya-therapeutics-reports-statistically-significant-130000484.html
2. 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 February 7, 2025. 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
3. 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.