Coya Therapeutics Advances ALS Combo Immunotherapy Into Phase 2 Trial

Speakers on a Coya Therapeutics webinar outlined the company's scientific rationale and clinical development plans for an investigational combination immunotherapy in amyotrophic lateral sclerosis (ALS), emphasizing a shift in the field toward more targeted, biology-driven approaches. The company presented a combination immunotherapy strategy using low-dose IL-2 to expand regulatory T cells (Tregs) together with CTLA-4 Ig (abatacept) to suppress macrophage-driven inflammation, aiming to target neuroinflammation as a core ALS disease mechanism.

During the discussion, presenters described an "huge need" for therapies that can more meaningfully slow or halt ALS progression—and raised the possibility that future approaches could potentially reverse some functional decline or even prevent disease, questions they said were not realistic to ask "many years ago."

Panelists pointed to the approval of tofersen for SOD1 ALS as a major milestone over the last decade, calling it an example of a highly targeted therapy that can "have a remarkable effect on the biology of the disease." At the same time, they noted this applies to a small subset of patients—about 2% of ALS cases—and argued that the next challenge is replicating that level of biological impact for broader ALS populations.

When asked why currently approved therapies tend to deliver only modest benefit and why so many ALS trials have failed, speakers suggested many prior efforts were "unfocused," often based on broad observations of neurodegeneration rather than specific disease-driving biology. They said the field has increasingly converged on neuroinflammation as a key target, noting that neuroinflammation is now widely viewed as a central component of ALS pathology.

Inflammation in ALS involves immune system alterations, including activated macrophages releasing pro-inflammatory cytokines, and multiple T cell subtypes (including CD4 T cells such as Th1 and Th17, as well as CD8 cytotoxic T cells) that can contribute to neurodegeneration. A central focus of the webinar was regulatory T cells (Tregs), which were described as neuroprotective due to their ability to suppress inflammatory responses. However, Tregs in ALS patients are often not suppressive "to the extent that they should be," characterized as dysfunctional and unable to adequately counter neuroinflammation.

While IL-2 can expand Tregs in animals and humans, administering IL-2 in ALS occurs within an inflammatory environment. Lab findings suggested activated macrophages can drive Tregs into dysfunction and "exhaustion" over several days in culture. In that context, the addition of CTLA-4 Ig (abatacept) was supported by in vitro data as a way to suppress inflammatory macrophage activity and help prevent Treg dysfunction.

In the proposed combination approach, IL-2 is intended to expand Tregs while abatacept suppresses macrophage-driven inflammation—an effort to address what speakers described as immune system complexity and "redundant pathways." The dual targeting was characterized as "very exciting," noting that IL-2 alone has shown limited benefit and that the feedback loop between macrophages and Tregs may help explain why.

A previously conducted study involved four ALS patients progressing at what was called an intermediate rate; one patient had a C9orf72 mutation. The combination was administered subcutaneously every two weeks for six months, with treatment extended beyond that period. According to presenters, the regimen "seemed to slow progression," and in some cases appeared to stop progression during the initial six months, though progression continued when followed more carefully over a longer period, albeit at a slower pace. Patients "felt tremendously" about the therapy and asked to continue.

A four-patient experience produced encouraging biomarker signals—IL-18 fell in 3/4 patients, oxidized LDL and 4-HNE declined in all four, and neurofilament light decreased in two patients who had elevated NfL at baseline, while two others did not have high NfL at baseline.

The principal investigator for the ALSTARS Phase 2 trial said the randomized, placebo-controlled study is planned across close to 25 sites in the U.S. and Canada. The trial aims to enroll 120 people with ALS, with one-third assigned to placebo for six months. The program is moving into the randomized, placebo-controlled ALSTARS Phase 2 trial comparing two abatacept dosing schedules with a blinded extension; investigators described low-dose IL-2 and abatacept as generally well tolerated but noted standard safety screening (e.g., latent TB) is required.

While four patients is a small sample, the decision to move forward was described as based on the "totality of the evidence," including longstanding Treg biology, macrophage activation, and the ability to track biomarker changes alongside clinical outcomes.