Recursion Pharmaceuticals has dosed the first patient in its Phase II ALDER trial (NCT06536465) evaluating REC-3964, an oral, non-antibiotic small molecule for recurrent Clostridioides difficile (C. diff) infection. This marks the first new chemical entity developed through Recursion's RecursionOS operating system to reach this stage of clinical development. The trial aims to address the significant unmet need for effective and microbiome-sparing treatments for C. diff, a bacterium responsible for nearly 500,000 infections and an estimated 29,300 deaths annually in the U.S., according to the CDC.
Novel Mechanism of Action
REC-3964 is designed to treat C. diff by selectively inhibiting the glucosyltransferase activity of toxin B, a key virulence factor produced by the bacterium in the gastrointestinal tract. This approach differs significantly from traditional antibiotics, which disrupt the gut microbiome and can paradoxically increase the risk of recurrent C. diff infections. By precisely targeting the bacterial toxin while sparing healthy tissue, Recursion aims to minimize adverse events and improve long-term outcomes for patients.
"While antibiotics can successfully clear the infection, they simultaneously pose an increased risk of developing C. diff. They are at once a treatment and a cause," said Chris Gibson, PhD, Recursion’s co-founder and CEO.
The Burden of C. diff Infection
C. diff toxin B disrupts the tight junctions in colonic cells and increases vascular permeability, leading to a leaky gut. Standard antibiotic treatments, while initially effective, fail to prevent recurrence in 20-30% of primary cases, with recurrence rates rising to 40% after the first recurrence and 45-65% after two or more. Given that up to 60% of C. diff cases are treated with antibiotics within the four months preceding the infection, Recursion believes REC-3964 offers a crucial alternative that aligns with antimicrobial stewardship principles.
Clinical Trial Details and Future Outlook
The Phase II ALDER trial is a multi-center, randomized study designed to investigate the safety, tolerability, pharmacokinetics (PK), and efficacy of REC-3964 at doses of either 250 mg or 500 mg. The study will also include an observation-only arm. Approximately 80 patients will be enrolled across the U.S. and Europe. Recursion anticipates sharing an update on the study, including enrollment, preliminary efficacy (rate of recurrence), and safety data, in Q4 2025.
"By specifically targeting the primary mediator of the symptomatic infection, there is a potential for REC-3964 to intervene during the maintenance stage, without the increased risk of developing infections associated with antibiotics," Gibson added.
Competitive Landscape
REC-3964 joins a growing field of therapies targeting C. diff. Recent developments include positive preclinical results for an mRNA-LNP vaccine developed by researchers at the University of Pennsylvania and the Children’s Hospital of Philadelphia, and positive topline Phase II results for Crestone Pharmaceuticals' CRS3123. However, Pfizer's C. diff vaccine, PF-06425090, failed to meet its primary endpoint in the Phase III CLOVER trial.
RecursionOS: AI-Driven Drug Discovery
RecursionOS is an AI-enabled platform that maps and navigates trillions of biological and chemical relationships within a vast proprietary dataset. This allows for the rapid identification and prioritization of promising drug candidates. According to Gibson, RecursionOS enables the company to reach IND-enabling studies three times faster and at half the cost compared to industry averages.
"Using the power of our massive connected datasets to surface novel opportunities, we’ve developed a small set of standardized and industrialized experiments to rapidly prioritize and confirm our in silico insights for tens of thousands of dollars each and in just weeks— as opposed to spending years and multiple millions of dollars to research one specific target," Gibson stated.
Preclinical studies presented at the 6th Edition of World Congress on Infectious Diseases demonstrated REC-3964's superiority over bezlotoxumab in a human disease-relevant C. diff hamster model. Phase I studies in healthy volunteers showed REC-3964 was well-tolerated with no serious adverse events.
