Artificial intelligence (AI)-based drug developer Recursion has dosed the first patient in its Phase II ALDER trial (NCT06536465) evaluating its first new chemical entity to be developed through its RecurionOS operating system, an oral, non-antibiotic small molecule for recurrent treatment Clostridioides difficile (C. difference) infection.

REC-3964 is designed to treat C. difference by selectively inhibiting the glucosyltransferase activity of toxin B produced by the bacteria in the gastrointestinal tract, offering a different mechanism of action than antibiotics. Unlike antibiotics, which alter the gut microbiome, REC-3964 precisely targets the bacterial toxin while sparing healthy tissue, an approach that Recursion says could potentially minimize adverse events.

This marks a shift from previous antibiotic-based treatment approaches toward C. differencea toxin-producing bacteria that causes diarrhea and colitis and can be life-threatening. According to the US Centers for Disease Control and Prevention (CDC), each year almost 500,000 cases of C. difference The infection is estimated to occur in the US, with the bacteria responsible for An estimated 29,300 deaths..

“While antibiotics can successfully clear the infection, they pose an increased risk of developing C. difference. They are both a treatment and a cause,” said Chris Gibson, PhD, co-founder and CEO of Recursion. GEN Edge.

C. difference Toxin B disrupts the tight junctions of colon cells and increases vascular permeability, causing a leaky gut. The standard treatment for C. difference. Infections are antibiotics that alter the gut microbiome due to their non-selective nature. Despite initial success, antibiotics fail to prevent recurrence in 20-30% of primary cases—a risk that increases to 40% after the first case and 45-65% after two or more cases, according to a study 2019.

Citing research indicating that up to 60% of C. difference Cases are treated with antibiotics within four months before infection, Gibson said, Recursion saw the need for new therapies and an emphasis on antimicrobial stewardship as expressed by the Infectious Diseases Society of America (IDSA) and other organizations .

“This is where we think a small-molecule oral drug like REC-3964 could initially step in,” Gibson said. “By specifically targeting the primary mediator of symptomatic infection, there is potential for REC-3964 to intervene during the maintenance phase, without the increased risk of developing antibiotic-associated infections.”

“We look forward to sharing an update on the study in terms of enrollment, preliminary efficacy (recurrence rate), and safety in high-risk (recurrent) rCDI.” C. difference infection) population in the fourth quarter of 2025,” Gibson said.

Jefferies equity analyst Dennis Ding wrote in a research note Oct. 21 that his company is awaiting trial results from REC-3964 and another candidate from Recursion is expected to show data next year, the MEK1/MEK2 REC-4881 for familial adenomatous polyposis: “In terms of data, we are looking at RXRX inhibitor MEK1/2 in H1:25 and REC-3964 phase II C-diff in 2025 to help validate platform”.

field full of people

REC-3964 joins an increasingly crowded field of drugs and vaccines in development against C. difference. Among the developments of recent weeks, researchers at the Perelman School of Medicine at the University of Pennsylvania and the Children’s Hospital of Philadelphia published a report on October 3. study in the magazine Science reporting positive preclinical results from animal models showing that its messenger RNA (mRNA)-lipid nanoparticle (LNP) C. difference The vaccine was found to protect against initial and recurrent infections by inducing a robust immune response.

The first vaccine of its kind for C. difference It also promoted the elimination of existing bacteria in the intestine and overcame deficits in host immunity to protect animals after infection. The research was funded in part by BioNTech, to which Penn has granted intellectual property rights related to the C. difference mRNA vaccine program, while Penn’s Perelman School of Medicine receives funding for BioNTech research and development related to the work.

Crestone Pharmaceuticals reported positive results last month in its Phase II trial (NCT04781387) evaluating its small molecule protein synthesis inhibitor CRS3123. Among 43 patients in the main population of the intention-to-treat analysis, C. difference Recurrence rates at day 40 were 4% for patients treated with CRS3123, compared with 23% for patients treated with the comparator drug vancomycin, the glycopeptide antibiotic marketed in different forms as Vancocin.^® by ANI Pharmaceuticals and as Firvanq^® by Azurity Pharmaceuticals.

However, Pfizer C. difference The PF-06425090 vaccine failed in the phase III CLOVER trial (NCT03090191), omitting its primary endpoint by not showing a significant reduced incidence compared to placebo of C. difference infection (CDI) in adults at risk after receiving two or three doses. According to results published on August 24 in Clinical infectious diseasesvaccine efficacy was only 31%, as 17 participants who received all three doses of PF-06425090 and 25 randomized to placebo had a primary CDI episode 14 or more days after the third dose. Among those who received two doses, 24 PF-06425090 and 34 placebo recipients had a first episode of CDI 14 or more days after the second dose, for a vaccine efficacy of 28.6%.

In the first works on C. differenceGibson said, Recursion researchers identified numerous compounds that mitigated the effect of C. difference toxin B in human cells, and that they probably function through a variety of different hosts or specific targets of the toxin. Based on subsequent orthogonal screens, REC-3964 precursors emerged as the most promising substrate for further work.

“Put another way, we did not enter this field with the goal of identifying an antitoxin molecule, but rather we leveraged RecursionOS to identify the non-antibiotic modality that the data supported as most promising,” Gibson added.

RecursionOS is an AI-enabled platform that enables the company to map and navigate trillions of biological and chemical relationships within one of the world’s largest proprietary biological and chemical data sets (over 50 petabytes across multiple data layers), including phenomic, transcriptomic, and patient and animal studies. data.

“Virtuous learning cycles”

By tightly integrating our wet lab experimentation and dry lab machine learning iteratively, we create virtuous learning cycles, where large fit-for-purpose wet lab data sets support better in silico model generation and enable future wet analyzes more focused. laboratory experiments,” Gibson said. “On average, we are three times faster and half the cost to conduct IND studies compared to the industry.”

Because RecursionOS goes through learning cycles, he added, the company expects greater efficiency and ability to gain novel insights and create new chemical entities.

What time or cost savings are achieved as a result?

“Using the power of our huge connected data sets to uncover novel opportunities, we have developed a small set of standardized, industrialized experiments to rapidly prioritize and confirm our insights in silico for tens of thousands of dollars each and in just weeks, unlike of spending years and several million dollars to investigate a specific target,” Gibson responded.

At the sixth edition of the World Congress of Infectious Diseases, held in June in Paris and online, preclinical studies demonstrated that REC-3964 is superior to bezlotoxumab (a C. difference-binding monoclonal antibody marketed by Merck & Co. as Zinplava^®) in a relevant human disease C. difference. hamster model. Furthermore, phase I studies in healthy volunteers showed that REC-3964 was well tolerated and no serious adverse events occurred.

The Phase II ALDER trial is a multicenter randomized study designed to investigate the safety, tolerability, pharmacokinetics (PK), and efficacy of REC-3964 at doses of 250 mg or 500 mg for the reduction of C. difference. and will include an observation-only arm.

Ultimately, approximately 80 patients in the United States and Europe will be enrolled in the study. Recursion says it is working with leading academic researchers in the C. difference space to raise awareness about the trial. As part of that effort, Andrew Skinner, MD, assistant professor of infectious diseases at the University of Utah, will discuss the REC-3964 program at the Peggy Lillis Foundation’s first scientific meeting. symposium on November 15.