Recursion brings AI-based C. Diff candidate to phase II

Artificial intelligence (AI)-based drug developer Recursion has dosed the first patient in its Phase II ALDER trial (NCT06536465) assessment of the first new chemical entity to be developed through the RecurionOS operating system, an oral, non-antibiotic small molecule for recurrent 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, providing a different mechanism of action than antibiotics. Unlike antibiotics, which disrupt the gut microbiome, REC-3964 precisely targets the bacterial toxin while sparing healthy tissue, an approach that could potentially minimize side effects due to recursion.

This is a departure from previous antibiotic-based treatment methods C. differencea toxin-producing bacteria that causes diarrhea and colitis and can be life-threatening. According to the U.S. Centers for Disease Control and Prevention (CDC), every year almost 500,000 cases by C. difference Infections in which the bacterium is responsible are estimated to occur in the US an estimated 29,300 deaths.

“Although antibiotics can successfully eliminate the infection, at the same time they pose an increased risk of development C. difference. They are both a treatment and a cause,” said Chris Gibson, PhD, co-founder and CEO of Recursion. GEN Rand.

C. difference toxin B disrupts the tight junctions in the cells of the colon and increases vascular permeability, leading to leaky gut. The standard treatment for C. difference. infections are antibiotics that disrupt the gut microbiome due to their non-selective nature. Despite initial success, antibiotics fail to prevent recurrence of the disease 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 from 2019.

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

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

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

Dennis Ding, an equity analyst at Jefferies, wrote in a research note on Oct. 21 that his company is awaiting results from trials of REC-3964 and another Recursion candidate expected to show data next year, MEK1/MEK2 inhibitor REC-4881 for familial adenomatous polyposis: “Data-wise, we are looking at RXRX’s MEK1/2 inhibitor in the first half of the year and REC-3964’s Phase II C-diff in 2025 to help validate the platform. ”

Crowded field

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

The first vaccine of its kind for C. difference also promoted the removal of existing bacteria from the intestines and overcame deficiencies in host immunity to protect animals after infection. The research was funded in part by BioNTech, to which Penn assigned and licensed intellectual property related to the software C. difference mRNA vaccine program, while Penn’s Perelman School of Medicine is receiving research and development funding from BioNTech related to the work.

Crestone Pharmaceuticals reported positive topline results from its Phase II trial last month (NCT04781387) assessment of the small molecule protein synthesis inhibitor CRS3123. Among 43 patients in the primary intent-to-treat analysis population C. difference the recurrence rate at day 40 was 4% for CRS3123-treated patients, compared with 23% for patients treated with the comparator vancomycin, the glycopeptide antibiotic marketed in various forms as Vancocin^® by ANI Pharmaceuticals, and as Firvanq^® from Azurity Pharmaceuticals.

But Pfizer’s C. difference vaccine PF-06425090 failed in the Phase III CLOVER trial (NCT03090191), missing its primary endpoint by not demonstrating a significantly reduced incidence compared to placebo C. difference infection (CDI) in high-risk adults after administration of 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 CDI episode 14 or more days after dose two, for a vaccine efficacy of 28.6%.

In the early work on C. differenceGibson said: Recursion researchers identified numerous compounds that mitigated its effect C. difference toxin B on human cells, and which would likely act through a variety of different host- or toxin-specific targets. Based on subsequent orthogonal screens, precursors of REC-3964 emerged as the most promising substrate for additional work.

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

RecursionOS is an AI-enabled platform that allows the company to map and navigate trillions of biological and chemical relationships within one of the world’s largest proprietary biological and chemical datasets – more than 50 petabytes across multiple data layers – including phenomena, transcriptomics and patient and animal data. facts.

“Cycles of virtuous learning”

By tightly integrating our wet-lab experiments and dry-lab machine learning in an iterative manner, we create cycles of virtuous learning, where large appropriate wet-lab datasets better support silico model generation and more targeted future law- enable lab datasets. laboratory experiments,” Gibson said. “On average, we are three times as fast and half cheaper for the IND than for the industry.”

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

What savings in time or costs result from this?

“Leveraging the power of our massive, connected data sets to uncover new possibilities, we have developed a small set of standardized and industrialized experiments to quickly prioritize and confirm our in silico insights, for tens of thousands dollars each and in just weeks – instead of spending years and several million dollars investigating one specific target,” Gibson responded.

At the 6th edition of the World Congress on Infectious Diseases, held in June in Paris and online, preclinical studies showed REC-3964 to be superior to bezlotoxumab (a C. difference-binding monoclonal antibody, by Merck & Co. marketed as Zinplava^®) in a disease relevant in humans C. difference. hamster model. Furthermore, phase I studies in healthy volunteers showed that REC-3964 was well tolerated without serious adverse events.

The Phase II ALDER study is a multicenter, randomized trial 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 US and Europe will participate in the study. Recursion says it is working with leading academic researchers in the C. difference space to increase awareness of the process. 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.