Both dosages of CRS3123 showed excellent efficacy at the day 12 test-of-cure visit, hitting the primary endpoint
CRS3123 had lower rates of recurrence (e.g., 4% for the combined CRS3123 dosages versus 23% for vancomycin at day 40), addressing the primary unmet medical need in C. difficile infections
Crestone also presented data from multi-omics analysis of Phase 2 samples showing CRS3123 preserved the gut microbiome and secondary bile acid synthesis better than vancomycin
These data warrant advancing CRS3123 into Phase 3 development for treatment of CDI
BOULDER, Colo.--(BUSINESS WIRE)--Crestone, Inc. (“Crestone”) today announced recent publication in the leading infectious disease journal, The Lancet Infectious Diseases, of positive results from a Phase 2 clinical trial evaluating CRS3123 in patients with a primary episode or first recurrence of Clostridioides difficile infection (CDI). The paper was published online January 22, 2026 and is available as an open access article at https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(25)00721-2/fulltext.
In this first study in patients with CDI, a serious infection that rarely resolves on its own, CRS3123 achieved clinical cure at day 12 test-of-cure in 28/29 (97%) patients receiving one of two dosages of CRS3123 versus 13/14 (93%) in those receiving vancomycin. Clinical cure was accompanied by rapid reduction in levels of C. difficile toxin, spore counts and diarrhea in all treatment groups.
However, the major unmet medical need in CDI is to reduce recurrence, which continues to impact 20% to 40% of CDI patients with existing therapies. It is well accepted that the key to avoiding recurrence is to preserve natural, healthy gut microbiota while selectively inhibiting C. difficile. CRS3123 was chosen for this ability. Consistent with its narrow spectrum, in this Phase 2 study rates of CDI recurrence were considerably lower in those patients who received CRS3123. In one analysis, at day 40 recurrence rates were 4% for the two dosages of CRS3123 combined versus 23% for vancomycin. Treatment-emergent adverse events were mild to moderate in severity and similar across treatment groups. Both dosages of CRS3123 were deemed safe and well tolerated, and no serious adverse events were reported with CRS3123.
Dr. Thomas Louie of University of Calgary, Canada, first author on the Lancet ID paper and principal investigator for this study, stated: “There are a lot of people who suffer from CDI repeatedly. It is essential that we improve patient access to clinical trials of new, more selective investigational agents like CRS3123 and to speed the development and approval of therapeutic options to avoid recurrences of CDI.”
Results of Multi-omics Analysis of Effects on the Gut Microbiome
Crestone also announced that multi-omics analysis of Phase 2 samples showed CRS3123 preserved the gut microbiome and secondary bile acid synthesis better than vancomycin. These data were generated in the laboratory of Dr. Catherine Lozupone at University of Colorado Anschutz and presented in a poster January 30, 2026 by Dr. Laurie Lyon at the Interdisciplinary Meeting on Antimicrobial Resistance and Innovation (IMARI) 2026 conference in Las Vegas, Nevada.
CRS3123 treatment retains bacterial diversity much better and impacts healthy gut microbiota considerably less than vancomycin treatment. CRS3123 preserves beneficial genera Bacteroides and Bifidobacterium, while vancomycin-treated patients displayed communities skewed away from Bacteroides toward Enterobacteriaceaedominance. Metagenomics analyses showed counts of bacterial genes responsible for secondary bile acid synthesis are significantly higher at test-of-cure in CRS3123 groups compared to vancomycin. Secondary bile acids are vital for preventing CDI, inhibiting germination of C. difficile spores. Untargeted metabolomics show a less disturbed metabolome with CRS3123 than with vancomycin.
Vancomycin-resistant enterococci (VRE), which was present at baseline in some patients in each group, increased in the vancomycin group but was rapidly eliminated in both CRS3123 groups. This is consistent with preclinical data showing CRS3123 to be one of the most potent agents against enterococci (including VRE) yet described. VRE can cause serious infections, particularly in hospitalized patients or those with weakened immune systems.
Results of Additional Supporting Studies
Based on earlier topline results of the Phase 2 CDI study, NIAID exercised its option under an existing contract with Crestone to fund these gut microbiome analyses and a series of other supporting efforts to prepare for Phase 3 development. Today Crestone announced that it has successfully completed the following projects:
- Improved chemical process for synthesizing CRS3123. This included reducing the number of synthetic steps by approximately half with a favorable reduction in projected cost of goods for CRS3123. Crestone has filed for patent protection covering methods of synthesizing CRS3123.
- Extended stability testing, confirming that CRS3123 is stable for more than five years. This enables stockpiling and inventory management and minimizes risks of future supply shortages.
- Phase 1 food effect study, with results suggesting it may be taken with or without food
- Nonclinical sub-chronic toxicity study and development and reproductive toxicity (DART) studies, with no clinically significant safety findings
- Phase 3 study designs and plan. Crestone and its collaborators have engaged with leaders of more than 50 infectious disease centers around the world to discuss, design and optimize planned Phase 3 clinical trials of CRS3123 in CDI.
“Taken together, these data suggest CRS3123 could become the leading option for treating CDI,” said Nebojsa Janjic, PhD, co-Founder, CEO and President at Crestone. “We are excited to have seen the enthusiasm among many infectious disease physicians for efficiently completing the Phase 3 program and delivering CRS3123 to CDI patients.” said Dr. Janjic.
The Phase 2 clinical trial and these related efforts have been funded with federal funds from NIAID, U.S. National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93019C00056.
About the Phase 2 Clinical Trial of CRS3123 in CDI
The Phase 2, randomized, double-blind, comparator-controlled, multicenter study evaluated safety and efficacy of two dosages of CRS3123 (200 mg and 400 mg) administered twice-daily compared with vancomycin 125 mg administered four times daily in 43 adults diagnosed with a primary episode or first recurrence of CDI. The duration of treatment for all study treatment arms was 10 days. Patients with clinically documented, toxin-positive CDI were enrolled at sites in the U.S. and Canada. The primary endpoint was defined as the rate of clinical cure at day 12 in the intent-to-treat (ITT) population. Secondary and exploratory endpoints included rates of recurrence and global cure, time to resolution of diarrhea and the effect of CRS3123 on commensal bacteria in the gut.
About C. difficile Infection
CDI is the most common hospital-acquired infection in the U.S. and is now even more prevalent in the community, including in younger patients. In the U.S. there are almost half a million infections each year and approximately 30,000 deaths. CDI has been identified by the Centers for Disease Control and Prevention (CDC) as an “urgent” threat. CDI is an infection of the gut causing severe diarrhea and, in severe cases, toxic megacolon or death. Currently, most patients are treated with suboptimal, broad-spectrum antibiotics that prevent healthy gut microbiota from recovering, contributing to CDI recurrence rates of 20-40%. Once CDI recurs, it is more likely to recur again and again even after further treatment with existing therapeutics, leading to substantially increased morbidity and mortality. 30-day CDI mortality rates ranging from 6% to 11% have been reported by CDC and multiple other sources. Among Medicare beneficiaries over 65 with a first CDI episode, mortality from all causes within 12 months was between 35% and 45%. An effective therapy that treats CDI while preventing recurrent CDI continues to be urgently needed.
About CRS3123
CRS3123 is a small molecule antibacterial agent that selectively inhibits one form of bacterial methionyl-tRNA synthetase, which is absent in other important bacterial species that are part of normal gut microbiota. This is the clear mechanistic basis of its narrow spectrum and consistent with the substantially lower recurrence rates observed in this Phase 2 study. As a protein synthesis inhibitor, CRS3123 blocks not only C. difficile growth, but also toxin production and spore formation. In Phase 1 trials in healthy subjects and in this Phase 2 trial in CDI patients, CRS3123 achieved high intestinal concentrations, low systemic exposure and was generally safe and well tolerated. The FDA has granted QIDP and Fast Track designations to CRS3123 for the treatment of CDI.
About Crestone, Inc.
Boulder, Colorado-based Crestone, Inc. is a clinical stage biopharmaceutical company focused on inventing and developing novel mechanism of action, small molecule antimicrobial drugs. Its lead candidate, CRS3123, is in clinical development to treat CDI and under investigation as a microbiome modulator to treat symptoms of autism spectrum disorder, symptoms of Pitt Hopkins Syndrome (a rare genetic disease), prevention of graft versus host disease (GvHD) and other indications. The company has been funded primarily through multiple research and development grants and contracts worth more than $50 million, including two ongoing NIAID contracts. The company is owned by its scientific founders and staff and currently retains worldwide, royalty-free rights to its programs.
Contacts
Investor Contact:
Crestone, Inc.
Nebojsa Janjic, CEO and President
(303) 913-0919
njanjic@crestonepharma.com
https://crestonepharma.com/
