Development of Antibiotic-Free Clostridium difficile Therapeutics Biotherapeutics Inc (BTI) is an emerging biotech company that synergistically combines the power of advanced computational modeling with translational experimentation to accelerate the development of novel products for precision medicine and health. Lead molecule, BT-11, is a novel small molecule therapeutic targeting the Lanthionine Synthetase C-Like 2 (LANCL2) pathway in inflammatory bowel disease (IBD) that has two open INDs and completed Phase I clinical testing in 2018. Preliminary data in mice demonstrates that modulating immune responses by activating the LANCL2 pathway with BT-11 provides broader Clostridium difficile strain coverage, improved survival, and relapse protection compared to antibiotic treatment. Background: C. difficile is an anaerobic bacterium that has re-emerged as a facultative pathogen and can cause diarrhea, colitis, and death. In the U.S. alone, C. difficile infection (CDI) was estimated to affect over 500,000 people with 29,000 deaths within 30 days of the initial diagnosis. The current treatment for C. difficile is an antibiotic-based therapy. Paradoxically, the at-risk population is adults on regular antibiotics due to the critical role of the gut microbiome in preventing and resolving C. difficile expansion. This SBIR develops a host-based antibiotic-free therapeutic that could combat antibiotic resistance and preserve the gut microbiome. Our Technology: BTI will investigate the therapeutic efficacy and mechanism of action of novel LANCL2- targeting drugs (BT-11) with the potential to prevent excessive tissue-damaging inflammation and modulate host responses to the gut microbiome during CDI.
The Specific Aims are to: (1) Investigate the effect of BT-11 on the post-antibiotic gut microbiome in healthy and C. difficile infected mice. (2) Determine BT-11 efficacy in the protection from disease recurrence in a mouse model of relapse. (3) Characterize the potential for human translation of BT-11 through the ex vivo C. difficile toxin response in human PBMCs and intestinal organoids. Expected outcomes: i) Establish the effects of BT-11 on beneficial gut microbiota (butyrogenic bacteria, Lactobacillus); ii) Demonstrate that BT-11 treatment results in >30% reduction of disease and 0% mortality during the recurrent phase; and iii) Generate a translational data package that guides the clinical development plan. The SBIR Phase II will perform in vivo validation studies with a neonatal pig model of CDI to assess broader C. difficile strain coverage, improved survival, and relapse protection. Further, we will compare therapeutic and prophylactic dosing of BT-11 to current standard (antibiotics) and developing (anti-toxin antibodies) therapies. Commercial Application: This application will develop new antibiotic-free technologies that prevent recurrence, maintain the indigenous gut microbiome, and offer a prophylactic intervention for CDI that fosters antibiotic stewardship for a $500 million market while lowering the $3 billion burden in the U.S. healthcare.
This SBIR Phase 1 application will develop new host-targeted, antibiotic-sparing interventions for Clostridium difficile infection. Given that 30% of adults who developed healthcare-associated diarrhea were positive for C. difficile and that this bacterium caused almost half a million infections in the U.S., this project is timely as it will guide the development of gut microbiome-preserving host-targeting alternatives to the widespread use of antimicrobials. The proposed C. difficile therapy is a non-antibiotic, anti-inflammatory LANCL2-targeting small molecule therapeutic (BT-11) that may become an alternative to anti-microbial usage, could disrupt a $500M market while lowering the $3 billion burden in U.S. healthcare.
