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BACKGROUND
Clostridium difficile (C. difficile), a spore forming bacteria, is the leading cause of hospital acquired diarrhea and antibiotic associated pseudomembranous colitis. Disruption of the protective gut microbiota by antibiotics creates a niche and enables colonization of opportunistic multidrug resistant C. difficile. Once colonized, C. difficile releases a highly potent toxin–TcdB–that destroys the colonic epithelial barrier, leading to watery diarrhea, fever, nausea, and abdominal pain. In the United States alone, C. difficile affects 500,000 patients annually, causing up to 30,000 deaths, and incurring inpatient hospitalization costs of close to $5 billion. One major clinical challenge with C. difficile is recurrent infection, which occurs in 20–30% of patients and more than 60% of patients that have had three or more C. difficile infection episodes.
Previous studies have shown neutralizing TcdB alone is sufficient to prevent primary C. difficile infection and recurrence, validating TcdB as a therapeutic target. The only TcdB-targeted therapy available on the market is an injectable monoclonal antibody known as Zinplava™. However, due to its high cost ($4,000 USD/dose), its marginal efficacy against emerging more virulent forms of TcdB, and inconvenient route of administration (intravenous infusion), Zinplava™ has not been approved in markets beyond the US. As such, there remains a major unmet need and an opportunity for novel small molecule based anti-TcdB therapies with lower costs, that can be orally administered, and possess a broader efficacy profile against TcdB toxin variants without disturbing the protective gut microbiota.
DESCRIPTION OF THE INVENTION
The Melnyk Lab at The Hospital for Sick Children (SickKids) discovered that certain naturally occurring bile acids bind to TcdB and prevent its ability to intoxicate cells (Tam et al., PNAS, 2020). This led to the hypothesis that bile acids could potentially be given orally to treat C. difficile disease. Bile acids, however, are rapidly absorbed in the gut by bile acid transporters, and thus, do not reach the colon where TcdB acts. This makes the naturally occurring bile acids not suitable for treating C. difficile infection without a careful modification to evade the transporters.
To address this, in collaboration with the Dosa lab at the University of Minnesota, SickKids researchers synthesized novel bile acid variants that were designed to not be recognized by bile acid transporters, and therefore, retained in the gut with TcdB. Initial testing of the lead molecule (to be optimized further) revealed that it is gut-restricted, highly potent to inhibit TcdB action in vitro, non-toxic to human cells and prevents disease recurrence in in vivo mice models (Figure 1).
COMMERCIAL APPLICATIONS & ADVANTAGES
- The global C. difficile infection treatment market is estimated at $1.1B USD in 2022 with a projected CAGR of 6–8% (2022–2025).
- Bile acid-based therapeutics are safe and do not disrupt the natural beneficial gut microbiota.
- FDA approval of Relyvrio™ (sodium phenylbutyrate/taurursodiol) for the treatment of ALS demonstrates a successful regulatory path for bile acid-based therapeutics.
- Bile acid variant-based therapeutics are a superior (potent against TcdB and its variants), cost effective (small molecule), and convenient (oral route of administration) alternative to treat C. difficile infection and prevent recurrence, compared to TcdB targeted monoclonal antibody-based Zinplava™.
DEVELOPMENT STAGE
Proof of concept is established. The research team is continuing to synthesize additional novel variants of the lead bile acid molecule.
PATENT STATUS
Preparing to file a US provisional patent application.
PUBLICATION
Tam et al. 2020. Intestinal bile acids directly modulate the structure and function of C. difficile TcdB toxin. PNAS. 17(12): 6792–6800
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Figure 1. Testing in C. difficile recurrence model. Mice were treated with an antibiotic to disrupt gut microbiota, then given C. difficile spores to allow disease development. Mice were then treated with vancomycin to decrease bacterial load and allow mice to recover. Upon removing vancomycin, C. difficile rapidly returns and disease relapses (yellow curve). However, mice treated with lead bile acid variant molecule did not develop any clinical sign of disease (blue curve).
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