A novel oral immunotherapy for chronic visceral pain of irritable bowel syndrome

Abstract: Chronic visceral pain is a defining feature of irritable bowel syndrome (IBS) that is currently considered as a disorder of brain-gut interaction. Although pain is the most common driver of healthcare visits for IBS patients, the current treatment options are often ineffective and associated with side effects. The use of

potent opioids for visceral pain has been reported to be associated with higher morbidity and mortality than other pain conditions and contribute to the opioid epidemic. Although the etiology of IBS is not clearly understood, the current studies indicate that neuroinflammation in gastrointestinal tract plays a critical role in

the pathogenesis of visceral pain. Gut inflammatory mediators modulate the intestinal nerve system, leading to long-lasting functional alterations after resolution of the inflammatory insult. Among inflammatory mediators, tumor necrosis factor-alpha (TNF-α) is a “master regulator” and found to be implicated in both

peripheral and central sensitization during pain induction in preclinical pain models and significantly elevated in some IBS patients especially patients with post-infection/inflammation IBS. This preclinical and clinical evidence supports the development of therapeutics targeting gut TNF-α for the treatment of IBS pain.

Fzata has developed a novel oral biotherapeutic, FZ006, an engineered probiotic yeast Saccharomyces boulardii that secretes a neutralizing antibody against TNF-α. We demonstrated that oral FZ006 delivers anti- TNF to gut and exhibited exceptional efficacy on relieving visceral pain in several animal models. To develop

FZ006 as a safe, non-addictive, first-in-class, oral therapeutic to treat chronic visceral pain, we propose the UG3/UH3 plan with the final aim of an IND submission requesting clearance for phase I clinical trials. Specifically, in the UG3 phase, we will determine the effective dose range of FZ006 and validate therapeutic

efficacy in humanized mice; perform small-scale manufacturing and generate a well-characterized research cell bank; and prepare and submit pre-IND meeting request with the FDA. In the UH3 phase, we will manufacture FZ006 under GMP to generate drug substance and drug product for clinical trials; perform

stability assessment and GLP toxicology studies; plan for first-in-human trial; and finally submit IND application to the FDA for approval. Our ultimate goal is to develop FZ006 as an effective, safe, convenient, and non- addictive oral therapeutic to treat chronic visceral pain in IBS patients.