Targeting Irritable Bowel Syndrome (IBS) with astressins

Abstract Sentia seeks to bring to fruition 40 years (1975 - 2015) of NIDDK-funded (P01 DK026741; PIs: W. Vale, C. Rivier, J. Spiess and J. Rivier) academic research to achieve translational drug candidacy by blocking both corticotropin-releasing factor (CRF) receptors CRF1/2 with potent astressin peptide antagonists. Present assets of Sentia include world-wide, patent-protected, andquot;first-in-classandquot; peptide drug candidates and intellectual property that targets, among others, the regulation of the stress response system. Scientific evidence documents that potentially dozens of current human ailments can benefit from the use of stress-neutralizing compounds to achieve temporal or permanent homeostasis. In particular, irritable bowel syndrome (IBS) is well established to be a stress-sensitive condition with visceral pain being the hallmark. Alleviating visceral pain in IBS patients is still an unmet need and the market for managing and/or curing the symptoms is conservatively estimated to be in the $5-10B range. Astressin therapeutics would represent a andquot;first-in-classandquot; opportunity to safely and effectively treat IBS patients with injectable peptide analogs that could represent a paradigm shift in therapeutic intervention away from conventional short-acting oral small molecules providing patients a different option for long-acting relief. In our Phase I SBIR studies, a new Fmoc synthetic process for making astressins was successfully validated and activity of these drug candidates was demonstrated after acute testing in an IP CRF-induced model of visceral hypersensitivity. The objective of the Phase II SBIR is to further supply relevant quantities of astressin CRF1/2 antagonists (compounds 1-3) manufactured following the Fmoc strategy to support non-GLP chronic pharmacology studies and to evaluate the drug metabolism and pharmacokinetic (DMPK) and toxicological profile of the compounds. In Aim 1, additional quantities of astressins required for the proposed non-GLP studies will be synthesized. Synthetic methods will be transferred to a CRO in preparation for future larger scale synthesis. The goal of Aim 2 will be to develop bioanalytical methods for detection of the astressin drug candidate as well as to establish the DMPK profile of the compounds and Aim 3 will evaluate the chronic efficacy of the astressin drug candidates in both prophylactic and therapeutic modalities in a pharmacological and disease model of IBS, respectively. Aim 4 will assess the in vivo and in vitro toxicological profile after acute and repeat dosing. The data package will provide sufficient information on efficacy and therapeutic margins to select a candidate(s) for further evaluation, IND-enabling studies and clinical development.Narrative Sentia Medical Sciences, Inc. of La Jolla, CA (J. Rivier, Founder) is a biotech company that designs and develops peptide antagonists targeting G-protein coupled receptors (GPCRs) with a focus on the corticotropin- releasing factor (CRF) pathways involved in the stress response. Sentia now seeks to translate 40 years (1975 - 2015) of NIDDK-funded (P01 DK026741; PIs: W. Vale, C. Rivier, J. Spiess and J. Rivier) academic research on CRF signaling to advance novel “first-in-class” injectable peptide CRF1/2 antagonists that, if approved, would represent a paradigm shift for patients with IBS, who are currently treated with short-acting oral small molecules that have limited efficacy, significant side effects and do not adequately address visceral pain. In this regard, the proposal seeks to assess the DMPK and toxicity profile of the antagonists and provide further preclinical evidence that novel, potent, long-acting, patented CRF1/2 astressin peptide antagonists can provide chronic benefit by addressing unmet needs in IBS, such as visceral pain and diarrhea, with a goal to select a clinical candidate(s) for further evaluation and progression into IND-enabling studies.