ABSTRACT Ulcerative colitis (UC) is a chronic, relapsing disease characterized by inflammation and ulceration of the colon and rectum that affects approximately 1.5 million people in the United States.1 Unfortunately, existing therapies have significant limitations. 5-ASA or mesalamine, which is approved as first-line therapy for UC, is effective in only 50% of UC patients and corticosteroids are not recommended for long-term use due to potentially serious side effects.6 While several classes of biologics and immunomodulators have been approved for UC in the last decade (e.g., anti-TNF-α, IL-12/23, α4β7, JAK and S1P), these drugs are approved only for moderate-to-severe UC, are incompletely effective, and have an increased risk of serious infection and malignancy.2 Moreover, biologics require parenteral administration, which is inconvenient and costly, and do not have durable effects for many patients.7 Thus, there is a critical unmet need for a safe, oral treatment as an alternative to immunosuppressive drugs for mild-to-moderate UC patients who are not well controlled by 5-ASA. Thetis Pharmaceuticals is developing TP-317, a first-in-class Resolvin E1 (RvE1) oral therapy for UC. TP-317 is a patented new molecular entity with enhanced stability compared to RvE1 as the natural material that can be formulated as an oral dosage form. Under a prior NIH SBIR Fast Track grant (RDK116460) completed in 2021, Thetis successfully conducted multiple investigational new drug (IND)-enabling studies with TP-317, including efficacy and pharmacokinetic studies, non-clinical toxicology and development and scale-up of a proprietary process for synthesis of TP-317. In a pre-IND meeting, the FDA indicated that Thetis can undertake clinical development under a Phase 1 study in healthy volunteers with no additional toxicology studies. The Phase 1 will be initiated in 2023. The goal of this Phase IIB SBIR program is to complete key non-clinical toxicology studies to enable rapid advancement of TP-317 into Phase 2 clinical trials in UC patients. Aim 1: Investigate TP-317 in Sub-chronic Toxicology Study in Rat (Year 1). We will conduct a 13-week GLP toxicology and toxicokinetic (TK) study in Sprague Dawley Rat with TP-317 administered via oral gavage. Aim 2: Investigate TP-317 in Sub-chronic Toxicology Study in Dog (Year 2). We will conduct a 13-week GLP toxicology and TK study in Beagle dog with TP-317 administered via oral gavage. Aim 3: Evaluation of TP-317 in Reproductive Toxicology Studies (Year 3). In Aim 3a, a fertility and early embryofetal development safety study will be conducted in Sprague-Dawley rats to assess the effects of TP-317 on gamete maturation, epididymal sperm maturation, reproductive function, mating behavior, rates of fertilization and implantation, and pre-implantation development. In Aim 3b, embryofetal development studies will evaluate the effects of TP-317 on embryonic organ formation, growth, and development in pregnant rat and rabbit. Succe...