Novel Immunoregulatory Drugs for Systemic Lupus Erythematosus 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. The company leadership has experience in advancing novel drugs from discovery to late-stage clinical development. Systemic lupus erythematosus (SLE) is an autoimmune disease that afflicts 1.5 million Americans. Through our previous research on abscisic acid, we discovered the anti-inflammatory and pro-regulatory immune effects of a novel class of oral lupus therapeutics. Our lead compound reduces key lupus biomarkers and overall disease severity in 3 mouse models and induces potent immunoregulatory effects in human PBMCs. This project will evaluate the comparative efficacy, safety and translatability of our novel agonists for the treatment of SLE. The Specific Aims for this SBIR Phase II application are to: (1) Evaluate the combinatorial and comparative efficacy of BT-96 in the NZB/W F1 model of SLE. NZB/W F1 mice will be therapeutically dosed with BT-96 at the maximally effective dose, independently or in combination with 5 standard-of-care or in-development drugs. Survival, anti-nuclear antibodies, proteinuria, and kidney histopathology will be assessed as endpoints. (2) Conduct IND-enabling genotoxicity and a 3-month repeat dose toxicity study in rats. We will perform an Ames test, chromosomal aberration study and micronucleus test to complete the FDA’s requirement for genetic toxicity. A 3-month toxicity study will be conducted to evaluate general safety. (3) Elucidate a translational signature of BT-96 to serve as a dose-ranging marker of target engagement. RNA samples from NZB/W F1 whole blood will be used to identify correlates between transcriptional changes and oral efficacy at various doses. Transcriptional changes will be aligned with mechanism of action and histological and biomarker results. Signature will be validated in SLE patient PBMCs. Expected successful outcomes will include: i) improved protection from proteinuria with BT-96 relative to other therapies; ii) NOAEL ≥ 500 mg/kg; and iii) validation of regulatory T cell and phagocytosis-mediated mechanisms. The long-term goal of this project is to develop a novel immunomodulatory therapeutic capable of serving as a safer and more effective treatment for SLE and provide a path towards commercialization of a product candidate with a target population of over 5 million resulting in a market of over $1.5 billion.