Novel Immunoregulatory Therapeutics for Systemic Lupus Erythematosus

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. Lead molecule, BT-11, is a new small molecule targeting the LANCL2 pathway in IBD with two open INDs, completed Phase I clinical testing and initiated a Phase II study in 2019. Systemic lupus erythematosus (SLE) is an autoimmune disease that afflicts 1.5 million Americans. Through our previous research on abscisic acid (ABA), we discovered the anti-inflammatory and pro-regulatory immunological effects of its receptor, lanthionine synthetase C-like 2 (LANCL2). Using a TLR7/8, resiquimod-induced model of SLE, we determined that the loss of LANCL2 increases susceptibility to severe disease and mortality. We have developed next-generation LANCL2-binding chemotypes, including the gut-restricted BT-11 and systemically distributed BT-96 that exert potent immune effects in vitro and in animal models of disease. This SBIR project will evaluate the therapeutic efficacy, pharmacokinetics (PK) profile and safety of novel LANCL2 agonists for the treatment of SLE. The Specific Aims for this SBIR Phase I application are to: (1) Evaluate the therapeutic efficacy and PK profile of BT-96 in the NZB/W F1 model of SLE. NZB/W F1 mice will be orally dosed with BT-96 at three dose levels therapeutically at 23 weeks of age. Survival, immunological signatures in blood and spleen, anti-nuclear antibodies, proteinuria, and kidney histopathology will be assessed as endpoints. Single and multiple dose pharmacokinetic profiles will be assessed in blood, spleen and kidney in NZB/W F1 mice. (2) Determine the immunomodulatory effects of BT-96 in primary human samples from SLE patients. We will test the efficacy of BT-96 in vitro to prevent inflammatory responses in primary human peripheral blood mononuclear cells (PBMCs) from SLE patients in response to general and nuclear antigen stimuli. Expected successful outcomes will include: i) a significant andgt;35% difference in survival with oral dosing of BT-96 in NZB/W F1 mice, ii) andgt; 50% in urine protein and serum anti-dsDNA at 36 weeks of age, and iii) andgt; 30% reduction in IFNα, TNF and IL-6 in SLE PBMCs with BT-96 treatment. The SBIR Phase II will elucidate the cellular mechanisms of efficacy of BT-96 in SLE, determine synergism and comparative efficacy to current and experimental therapeutics (low-dose IL-2), characterize the role of LANCL2 in the pathogenesis of human SLE, and advance BT-96 through IND-enabling studies. 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 an asset with an unmet need and a target population of over 5 million resulting in a market of over $3 billion by 2025.Public Health Relevance Systemic lupus erythematosus (SLE) is a difficult to manage autoimmune disease that afflicts 1.5 million Americans and over 5 million worldwide that often results in an unrelenting progression to kidney failure, cardiovascular disease and other physical impairments that significantly reduce quality of life while causing a disproportionally high health care burden. Lanthionine synthetase C-like 2 (LANCL2) ligands have displayed efficacy and safety in other autoimmune indications including inflammatory bowel disease (IBD). This SBIR Phase I project will develop a new class of safer, more efficacious, orally active, systemically distributed LANCL2- based immunomodulatory therapeutics for SLE patients in preparation for advancement along the FDA regulatory pathway toward clinical development.