Novel Therapeutic for SLE

Biotherapeutics, Inc., Blacksburg VA

Investigators

Abstract

Novel Therapeutic for SLE BioTherapeutics Inc (BTI) is a clinical-stage biopharmaceutical company focused on the discovery and development of innovative first-in-class oral therapeutics for patients with inflammatory and autoimmune diseases. We have developed a novel oral small molecule product candidate for the treatment of systemic lupus erythematosus (SLE). An unmet clinical need for safer, more effective SLE drugs remains, as current therapies have limited efficacy and significant adverse side effects. Systemic lupus erythematosus (SLE) is an autoimmune disease that afflicts 1.5 million Americans. Lupus nephritis (LN) is a complication of SLE that afflicts up to 60% of patients. We have identified a novel anti- inflammatory pathway that supports immune tolerance through both regulatory CD4+ T cells (Tregs) and myeloid cells. In a model of TLR activation that mimics the pathogenesis of SLE, the loss of this immunological target results in a significant increase in mortality and overall disease severity. As a result, we developed a small molecule therapeutic to activate this new target. In three mouse models of lupus, oral dosing with our novel product candidate results in a significant decrease in proteinuria, increased Tregs, reduction of inflammatory cells and other signs of disease. Further, our product candidate has successfully completed IND-enabling studies with no identification of dose-limiting toxicities or target organ systems. The Specific Aims for the SBIR Fast-Track Phase I application are to: (1) Determine minimally effective and saturated concentrations. Mixed leukocyte reactions will be conducted to estimate the amount of drug needed to elicit a response from immune cells. Transition Milestones are: i) increase in abundance in Tregs at one or more dose levels; ii) decrease in MCP1; and iii) statistical differences in tested blood markers at one or more dose levels. The Specific Aims for the SBIR Fast-Track Phase II application are to: (2) Conduct chronic toxicity studies. We will conduct 6-month rat and 9-month dog chronic repeat dose toxicity studies at 0, 250, 500 and 1000 mg/kg. (3) Evaluate combinatorial therapeutic efficacy with current standard of care drugs in mouse models of SLE. We will use NZB/W F1 and MRL/lpr models of SLE to determine if mechanistic synergisms exist with current standard of care. Expected successful outcomes will be: i) NOAEL ≥ 1000 mg/kg in all toxicology studies; ii) equal or greater efficacy relative to current SLE drugs; and ii) absence of destructive effects. The long-term goal of this SBIR application is to develop a novel lead compound as a safer, more effective first- in-class oral therapeutic for SLE through translational, toxicological and preclinical studies. This research will address an unmet clinical need for a market exceeding $2.6 billion and growing 11% annually.