Novel first-in-class Therapeutics for Rheumatoid Arthritis

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Novel first-in-class Therapeutics for Rheumatoid Arthritis 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. This SBIR application will advance the development of a novel oral first-in-class therapeutic for rheumatoid arthritis (RA). Our Product: We have identified a family of small-molecule therapeutics that bind and activate a novel therapeutic target with immunological and metabolic functions. The goal of this project is to develop our lead binding-agonist, as an oral, first-in-class therapeutic for RA. Background: RA is a disabling chronic inflammatory disorder affecting 1.5 million patients in the U.S., with a total annual societal cost exceeding $39 billion. Limited therapeutic efficacy and abundant safety concerns, among the classes of current therapeutics in the market, result in an unmet clinical need for the development of safer and more effective RA therapeutics with novel mechanisms of action. Our novel drug candidate binds and activates a newly identified pathway with therapeutic properties that ameliorates disease severity and inflammation in animal models of RA, suppressing inflammatory responses in immune cells plus modulating fibroblast-like synoviocytes (FLS) activation. This SBIR Phase I project will develop our lead-binding agonist for RA, validate its therapeutic efficacy and safety and characterize its mechanisms on FLS activation during RA. The Specific Aims are to: AIM 1. Conduct pharmacokinetic (PK) and safety studies to determine oral bioavailability, tissue distribution and half-life as well as a 14-day repeat-dose toxicity in rats. AIM 2. Characterize the effects of our lead compound on human fibroblast-like synoviocyte metabolism and activation through analysis of metabolic profile and assessment of key metabolic enzyme activity. AIM 3. Compare the therapeutic efficacy of the lead compound to current approved RA therapeutics in two rat models by clinical scores, joint histopathology, inflammatory markers, and flow cytometric analysis. Expected Outcomes: Validation of our lead compound as a novel therapeutic candidate for the treatment of RA that: i) inhibits the increased glycolytic usage in activated FLS from RA patients, ii) ameliorates synovial inflammation in vivo; and iii) has a benign safety profile with NOAEL ≥ 1,000 mg/kg. SBIR Phase II will validate the therapeutic efficacy of this novel drug candidate in chronic models of RA, perform ADME and off-target assays and advance our novel drug candidate to IND-enabling studies. Commercial Application: This project will develop a new drug program of small molecule therapeutics that exert anti-inflammatory functions through modulation of multi-pronged mechanisms of action. This new drug development program could disrupt the RA expanding market of $25 billion.