Targeting the Immunometabolic Hub Nlrx1 as a Novel Therapeutic for Asthma

Targeting the Immunometabolic Hub Nlrx1 as a Novel Therapeutic for Allergic Asthma 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 stems from data showing a vital role for nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) as a new therapeutic target for allergy and asthma. Our Product: BTI has developed first-in-class, small-molecule therapeutics that bind and activate the novel regulatory molecule, NLRX1. The goal of this project is to validate NLRX1 as a target for allergic asthma and develop NX-73 as an oral therapeutic to treat mild to moderate to severe asthma. Significance: Asthma is a chronic disease afflicting over 330 million individuals globally and 40 million in the U. S. Asthma is a chronic, widespread allergic disease with total expenses exceeding $80 billion annually in the U.S. In particular, neutrophilic, non-type 2 asthma has a lower responsiveness to current treatments. Though recent years have witnessed an increase in the number of biologics for asthma, these biologics are specific to certain endotypes, are very costly, and require up to 26 visits per year for treatment via injections. Inhaled corticosteroids, another common form of treatment have moderate to serious adverse side-effects and are thought to reduce in effectiveness overtime. Thus, there is an unmet medical need for safer and more efficacious oral therapeutics for asthma. This SBIR Phase I application will develop NX-73 as a novel NLRX1-binding product candidate and validate its safety, efficacy, and specificity for the NLRX1 target. Success in this project will launch a new drug development program centered on NLRX1-activating orally active therapeutics with a long-term goal of entering clinical trials for asthma by 2022. The Specific Aims are to: Aim 1. Determine the in vivo proof-of-concept therapeutic efficacy of NX-73 in mouse models of allergic asthma. Aim 2. Evaluate whether NX-73 reduces Th2 and/or Th17 responses by dendritic cells and airway epithelial cells. Aim 3. Conduct preliminary pharmacokinetic (PK) and toxicity studies with NX-73 to determine the oral bioavailability and pulmonary distribution and 7-day repeat-dose toxicity in rats. Expected Successful Outcomes: i) Validation of the therapeutic efficacy of NX-73 as a lead molecule for suppressing asthma by targeting Nlrx1; ii) Reduction of asthma symptoms with oral doses of NX-73 ≤ 10 mg/kg; iii) Loss of NX-73 function in Nlrx1-/- mice and cells; and iv) Benign safety profile with NOAEL ≥ 1,000 mg/kg oral in rats. SBIR Phase II: Will validate the translation of NX-73 effects in human CD141hi dendritic cells and airway epithelial cells from individuals with mild-to-moderate and moderate-to-severe asthma, assess the therapeutic efficacy of NX-73 in a guinea pig model of asthma, and advance NX-73 to IND-enabling GLP toxicology studies. Commercial Application: At the conclusion of this Randamp;D effort BTI will have the preliminary validation necessary to select NX-73 as an IND-ready lead NLRX1-targeting small molecule. The impact of new oral, NLRX1-activating asthma therapeutics has the potential to disrupt a $56 billion industry that is anticipated to compound annual growth rate of 7%.PUBLIC HEALTH RELEVANCE Asthma is a common disease affecting nearly 10% of the U.S. population with high proportions of patients unresponsive to current medications. This SBIR Phase I has the potential to rapidly develop a novel class of oral therapeutics that target the Nod-like leucine rich repeat protein, Nlrx1, for the long-term control of allergy and asthma, and advance them through the FDA-regulatory pipeline into IND and clinical testing by 2022. The proposed studies will provide both the physiological relevance, safety profile, and mechanistic foundation for how NX-73 targets Nlrx1in the lungs to enhance immunometabolic effects that reduce the development of respiratory allergy and asthma.