Small Molecule Therapeutics for Renal Disease

DESCRIPTION (provided by applicant): Diabetic and non-diabetic nephropathies and the Metabolic Syndrome are associated with chronic kidney disease (CKD) - a program comprising proteinuria, accumulation of profibrotic collagen in the renal interstitium and relentless decline in renal function. CKD remains an unsolved challenge for the nephrologist, as it almost inevitably leads to end-stage renal disease, a life-threatening condition that necessitates renal replacement therapy. Currently approved therapies aimed at halting CKD are incompletely effective, evidenced by the dramatic and rising rates of requirement for renal replacement therapy. Scatter factor/hepatocyte growth factor (SF/HGF) is a renotrophic factor that is mitogenic for renal epithelial cells, exerts antifibrotic effects within the renal interstitium and stimulates renal repair. Clinical feasibility of SF/HGF administration is however limited by a number of logistical and financial issues relating to gene or protein therapy, especially in the setting of chronic diseases wherein orally bioavailable therapeutics are preferred. Using a drug-discovery engine comprising phage display, molecular modeling, rational drug design, targeted proteomics and preclinical biology, Angion Biomedica Corp. has identified BB3, an orally bioavailable small molecule SF/HGF mimetic. BB3 activates the SF/HGF receptor c-Met and recapitulates the bioactivities of SF/HGF in every assay tested to date. Similar to SF/HGF, BB3 downregulates the fibrotic program in activated astrocytes, hepatic stellate cells and renal fibroblasts. In preclinical models of dermal, pulmonary and hepatic fibrosis, BB3 is therapeutic, opposing profibrotic collagen deposition and preserving tissue microarchitecture. Our SBIR Phase I data indicate that orally administered BB3 is therapeutic in experimental CKD, attenuating mortality, limiting proteinuria and opposing renal interstitial collagen deposition. Additionally, data from a pilot study suggest that in a preclinical model of Metabolic Syndrome, oral administration of BB3 reduces proteinuria and attenuates renal interstitial collagen accumulation. From a drug development and regulatory perspective, a chronic (6- month), oral, escalating-dose, good laboratory practice safety study of BB3 in rat and dog is ongoing under the aegis of the NIH Rapid Access to Intervention Development program. Of significant clinical relevance, BB3 has successfully completed a Phase I acute safety clinical trial in healthy volunteers; a Phase IIA pharmacokinetics and tolerance study of BB3 in patients presenting with renal insufficiency is underway. The present SBIR Phase II application is designed to make a comprehensive and in-depth analysis of BB3 efficacy in preclinical models of CKD. Dose-dependence, dose schedule and therapeutic time window of BB3 will first be established in experimental CKD. Renal antifibrotic effects of BB3 will be evaluated together with standard-of-care and in models comprising co-morbid disease. Successful completion of the proposed work, together with the current clinical status of BB3, will enable us to enter this drug candidate into a safety and efficacy trial in CKD. PUBLIC HEALTH RELEVANCE An orally bioavailable small molecule antifibrotic has significant clinical potential for the treatment of chronic kidney disease.