Abstract. Chronic kidney disease (CKD) is a progressive disorder affecting almost 14% of the general population, and this disease has shown a relentless growth over the past 2 decades. Patients with CKD have higher rates of hospitalization, greater mortality, shorter life expectancy, and their healthcare costs are up to 5 times more expensive than non-CKD patients. Thus, treatments to slow, halt, or reverse the progression of CKD could have a significant financial and clinical impact. Chronic renal vascular disease (RVD), often associated with renal artery stenosis, can deteriorate renal function and lead to CKD and end-stage renal disease in up to 15% of patients. Despite the availability of treatments for RVD including drugs and percutaneous transluminal renal angioplasty, renal function does not improve or even deteriorates in over half of the patients undergoing these treatments. Leflore Technologies has developed a biopolymer-stabilized form of vascular endothelial growth factor (VEGF) with high renal binding. Leflore Technology’s overall strategy is to use the biopolymer-VEGF fusion for therapeutic angiogenesis to restore renal microvasculature and improve renal function in RVD and/or CKD. During the Phase I portion of this STTR, non-GLP efficacy and toxicity testing were conducted with the biopolymer-fused VEGF. Using a swine model of renal artery stenosis – induced RVD, angioplasty and stenting with or without therapeutic renal angiogenesis using our biopolymer-stabilized VEGF was tested in a preclinical trial. In the treatment arm, renal function and renal vascular density were significantly improved, and histological markers of renal injury were reduced, relative to angioplasty and stenting alone. We also performed a dose- escalating toxicology study in rats, which demonstrated that the biopolymer-stabilized VEGF induced no significant side-effects at doses up to 100 times the planned therapeutic dose. The proposed Phase II studies will advance the lead agent through cGMP manufacturing; chemistry, manufacturing and controls testing; and expanded preclinical IND-enabling GLP toxicology. The planned studies will also extend our prior efficacy studies by testing in animals with progressively more severe renal disease, with longer follow-ups, and using multiple rodent models of CKD caused by diabetes or hypertension as well as extended studies in our translational swine model of CKD to expand the potential target market beyond RVD treated with stenting to chronic kidney disease as a whole.

Narrative. Chronic renovascular disease can deteriorate renal function leading to chronic kidney disease and the need for dialysis, and it increases the risk of heart attacks, strokes, and death. Current treatment for renovascular disease involving renal angioplasty and stenting combined with anti-angiotensin agents and statins are ineffective in up to half of the patients. The goal of this Phase II STTR is to extend efficacy and safety studies completed in Phase I using a biopolymer-stabilized vascular endothelial growth factor to recover the kidney microvascular density and function, including performing cGMP manufacturing; GLP toxicology in rats, minipigs, and beagles; and extended efficacy testing in multiple chronic kidney disease models of varying etiology.