SBIR-STTR Award

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 (PTRA), 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. This Phase I STTR will test the feasibility of PTRA and stenting plus therapeutic renal angiogenesis with our biopolymer-stabilized VEGF in a preclinical trial using a swine model of chronic RVD. Recently, we have demonstrated that our biopolymer fusion greatly stabilizes the growth factor from degradation and plasma or tissue clearance and mediates deposition in the kidney following intrarenal administration. Furthermore, we have compelling preliminary evidence that our biopolymer- delivered VEGF is highly efficacious for restoring renal function in the swine model. The proposed Phase I studies will carry out preclinical efficacy and safety trials of PTRA and stenting in combination with our biopolymer-delivered VEGF compared to PTRA and stenting alone or PTRA and stenting with standard of care pharmacotherapy. These studies will examine the efficacy of this strategy relative to current clinical standard of care, the efficacy of this strategy at early-, middle-, and late-stage RVD, and the long-term efficacy and safety of the intervention. Future Phase II studies will involve good manufacturing and practice (GMP) production of our recombinant biological agent; chemistry, manufacturing and controls testing; and expanded preclinical IND-enabling toxicology.

Public Health Relevance Statement:
Narrative. Chronic renovascular disease can deteriorate renal function leading to 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 pharmacotherapy with anti-angiotensin agents and statins are ineffective in up to half of the patients. The goal of this Phase I STTR is to test the efficacy and safety of a novel biopolymer-stabilized vascular endothelial growth factor to recover the kidney after renal angioplasty using a swine model of chronic renal vascular disease that is very similar to human disease.

Project Terms:
3-Dimensional; Adverse effects; Affect; Affinity; angiogenesis; Angioplasty; Angiotensins; Architecture; Binding; Biocompatible; Biological Availability; Biological Products; biomaterial compatibility; Biomedical Engineering; Biopolymers; cardiovascular risk factor; Carrier Proteins; Cessation of life; Chemistry; Chimeric Proteins; Chronic; Chronic Kidney Failure; Clinical; Collection; commercialization; density; Deposition; Deterioration; Dialysis procedure; Disease; Dose; Drug Carriers; efficacy testing; Elastin; End stage renal failure; Engineering; Family suidae; Fibrosis; Future; General Population; Glomerular Filtration Rate; Goals; Gold; Growth; Growth Factor; Half-Life; Health Care Costs; hemodynamics; Hospitalization; Human; human disease; immunogenicity; improved; In Vitro; in vivo; Infusion procedures; Injury; Intervention; Kidney; Kidney Diseases; kidney vascular structure; Lead; Licensing; Life Expectancy; Link; Mediating; Microcirculation; Modeling; Morbidity - disease rate; mortality; Mus; Myocardial Infarction; Nature; NOEL; novel; novel therapeutic intervention; patient population; Patients; peptide drug; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; phase 1 study; phase 2 study; Plasma; polypeptide; pre-clinical; preclinical efficacy; preclinical evaluation; preclinical trial; Predisposition; Prevalence; Production; Proteins; Recombinants; Recovery; Renal Artery Stenosis; Renal Blood Flow; Renal Cell Carcinoma; Renal function; Renal Vascular Disorder; residence; Resolution; response; Risk; Safety; Schedule; Signal Transduction; Small Business Technology Transfer Research; small molecule; standard of care; Stents; stroke; Technology; Testing; Therapeutic; therapeutic angiogenesis; therapeutic development; Time; Tissues; Toxic effect; Toxicology; Treatment Efficacy; Tubular formation; tumor growth; United States; Vascular Endothelial Growth Factors; X-Ray Computed Tomography

Chronic kidney disease (CKD) is a progressive disorder affecting almost 14% of the general population, andthis disease has shown a relentless growth over the past 2 decades. Patients with CKD have higher rates ofhospitalization, greater mortality, shorter life expectancy, and their healthcare costs are up to 5 times moreexpensive than non-CKD patients. Thus, treatments to slow, halt, or reverse the progression of CKD could havea significant financial and clinical impact. Chronic renal vascular disease (RVD), often associated with renalartery stenosis, can deteriorate renal function and lead to CKD and end-stage renal disease in up to 15% ofpatients. Despite the availability of treatments for RVD including drugs and percutaneous transluminal renalangioplasty, renal function does not improve or even deteriorates in over half of the patients undergoing thesetreatments. Leflore Technologies has developed a biopolymer-stabilized form of vascular endothelial growthfactor (VEGF) with high renal binding. Leflore Technology's overall strategy is to use the biopolymer-VEGFfusion for therapeutic angiogenesis to restore renal microvasculature and improve renal function in RVD and/orCKD. During the Phase I portion of this STTR, non-GLP efficacy and toxicity testing were conducted with thebiopolymer-fused VEGF. Using a swine model of renal artery stenosis - induced RVD, angioplasty and stentingwith or without therapeutic renal angiogenesis using our biopolymer-stabilized VEGF was tested in a preclinicaltrial. In the treatment arm, renal function and renal vascular density were significantly improved, and histologicalmarkers 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 nosignificant side-effects at doses up to 100 times the planned therapeutic dose. The proposed Phase II studieswill advance the lead agent through cGMP manufacturing; chemistry, manufacturing and controls testing; andexpanded preclinical IND-enabling GLP toxicology. The planned studies will also extend our prior efficacystudies by testing in animals with progressively more severe renal disease, with longer follow-ups, and usingmultiple rodent models of CKD caused by diabetes or hypertension as well as extended studies in ourtranslational swine model of CKD to expand the potential target market beyond RVD treated with stenting tochronic kidney disease as a whole.

Public Health Relevance Statement:
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.

Project Terms:
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