SBIR-STTR Award

The objective of this proposal is to examine the efficacy of CLT-005, a novel small molecule inhibitor of Stat3, for treating inflammatory and vascular leakage of the retina of diabetic retinopathy. Retinal blood vessel formation is known to be mediated by the vascular endothelial growth factor (VEGF) protein, and current FDA approved treatments for AMD are inhibitors of this protein and its ability to signal. These drugs are a great advancement in the treatment of AMD, but they 1) fail to address the inflammatory nature of the disease; 2) are not effective in all AMD patients; 3) require monthly injections into the eye to deliver the drug; 4) can only be used once visual loss has already occurred. Although these therapies have shown promise in the clinic, new treatments that target novel pathways are highly desirable for better disease management and combinatorial therapeutic options. Several lines of evidence in the peer reviewed literature suggest the intimate involvement of Stat3 in retinal inflammation and neovascularization: 1) In humans, significantly elevated levels of Leptin are observed in the vitreous of patients with diabetes or some other form of retinopathy. 2) Leptin is a strong pro- angiogenic factor that initiates an activation cascade resulting in the phosphorylation/activation of Stat3 (pStat3). 3) pStat3 is a transcription factor that promotes expression of several inflammatory and neovascular genes, such as VEGF. 4) In animal models of acute retinal neovascularization, pStat3 is observed solely in the neovascular areas of the retina. 5) The inflammatory cytokine IL-6 also causes phosphorylation of pStat3 in the retina which causes choroidal neovascularization, and blockade of this pathway inhibits neovascular events. As pStat3 can rapidly change cellular gene expression and appears to be the effector molecule of these pathways, we developed a small molecule (CLT-005) that specifically inhibits phosphorylation and subsequent dimerization of Stat3. In our preliminary data, we have shown the CLT-005: 1) is predicted to bind to the phosphorylation site of Stat3, thus blocking dimerization and activation of this transcription factor; 2) selectively inhibits endothelial cell proliferation without any strong effect on pericyte cell viability; 3) reduces retinal ICAM-1 and VEGF levels in a rat model of diabetes. Based on these promising data, we propose to further evaluate the efficacy of CLT-005 in reducing retinal inflammation and vascular permeability in rodent models of diabetes and retinopathy. In this Phase I proposal, we will intravitreally administer varying concentrations of CLT-005 to the diabetic rat eyes and quantify the levels of the pro-inflammatory cytokines IL-6, TNF-1, and MCP-1. We will also assess and quantify leukostasis in these retinas as an early marker of inflammation. In addition, we will also quantify the efficacy of CLT-005 in reducing vascular leakage in the diabetic rat eye and in the rat model of oxygen-induced retinopathy which presents with acute retinal neovascularization. If this Phase I project proves the efficacy, these experiments will lay a solid ground for Phase II studies to further substantiate the promise of CLT-005 as a treatment for retinal inflammatory and macular edema.

Public Health Relevance:
Neovascular diseases of the retina, including Diabetic Retinopathy (DR) and Age-related Macular Degeneration (AMD), are the leading cause of blindness worldwide in patients over the age of 50. In several in vitro and in vivo models, activation of Stat3 has been shown to play a major role in initiating inflammatory and neovascular events in the retina. We have recently developed a novel small molecule (CLT-005) that inhibits this activation of Stat3, and thus presents as an ideal therapeutic for treating DR and AMD. The goal of this proposal is to prove the efficacy of CLT-005 is preventing retinal inflammation and vascular leakage in rodent models of diabetes and retinopathy.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
There Are No Thesaurus Terms On File For This Project.

The objective of this proposal is to finalize development of CLT-005, a novel small molecule inhibitor of Stat3, through the performance of studies required for the submission of an investigative new drug application with the US Food and Drug Administration (FDA). Activation of the Stat3 pathway in retinal inflammatory and angiogenic diseases has been observed in both clinical and basic science studies. We have demonstrated that CLT-005 prevents Stat3-induced cellular changes in an animal model of diabetes. Following intravitreal administration, CLT-005 reduces retinal vascular permeability, and the expression of numerous angiogenic and inflammatory genes and proteins. Additionally, both CLT-005 and the PEG-based depot-forming formulation were well tolerated following intravitreal injection, had no effect on visual physiology, and produced a favorable in-vitro safety profile. The goal of this proposal is to: 1) Produce GMP amounts of CLT-005 sufficient for toxicity studies and human clinical trials;2) Perform formulation of CLT-005 into sterile fill vials and conduct stability studies;3) Complete preparation of the CMC section for the IND application;4) Perform pharmacokinetic studies of formulated and unformulated CLT-005;5) Perform ocular distribution studies of formulated CLT-005;5) Conduct single and multiple dose GLP toxicology and toxicokinetic studies;6) Perform genetic toxicology studies;and 7) Perform in-vitro cardiac safety pharmacology studies. These studies are mandated by the FDA in order to receive approval for the initiation of human clinical trials. For ocular drug development, the FDA also requires that toxicology studies be performed in two large eye animal models, such as monkeys and rabbits, which will be utilized for completion of the experiments outlined above. As CLT-005 has a profound effect on reducing retinal vascular leakage we intend to seek an indication for treating Diabetic Macular Edema, a disease that currently has no FDA-approved pharmaceutical therapy. We believe that CLT- 005 will also be efficacious in patients suffering from Age-Related Macular Degeneration (AMD) and Diabetic Retinopathy (DR). Following the successful completion of Phase II human clinical studies of CLT-005, we intend to file new IND applications to investigate the use of CLT-005 in treating AMD and DR. CLT-005 could also prove to be an effective combinatorial therapy with existing anti-VEGF treatments to reduce the frequency of clinical dosing.

Public Health Relevance:
Retinal vascular leakage, inflammation, or breakdown of the blood-retina barrier are pathogenic features of Diabetic Macular Edema (DME) and cause a subsequent loss of vision. Currently, there are no FDA-approved drug treatments for DME. In this Phase II project, we will finalize studies of CLT-005, a novel small molecule therapeutic, to enable the submission of an investigative new drug application to the FDA. These studies include preparation of sterile materials and formulations, performance of pharmacokinetic studies, and performance of rigorous toxicology/safety studies that are mandated by the FDA and essential for human clinical trials. Although we intend to seek an initial indication for DME, it is likely that CLT-005 will also confer a significant therapeutic benefit to patients suffering from Diabetic Retinopathy and Age-Related Macular Degeneration.

Thesaurus Terms:
Adme Study;Absorption;Absorption, Distribution, Metabolism, And Excretion Study;Adhesion Molecule;Adipocytes;Adipose Cell;Adverse Effects;Affect;Age Related Macular Degeneration;Ames Assay;Animal Model;Animal Models And Related Studies;Assay;B Cell Differentiation Factor;B Cell Stimulating Factor 2;B-Cell Differentiation Factor-2;B-Cell Stimulatory Factor-2;Bcdf;Bsf-2;Bsf2;Bsf2 (B Cell Stimulating Factor 2);Bacteria;Basic Research;Basic Science;Binding;Binding (Molecular Function);Bioassay;Biologic Assays;Biological Assay;Blindness;Blood;Blood Vessels;Blood Capillaries;Blood-Retinal Barrier;Cd54 (Icam 1);Cd54 Antigens;Cachectin;Cachectin-Tumor Necrosis Factor;Capillaries;Capillary;Capillary, Unspecified;Cardiac;Cell Adhesion Molecules;Chemistry;Chemotherapy-Hormones/Steroids;Choroidal Neovascularization;Clinical;Clinical Research;Clinical Sciences;Clinical Study;Clinical Trials;Clinical Trials, Unspecified;Complex;Crab-Eating Macaque;Dna Alteration;Dna Mutation;Data;Development;Diabetes Mellitus;Diabetic Retinopathy;Differentiation Factor, B-Cell;Dimerization;Disease;Disease Progression;Disorder;Dose;Drug Formulations;Drug Kinetics;Drugs;Electroretinography;Endocrine Gland Secretion;Enzymes;Event;Excretory Function;Extravasation;Eye;Eyeball;Fda;Fat Cells;Food And Drug Administration;Food And Drug Administration (U.S.);Formulation;Formulations, Drug;Frequencies (Time Pattern);Frequency;Future;Gene Alteration;Gene Expression;Gene Mutation;Gene Proteins;Genes;Genetic Toxicology;Genetic Mutation;Glycoprotein Icam 1 (Human Clone Phrvr1 Deblocked Protein Moiety Reduced);Goals;Hpgf;Hepatocyte-Stimulating Factor;Hormones;Hour;Human;Human, General;Hybridoma Growth Factor;Icam-1;Ifn-Beta 2;Ifnb2;Il-6;Il6 Protein;Inflm;Iv Drip;In Vitro;Inflammation;Inflammatory;Injection Of Therapeutic Agent;Injections;Intercellular Adhesion Molecule 1;Interleukin 6 (Interferon, Beta 2);Interleukin-6;Intermediary Metabolism;Intravenous Drip;Intravenous Infusion;Ischemia;Leakage;Leptin;Ligands;Lipocytes;Metbl;Mgi-2;Macaca Fascicularis;Maculopathy, Age-Related;Mammals, Rabbits;Man (Taxonomy);Man, Modern;Mature Lipocyte;Mature Fat Cell;Measurement;Mediating;Medication;Metabolic Processes;Metabolism;Method Loinc Axis 6;Methodology;Molecular Interaction;Monkey, Crab-Eating;Monkey, Cynomolgus;Monkeys;Monocyte Chemoattractant Protein-1;Monocyte Chemotactic Protein-1;Monocyte Chemotactic And Activating Factor;Monocyte Chemotactic And Activating Protein;Monocyte Secretory Protein Je;Myeloid Differentiation-Inducing Protein;Neovascularization, Choroid;Nuclear Translocation;Ob Gene Product;Ob Protein;Obese Gene Product;Obese Protein;Ocular Physiology;Ophthalmologist;Oryctolagus Cuniculus;Pathogenesis;Pathway Interactions;Patients;Performance;Permeability;Pharmaceutic Preparations;Pharmaceutical Agent;Pharmaceutical Preparations;Pharmaceuticals;Pharmacokinetics;Pharmacologic Substance;Pharmacological Substance;Pharmacology;Phase;Physiology Of The Eye;Plasmacytoma Growth Factor;Preparation;Prevalence;Process Of Absorption;Production;Protein Dimerization;Protein Gene Products;Proteins;Rabbit, Domestic;Rabbits;Rat Model Of Diabetes;Rats, Norway;Rattus Norvegicus;Receptor Activation;Receptor Protein;Recovery;Reporting;Reticuloendothelial System, Blood;Retina;Retinal;Retinal Diseases;Retinal Disorder;Retinal Neovascularization;Risk;Sh2 Domains;Stat Protein;Safety;Science Of Chemistry;Sequence Alteration;Signal Transducer And Activator Of Transcription;Small Inducible Cytokine A2;Spillage;Sterility;Tnf-Alpha;Therapeutic;Therapeutic Hormone;Toxic Effect;Toxicities;Toxicogenetics;Toxicokinetics;Toxicology;Toxicology Genetics;Treatment Side Effects;Tumor Necrosis Factor;Tumor Necrosis Factor-Alpha;Usfda;United States Food And Drug Administration;Vegfs;Variant;Variation;Vascular Endothelial Growth Factors;Vascular Permeabilities;Vegf;Vial;Vial Device;Visual;Visual Physiology;Absorption;Angiogenesis;Base;Capillary;Cell Adhesion Protein;Clinical Investigation;Combinatorial;Cost Effective;Cytokine;Diabetes;Diabetic;Diabetic Patient;Diabetic Rat;Diabetic Rat Model;Disease /Disorder;Disease/Disorder;Drip Infusion;Drug /Agent;Drug Candidate;Drug Development;Drug/Agent;Effective Therapy;Electroretinogram;Excretion;Experiment;Experimental Research;Experimental Study;Gene Product;In Vivo;Inhibitor;Inhibitor /Antagonist;Inhibitor/Antagonist;Interferon Beta 2;Interleukin 6;Intravenous Administration;Mrna Expression;Macula;Macular;Macular Edema;Model Organism;Monocyte Chemoattractant Protein 1;Neovascularization;Novel;Ob/Ob Mouse;Pathway;Preclinical Safety;Preclinical Study;Prevent;Preventing;Protein Expression;Receptor;Research Study;Response;Retina Disease;Retina Disorder;Retinopathy;Safety Study;Senile Macular Disease;Side Effect;Small Molecule;Src Homology Region 2 Domain;Sterile;Therapy Adverse Effect;Transcription Factor;Treatment Adverse Effect;Tumor Necrosis Factor Alpha;Vascular;Vein Infusion