Phase II year
2017
(last award dollars: 2019)
Phase II Amount
$1,499,461
Radikal Therapeutics (RTX) is developing a pioneering therapy to restore immunotolerance and arrest progressive depigmentation in vitiligo. At our partnering institution, Loyola University Chicago, a variant to inducible Heat Shock Protein 70 was developed with remarkable potential for the prevention and treatment of autoimmune vitiligo. Carrying only a single amino acid modification to the protein, this variant HSP70iQ435A (CM) was found to have a curative effect involving long-lasting tolerization of dendritic cells (DCs) and inhibition of T cell influx to the skin. In the Phase 1 SBIR we examined the CM in a model of spontaneous depigmentation in Sinclair swine, characterized by regressing melanoma and newly developing vitiligo. Paralleling the clinical presentation, in this system the inflammatory CD11b+CD11c+ subset of DCs held responsible for precipitating and perpetuating vitiligo is found in increased abundance among circulating and skin infiltrating DC. We observed that untreated lesions in the control group gradually increased in size by 32%, whereas repigmentation of 37% was observed in CM treated lesions (p=0.0045). This change in cutaneous pigmentation was associated in treated pigs with a 50% reduction in infiltrating T cells (p<0.04). We thus hypothesize that the CM-encoding DNA will likewise interfere with progressive depigmentation in human vitiligo patients, providing incentive for the development of the CM into a marketable drug. Aim #1: Scale-up and produce GMP-grade CM The PI will synthesize de novo a high-producing E. coli clone expressing the CM plasmid. RTX will finalize optimization of the growth conditions, develop product-specific HPLC release assays, and generate a reference standard. Aldevron will generate a Master Cell Bank and Working Cell Bank expressing the CM, and generate a g GMP batch of the CM in order to support clinical Phase 1a safety and efficacy investigations in clinical vitiligo, and to perform stability analysis. Analytical methods will be developed to characterize the CM for GMP release and stability studies. Aim #2: Relate CM treatment efficacy to disease duration in a murine model of vitiligo. RTX will measure efficacy of the CM in relation to disease duration in h3TA2 mice with progressive vitiligo. We will treat mice 6-36 weeks at age at onset to measure disease arrest and repigmentiation by scanning. Aim #3: Establish the acute safety, toxicity, and tolerance of CM in GLP toxicology studies required for FDA IND application. RTX will carry out a 13-week GLP study wherein the CM is dosed via a subcutaneous route of administration in order to elucidate the NOAEL in mice and provide the basis for the dose range to test for safety and tolerance in man. Aim #4: Compile and prepare a pre-IND application to the FDA RTX will prepare and submit regulatory documentation to support a clinical GCP Phase 1a study to evaluate the safety of the CM in human volunteers with active vitiligo. RTX will meet with the FDA to present our efficacy data to gain concurrence on a clinical registration pathway leading to drug registration in 2022.
Public Health Relevance Statement: We are proposing a novel pharmaceutical therapy to block the progression of vitiligo, a disease in which skin pigment is lost, resulting in progressive growth of lesions with out skin color. Our drug is a novel entity that targets the basic mechanisms of vitiligo and is intended as a lifelong therapy. We will undertake requisite manufacturing to prepare a supply of drug for preclinical and safety examination, carry out FDA- mandated toxicology studies in mice, and prepare to perform the first trial of the drug in humans with active vitiligo.
Project Terms: Acute; Address; Affect; Aftercare; Age; Amino Acids; analytical method; Animals; Appearance; Autoimmune Diseases; Autoimmune Process; Basic Science; Biological Assay; cell bank; Chicago; Clinical; clinically relevant; Collaborations; Control Groups; Cutaneous; Data; Dendritic Cells; Development; Disease; DNA; Documentation; Dose; drug market; Ensure; Escherichia coli; Family suidae; FarGo; Goals; Growth; GTP-Binding Protein alpha Subunits, Gs; Hair; Heat-Shock Proteins 70; High Pressure Liquid Chromatography; Human; Human Volunteers; illness length; Incentives; Inflammatory; innovation; Institution; Investigation; ITGAM gene; ITGAX gene; Laboratories; Lesion; man; manufacturing facility; Measures; Medical; meetings; melanocyte; Methods; Modeling; Modification; mouse model; Mus; No-Observed-Adverse-Effect Level; novel; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Pigmentation physiologic function; Pigments; Plasmids; preclinical safety; Prevention; Preventive; Production; professor; Proteins; Published Comment; quality assurance; Records; Recruitment Activity; Reference Standards; Regressing Melanoma; Reporting; Route; Safety; safety study; safety testing; scale up; Scanning; Skin; skin color; Small Business Innovation Research Grant; Social Interaction; Stem cells; subcutaneous; Suggestion; System; T-Cell Receptor; T-Lymphocyte; Technology Transfer; Therapeutic; Toxic effect; Toxicology; Transgenic Mice; Translating; Treatment Efficacy; Universities; Variant; Vitiligo
