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A novel immunotolerizing therapy for autoimmune vitiligo

Award Number: R44AR065886
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2014
PERIOD OF PERFORMANCE END DATE: 08/31/2020

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A novel immunotolerizing therapy for autoimmune vitiligo - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = -$461 )
2022	2019	SALZMAN GROUP, INC.	8 SOLVIVA RD	WEST TISBURY	MA	02575	DUKES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	3/24/2022	NON-COMPETING CONTINUATION	$0
2022	2019	SALZMAN GROUP, INC.	8 SOLVIVA RD	WEST TISBURY	MA	02575	DUKES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	6/29/2022	NON-COMPETING CONTINUATION	-$461
2022	2017	SALZMAN GROUP, INC.	8 SOLVIVA RD	WEST TISBURY	MA	02575	DUKES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/29/2022	COMPETING CONTINUATION	$0
														Subtotal = -$461

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	SALZMAN GROUP, INC.	8 SOLVIVA RD	WEST TISBURY	MA	02575	DUKES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	11/9/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $460,375 )
2019	2019	SALZMAN GROUP, INC.	8 SOLVIVA RD	WEST TISBURY	MA	02575	DUKES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	9/9/2019	NON-COMPETING CONTINUATION	$460,375
														Subtotal = $460,375

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	RADIKAL THERAPEUTICS INC.	8 SOLVIVA RD	WEST TISBURY	MA	02575	DUKES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/2/2018	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $1,039,086 )
2017	2017	RADIKAL THERAPEUTICS INC.	8 SOLVIVA RD	WEST TISBURY	MA	02575	DUKES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	9/22/2017	COMPETING CONTINUATION	$1,039,086
														Subtotal = $1,039,086

Grand Total All Awards = $1,499,000

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A novel immunotolerizing therapy for autoimmune vitiligo

Award Number: R44AR065886

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2014

PERIOD OF PERFORMANCE END DATE: 08/31/2020

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