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A pro-resolution lipid mediator for treatment of rheumatoid arthritis

Award Number: R44AR070686
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: 09/01/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2019

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A pro-resolution lipid mediator for treatment of rheumatoid arthritis - Radikal Therapeutics is developing the first therapeutic Resolvin molecule intended for the management of rheumatoid arthritis (RA). Resolvins are endogenous picomolar-potent small molecules that activate a complex intracellular mechanism by which tissue inflammation is modulated and ultimately resolved. Our technical approach is supported by research demonstrating the utility of our candidate therapeutic Resolvin (R-10001) in reducing injury in clinically-relevant rodent models of RA. R-1001 is potentially superior to its competitors by virtue of: 1) a novel mechanism of action, distinct from existing therapies and those in development, and 2) its ability to increase host immune defense, as opposed to the more typical immunosuppression that is associated with methotrexate, calcineurin inhibitors, and anti-TNF-a inhibitors. Safety studies in rats, dogs, and humans do not reveal toxicity at doses 1-2 logs in excess of the intended therapeutic exposure. Aim #1: Establish the PK properties of enteral R-10001, including joint tissue distribution following gavage delivery to mice with arthritis. We will undertake a full analysis of the PK profile of R-10001. Plasma and joint tissue concentrations of 13C-labeled R-10001 will be measured following administration to male SD rats with collagen-induced arthritis. A full PK profile of R-10001 will be constructed. Aim #2: Scale up the synthetic route of R-10001 and generate batches sufficient for primary reference standard and pharmacology studies. To lower cost and allow for large-scale manufacturing, RTX has invented a novel, proprietary, 14-step synthetic route performed as a proof-of- concept at a 10 mg scale. Even at this early stage, the overall yield is 5% and represents an improvement in efficiency of over 5-times that of any prior synthesis and a 3-fold cost saving. We now wish to utilize this new synthesis as a platform for the production of gram amounts of research grade material in the first instance and to develop this into a viable manufacturing process for 100 g and ultimately kg amounts of R- 10001. We now propose to optimize our new process with the intent of achieving a further 3-fold increase in yield and elimination of half of the chromatographic isolation steps. The campaign will include: (i) identification and improvement of those synthetic steps that are rate and/or yield limiting. (ii) identification of those telescoping steps that do not require discrete purification of each intermediate; (iii) consideration of protection/deprotection strategies and protecting groups. (iv) assessment of the shelf-life - use of unstable intermediates within an appropriate window; (v) analysis of by-products to understand and reduce competing side-reactions. (vi) choice of reagents for scale-up – replace, where possible, with safe, routine, cheaper reagents; (vii) examination of alternatives to chromatographic separations; (viii) development of analytical methods for analysis of intermediates and relevant impurities; (ix) generation of multi-10 g batches; and (x) development of analytical methods for batch analysis and release of the API.


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 = $0 )
2022	2017	RADIKAL THERAPEUTICS INC.	8 SOLVIVA RD	WEST TISBURY	MA	02575	DUKES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/25/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2017	SALZMAN GROUP, INC.	8 SOLVIVA RD	WEST TISBURY	MA	02575	DUKES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	11/9/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $750,000 )
2017	2017	RADIKAL THERAPEUTICS INC.	8 SOLVIVA RD	WEST TISBURY	MA	02575	DUKES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	9/12/2017	NON-COMPETING CONTINUATION	$750,000
														Subtotal = $750,000

Issue Date FY: 2016 ( Subtotal = $750,000 )
2016	2016	RADIKAL THERAPEUTICS INC	8 SOLVIVA ROAD	WEST TISBURY	MA	02575	DUKES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	9/1/2016	NEW	$25,143
2016	2016	RADIKAL THERAPEUTICS INC	8 SOLVIVA ROAD	WEST TISBURY	MA	02575	DUKES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/31/2016	NEW	$724,857
														Subtotal = $750,000

Grand Total All Awards = $1,500,000

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A pro-resolution lipid mediator for treatment of rheumatoid arthritis

Award Number: R44AR070686

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: 09/01/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2019

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