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INOSINE PRO-DRUG: NOVEL THERAPY FOR ARTHRITIS

Award Number: R44AR049697
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: 09/30/2003
PERIOD OF PERFORMANCE END DATE: 09/14/2005

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INOSINE PRO-DRUG: NOVEL THERAPY FOR ARTHRITIS - DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is mediated by articular expression of pro-inflammatory cytokines and chemokines. We have discovered that the purine degradation product inosine exerts multiple anti-inflammatory and immunomodulatory effects via combined A2a and A3 agonism, resulting in suppressed expression of TNF-alpha, IL-1 beta, IL-12, MIP-lalpha, and IFN-gamma and enhanced expression of IL-10. We have recently developed a proprietary pro-drug of inosine, 5'-inosine monosulfate (IMS),that is more potent than inosine in vivo and shows dramatic protection against inflammatory injury. In a collagen-induced murine model of autoimmune arthritis, IMS profoundly reduced the incidence and severity of arthritis, reduced TNF-alpha and MIP-lalpha expression, and virtually eliminated neutrophil infiltration and lipid peroxidation. Coupled with the fact that free inosine is an approved OTC nutritional supplement and has an excellent record of safety in man, we envision the introduction of its prodrug IMS as a novel pharmaceutical for the treatment of RA. The Specific Aims of this Fast-Track proposal are: Phase I: Establish that IMS reverses established experimental arthritis and is effective in combination with current clinical anti-arthritic therapies. IMS will be provided to DBA/1J mice rendered arthritic by repeated injection of collagen. Our preliminary data show that introduction of IMS prior to the onset of disease is nearly fully protective. In order to establish the reversibility of established disease, IMS therapy will be introduced at day 35, after the onset of joint disease in this model system. We will also determine whether a one-week pulse of IMS therapy, initiated at day 20, will provide persistent protection against the development of arthritis in the DBA/1J model. Finally, we will establish the synergy of IMS, begun on day 20, with traditional anti-arthritic therapies, including ibuprofen and methotrexate. Progression to Phase II SBIR will require that IMS produces a 50% reduction in the severity of established collagen-induced arthritis and that IMS is synergistic with ibuprofen or methotrexate. In the Phase 2 SBIR, we will determine the pre-clinical pharmacokinetics and biochemical, hematologic, and histopathologic toxicology, and safety pharmacology profile of IMS. The proposed studies will provide the foundation for Phase la and lb clinical safety trials of IMS.


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: 2004 ( Subtotal = $1,396,706 )
2004	2004	INOTEK PHARMACEUTICALS CORPORATION	100 CUMMINGS CENTERSUITE 419E	BEVERLY	MA	01915	ESSEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	9/6/2004	EXTENSION WITH OR WITHOUT FUNDS	$1,396,706
														Subtotal = $1,396,706

Issue Date FY: 2003 ( Subtotal = $212,416 )
2003	2003	INOTEK PHARMACEUTICALS CORPORATION	100 CUMMINGS CENTERSUITE 419E	BEVERLY	MA	01915	ESSEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/22/2003	NEW	$212,416
														Subtotal = $212,416

Grand Total All Awards = $1,609,122

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INOSINE PRO-DRUG: NOVEL THERAPY FOR ARTHRITIS

Award Number: R44AR049697

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: 09/30/2003

PERIOD OF PERFORMANCE END DATE: 09/14/2005

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