A Phase II, Multi-center, Randomized, Double-blind, Methotrexate Controlled Study to Assess the Clinical Efficacy, Safety, and Tolerability of CH-1504 in Subjects With Active Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a chronic inflammatory disease of unknown cause that leads to pain, stiffness, swelling and limitation of joint function. If left untreated, RA produces serious destruction of joints that frequently leads to permanent disability.

Methotrexate (MTX) is currently the most commonly prescribed first-line disease modifying anti-rheumatic drug (DMARD) because of its early onset of action, good efficacy, and ease of administration. In addition, MTX can be combined with other FDA approved DMARDs, including gold compounds, sulfasalazine, hydroxychloroquine, TNF inhibitors, anakinra and leflunomide. However, the administration of MTX has been associated with serious side effects such as skin reactions, pneumonitis, gastrointestinal disturbances including diarrhea, ulcerative stomatitis and hemorrhagic enteritis, hepatotoxicity and renal toxicity. Overall it is estimated that up to 30% of all patients discontinue MTX therapy due to side effects.

MTX enters cells via the Reduced Folate Carrier (RFC) system. Once inside cells, it is converted enzymatically to polyglutamylated derivatives. These metabolites cannot be readily effluxed and are retained in tissues. The accumulation of polyglutamyl metabolites of MTX for prolonged periods may play a significant role in both the efficacy and the toxicity of this compound. Methotrexate in its parent form only has activity against dihydrofolate reductase (DHFR). In order for it to have significant activity against other enzymes (i.e. Thymidylate Synthase (TS)) it must be polyglutamylated. However by being polyglutamylated the MTX metabolite is retained in the cell and may potentiate the cytotoxicity of MTX. In addition to polyglutamylation metabolism, MTX is also hydroxylated in the liver to a metabolite known as 7-hydroxymethotrexate, which is also subject to polyglutamylation and cell retention. This metabolite has been implicated in liver and kidney toxicity of the parent compound, while contributing no role in efficacy.

CH-1504 has been shown in vitro to be a nonpolyglutamylatable and nonhydroxylatable antifolate that is more efficiently taken up into cells by the reduced folate carrier (RFC) system than is MTX. CH-1504 has significant activity on both DHFR and TS enzymes without the need for polyglutamylation. The lack of hydroxylation potentially leads to enhanced levels of the active drug in the cell. Furthermore, the glutamyl moiety is not susceptible to being cleaved by carboxypeptidase. Thus CH-1504 may be referred to as a metabolically stable antifolate. It is our hypothesis that in the clinical setting CH-1504 will demonstrate the efficacy of classical antifolates (via folate enzyme inhibition) but will be devoid of the toxicity secondary to the formation of the polyglutamylated and hydroxylated metabolites, providing a significantly improved therapeutic index compared to classical antifolates, such as MTX.

This study is a randomized, double-blind, methotrexate controlled study to assess the clinical effect of CH-1504 in patients with active rheumatoid arthritis by determining the proportion of patients achieving an ACR20 response after 12 weeks of treatment.