The Treatment of Methotrexate Resistant Rheumatoid Arthritis With Aminopterin

DESCRIPTION (provided by applicant): The long term goal of this project is to develop aminopterin (AMT), an antifolate medication, as an improved treatment for patients with rheumatoid arthritis (RA) and other inflammatory diseases. This application focuses on RA which occurs in ~1% of the population, and is associated with progressive joint destruction, functional disability and decreased life expectancy. Methotrexate (MTX), an antifolate used alone or in combination with other medicines, is the current mainstay and reference standard for RA treatment. Oral MTX, however, is poorly absorbed by many individuals which contribute to ineffective responses in 30-40% of RA patients and remission in only 20%. Furthermore, only half the patients with effective responses tolerate MTX for 5 years because of its side effects. Especially troubling are gastrointestinal and central nervous system side effects that include nausea, stomatitis, liver irritation, headache, fatigue, disorientation and poor memory. Alternative treatments include oral drugs that are more toxic, injectable MTX, or injectable recombinant proteins (biologics) that are very expensive. A well-absorbed oral antifolate that is less toxic would be an important, cost-effective option that sets a new standard for RA treatment. Our clinical trials have established that AMT, which is similar in structure to MTX, has near 100% oral absorption while sparing many of the side effects that involve the gastrointestinal and central nervous systems. Thus, we hypothesize that AMT, compared to MTX, will provide RA patients with better disease control and less side effects. If AMT is effective in patients who fail MTX treatment, then AMT will have important economic consequences by obviating treatments with expensive biologics. Therefore, in this application we propose the AFFORD (Aminopterin First For Rheumatoid Disease) clinical trial. The AFFORD trial investigates if RA patients with inadequate responses to MTX can be treated effectively with AMT. Initially, all enrolled patients receive AMT and subsequently those with an effective response to AMT enter a double-blind stage comparing AMT and placebo-control. The AFFORD trial, in a rapid, cost-effective fashion, will determine if AMT can effectively treat a significant proportion of MTX-resistant RA patients. The trial will use standard criteria to determine safety and efficacy. The specific aims of the AFFORD trial and this SBIR Fast-Track application are to: 1) Evaluate the efficacy of oral AMT in the treatment of MTX-resistant RA patients. 2) Assess the safety of oral AMT in the treatment of MTX-resistant RA patients. Completion of the AFFORD trial will firmly establish if AMT is a safe and effective treatment for MTX- resistant RA patients. For most RA patients MTX is a critical component of their therapy, and the clinical development of a superior antifolate for RA will have a large, positive, and cost-effective impact for millions of RA patients. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is a leading cause of human disability effecting ~1% of the population. Methotrexate, the current mainstay of RA treatment, is both poorly absorbed and tolerated by many individuals contributing to ineffective responses in 30-40% of patients, remission in only 20% and even less effective long term use. This project is developing aminopterin; a better absorbed and tolerated medicine, as an important new cost- effective treatment option for RA.