MDAM: A Novel Nonpolyglutamylatable Antifolate

Overview

MDAM is a patented non-polyglutamylatable antifolate for the treatment of solid tumors, rheumatoid arthritis and psoriasis. MDAM is chemically related in its structure to methotrexate (MTX), which is widely used for cancer, rheumatoid arthritis and immunosuppression. Unlike MTX, MDAM does not undergo the same intracellular metabolism as MTX and it also appears to bypass the common forms of antifolate-type drug resistance and in preclinical studies has demonstrated selective cancer cell uptake and superior dose intensity, safety and antitumor activity relative to MTX. Phase 1 oncology clinical trials for racemic MDAM have been completed at The Johns Hopkins Oncology Center and M.D. Anderson Cancer Center.

Preclinical and Clinical Summary

In preclinical studies, MDAM has demonstrated antitumor activity and increased dose intensity and safety relative to methotrexate. We have completed Phase 1 testing of MDAM in order to determine the maximum tolerated dose of MDAM in patients with incurable advanced solid cancers. A total of 46 cancer patients have been treated with MDAM in Phase 1 clinical testing. Irritation of the mouth and throat was observed to be the most common side effect, and all toxicities from MDAM appear to be reversible.

Our Phase 1 clinical trial was conducted using racemic MDAM. Racemic compositions contain an equal mixture of two different forms that have identical chemical structures but are mirror images of each other. In general, despite their structural similarities, these mirror image forms can have very different biological properties. Racemic MDAM contains the L-MDAM and D-MDAM forms. We have hypothesized that L-MDAM is largely responsible for the antitumor activity of racemic MDAM and that L-MDAM potentially could be administered orally at reduced doses relative to racemic MDAM. We also have hypothesized that D-MDAM is biologically inactive, which may explain the need for higher dosage of racemic MDAM relative to L-MDAM alone. In preclinical studies, we have observed that oral L-MDAM has similar antitumor activity relative to intravenously administered racemic MDAM.