Trial on experimental antifolate PDX (Pralatrexate)

Allos Therapeutics announced they will start a Phase 2b, randomized, multi-center study comparing PDX (pralatrexate)and erlotinib.

PDX is the shorthand name for Pralatrexate, also known as 10-propargyl-10-deazaaminopterin. It is what researchers call a “small molecule” drug. (In chemotherapy research, new drugs are usually divided into small molecules and immunotherapy drugs, which are large monoclonal antibody molecules.)

Allos drug developers are exploring the possibility that PDX may have a favorable safety and efficacy profile relative to methotrexate and certain other DHFR inhibitors. (DHFR inhibitors are also used to treat malaria as well as the chronic inflammatory bowel disease Chrohn’s Disease.)

Antifolates, also called folic acid metabolism antagonists, compete within cells for the folate binding site of the enzyme dihydrofolate reductase. This stops tetrahydrofolate synthesis and hence depletes precursots for nucleotides. Without enough nucleotides, cells cannot produce enough DNA or RNA, or protein for that matter. The cells are unable to replicate. This stops the tumor in its tracks.

While early antifolates were discovered more or less by accident, PDX was rationally designed for efficient transport into tumor cells via the reduced folate carrier and for effective intracellular drug retention.

The first antifolate to gain attention was aminopterin, used against leukemia in the 1940s and 1950s. Methotrexate was a new antifolate approved in 1953; it was less toxic and easier to make than aminopterin and methotrexate found wider use. New chemotherapy drugs in the 1960s and on made the antifolates less popular, but the introduction of Alimta in the 2000s reignited interest in antifolates.

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