Because the active drug is not produced in oxygenated tissues, treatment with tarlox has significantly lower occurrence of EGFR-related toxicities, which typically are seen in the digestive tract or skin. Clinical studies of tarlox demonstrate that the occurrence of diarrhea, rash and pruritis (itching) are twice to five times less likely than from treatment with other EGFR inhibitors in development for Exon 20 tumors.
Tarloxotinib (tarlox) is a prodrug of a potent EGFR / HER inhibitor that only produces the active drug in low-oxygen (hypoxic) conditions. In the presence of oxygen, the inactive tarlox is stabilized, avoiding the production of the active drug in healthy, oxygenated tissues.
Preclinical studies with tarlox in EGFR Exon 20 tumor models have demonstrated robust tumor regression, with selective activation of tarlox in the tumor versus skin or blood.
Mechanisms of Action
Physiologic Oxygen (Normoxic): Tarlox (prodrug) gains an electron (black circle) to produce a reactive intermediate, however oxygen quickly scavenges the electron to revert the intermediate to inactive tarlox
Low Oxygen (Hypoxic): Absence of oxygen enables the fragmentation of tarlox into the trigger moiety (dark blue structure) and a highly lipid-soluble tarlox-TKI (light blue structure), with the TKI now able to enter the cell