Ezatiostat

Summary

Ezatiostat hydrochloride (TLK199) is a peptidomimetic prodrug and inhibitor of GST Pi investigated primarily for myelodysplastic syndromes (MDS). It stimulates hematopoietic progenitor proliferation via JNK pathway activation. Clinical trials demonstrated improvements in cytopenias in low- to intermediate-risk MDS patients. It has been studied in both intravenous and oral liposomal tablet formulations.

Mechanism of Action

Ezatiostat (TLK199) is a glutathione analog prodrug that inhibits Glutathione S-transferase Pi (GST P1-1), leading to activation of the Jun N-terminal kinase (JNK) pathway and downstream stimulation of hematopoietic progenitor cell proliferation and differentiation. It promotes myeloid and erythroid colony formation by relieving GST P1-1-mediated suppression of JNK signaling.

Routes of Administration

Goals & Uses

• Improvement of cytopenias (anemia, neutropenia, thrombocytopenia)Hematopoiesis StimulationModerate
• Treatment of myelodysplastic syndromes (MDS)OncologyModerate
• Anticancer/antineoplastic activityOncologyLow
• Reduction of transfusion dependenceSupportive OncologyModerate

Contraindications

• Severe hepatic impairmentOrganModerateLiver function concerns
• Known hypersensitivity to ezatiostat or excipientsAllergyHigh

Adverse Effects

• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• FatigueGeneralCommonLow energy or tiredness
• VomitingGastrointestinalCommonForceful expulsion of stomach contents
• Elevated liver enzymes (transaminases)HepaticUncommon
• Infusion-related reactionsHypersensitivityUncommon
• DiarrheaGastrointestinalCommonLoose or frequent stools

Drug Interactions

• Cytotoxic chemotherapy agentsModerate
• Other glutathione-modulating agentsLow

Population Constraints

• Severe renal impairmentOrgan ImpairmentRelative
• Pediatric patientsAgeRelative
• Lactating womenReproductiveRelative
• Pregnant womenReproductiveRelative

Regulatory Status

• European UnionInvestigationalNot approved by EMA. Investigational status only.
• United StatesInvestigationalReceived FDA Orphan Drug Designation for MDS. Not approved. Phase 2 trials completed; no NDA filed as of last available data.
• United KingdomInvestigationalNot approved by MHRA. Investigational status only.

Ezatiostat received Orphan Drug Designation from the FDA for myelodysplastic syndromes. It has not received full FDA or EMA approval. Development was led by Telik, Inc. Phase 2 trials showed clinical activity but no Phase 3 approval has been granted.

Evidence & Sources

No sources recorded yet.