1.Ezatiostat hydrochloride for the treatment of myelodysplastic syndromes.
Mahadevan D1, Sutton GR. Expert Opin Investig Drugs. 2015 May;24(5):725-33. doi: 10.1517/13543784.2015.1021003. Epub 2015 Feb 27.
INTRODUCTION: Myelodysplastic syndromes (MDSs) are associated with significant morbidity due to ineffective hematopoiesis. Given the limited number of drugs approved by the FDA, there is a need for new therapeutic options. Ezatiostat is a novel agent targeting oxidative stress via inhibition of glutathione S-transferase 1.
2.Prediction of response to therapy with ezatiostat in lower risk myelodysplastic syndrome.
Galili N1, Tamayo P, Botvinnik OB, Mesirov JP, Brooks MR, Brown G, Raza A. J Hematol Oncol. 2012 May 6;5:20. doi: 10.1186/1756-8722-5-20.
BACKGROUND: Approximately 70% of all patients with myelodysplastic syndrome (MDS) present with lower-risk disease. Some of these patients will initially respond to treatment with growth factors to improve anemia but will eventually cease to respond, while others will be resistant to growth factor therapy. Eventually, all lower-risk MDS patients require multiple transfusions and long-term therapy. While some patients may respond briefly to hypomethylating agents or lenalidomide, the majority will not, and new therapeutic options are needed for these lower-risk patients. Our previous clinical trials with ezatiostat (ezatiostat hydrochloride, Telentra®, TLK199), a glutathione S-transferase P1-1 inhibitor in clinical development for the treatment of low- to intermediate-risk MDS, have shown significant clinical activity, including multilineage responses as well as durable red-blood-cell transfusion independence. It would be of significant clinical benefit to be able to identify patients most likely to respond to ezatiostat before therapy is initiated.
3.Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome.
Raza A1, Galili N, Smith S, Godwin J, Lancet J, Melchert M, Jones M, Keck JG, Meng L, Brown GL, List A. Blood. 2009 Jun 25;113(26):6533-40. doi: 10.1182/blood-2009-01-176032. Epub 2009 Apr 27.
Phase 1 testing of ezatiostat, a glutathione S-transferase P1-1 inhibitor, for the treatment of myelodysplastic syndrome was conducted in a multidose-escalation study. Patients received 10 dose levels (200, 400, 1000, 1400, 2000, 2400, 3000, 4000, 5000, and 6000 mg) of ezatiostat tablets in divided doses on days 1 to 7 of a 21-day cycle for a maximum of 8 cycles. The safety and pharmacokinetics of ezatiostat were evaluated. Forty-five patients with low to intermediate-2 International Prognostic Scoring System risk myelodysplastic syndrome were enrolled. No dose-limiting toxicities were observed. The most common grade 1 or 2, respectively, treatment-related adverse events were nonhematologic: nausea (56%, 9%), diarrhea (36%, 7%), vomiting (24%, 7%), abdominal pain (9%, 0%), constipation (4%, 9%), anorexia (3%, 7%), and dyspepsia (3%, 7%). Concentration of the primary active metabolite, TLK236, increased proportionate to ezatiostat dosage.
4.Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS).
Raza A1, Galili N, Mulford D, Smith SE, Brown GL, Steensma DP, Lyons RM, Boccia R, Sekeres MA, Garcia-Manero G, Mesa RA. J Hematol Oncol. 2012 Apr 30;5:18. doi: 10.1186/1756-8722-5-18.
BACKGROUND: Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells.