TELINTRA® (Ezatiostat HCl, TLK199) is a small molecule product candidate designed to inhibit the enzyme, glutathione S-transferase P1-1 (GSTP1-1). Through GSTP1-1 mediated effects on key regulatory proteins called MAP kinases, normal blood stem cells are induced to make more blood elements while cancerous or premalignant cells are induced to die. We have reported on the role of GSTP1-1 as a regulatory protein in stimulating the growth and differentiation of normal blood cells and its ability to promote cancerous cells to undergo programmed cell death (apoptosis). In preclinical testing, TELINTRA® has been shown to increase white blood cell production in normal animals and in animals where white cells were depleted by treatment with standard cancer drugs. TELINTRA® treatment also has been shown to increase the numbers of white blood cells, red blood cells and platelet progenitors from normal human stem cells as well as cancer cell death of human leukemia cells.
Many conditions are characterized by a depleted bone marrow and premalignant or malignant blood derived cells, including myelodysplastic syndrome (MDS), a form of pre-leukemia in which the bone marrow produces insufficient levels of one or more of the 3 major blood elements (white blood cells, red blood cells and platelets) and may ultimately progress to leukemia.
TELINTRA® has been studied in clinical trials of patients with MDS using two formulations. A liposomal formulation was developed for intravenous administration of TELINTRA® and was used in Phase 1-2A studies in MDS patients. The results from the Phase 1-2A liposomal TELINTRA® clinical trials have been published in the Journal of Hematology & Oncology:Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra®, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome; Raza, A et al., Journal of Hematology & Oncology 2009, 2:20 doi:10.1186/1756-8722-2-20. Data from the study suggests that TELINTRA® treatment was associated with improvement in all three types of blood cells in patients with all types of MDS, including those in intermediate and high-risk groups.
An oral dosage formulation (tablet) was subsequently developed and a Phase 1 trial of orally administered TELINTRA® was completed. Results from this Phase 1 trial in MDS suggest that TELINTRA® is well tolerated and shows clinical activity. Results from this trial have been published in the journal Blood: PHASE 1 MULTICENTER DOSE-ESCALATION STUDY OF EZATIOSTAT HYDROCHLORIDE (TLK199 TABLETS), A NOVEL GLUTATHIONE ANALOG PRODRUG, IN PATIENTS WITH MYELODYSPLASTIC SYNDROME; Raza, A. et al., Blood 2009 113: 6533-6540, doi:10.1182/blood-2009-01-176032.
The tablet formulation was then studied in a Phase 2 clinical trial, and the results were published in the Journal Cancer:A PHASE 2 MULTICENTER STUDY OF TWO EXTENDED DOSING SCHEDULES OF ORAL EZATIOSTAT IN LOW TO INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROME (MDS); Raza, A., et al., Cancer, doi: 10.1002/cncr.26469, September 1, 2011.
Results from our TELINTRA® clinical trials suggest that the agent has a favorable safety profile and provided clinical benefit to some of the patients.
TELINTRA® was also profiled is a news article published in The MDS Beacon: EXTENDED TELINTRA DOSING IMPROVES BLOOD CELL COUNTS IN LOWER-RISK MDS PATIENTS. It may be found at http://www.mdsbeacon.com/news/2011/10/03/extended-telintra-ezatiostat-dosing-improves-blood-cell-counts-in-lower-risk-myelodysplastic-syndromes-patients/.
The MDS Beacon article indicates that extended dosing of TELINTRA® improves blood cell counts and reduces dependence on red blood cell transfusions in patients with lower-risk myelodysplastic syndromes. The article also includes comments from Dr. Azra Raza of Columbia University who said, “… [Telintra] potentially would be a significant clinical benefit for myelodysplastic syndromes (MDS) patients” In addition, the news article describes the two ongoing trials in the development program for TELINTRA®.
In addition to MDS, TELINTRA® has been studied for the treatment of severe chronic idiopathic neutropenia (SCIN), which is a blood disorder typified by very low neutrophil counts. Neutrophils are important in defending the body against bacterial infections and, therefore, a patient with too few neutrophils is more susceptible to bacterial infections. The case report of one patient who had a complete response following TELINTRA® treatment was published in the Journal of Hematology & Oncology: ORAL EZATIOSTAT HCL (TELINTRA®, TLK199) AND IDIOPATHIC CHRONIC NEUTROPENIA (ICN): A CASE REPORT OF COMPLETE RESPONSE OF A PATIENT WITH G-CSF RESISTANT SEVERE CHRONIC IDIOPATHIC NEUTROPENIA FOLLOWING TREATMENT WITH TELINTRA; Roger M. Lyons, MD et al. from the Cancer Care Centers of South Texas; Journal of Hematology & Oncology 2011, 4:43; doi:10.1186/1756-8722-4-43, November 2, 2011.
TELINTRA® has also completed a clinical trial in combination with Revlimid® and the results will be reported at the 2011 annual meeting of the American Hematology Society. In addition, the results of a genomic signature analysis of TELINTRA® responders versus non-responders will be announced at that meeting.
For further information on ongoing TELINTRA® trials, please see http://www.clinicaltrials.gov
Physicians and patients seeking additional information on TELINTRA® may contact firstname.lastname@example.org.