Telik announces positive results from Phase 2 trial of ezatiostat in patients with MDS

Telik, Inc. (Nasdaq: TELK) today announced positive results from a Phase 2 multicenter trial of oral ezatiostat hydrochloride (TELINTRA, TLK199) in patients with an International Prognostic System Score (IPSS) of low to intermediate-1 risk myelodysplastic syndrome (MDS).

The presentation entitled Phase 2 Randomized Multicenter Study of Extended Dosing Schedules of Oral Ezatiostat HCl (Telintra), a Glutathione Analog, Glutathione-S-transferase P1-1 (GSTP1-1) Inhibitor, In Low to Intermediate-1 Risk Myelodysplastic Syndrome (MDS), Raza, A., Galili, N., Smith, S., Godwin, J., Boccia, R., Myint, H., Mhadevan, D., Mulford, D., Rarick, M., Allison, M A., Melnyk, O., Meng, L., Jones, M., Brown, G., Young, S., List, A., Komrokji, R., Sekeres, M., was given at the 52nd Annual Meeting of the American Society of Hematology in Orlando, FL.

MDS is a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis (blood cell production) involving one or more cell lineages (red blood cells, white blood cells or platelets) and a variable risk of developing acute myeloid leukemia (AML).  Ezatiostat is an inhibitor of the enzyme glutathione S-transferase P1-1 (GST P1-1), a validated clinical target in MDS.  Inhibition of this enzyme results in the activation of the signaling molecule Jun kinase resulting in cell death (apoptosis) of leukemic and pre-leukemic cells, and the growth and maturation of normal blood progenitor cells.

"We are very pleased to present the positive results of this study that was conducted at 22 clinical sites," stated Dr. Azra Raza, Professor of Medicine and Director, MDS Center at Columbia University Medical Center. "Telintra is the first GSTP1-1 enzyme inhibitor-based treatment for low to intermediate-1 risk MDS patients.  In addition to advancing our understanding of this disease, we have the opportunity to develop a new targeted agent that potentially, can transform the treatment of MDS in these low to intermediate-1 risk MDS patients."

The primary objective of the study was to determine the efficacy of ezatiostat, defined by Hematologic Improvement (HI) rate according to the International Working Group criteria (IWG, 2006), as well as its safety and tolerability. An additional goal of this study was to identify those patients whose disease characteristics may allow us to prospectively target patients most likely to respond to Telintra treatment.  A multivariate logistic regression analysis was conducted to identify significant MDS disease factors associated with HI-E rates, including prior MDS treatment, age, gender, IPSS risk, Eastern Cooperative Group (ECOG) performance status, years from MDS diagnosis, MDS World Health Organization (WHO) subtypes, anemia only versus anemia plus other cytopenias, dose schedule and starting dose.

Eighty-seven patients were randomized and treated at 22 investigational sites.  After initial dose ranging in 14 patients, two dose levels were selected for further study.  Thirty seven patients were treated at 3 gm daily for two weeks followed by a one week rest period, and 36 patients were treated at 2 gm daily for three weeks followed by a one week rest period.  Treatment was given until lack of MDS response or unacceptable toxicity.  Patients received up to 6 months of the planned randomized treatment, after which patients exhibiting ongoing clinical benefit could continue treatment for an additional 6 months of continuous daily dosing.

Patient demographics and MDS disease characteristics:  Seventy-three patients; median age 73 years (range 48–89), 70% male, and WHO classification subtypes: 9 refractory anemia (RA), 11 RA with ringed sideroblasts, 4 RA with excess blasts-1, 24 refractory cytopenia with multilineage dysplasia, 14 refractory cytopenia with multilineage dysplasia with ringed sideroblasts, 4 MDS-unclassified, 2 MDS/Myeloproliferative disorder-U, 4 MDS-del 5q, and 1 unknown.  Fifty patients (68%) were INT-1 risk, 23 (32%) were Low risk; 28 pts (38%) had abnormal karyotypes with 23 (82%) complex/poor prognostic types. Forty-four patients (60%) were red blood cell (RBC) transfusion-dependent (defined as patients who required at least four units of RBC transfusion over an eight week period at pretreatment baseline), and required a median of 6 (range 4–19) units of RBC per 8 week period prior to study entry. Patients were heavily pretreated, with a median of 3 prior therapies, including: 34 (47%) received DNA methyltransferase inhibitors (DMTI) such as 5-azacitidine (Vidaza) and decitabine (Dacogen), 28 (38%) lenalidomide (Revlimid), 56 (77%) erythropoietin and 32 (44%) other growth factors.

Efficacy: The HI-E response rate was similar for evaluable patients on the two schedules, therefore the data were combined.  The overall HI-E rate was 22%, 13 of 60 evaluable patients, (95% CI, 12–34).  The median duration of HI-E response was 34 weeks (range 2–63). The median duration of response for patients undergoing 3 week dose schedule was 46 weeks, the median duration of response for patients undergoing 2 week dose schedule was 18 weeks. The median hemoglobin level increased by 2.0 gm/dL in responders.  Eleven of 38 RBC transfusion-dependent patients (29%) had clinically significant RBC transfusion reductions (reduction of 4 units of RBC per 8 week period, IWG 2006) with 4 patients (11%) achieving RBC transfusion independence.  Two cases of complete cytogenetic response were seen.

Telintra demonstrated multilineage hematologic improvement. There was a 19% Hematologic Improvement - Neutrophil (HI-N) rate observed in 4 of 21 patients, (95% CI, 5–42), and the bilineage HI rate (HI-E and HI-N) was 20%, with 4 of 20 patients (95% CI, 6–44) and 1 of 11 patients had a trileneage HI response.

A multivariable stepwise logistic regression analysis was used to evaluate all known prognostic characteristics in order to identify those patients who have an increased likelihood of HI-E response to Telintra.  Prior DMTI treatment predicts a six-fold decrease in the odds for a HI-E response to Telintra>

• There was a 28% HI-E rate (5/18 patients, 95% CI 10%-54%) in patients who were Revlimid and DMTI naive, with 4/8 (50%) of patients in this subgroup achieving clinically significant RBC transfusion reduction.
• There was a 40% HI-E rate (6/15 patients, 95% CI 16%-68%) in patients with prior Revlimid and no prior DMTI treatment.
• There was a 31% HI-E rate (8/26 patients, 95% CI, 14%–52%), in patients who had prior Revlimid treatment, versus 15% rate (5/34 patients, 95% CI 5%-31%) in patients without prior Revlimid treatment.  Within this Revlimid exposed patient group, 7/18 patients (39%) achieved significant RBC transfusion reduction and 4/18 patients (22%) achieved transfusion independence versus 0% in patients with no prior Revlimid therapy>
• Comparison of Telintra efficacy in patients with prior DMTI treatment vs no prior DMTI treatment showed an HI-E rate of 7% (2/27, 95% CI 1%-24%) vs 33% (11/33, 95% CI 18%-52%)>

Notable case studies of sustained hematologic improvement:  As shown in the case of a 77 year old Caucasian male with del 5q MDS that had progressed to RAEB-1 after Revlimid treatment, a short exposure (1.5 cycles, with drug discontinuation due to non-drug related complications) to Telintra resulted in a striking improvement in all three blood counts with continuing complete response a year post-therapy discontinuation – case study reported in Quddus et al., Journal of Hematology and Oncology, April, 2010, 3:15.  Transfusion independence was achieved in four patients, including an 85 year old Caucasian female with RCMD subtype MDS, IPSS intermediate-1 risk and normal cytogenetics and baseline RBC transfusions of 5 units of RBC per 8 week period, who became transfusion independent for 8 months with a best response of HI-E and HI-N.  A 78 year old African American male with del 5q MDS intermediate-1 risk IPSS who became MDS unclassified after Revlimid treatment failure, achieved a substantial improvement in Hgb from 8.3 g/dL to 14.5 g/dL and an HI-E for 11 months and continues on therapy with sustained HI-E and HI-N response.

Safety: Data are based on all patients treated.  A total of 447 cycles of Telintra were given in the study, with a median of 4 cycles/patient (range 1-18), with only 3% requiring dose reduction and 9% requiring dose delays.  There were 11 drug-related serious adverse events (AEs) which resolved without sequelae.  Six patients discontinued treatment due to related AEs.  The most common nonhematologic AEs were Grade 1 and 2 gastrointestinal; respectively, nausea (45%, 17%), diarrhea (26%, 7%) and vomiting (30%, 12%).  Grade 3 events were uncommon: nausea (1%), diarrhea (3%) and vomiting (2%).  Prior DMTI treatment was associated with an increased incidence and severity of GI AEs.

Conclusions:  

• TELINTRA is the first GSTP1-1 enzyme inhibitor shown to cause clinically significant reductions in RBC transfusions, including transfusion independence in low to intermediate-1 risk MDS patients, as well as trilineage improvement, providing a unique activity profile with attractive tolerability and safety, including lack of cytopenia.  Telintra's twice daily oral administration may be convenient for flexible chronic administration schedules in low-intermediate risk MDS.  
• The HI rates were consistent with the Phase 1 results with Telintra, and the duration of response was enhanced using the extended dose schedules.  These data suggest that Telintra is active in MDS patients who are Revlimid-naive, Revlimid intolerant, Revlimid refractory (no response to treatment), and patients who initially respond to Revlimid but become resistant.
• A notable observation from this study is that prior Revlimid or DMTI treatment may influence HI-E response to subsequent Telintra treatment. Telintra has shown clinically significant activity in Revlimid naïve or prior Revlimid pretreated patients, and HI-E response in prior Revlimid treated patients with del 5q in relapse was an intriguing finding.  On the other hand, prior history of DMTI treatment appears to be an important predictor of decreased Telintra efficacy and tolerability.  These findings assist ongoing pharmacogenomic studies to characterize the genomic profile of responders.  

The results of this study support the further development of Telintra in MDS and other hematologic malignacies.

Background on MDS and TELINTRA

The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis (blood cell production) involving one or more cell lineages (red blood cells, white blood cells or platelets) and a variable risk of transformation to acute myeloid leukemia (AML).  MDS becomes more common with age.  It is estimated that MDS affects approximately 300,000 people worldwide.  According to the American Cancer Society, 10,000–20,000 new cases of MDS are diagnosed each year in the United States, with survival rates ranging from six months to six years.  MDS patients often require blood transfusions to manage their disease.

There remains a critical need for effective, well tolerated therapies for MDS.  Telintra has a novel mechanism of action that inhibits an enzyme called glutathione S-transferase P1-1 which may activate Jun kinase, a key regulator of cellular growth and differentiation of blood precursor cells.  Telintra has been shown to stimulate normal multilineage differentiation of blood stem cell precursors and induce cancer cell death, or apoptosis, in human leukemia cell lines.