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TELINTRA(Ezatiostat HCl, TLK199)

2011-09-25 16:53:48  作者:新特药房  来源:中国新特药网天津分站  浏览次数:119  文字大小:【】【】【
简介: TELINTRA® (Ezatiostat HCl, TLK199) is a small molecule product candidate designed to stimulate the production of blood cells in the bone marrow. TELINTRA® inhibits the enzyme, glu ...

TELINTRA® (Ezatiostat HCl, TLK199) is a small molecule product candidate designed to stimulate the production of blood cells in the bone marrow. TELINTRA® inhibits the enzyme, glutathione S-transferase P1-1. GSTP1-1 is a key regulatory protein that can signal the cell to either make more blood elements or if the cell is cancerous to die. We have reported on some aspects of the mechanism of TELINTRA®. The role of GSTP1-1 as a regulatory protein and its ability to promote cancerous cells to undergo programmed cell death (apoptosis) has been reported in these leading references.

Many conditions are characterized by depleted bone marrow, 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). In preclinical testing, TELINTRA® was shown to increase white blood cell production in normal animals as well as in animals in which white cells were depleted by treatment with standard cancer drugs.

TELINTRA® has been studied in Phase 2 trials in MDS using two formulations. A liposomal formulation was developed for intravenous administration of TELINTRA® and was used in Phase 1 and Phase 2 studies in MDS patients. The results from the Phase 2 liposomal TELINTRA® clinical trials are complete and the results have recently been published. The results demonstrated 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 with TELINTRA® orally administered was completed. Results from this Phase 1 trial in MDS shows that TELINTRA® is well tolerated, and shows clinical activity. Results from this trial has been recently published.

Results from our TELINTRA® clinical trials show that is has a favorable safety profile and provides clinical benefit to some of the patients. Because of the activity and safety of TELINTRA® tablets, we recently initiated a Phase 2 trial of TELINTRA® Tablets in MDS.

Telintra Improves Blood Cell Counts And Is Safe For Lower-Risk MDS Patients (ASH 2010)

In addition to MDS, we are studying the use of TELINTRA® for the treatment of severe chronic neutropenia (SCN). SCN is a blood disordered typified by a very low neutrophil counts. Neutrophils are very important in defending the body against bacterial infections, and therefore, a patient with too few neutrophils is more susceptible to bacterial infections. We have recently launched a Phase 1 trial investigating the use of TELINTRA® tablets for the treatment of SCN.

The experimental drug Telintra improves blood counts and is well-tolerated in patients with lower-risk myelodysplastic syndromes, according to a Phase 2 trial conducted at multiple American cancer centers.

The study authors also found that patients taking Telintra (ezatiostat hydrochloride) who had prior Revlimid (lenalidomide) treatment showed better results than patients previously treated with Vidaza (azacitidine) or Dacogen (decitabine).

The trial results were presented by Dr. Azra Raza of Columbia University Medical Center in New York City during a poster session on Sunday at the 2010 meeting of the American Society of Hematology in Orlando.

Telik, a biopharmaceutical company based in Palo Alto, California, is developing Telintra to treat myelodysplastic syndromes (MDS) and a condition called chronic low white blood cell counts. Telintra, a glutathione S-transferase inhibitor, is being developed as an oral drug and an infusion. It works by promoting the growth and maturation of bone marrow stem cells and by killing immature blood cells.

The researchers sought to determine if extended oral Telintra use is safe and effective in lower-risk MDS patients.

The 73 patients who participated in the study were divided into two dosing groups. One group (37 patients) received 3 milligrams of Telintra once daily for two weeks followed by one week of rest. The other group (36 patients) received 2 milligrams of Telintra once daily for three weeks followed by one week of rest.

The patients were treated until they no longer responded or developed severe side effects.

The response rates of the evaluable patients were very similar among the two treatments groups. The study authors therefore decided to do a pooled data analysis for both treatment groups.

The study authors observed an increase in white blood cell counts in four (19 percent) of the 21 patients who had low white blood cell counts and an increase in platelet counts in one (3.7 percent) of the 27 patients who had low platelets.

An improvement in red blood cell counts was seen in 22 percent of all patients for a median of 34 weeks. Of the 38 patients who were red blood cell transfusion-dependent, eleven patients (29 percent) needed reduced transfusions and four patients (11 percent) achieved transfusion independence after Telintra treatment.

Of the 15 patients who had been previously treated with Revlimid (lenalidomide), six patients (40 percent) showed improved red blood cell counts. Of the eleven red blood cell transplant-dependent patients who received Revlimid prior to the study, five patients (45 percent) needed reduced transfusions and three patients (27 percent) became transfusion independent.

The 16 patients who were previously treated with Vidaza or Dacogen showed no improvement in red blood cell counts. The researchers found that prior treatment with Vidaza or Dacogen decreased by six fold the chance of achieving higher red blood cell counts through Telintra treatment.

Side effects were generally mild and included nausea, diarrhea, and vomiting. Patients previously treated with Vidaza or Dacogen were more likely to experience side effects while taking Telintra.

最近进行的一项II期临床试验显示,对于接受了大量预处理的低度至中度风险的骨髓增生异常综合征患者,扩大剂量的口服ezatiostat可减少输血需要。
主要作者、纽约哥伦比亚大学Azra Raza博士通过电子邮件告诉路透社健康,Ezatiostat可以产生所谓的多向应答(即在一种以上的血细胞中),并且没有骨髓抑制。
Raza博士称ezatiostat为一种“令人兴奋的药物”,并且“正是低风险老年MDS患者的所需”。
Raza博士和他的同事指出,ezatiostat可逆性抑制谷胱甘肽- S-转移酶P1-1并刺激骨髓产生血细胞。Ezatiostat由Telik公司开发用于治疗低风险MDS相关的血细胞减少。
         
据9月1日在线发表在《Cancer》的报告,89例伴或不伴另外的血细胞减少的贫血患者(平均年龄为73岁),被随机分配接受两种治疗方案中的一种,分别为:在三周的治疗周期中,1,500mg每日两次,两周,随后为一周的休息期;在四周的治疗周期中,1,000 mg每日两次,三周,随后为一周的休息期。
最终,意向性治疗分析纳入75例患者,疗效评价纳入61例患者。
         
在意向性治疗分析中,通过红细胞系统应答反映的多向血液学改善(HI)的患者比例为19%,在有效性分析中为22%。汇集数据显示两个方案组可评估患者的结果相同。
38例红细胞输血依赖的患者中的11例在八周内输血减少了至少4个单位,4例患者(11%)达到不输血。
         
之前的治疗对应答有重要作用。先前接受来那度胺治疗和没有接受hypomethylating药物的患者红细胞应答率为40%,与之相比,先前没有接受来那度胺和HMA的患者的红细胞应答率为28%。16例接受HMAs但没有来那度胺的患者没有红细胞应答。之前的HMA治疗还与ezatiostat相关的不良事件发病率增加有关。
红细胞应答持续时间较长和不良事件较少的趋势使研究人员选择为期四周的治疗方案进行进一步的ezatiostat研究。
研究人员总结到,ezatiostat的耐受性和活动特点可为MDS患者提供新的治疗选择。

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