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吉利德NASH新药selonsertib首个III期临床失败

医药魔方 医药魔方 来源:医药魔方
2019-02-12
NASH 吉利德
原文

吉利德科学2月12日宣布,NASH在研药物、ASK1抑制剂selonsertib(GS4997)在其第一个III期临床试验(STELLAR-4)错过一级终点。


STELLAR-4是一项III期随机,双盲,安慰剂对照研究,用以评估NASH新药selonsertib对NASH引起的代偿性肝硬化(F4)患者的安全性和有效性。试验共招募了877位NASH诱发代偿期肝硬化患者,比较两个剂量组的selonsertib和安慰剂对纤维化的影响。

符合条件的18至70岁成年人随机分组接受selonsertib 18mg(n=354),selonsertib 6mg(n=351)或安慰剂(n=172),最长用药240周;每天口服一次selonsertib或安慰剂。该研究的主要终点是根据NASH CRN分类在第48周时没有NASH恶化且在第240周达到无事件生存的患者中少改善1级纤维化(纤维化改善≥1期)的患者比例的综合评估。


STELLAR-4试验结果显示:在接受研究药物的877名受试患者的研究中,使用selonsertib 18mg治疗的患者中有14.4%,使用selonsertib 6mg治疗的患者中有12.5%达到纤维化改善≥1期,治疗48周后NASH没有恶化;接受安慰剂的患者达到纤维化改善≥1期为12.8%。Selonsertib通常具有良好的耐受性,安全性结果与之前的研究一致。但是错过预先设置的48周临床终点。


吉利德表示对调查结果的进一步深入分析正在进行中,数据将提交给即将召开的科学会议,并将与数据监测委员会和研究人员合作,以符合每位患者最佳利益的方式完成STELLAR-4研究。


“虽然我们对STELLAR-4研究没有达到其主要终点感到失望,但我们仍然致力于为因NASH引起的晚期纤维化患者推进治疗,尤其是该领域对有效且耐受良好的治疗存在显著未满足需求。”吉利德首席科学官John McHutchison医学博士在新闻通稿中透露,“吉利德公司还正在收集因NASH引起的代偿性肝硬化的研究数据,其中包括大量生物标记物,这将进一步提高对该疾病的认识,并为更广泛的NASH开发计划提供信息。”


Selonsertib属于ASK1抑制剂,是一种高选择激酶抑制剂。ASK1全名为细胞凋亡信号调节激酶,可以激活JNK、P38等关键调节蛋白诱发炎症和纤维化。


NASH是一种慢性和进行性肝病,其特征在于肝脏中的脂肪积聚和炎症,其可导致损害肝功能的瘢痕形成或纤维化。患有晚期纤维化的个体,包括桥接纤维化(F3)或代偿性肝硬化(F4),肝脏相关死亡率和全因死亡率的风险显著增加。


吉利德正在推进多种新型研究化合物用于治疗NASH引起的晚期纤维化,评估针对与NASH相关的的单药和联合治疗方法。近年来先后收购了ACC2抑制剂 GS-0976、FXR 激动剂GS-9674、ASK1 抑制剂selonsertib、LOXL2 抑制剂SIM。2018年年底又从Scholar Rock买了三个TGFbeta抗体全球权益的独家优先收购权。


John McHutchison也表示,期待selonsertib另一个III期STELLAR-3试验以及桥接纤维化(F3)患者联合selonsertib,cilofexor(GS-9674)和firsocostat(GS-0976)用药的II期ATLAS试验结果。


机器翻译

Gilead Sciences announced February 12 that NASH is developing drugs.The ASK1 inhibitor selonsertib (GS4997) missed the primary endpoint in its first phase III clinical trial (STELLAR-4).

STELLAR-4 is a phase III randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of the new NASH drug selonsertib in patients with compensated cirrhosis (F4) due to NASH.The trial enrolled 877 patients with NASH-induced compensated cirrhosis and compared the effects of selonsertib and placebo on fibrosis at two doses.

Eligible adults aged 18 to 70 years were randomized to receive selonsertib 18 mg (n = 354), selonsertib 6 mg (n = 351), or placebo (n = 172) for up to 240 weeks; selonsertib or placebo was administered orally once daily.The primary endpoint of the study was a comprehensive assessment of the proportion of patients with less improvement in grade 1 fibrosis (fibrosis improvement ≥ stage 1) according to the NASH CRN classification who did not have worsening NASH at week 48 and achieved event-free survival at week 240.

STELLAR-4 trial results showed that in a study of 877 subjects who received the study drug, there were 14 patients treated with selonsertib 18 mg.4% in patients treated with selonsertib 6 mg.Five percent achieved fibrosis improvement of stage ≥ 1 and NASH did not worsen after 48 weeks of treatment; patients receiving placebo achieved fibrosis improvement of stage ≥ 1 of 12.8%.Selonsertib was generally well tolerated, and safety results were consistent with previous studies.But missed the prespecified 48-week clinical endpoint.

Gilead indicated that further in-depth analysis of the findings is ongoing, that the data will be presented to an upcoming scientific meeting, and that the STELLAR-4 study will be completed in a manner that is in the best interest of each patient, in collaboration with the Data Monitoring Committee and researchers.

"While we are disappointed that the STELLAR-4 study did not meet its primary endpoint, we remain committed to advancing therapy for patients with advanced fibrosis due to NASH, particularly as there is a significant unmet need for effective and well-tolerated therapies in this area."Gilead is also collecting data on compensated cirrhosis due to NASH, including a number of biomarkers, which will further improve understanding of the disease and inform broader NASH development programs," said John McHutchison, MD, Chief Scientific Officer of Gilead, in a news release.

Selonsertib is an ASK1 inhibitor and is a highly selective kinase inhibitor.The full name of ASK1 is apoptosis signal-regulating kinase, which can activate JNK.P38 and other key regulatory proteins induce inflammation and fibrosis.

NASH is a chronic and progressive liver disease characterized by fat accumulation and inflammation in the liver, which can lead to scarring or fibrosis that impairs liver function.Individuals with advanced fibrosis, including bridging fibrosis (F3) or compensated cirrhosis (F4), have a significantly increased risk of liver-related mortality and all-cause mortality.

Gilead is advancing a variety of novel investigational compounds for the treatment of advanced fibrosis caused by NASH, evaluating single agent and combination therapies for NASH-related diseases.ACC2 inhibitor GS-0976 has been acquired in recent years.FXR agonist GS-9674.ASK1 inhibitor selonsertib.LOXL2 inhibitor SIM.At the end of 2018, he bought three exclusive priority acquisitions of TGFbeta antibodies from Scholar Rock.

John McHutchison also said he was looking forward to the results of another phase III STELLAR-3 trial of selonsertib and the phase II ATLAS trial of selonsertib, cilofexor (GS-9674) and firsocostat (GS-0976) in patients with bridging fibrosis (F3).

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