Gilead Sciences announced that its selonsertib to treat compensated cirrhosis from nonalcoholic steatohepatitis (NASH) did not meet its primary endpoint in the STELLAR-4 Phase III trial.
NASH is a progressive fatty liver disease similar to cirrhosis, but in patients who drink little or no alcohol. It is related to the obesity epidemic. There are currently no specific treatments except for lifestyle changes—diet, weight loss and exercise. The market for NASH treatments is projected to hit $20 billion to $35 billion.
Selonsertib is a once-daily, oral inhibitor of apoptosis signal-regulating kinase (ASK1). The trial enrolled 877 patients. In the trial, 14.4 percent of patients receiving selonsertib 18 mg and 12.5 percent receiving 6 mg doses had a ³1-stage improvement in fibrosis without NASH growing worse after 48 weeks of treatment. This compared to 12.8 percent in the placebo group. The drug was generally well-tolerated.
“While we are disappointed that the STELLAR-4 study did not achieve its primary endpoint, we remain committed to advancing therapies for patients with advanced fibrosis due to NASH, where there is a significant unmet need for effective and well-tolerated treatments,” stated John McHutchison, Gilead’s chief scientific officer and head of Research and Development.
He went on to say, “Data from this large study of patients with compensated cirrhosis due to NASH, including the extensive set of biomarkers collected, will further advance our understanding of the disease and inform our broader NASH development programs. We are grateful to the patients and investigators who participated in the STELLAR-4 study, and we now await the upcoming results from the Phase III STELLAR-3 trial of selonsertib in patients with bridging fibrosis due to NASH and the Phase III ATLAS combination trial of selonsertib, cilofexor (GS-9674) and firsocostat (GS-0976) in patients with advanced fibrosis due to NASH later this year.”
Given Gilead’s expertise in liver diseases, the setback is particularly discouraging. The company is still the dominant player in the hepatitis C market (HCV), but their success has been their downfall. Their HCV drugs are so successful they have essentially cured the disease, creating a smaller and smaller patient pool to draw on.
The company’s recent 2018 fourth-quarter and year-end financial report told the story. Total revenues for 2018 were $22.127 billion, down from $26.107 billion in 2017. HIV product sales were up from $3.4 billion in the fourth quarter 2017 to $4.1 billion in the fourth quarter 2018, but HCV product sales were $738 million for the 2018 fourth quarter down by about half form $1.5 billion in the fourth quarter the previous years. HCV sales for 2018 were $3.7 billion compared to $9.1 billion in 2017.
The company has put a lot of money and energy into bolstering its efforts in the NASH arena. On Jan. 7, 2019, it acquired global rights to develop and commercialize novel small molecules against two targets from South Korea’s Yuhan Corporation. Both drugs will be developed to treat advanced fibrosis related to NASH.
In Dec. 2018, Gilead signed a strategic collaboration deal with Cambridge, Mass.-based Scholar Rock to discover and develop highly specific inhibitors of transforming growth factor-beta activation for fibrotic diseases, including NASH. Gilead paid Scholar Rock $80 million up front, made up of $50 million in cash and the acquisition of $30 million in common stock. Scholar Rock is eligible for up to $1.425 billion in potential payments across all three programs in addition to high single-digit to low-double-digit tiered royalties on future product sales.
Because NASH is considered a multifactorial disease including fibrosis, inflammation and metabolism, Gilead and many other companies working in the field are approaching it with combination therapies, each of which focuses on a specific aspect of the disease.
吉利德科学（Gilead Sciences）宣布其用于治疗非酒精性脂肪性肝炎（ NASH ）补偿的肝硬化的药物在 STELLAR-4三期试验中没有达到主要终点。
NASH 是一种进行性脂肪性肝病，类似于肝硬化，但在饮酒很少或不喝酒的患者。这与肥胖流行有关。除了生活方式的改变——饮食、减肥和锻炼，目前还没有具体的治疗方法。NASH 治疗的市场预计将达到200亿至350亿美元。
Selonertib 是一种每日一次的口服细胞凋亡信号调节激酶抑制剂（ ASK1）。试验共纳入877例患者。在试验中，14.4%接受 selonsbert 18mg 和12.5%接受6mg 剂量的患者在48周的治疗后，在没有 NASH 的情况下，纤维化有了一个阶段的改善。而安慰剂组的这一比例为12.8%。这种药物通常是耐受性好的。
“尽管我们对 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 NASH 导致的晚期纤维化患者提供治疗，因为 NASH 对有效和耐受性良好的治疗需求仍未得到满足。”吉利德（Gilead）的首席科学官兼研究与发展主管。
他接着说，“来自 NASH 补偿肝硬化患者这一大型研究的数据，包括收集的大量生物标志物，将进一步加深我们对该疾病的理解，并为我们更广泛的 NASH 发展计划提供信息。我们感谢参与 STELLAR-4研究的患者和研究人员，我们现在等待着即将到来的第三期 STELLAR-3期试验的结果，即由于 NASH 引起的桥联纤维化患者的 selonertib 试验和今年晚些时候由于 NASH 引起的晚期纤维化患者的 selonertib 、 ciloforexer （ GS-9674）和 fironostat （ GS-0976）的 III 期 ATLAS 联合试验。”
鉴于吉利德（Gilead）在肝病领域的专长，这种挫折尤其令人沮丧。该公司仍然是丙肝市场（ HCV ）的主要参与者，但他们的成功是他们的失败。他们的 HCV 药物是如此成功，他们已经基本治愈了疾病，创造了一个更小和更小的病人池来利用。
该公司最近发布的2018年第四季度和年终财务报告告诉了这一消息。2018年总收入为22.127亿美元，低于2017年的26.07亿美元。艾滋病毒产品销售额从2017年第四季度的34亿美元增加到2018年第四季度的41亿美元，但2018年第四季度的 HCV 产品销售额为7.38亿美元，比上年第四季度的15亿美元下降了约一半。2018年 HCV 销售额为37亿美元，2017年为91亿美元。
该公司投入了大量的资金和精力来支持其在 NASH 领域的努力。2019年1月7日，该公司从韩国余汉公司( Yuhan Corporation )获得了针对两个目标开发和商业化新型小分子的全球权利。这两种药物都将用于治疗与 NASH 相关的晚期纤维化。
2018年12月，吉利德（Gilead）与马萨诸塞州剑桥市签署了战略合作协议。-设在斯科尔罗克发现和发展高度特异性抑制剂转化生长因子-β激活纤维疾病，包括 NASH 。吉利德（Gilead）预先向 ScholarRock 支付了8000万美元，包括5000万美元的现金和3000万美元的普通股。除了未来产品销售的高个位数至低两位数的分层版税外， Scholar Rock 有资格在所有三个项目中获得高达14.25亿美元的潜在付款。
由于 NASH 被认为是一种多因素的疾病，包括纤维化、炎症和代谢，吉利德（Gilead）和其他许多在该领域工作的公司正在用联合疗法来治疗它，每一种方法都集中在疾病的特定方面。