非酒精脱脂性肝炎（NASH）可导致严重的病症，如肝硬化及其并发症，肝癌和肝移植。许多患者最终死于肝脏相关的问题或心血管疾病。发展纳什毒物的挑战是在临床结果中表现出改善。肝硬化需要几年才能发展，执行这么长的研究是不切实际的，以确定治疗效益。因此，为了加快该过程并向患者提供新药，生物制药公司必须考虑可靠的替代端点，可以在合理的时间内获得，与疾病的进展相关。
一系列与肝相关的结果
NASH patients face many potential disorders and complications. In addition to overall death and liver-related mortality, the following endpoints should be evaluated in a clinical
outcomes study:
- Portal hypertension.Chronic injury to the liver results in a wounding response that leads to fibrosis, scarring and ultimately replacement of normal liver architecture with regenerative nodules. As a result of these changes, portal hypertension develops.
- The accumulation of fluid in the abdomen results from portal hypertension. Using diuretics and reducing sodium intake often helps, but some cases are difficult to treat.
- Hepatic encephalopathy.Patients with cirrhosis may suffer damage to the nervous system and cognitive dysfunction, due to the buildup of toxic substances that the liver would normally remove. Hepatic encephalopathy spans a continuum from normal cognitive function (grade 0) to minimal hepatic encephalopathy (within grade 0) to overt hepatic encephalopathy (grade 1–4).
- 胃食管各种变化和静脉血出血。About half of patients with cirrhosis develop enlarged blood vessels, which also are caused by portal hypertension and can lead to variceal hemorrhage.
- Hepatorenal综合征。Kidney deterioration and failure can arise as a result of chronic liver injury. This is an extremely serious complication.
- 肝细胞癌（HCC）。慢性肝病和肝硬化患者可以培养这种类型的癌症。最近的一项研究表明，发病率非酒精脂肪肝病(NAFLD) patients without cirrhosis who develop HCC is increasing, while the incidence of NAFLD HCC patients with cirrhosis is not. These results suggest that people with fatty liver still face a serious risk of liver cancer, even if they do not have cirrhosis.
Due to the reduced number of clinical outcomes that will occur in a reasonable timeframe, surrogate endpoints are accepted at present as part of the primary endpoint in a clinical outcome trial.
- Progression to cirrhosis.通过组织学通过组织学阶段F4的进展是预测临床结果。因此，通过组织学预防进展到肝硬化是一个长期试验中合理的代理终点。
- Model For End-Stage Liver Disease (MELD) score.该得分是青少年和成年患者终末期肝病患者的死亡率风险可靠的衡量标准。它被用作疾病严重程度和生存的可能性。MELL包括患者对血清胆红素，血清肌酐和国际标准化比（INR）进行凝血酶蛋白时间的值。分数≥15是适当的端点;评分从10到19预测住院患者的6％三个月死亡率。
Short-term surrogate endpoints
虽然肝活检具有多个限制，但仍然是跟踪纳什进展的最佳方法。如上所述，养猪治疗的主要目标是预防肝相关的发病率和死亡率，这主要是由于肝硬化的发育。虽然通过组织学预防进展的肝硬化是一个合理的替代端点，但它可能需要大约6〜7年才能看到尿液患者纤维化的1点进展。因此，其他替代终点如改善NAFLD活动评分（NAS），通过组织学通过组织学改善纳什和改善肝纤维化是相位IIB的有效替代端点或Phase III trials。
NAS提供了一个relatively objective way to evaluate severity of the liver injury and is useful for assessing changes in clinical trials. This score, which ranges from 0 to 8, incorporates measurements of steatosis, lobular inflammation and ballooning. A NAS of 5 or more is associated with a greater likelihood of NASH; however, it does not confirm NASH. The diagnosis of NASH is defined by the presence and pattern of specific histologic abnormalities.
A validated method for the staging of NASH should be used to assess changes in disease stage in clinical trials. The NASH Clinical Research Network (CRN) fibrosis staging system is the most validated system currently available. Total scores range from no fibrosis to cirrhosis (0 to 4).
Progressing through the NASH development pathway
As development progresses from proof of concept through Phase III, the following surrogate endpoints can be assessed to evaluate efficacy:
- 证明概念。通常，活组织检查驱动的终点在12到24周的概念试验证明中不可行。患者可能不愿意在16至24周的时间内具有两个肝脏活组织检查，并且在这种短时间内，组织学变化可能不明显。相反，通过磁共振技术确定的肝脏脂肪变性的改善可能是合适的。理想情况下，丙氨酸氨基转移酶（ALT）和其他非侵袭性生物标志物的改善，炎症，凋亡和纤维化也可以帮助研究人员评估化合物的疗效。
- 阶段IIB。Two histological endpoints can be used: (1) change of at least two points in NAS without worsening of fibrosis, and (2) complete resolution of NASH (scores of 0 for ballooning and 0-1 for inflammation) without worsening of fibrosis. Secondary or exploratory endpoints may include changes in the NAS components (steatosis, ballooning, inflammation), changes in fibrosis, improvement in symptoms, changes in BMI, insulin sensitivity, cardiovascular risk profile, biomarkers of cell damage/inflammation/oxidative stress, quality of life, rates of hospitalization and economic endpoints.
- Phase III.A typical primary endpoint is resolution of NASH without worsening of fibrosis, with a co-primary endpoint of improvement of at least one point in fibrosis and no worsening of NASH. Secondary or exploratory endpoints are similar to those in Phase IIb.
Covance’s liver disease experts can help develop unique study designs that shorten clinical trials and reduce costs. As a CRO that spans all phases of development, Covance offers the complete continuum of expertise needed to bring a纳什治疗to market.
To find out more,看网络研讨会on NASH development。
