Non-alcoholic steatohepatitis (NASH) can lead to serious conditions such as cirrhosis and its complications, liver cancer and hepatic transplantation. Many patients eventually die from liver-related problems or cardiovascular disease. The challenge in developing drugs for NASH is to demonstrate an improvement in clinical outcomes. Cirrhosis takes several years to develop, and it is impractical to perform such long studies to identify treatment benefits. Therefore, to expedite the process and deliver new drugs to patients, biopharmaceutical companies have to consider surrogate endpoints that are reliable, can be obtained within a reasonable amount of time and are associated with progression of the disease.
A range of liver-related outcomes
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).
- Gastroesophageal varices and variceal hemorrhage. About half of patients with cirrhosis develop enlarged blood vessels, which also are caused by portal hypertension and can lead to variceal hemorrhage.
- Hepatorenal syndrome. Kidney deterioration and failure can arise as a result of chronic liver injury. This is an extremely serious complication.
- Hepatocellular carcinoma (HCC). Patients with chronic liver disease and cirrhosis can develop this type of cancer. A recent study revealed that the incidence of non-alcoholic fatty liver disease (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. Progression to stage F4 by histology is predictive of clinical outcomes. Therefore, prevention of progression to cirrhosis by histology is a reasonable surrogate endpoint in a long-term trial.
- Model For End-Stage Liver Disease (MELD) score. This score is a reliable measure of mortality risk in teenagers and adult patients with end-stage liver disease. It is used as an index of disease severity and likelihood of survival. MELD incorporates the patient’s values for serum bilirubin, serum creatinine and the international normalized ratio (INR) for prothrombin time. A score ≥ 15 is an appropriate endpoint; scores from 10 to 19 predict a 6% three-month mortality rate in hospitalized patients.
Short-term surrogate endpoints
Although liver biopsy has multiple limitations, it remains the best method for tracking the progression of NASH. As mentioned above, the primary objective of a NASH treatment is to prevent liver-related morbidity and mortality, which occur mainly due to development of cirrhosis. While prevention of progression to cirrhosis by histology is a reasonable surrogate endpoint, it can take approximately 6 to 7 years to see a 1-point progression in fibrosis in NASH patients. Therefore, other surrogate endpoints such as improvement in the NAFLD activity score (NAS), resolution of NASH and improvement in liver fibrosis by histology are valid surrogate endpoints for Phase IIb or Phase III trials.
The NAS offers a 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:
- Proof of concept. In general, biopsy-driven endpoints are not feasible in a 12- to 24-week proof of concept trial. Patients may be reluctant to have two liver biopsies in a 16- to 24-week period, and histological changes may not be apparent over this short timeframe. Instead, improvement in hepatic steatosis, as determined by magnetic resonance technology, might be suitable. Ideally, improvement in alanine aminotransferase (ALT) and other non-invasive biomarkers of inflammation, apoptosis and fibrosis also could help researchers evaluate the efficacy of the compound.
- Phase 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.
Our 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, we offer the complete continuum of expertise needed to bring a NASH treatment to market.
To find out more, watch the webinar on NASH development.