The recent failure of several Phase 2 and 3 trials (e.g. that of obeticholic acid, pegbelfermin, and cenicriviroc) evinces the existence of major obstacles impeding the development of NASH therapeutics. Despite the discouragement they may provoke, however, such challenges offer invaluable insight into potential areas of improvement for future trials.
This editorial aimed to propose potential explanations for the failure of Phase 2 and 3 NASH trials.
Potential explanations for NASH trials’ lack of success include unnecessarily rigorous endpoints, NASH’s pathophysiological complexity, heterogeneous study populations, and compounds’ general lack of efficacy. To begin, in the context of preventing liver decompensation in non-cirrhotic NASH patients, averting fibrosis progression may be plausibly just as desirable as achieving fibrosis regression. Adjusting for this endpoint increases the effect size of several drugs, indicating that current trial endpoints may be setting an excessively demanding standard of efficacy. Moreover, to improve future trials, research efforts must investigate NASH’s pathophysiological complexity, e.g. disease-driving pathway alterations from patient to patient. This will contribute to the development of personalised NASH therapies. Similarly, more stringent recruitment criteria are needed in terms of metabolic optimisation to minimise study population heterogeneity, reduce placebo rates, and better demonstrate a compound’s efficacy. Lastly, to maximise the chances of future trials’ success, it is necessary to control for a compound’s effects on 1) NASH’s metabolic drivers and 2) a combination of relevant features (e.g. histology, liver fat content, liver stiffness) in pre-clinical settings. This will increase the likelihood of pre-clinical results translating into efficacy in clinical contexts.