Rational combination therapy for NASH: Insights from clinical trials and error.

So far without an approved therapy, non-alcoholic steatohepatitis (NASH) remains at the beginning of its therapeutic cycle, whereby many pharmacological agents are initially developed as monotherapies. Given the complex pathogenesis of NASH, the prevailing opinion is that combination therapy will be key to its treatment and that therapeutic efforts should be aimed at developing combinations rather than monotherapies. However, the development of combination therapies is associated with multiple challenges, which we attempt to describe here, and which extend beyond the perceived biological rationale of combining two different mechanisms of action. Important hurdles include predicting the added benefit of a specific combination regimen over monotherapies, given the limited data provided by early phase trials. Regulatory requirements for approving a combination span from preclinical models, through initial demonstration of the efficacy of the combination, to complex late-stage therapeutic trials. Development pathways for combination therapies are, in this paradigm, highly demanding in terms of patient and sponsor resources. In light of recent, negative, late-stage trials of monotherapies, well-designed combination development programmes could be essential to avoid additional failures that may hold back therapeutic research and access to treatment for patients. Enthusiasm for combination therapies should be maintained but realistically balanced against the complexity of demonstrating their therapeutic value.