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Abstract Details
Rational Combination Therapy for NASH: Insights from Clinical Trials and Error
J Hepatol. 2023 Jan 2;S0168-8278(22)03477-8. doi: 10.1016/j.jhep.2022.12.025.Online ahead of print.
1Sorbonne Université; Institute for Cardiometabolism and Nutrition (ICAN); Hospital Pitié-Salpêtrière, Paris, France. Electronic address: vlad.ratziu@inserm.fr.
2Center for Liver Diseases; Transplantation Institute, University of Chicago, Chicago, Illinois, USA.
Abstract
So far, without an approved therapy, nonalcoholic steatohepatitis (NASH) remains at the beginning of its therapeutic cycle, characterized by the development of many pharmacological agents, initially tested as monotherapies. Given the complex pathogenesis of NASH, the prevailing opinion is that combination therapy will be key for treating NASH and that therapeutic efforts should aim at developing combinations rather than monotherapies. Developing combination therapies, however, comes 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, to 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 programs are 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 the demonstration of their therapeutic value.