Editorial: Combination Therapies for <scp>MASH</scp> : A Step Forward or More Complexity? Authors' Reply

We thank Drs. Zhou, Yilmaz, Noureddin, Luu and Zheng for their comments on our article, Clinical Trial: A Phase 2 Randomised Platform Study to Assess Monotherapy and Combination Treatment Regimens in Metabolic Dysfunction-Associated Steatohepatitis [1] including their perspective on the challenges to conducting clinical trials with combination therapies and potential opportunities for platform trials to address these challenges. We agree that determining the efficacy for each of the combination partners as monotherapy is an important component of interpreting the additional efficacy that can be achieved with the combination. The operational and regulatory hurdles and costs associated with this requirement remain significant impediments to the development of combination therapies for MASH. The NEXSCOT platform study was intended to efficiently screen promising combination (and mono) therapies for further development for MASH. In addition to the prespecified efficacy thresholds included in our analytical plan, we were also able to leverage extensive internal tropifexor monotherapy data sets and innovative subtractive and additive analyses to confirm that the addition of LYS006 to tropifexor did not result in greater efficacy than tropifexor monotherapy. Other Sponsors who have similarly robust monotherapy datasets may be able to utilise similar approaches to efficiently identify high potential combinations and perhaps, more importantly, deprioritize those combinations which are unlikely to provide additional benefit over monotherapy. In their editorial, Zhou et al. [2], highlight the challenge to achieve clinically meaningful efficacy in patients who are monotherapy nonresponders and suggest that a personalised approach to selecting combination therapies may be warranted, such as starting with monotherapy and adding a second therapy for nonresponders and intensive initial combination therapy for patients with advanced fibrosis or severe metabolic dysfunction. Because MASH is a systemic disease with liver manifestations, an ideal strategy might be to lead with a systemic intervention prior to the more targeted therapy which can be added based on initial response. Given that the liver is both a receiver of metabolic stress and also a further driver of metabolic dysfunction, combination therapies that modulate both systemic and liver targets may have the optimal opportunity to impact liver endpoints but also target combinations that improve insulin resistance, systemic inflammation and lipid metabolism dysfunction. These systemic considerations should be included as endpoints of combination therapy rather than secondary benefits. Future refinement of adaptive trial designs like NEXSCOT may provide the flexibility to consider innovative treatment sequencing strategies and inclusion of both systemic and liver specific endpoints to facilitate our understanding of combination therapy. Trial design optimization and dynamic dosing adjustments may be used to accelerate optimal regimens while also mitigating risks associated with the development of combination therapies. The authors' declarations of personal and financial interests are unchanged from those in the original article [1]. Eric Lawitz: conceptualization, writing – original draft, writing – review and editing. Linda Greenbaum: conceptualization, writing – original draft, writing – review and editing. The authors have nothing to report. This article is linked to Frias et al. papers. To view this article, visit https://doi.org/10.1111/apt.70475 and https://doi.org/10.1111/apt.70487. The data that support the findings of this study are available from the corresponding author upon reasonable request.