combinationtherapy

In a monumental moment in the never-ending pursuit of putting a major dent in Fatty Liver disease, Madrigal Pharmaceuticals announced positive topline results from the pivotal Phase 3 MAESTRO-NASH clinical trial of resmetirom for the treatment of NASH and liver fibrosis. Madrigal’s leadership intends to file for resmetirom’s accelerated approval with the FDA in the first half of 2023. If approved, the drug may become the first NASH medication introduced to market, depending on the outcome and timing of Intercept Pharmaceuticals’ refiling of obeticholic acid.

To recognize this special occasion, Surfing the NASH Tsunami hosts its largest ever suite of panelists who react to the enthusiasm, synergy and implications surrounding the news. This final conversation starts with Roger Green following up on a couple of earlier comments. First, he notes the fact that in other diseases, a combination therapy can get approved before each element of monotherapy has been approved. Second, he notes that semaglutide’s Phase 2 result, with 72-week effects on steatosis and NAS activity score but not fibrosis regression, aligns with Scott Friedman’s earlier statement that not all fat lowering may mean the same thing in the liver. Jörn Schattenberg and Mazen Noureddin follow-up with other comments about NAS, fibrosis and lipotoxicity. This leads Jörn to note that there is already a second THR-beta in trial, from Viking Therapeutics, and asks what this trial might mean for Viking. Mazen cites Terns as another company with other drugs, including a THR-beta in the pipeline, and believes they will benefit as well. Scott asks what all this means for patients with cirrhosis. Rachel Zayas then discusses some of the development work her company is doing and how these results might affect her work and ability to raise resources. As the session winds down, Kris Kowdley describes one more way that the use of companion diagnostics against dose response and non-response will aid payers. For her final thoughts, Louise Campbell discusses how we might consider this a major anti-cancer advance given how the liver is implicated not only in HCC but also in non-hepatic cancers. Surf on to hear the diverse array of closing takeaways from the rest of the group.

In Season 3, Episode 6, Roger Green assembles audio clips from Surfing the NASH Tsunami’s coverage of NASH-TAG 2022 to reveal an evolving view of the role combination therapies will play in the treatment and management of NASH patients. Discussion about “combination therapies” typically focuses on the idea of multiple agents prescribed concurrently to address a medical condition when monotherapy will not achieve desired goals. At NASH-TAG 2022, the concept of combination therapies took some interesting directions:

1. Longitudinal drug combinations — initial intervention designed to cause a fast reversal of fibrosis or defatting of the liver, followed by a longer-term therapy (mono or combination, but not with the first-round agent) designed to provide longer-term, more complete metabolic benefits in a regimen that is safer, more tolerable, less expensive, or some combination of these.
2. Longitudinal diagnostics — an early, inexpensive “rule out” test like FIB-4, followed by a liquid or machine-based test that provides more accurate disease staging.
3. Logical combinations — so far, most drug combination trials have resulted from a manufacturer trying to resuscitate a developmental agent that missed endpoints in monotherapy trials. It would be more logical to design combinations based on complementary modes of action.

This episode explores these and other combination therapy issues using quotes from the NASH-TAG 2022 coverage and Roger’s commentary.

After a month of major Fatty Liver medical meetings, Jörn Schattenberg, Louise Campbell and Roger Green explore emerging stories that will shape the next 6-12 months in Fatty Liver disease. In this final conversation, the group discusses the importance of combination NIT biomarkers in developing a viable system for treating patients. The key is that NITs provide a viable strategy for widespread patient screening and staging, whereas biopsy does not.

Roger also asks about several other issues that will come to the fore in the next year. The first item is the Nomenclature conference. Jörn describes it as a moving target with a clear split between the hemispheres. Asia is moving toward a concept more like metabolic-associated disease, however, Europe and North America are not. He notes that an ongoing process of consensus leaves him hopeful. Roger suggests that redefining the disease itself might lead regulators to disregard the vast amounts of research accomplished. Unfortunately, this has the potential to set the field back several years. Jörn agrees that it is imperative that any solutions do not push back drug or diagnostic approvals. The existing data and procedures around patient enrolment in trials remain clear.

The final question returns to the issue of what changes might take place over the next year. Each answer differs and continues themes found in the earlier conversations. Surf on for the group’s predictions.