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This episode explores the future of combination agents in NASH Therapy. First author Naim Alkhouri and last author Mazen Noureddin join the Surfers to discuss their recently published article, Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial (JHEP, 2022). While the conversation starts by focusing on this article, the discussion itself takes a far broader look at the strategies behind developing combination agents, the likely role these combination therapies will play in treating patients, and, more generally, what Mazen Noureddin describes as the coming “combo-combo” world.

At the outset, Naim notes that while this study was published in 2020, it was first presented at AASLD in 2020. The rationale? As he explains, “semaglutide hits every point” in terms of effects on metabolic syndrome, cardiovascular outcomes, obesity and liver fat, but has not yet been proven in monotherapy to regress fibrosis. Novo Nordisk and Gilead Sciences had formed a partnership to develop NASH drugs, and Gilead had two agents with anti-fibrotic effects, the FXR-agonist cilofexor and the ACC agent firsocostat, that might regress fibrosis.

This conversation is dense with excellent questions and important observations. Here are some of them:

• Jörn notes one very important aspect of combination agents: by requiring lower levels of each individual agent, they have the potential to exhibit superior safety and side effect profiles that a higher-dose monotherapy might. In agreeing, NAIM notes with particular enthusiasm how many patients achieved greater than 30% relative fat reduction in such a short study.
• Mazen raises an intriguing prospect by starting with an interesting acknowledgment: this is an open-label study with neither biopsies nor a placebo arm. However, he suggests, this kind of design will become far more prevalent in a future when one agent in the study has already been approved and is widely used with patients.
• Louise notes that the ability to show patients “real-world results” quickly will motivate them to maintain therapy and lifestyle modification.
• Naim proposes a 6-month “futility” standard: if the drug does not provide results in 6 months, discontinue.
• Roger notes the importance of combination therapy in a disease that has so many theoretical target points and pathways within the liver.
• Mazen calls on the “larger companies” to work with the smaller ones to make these studies more common, noting that the economics and risk profiles of smaller companies require them to focus on getting a single drug to market as quickly as possible.
• A debate emerges when Naim describes LEGEND, a trial combining the promising PPAR agonist with the SGLT-2 agent, empagliflozin. Naim describes empa as an excellent agent to counteract potential weight gain with lani. Mazen shares his believe that the trial should have combined lani with a drug that provides greater weight loss, possibly an GLP-1 agonist or dual agonist. Roger suggests it depends on the target: liver and metabolic disease targeting might lead to a PPAR/GLP-1 combination, while a more holistic look at metabolic outcomes might prefer SGLT-2s for their proven beneficial effects on kidney and cardiovascular diseases. 
• The group agrees that 2 or 3 agents are the most they can see in a combination therapy at this time. They all agree that some patients will require combination therapies while others will succeed with monotherapies. This will be linked with disease severity.
  
  There are more observations here and a raft of supporting data points and arguments. We lack sufficient space to cover all these in this summary, so read and enjoy yourself!