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This discussion begins with Naim offering an in-depth look into the mechanics of the recently published combination study. He explains that “semaglutide hits every point” in terms of effects on metabolic syndrome, cardiovascular outcomes, obesity and liver fat, but it has not yet been proven in monotherapy to regress fibrosis. Gilead Sciences had three agents whose potential anti-fibrotic effects the company wanted to explore fully, so Gilead and Novo Nordisk, which owns semaglutide, formed a partnership to develop these drugs.

One agent, selonsertib, turned out to be ineffective, but the other two, the FXR agonist cilofexor and the ACC agent firsocostat proved efficacious in combination with semaglutide. Naim goes on to describe the mechanics of the study and presents results demonstrating that even in a six-month trial, the triple therapy proved efficacious with a favorable side effect profile.

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.

The rest of this conversation features additional comments by Mazen, namely addressing the short duration of the study. He suggests that if extended, the study quite possibly had more positive results to be shown, namely, through further weight loss. Mazen also raises an intriguing prospect 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.

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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!

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Louise Campbell convenes liver nursing and nurse educator experts Kathryn Jack, Michele Clayton, Pam O'Donoghue and Patrizia Kunzler to consider where liver nurses and advanced nursing practitioners should fit into treatment and communication paradigms and what support they will need. Stephen Harrison joined to offer a different viewpoint.

This conversation explores the need for and value of patient education in the NASH Patient Care process. It starts with almost a tangential request that some of the money budgeted for expensive systemic HCC therapies in the UK be rededicated to patient education earlier in the treatment process.

From there, the conversation shifts to consider the value of the need for early-stage treatment strategies in poorer countries that are never likely to be able to afford the expense of drugs or treatment modalities. In the end, each panelist describes a change she would like to see in the next 2-3 years.

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Surfers Louise Campbell and Jörn Schattenberg are joined by patient advocate Robert Mitchell-Thain, liver nurse Michelle Clayton, and healthcare consultant Stephen Callaghan to talk about their unique perspectives in the process of pathway development for NAFLD. In doing so, the group looks for ways to incorporate the 17 Sustainable Development Goals (SDG) established by the United Nations - an urgent call for action on health, economy, and starvation amongst other human rights issues.

This final conversation of Season 3 - Episode 42 discusses the power of education to place liver disease on a higher agenda. Louise notes that liver health is not engaged with at a school level. She suggests that liver health as an outcome be incorporated from an earlier age. This familiarity could fundamentally assist the more ‘generalist’ approach that Stephen promotes. Michelle mentions potential pushback and the group revisit the need for more patient resources. Beyond access to affordable nutrition, communities need safe spaces and opportunities for exercise.

Next, the group expresses their eagerness for building an inclusive, robust framework for a NAFLD pathway. Michelle reiterates her position that the success of such a framework requires the contributions of nurses and allied health professionals. Robert also hopes to see uniform action on this pathway to tap into an immense knowledge base. Stephen enjoyed his first podcast feature and is looking to translate successful strategies from previous pathways to the liver space. Jörn is appreciative of joining this conversation on inclusion, placing a great value on honest and open feedback.

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Surfers Louise Campbell and Jörn Schattenberg are joined by patient advocate Robert Mitchell-Thain, liver nurse Michelle Clayton, and healthcare consultant Stephen Callaghan to talk about their unique perspectives in the process of pathway development for NAFLD.

Louise begins this conversation by asking Stephen about a successful HIV pathway that he had contributed to, and how it may be applicable to liver disease. Stephen maintains that “it’s about identifying the most important measures across a pathway.” A pathway can be measured both stepwise and incrementally by indicators within the larger framework. Stephen provides an example of application through the aforementioned HIV pathway. Next, Robert explores the gamification of digital health, and what that may provide in terms of patient empowerment. This movement appeals to Jörn because it can help define goals. Both patients and health professionals are working under mutual motivators.

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Surfers Louise Campbell and Jörn Schattenberg are joined by patient advocate Robert Mitchell-Thain, liver nurse Michelle Clayton, and healthcare consultant Stephen Callaghan to talk about their unique perspectives in the process of pathway development for NAFLD. In doing so, the group looks for ways to incorporate the 17 Sustainable Development Goals (SDG) established by the United Nations - an urgent call for action on health, economy, and starvation amongst other human rights issues.

This conversation begins by discussing the role of patients in the scope of allied health. Louise prompts the question, where do they fit into the pathway? Robert identifies the many touch points and opportunities presented for patient inclusion. He also suggests that patients tend to communicate in terms of quality of life issues - not in the language of diagnostic scores. Michelle joins to highlight the importance of nurses and allied health professionals in the context of patient interactions. Nurses and allied health professionals can offer conversational insights that promote liver health. However, Jörn expresses the shared concern that a lack of funding tends to stretch nursing resources thin.

The discussion shifts to promoting liver health in a wider professional setting. Stephen speaks to the reality that “everyone is fighting their own corner” in advocacy and diagnostics. The group then explores ways by which more generalist testing can identify and capture at-risk patients earlier in the pathway. Patients presenting comorbidities need more than one therapy, more than one organ monitored, and more than one answer to their questions.

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Surfers Louise Campbell and Jörn Schattenberg are joined by patient advocate Robert Mitchell-Thain, liver nurse Michelle Clayton, and healthcare consultant Stephen Callaghan to talk about their unique perspectives in the process of pathway development for NAFLD. In doing so, the group looks for ways to incorporate the 17 Sustainable Development Goals (SDG) established by the United Nations - an urgent call for action on health, economy, and starvation amongst other human rights issues.

Earlier this year, Jörn co-authored a paper titled, A sustainable development goal framework to guide multisectoral action on NAFLD through a societal approach (2022). Jörn talks about the process and intention behind the paper. He recalls that leading author, Jeff Lazarus, sought to incorporate the SDG and its applicable targets to the challenges posed specifically by NAFLD. The group identifies a lack of representation in authorship and discusses how to improve on this. It is agreed that developing a pathway requires the contribution of nurses, patients and patient advocates, and other allied health professionals.

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Surfers Louise Campbell and Jörn Schattenberg are joined by patient advocate Robert Mitchell-Thain, liver nurse Michelle Clayton, and healthcare consultant Stephen Callaghan to talk about their unique perspectives in the process of pathway development for NAFLD. In doing so, the group looks for ways to incorporate the 17 Sustainable Development Goals (SDG) established by the United Nations - an urgent call for action on health, economy, and starvation amongst other human rights issues.

Earlier this year, Jörn co-authored a paper titled, A sustainable development goal framework to guide multisectoral action on NAFLD through a societal approach (2022). Louise begins by asking Jörn about the process and intention behind the paper, and how it champions the SDG. Jörn recalls that leading author, Jeff Lazarus, sought to incorporate the SDG and its applicable targets to the challenges posed specifically by NAFLD. The paper is formulated by consensus using The Delphi Process, whereby two rounds of interdisciplinary discussion decided on 16 deliverable targets relevant to NAFLD. It aims to determine what is important to be addressed by politics and those involved with research funding.

Michelle notes this paper is absent of nurses, patient advocates or other allied professional contributors. Robert joins to reframe Michelle’s concerns, asking how do we do it better next time? He seeks a more genuine multisectoral representation in what could only then be dubbed as a truly societal approach. Jörn acknowledges these shortcomings and agrees that, as the paper stands, it can be seen as a physician’s viewpoint. Louise reckons that the paper serves a foundation and that if it were to be further developed, now is the time to introduce different perspectives.

The conversation turns to the next steps of establishing such a framework. Stephen Callaghan provides an anecdote from his time contributing to the development of a pathway for HIV. The driving message is that not every stakeholder comes from a clinical environment. As such, the group agrees that herein lies the importance of communication. Robert states that most patients are relating in terms of describing symptoms and other quality of life issues. Some of the more complex metrics understood by specialists may not translate outside of the professional circle. Michelle then highlights the critical role of nurses positioned as a more conversational contact with the ability to identify risk factors and promote liver health. Both points resonate with Jörn. He explains that the SDG paper emphasizes a need for funding for nurses. He also shares Robert’s concern surrounding the power gap that can negatively impact the patient’s ability to contribute pathway development.

Next, Stephen speaks to the reality that “everyone is fighting their own corner” in advocacy and diagnostics. Robert relates, stating the matter is complex and that the community should come together to offer more than one answer to patient questions. Jörn alludes to Stephen’s position as a generalist to combat this issue. The conversation then shifts to education. Louise notes that liver health is not engaged with at a school level. She suggests that liver health as an outcome be incorporated from an earlier age. This familiarity could fundamentally assist the more ‘generalist’ approach. Michelle mentions potential pushback and the group revisit the need for more patient resources. Beyond access to affordable nutrition, communities require safe spaces and opportunities for exercise.

Final thoughts are shared and each expresses their eagerness for building an inclusive, robust framework. The success of such a framework requires many players, and Stephen hopes to transla

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Jörn speaks about co-authoring an article, “The Nonalcoholic Steatohepatitis (NASH) drug development graveyard: established hurdles and planning for future successes.” In doing so, he discusses areas for improvement he feels clinical trial strategy and design will require. Joining the conversation is Stephen Harrison and Global Liver Institute Founder and CEO, Donna Cryer. Both Stephen and Donna approach the conversation from the patient and patient advocate perspectives. 

This episode From the Vault provides an amazing and complementary comparison to how far this topic has come in just two years. Notably, much has developed in the space of NITs since this paper in 2020. In this week's Surf, Season 3 - Episode 41, Roger, Louise, Stephan and Jörn reflect on what has improved in the intervening time period, what has not, and where this space is headed.

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THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. The group speculates what can still be accomplished. 

This conversation begins with Roger suggesting that tertiary care research universities that have their own primary practice be utilized as an accessible point of referral. The group agrees that while a good idea, this may not translate to the European system.

Roger poses the closing question: what is there to look forward to in the space of NASH clinical trials and improving screen fail rates in the next 6 months to a year? Louise is looking for the approval of FibroScan for primary care in the UK. Jörn is hoping for an opportunity to offer health care services through referral systems. Stephen talks about getting a drug approved. In response to the latter, Roger finishes with a Stephen quote: is the juice worth the squeeze? This "juice" takes forms of cash and optimism, and it will be worth the squeeze if a drug sees successful development.