lanifibranor

This week, Surfing the NASH Tsunami celebrates its 3rd anniversary since the debut episode posted on April 15, 2020. We are offering a jam-packed special featuring individual interviews with guests Amy Articolo of Novo Nordisk, Donna Cryer of the Global Liver Institute, and Frédéric Cren of Inventiva Pharma.

In this final interview, Frédéric, Louise Campbell and Roger Green exchange ideas around, among other topics, the history and development of Inventiva’s lead product candidate, PPAR agonist lanifibranor.

If you enjoy the special, have questions or interest around Fatty Liver disease, please let us know your ideas by writing to questions@SurfingNASH.com and leaving a review wherever you download the discourse.

Stay Safe and Surf On!

SurfingNASH is covering each day of NASH-TAG 2022. This episode is a "morning after" conversation with Stephen Harrison, Louise Campbell and Jörn Schattenberg reviewing key points of the Day Two discussions, with particular focus on the two "fireside chats" that wrapped up the program.

Day Two of NASH-TAG included presentations of new data on wet markers, imaging and combination therapy, discussion of novel targets and advances in our understanding of basic science. All this led up to the meeting's climax + denouement: David Shapiro's talk on why the current trial and approval system is unsustainable and places unnecessary burden on patients, developers and investors, followed by two "fireside" chats that were, in fact, calls to action to rethink the appropriateness of clinical trial endpoints driven by so-called "semi-quantitative" histopathology reads driven by liver biopsy.

The day produced bold arguments, exceptional images, and some compelling new facts and perspectives. It was also long: Roger, Stephen and Louise started with a 6:15a MST SurfingNASH recording session and went through until the 8:15p MST program adjournment (for Louise in the UK, the cirrhosis fireside chat ended after 3:00a Sunday morning!) The next morning, the group met to review the speeches, slides and impassioned moments of a compelling, powerful day.

In the process, they revisited some of the day's high points, culminating in powerful statements on the problems with current clinical trial endpoints articulated by Stephen Harrison for non-cirrhotic trials and Vlad Ratziu for cirrhotic trials and supported by a powerful statement by Global Liver Institute Founder and CEO Donna Cryer focusing on how the current trial endpoint system places patients under undue burden and unnecessary, sometimes mortal, risk.

This conversation is part of SurfingNASH's 2021 NAFLD Year-In-Review. Co-host Dr. Stephen Harrison joins Louise Campbell and Roger Green to review five key NASH themes that emerged in 2021, while simultaneously discussing the year for Surfing the NASH Tsunami.

It seems fitting that the first SurfingNASH event of 2022 should include Stephen, Louise and Roger. In this thoughtful, fast-moving conversation, Stephen identifies what he considers five key areas where the Fatty Liver community has progressed in the past year:
1. Call to action -- 2021 saw two separate, vitally important calls to action to share the scope of the upcoming NASH pandemic with the medical community at large and begin to create forums and processes to develop an agenda and care practices that would reach far beyond hepatolotgy all the way to primary care and other specialties that have historically had little to do with the liver. Jeff Lazarus work with colleagues at Wilton Park and in over 100 countries to evaluate the current status of NASH diagnosis, treatment and screening around the world and to being developing a public health agenda. At around the same time, a multidisciplinary panel of US opinion leaders organized by AGA published a general call to action and a specific Clinical Care Pathway, starting at diagnosis, that included multiple specialties and, for the first time, set out to define a way specialties can work together in identifying patients at risk, screening them for disease, and then treating as appropriate.
2. Natural History -- 2021 saw publication of two major papers on the natural history and progression of the disease. One paper produced by Stephen, Naim Alkhouri and a range of associates, evaluated a large group of seemingly healthy middle-aged men who receive treatment at the San Antonio Military Medical Center and mirrored a smaller study 10 years earlier. The two studies were fairly consistent in determining that slightly over one adult in three has demonstrable NAFLD and one in seven or eight has documentable NASH. The difference in the populations was that while approximately 2% of the 2011 sample exhibited F2 or F3 NASH, that number almost tripled ten years later. These papers and Dr. Arun Sanyal's work published later in the year in the New England Journal of Medicine indicated that we can project a steadily increasing trend line for cirrhosis cases, with growth in most major markets at 10-12% per year.
3. Drug Development --news here was mixed, although Stephen points out that we have learned from each failed trial. SurfingNASH discusses this topic frequently, so suffice it to say that as the year ends, three medications recruiting or conducting Phase III trials and several other exciting, innovative agents have already demonstrated some positive Phase II results.
4. Weight loss surgery -- Stephen feels that the SPLENDOR study, which we discussed recently on the podcast (S2 E60), merits notice because of what it suggests about the ability of dramatic weight loss to halt or reverse cirrhosis. There are drugs in development right now that appear capable of producing the same levels of weight loss shown with bariatric surgery, which provides hope that we can eventually stabilize and perhaps regress fibrosis levels in cirrhotic patients.
5. Non-invasive testing -- Several different modes of non-invasive testing have made progress during the year, ranging from liquid tests that received FDA approval and/or enhanced their commercialization capabilities to published research suggesting that MR Elastography (MRE) has compiled much of the data necessary to prove outcomes with greater clarity and confidence than biopsy. Stephen shared his belief that 2022 will be the year when academics, drug developers and regulators begin to align around a strategy to move beyond biopsy with deliberate speed.

None of these items are new, but the way Stephen organizes them is clearly worth a long listen.

The last half of December marks our annual NAFLD Year-in-Review. Episodes 62-64 each include ~20 minute segments of longer interviews with Stakeholders who have made a dent in Fatty Liver disease in 2021.

In this episode, Louise Campbell and Roger Green are joined by Stephen Harrison, Jeff Lazarus and Andrew Scott. Conversation topics vary widely, with Stephen describing on what he sees as the five key themes in his NAFLD 2021 Year-in-Review, Jeff focusing largely on the public health agenda and Andrew discussing the steps by which patient advocacy is becoming an increasing force in public and private Fatty Liver disease discussions. Each guest is a leader in his topic. Each brings intellect, insight, experience and energy to the topic and this interview. Each is worth a serious listen...

The conversation with Stephen also provides the three weekly episode co-hosts an opportunity to look back on the breakthrough year for Surfing the NASH Tsunami in 2021.

This vacation is posting after SurfingNASH.com shut down for a year-end break, so timestamps will be coming early the first week in January.

This conversation is part of SurfingNASH's 2021 NAFLD Year-In-Review. Professor Kenneth Cusi of the University of Florida joins Louise Campbell and Roger Green to discuss the NASH multidisciplinary initiative organized under the aegis of AGA the resulting paper of Clinical Care Pathways.

In 2021, Ken Cusi played an integral role in the NASH Multidisciplinary initiative fostered under the aegis of the American Gastroenterological Association (AGA) and leading to the paper "Clinical Care Pathway for the Risk Stratification and Management of Patients With Nonalcoholic Fatty Liver Disease," originally published in "Gastroenterology". This conversation begins with Ken mentioning some of the motivations and sources that led to the creation of the multidisciplinary group behind the Clinical Care Pathway paper and the earlier "Preparing for the NASH Epidemic: A Call to Action." Ken starts this conversation by discussing the momentum that is building around taking a disciplined, multidisciplinary approach to the emerging NASH pandemic. He cites recent US publications based on the NHANES database and work done in Europe by Jeff Lazarus and Wilton Park as being major driving forces. The discussion moves on to Ken's prediction that 2022 will be a "great year" based on new or updated guidelines from AASLD, AACE and the American Diabetes Association plus Phase 3 studies coming forward for semaglutide, lanifibranor and resmetirom. Louise Campbell notes that not only are medical groups collaborating, but in the UK, food companies have requested more robust food labeling guidelines from the government there. Ken goes on to predict "a convergence of awareness" around the clinical care pathway and using FIB-4 as a first stage test. He notes that ELF and ProC3 will become commercially available, which will augment testing capabilities and goes on to discuss some larger studies taking place to better define risk for different elements of the population. Louise Campbell asks what is likely to change over the next 2-3 years, at which point Ken discusses the increasing momentum he believes will lead to more testing, increased data generation and studies and a broader awareness of the role the liver plays in overall metabolic health. Roger asks how the new testing and patient vigilance will fit into an already overcrowded patient visit workload. Ken suggests that placing FIB-4 results and guidance on electronic medical records will increase primary care awareness and action by itself. This energy is offset somewhat by a lack of compensation for primary care and endocrinologists who identify patients with cirrhosis and also by the emotional exhaustion of treating patients through the COVID-19 pandemic. From here, the group goes on to discuss the processes through which screening and diagnosis are likely to become more widespread and treatment will become better integrated. In the end, Ken discusses the reasons he is highly optimistic about where the entire NASH field is heading in the years to come.

The last half of December marks our annual NAFLD Year-in-Review. Episodes 62-64 each include ~20 minute segments of longer interviews with Stakeholders who have made a dent in Fatty Liver disease in 2021. In this episode, Louise Campbell and Roger Green are joined by Manal Abdelmalek, Kenneth Cusi and Jörn Schattenberg.

Highlights:
3:26 – Manal Abdelmalek introduction and discussion: opportunities in the new drug pipeline and ways to treat using older agents until new agent arrive
5:06 – Manal: urgent to treat cirrhosis when it appears. Reversal may not be “achievable;”  but blunting progression can provide stability 
9:51 – We learn more about heterogeneity of cirrhosis patients all the time. Some day, genetics will pinpoint each patient's outcome to avoid so we can treat accordingly
12:20 – Louise: would a combined database of multiple cirrhosis drug study patients provide richer insights?
14:05 – Manal: let’s “shelf,” not "trash," drugs that had promising NIT results but missed in Phase 2b or 3 histology
18:57 – Louise: Manal does well to remind us how to use older drugs to stabilize cirrhosis patients.
21:05 – Manal: until new drugs become commercially available in 2-5 years, using older drugs better will be key
23:07 – Ken Cusi introduction and discussion: development of multi-disciplinary activities and clinical care pathways
24:10 – Ken: New data on prevalence and etiology of NASH cirrhosis spurred multi-specialty activities
24:41 – Key insight drivers: NHANES analyses, endorsements from medical societies and global journals, work of Jeff Lazarus and Wilton Park
27:01 – 2022 a “great year:"  new/updated guidelines, major Phase 3 trials progressing
 30:00 – Louise:  AGA critical care pathway work and collaboration among specialties pivotal, positive and extending to related consumer industries
 31:26 – Ken: 2-3 years from now, foresees “convergence of awareness” to expand FIB-4 and other simple tests to more patient risk subgroups.
33:25 – Study in progress: screening large number of patients to determine NASH prevalence among non-diabetic patients
35:34 – There was significant debate whether to include screening for T2D patients in  the 2018 AASLD guideline recommendations
37:03 – Louise: Fatty Liver disease has far broader implications than simply for the liver
38:41 – Roger: asks how liver testing and vigilance will fit in  schedules and practices of already overburdened providers
39:55 – Ken:  requires a of simple, inexpensive, easily accessible  Stage 1 tests like FIB-4, was key to its selection
42:22 – Jörn Schattenberg introduction and question: how are cost effectiveness analyses progression
44:25 – Jörn: 2021 has been “an exceptional year” for NASH
46:04 – Collaborated with Vlad Ratziu and others to produce cost of illness study published in Liver International in 2021
49:39 -Louise:  why does it feel like we study cost effectiveness only for expensive new drugs and never measure cost effectiveness of inaction?
50:38 – Jörn: value of monitoring relies on measuring related risks from cardiovascular and other systems
52:22 – Roger:  re Louise’s question, most cost effectiveness work evaluates a specific new expenditure, not a global “what if”
55:44 – Jörn: quality-of-life, which has clear economic costs, strongly associated with NAFLD
57:14 – Roger: Using HER to identify patients at risk might be a more palatable way to target education and information
59:50 – Jörn: An Optum database algorithm built by NIDDK provides a look at how to target
1:01:09 – Episode ends

Drs. Michael Charlton and Mazen Noureddin and Global Liver Institute Director of Global NASH Programs Jeff McIntyre join Dr. Stephen Harrison, Louise Campbell and Roger Green to review some of the most important and exciting presentations from the final two days of the 2021 TLMdX, the annual meeting of AASLD.

 Each panelist chose 1-2 presentations or posters from the 2021 TLMdX from AASLD that they thought conveyed a major topic or question in the meeting. The group discussed each paper, sometimes moving far afield the original topic. As usual with SurfingNASH, conversations were interspersed with challenging insights and comments, debate and laugher.More additional info about this episode?

Highlights include:
3:31 - Introducing tonight's panelists
17:51 - Michael Charlton and Mazen Noureddin kick off reconsideration of "Efficacy and Safety of Pegbelfermin in Patient with NASH and Stage 3 Fibrosis: Results from the Phase 2b FALCON 1 study" (Late Breaker 1.) Group discussion ensues throughout this section
35:21 - Mazen discusses "PROXYMO Demonstrates Safety and Efficacy of Cotadutide, a novel Incretin Co-Agonist in Biopsy-Proven Non-Cirrhotic NASH with Fibrosis" (Late-Breaker 1)
43:09 - Group discussion
48:36 - Stephen Harrison discusses "Vonafexor, a FXR Agonist, Induced Hepatic and Renal Improvement in the Randomized, Double-Blind, Placebo-Controlled LIVIFY NASH Trial" (Late-Breaker 1)
55:36 - Group discussion
1:03:12 - Louise Campbell discusses "Impact of Modest Weight Reduction on Serum Markers, Liver Histology and Disease Progression in Patients with Advanced Fibrosis Due To Nonalcoholic Steatohepatitis (NASH)" (Parallel 29)
1:09:12 - Group Discussion
1:15:13 - Louise Summarizes "The Fibrosis-4 Index and Severe Liver Disease Outcomes in Primary Care: a Stratified Cox Analysis" (Parallel 29)
1:20:29 - Group discussion
1:21:59 - Michael discusses "ARO-HSD, an Investigational RNAi Therapeutic, Demonstrates Reduction in ALT and Hepatic HSD17B13 mRNA and Protein in Patients With NASH or Suspected NASH" (LP11)
1:26:23 - Group Discussion
1:28:16 - Jeff McIntyre discusses "Lifestyle Management of NAFLD with Obesity" (Emerging Trends Symposium, "Tailoring NASH Therapy"
1:39:11 - Group discussion
1:46:08 - Final question: "What's the one thing that you hope that the part of the community that you touch most directly is going to take out of this meeting?"

Manal Abdelmalek, Ken Cusi and Jörn Schattenberg join Louise Campbell and Roger Green to discuss key presentations at AASLD 2021 and preview SurfingNASH's coverage of the event. This virtual meeting runs from November 12-15 and is scheduled on East Coast time.

Highlights include:
9:19 – Roger begins the conversation, by describing the AASLD program elements and what SurfingNASH will cover.
10:46 – Manal Abdelmalek kicks us off by focusing on Dr. Neil Henderson’s Hans Popper (Basic State of Science) Lecture and the relevance his talk will have meaning for NAFLD and NASH.
12:53 – Ken Cusi links this talk to Monday’s Emerging Trends Symposium on “Tailoring NASH Therapy.”
15:26 – Manal identifies Friday’s Liver Cell Biology SIG, with its focus on gut-liver access and gut microbiota triggering, as another source of knowledge and insight for future potential NASH therapies
16:45 – Jörn Schattenberg raises Parallel Session 10 on Diagnostics and Biomarkers of NAFLD (Sunday, 10:00a) which will focus on LITMUS work in which he participated. He goes on to describe the research and how it can drive better patient treatment in advance of medications.
19:05 – Louise discusses the Public Health and Healthcare Delivery SIG (Friday, 5:30p). She is excited that the session will discuss the foundational role a behavioral approach health can play, particularly in the absence of medications. 
19:58 – Roger, Louise, Jörn and Manal mention Friday afternoon sessions of particular interest. 
22:51 – Louise identifies “a couple of really good sessions on Saturday,” the Women’s Health Program (4:00p) and Parallel Session 2 on “Health Services and Public Health” (10:00a)
23:20 – Ken Cusi summarizes some high points of the post-graduate course. 
25:34 – Manal kicks off our conversation of Sunday presentations by discussing two talks from the plenary sessions: the presentation of the Alpine 2/3 results by Stephen Harrison and the longitudinal association between MRE and liver-related and cardiovascular events in NAFLD.  Jörn adds a though by noting the inclusion of CVD results and then discussing their meaning.
28:03 – Manal notes the presentation from the Million Veteran program, 
28:33 – Roger discusses some speculation from the podcast around the time of the aldafermin withdrawal and expresses the hope we will learn whether aldafermin was more a clinical or commercial failure. Jörn questions whether the decision to read out biopsies at 24 weeks may have been part of the reason the trial missed its primary endpoint
29:42 – Louise points out Parallel Session 17 titled “NAFLD and NASH: Predicting Outcomes and Response to Interventions” (Sunday, 4:00p) and its possible connection to some recent podcast topics
30:08 – Manal refers to the diagnosis and biomarker session Sunday as an opportunity to delve deeper into machine learning and artificial intelligence, after which Roger and Manal discuss the insights that AI  improves and those it does not. 
32:14 – Ken raises the joint AASLD-ALEH symposium Sunday (1:00p) as an excellent opportunity to learn more about the challenges stakeholders face in Latin and South Ameria and the southwestern US.
33:29 – Jörn notes that the panel has not discussed the sessions covering clinical trials of novel therapies and identifies some trials of interest.
36:14 – Manal mentions a paper at Parallel Session #33, Experimental Advances in NAFLD (Monday, 3:00p) that looks at single-cell RNA sequencing in mice to identify that hedgehog signaling in hepatocytes is a critical early event for NAFLD fibrosis in humans.
37:25 – Ken expresses optimism about the quality of the meeting, departs. 
39:01 – Louise, Jörn and Roger identify other sessions of interest on Monday.
42:23 – Final question focuses on what panelists anticipate will be the most powerful takeaway from the meeting. 
46:33 – Business Section 

Mazen Noureddin joins Stephen Harrison, Louise Campbell and Roger Green to close our series of "Biggest Stories of NASH Summer" with his own unique slant on recent events and publications.

Mazen's take on the 'Biggest Stories of NASH Summer" integrates the content of papers, the journals in which they were published and the attention they received to form a message that says, "Fatty Liver has more good news to report and more people who want to learn about it." Halfway through, Stephen Harrison "hijacks" the episode to ask a common sense question about how the Fatty Liver community uses slides from biopsies today. This leads to a conversation in which each participant comes at the issue from a dramatically different angle.

Highlights include:
8:49 - Mazen Noureddin begins to discuss his "Biggest Stor(ies) of Summer"
9:54 - Mazen focuses specifically on the efruxifermin (EFX) paper in Nature Medicine
12:56 - Mazen shifts focus to the recent paper from the Mayo Clinic group that used a retorspective study of MRE results and longer-term outcomes to demonstrate that MRE improve prognosis accuracy in CLD patients
15:24 - Stephen Harrison begins his response to Mazen
16:45 - Stephen discusses what he considers the most important lessons from the EFX trial
18:33 Mazen on where FGF-21s are likely to be used and what what duration
22:21 - Stephen "hijacks" the discussion to raise the idea of one H & E slide per biopsy.
25:12 - Mazen agrees with Stephen's statement about multiple slides
26:51 - Roger concurs from a probability sampling point of view
27:18 - Louise begins her reply by discussing the impact of side effects on patients, using Hep C as an earlier example, and the hope that clinical trials can more closely resemble care in everyday practice
29:06 - Stephen comments on why trials and clinical practice are so different and why it continues to be this way
31:38 - Mazen discusses FGF-21 side effects in the context of GLP-1s
32:47 - Louise notes that biopsy samples are valuable and costly to the patient (in terms of discomfort, at least) and that we show the patient respect by extracting the maximum possible value from each tissue sample
33:31 - Roger asks the historical logical for doing only one H & E slide per patient. Mazen speculates, then Stephen explains.
37:05 - Roger asks whether the goal is to improve screen fail rates and reduce placebo scores at the same time. Stephen confirms this.
37:58 - Roger asks group to assign scores to the relative importance of multiple slides, new medications and moving to NITs. Answers vary. The reasons are even more interesting than the answers themselves

Quentin Anstee, Louise Campbell, Stephen Harrison, Mazen Noureddin, Ian Rowe and Roger Green convene to review #ILC2021 and share key takeaways and insights. This conversation covers issues around drug development.

The conversation addressed the various ways that the challenges that the COVID-19 pandemic created for clinical trials in 2020 played out in the drug development presentations at #ILC2021: a higher level of retrospective analysis of earlier trials and relatively few pieces of novel Phase 2b or Phase 3 research adding to knowledge and insight. The group noted that cirrhosis received relatively more attention and even some fresh data as with the efruxifermin late-breaker publication. Finally, the group discussed some of the studies and insights we can expect to see between now and 2022.

Key opinion leaders Quentin Anstee, Mazen Noureddin and Ian Rowe join Stephen, Louise and Roger to discuss the major lessons and dangling questions from #ILC2021.

The group shares perspectives, insights and questions on four key topics: diagnostics (including both non-invasive technologies and AI/machine learning), drug development, patient populations and policy.Mixed in here you will find discussions on food insecurity, polygenic risk and multi-disciplinary medicine. A great session to hear if you are still organizing your takeaways and questions emerging from the Congress.

Donna Cryer, Vlad Ratziu, Michael Charlton and Mazen Noureddin join Roger Green in reviewing the final day of #ILC 2021.

The conversation revolved around three themes: non-invasive tests as presented at the morning LITMUS session; two promising but incomplete drug trials for a new class of agents and a possible therapy for controlled cirrhotics, and the opportunities and challenges presented by digital meetings (with kudos to EASL for all the platform elements they strengthened from 2020).

Manal Abdelmalek, Ian Rowe and first-timer Ken Cusi join Louise Campbell and Roger Green to review a thought-provoking, assumption-challenging Day Three of #ILC2021.

Most of the presentations the panel covered focused on medications, the core ideas and discussions spoke to changes in thinking. One theme that ran through the discussion was about multi-disciplinary care...and not only because Fatty Liver Endocrinologist Ken Cusi was on the panel. Another was to think about drugs for NASH holistically. In all, this podcast takes the broad view and the long view on treating Fatty Liver diseases, and should provoke new thoughts and ideas in you the listener.

Incoming EASL Secretary General Prof. Thomas Berg, Global Liver Institute President and CEO Donna Cryer and Genfit Head of Global Diagnostics Suneil Hosmane share their unique perspectives on Digital ILC 2021 with Roger Green.

In our lead-in episode for #ILC2021, Roger Green conducts interviews with three leaders, each with a unique perspective on what they value about this week's Congress. Incoming EASL Secretary General Prof. Thomas Berg discusses his view on the various ways the Congress will enrich knowledge and interaction in the global Fatty Liver community. Global Liver Institute President and CEO Donna Cryer shares the many ways that ILC has made patients and advocates feel they are welcome at the Congress and capable of making a contribution. Finally, Genfit Head of Global Diagnostics Suneil Hosmane identifies several areas of knowledge that he considers in assessing commercial opportunities. This can serve as a helpful introduction to the Congress or an opportunity to process what you have just seen and learned.

Jörn Schattenberg and the regular Surfers identify one thing about the Digital ILC 2021 meeting they anticipate eagerly and fall into a discussion about pharmacologic and non-pharmacologic approaches to managing metabolic issues.

As the group looked forward to Digital ILC 2021, each panelist identified one source of particular excitement. The answers varied all the way from process (enough time for interaction between speakers) to session themes to individual pieces of content. In the end, discussion of a NAFLD Therapy abstract session served as a springboard to a broader discussion about different ways to reduce or resolve steatohepatitis regardless of effect on fibrosis. The end of the discussion focused on the under-appreciated issue of omega-oil types found in diet.

 Joern Schattenberg joins the Surfers to identify exciting presentations and sessions from the Digital ILC 2021 meeting.

 Digital ILC 2021 kicks off one week from today, with four days of sessions covering the entire range of liver topics. Professor Schattenberg joins Dr. Stephen Harrison, Louise Campbell and Roger Green in identifying presentations, sessions and major themes they believe will import new knowledge and even change the ways we look at NAFLD and NASH. Want to get revved up for the Congress? Listen here.

Roger Green narrates a series of interviews, conversations and viewpoints about NGM Biopharmaceuticals discontinuing its F2/F3 aldafermin program

The SurfingNASH team weaves interviews, conversations and text notes from 9 stakeholders, including US and EU KOLs, program heads, treating physicians, patient advocates and NASH patients into a narrative addressing key issues. Was the ALPINE 2/3 trial a clinical failure? What commercial considerations might have played into NGM BIo's decision? What lessons can we learn about clinical development strategies? NITs vs. biopsy? When to trust headlines and when not. There is a great deal to unpack in a 25-minute episode.

Mazen Noureddin returns to discuss the roles different drugs and drug classes will play in NASH therpy after current Phase 2b and Phase 3 candidates have been approved. This conversation examines the prospect for different kinds of backbone strategies. 

At one extreme, many chronic therapies have a single monotherapy backbone agent, like what metformin has been to Type 2 diabetes. At the other, there are diseases where prescribers start with multiple different agents, or even different modes of action. The Surfers explore what is likely to happen in the future of NASH: one backbone vs. one for F4 and others for earlier stages vs. the idea that different patients' metabolic issues might suggest different starting points. Louise Campbell goes so far as to ask whether diet and exercise not only should be the starting point but whether it should be taken seriously as a discrete line of therapy. This is an interesting window into our treatment future.

Mazen Noureddin returns to discuss the roles different drugs and drug classes will play in NASH therpy after current Phase 2b and Phase 3 candidates have been approved. This conversation lays out basic premises. 

In this conversation, Stephen Harrison and Mazen focus on how treatment guidelines and therapeutic choices might vary for patients starting at F2 vs. F3 vs. compensated (maybe even decompensated?) cirrhosis. One key issue is "de-escalation" -- whether guidelines will suggest treating with agents that are more potent injectible anti-fibrotics for later stage patients, then retreating to orals with broader metabolic effects when patients' fibrosis has regressed to F2 or F1. The subject of "backbone therapy" comes up for the first time here, although it will be in later conversations of this episode as well. Louise Campbell and Roger Green round out the conversation with questions and observations. There is a lot to unpack here, so listen, learn and enjoy.

Mazen Noureddin joins the Surfers to explore the issues and needs that will shape treatment guidelines in a world after NASH drugs come to market.

In Season 2 Episode 16, a discussion of cost-effectiveness led to the question, "How will treatment pathways and rules evolve as new NASH drugs come to market." Mazen Noureddin, who raised this issue with Stephen Harrison in the earlier episode, returns to explore the answer ten episodes later.

The discussion considers what the phrase "backbone therapy" will mean in the future of NASH therapy and which agent(s) might attain that status. It considers how treatment models might vary for patients with cirrhosis vs. those with NASH, and for compensated cirrhosis vs. decompensated cirrhosis. It explores the role that AI-driven algorithms powered through electronic records will play in helping primary care physicians, general gastroenterologists and general hepatologists (if there is such a thing) treat patient who might have not only NASH but a range of accompanying metabolic conditions.

This discussion covers a lot of ground in a very short time. It stimulates and challenges. Enjoy it!