efruxifermin

This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers what the panelists found exciting, important or striking about the presentations of clinical trial results at TLM2023.  

Instead of focusing immediately on MASH drugs, Scott suggested we should not overlook the idea that elafibranor is preparing to come to market in the US as a novel medication for PBC with good efficacy and safety from patients who do not respond well to ursodiol or obeticholic acid. I note that elafibranor is only one of two PPARs speeding toward market in PBC with exciting data given what we all heard in the late-breaker presentation on seladelpar. Scott also mentions to integrin antagonist from Pliant in PSC, a disease with no available solutions today. Laurent agrees with Scott that the rare disease drug advances were more exciting than the advances in more common liver diseases.

I bring up papers addressing the value of FGF-21 and FGF-19 agents in cirrhosis, which showed some promise for compensated cirrhotic patients. Scott politely disagrees, feeling that while these agents might hold disease steady, they do not address the challenges and mechanisms necessary to meaningfully regress disease. We agree there is a benefit to any agent that slows or reverses the course of disease even slightly in that this buys the patient more time to be treated with more exciting medications still in the pipeline. 

Scott notes that for Hepatitis C, a far simpler disease it took 25 years from discovery to cure on a path of incremental process. Scott notes that drug development successes are keeping investors interested, which is encouraging in a challenging environment for investment. 

Laurent returns to the issue of cirrhosis, noting that there are multiple challenges and concomitant bad behaviors like alcohol consumption. He points out that where good studies exist, these are short studies with small samples. Scott points out that MASH is less like hepatitis and more like inflammatory diseases like IBD, where causes of underlying disease are difficult to determine and there is no single pathway in drug development. He buttresses this by noting that in clinical trials, resmetirom provided benefit to only 25% of patients. 

SurfingNASH is covering each day of NASH-TAG 2022. This episode includes two separate conversations, with Stephen Harrison, Louise Campbell, Mazen Noureddin and Quentin Anstee in the first and Donna Cryer and Scott Friedman in the second. Several common themes emerged in the two conversations, including the ideas that the future of NASH therapy lies in combination therapies and how impressive the field's advances in basic science are.

This episode includes two separate conversations. In the first, the group focuses on some of the specific presentations and topics covered on Friday: the emerging consensus that the future lies in combination therapies, the ways in which NIMBLE and LITMUS data (and differences between them) are instructive, and the dramatic advances in utilization of artificial intelligence. The second conversation included more patient perspective. It will take thousands of words to capture the depth of this episode in adequate detail and even then we couldn't do it justice.

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 Manal Abdelmalek of Duke University joins Louise Campbell and Roger Green to discuss the use of older drugs to treat cirrhosis patients today and her views on where NASH drug development is heading.

Manal begins by discussing the inherent tension between the research world, which reveals several promising modes of action and drugs in development but are unlikely to yield a first approval less than two years from now, compared to patient treatment, where people living with cirrhosis are looking for help today. Her talk focuses on the value of stabilization as a goal for cirrhotic patients being treated today and in part on the advances in basic disease knowledge and specific drug and diagnostic development will empower HCPs to prescribe the exact drug therapy that is right for the individual patient.

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

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 Mazen Noureddin,  Alina Allen, Wayne Eskridge.

Highlights: 
7:51 – Mazen Noureddin begins talking about AI and histopathology by pointing to recent review papers listeners should read, one from Mayo Clinic and another from Mazen and colleagues. 
8:21 – AI tools: machine learning and deep learning. Key AI targets: non-invasive testing and histology. More recent progress in histology.
10:09 – History of why histology in NASH has become increasingly controversial over time and how the challenge will grow. AI can address many of these controversies.
12:42 – Paper earlier this year: three expert pathologists working in tandem can strengthen reliability AND their results correlated with PathAI. AI also provided more granularity on specific disease levels within a cirrhotic liver and reduced placebo success rate.
17:10 – Louise: Should Intercept use AI methods in their re-read of 18-month biopsy data? Mazen: yes. We need a path to get regulators to accept AI this way.
19:40 – Louise: Why don’t we use Ishak instead of Metavir for cirrhosis coding? Mazen:  another great question!  
22:01 – Alina Allen begins
23:20 –  In the past year, we have learned that not only is MRE the most accurate estimator of fibrosis, but we can diagnose now based on liver stiffness (LSM) + PDFF, all in an automated 5-minute process.
24:51 – Mayo CGH study (2021) proves we can correlate LSM today with five-year outcomes. Provides far better trial screening and matching data than simple biopsy.
 27:07 – Roger: how can this change how we coach and advise patients?  
29:04 – Alina: we can use LSMs today to inform patients better, improve their care and allocate use of expensive tests more properly.  
30:55 – Roger: how does this fit into a Critical Care Pathways world. Alina: we can improve 1st-line granularity via AI analysis of patient’s medical history. If this filters more people out, it makes elastography or a blood-based biomarker more efficient, therefore more affordable,.
33:07 – Roger notes that sounds more like common commercial uses of AI than the AI-based histology reading we discussed with Mazen.   
35:43 – Louise: if you had a magic wand, what model would you create to make MRE available when appropriate. Alina – first, teach people it is not too expensive or  difficult, then create regional centers of excellence by putting software on existing MRI machines. Finally, educate patients and physicians. 
38:10 – Alina: you do not need a full 45-minute MRI to get an MRE, but only a  5-10 minute process. thereby saving time and money.
41:03 – Wayne Eskridge begins
42:35 – Wayne: decision to start the SUNN study borne of dissatisfaction over recommended standard NOT to screen for NAFLD. 
43:35 – Study pitch received unexpectedly positive reception from industry but learning about IRBs and trial management was a “real education.” 
46:12 – Wayne: point of study was to go outside medical system to asymptomatic, uninformed people, in the belief they had underlying health concerns and would tbe motivated to learn.
47:48 – Louise: "Amazing" study identified potential clinical trials candidates.  Why does SUNN show far higher levels of fibrosis than the other studies?
48:56 – Wayne: this is not a general population study, numbers probably are higher. 
52:19 – Peak age of 40-50 is younger than with most studies; we know it progresses steadily. Message: we should be screening high-risk patients younger.
55:14 – Wayne: Hard cost was ~$120. Took 8 months to complete running heavy patient loads.

NASH-TAG 2022 takes place in Deer Valley Utah and on-line from January 7-8, 2022. Join Surfing NASH to learn about the important and innovative drug development and basic science talks in the meeting.

Co-chair Stephen Harrison leads the panel through each of the sessions during the conference's first morning. The session starts with Michael Charlton's annual "Year in Review" talk, includes discussions on an array of drug classes and ends with a session on the biologic basis of NASH progression. He pauses at the end of his review of each session, thus leaving Steering Committee member Jörn Schattenberg and Surfers Louise Campbell and Roger Green to comment on favorite presentations, ask questions and place this information in the context of what we are learning elsewhere about Fatty Liver disease and the drugs that are being developed to treat it.

This episode follows S2 E43 in discussing the possible role of NASH cirrhosis clinical trials in the transition from biopsy as gold standard to a post-biopsy world. Terns Pharma CEO Sen Sundaram joins this conversation from the audience to ask whether the term "cirrhosis" is medically helpful or might warrant replacement with "end stage liver disease." After vigorous discussion on this point, Sen departs and Stephen Harrison leads the group through a review of four ongoing NASH cirrhosis trials. The discussion veers into the issue of which analytics methods designers are specifying and why. At one point, Naim Alkhouri, frequent guest and principal investigator on the Gilead combination agent trial before the session ends. His specific contribution: MRE was not included in the Gilead trial largely for cost reasons.

The most striking fact to emerge from this conversation relates to the "beyond the biopsy" question. MRE is emerging as a highly reliable NIT that appears to produce reliable results regardless of mode of action and is generating correlations and ratios to fibrosis level decreases and other key metrics, yet it is not included in the designs of any ongoing NASH cirrhosis trial. Stephen describes this as the "stovepiping" of data. Companies consider the data they need, not ways it can be aggregated with other trials to solve larger issues. This issue bears further exploration in later episodes.

Manal Abdelmalek, Jörn Schattenberg and Ian Rowe join regulars Stephen Harrison, Louise Campbell and Roger Green to recap this week's just-concluded TLMdX 2021, the AASLD annual liver meeting. 

When AASLD announced that the 2021 TLMdX would be held as a purely virtual meeting, attendees and observers feared a loss of focus and the kind of amplifying energy that comes from being with colleagues. That did not happen. Instead, the breadth, quality and novelty of the meeting's presentations generated exceptional positive energy despite the virtual setting. 

4:10 - Roger starts by saluting Manal for giving the NAFLD Wrap-up Talk at TLMdX 2021, then introduces other panelists
6:58 - Icebreaker question: Where did this meeting "make the biggest dent" in Fatty Liver disease?
12:21 - Manal discusses how she organized and prepared for talk and describes "somewhat surreal" feeling of seeing semi-quantitative histology fail in trials where so many non-invasive markers suggested proof of efficacy
16:13 - Jörn points out the inherent tension between needed accelerated endpoints and being tied to a severely flawed "gold standard" of biopsy
17:15 - Stephen's simplest solution: capitalize on existing study results to link MRE, fibrosis and outcomes
18:56 - Manal counters: this assumes  biopsy is the gold standard, when we know it is seriously flawed
21:02 - Stephen: it's time to "reach a common ground on what it takes to achieve replacement of histology with an NIT"
24:02 - Ian suggests that the FALCON trial history will strengthen FDA's attachment to biopsy
26:13 - Stephen's key to moving beyond biopsy: strengthening the data that supports credibility of NITs
28:13 - Jörn: having a combination of NITs that each reflect different elements of the disease makes effort easier and more credible
28:45 - Ian: controlled cirrhosis studies might allow quick validation and acceptance
29:35 - Manal: we know how to design better trials now,  cites story of ALPINE 2/3 as proof
32:17 - Stephen: the path to the data-driven future explodes when the first drug is approved
33:32 - Lars Johansson (Antaros Medical)  joins from audience to ask Stephen whether we can reanalyze spleen volumes from old trials  and reanalyze imaging data possibly with AI
34:52 - Stephen salutes Lars's "very good insight" about the potential to reanalyze the "huge" bodies of data from older trials
35:54 - Jörn agrees, but cautions that we need to keep primary focus on getting a drug approved
38:41 - Lars returns to audience
39:25 - Manal returns to Louise's  thought that one thing coming from meeting has to do with genomics, citing Million Veteran database
40:16 - Manal describes how single cell RNA data will shape the future of diagnostics and treatment in Fatty Liver diseases
41:10 - Louise refers back to various talks involving the patient-treatment impact of genomics and others implicating genetics as a possible reason for high variability in placebo response between trials.
43:42 - Stephen raises the diversity inherent in microbiome data as playing a role in making Fatty Liver so complex to characterize and treat
45:10 - Jörn points out that any drug that can "elevate above all these thresholds" and complexities will have to be "quite robust"
46:23 - Stephen envisions the day when drugs are approved based on MRE and the scarcity of MREs around the world creates a new set of challenges
47:37 - Manal observes that "precision medicine has been hot and heavy," which spurs Roger to note that all the key advances mentioned in the meeting are tied to advances in computing and modeling power
48:12 - Closing question: The biggest story a year from now? Stephen, Manal and Ian focus on "Phase 3 results." Jörn, Louise and Roger focus on ways patient empowerment will focus attention on better patient solutions.
57:05 - Business section

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?"

Profs. Scott Friedman and Michelle Long, Dr. Naim Alkhouri and Global Liver Institute DIrector of Global NASH Programs Jeff McIntyre join Louise Campbell and Roger Green to review some of the most important and exciting presentations from the first three days of the 2021 TLMdX, the annual meeting from AASLD.

Description: 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.

Highlights include:
5:27 - Introducing tonight's panelists
15:27 - Naim Alkhouri discusses "The Prevalence of Alcoholic and Nonalcoholic Fatty Liver Disease in Adolescents and Young Adults in the US" (Parallel 5)
20:33 - Group discussion
28:56 - Louise Campbell discusses "An advanced practice provider (APP) pathway achieves more effective weight loss in NAFLD patients compared to standards of care" (Parallel 2)
37:40 - Group discussion
46:28 - Scott Friedman discusses "The influence of host genetics on liver microbiome composition in patients with NAFLD" (Poster #`1654)
48:39 - Scott transitions to "The influence of host genetics on liver microbiome composition in patients with NAFLD" (Poster #1781)
50:31 - Scott ties these two results together in addressing the importance and complexity of microbiome: "I say that ...in part based on the work of Marty Blazer...an infectious disease doctor, who's sort of convinced me that epidemiologically it's very hard to explain how a disease showed up on our radar screens in a 20 to 30 year period, uh, that didn't exist before...Certainly our genes haven't changed over hundreds, if not thousands of years, to any extent. And so something external has changed. It comes back to the environment," and dietary changes.
52:53 - Group discussion
58:48 - Michelle Long discusses "Longitudinal association between MRE and liver-related events and CV events in NAFLD" (Sunday Presidential Plenary session)
1:07:56 - Group discussion
1:09:08 - Group discussion shifts toward the question of whether and when FDA might move away from biopsy as the requisite endpoint in drug trials
1:15:03 - Roger shares audience question on probiotics and NAFLD. Scott provides primary answer
1:16:37 - Jeff discusses Donna Cryer's talk on "Grit, Grace, Gratitutde and Resilience: What You Wish Your Doctors Knew about You" (Sunday Patient Forum)
1:22:53 - Group discussion starts by considering the best word to describe the optimal provider:patient interaction ("partnership" emerges as preferred choice)
1:28:23 - Roger discusses "Topline Results from the Alpine 2/3 Study," a Phase 2b trial evaluating 3 doses of the FGF19 Analogue Aldafermin,(Sunday Presidential Plenary session) and "Efficacy and Safety of Pegbelfermin in Patient with NASH and Stage 3 Fibrosis: Results from the Phase 2b FALCON 1 study." He connects these results by saying "What was striking is that if all you were doing was scoring the balls and strikes, then you'd say that those were both the same thing because neither one of them was going to point to a commercial success in launch." However, he continues, "the differences between the two vastly outweigh the similarities" in that pegbelfermin demonstrated minimal ability to differentiate from placebo while aldafermin clearly differentiated from placebo but might not have presented a strong enough commercial profile given other drugs in development.
1:33:07 - Group discussion
1:36:25 - Scott adds one comment on the importance of digital pathology if we are to continue relying on biopsy.
1:37:04 - 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?"

Jörn Schattenberg and Mazen Noureddin join the Surfers to discuss five recently-reported or ongoing clinical trials in NASH cirrhosis. The reviews focus on study findings and their implications, but also on the methods used to conduct each trial and the implications of these designs on generalized learning and ability to move beyond the biopsy.

Stephen Harrison leads the group in discussing recent results from NASH cirrhosis trials, including the REVERSE trial with obeticholic acid, the FALCON 2 trial with pegbelfermin and a post-hoc analysis of Galectin Therapeutics' Phase 2 trial for belapectin. The group also discussed ongoing trials including the FGF-21 efruxifermin, the FGF-19 aldafermin, the Galectin-3 inhibitor belapectin and the combination agent trial from Gilead Sciences. Along the way, Terns Pharma CEO Sen Sundaram joins from the audience to ask whether the name "cirrhosis" is the most appropriate way to define the disease, given all that we are learning. This session takes a deep look at cirrhosis, with focus on clinical trials, disease pathology and patient management.

Mazen Noureddin joins Stephen Harrison, Louise Campbell and Roger Green to close our series of "Biggest Stories of NASH Summer." In this conversation, Roger uses a classical Marketing Research question to help the group sort out the relative impact potential of the ideas they have been discussing.

This conversation starts with Roger Green using an old marketing research question. He asks each panelist to divide 100 points of potential to change between Stephen's multi-slide concept, drug development as exemplified by the EFX trial and advances in NITs as exemplified by MRE. The group each comes to different answers and uses different logic to get there. Listen to their thinking to decide what you can learn from each of them and where you disagree.

Mazen Noureddin joins Stephen Harrison, Louise Campbell and Roger Green to close our series of "Biggest Stories of NASH Summer." In this conversation, Louise Campbell raises two very different points about the earlier conversation.

Louise's first point has to do with steps taken to maintain compliance with clinical trials and whether researchers can analyze these in a way that will help front-line treaters understand what are keys to patient pharmaco-adherence. This leads to a conversation about why trials are managed the way they are and what it is reasonable to expect from front-line practices. Louise's second point asks us all to envision the biopsy the patient provides as a "gift" and to consider how we might treat samples differently if we viewed them that way. The conversation circles back to Stephen's multiple sample slide idea, with Stephen and Mazen discussing what the impact of this approach might be in terms of screen fail rate and placebo response. Finally, Stephen makes predictions for the Ole Miss - Alabama football game, which will have occurred by the time you listen.

Mazen Noureddin joins Stephen Harrison, Louise Campbell and Roger Green to close our series of "Biggest Stories of NASH Summer." In this conversation, Stephen Harrison starts by discussing some issues and insights around the use of FGF-21s and then "hijacks" the conversation to explore a standard practice in histopathology that he would like to change.

This conversation starts with Stephen talking about the differences between FGF-21s and discussing why these results are so compelling. He asks Mazen to comment on how he expects to use FGF-21s in practice and Mazen provides a thoughtful, nuanced reply.

At this point, Stephen shifts gears to ask why we do not produce more slides from a given liver sample. He and Mazen agree that they have wondered about this for a while and believe it would strengthen results. Speaking from more of a straight statistical perspective, Roger Green agrees.

Mazen Noureddin joins Stephen Harrison, Louise Campbell and Roger Green to close our series of "Biggest Stories of NASH Summer." In this conversation, Stephen Harrison provides an image to suggest the enormity of the coming NASH pandemic and Mazen identifies his two biggest stories of summer.

Mazen's "biggest things of summer" include Stephen's recent article on the efruxifermin Phase 2a trial that was published in Nature and the Mayo Clinic group's work on MRE. For the efruxifermin, he cites some remarkably positive trial results, with a second related point. The study was published in Nature Medicine, which is only now and its various publications are now looking to publish original clinical trial research on NASH and Fatty Liver disease. To Mazen, this demonstrates the growing focus on NASH as a coming challenge.

Earlier in this conversation, Stephen makes the same point a different way by noting that according to estimates published by some of our leading hepatologists, the number of NASH-related deaths from 2016-2030 in the US will dwarf the number of COVID-19 deaths to date.

On Mazen' second point, he discusses why MRE is such an important diagnostic testing method for clinical trials and why papers like this one will be so critical in moving "Beyond the Biopsy."

Stephen wraps up this conversation by noting how quickly Fatty Liver research and knowledge are developing on multiple paths, all in common.

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

Newly-appointed Professor Ian Rowe joins Louise Campbell and Roger Green to discuss the important Fatty Liver stories of the last few months. He focuses on the recent FDA approval of the ELF test for prognosis of cirrhosis.

To Professor Rowe, the ELF approval was the most important story of summer because it promises a brighter future for non-invasive tests and, eventually, decreased reliance on biopsy. Dr. Rowe points out that transitioning from the ordinal results that biopsy generates (fibrosis score level) provide limited, unrealistic guidance in determining the probability of a downstream negative event (transplant, cancer, death). He contrasts this to continuous test results, including blood-based and device-driven tests, which provide clearer guidance about downstream risks. Louise Campbell adds her own reflections about the importance of inexpensive, blood-based tests to address the emerging NASH pandemic in poorer Third World Countries. This is not a long conversation, but it looks at the issue from some unusual, enlightening angles.

Ian Rowe, Michelle Long and Manal Abdelmalek reveal what they consider the most important NAFLD/NASH stories of summer.

Which NAFLD/NASH stories did they choose? The newly-appointed Professor Rowe discusses the importance of the FDA approval of the ELF test as a prognostic for cirrhosis. True to her epidemiological background, Professor Long reviews the prospective prevalence study that Stephen Harrison, Naim Alkhouri and others conducted in San Antonio. Finally, Professor Abdelmalek uses a comment she received at a presentation this summer as a jumping-off point to discuss potential value currently available generic drugs -- metformin, statins, carvedilol -- in treating portal pressure among cirrhosis patients. Some highlights:

4:39 - Ian Rowe's understated announcement
6:31 - Ian's event: FDA approves ELF
9:49 - ELF (and other NITs) will improve risk stratification by replacing ordinal Fibrosis scores with continuous test results
11:37 - Louise Campbell raises the issue of testing for the increasing NAFLD/NASH prevalence in Third World countries with fewer resources than the West has
13:02 - Ian notes that widespread population screening must start with a simple, inexpensive test, even in wealthier countries
14:54 - Roger Green raises the value of visual (picture) test results and asks how blood-based tests can overcome the fact that they do not produce pictures. Discussion and friendly debate about relative value of risk scores and visual outputs ensues.
18:39 - Ian discusses his work on patients' understanding of cirrhosis, which demonstrates the value of nursing in cirrhosis care clinics. Louise amplifies his point.
22:34 - Wrap-up question for Ian's interview
24:20 - Conversation with Michelle Long begins
26:49 - MIchelle's event: Stephen Harrison and Naim Alkhouri's paper on "Prospective Evaluation of the Prevalence of Fatty Liver Disease and NASH in an Unselected Middle-age Cohort"
28:28 - MIchelle mentions NAFLD/NASH prevalence rates among study participants
32:35 - Louise revealed what she learned in a high-level qualitative scan of patient records
33:36 - Louise discusses recent paper on the long-term of simple steatosis
35:27 - Louise wonders about the level of NAFLD/NASH education and awareness among endocrinologists.
40:10 - Louise raises the idea of scanning patients who have come to physician for other procedures, just as Stephen did in the prevalence study
44:56 - Conversation with Manal Abdelmalek begins
47:40 - Manal's event: NIH funding the new liver cirrhosis network
49:22 - Manal focuses on the urgency of doctors and patient today, the need to propose helpful therapies. At 50:30, she discusses a recent single-dose 1000mg metformin study checking its effect on portal pressure in patients with cirrhosis.
53:35 - Manal notes that statins, beta blockers have some reported positive effects in cirrhosis
56:27 - Roger raises the idea of maintaining fibrosis level as a clinically meaningful endpoint for approval
59:28 - Louise describes a way that even general practice physicians can track cirrhosis using their FibroScan machines or other equipment
1:03:19 - Manal raises the idea that this is drug help we can provide for some patients now, before approval
1:07:19 - Closing question for the third conversatio