fibrosis level 4

NASH-TAG 2022 takes place in Deer Valley Utah and on-line from January 7-8, 2022. Join Surfing NASH to learn about the last three sessions of the meeting, which include multi-stakeholder "fireside chats" about how to make progress in non-invasive testing for non-cirrhotic NASH and NASH cirrhosis.

Co-chair Stephen Harrison leads the panel through key sessions from NASH-TAG. This conversation starts with a review of Session 7, which features presentations on PNPLA3 and HSD17B13 knockdowns and a range of novel targets. Discussion proceeds to Session 8, which includes presentations on several key basic science topics ranging from transcriptomics to integrin. Finally, Stephen leads the group through discussion of the two fireside chats, where collections of governmental, commercial and academic stakeholders discuss how to make progress in using novel tests for products designed to treat patients with non-cirrhotic NASH and, separately, NASH cirrhosis.

NASH-TAG 2022 takes place in Deer Valley Utah and on-line from January 7-8, 2022. Join Surfing NASH to learn about important updates from the three consortia (LITMUS, NIMBLE and the NIH Cirrhosis Network), "new news" in wet biomarkers and combination therapy and a stimulating session with PathAI and Histoindex covering artificial intelligence.

Co-chair Stephen Harrison leads the panel through key sessions from NASH-TAG. This conversation starts with a review of Session 4, in which Quentin Anstee presents updates from the LITMUS consortium, Arun Sanyal presents updates from NIMBUS, and Vijay Shah provides information about the NIH Cirrhosis Network. From there, Stephen reviews Session 5 with its focus on artificial intelligence leaders PathAI and Histoindex. The conversation concludes by reviewing the eclectic and intriguing Session 6, "What's New Out There and How To Interpret What It All Means," which has talks on the AASLD NASH Task Force, news on wet biomarkers and an update on combination therapy.

NASH-TAG 2022 Co-chair Stephen Harrison and Steering Committee Member Jörn Schattenberg review the upcoming conference, focusing on major issues in NAFLD and NASH diagnosis, staging, treatment and monitoring.

NASH-TAG 2022 faculty, format and schedule suggest that this conference will produce breakthroughs in knowledge and consensus about NAFLD therapy. This week, NASH-TAG 2022 Steering Committee member Jörn Schattenberg joins the Surfers to discuss key presentations and critical issues in the conference. NASH-TAG co-chair Stephen Harrison walks the panel and audience through the entire NASH-TAG agenda, with Jörn, Louise Campbell and Roger Green contributing questions and comments throughout the session.

Highlights from the program:

8:54 – Stephen provides a little background on NASH-TAG
9:44 – Stephen begins to discuss Friday morning program
10:34 – Describing the first session, “A one-stop shop”
13:10 – Jörn Schattenberg comments on Session One
14:09 – Roger Green comments on Session One
15:10 – Louise Campbell comments on Session One
15:26 – Stephen discusses Sessions Two and Three, with comments on the oral presentations thrown in
18:24 – Louise comments specifically on the talk about why NASH-related HCC is resistant to treatment; Stephen agrees and amplifies
19:02 – Jörn comments on Sessions Two and Three
20:19 – Stephen discusses the break session and goes on to discuss Session Four
23:18 – Roger asks about which oral presentations will appear at the conference, Stephen demurs
23:55 – Jörn expresses enthusiasm that the LITMUS, NIMBLE and the NIH Cirrhosis Network
25:15 – Stephen discusses Session 5 
26:43 – Roger expresses enthusiasm for the entire afternoon program (Sessions 4 and 5)
27:09 – Stephen discusses the scope and scale of the efforts LITMUS and NIMBLE are making, and goes on to discuss recent progress against cirrhosis in the context of mentioning the cirrhosis network
28:29 – Jörn expresses positive outlook on the Path AI and HistoIndex presentations
29:05 – Stephen begins review of Day Two, Session Six.
]31:14 – Stephen: “This may be one of the most intriguing sessions”
32:25 – Roger begins comments on Session Six
33:02 – Louise comments on Session Six
35:07 – Stephen begins review of Session Seven
36:24 – Louise begins comments on Session Seven
37:06 – Stephen begins discussion of the second evening with Session Seven
37:56 – Jörn comments on Session Seven
38:22 – Stephen discusses the last two hours of the meetings – “fireside chats” with governmental, corporate and academic stakeholders about whether it is time to pivot away from semi-quantitative biopsy-based endpoints toward NITs.
40:04 – Roger agrees with Stephen’s exceptional excitement about the potential of the fireside chats; Stephen elaborates on what will make the chats so special
42:23 – Final question: one more thing each panelist would like to point out in the agenda?
42:34 – Jörn praises “great program,” wonders whether the fireside chats should have included a patient representative
43:04 – Louise echoes Jörn’s comments on program quality and wish for a patient representative in the fireside chats
43:50 – Roger asks whether talks on the PNPLA3 and HSD17B13 knockdowns presage a longer-term future for therapies
44:42 – Stephen is partial to the fireside chats, expresses belief that researchers will take away from this meeting something they can use in research
454:52 – Business section

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.

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 

 Alina Allen and Ian Rowe lead the Surfers in considering biopathological shortcomings in fibrosis as a solitary endpoint. Their comments stem from Alina's presentation of the recent Mayo Clinic paper, "MRE for Prediction of Long-Term Progression and Outcome in Chronic Liver Disease: A Retrospective Study." In this conversation, Alina summarizes the paper, after which Stephen Harrison asks questions about availability of subgroup analysis.

This conversation focuses on flaws in biopsy as a measurement device and also in fibrosis as a solitary endpoint.

In the rest of the discussion, the group discusses challenges in proving that NITs can accurate measure and differentiate between different drugs in terms of therapeutic efficacy. One challenge is with the current metrics. We speak frequently about the challenges with biopsy and with fibrosis being an ordinal variable, but as Alina notes, being too tied for fibrosis means we focus solely on one measure of improvement and downplay others, such as steatosis.

The conversation is too rich and nuanced to be captured in a paragraph or two. This episode is worth two or three listens to capture all its points.

Alina Allen and Ian Rowe discuss how Liver Stiffness Measurements (LSM) can improve individual patient treatment in pre-cirrhotic and compensated cirrhotic patients. Their comments stem from Alina's presentation of the recent Mayo Clinic paper, "MRE for Prediction of Long-Term Progression and Outcome in Chronic Liver Disease: A Retrospective Study." In this conversation, Alina summarizes the paper, after which Stephen Harrison asks questions about availability of subgroup analysis.

Ian starts this section by noting the challenges in relying on fibrosis when managing individual patients practically and wonders whether LSM might do a better job here. Alina endorses this thought emphatically. She notes that while there may be a benefit in clinical trials to separate an F2 from an F3, F levels have minimal impact on clinical recommendations for pre-cirrhotic patients. Conversely, LSM provides guidance on how quickly a patient is progressing toward cirrhosis regardless of fibrosis level, which can affect aggressiveness of recommendations and frequency of monitoring, among other issues.

During this conversation, Ian shares that he is conducting community-based research with over 3,000 patients so far in Leeds. This study is revealing similar results, with liver stiffness predicting progression up to a "tipping point" at which liver function begins to matter more. This can become germane to any specialist or primary care physician when treating patients.

Toward the end of the conversation, Louise Campbell notes that these same metrics can help identify patients who are failing sooner, which will leave more time for compassionate palliative care and end of life planning.

Alina Allen and Ian Rowe join the Surfers to discuss the recent Mayo Clinic paper, "MRE for Prediction of Long-Term Progression and Outcome in Chronic Liver Disease: A Retrospective Study." In this conversation, Alina summarizes the paper, after which Stephen Harrison asks questions about availability of subgroup analysis.

 This paper was recently published in the journal Hepatology. While previous Mayo Clinic work focused solely on NASH patients, this retrospective look focused on 1,200 patients with assorted liver diseases who underwent MRE for the first time between 2007 and 2009 and tracked patients through 2020. In this analysis, MRE had strong ability to predict future outcomes, with the strongest results predicting which patients with some level of fibrosis would progress to compensated cirrhosis. In this group, every one-level increase in LSM translate into slightly more than a two-fold increase in risk of cirrhosis. MRE also provides robust prediction of progressing from compensated cirrhosis to decompensation, with every one-level increase in LSM translating to a 22% increase in the likelihood of progressing to decompensation. Prediction is lower in predicting outcomes for decompensated patients, largely because at this point liver function assumes greater relevance than stiffness. As Alina states, "this is why we use a MELD score for transplantation priorities" and similar issues.

The other important point Alina makes (and Ian Rowe has made in past episodes) is that biomarkers provide continuous numbers to plot progression over time, as compared to fibrosis level which is ordinal with four levels, or other metrics that have a high zone, a low zone and a gray zone between them. Continuous variables are easier to track for individual patients and provide richer statistical analyses.

When Alina finishes, Stephen Harrison asks questions about population subtypes in this study. Alina points out that the northern midwest is fairly homogenous demographically and the clinical charts from which researchers derived data did not have genetic information.

Professor Manal Abdelmalek joins Louise Campbell and Roger Green to discuss the important Fatty Liver stories of the last few months. She focuses on NIH's recent decision to stand up and fund the Liver Cirrhosis Network.

To Dr Abdelmalek, the NIH action signifies increased focus on the significant long-term consequences of Fatty Liver disease. She discusses a Q&A at a talk she gave this summer where a physician noted that drug development is exciting but three years in the future and asked, "What can I do for my patients NOW?" She cites a recent small, early-stage study that suggested a single dose of metformin might have an impact on portal pressure and goes on to suggest that statins and beta blockers might also have a role to play in treating compensated cirrhosis patients. Louise Campbell contributes a strategy for evaluating patients taking these older drugs using FibroScan and blood-based tests. This is an innovative way to look at providing immediate benefit for patients who need it most urgently.

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

Jörn Schattenberg joins the Surfers to discuss drug development in cirrhosis. This conversation constitutes a call to action for the Surfers and our listeners. 

In terms of cirrhosis and drug development, the earlier conversations identified two goals: Focus on NASH cirrhosis as a possible an easier and faster path to approval than the traditional "start with F2/3" approach, and push to move the codification of disease knowledge and best practices from guidance documents that might be upgraded every five years to a real-time, on-line document similar to what we see today in Hepatitis C. As the conversation wraps up, all four panelists (Stephen Harrison, Louise Campbell, Jörn Schattenberg and Roger Green) consider what they each might do to push these ideas forward. If you are captivated or even intrigued by the earlier parts of the episode, listen to this conversation asking what you, yourself, can do to help bring about the changes Fatty Liver stakeholders need.

Jörn Schattenberg joins the Surfers to discuss drug development in cirrhosis. This conversation focuses on how to drive a broader change in perspective.

Once we accept the idea that cirrhosis can make an excellent target for drug development driven using non-invasive testing, the question is take the lead in bringing the appropriate initiative forward. Stephen Harrison points out that principal investigator KOLs are the group with the most knowledge and perspective but later notes that work-life balanced for these exceptionally busy people might limit their involvement. The group considers other stakeholders until Louise Campbell asks a question toward the end of this conversation that shifts panelists' focus from traditionally, static guidance documents to a continuously updated living document similar to what exists for Hepatitis C.

Jörn Schattenberg joins the Surfers to discuss drug development in cirrhosis. This conversation focuses on why F4 might be a better target than F2/3.

This conversation focuses on specific reasons that initiating drug development in cirrhosis might offer unique benefits against the traditional model. Stephen Harrison starts off by discussing changing views of which cirrhosis patients are mostly likely to respond. After some comments from Louise Campbell about patient engagement, Stephen and Jörn Schattenberg discuss reasons that improvements in non-invasive testing, and particularly MR Elastography, might make cirrhosis the preferred target for drug development. As Stephen and Jörn explain, cirrhosis might make an easier target for the transition from a biopsy standard to an NIT standard, and both FDA and EMA have indicated that a drug could receive full approval based on a Phase 3 cirrhosis result, instead of the conditional approval the agencies are willing to grant in F2/3.

Jörn Schattenberg joins the Surfers to discuss drug development in cirrhosis. This conversation focuses on the unique challenges in treating NASH cirrhosis.

This conversation focuses on challenges in treating patients with NASH cirrhosis and implications for drug development. Jörn Schattenberg begins by discussing several of the elements that make treating patients with NASH cirrhosis especially challenging because treating cirrhosis is challenging, treating NASH is challenging and NASH cirrhosis presents complications of its own. Stephen Harrison continues the discussion by considering drug development, starting with the historic view that we develop drugs for advanced fibrosis first and cirrhosis later. He then raises several reasons this perspective might be changing.

Jörn Schattenberg joins the Surfers to discuss drug development in cirrhosis, which evolves into a discussion about how to drive NITs forward.

Historically, NASH drug development strategy has started in advanced fibrosis with the goal of progressing to cirrhosis next. This episode suggests an entirely different approach.

The episode starts by discussing the complexities of treating cirrhosis and evolves into a discussion on why compensated cirrhosis might be the BEST place to achieve fast, successful drug development today.

Key moments include:

10:12 - Why discuss cirrhosis?

11:40 - Challenges in cirrhosis treatment and drug development

13:08 - A changing viewpoint on cirrhosis as drug development target

17:24 - NASH and cirrhosis disease progression

20:10 - Diagnosing and stratifying cirrhosis patients

24:20 - NITs might make cirrhosis a better drug development target than F2/3

30:06 - Building momentum to reconsider NASH and cirrhosis drug development

33:47 - Identifying the conceptual road block in the move toward NITs in cirrhosis

39:09 - Formulating a plan of action to strengthen cirrhosis drug development and treatment

40:53 - A "disruptive technology" to pool clinical trial results

44:28 - The challenge: pushing cirrhosis treatment and drug development forward

50:09 - Business section

This week's celebration podcast featured interviews including seven of our favorite Surfers. In this week's conversations, we are publishing the interviews in full. Third up, Jörn Schattenberg and Ian Rowe

Louise Campbell and Roger Green interview two frequent podcast guests, Jörn Schattenberg and Ian Rowe. In addition to reminiscing about the podcast, Jörn discusses the energy he gets from discussions with colleagues (and from learning interesting things about their lives, like Mazen Noureddin's pro basketball career), while Ian discusses how a surprise in medical school led him to focus much of his research on community-generated data and systems issues. If you enjoy their episodes, you should find this fascinating and fun, all at the same time.