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Last weekend's NASH-TAG 2022 was the best attended event in the conference's six-year history, and probably the one that will have the greatest long-term impact on diagnosis, treatment and monitoring of Fatty Liver patients. In this wrap-up conversation, our seven-person panel (including two Pharma execs and one diagnostics entrepreneur) identifies what each participant considered the high-impact presentations of the conference.

This conversation is triggered by Roger Green's question, "What was the one thing about NASH-TAG that most surprised you." All group members mentioned the incredible passion and energy that fueled the meeting, but there were other, more specific mentions as well. Rachel Zayas mentioned a study presented at the meeting in which nine pathologists reviewed 80,000 cells looking for balloon hepatocytes. 1,138 of these cells (~1.5%) were identified by at least one pathologist as having a balloon hepatocyte, but only ONE (!) of these was identified by all nine. Clearly, this raises questions about whether the balloon hepatocyte is a robust enough metric to play such a pivotal role in steatosis scoring. Erin Quirk commented on a point Michael Charlton made during his presentation, that we neither control nor know enough about the dietary habits of respondents, even though a disparity between cells has the potential to confound results. From there, the group switched to discuss high-impact papers and concepts ranging from single cell transcriptomics to consider collagen control as a balance between reducing fibrosis and leaving sufficient collagen for hepatic self-repair. Toward the end of this discussion, two more ideas gained traction: Michael Charlton's focus on how to develop the optimal combination therapy and Erin Quirk's general observation on how gratifying it was to see big and small pharma working together.

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SurfingNASH invited four attendees to the NASH-TAG wrap up (three first-timers, two corporate executives) to focus on presentations and discussion from the fireside chats. Highlights include:
4:20 – Introduction of first-time panelists Amy Articolo (Novo Nordisk), Erin Quirk (Terns Pharmaceuticals), Rachel Zayas (AGED Diagnostics) and the returning Ian Rowe (University of Leeds)
12:55 – Opening question: what about NASH-TAG 2022  surprised you most?
13:04 – Consensus: energy and passion. Rachel mentioned the vast divergence in  balloon hepatocyte readings
16:19 – Led by Stephen, group discusses powerful single slides
22:51 – Question: What single presentation had a real impact on your thinking?
23:04 – Rachel: Single Cell Transcriptomics, which can identify disease drivers.
25:53 – Ian: Scott Friedman’s point about the need to balance blocking fibrosis with maintaining sufficient collagen for scar healing.
27:16 – Amy: Talks about upstream effects resonated because Novo Nordisk works to develop combination therapies.
28:53 – Erin: One “pleasant takeaway” was big companies sharing findings “shoulder to shoulder” with smaller ones.
30:04 – Roger: Rate reaction to fireside chats using 6-point scale. Erin, Amy, Rachel all say 5. Liked diverse viewpoints, high energy level. Ian says 4, maybe 3. Fears that following the path laid out in meeting will lengthen drug development.
36:06 – Stephen: We need to improve use of histopathology, design and implement a multi-year path to NITs as outcome drivers and develop NAIL-NIT, a multi-company, “agnostic” data repository to utilize everyone’s data to “ask the big questions” and drive large prospective trials. Also, we should provide analytics and perspective on unresolved issues that are delaying final FDA guidance document
47:02 – Amy: Key is to impact patients’ lives, which is more “function and feel,” less survival. We’ll look back on this as "The moment of change”
48:59 – Roger: FDA has becoming more open and encouraging since 01/21 webcast
50:33 – Roger: Stephen’s push to lower screen fail rates from 80% to 50% will drive 2.5x increase in eligible patients, thus shortening trials, reducing costs
52:35 – Stephen: This can also reduce placebo response rates, which are a major issue in interpretation
54:27 – Erin: Should we even be looking at liver tissue when pathologists are so mislaligned on balloon hepatocytes? Stephen: Eventually, perhaps not. But the ongoing trials today have to rely on histology
55:02 – Erin: Are we creating medications that patients actually will want to take, given that many choose not to participate in trials? Louise: Decision is individual, but those who take time to make it wisely have the greatest prospects for success
57:14 – Ian: Findings from trial populations and natural history populations can vary widely. Also, the NITs we use in trial need to work financially for the larger population
59:20 – Amy: Expanding trial population into primary care or OB/GYN would broaden target dramatically
1:01:02 – Question: something you hope to see that is different in a year and something you believe you will see
1:01:14 – Louise: Patients and advocates at future Fireside chats
1:01:29 – Rachel: Tests that look separately at the different NAS elements instead of creating composite scoring
1:02:02 – Erin: A positive Phase 3 study result
1:02:31 – Amy: Solid and actionable programs to create solutions to issues identified this past weekend
1:03:03 – Ian: Expect positive Phase 3 data. Hope to see discussion around NITs that correlate consistently with histology and drive changes in outcomes
1:03:21 – Stephen: Hope to report positive Phase 3 trial
1:05:04 – Roger: Believe AI h

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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.

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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.

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In advance of NASH-TAG 2022 this weekend, Jörn Schattenberg joins the Surfers to answer a key conference question: are we ready to pivot toward non-invasive tests and better uses of histopathology? The group explores a range of questions and ideas that are likely to emerge during Saturday night's fireside chats.

The group explores a range of questions and ideas that are likely to emerge during Saturday night's fireside chats.

 Highlights include:
7:03 – Stephen Harrison begins to discuss NASH-TAG 2022
7:45 – Jörn Schattenberg: we’re not ready to move beyond biopsy in 2022. Hope that we will bring forward the right program by end of year
8:31 – Roger agrees
8:43 – Stephen agrees, but looks to determine how to resolve pivotal challenges
9:46 – Stephen lists discussants for the fireside chats, including regulators, researchers and industry representatives
10:30 – Stephen lists  key topics for his talk on non-cirrhotic trial endpoints
11:37 – Stephen lists “hurdles” biopsy  "needs to overcome" 
12:40 – Stephen’s key issue for histopathology : why we only score one H&E and one tri-chrome read per sample. He suggests three H & E and promises to reveal data on this in his talk.
15:08 – Jörn: "Why three?” 
16:08 – Stephen: no magic, three non-contiguous reads “just makes sense.” The goal is to is to find ballooned hepatocytes or clustering, which might not appear in one slide but will frequently elsewhere in the sample.
18:11 – Stephen: choose the slide with the strongest presence of disease
18:47 – Key benefit: we screen fail fewer people on ballooned hepatocytes
19:59 – Potential secondary benefit: reducing resolution scores in the placebo group
21:09 – Stephen: three companies looking at this. All see a major difference.
21:29 – Stephen: there are commercial issues as well: high screen fail rates inflate costs and take lots of time. This approach will save money and time.
24:13 – Stephen: I like Jörn’s idea about using AI here. It will enhance reproducibility.
24:52 – Stephen: another issue is the shift from one to multiple pathologists. Multiple pathologists turns out to drive screen fail rate higher. We need something to counter that.
26:49 – Louise Campbell: getting more tissue is beneficial for the patient
27:52 – Louise: a lot of NIT evaluation comes from pairing to biopsy samples. The more samples, the more opportunity to test NITs.
29:14 – Stephen shifts to getting beyond the biopsy. FDA issue: link an NIT to outcome. The cirrhosis chat gives us our first shot on goal.
30:55 – Stephen: one challenge with non-cirrhotics is that NITs are not included in the major Phase 3 trials
32:07 – Jörn: this is a pivotal issue and NASH-TAG is the right place to discuss it
33:33 – Louise: consider quality-of-life as a high value outcome measure
33:57 – Jörn: how do we explore stabilization of disease with NITs?
34:31 – Stephen: all these are reasons to “set the stage” with cirrhotic cohorts first, learn the lessons, then extend to non-cirrhotics
37:56 – Closing question: what will make 2022 successful to you in terms of moving this agenda forward?
38:17 – Jörn: data from the consortia
38:50 – Stephen: a clear idea of what will get us to a surrogate endpoint with NITs. Until then. improve histopathology practices.
39:54 – Louise: anything with histopathology that leads us toward NITs is good. Also, we will need to do more remotely as long as COVID keeps rearing its head.
40:51 – Roger: let’s learn more and make two cases one on economics and the other on data quality
41:17 – Stephen: one more thing: better economics and stronger data will motivate Big Pharma to invest
43:53 – Stephen: at the end of the day, it’s all about economics
44:53 – Roger: burnt money feels wasted, makes s

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This conversation is part of SurfingNASH's 2021 NAFLD Year-In-Review. Andrew Scott, Global Policy Lead for the Global Liver Institute joins Louise Campbell and Roger Green to discuss the growing energy and impact of NASH patient advocacy.
This episode focuses on the steps that have increased reach and effectiveness of NASH patient advocacy dramatically in 2021. Andrew starts by noting some of the pivotal steps this year through which patient advocates began or expanded collaborations with the medical community in 2021, and then describing the activities that resulted from these collaborations: Global Liver Institute's (GLI) US NASH Action Plan, the range of guidelines and recommendations emerging from medical societies, the externally-led Patient-Focused Drug Development (PFDD) meeting with FDA, and a range of legislative initiatives in the US Congress and many states. Andrew notes that much of this activity emanated from decisions GLI took in 2017 to promote the importance of NASH in the constellation of liver diseases. Also, he notes the importance of discussing not only Fatty Liver disease but also the constellation of non-communicable metabolic conditions linked to it.
Today, GLI focuses on providing appropriate therapeutic options and support for every stage of NAFLD. Activities like the PFDD meeting focus on the need for drug development and approvals. Others, like GLI's collaboration in building and promoting a nutrition app, focus on earlier stage disease and helping patients live healthier lives before they experience disease. All activities address the needs to educate stakeholders and develop products to support, diagnosis, treatment and management at every stage of disease progression.
The conversation shifts to the need to conceptualize Fatty Liver in a broader context. Louise notes the statement that the liver is a mirror on the metabolism, or perhaps the patient. Andrew states that GLI will increasingly focus on the idea that LIVER HEALTH IS PUBLIC HEALTH and on overall wellness.
This leads Roger to wonder why other patient advocacy organizations silo patients so that the focus is on an individual disease as compared to overall patient wellness. Andrew observes that focusing narrowly on a single disease and serving as advocate for patients with that disease has been extremely effective for some patient advocacy groups  in fund raising and public clout. However, Andrew notes, we are coming to a place in society where we need to view many of these issues in a more integrated way.
Louise observes from experiences in the UK that organizations competing for funds will not collaborate if they foresee an economic or PR downside. Andrew acknowledges this possibility, but reports that GLI has found success by collaborating with community liver groups to help them raise more money. This engenders good will and strengthens bonds within the community.
Roger shifts the conversation in the direction of metrics to point out that we do not yet have a concise, widely used and accepted test or metric to indicate success in slowing or stopping the growth in NASH. Andrew agrees and notes this is a particular challenge on Capitol Hill, where legislators are looking for hard numbers to demonstrate the need for (and later success of) programs. The GLI-supported NASH Care Act, which was initially entered in 2021 and will  hopefully be passed this year, creates a Task Force charged with determining what the national metric(s) should be.
The next phase of this conversation reverted to broader issues around the liver as part of a holistic health system. Andrew's key points: (i) GLI recognizes that given the diverse levels and settings in which it operates, there is no viable "one size fits all" approach; and (ii) GLI is finding effective strategies for working more closely with government regul

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This conversation is part of SurfingNASH's 2021 NAFLD Year-In-Review. Professor Jeffrey Lazarus of ISGlobal and the University of Barcelona joins Louise Campbell and Roger Green to discuss the emerging NAFLD public health agenda.

Jeff Lazarus comes to the effort to create a global NAFLD Public Health agenda from his experiences spearheading similar efforts in HIV and Hepatitis C. The conversation begins with Jeff describing the path by which he shifted focus from each liver disease to the next. Just as reduction in HIV transition rates revealed the high level of Hepatitis C infections among HIV patients (particularly intravenous drug users), the reduction in Hepatitis C incidence following advent of the direct-acting antivirals revealed still-significant levels and growth rates of liver cirrhosis. This in turn revealed the degree to which NASH is driving the continuing growth of cirrhosis in the global population. It also revealed the degree to which efforts to reduce or eliminate NAFLD were lacking a strategy, an idea of the burden or sense of economic consequences.

From here, the discussion shifts to looking at similarities and differences between HIV and Fatty Liver Disease. One key similarity: a patient can have this disease for a long time before having to address it. A key difference: the steps one takes to combat infectious disease vs. what is more of a "lifestyle" disease.
Next, the group discussed  Jeff's path to help shape a global consensus around the need to treat Fatty Liver and an action plan regarding how to do so. The first key was to determine how many countries are prepared to deal with NAFLD. Answer: out of 102 the group explored, none were prepared. This led to a two-year process with 218 global stakeholders to develop a global consensus statement on goals and actions, which we discussed on S2 E59. With these pieces in place, the global stakeholder group is working on a framework of sustainable development goals.
In response to a question from Louise regarding the impact of COVID-19 on these efforts, Jeff stated public leaders have not and will not educate the public on the impact of diet and exercise on the disease.. As a result, NAFLD Public Health advocates need to educate leaders on why public safety and nutritious diets are goals for fighting Fatty Liver.
NOTE: It emerges that the countries with the best public preparedness for NAFLD are those that take guidance from hepatologists.
In response to a question from Roger, Jeff suggested the attitude that bad health behavior is an individual right but paying the costs of the result disease is a social cost is not new.  Specifically, he noted that this attitude is not different from what we see with tobacco or alcohol. He went on to discuss the importance of promoting public health, not only as a way to improve individual behaviors but also to create and focus advocates. Today, he states, we are failing both to diagnose the disease earlier and to invigorate providers, patients and social actors to behave in ways that reduce the rate and severity of what is in many ways a lifestyle disease.
A comment by Roger about the relationship between urgency and action leads Jeff to discuss the "terribly unsexy"attribution fraction, a statistical analysis that estimates the percentage of severe liver outcomes that are attributable to a specific disease (for example, NAFLD vs. Hep C.)
As the conversation closed, Jeff discussed his priorities for 2022: (i) to create and work with partnerships to take actions that give life and substance to the consensus recommendations; and (b) to create more consensus opportunities around the work of Wilton Park and possibly a similar meeting in the Americas. 

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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

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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.

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This conversation is part of SurfingNASH's 2021 NAFLD Year-In-Review. Professor Jörn Schattenberg of the University of Mainz joins Louise Campbell and Roger Green to discuss research and insights regarding NASH cost effectiveness studies and related issues of quality of life.

Jörn Schattenberg begins our discussion simply by reviewing some of the year's highlights. His "proof of momentum" statement is unique and dead-on at the same time: Fatty Liver topics were addressed in three New ENgland Journal of Medicine articles this year despite not having a new drug approval. When discussing the Liver International paper on which Jörn was first author (and Vlad Ratziu was the last author), he noted two key non-economic issues. First, countries tabulated and manage patient populations differently. Second, Jörn notes that most countries underdiagnose NASH and NAFLD and spend most of the money with end-stage disease. Roger and Louise both suggest that we might be able to save much of the late-stage money with better early diagnosis or, as Louise puts it, "early opportunity to stop something." Jörn expands on the point by noting that Fatty Liver is a mirror on the entire metabolic system, so early diagnosis of Fatty Liver has benefits far beyond impact on the liver end point. Louise continues to drive a spirited discussion about the importance of early diagnosis, at one point noting that her car gets a complete check-over but our bodies don't. As the conversation continues to cover a broad landscape, Jörn notes the well-documented links between fibrosis stage and quality of life and that the economic benefits of high quality of life are well known. Roger raises Alina Allen's suggestion of using AI to analyze Electronic Health Records, after which Jörn expresses his appreciation for the efficiency and data richness of this idea. The group continues to review different metrics (age, which is more common, dental care, which are less so). The conversation continues to move quickly, shifting from global screening to German medical studies teaching health and diet in public schools to the non-productive (perhaps even counter-productive?) budgeting practices of the NHS. In the end, the group comes back to Louise's fascinating vision of the body as an integrated system.