fibrosis level 4

Co-director Mazen Noureddin and Steering Committee members Amy Articolo of Novo Nordisk and Senthil Sundaram of Terns Pharmaceuticals join the Surfers (Stephen Harrison is also a co-director) to discuss the NAIL-NIT Consortium, an ambitious effort to link non-invasive testing (and specific tests) directly to outcomes.

 NAIL-NIT's activities include a prospective six-year study of 1,000 - 1,300 patients and, separately, retrospective analysis of thousands more cases to establish the best ways to make use of the growing array of non-invasive testing methods in the treatment, diagnosis, and monitoring of NASH patients.

Participants in this episode anticipate that the retrospective element will start generating elements within one year, and the prospective within four years. They describe the program's goals as being practical and business-like (better drug and NIT development), but also profoundly human (never denying a patient with clear F3 fibrosis access to a trial because the pathologist could not find a balloon hepatocyte on the cell.

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

It starts with almost a tangential request that some of the money budgeted for expensive systemic HCC therapies in the UK be rededicated to patient education earlier in the treatment process. From there, the conversation shifts to consider the value of the need for early-stage treatment strategies in poorer countries that are never likely to be able to afford the expense of drugs or treatment modalities. In the end, each panelist describes a change she would like to see in the next 2-3 years.

This conversation explores the different challenges that liver nurses and advanced practitioners face when providing NASH patient education.

It starts with Stephen Harrison noting that this weeks' reported results from Madrigal's MAESTRO-NAFLD Phase 3 trial promises a day when we can reduce HCC and cirrhosis if we can counsel patients early enough in the process. 

From there, the conversation shifts to consider the different specialties that can play a role, including not only hepatologists and nurses, but also podiatrists, bariatricians, endocrinologists and gynecologists. The rest of the conversation covers an array of prospective educational tools and the need for specific education that hits specific key points.

This conversation explores the different challenges that liver nurses and advanced practitioners face when providing NASH patient support.

It focuses on issues including health discrimination, the general challenges in deploying nursing care early in the disease progression and the mismatch of needs and resources. In the end, we learn about nurses who make their own recordings and encourage patients to create their own discussion groups in the medical office.

Episode 9 asks the question, "Are We Taking Full Advantage of the Skills and Knowledge that Liver Nurses and Advanced Nurse Practitioners Bring To NASH Patient Care and Education?" 

In this conversation, we meet the four key nursing opinion leaders who have joined Louise Campbell and Stephen Harrison for the full episode. You will get to meet Kathryn Jack, Michelle Clayton, Pam O'Donoghue and Patrizia Kunzler and learn about the broad sets of skills and experiences each brings to this episode.

At the start of the episode, Stephen Harrison responds to a question that a patient e-mailed to SurfingNASH.com during the previous week.

Program co-chairs Jeff Lazarus and Jörn Schattenberg join the Surfers to discuss their "Innovations in NAFLD Care 2022" series and how it promotes the broader NAFLD Public Health Agenda.

This far-ranging discussion focuses on the Innovations in NAFLD Care 2022 webinar and event series with the goal of understanding what makes this series special and why it is so important today. The NAFLD Public Health Agenda is challenged with high prevalence levels, year-on-year double-digit increases in the number of newly-diagnosed cirrhosis patients, worsening of diets and exercise regimens brought about by the COVID-19 pandemic and an array of issues stemming from the lack of efficacious and tolerable medicines approved for this indication.

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 histopathology will play larger role; hope this entails more than simply emulating human brain 
1:08:03 – Busines

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 study investment feel like an expense
46:09 – Stephen: listen for more Saturday night
47:16 – Business report

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.

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.

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.

This conversation is part of SurfingNASH's 2021 NAFLD Year-In-Review. Fatty Liver Foundation Founder and President Wayne Eskridge joins Louise Campbell and Roger Green to discuss the recently-completed SUNN study that was initiated and shepherded by FLF. Wayne discusses study results and the challenges for an orgganization like FLF in conducting this kind of study. 

Wayne focuses intently on what the study tells us about prevalence of disease in the US. Like the San Antonio Military Medical Center research that Stephen Harrison et al. authored in 2011 and 2021, the study suggested a far higher rate of NAFLD and NASH than typical estimates project, with a NASH rate of 17% in the study population! He also discusses frustrations with the existing order and prior estimates that motivated him to champion the study and some specific issues in actually conducting, analyzing and publishing it. Finally, he discusses the far larger, more ambitious SUNN 2 study currently in the works.

This conversation is part of SurfingNASH's 2021 NAFLD Year-In-Review. Professor Alina Allen of the Mayo Clinic joins Louise Campbell and Roger Green to discuss the rapid progress the profession has made in improving user-friendliness and ease of interpretation of MRE and the coming expansion in the role that non-invasive liver testing will play in the years to come.

Alina notes some specific new information about MRE and other non-invasive testing methods that have come to light in the past year. Key new points about MRE include (1) Alina's statement that "we an actually diagnose NASH" using MRE and MRI-PDFF, (2) Alina's comment that we can execute MRE in a five-minute session, and (3) there are demonstrated correlations and precision prediction data for MRE and cirrhosis. The predictive power of MRE on likelihood of progression allows a way to match pairs in clinical trials more accurately by adding the act of pairing by active and control groups. Alina also notes that the same probability metrics that allow researchers to match pairs in a trial will also power the treating physician to schedule the next MRE in 1-5 years depending on relative risk of progression. In the end Alina suggests that we do not need MORE biomarkers, but instead we need to determine the best way to explore the ones that have been developed in the last few years.

If you listen closely, you will hear Alina discuss some questions that will be answered and data that will be presented at NASH-TAG 2022.

This conversation is part of SurfingNASH's 2021 NAFLD Year-In-Review. Dr. Mazen Noureddin, Director of the Fatty Liver Program at Cedars Sinai, Los Angeles, joins Louise Campbell and Roger Green to discuss advances in AI in histopathology.

Mazen Noureddin notes that while non-invasive tests are important and likely to become more so over time, drug development today will need to rely on AI to interpret and ultimately improve histology reads. One benefit he notes is the ability of AI reads to reveal differences between cirrhosis patients in terms of percentage of liver that is F4 vs. F3. In one study, AI also reduced the percent efficacy in a placebo group when compared to human readers. Mazen raises the pivotal question, "When are we going to use these AI techniques in clinical trials?" He and Louise Campbell suggest that we might have enough confidence today to analyze via AI, if only to compare results to what traditional, error-ridden approaches. He notes thats Louise suggests strongly that adopting the Ishak score might be a good way to go. Ultimately, Mazen suggests we can detect more liver features and also clarify unclear results.

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.

SPLENDOR lead author Ali Amirian, the Surfers and audience member Shardool Jain of Altrix Bio debate whether and when bariatric surgery might become first line therapy for multi-morbid metabolic patients. 

Dr. Jain takes the position that for many patients with metabolic co-morbidities, drugs tends not to work over time, so why not go to bariatric earlier in therapy...even in first line? Panelists disagree to varying degrees. After Dr. Jain leaves, the group answers Roger's question about what they anticipate might be long-acting effects of this pivotal study.

A question from Ali Aminian leads the group to ponder whether cirrhosis can truly be regressed. The consensus is that many good things can happen (for example, fibrosis can be regressed) but that platelet levels never rebound.

From there, the panel considers the likely effect of the later-generation GLP-1s like semaglutide or tirzepatide, which report 10-15% overall weight loss, on MACE and MALO, as well as the in-development double and triple-agonists that report weight loss >20% in early studies.

The Surfers, joined by SPLENDOR lead author Ali Aminian, broaden their discussion into considering MACE and MALO patients into clinical trials.

After Roger Green notes that the percentage reductions in MACE (7.2%) and MALO (7.3%) were virtually identical, the group returns to explore the question of including co-morbid metabolic patients in clinical trials. To spur the discussion forward, Ali shares some additional insights on differences in how the bariatric surgery group performed in SPLENDOR vs. the group that did not receive surgery.

Lead author Ali Aminian shares key findings from SPLENDOR on the impact of bariatric surgery on Major Adverse Cardiovascular Events (MACE) and Major Adverse Liver Outcomes (MALO).

Top-line: over a ten-year followup period, bariatric surgery led to a fourfold decrease in MALO and almost a twofold decrease in MACE. This led Stephen Harrison to ask whether it makes sense to combine MACE and MALO as an endpoint in future studies and to comment on the oddity that most specialties seek to include patients with relevant co-morbidities in their clinical drug development trials but NASH drugs seek to exclude them.

Lead author Dr. Ali Aminian of the Cleveland Clinic joins the Surfers to discuss the recent SPLENDOR Study, which focuses on the effects of bariatric surgery on Major Adverse Cardiovascular Events (MACE) and Major Adverse Liver Outcomes (MALO). 

Stephen Harrison and Roger Green are joined by Fatty Liver Foundation President Wayne Eskridge.

9:02 - Ali Aminian begins to discuss the SPLENDOR study
11:38 - Ali explains the dual study outcomes
13:31 - Wayne has the first comment, then Stephen asks about sub-populations. Ali notes that the small sample size  of events limits the ability to do so.
16:25 - Stephen asks whether it will be a good idea to analyze for MACE and MALO together, rather than separately, and describes the large shift in trial enrollment thnking this might cause.
17:53 - Stephen asks whether study explored renal disease in a cardio-hepatic context. Ali discusses why not  
20:20 - Roger notes virtually identical declines in MACE (7.3%) and MALO (7.2%), asks whether  patients in the trial exhibited both 
23:30 - Ali shares preliminary analyses (not ye released) about the impact of bariatric surgery on disease outcomes. (CAN'T MISS)
24:35 - Stephen notes that these numbers look similar to the placebo group in the cenicriviroc trial
26:19 - Ali comments that having 100 F4 patients  does not provide much power for analysis. Stephen says it might be "25 times" what anyone else has.
28:51 - Ali asks Stephen whether he can envision new agents having the potential to drive regression in  cirrhosis patients.
30:02 - Stephen describes a small, recently reported efruxiferman trial that appears to do so,
goes on to hypothesize that over time we will find a strategy 
35:13 - Wayne worries whether "the siren song of surgery" will stop people from doing the hard behavioral work 
35:59 - Ali: the problem is 40% obesity, 10% severe and until recently, no way to treat it. Expresses optimism and hope for semaglutide and the GLP-1s to come
38:10 - Roger asks how the coming double and triple agonists that report 20+% weight loss will compare to surgery in outcomes
38:49 - Ali: we need to do trials, but effect should be the same. Stephen agrees
40:31 - Shardool Jain, Director of R&D at Altrix Bio, joins from audience to ask if members can envision a time where bariatric surgery becomes first line therapy for extremely obese patients
42:40 - Ali suggests it may make sense for severely obese patients with multiple weight-related morbidities, not otherwise
44:50 - Stephen asserts we do not have enough surgeons in the US to execute the strategy. His preference: solve challenges that will reduce adherence with the new weight loss medicines
46:29 - Roger makes three points. 1 -  surgery in cancer is not an early-stage strategy as Shardool suggests; 2 - from his own experience, diet and exercise can be exceptionally effective in the motivated patient; 3 - you get one shot at surgery, many at medication 
47:31 - Diet conversation continues...
50:57 - Shardool and Stephen exit
51:04 - Ali addresses NIT issue by noting that when data for these first patients were generated in 2004,  there were no practical NITs available
51:43 - Last question: the most powerful long lasting effects of SPLENDOR
52:03 - Ali: 1. Obesity is the main driver in Fatty Liver Disease. 2. Well populated, well-followed populations may provide unique insights
53:29 - Wayne: "the guidance that the heart-liver axis can be affected so dramatically is something we can use" with patients
54:12 - Roger: 1. Forecaster says investment in the double agonists and triple agonists becomes more attractive. 2. Advocate notes that weight loss can help patients all along the NASH spectrum
56:22 - Business section