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This conversation ties up several issues related to MASH and the new MASLD nomenclature that the panel did not touch on earlier in the episode. These range from the impact the nomenclature might have on other elements of treatment to the impact of this effort over time. Finally, the panelists grade the process to date (they admit, their views might be a bit biased) and signs of success. 

Roger Green starts this conversation by asking what impact panelists believe the new MASLD nomenclature might have on NITs. From one perspective, Meena Bansal notes that it should have no impact given that NAFLD/NASH and MASLD/MASH map so similarly on top of one another. From a different perspective, Jeff Lazarus asks whether the nomenclature and accompanying guidelines from professional societies will result in more testing. The group aligns around the idea that patients living with Type 2 diabetes are an excellent target for increased testing with NITs given the high overlap of the two groups. Maru Rinella comments specifically that all efforts to tie T2DM to MASLD as frequently common metabolic diseases will be helpful and that discussing the proper use of NITs might be one way to make this connection. Louise Campbell agrees that increased focus on "Healthy Livers, Healthy Lives" will drive exactly these kinds of discussions. The rest of the episode consists of Roger asking panelists three questions, to which they respond: 

1. What might change over the next year or two? Meena believese that approval of a drug will drive significant growth in the learning curve and, with that, enhanced disease awareness and understanding. Jeff suggests that this will not take the form of a transition from NAFLD to MASLD, but instead that people first learning about the disease will use the new nomenclature properly. Mike Betel notes that on the Fatty Liver Alliance website, ~98% of searches are simply for "fatty liver disease." Over time, he anticipates this will change and also that websites like FLA will address "fatty liver" queries in terms of new nomenclature. 
2. Impact on ICD codes. Meena, who is doing significant work in this area, answers that the goal is to have no impact but simply a smooth cutover. 
3. How the group would grade its work on this activity to date. As Jeff notes, answers from the people who led the process are likely to be quite biased, but all gave fairly high grades. 

This conversation focuses on how the new MASLD nomenclature might improve providers' explanations of MASH to patients. Louise Campbell describes new opportunities, while Meena Bansal describes how focusing on metabolism provides a richer opportunity for providers to explain to MASH patients why fat on the liver matters.

Louise Campbell starts this conversation by discussing a new NHS program providing primary care centers with VCTE units they can use to screen patients for MASLD and MASH. She points out that this will provide a unique opportunity to present the new MASLD nomenclature to primary care and allied health providers in a way that connects immediately to diagnosing patients and educating them properly about their disease. She notes that at the patient level, the discussion is still likely to focus on excess fat on the liver but presents the idea of "fat" in a less stigmatizing way.

Meena Bansal focuses more specifically on exactly how provider-patient conversations might change. For years, she suggests, physicians have written "hepatic steatosis" on patient charts, but then told patients they "just have a little fat on the liver." In her view, the new nomenclature will take the word "just" out of the discussion and present the "little fat on the liver" as part of a metabolic syndrome that requires treatment. She goes on to mention another source of excitement: the ability to consider MetALD patients as part of the same MASLD community and add them to Mt. Sinai's longitudinal patient registry, which will likely become a rich source of MetALD data.
Earlier in the episode, Jeff Lazarus had mentioned his excitement at the growing role and publicity for the "Healthy Livers, Healthy Lives" initiative. Louise notes that increasing focus on liver awareness and awareness of the importance of liver health, as discussed in Season 5 Episode 2, aligns neatly with Meena's disease description and the new communication opportunities for new physician and allied health specialties.

This conversation shifts from the rearview to the path ahead. Louise Campbell starts by asking about the role of Allied Health Providers in the process. After this issue, process leaders Maru Rinella, Jeff Lazarus and Meena Bansal discuss how this will roll out as we move ahead.

It starts with Louise Campbell asking why there Allied Health Providers did not play a larger role in the Delphi process. Maru Rinella replies that, in her vision, this group’s involvement will be critical in the rollout and message development but less so in a Delphi process that was mostly about hashing out, as Maru puts it, “the nuances of the disease.” To Maru, this is also the place where patient voice brings the most pivotal value. Meena Bansal notes that there were some PAs and NPs in the Delphi process. Meena Bansal agrees that their role will be critical in discussions on how to communicate the disease to the patient (a topic we return to in later conversations). Louise appreciates, accepts and largely agrees with this discussion. 

Roger Green shifts focus from the past process to ask about the rollout phase: when it began, what it will include and when it might end. Meena says it will never end. Jeff Lazarus comments that while publication was the formal rollout, even before then groups were vying to be the first to change their names. He also noted that the article was published simultaneously in several journals with broad, rapid uptake in the literature. Since the key is to raise awareness and educate the population, he considers the speed and breadth of uptake a major sign of success. Maru Rinella comments that journal participation has been generally excellent.

This conversation focuses on the Delphi process for a new MASLD nomenclature. It starts with Jeff Lazarus describing what a Delphi process is and how it worked here. Jeff and two other key players in this process, Maru Rinella and Meena Bansal, describe what they consider some of its greatest strengths as well as one thing they wish had worked out better.

Jeff's description focuses on the four rounds of data gathering and some key activities that transpired before the formal process began. He goes on to identify what he considers some of the pivotal outputs of this one. In particular, Jeff describes the focus on patients with alcohol and diet issues, and the naming of a new discreet disease for these patients (MetALD) as being “revolutionary.” 

Roger Green agrees with Jeff's assessment that the naming of MetALD was an important outcome and that the process had clear benefits in this way. He goes on to ask why people opted out of the process. Maru Rinella comments that some people opted out after the third phase due to disagreements with the direction of the activity. Roger refines the question to ask why people opted out in the first place. Jeff and Maru note the amount of work required for this kind of activity, and he, Maru Rinella and Meena Bansal all describe that not all invitees understood how important this process would be upon first invitation. Jeff and Maru go on to mention that the participation rate was high, somewhere around 80%.

Roger asks what could have gone better. Maru, Jeff and Meena Bansal each note groups for which they wish participation had been broader, including possibly a broader representation of stakeholders (notably, more patients, although Maru notes this was not for lack of trying) and more organizations or countries.

This conversation focuses on the issues and visions that led to the identified need for a new MASLD nomenclature. Maru Rinella and Jeff Lazarus discuss the original goals of the process and how focus broadened and shifted throughout.

It starts with Maru Rinella describing what she terms “an existential crisis” for the field around a publication suggesting changing the name of the disease from “non-alcoholic” fatty liver disease to “metabolic” fatty liver disease. She considers this the main impetus for key global players to converge. Jeff Lazarus notes that stigma and several other processes came into the discussion. Maru and Jeff agree that the participant recruitment process came in two phases, one where it was hard to get participants and a later point where it was to manage the size of the exercise. Jeff felt the tipping point happened when people understood how the Delphi process would work and also the need for this to succeed. Maru felt that people had to grasp the implications of a consensus process, which Delphi is. As the conversation ends, another leader in the process, Meena Bansal and a patient advocate participant, Mike Betel of the Fatty Liver Alliance, describe how they came to enroll.

This Vault conversation stems from the wrap-up to TLM2022. In the episode, the panel (Jörn Schattenberg, William Alazawi, Naim Alkhouri, Laurent Castera, Ken Cusi, Wayne Eskridge and Roger Green) addresses several topics from the program. This one focuses largely on NITs. 

This conversation focuses on several papers of interest to Laurent. The first is a prospective screening study on patients with diabetes seen in either primary care or a diabetes clinic in the US. Using NITs to screen for NASH and MRE to screen for advanced disease, they identified 65% with NAFLD, 14% with advanced fibrosis and 5% with cirrhosis. When 164 of these patients moved into biopsy, they identified 61% with NAFLD, 30% advanced NASH and 9% cirrhosis. Laurent contrasts these results to a similar study conducted in a French diabetes clinic-treated cohort with transaminase greater than 20 in women and 30 in men. This yielded 58% NASH, 38% advanced fibrosis and 10% cirrhosis.

The panelists then explore the implications of both studies in terms of how screening should be conducted today. Laurent estimates that we might miss ~25% of advanced patients using current VCTE cutoffs without additional parameters. He also notes that neither duration of diabetes nor A1c levels were predictive. The group concludes that, as Ken puts it, studies like these push the needle toward action in both primary care and diabetes settings.

Last week's posting consisted of 1:1 interviews with four KOL from different spheres, each talking with Roger Green about what they are looking forward to seeing at this week's The Liver Meeting 2023. This week, two of those KOLs, co-host Jörn Schattenberg and hepatology KOL Naim Alkhouri, join Roger and co-host Louise Campbell, FRCP, in a free-wheeling review of key abstracts that will be presented at TLM2023.
The discussion begins with Jörn spotlighting the first item in the abstract book, a presentation titled MASH Resolution Without Fibrosis Worsening After Bariatric Surgery Improves Long-Term Survival. Jörn spotlights this study for demonstrating survival benefits, a significant benchmark for drug approval processes. This study of bariatric patients with concomitant MASH and fibrosis reveals that MASH resolution often comes before fibrosis regression. This suggests that MASH resolution itself might predict improved long-term outcomes, contrasting with earlier beliefs that only linked fibrosis regression to positive prognoses. Louise comments that reducing inflammation should logically lead to fibrosis regression, comparing it to the treatment of hepatitis C. Naim agrees, emphasizing the liver's remarkable ability to heal if the initial injury stops, such as with alcohol cessation or hepatitis treatment. However, he points out challenges in clinical definitions and trial inclusions based on the current focus on MASH histology.
The conversation shifts as Naim shares his excitement that both the ENLIVEN trial with FGF-21 agent pegozafermin and the ALPINE-4 trial with FGF-19 agent aldafermin demonstrate the potential for these agents to reduce fibrosis one level (and occasionally even two!) in patients with cirrhosis. The group agrees that treating cirrhosis is the most urgent challenge facing MASLD hepatology today because patients are close to decompensation and antifibrotic pharmacotherapy does not exist. This leads Roger to ask whether the presence of these agents will drive more aggressive screening for cirrhosis patients and for the group to list the benefits early screening will offer.
Louise shares two papers she intends to follow, both of which focus on gender disparities in liver health. She reminds the group of Roberta Forlano's research (shared in S4 E44) and comments during that discussion that women in liver failure experience higher rates of death that man -- they do not fare as well  on liver transplant lists and exhibit higher rates associated with hepatic renal syndrome. The group concurs that this disparity needs more attention and fits into a broader issue of inequality in medical treatment based on gender and other demographic factors.
Roger shares two posters on lanifibranor with an eye toward how payers are likely to assess agents when they come to market. As the group discussed in earlier episodes, there are significant challenges identifying which patients are likely to succeed prospectively on a MASH drug and another on determining in a reasonable timeframe whether the medication is working. Of the two lanifibranor posters, one suggests that changes in adiponectin levels can predict level of therapeutic success, while the other shows that presence of a mutated PNPLA3 gene has minimal or no impact on the likelihood of therapeutic success.
The group discusses a few other papers and concepts. One paper of note came from the NAIT-NIT consortium and suggests that biopsy can lead to an overestimation of liver fat levels compared to MRI-PDFF. Naim and Jörn comment on behavioral or attitudinal constructs from hepatologists that might lead to this result.
Finally, the group comments on the importance of late-breakers as a vital conduit or cutting edge research and each member notes one other paper or session at the meeting they find intriguing.

STAY SAFE AND SURF ON!

In the final conversation on AASLD’s new practice guidance, Roger Green contextualizes a new project he is embarking on with Ken Cusi. Together as co-hosts, they will be debuting a new podcast series from next week titled The NASH Tsunami in Diabetes: Getting Ahead of the Rising Tide. The content featured will largely be targeted toward healthcare professionals who treat diabetic patients, the patients themselves and their caregivers. The NAFLD-diabetes dual prevalence is alarmingly high:

• 15% of diabetic patients may have fibrosis
• In one study, 70% of diabetics had fatty liver and 35% had NASH
• 25% of deaths in people with NAFLD are related to cardiovascular disease
• NAFLD is an independent risk factor for development of diabetes, cardiovascular and chronic kidney diseases

After the group exchanges comments around this exciting news, conversation shifts back toward the practice guidance. Louise Campbell notes approvingly of its array of considerations which include polycystic ovary, menopause, testosterone alteration and the thyroid to name a few. She goes so far as to describe its succinct qualities as “one of the best written guidance documents I think I've ever read.” Jörn Schattenberg adds his appreciation for the inclusion of some high level hepatology concepts around histology and cell ballooning. Roger compares this document to the new generation of hard-cover suitcases that can appear sleek and compact while in fact being stuffed full of important, neatly organized materials. After which, he prods the group in a final question focused on the greatest practical impact of this guidance in the next couple of years. Louise believes it may be the document that strikes the ultimate chord in raising awareness in primary care: “It’s readable, it's digestible and it's implementable.” Jörn reckons the document is a strong step toward embracing multidisciplinary models of care where the NAFLD patient sits at the intersection of many different disciplines. Ken follows with a sizeable wishlist and offers an apt final comment: “If a dream comes true in a lifetime, you didn't dream big enough.” Surf on to discover these thought-provoking final insights.

Late last week, AASLD published new practice guidance on the clinical assessment and management of NAFLD. The Surfers convene with Ken Cusi, who contributed to the previous iteration published in 2018, to explore its key features and implications. The updated document reflects the many advances pertinent to any practitioner caring for patients with NAFLD. This conversation focuses around the influence the guidance imparts outside of the US.

Jörn Schattenberg shares that an EASL guideline commission has been set forward which will refer to the AASLD guidance in supporting its development. Louise comments on the density of information made available through the guidance, commending its extensive list of references. She expresses concern that NICE will not tap into what’s available here by remaining restricted to data obtained exclusively within the UK. She goes on to advocate for the enormous potential in constructing a guideline that collectively harnesses the “masses of evidence” available in the different guidances emerging throughout the world. When Roger Green asks whether this will be possible, Louise suggests that NICE might be headed in a less insular direction and cites the approval of FibroScan in primary care settings as a recent “leap of faith.” Lastly, she discusses her desire for an investigation into the dynamics of CAP scores to be included in these documents. Jörn agrees and adds that CAP ultimately provides a barometer for metabolic health. At the end of the session, Ken circles these ideas back to the importance behind screening in at-risk populations. 

Late last week, AASLD published new practice guidance on the clinical assessment and management of NAFLD. The Surfers convene with Ken Cusi, who contributed to the previous iteration published in 2018, to explore its key features and implications. The updated document reflects the many advances pertinent to any practitioner caring for patients with NAFLD. This conversation focuses on the impact this guidance may have on patients: will it make a difference and if so, how?

Ken asserts his position that both patients and providers need to be educated on solutions available today. Measures range from effective diet modifications to bariatric surgery and anti-obesity drugs. Louise Campbell reminds that not all patients interact with physicians and that nurses, dieticians and other allied health professionals experience more numerous contact points in terms of co-morbidity management. She asserts that guidances and guidelines need to make an effective impression on the frontline professionals, caretakers and even the patients themselves. This prompts Ken to share some exciting news with regards to the ADA formally recognizing NASH as a problem associated with diabetes. He reveals that he is chairing a committee which will work to create a consensus statement on this subject through consulting an array of stakeholders. Notably, they are inviting the participation of dieticians, diabetes educators, pharmacy representatives, obesity management leaders, primary care representatives and hepatologists among other groups. Ken expresses his optimism for the momentous energy and convergence of fields in an unprecedented effort to collectively combat Fatty Liver diseases. Jörn adds that such collaboration will drive stronger patient advocacy and better education around what specific questions they should be asking their treaters. 

Late last week, AASLD published new practice guidance on the clinical assessment and management of NAFLD. The Surfers convene with Ken Cusi, who contributed to the previous iteration published in 2018, to explore its key features and implications. The updated document reflects the many advances pertinent to any practitioner caring for patients with NAFLD. This conversation introduces differentiating factors which define a Guidance document versus Guidelines.

The conversation starts with Ken introducing the new guidance by placing it in the context of the last five years of thinking about screening and treatment of Fatty Liver patients. He highlights significant events including both let downs in terms of drug development and the emerging optimism surrounding new candidates in the NASH therapeutics pipeline. He notes that this guidance offers an affirmative consensus on the screening of patients with Type 2 diabetes - a contentious topic for the committee Ken participated in formulating the preceding guidance. In this initial high-level overview it already becomes evident that the new practice guidance is comprehensive in a myriad of applications, presaging it to be a highly effective resource.

Jörn Schattenberg joins to voice his initial impression and suggests this document offers an excellent viewpoint as to how the field is moving forward. He points to Table 7 - a summary of key concepts to guide clinical practice - as a particularly comprehensive point of reference for the latest recommendations. Roger Green also commends Table 7, highlighting four bullet points embedded which are dubbed Pearls for the assessment of NAFLD: 

• Aminotransferase levels are frequently normal in patients with advanced liver disease due to NASH and should not be used in isolation to exclude the presence of NASH with clinically significant fibrosis.
• Normative values for ALT reported by most laboratories exceed what is considered a true normal. As a general rule, ALT >30 U/L should be considered abnormal.
• Although standard ultrasound can detect hepatic steatosis, it is not recommended as a tool to identify hepatic steatosis due to low sensitivity across the NAFLD spectrum.
• CAP as a point-of-care technique may be used to identify steatosis. MRI-PDFF can additionally quantify steatosis. 

Ken notes that this document will “rectify some confusion from past guidelines." Specifically, it holds special value for primary care professionals who may not be familiar with the field but whose role is expected to grow dramatically over time. One key point: the role of front-line treaters will not be simply to screen for fat in the liver, but to identify patients in high-risk subgroups with clinically significant fibrosis. He notes that we can support these patients today through a combination of lifestyle interventions and currently available anti-obesity and diabetic medications.

As the session winds down, Jörn previews more detailed discourse around follow-up data on NITs and how best to establish evidence for progressing patients. Lastly, Louise Campbell adds her ideas on using this document to further support and develop local pathways and areas of care. In example, she would like to see updated guidelines from NICE following access to FibroScan in the community setting.

Given the vast amount of information and insight from The Liver Meeting, this episode sought to identify and explore a few key highlights. The panel (Jörn Schattenberg, William Alazawi, Naim Alkhouri, Laurent Castera, Ken Cusi, Wayne Eskridge and Roger Green) addresses several topics from the program.

This final conversation examines the diversity of populations with NASH and other ways we can learn from and about them. Naim begins by discussing work with pediatric NASH, specifically noting the shortcomings of NITs for these patients. Ken and Roger note the diverse forms of NASH, including both lean and pediatric, that are receiving increasing attention. Roger also recalls the SPLENDOR Study and what it tells us about the ability of bariatric surgery-driven 20% weight loss to regress fibrosis in non-cirrhotic patients. The group touches briefly on Scott Friedman’s observation from last week's coverage about the impact of environmental factors on the microbiome and how that might affect these metabolic issues.

Roger closes by asking the group for one thing, besides a drug approval, that will change how we think about or treat this disease in the next year. Surf on to discover their predictions.

Given the vast amount of information and insight from The Liver Meeting, this episode sought to identify and explore a few key highlights. The panel (Jörn Schattenberg, William Alazawi, Naim Alkhouri, Laurent Castera, Ken Cusi, Wayne Eskridge and Roger Green) addresses several topics from the program.

Naim begins this conversation with mentioning Labcorp’s announcement that a reflex ELF test is available for patients with high FIB-4. The latter will be computed if the patient has a complete blood count (CBC) and a comprehensive metabolic panel (CMP). As Naim notes, this is similar to the Hep C paradigm where patients with a positive Hep C antibody test receive the Hep C RNA. For Naim, this is “a game changer” in primary care where patients with the basic CBC and CMP results can be flagged for advanced fibrosis using two widely-studied NITs.

Will segues to discuss John Dillon’s work with the intelligent Liver Function Test (iLFT), which was covered on the podcast earlier in the year. Since then, an abnormal iLFT result now leads to an ELF test. Like the Labcorp program, this follow-up makes it easier for primary care to identify patients with abnormal livers. Will cautions that more research on different ethnicities and disease levels ought to be conducted. At this point, Will exits the discussion due to a poor internet signal. While signing off he raises one last trend that has likewise surfaced on the podcast earlier this year. The encouraging note is that researchers are working to link NITs directly to outcomes instead of biopsy.

In the remainder of this session, Ken discusses advances in the use of PPARs. He first notes the ongoing work with the pan-PPAR, lanifibranor, followed by Poxel’s work with PXL-065. The latter is a deuterium-stabilized form of pioglitazone that generates greater activity of the r-enantiomer and less of the s-enantiomer.  These are linked to mitochondrial benefit versus weight gain, respectively. Stephen Harrison discussed this molecule early last month in review of a recent string of press releases presaging some of the most promising data of the last decade in NASH drug development.

Given the vast amount of information and insight from The Liver Meeting, this episode sought to identify and explore a few key highlights. The panel (Jörn Schattenberg, William Alazawi, Naim Alkhouri, Laurent Castera, Ken Cusi, Wayne Eskridge and Roger Green) addresses several topics from the program.

This conversation focuses on several papers of interest to Laurent. The first is a prospective screening study on patients with diabetes seen in either primary care or a diabetes clinic in the US. Using NITs to screen for NASH and MRE to screen for advanced disease, they identified 65% with NAFLD, 14% with advanced fibrosis and 5% with cirrhosis. When 164 of these patients moved into biopsy, they identified 61% with NAFLD, 30% advanced NASH and 9% cirrhosis. Laurent contrasts these results to a similar study conducted in a French diabetes clinic-treated cohort with transaminase greater than 20 in women and 30 in men. This yielded 58% NASH, 38% advanced fibrosis and 10% cirrhosis.

The panelists then explore the implications of both studies in terms of how screening should be conducted today. Laurent estimates that we might miss ~25% of advanced patients using current VCTE cutoffs without additional parameters. He also notes that neither duration of diabetes nor A1c levels were predictive. The group concludes that, as Ken puts it, studies like these push the needle toward action in both primary care and diabetes settings.

Given the vast amount of information and insight from The Liver Meeting, this episode sought to identify and explore a few key highlights. The panel (Jörn Schattenberg, William Alazawi, Naim Alkhouri, Laurent Castera, Ken Cusi, Wayne Eskridge and Roger Green) addresses several topics from the program.

Ken leads this conversation with an analogy from the diabetes field. He describes the impact of albumin screening in urine on helping primary care treaters focus on diabetes screening and, ultimately, providing better information to patients. He shares his hope that a simple test, like FIB-4, will illuminate direction in the recent guidelines for liver diagnostics. Will suggests a few additional challenges face Fatty Liver disease. Treaters have one hand tied behind their backs because basic blood panels and screens do not provide the information necessary for algorithms to seamlessly assess liver health. He adds that “not having that information at your fingertips is one thing, but not knowing what to do with it afterwards is something else.”

Ken notes most patients in the US healthcare system receive an annual metabolic profile which often includes liver enzymes and a complete blood count. As such, he emphasizes the importance of educating on how to build the right equations into medical records. Roger notes a significant barrier: the US is one of the only countries whereby AST is standardized. It is frequently implored on this podcast that patient advocates outside the US make standardized testing for AST a priority. This is especially important for all diabetic patients.

Laurent Castera describes the French system which provides free medical checkups, but does not measure for AST. He suggests a problem that in France, doctors generally still link cirrhosis to alcohol and not NASH. As a result, they may not see the value in screening patients who do not consume alcohol. It’s noted that identifying patients with advanced fibrosis is critical even in the absence of pharmacological treatment. Ken points out that there are drugs for obesity and diabetes that also help in NASH, like pioglitazone and the GLP-1 agonists. With steps to help patients beyond diet and exercise, it is important to educate primary care to test for NASH.

As the conversation winds down, Naim provides two pieces of encouragement. The first, from a resmetirom open-label cirrhosis study, suggested that the drugs in development and close to market today may provide benefit for cirrhotic patients. The second, more encouraging to payers, came from a study he conducted with colleagues to assess how much burden the AGA pathway would place on the US system. The result: only 8% of patients would need to be treated by a hepatologist. This suggests that even with nearly 100 million people with NAFLD, only 4-5 million would require expensive NASH drugs.

Given the vast amount of information and insight from The Liver Meeting, this episode sought to identify and explore a few key highlights. The panel (Jörn Schattenberg, William Alazawi, Naim Alkhouri, Laurent Castera, Ken Cusi, Wayne Eskridge and Roger Green) addresses several topics from the program. This conversation focuses on an ongoing initiative of the Fatty Liver Foundation called the Annual Survey of Patient Perspectives.

Wayne introduces this 713-patient survey which sought to understand and monitor the evolving social and medical experiences of NAFLD patients in the US. The results of the study were presented at The Meeting. Notably, 80% of patients reported they were given either no or not enough information at diagnosis. One in three did not receive a referral to a specialist at diagnosis, and 60% of those who saw a specialist left the visit with little or no understanding of the disease. Wayne also notes a relatively small percentage of patients felt they were offered help at the time of visit in terms of diet and nutrition, or mental wellness as related to the diagnosis. Roger asks what would be the key message for treaters, pharma and diagnostic companies to take away. Wayne highlights two: patients are not well-informed or supported at time of diagnosis, and primary care providers lack the disease information and treatment insights to better support these patients.

As the session winds down, conversation shifts focus to consider the breadth of this physician challenge and address what remedial steps make most sense.

Over 7,000 in-person attendees from around the world convened at the 73rd Annual AASLD Liver Meeting for a lively and momentous event in Washington DC. Surfing the NASH Tsunami hosted two recording sessions throughout the event to discuss key takeaways. This conversation is a composite featuring impressions from both sessions.

The first session features Scott Friedman, Jörn Schattenberg, Rachel Zayas and Roger Green. Jörn starts this conversation by discussing a presentation delivered by Mazen Noureddin on the developmental mitochondrial uncoupler, HU6. While mitochondrial uncouplers are not new, they are to the field of NASH. Jörn goes on to describe a short, 61-patient trial. The trial yielded large percentages of patients reducing their liver fat more than 30% – around 40% at the lowest dose and 71 or 72% at the two higher doses – and HbA1C in a medication that appeared safe in this two-month trial. Scott goes on to credit Gerald Shulman at Yale for his role in developing knowledge about mitochondria and the liver. Jörn and Roger then recall Marcus Ranney, the self-described mitochondrial fan and biohacker, who discussed his affection for and belief in the importance of mitochondria during his talk in Barcelona and a subsequent NASH Tsunami interview. As the conversation wraps up, Jörn raises the idea that a mitochondrial uncoupler might be a short-term intervention at the start of a longer therapeutic regimen. Scott notes that the idea of induction therapy vs. maintenance is gaining traction.

The second part of this conversation comes from a session on the final morning featuring Stephen Harrison, Sven Francque, Jörn Schattenberg, Ian Rowe, Jeff McIntyre and Roger Green. Roger begins with discussion of the REGENERATE trial, a Phase 3 from Intercept for obeticholic acid in non-cirrhotic NASH. Arun Sanyal  presented a reanalysis of the results as a late-breaker on Monday. Roger describes the change in pathology-reading technology from the original analysis, in which the entire deck was distributed randomly between two readers. The two readers represented for the consensus and adjudication process in consideration. Slides where agreement could not be reached were not used. Roger reviews his take on the important elements of the results:

Improved resolution of what now appears to be transitory LDL elevations

A slight drop in placebo performance and slight increase in high-dose performance

The latter indicates the higher dose is roughly three times as effective as placebo instead of two-fold in the original analysis. Stephen continues to comment on the larger, vastly enhanced safety database in this study. Sven notes the study suggests there may be significant benefit in halting progression even in patients who do not regress. 

Last month, Stephen Harrison joined the Surf to cover a recent string of press releases presaging some of the most promising data of the last decade in NASH drug development. As Principal Investigator, he reviewed Phase 2b results from Akero’s HARMONY Trial. This is a 24-week study evaluating the efficacy and safety of the FGF-21 agonist efruxifermin (EFX) in patients with clinically relevant NASH (F2-F3). The topline results he previously shared:

The study met its primary endpoint for both the 50mg and 28mg EFX dose groups.

Respectively, 41% and 39% of EFX-treated patients experienced at least a one-stage improvement in liver fibrosis with no worsening of NASH by week 24 (compared with 20% for the placebo arm).

In this follow-up conversation, Stephen walks through his presentation on Akero’s lead product candidate EFX. After detailing the data, two important points emerge. First, Stephen and Sven Francque share the idea that “not all FGF-21’s are created equal.” FGF-21’s themselves need to be stabilized due to their two-hour half-lives. The first FGF-21, pegbelfermin, was PEGylated and revealed significant challenges in clinical development. EFX is a bivalent structure - two molecules stabilized by a fusion protein. This appears to work far better. The conversation continues with more points and questions about the study results and implications. An interesting idea surfaces: EFX might function better as an induction therapy to be followed by an oral maintenance therapy as a long-term monotherapeutic solution. As the session winds down, the group speculate the dynamics of what happens when disease regresses to a point where there is far less liver damage.

Sven Francque begins this conversation by discussing Laurent Castera’s paper comparing a range of NIT diagnostic tests: MAST, FAST, MEFIB, FIB-4 and NFS. When introducing the paper, Sven shares two items that Mazen Noureddin did not cover in an earlier preview. Professor Castera and his team used fairly low ALT cutoffs of 20 for women and 30 for men as the sole liver entry criterion for the study. The implication of this was to produce a relatively unbiased population sample in which more than 50% of patients exhibited NASH. Stephen Harrison joins to share data from his presentation on the FASN inhibitor that Scott Friedman referred to in the first review episode. Stephen describes that AI-based percent collagen computations in the FASN study indicated its highest correlation was with the FAST score. Additionally, MAST was comparable and AST alone holds significant power.

Roger Green looks to broaden the conversation by asking what we have learned about tests in this meeting. Ian Rowe summarizes the message he has derived from a range of studies to link the screening target - fibrosis vs. advanced fibrosis - with the value of a two-step testing strategy. As both Stephen and Mazen have suggested on recent episodes, Ian considers a compelling argument for moving straight to FAST. Roger expands that, as Professor Castera pointed out, the low gray zone number on the MAST test promises a far higher level of true positive and true negative results. It also promises significant cost savings in terms of reduced biopsy demand when screening for clinical trials. Ian builds on these considerations to make a final statement as this session winds down. If we have drugs available to treat patients in the community, providers need to become far clearer about diagnostic goals and then find the right test to link to each goal.

In this conversation, Jeff McIntyre leads with his impressions on the pan-society presentation of NAFLD nomenclature consensus process. He begins with an objective account of the parameters around an extensive Delphi process. Notably, Jeff points out that the discussion appears to be shifting away from the phrase “metabolic.” This is important because in many cultures and settings, “metabolic” may be no easier to explain to patients than “non-alcoholic,” although the specific challenges differ. Jeff also highlights that discussion appears to be moving away from redefining the target patient population. Any change in patient definition threatens to set back the ongoing clinical development work on drugs and diagnostics by a matter of years. Such a setback is clearly not in the interest of patients.

Jeff then engages in a critique of process elements that he felt were not supportive of patients. While every statement needed to surpass a two-thirds “supermajority” threshold to be incorporated in the consensus document, the group comprised more than 70% clinical researchers. If clinical researchers supported a statement heavily enough, no other group input would matter. He also notes the general sense of intimidation felt by patient advocates in the audience of the public debate. While the debate included 5-minute statements from GLI CEO, Donna Cryer, and PBC Foundation CEO, Robert Mitchell-Thain, advocates in the audience didn’t feel welcome to make any statements.

At this point in the conversation, panelists Stephen Harrison, Sven Francque, Jörn Schattenberg, Ian Rowe and Roger Green join to offer their perspectives:

Stephen describes Jeff’s passion as a breath of fresh air. Sven, who was quite involved in the process, responds with his experience and outlook. Jörn acknowledges this to be a complex challenge for the field and that there is no model to measure the potential consequences. Ian voices concern for “a real risk” in having alternate definitions without genuine consensus. Roger responds from his unique position of being neither a patient nor a physician.

Overall, the reactions are unique, interesting and varying. Surf on to hear their full takes.