Surfing the MASH Tsunami

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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.

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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.

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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.

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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.

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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.

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Given the vast amount of information and insight from The Liver Meeting, this episode sought to identify and explore a few key highlights. Even so, there is more in this episode than a brief summary can capture. The panel (Jörn Schattenberg, William Alazawi, Naim Alkhouri, Laurent Castera, Ken Cusi, Wayne Eskridge and Roger Green) addresses several topics from the program:

• Wayne presents information from a survey Fatty Liver Foundation conducted with NAFLD patients. The study reported that very few patients received adequate information at time of diagnosis, and one in three do not even receive a specialist referral. This sparks general discussion on how to drive stronger provider-to-patient communication. The group goes on to consider the value of testing and standardized score computation in medical records, which can improve screening and provider education to patients. One challenge here: AST, which is a key test in its own right and as part of FIB-4, is part of the standard test battery only in the US.
• In the minds of the panelists, provider information and education is and will remain a major challenge. Laurent notes that in France, providers associated cirrhosis with alcohol consumption, but not diet. Ken suggests that getting primary care providers to associate cirrhosis with fatty liver is a key step to improving screening and education.
• Naim points to the open-label resmetirom study with cirrhotic patients as providing “very promising results” in a range of non-invasive tests. He shares his enthusiasm that so many of the emerging guidelines rely on the same cut points in NITs. He goes on to discuss a study in which he and others evaluated the impact of using these guidelines (FIB-4 cut points, VCTE as second step, T2DM and metabolic patients as targets). Naim notes that if applied appropriately, the paper estimated only 8% of the US population would have any need to be treated by a hepatologist, and perhaps only 4-5 million would require intervention with expensive medications.
• Laurent shares a prospective screening study on patients with diabetes located in primary care settings or diabetes clinics based 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. The panelists explore the implications of both studies in terms of how should screening be conducted today. Jörn notes that we must consider the incentive for a physician to screen or enroll a patient.
• Ken discusses advances in the use of PPARs, noting first 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.
• Naim calls attention to the failing performance of NITs in pediatric NASH. Roger recalls the SPLENDOR Study (discussed on Season 2, Episode 60) and what it reveals of the ability for bariatric surgery-driven 20% weight loss to regress fibrosis in non-cirrhotic patients. Panelists then briefly discuss 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.

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Inventiva is a clinical-stage biopharmaceutical company that develops novel and differentiated oral small molecule therapies for patients suffering from diseases with significant unmet medical need.

In an exclusive interview, Inventiva's Chief Medical Officer Michael Cooreman joins Stephen Harrison and Roger Green to talk about the company. Specifically, Michael provides detail and color on key elements of the Inventiva clinical development strategy for its pan-PPAR, lanifibranor. The group also discusses the Phase 2b NATIVE trial, Phase 3 NATiV3 trial and combination trial with the SGLT2 inhibitor empagliflozin that had just begun to recruit.

Surf on for a rich conversation and learn more about this innovative company!

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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. 

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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.

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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.