Surfing the MASH Tsunami

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Last week, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022,) the first major hepatology Congress to be held in person since the start of the pandemic (smaller, but very valuable, meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not). On the last full day of the program, several vitally important drug development studies were presented during the late-breaker and dedicated sessions. The conversations in this episode will review some of the most important findings. This particular conversation focuses largely on Stephen Harrison's presentation of results of a Phase 1 trial for pemvidutide, a dual GLP-1/glucagon agonist, at this meeting.

The conversation starts with a brief discussion about the appropriate context for using and interpreting FIB-4 results. The closing comment for this discussion comes from Michelle Long, who suggests that use of FIB-4 is context-sensitive: "You have to know what's your question and how are you thinking of using this test" because its usefulness changes depending on the disease prevalence in the population being studied.

From here, Stephen starts to discuss a Phase 1 trial for pemvidutide that he presented at #ILC2022. Of the 34 patients in this trial, 8 had fat in their livers; all were overweight or obese. Stephen describes the GLP_1/glucagon combination as being like "not eating and exercising at the same time" because GLP-1s work on satiety control and gastric emptying (not eating) while glucagon increases overall metabolism and specifically revs up lipid metabolism (exercise) "because you're cutting the intake of calories [while] increasing the burn rate through the liver. He goes on to note the reason that by lowering Cmax and increasing Tmax, it demonstrates the pharmacokinetic profile of a q1w drug. Of the 8 patients with measurable liver fat, all dropped below the level of detection at the 1.8 and 2.4 doses (representing a 90% reduction). Stephen closes his discussion of the trial by mentioning dramatic weight loss levels and a 14-15% drop in liver volume over 12 weeks.

All the panelists express positive reactions to these results. In response to a question from Roger, Mazen says they are as good as endo-bariatric surgery or better. As the conversation ends, Mazen goes on to ask whether this is an acute or maintenance medication and states he suspects it will be lifetime maintenance.

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Last week, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022,) the first major hepatology Congress to be held in person since the start of the pandemic (smaller, but very valuable, meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not). On the last full day of the program, several vitally important drug development studies were presented during the late-breaker and dedicated sessions. The conversations in this episode will review some of the most important findings. This particular conversation includes reactions to the two major resmetirom presentations from the rest of our panel.

It starts with Jörn Schattenberg responding to the spleen and liver volume statements in Stephen's presentation. He signals partial agreement and acceptance, then goes on to comment on ways the study methodology might have led to clearer volume data to interpret. In the end, though, he notes that other papers have linked spleen volume to clinically significant changes in portal hypertension. Stephen acknowledges Jörn's comments and suggests that the upcoming MAESTRO Outcomes study might be an excellent place to resolve these issues. 

Mazen Noureddin provides a more upbeat assessment of this data. He notes that when treating patients, the positive signs he seeks are reduction in spleen size and liver volume accompanied by a change in platelets. Since all three of these occurred in the cirrhotic cohort, he is somewhat optimistic about what future studies will prove. On the MAESTRO NAFLD-1 Phase 3, he states that this is the first trial he can recall (perhaps the first, period) where MRE is reduced. He "hopes this is fibrosis" and is excitedly awaiting confirmation when biopsy results are released.

Michelle Long agrees with Mazen and further notes that in the non-cirrhotic trial, the idea that patients missed two months of doses made the results more "generalizable" to what we might expect in standard clinical practice. Louise Campbell follows this up with the statement that many MAESTRO NAFLD-1 patients will likely be referred back to primary care for treatment and expresses her confidence that resmetirom might be a good option for PCPs when treating these patients. 

The rest of the season focused on issues of biomarker inaccuracy. Jörn shares results from a presentation by Jerome Boursier on the accuracy of FIB-4 in Type 2 Diabetes patients and an analysis of the MAESTRO NAFLD-1 data he presented. In his presentation, 26% of patients with NAS >= 4 and biopsy-confirmed F2 or F3 NASH had normal ALT scores, and 80% had ALTs less than 2x normal. In Germany, where ALT is the test PCPs conduct before referring patients, Jörn expressed concerns about how many patients needing treatment are missed due to false ALT negatives. The rest of the discussion centers around defining the proper use of FIB-4 and areas with vast potential for misuse.

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Last week, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022,) the first major hepatology Congress to be held in person since the start of the pandemic (smaller, but very valuable, meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not). On the last full day of the program, several vitally important drug development studies were presented during the late-breaker and dedicated sessions. The conversations in this episode will review some of the most important findings. This particular conversation discusses two presentations on resmetirom, the late-breaker safety results (and some preliminary, secondary efficacy markets) from the Phase 3 MAESTRO NAFLD-1 trial, and a separate study looking at 180 cirrhotic patients in the open-label cohort of MAESTRO.

MAESTRO NAFLD-1 was a double-blind, randomized, placebo-controlled trial of 80 or 100 milligrams of resmetirom versus placebo, with close to 1,200 patients in these three cohorts. There was a fourth 100mg open-label cohort as well, with 180 cirrhotic patients among the trial population. For MAESTRO NAFLD-1, the primary endpoint was safety. In addition, there were several key secondary endpoints, including pathogenic lipids, and certain MRI characteristics, along with FibroScan (both KAP and KPA). To primary author Harrison, the "take-home point" from this study was "there was no bad news from MAESTRO NAFLD-1, and it did meet its primary endpoint with all the key secondary endpoints under hierarchical control having statistical significance as well. 

One more interesting point from this presentation. Because the study was fielded during the COVID-19 pandemic, patients in the three closed-label arms missed an average of two months of doses due to pandemic-related logistical challenges. Despite this, the secondary endpoints demonstrated efficacy, although some demonstrated reduced efficacy compared to what we would expect from a full course of therapy.

Stephen then shares significant data from the first 105 patients in the open-label cirrhosis group. Without going into detail, the "take-home point" here is that "in addition to the safety and tolerability... we were moving noninvasive tests in a way that made us feel like something positive was happening relative to maybe some early portal hypotensive changes." Stephen notes the caveat that the researchers performed neither endoscopy nor HPG measurements in this population.

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Last week, roughly 5,000 hepatology stakeholders met at the ExCel Centre in London for #ILC2022, the first major hepatology Congress with significant in-person attendance since the start of the COVID-19 pandemic. This wrap-up episode covers some of the major drug development and patient screening themes that emerged from ILC.

The previous ILC2022 episodes spent virtually no time on NASH drug development, so moderator Roger Green starts by suggesting this episode pay specific attention to the medications covered in the late-breaker session and Friday press conference. Stephen Harrison, who presented the resmetirom late-breaker and two other resmetirom studies at the conference, started by talking about the resmetirom late-breaker, which reported initial Phase 3 results from the MAESTRO NAFLD-1 trial. The trial's primary endpoint was safety, with several secondary metabolic endpoints. Stephen describes the drug as "safe and well-tolerated in over 1200 patients treated for one year with 80mg or 100mg versus placebo." On the secondary endpoints, there were "statistically significant reductions in anthropogenic lipids, LDL, APO B ,triglycerides , lipo A" and MRI- PDFF.  Also, Stephen notes that because this study took place at the height of the COVID-19 pandemic, patients in the 80mg, 100mg and placebo cohorts missed an average of two months of doses over a 12-month study. Despite this challenge, the drug showed significant effects in MRI-PDFF and MRE. All told, Stephen sees "no bad news" in MAESTRO NAFLD-1.

He shifts focus to the cirrhotic study. Resmetirom was safe and well-tolerated in this population and, non-invasive tests moved in a way that suggested possible movement on early portal hypertensive changes. Stephen notes that the upcoming MAESTRO Outcomes study will allow researchers to learn whether the pathophysiologic changes are linked to outcomes. Mazen and Jörn make generally supportive comments. 

Michelle picks up by describing the late-breaker as "generalizable." As she notes, most patients in practice miss doses, which makes these results more akin to real practice. Louise reads this data to say that even in primary care, patients can improve if screened and treated properly. 

Jörn takes lead to review the accuracy of biomarkers, specifically ALT and FIB-4. He discusses his presentation based on 2000 liver biopsied patients in the MAESTRO  NAFLD-1 population. Of these advanced patients, 26% had normal ALT levels and 80% had ALT levels less than 2x normal. Jörn makes the point that we must find ways not to miss these patients when they appear in hepatology practices since cannot rely on ALT, or even FIB-4, to identify significant disease. 

Stephen moves on to discuss the dual GLP-1/glucagon agonist pemvidutide. The pemvidutide study is a Phase 1 with 34 patients focusing on safety and pharmacokinetics. He comments that atherogenic lipids were reduced more than with standard weight loss, points out highly promising results around liver fat, mentions a 14-15% drop in liver volume over 6 weeks and notes a highly tolerable safety/side effect profile. Mazen notes how remarkable he found it that after 12 weeks, 100% of patients on the 1.8mg dose achieved 5% weight loss and 55% achieved 10%. 

Jörn shifts the conversation to discuss the semaglutide late-breaker.  While semaglutide showed no efficacy in reducing fibrosis for cirrhotic patients over a 48-week period, the group saw  positive signs in sema's  high level of safety coupled with the ability to meet secondary goals: weight loss, HbA1c reduction. Michelle suggested that this study and others like it might give hepatologists comfort in prescribing GLP-1 today for obese or diabetic patients with NAFLD or NASH. Louise mentions a statin presentation she attended with a similar message about the benefit of non-NASH drugs against targets that matter to NASH patients. 

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The International Liver Congress (#ILC2022) is the first major hepatology Congress to be held in person since the start of the pandemic (smaller, but very valuable, meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not).

The conversation takes place against the schedule of a live Congress on the day that focused on drug development. This presented scheduling challenges, which Louise Campbell addressed by combining two shorter conversations.

The first conversation included Jörn Schattenberg, Mazen Noureddin and Ian Rowe and focused on a morning session titled "NAFLD: Diagnostics and non-invasive assessment." This conversation focused on several elements of this session: papers demonstrating the relative lessons and values of FAST, MAST and MEFIB, an analysis from the LITMUS Metacohort identifying the combination of metrics that did the best jobs of specifically predicting fibrosis, steatosis, ballooning and inflammation, and papers looking at the ability of FIB-4 to identify at-risk patients. The most important conclusions: (i) the LITMUS presentation attempted to correlate to biopsy, which is a suboptimal target; researchers should consider the limitations of biopsy in planning future trials; and (ii) many tests have significant value as long as we use them properly with an appreciation of what the test seeks to determine and why for that purpose, one test might be better or weaker than others.

As this conversation winds down, Louise Campbell discusses interpretive challenges caused by the fact that studies do not list the generations of technology researchers use. She points out specifically that successive generations of FibroScan demonstrate significant differences in terms of tools that are available and the reliability of different tools. 

Finally, Jörn discusses a study in the Public Health session from the SEAL program suggesting that roughly half the patients never return for their second visits. After this, Mazen asks Jörn to discuss his presentation in the NAFLD Diagnostics session. Jörn presented results of a MAESTRO-NASH analysis in which the researchers assessed the ability of FIB-4 to identify and diagnose at-risk F2 and F3 patients from among a 2,000 patient cohort. Key point: 37% of patients in this trial had normal ALT and 80% had <2x normal ALT. The second finding was that FIB-4 with a cutoff of 1.3 will miss a significant number of at-risk patients defined by F2 and F3. In this session, Jerome Boursier presented a study with a similar finding for diabetic patients. Louise mentioned a presentation from Rohit Loomba that made similar points with cirrhotic patients. 

With this, the episode shifts to Louise's interview with Robert Mitchell-Thain, CEO of the PBC Foundation and long-time patient advocate with The Global Liver Institute. Robert commends the "really holistic, complete" agenda that, from a patient perspective, "really sets the standard of where we need to go in the future." He advocates bringing more patient perspectives into symposia and other events and programs. In response to Louise, Robert highlights several items that "rocked his world": the number of patients whose disease is missed when we rely on a FIB-4 test as the sole screening tool; the importance of bringing patients into the disease discussion early in the course of the disease. From here Louise and Robert go on to discuss the roles of doctors, nurses, other professionals and patients in maintaining an open discussion of the real-world challenges of therapy. They focus on two pertinent, realistic challenges: sexual dysfunction and physical appearance. Words cannot do this conversation justice...you will simply have to listen.

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The International Liver Congress (#ILC2022) is the first major hepatology Congress to be held in person since the start of the pandemic (smaller, but very valuable, meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not).

The conversation takes place against the backdrop of a live Congress, which means background noise, challenges finding a meeting location and more background noise than you will find during a studio episode.

Once everyone had settled in, this episode covered a range of topics, the most important of which revolved around the value of FIB-4 and the need for integrated, strategic thinking about care. The FIB-4 discussion addressed both strengths and weaknesses of the test, which is inexpensive and produces a relatively high level of false-positive tests. One key point from both Zobair and Michelle: in the US, the quality and standards organizations such as NCQA and HEDIS, should include FIB-4 screening and automatic EHR inclusion as a quality criterion with a point value in the scoring criteria. The discussion allowed the group to discuss several other important issues from the day's events. There was limited discussion of drug trials since most of the major trials will be presented on Saturday. Listen to Episodes 33 and 34 for more feedback on those presentations.

At the end of the session, Michelle Long announced that she is leaving academia in July to join Novo Nordisk and get involved full-time in helping her new employer develop good drugs and shape overall treatment paradigms and pathways.

This episode is sponsored by DiaPharma. DiaPharma is proud to support Surfing the NASH Tsunami in its activities to raise awareness of,  and foster discussions about,  the NASH epidemic.   DiaPharma offers noninvasive mechanistic biomarkers,  like CK18, that provide early biologically plausible indications of changes in disease activity for use in NASH drug development studies.   For research use only,  In the US and Canada,  and not for use in diagnostic procedures.  

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Next week, >10,000 Fatty Liver stakeholders are expected to journey to London (rail strike and all) for the International Liver Congress (#ILC2022), the first meeting at this level since the pandemic started to include an in-person attendance option. This week, NASH Tsunami identifies some of the most important and intriguing non-embargoed presentations at #ILC2022. This conversation focuses largely on OS025 Non-invasive fibrosis scores as prognostic biomarkers of liver events, cardiovascular events and all-cause mortality in people with obesity and/or type 2 diabetes in the UK: a longitudinal cohort study, from Quentin Anstee (UK).

Stephen introduces this paper as one he found exceptionally important. He points out that the link from FIB-4 to major liver-associated outcomes (MALO) is not particularly novel, but the effort to link FIB-4 scores to MACE (cardiovascular events) and all-cause mortality is unique. In this case, the study tracked >45,000 patients with obesity or Type 2 diabetes plus a fibrosis score of F1 or higher for a ten-year period, over which time they observed almost 1,000 liver events, all either cirrhosis or events tied to cirrhosis. When tabulating these events against FIB-4 level, the researchers found 1% in the "low" group (FIB-4 2.45). 

The picture changes in interesting ways when looking at CVD and all-cause mortality. The percentages for CVD mortality were 11% for low, 27% for intermediate and 33% for high. For all-cause mortality, the numbers were 13%, 37% and 61% respectively. Stephen notes that FIB-4 looks like a more valuable test when measured against real-world endpoints instead of biopsy, which he describes as the "bronze standard."

Roger joins the conversation to look at these results from a primary care patient screening perspective. He notes that for CVD mortality, the indeterminate score was almost as good as high for predicting 10-year outcomes, and it was significantly better than the low score for all-cause mortality. He suggests that these numbers provide a strong case for integrating FIB-4 into primary screening for all obese or diabetic patients, as some guidelines are beginning to recommend. 

Louise goes on to consider the 10-year outcomes in the context of how much juvenile obesity and Type 2 diabetes we are beginning to see in population assessments and suggests that there results forebode declines in longevity, health and quality-of-life in the years to come. 

After Stephen notes that there are some excellent clinical trial presentations in #ILC2022 (but these are embargoed), each Surfer picks one session that intrigues them. Stephen looks at the Wednesday morning "think tank" titled "Think Tank on Risk Stratification and Drug Development." Jörn selects the Friday morning joint EASL-EASD session titled "One or many fatty liver diseases? Clinical impact of disease heterogeneity." Louise selects Saturday's Public Health session and Roger selects an abstract session from Saturday morning titled, "NAFLD: Diagnostics and non-invasive assessment."

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Next week, >10,000 Fatty Liver stakeholders are expected to journey to London (rail strike and all) for the International Liver Congress (#ILC2022), the first meeting at this level since the pandemic started to include an in-person attendance option. This week, NASH Tsunami identifies some of the most important and intriguing non-embargoed presentations at #ILC2022. This conversation continues our discussion of OS044, NAFLD patients have worse health-related QoL compared to the general population irrespective of their fibrosis stage: results from a prospective multicenter UK study, from Margarita Papatheodoridi (UK) and discusses THU051, Health-related quality of life is impaired in people living with HIV and hepatic steatosis, from Maurice Michel (DE).

This conversation starts by picking up on the far-ranging discussion of quality-of-life that ends Episod 30.2. It starts with Roger making two points: one about the impact that clinician/clinical trial design consultants can have on bringing quality-of-life endpoints to a more central role in Phase 3 trials and another that drug revenue forecasts might grow if forecasters integrate the impact of quality-of-life metrics into the target patient population. Louise notes the secondary impact of quality-of-life of work days lost and quality of work time. Jörn mentions THU051, a paper from his group that focuses on similar quality-of-life issues in patients with NAFLD living with HIV as well.

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Next week, >10,000 Fatty Liver stakeholders are expected to journey to London (rail strike and all) for the International Liver Congress (#ILC2022), the first meeting at this level since the pandemic started to include an in-person attendance option. This week, NASH Tsunami identifies some of the most important and intriguing non-embargoed presentations at #ILC2022. This conversation explores two of these: FRI 100, Shear wave elastography, transient elastography and enhanced liver fibrosis test use in the assessment of NAFLD in real-world practices, from Zobair Younossi (US); and OS044, NAFLD patients have worse health-related QoL compared to the general population irrespective of their fibrosis stage: results from a prospective multicenter UK study, from Margarita Papatheodoridi (UK). In the middle, the Surfers briefly discuss why the balance of papers discussed in this episode tilts so strongly toward real-world data and large databases.

Louise starts this conversation by bridging from her discussion of FRI094 to another poster (FRI100) that assesses the real-world value of three different techniques for assessing NAFLD levels. She shares the paper in the context of this year's papers tilting heavily toward real-world data. In this case, the researchers utilized a database of over 13,000 respondents, reduced the size down to ~4,000 with FIB-4>1.46, and then attempted to stage patients using Electronic Health Record data and elastography (shear wave of VCTE). The paper concluded that the combination of these measures in EHR provided excellent guidance in staging without having to resort to special blood tests on the first round.

The conversation shifts briefly into the issue of how the pandemic slowed clinical drug development trials. Stephen shares his experience on where trials slowed down the most to support the idea that the pandemic is the factor driving a lower number of drug development papers and to say that this will increase in the years ahead.

From here, Roger begins his discussion of OS044, a prospective study over 561 UK patients exploring associations of fibrosis severity and metabolic comorbidities with QoL score levels. The pivotal finding of the abstract is that there is a clear significant difference between patients with and without NAFLD, and another clear difference between cirrhotic and non-cirrhotic NAFLD patients, but no significant difference between patients with NAFLD and pre-cirrhotic NASH. Roger comments that this is important for two reasons: it attests to the logic of Global Liver Institute's #StopNASHNow slogan for International NASH Day, and it strengthens the case for making Quality-of-Life an endpoint in clinical trials. Jörn comments on the rigor of the design and speculates on the degree to which diabetes might underlie these findings. Stephen closes the conversation by focusing on the importance of physicians checking patients' quality-of-life as part of their screening and regular visits, hard as it might be to find the time to ask.

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Next week, >10,000 Fatty Liver stakeholders are expected to journey to London (rail strike and all) for the International Liver Congress (#ILC2022), the first meeting at this level since the pandemic started to include an in-person attendance option. This week, NASH Tsunami identifies some of the most important and intriguing non-embargoed presentations at #ILC2022. This conversation explores two of these: OS097, Machine learning algorithms identify novel biomarker combinations for NAFLD, from Jenny Lee (Netherlands); and FRI094, Clinical and economic evaluation of community-based preventative screening strategies for NAFLD in people with Type-2 diabetes melllitus, from Roberta Forlano (UK).

Jörn Schattenberg selected OS097 as the first paper for the Surfers to discuss due to its robust dataset (720 liver-biopsied patients recruited prospectively at centers across Europe; 53% with NASH, 26% with advanced fibrosis and 7% with cirrhosis.) and intriguing task (identify the most robust biomarkers for predicting levels of steatosis, ballooning, inflammation and fibrosis independently). The AUCs for fibrosis were robust (0.90 in the test group and 0.84 in the validation set), while the AUCs for the steatosis measures were weaker (0.79 and 0.74, respectively.) Jörn notes that the histological markers vary between the four targets, with steatosis and ballooning predicted most strongly by BMI, inflammation by hemoglobin and fibrosis by VCTE. After questions, Jörn goes on to note that the CK-18 M 30 emerges as a predictor for both steatosis and fibrosis.

The key question comes from Stephen, who asks how diabetes came into this equation in terms of metric, severity and length of disease. Jörn states that the only diabetes metric in the set was A1c, which was the 5th strongest for fibrosis. He also notes that length of disease is exceptionally challenging to determine in a study that relies on patient self-reports.
Louise Campbell responds next, selecting FRI094, a clinical and economic assessment of community-based screening of Type 2 diabetes mellitus patients for Fatty Liver disease. This study began at Imperial while Louise still worked there. The study reported 17% of NAFLD patients with "significant" fibrosis (kPa>8.1 by VCTE), 11% had advanced fibrosis and 3% had cirrhosis (defined as kPa >12,1 by VCTE.) Any of these patients might have been defined by clinical, radiological or histological means.

After questions, Louise would go on to note that all approaches were determine to be cost effective against a metric of 20,000 English pounds.

Again, the pivotal question came from Stephen, who suggested that a kPa of 12.1 (the definition of cirrhosis here) would fit half of his practice. He used this point to remind listeners of the poor positive predictive value of VCTE as a single measure.

When Stephen and Louise finish this point, Louise notes the positive recommendation on cost-effectivesness of community screening while acknowledging the issue around scoring of cirrhosis. Jörn then closes the discussion of this paper (and the conversation) by agreeing with Stephen's comment on the VCTE kPa and cirrhosis, but noting that the high levels indicate a serious challenge (even if not a level of cirrhosis).