This episode addresses the other talks in Session 5 focusing on clinical trial innovation, after Frank Anania's opener.Roy Sabo presented a cogent, comprehensible discussion of the value of adaptive trial strategies. Roger relates the presentation to a conversation on the NASH Tsunami last month with Stephen Harrison. Stephen introduced an example of adjusting FibroScan thresholds to boost the number of patients who could enter clinical trials. Roger commends Sabo on the “wizardry Bayesian statistics.”The following two talks discussed organizing patient databases in ways that simplified trial recruitment and had the potential to reduce screen fail rates. Lastly, the group explores the pros and cons of educating patients on improving self-care. The benefit is that it creates a larger, ready-made patient pool and improves overall health. The drawback is that it increases placebo rates in clinical trials, thereby requiring drugs to perform better to demonstrate statistical difference. However, in a world of well-informed patients practicing aggressive health self-management, there should be the expectation that drugs offer better performance.The conversation finishes with covering the rest of the day one program.
This week, Surfing the NASH Tsunami discusses a preview of the 8th Paris NASH Meeting taking place on September 8th & 9th, 2022. Paris NASH is a meeting for basic science and interdisciplinary thinking. Key opinion leaders from both sides of the Atlantic come together to present pivotal learnings and host exciting discussions on fatty liver diseases.In this conversation from September, 2021, Jörn Schattenberg, Stephen Harrison and Roger Green review some highlights from last year's Paris NASH conference. This conversation is the summary of conference high points and lessons. From the second day, Jörn chose to mention several talks he felt made particularly important points. This includes a session, “NASH Around the World,” that demonstrates the scale of the global challenge by looking at major countries around the world. Finally, Stephen and Roger join Jörn in selecting one key takeaway from the meeting and their conversation together.
This conversation from The Vault - Season 3, Episode 25.3 is part of a broader overview of NASH drug development in 2022, led by Stephen Harrison and Jörn Schattenberg. It starts with Louise Campbell asking whether design and management of the ongoing trials will provide sufficient granularity on matching patient types to medications or drug classes. Stephen Harrison notes that we have not paid sufficient attention to this issue historically. In fact, he notes a range of key variables we do not explore at baseline: genotype disease markers like PNPLA3, microbiome and non-Caucasian population segments, to name three. He also notes that some promising drugs have been killed because of trial design issues. In the end, he returns to core positive concepts: combination therapies, looking for agents with multiple positive metabolic effects and safety.At this point in the conversation, Stephen's transmission starts to fail. Eventually, he leaves the conversation and focus shifts to cirrhosis.This episode from the Vault is sponsored by Madrigal Pharmaceuticals.
This is the 2nd part of my interview with Lt Col. Stephen Harrison, MBE who served for two years as a full-time Touring Officer with BRIXMIS. The tours were hazardous three-man, vehicle-borne patrols collecting intelligence on the Warsaw Pact forces in East Germany for up to five days and nights over a series of four-month patrolling periods. In this episode, we hear of Stephen's imprisonment in a Soviet Army gaol, following detention in a Soviet Army garrison town as well as East German and Soviet Army press coverage about his activities. Stephen's speciality was using his language skills to engage and befriend opposition troops and thereby gaining valuable intelligence. He used to go into bars frequented by Soviet officers and recalls one particular drunken night in Potsdam.. We also hear about his visit to the infamous World War 2 prison camp of Colditz castle where he befriends the staff enabling other BRIXMIS tours to visit regularly.Stephen also shares details of the top-secret Operation Tomahawk, a particularly unpleasant mission which may not be for those of a sensitive disposition.In later years Stephen obtained his Stasi file which reveals that the surveillance on him was far closer than he'd ever believed.Don't miss part 1 of this fascinating interview here.Cold War history is disappearing; however, a simple monthly donation will keep this podcast on the air. You'll become part of our community and get a sought after CWC coaster as a thank you and you'll bask in the warm glow of knowing you are helping to preserve Cold War history. Just go to https://coldwarconversations.com/donate/If a financial contribution is not your cup of tea, then you can still help us by leaving written reviews wherever you listen to us as well as sharing us on social media. It really helps us get new guests on the show.I am delighted to welcome Stephen to our Cold War conversation…Episode notes here https://coldwarconversations.com/episode251/Follow us on Twitter here https://twitter.com/ColdWarPodFacebook here https://www.facebook.com/groups/coldwarpod/Instagram here https://www.instagram.com/coldwarconversations/There is nothing like hearing history from those that were there...The Jordan Harbinger ShowApple Best of 2018-Learn the stories, secrets & skills of the world's most fascinating pplListen on: Apple Podcasts SpotifySupport the show
Louise Campbell convenes liver nursing and nurse educator experts Kathryn Jack, Michele Clayton, Pam O'Donoghue and Patrizia Kunzler to consider where liver nurses and advanced nursing practitioners should fit into treatment and communication paradigms and what support they will need. Stephen Harrison joined to offer a different viewpoint.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.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.
Lt Col. Stephen Harrison, MBE served for two years as a full-time Touring Officer with BRIXMIS. These Tours were hazardous three man, vehicle-borne patrols collecting intelligence on the Warsaw Pact forces in East Germany for up to five days and nights over a series of four-month patrolling periods. They lived in the field and did not carry weapons while Soviet and East German troops were nearly always armed, and their ever-present sentries carried live ammunition. The Tours operated in the closest proximity to these hostile and aggressive Warsaw Pact troops whose orders permitted them to use whatever force necessary, including opening fire, to protect the property they are guarding.We hear in detail about Stephen's experiences in these demanding and frequently dangerous situations, as well as how he used his language skills to engage and befriend opposition troops gaining valuable intelligence which made him a particular threat to the Soviets.Don't miss part2 of this fascinating interview next week.Cold War history is disappearing; however, a simple monthly donation will keep this podcast on the air. You'll become part of our community and get a sought-after CWC coaster as a thank you and you'll bask in the warm glow of knowing you are helping to preserve Cold War history. Just go to https://coldwarconversations.com/donate/If a financial contribution is not your cup of tea, then you can still help us by leaving written reviews wherever you listen to us as well as sharing us on social media. It really helps us get new guests on the show.I am delighted to welcome Stephen to our Cold War conversation…Episode notes here https://coldwarconversations.com/episode250/Follow us on Twitter here https://twitter.com/ColdWarPodFacebook here https://www.facebook.com/groups/coldwarpod/Instagram here https://www.instagram.com/coldwarconversations/Support the show
THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. The group speculates what can still be accomplished. This conversation begins with Roger suggesting that tertiary care research universities that have their own primary practice be utilized as an accessible point of referral. The group agrees that while a good idea, this may not translate to the European system.Roger poses the closing question: what is there to look forward to in the space of NASH clinical trials and improving screen fail rates in the next 6 months to a year? Louise is looking for the approval of FibroScan for primary care in the UK. Jörn is hoping for an opportunity to offer health care services through referral systems. Stephen talks about getting a drug approved. In response to the latter, Roger finishes with a Stephen quote: is the juice worth the squeeze? This "juice" takes forms of cash and optimism, and it will be worth the squeeze if a drug sees successful development.
Jörn speaks about co-authoring an article, “The Nonalcoholic Steatohepatitis (NASH) drug development graveyard: established hurdles and planning for future successes.” In doing so, he discusses areas for improvement he feels clinical trial strategy and design will require. Joining the conversation is Stephen Harrison and Global Liver Institute Founder and CEO, Donna Cryer. Both Stephen and Donna approach the conversation from the patient and patient advocate perspectives. This episode From the Vault provides an amazing and complementary comparison to how far this topic has come in just two years. Notably, much has developed in the space of NITs since this paper in 2020. In this week's Surf, Season 3 - Episode 41, Roger, Louise, Stephan and Jörn reflect on what has improved in the intervening time period, what has not, and where this space is headed.
THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. The group suggest that researchers are making progress in reducing screen fail rates, but not in the critical issues of accessibility and equity.In this excerpt, Jörn asks whether these new, more focused approaches might lead to investigators overfitting patients. The positive of this outcome, he notes, is that sweet spot patients will be in a position to respond to drug. Louise takes on an additional issue: what is the affect of patient lifestyle mitigation on these trials. Her concern: patients who work hard enough to improve their liver condition after learning they have the disease may be so successful that they no longer qualify by the time they would be called for biopsy. The conversation strays into discussing the high value of bring artificial intelligence assists into histopathological interpretation before Stephen returns to the question of recruiting more patients. He notes that the goal is not merely to pull more patients into the first stages o recruitment ("the top of the funnel") but to improve our distribution of different kinds of minorities and subpopulations with high rates of NASH. He points out the fallacy of treating only mainstream Caucasian Americans and assuming results of these trials will hold true for everyone given what we now know about the important of genotyping and mutations tied to race or ethnicity. As this conversation ends, Stephen outlines potential solutions based on shifting recruitment out of brick-and-mortar trial sites and to recruiting and testing at primary care offices or even patients' homes.
THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. After Roger Green sets the stage for this conversation, Jörn reflects back on the 2020 paper he co-authored with Joost Drenth and considers important changes in patient screening since then. In his own words, “The way we use biomarkers and AI to augment outcomes has changed the field dramatically.” Whereas biopsy used to be the core method used to recruit patients, Jörn notes that many practitioners now rely on NITs to assess the patient's likelihood of screening into a trial before conducting a biopsy. The result is a significant reduction in non-essential biopsies. Stephen follows Jörn by discussing ways his own practice has benefitted greatly from the developing a prescreen strategy that relies heavily on NITs. Instead of doing "five biopsies a day, maybe 25 or 30 a week," he now starts with FAST scores and cT1 and, if these seem promising, moves to multiparametric MRI before deciding who to biopsy. Specifically, his practice is now able to utilize VCTE (FibroScan) and other NITs to mine data in real time and refer patients to the proper clinical trial as a result. As the episode winds down, Stephen alludes to the idea of "mid-trial corrections" in pre-biopsy NIT screening criteria and advances in how biopsies are read in trials today as other areas where procedure has improved markedly.
THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. The group suggest that while non-invasive techniques (NITs) have made a significant contribution to patient enrolment, there remains reliant on additional screening methods.This conversation opens with Jörn's observation that NITs are not always part of the protocol when assessing patients for their inclusion or exclusion in clinical trials. However, he states, experienced researchers will rely on these tools along with presence or absence of other metabolic diseases to decide which patients should not progress to biopsy due to high likelihood of screening out of the study anyway. Stephen concurs, adding that by considering these other risk factors, the clinical trials benefit from a more enriched patient population. and fewer unnecessary biopsies. From here, Stephen goes on to discuss two other pivotal issues: advance in strategies for reading biopsies and the impact of high screen fail rates on staff morale. On the first point, he states that good drugs have been lost in development because the strategy for reading biopsies, which relied on a single pathologist to read, created interpretative barriers that led to trials failing or being discontinued. This has led to a place today where all trial design incorporate consensus histopathology reads. On the second, he contrast staff performance for two studies on the same drug: an obesity study with a 25% screen fail rate and a NASH study with an 80% rate. He describes the palpable difference how staff feels about working on each of these projects. As the conversation ends, Louise comments on changing FibroScan thresholds for admission to some trials and Stephen describes how inclusion thresholds might vary from trial to trial and ways he uses other NITs to complete his assessments.
THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. Large metropolises are identified as missed opportunities. Stephen starts this conversation by shifting focus from issues surrounding trial criteria to the challenge of finding the right patients for these trials. He notes that of the millions of patients with NASH in the U.S. today, only a small fraction might ever realistically find their way to a NASH trial. The biggest factor is that they can only find their way to a trial if they live with clear access to a trial center. This is not simply a question of rural and exurban residents having too far to travel. He cites Chicago as a city that contributes minimal patient enrollment, despite being a large cites whose population suffers from high levels of metabolic disease. Jörn adds that while we might believe that European countries with more socialized, government-centered systems would not exhibit this maldistribution in where trial patients live, that belief would be wrong. Roger suggests that the U.S. system, with its highest levels of investment in medical technologies and broader distribution of care sites, might actually be better equipped to attack this issue. At that point, Roger returns to an earlier comment to ask Stephen addresses how mid-trial reassessment of screening criteria works and why it improves screen fail rates. Stephen's answer takes up the rest of this conversation.
THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. The group suggest that researchers are making progress in reducing screen fail rates, but not in the critical issues of accessibility and equity. As the conversation begins, Jörn harkens back to the 2020 paper and reflects on improvements in cost-effectiveness and duration of the trial process since. “The way we use biomarkers and AI to augment outcomes has changed the field dramatically.” Yet clinical trials are still reliant on the same endpoint. A surrogate is required for conditional drug approval. Roger asks for the most important improvements that have resulted from conversations around patient selection for a trial. Jörn recalls the past reliance on biopsies and compares today's focus on non-invasive techniques (NITs). Stephen joins to highlight improvements in the way practices utilize VCTE (FibroScan) and other NITs to mine data in real time and refer patients to the proper clinical trial. One idea Stephen mentions: evaluating NIT values during the recruiting process to reset cutoff levels. He also discusses expanding screening criteria to include non-hepatic metabolic risk factors such as obesity and diabetes. Both approaches to patient refinement are contributing to more successful studies and limiting unnecessary biopsies. With fewer screen failures, sites remain engaged. Louise Campbell agrees that mitigating screen fail rate is key to fighting study fatigue. The conversation shifts to finding patients for these trials. Stephen notes that major metropolises still do not have access to NASH clinical trials. "We're putting almost zero NASH patients in clinical trials out of a city as large as Chicago that has high rates of obesity, diabetes and metabolic syndrome.” NITs like the FibroScan are unavailable in large swaths of the country. Even where they are available, a lack of education around NASH diagnostics tests remains a barrier. Jörn adds that multiple hurdles prevent patients from accessing NASH trials in socialized healthcare systems. Roger believes the US system may have a better shot than Europe at broadening recruitment processes because the technology developed under larger U.S. budgets means that some pivotal technologies are more widely available.Next, Roger comments that for as long as screen fail rate has been discussed on this podcast, we had never discussed the idea of mid-trial adjustments. Stephen gives an example of adjusting FibroScan thresholds mid-trial to boost the number of eligible patients. Jörn shares his belief that the use of NITs outside the formal qualification criteria has helped reduce screen fail rates.Stephen shifts focus to a bigger issue: equity in the representation of underserved patients in these trials. There is an issue of decentralized trials, whereby at-risk groups are under-referred due to several factors. Stephen outlines potential solutions. Roger suggests tertiary care research universities that have their own primary practice as suitable to become an accessible point of referral. He notes this may not translate to the European system and Louise agrees. What is there to look forward to in this space in 6 months to a year? Louise is looking for the approval of FibroScan for primary care in the UK. Jörn is hoping for an opportunity to offer health care services through referral systems. Stephen says we'll hopefully be a step closer to getting a drug approved. Roger finishes with a Stephen quote: is the juice worth the squeeze? This "juice" takes forms of cash and optimism, and it will be worth the squeeze if a drug sees successful development.
Episode 40 focuses on lean NASH, and Michelle Long notes that many patients with lean NASH are diagnosed in the Emergency Department when they present with symptoms of decompensating cirrhosis. This conversation from November 2021 considers cirrhotic patients from a different perspective: their uniquely valuable role in clinical trial strategy as the world evolves beyond biopsy as gold standard.Mazen Noureddin notes during this week's episode that when he identifies lean NASH patients, he encourages them strongly to participate in clinical trials. This conversation also looks at the value of cirrhosis studies in clinical trial design, although from a quite different perspective.From the initial description of this conversation: In this conversation, Stephen Harrison starts by pointing out that non-cirrhotic NASH trials and NASH cirrhosis trials differ significantly in goals, endpoints and patient severity. From there, he dives into the NASH cirrhosis trial group with his review of REVERSE, which Vlad Ratziu presented at AASLD. Jörn Schattenberg and Mazen Noureddin also comment on design of this trial. The conversation focuses on two issues: who is the optimal patient for a NASH cirrhosis trial and what is the most appropriate attainable endpoint and, therefore, clinical design? On the optimal patient issue, the group agrees the ideal patient is a well-compensated cirrhotic, because the presence of portal hypertension makes the entire healing issue so much more complex. There was less agreement on the optimal design question.
One serious challenge in the overall management of Fatty Liver disease involves creating cost-effective methods for "early" diagnosis. The term "early" is relative because, as Ian Rowe puts it, a "substantial proportion" of people admitted to hospital with various symptoms of decompensating cirrhosis or hepatic encephalopathy never received a diagnosis of advanced liver disease before they presented. Simply diagnosing these patients during advanced fibrosis (F2 or F3) can save lives, improve longevity and quality of life for these patients and save money for healthcare systems, all at the same time. Ian spends the first ten minutes of this episode describing a model he and Richard Parker developed to evaluate five diagnostic strategies:Targeted -- simple non-invasive liver screening Targeted + risk stratification -- targeted assessment plus FIB-4 or VCTE (FibroScan) for patients believed to be at high riskiLFT -- automated assessment of abnormal LFTs analyzed with other systemic measures in a medical record system "Comprehensive" -- a "kitchen sink" approach that runs iLFT analysis and conducts FIB-4 +/- VCTE on every patient"Fibrosis first" -- an approach that deploys viroserological and iron testing plus FIB-4 +/- VCTE for every patient "Fibrosis first" scored best in cost effectiveness (cost per correct diagnosis of treatable liver disease) and "decision curve analysis", which looks at true positive outcomes and false positive outcomes, correctly identifying 85% of treatable liver disease patients (vs. 90% for the comprehensive approach and less than 15% for the current targeted approach.) Fibrosis first has the added benefit of not progressing treatment for people who may have steatosis without fibrosis. The rest of the conversation entails Ian, Louise Campbell and Roger Green sharing questions and observations. Highlights:Louise agrees that the current targeted pathway approaches do not work and identifies lack of access to advanced testing in primary care as a central issue. She asks how many additional patients with Type 2 Diabetes, other metabolic diseases or CVD could be identified through this approach. Ian cannot answer because the question is outside the scope of the research. He points out that to assess different approaches accurately, researchers and policymakers need to settle on whether the goal is to identify steatohepatitis or something broader. Louise asks about the frequency and nature of referrals. Ian notes that one issue with iLFT is a high level of referrals for conditions that might not require treatment, the most common of which is "abnormal LFT without fibrosis."Roger notes that iLFT might help patients who complain they never heard about their NASH earlier. He also recalls Quentin Anstee and Stephen Harrison discussing recently that FIB-4 can serve as a prognostic measure not only for liver-related deaths, but also CV deaths and all-cause mortality. Louise suggests that patients will do better if they adopt a behavior belief model instead of a sick patient approach and that the earlier in disease we intervene, the more success we will have. Roger and Ian note that Louise's focus is broader in scope than his model. Ian further notes that we do not know when non-fibrotic patients should be tested again, although he has some thoughts about this. Louise notes that one element that might make iLFT costly is that only 45% of patients picked up on iLFT are referred into the model. Ian notes that this insight might require changes in the model.As the conversation winds down, it shifts toward policy issues: should we focus testing on the workforce (Louise) and it the best point of intervention to limit advertising of unhealthy foods (Ian).
Our week of "Greatest Hits" episodes from the vault continues with this conversation from the episode discussing systematic failures of NAS scoring due to inconsistencies in how different pathologists interpret slides. This conversation explores the reasons for different histopathologists differing consistently in how they interpret liver slides.One of the primary drivers of reassessing the role of semi-quantitative histopathology in assessing developmental drugs was the paper "Complexity of ballooned hepatocyte feature recognition: Defining a training atlas for artificial intelligence-based imaging in NAFLD," e-published in January 2022 in the Journal of Hepatology. This paper demonstrated strong systematic flaws in the reading of ballooned hepatocytes, which is one of the pivotal factors in assessing drug efficacy. This paper showed that low levels of inter-reader consistency led to an array of interpretive challenges. In this episode, last co-author Quentin Anstee led the Surfers, including co-author Stephen Harrison, through a review of the paper and a discussion of how to resolve this issue. This conversation starts with Stephen Harrison noting that the single largest problem facing drugs in development is the inconsistency in efficacy reads (and particularly placebo response rates) at the back end of clinical trials. From here, the group explores how histopathology training leads to variability in the interpretation of slides and inconsistent assessments of drug efficacy.
Our week of "Greatest Hits" episodes from the vault continues with our most popular conversation ever, as Stephen Harrison and Jörn Schattenberg synopsize the Basic Science segment of the recent Paris NASH meeting. This segment, which focuses largely on a state-of-the-art look at fibrosis, is by far our most downloaded conversation every, with more volume than the next four posts combined!As I wrote at the time: Paris NASH is a meeting for basic science and interdisciplinary thinking. Since Stephen Harrison was drafted into co-chairing the session titled "Deep Dive into Fibrosis," he led this conversation. The session included three presentations with a powerful collective message about stellate cells: that different stellate cell subtypes perform in unique ways in terms of how they function, the process(es) through which they become modified and what this represents in terms of performance. This description does not do Stephen and Jörn's comments justice. It's a short session, so listen for yourself...
Our week of "Greatest Hits" episodes from the vault continues with this conversation from the episode announcing the launch of the NAIL-NIT consortium. Stephen Harrison and Mazen Noureddin discuss the thinking behind their new consortium and its targets. In this conversation, they discuss challenges with the NAS score.The early part of 2022 had several episodes discussing the increasing need to move beyond biopsy (yes, semi-quantitative, but even AI-assisted at some levels) to a future shaped by NITs. One pivotal issue that emerged regarded ballooned hepatocyte evaluation and its impact on NAS scores. As I wrote: The first section focuses mostly on what we can and cannot learn from a NAS score, and implications of its shortcomings on the drug development process. After this, Stephen Harrison notes the complex role the liver plays in energy transfer throughout the entire metabolic process. This suggests that the effects of Fatty Liver disease vary among individual patients and, as a result, drug development and patient diagnosis and treatment should provide sufficient insight to optimize each patient's therapy. As the conversation closes, Mazen Noureddin is responding to a question from Louise Campbell about what we will learn about optimal testing strategy. Mazen suggests there is unlikely to be a single "winning" test but, instead, a combination of NITs probably will be necessary to answer all the questions necessary to optimize therapy.
Our week of "Greatest Hits" episodes from the vault continues with our second most popular conversation ever, which came from the wrap-up episode for AASLD2021. In this episode, Manal Abdelmalek, Jörn Schattenberg and Ian Rowe joined Stephen Harrison, Louise Campbell and Roger Green to recap NAFLD and NASH-related insights from AASLD2021 TLMdX and specifically to focus on how NITs will help, in the words of Stephen Harrison, "put a big, fat dent in Fatty Liver disease."As I wrote at the time: The conversation starts with the group congratulating Manal Abdelmalek on her wrap-up NAFLD talk at the 2021 TLMdX. From there, the group focuses on the shortcomings of using biopsy as the clinical trial gold standard and how strategic clinical trial design and interpretation of existing NIT data can build a bridge from biopsy through MRE/biopsy correlations to a total NIT future.
On July 7, Intercept Pharmaceuticals released new results from the continuation of the REGENERATE trial and announced their intent to file a new NDA for obeticholic acid (OCA) in NASH fibrosis. In this conversation, Stephen Harrison leads Jörn Schattenberg, Louise Campbell and Roger Green in considering whether the evidence in the new release will be sufficient to get the drug approved.Stephen starts by noting that we have not heard anything about the results of the REVERSE trial, which evaluated obeticholic acid (OCA) in patients with compensated cirrhosis. As he notes, even if OCA is not approved for cirrhosis, many hepatologists will consider giving this drug to cirrhotic patients, particularly compensated cirrhotics who face a significant worsening of their condition in a fairly short period of time. Jörn comments on this briefly to agree that the cirrhosis data will create a complete data set, then returns to the pruritus issue. Mostly, his point about cirrhosis is that given the high placebo rate suggests there is "something about how the question is asked." He finishes this comment by discussing the importance of getting a first drug approved and stating his anticipation of what happens when FDA reviews these data. Roger goes on to note that he has a unique experience in this group: he has discontinued a drug therapy based on pruritus (in his case, a cancer drug). Having lived through that experience, he expresses skepticism that pruritus that resolves on discontinuation will be a reason for the drug to be rejected. Stephen concurs, and Roger goes on to state that the perceived cardiovascular risk in 2020 made sense as a reason not to approve, but not pruritus. Stephen and Louise concur that we will not know the entire story until we know the lengths to which providers went to keep patients in this study, but both are hopeful (and pretty much expect) that while there may be boundaries on patient types and guidance on treatment, the case for approval appears likely to succeed. During the second half of this conversation, panelists share their common hope that this data will be sufficient to get OCA approved and discuss what this could mean for the entire Fatty Liver stakeholder community.
On July 7, Intercept Pharmaceuticals released new results from the continuation of the REGENERATE trial and announced their intent to file a new NDA for obeticholic acid (OCA) in NASH fibrosis. In this conversation, Stephen Harrison leads Jörn Schattenberg, Louise Campbell and Roger Green in considering less obvious questions surrounding efficacy and safety.Stephen starts this conversation by asking the group how important it is for a drug (in this case, obeticholic acid) to show a combined endpoint of fibrosis improvement and NASH resolution. He notes this is a tougher standard to hit but notes that it might be quite important.Jörn describes this comment as a "good point" that probably was not addressed due to the low level of NASH resolution when viewed as a primary endpoint. Louise says she would need to know more about the diets patients were on while in the trial given the effect diet can have on liver fat. She then goes on to say that one question she would like to have answered is how many patients needed counseling on their pruritus to stay in the study and what exact steps did researchers take to keep these patients in. She points out that knowing the steps necessary to maintain patient adherence is vitally important to caregivers but rarely reported for trials, if ever.Roger makes two points. His first basically supports Jörn's comment that the low level of NASH resolution as a primary endpoint virtually guarantees that the number of patients achieving the dual endpoint will be minimal at best. His second harkens back to Stephen's earlier point about including a larger post-18 month patient pool in the efficacy analysis. To Roger, it appears that Intercept made the sound commercial decision to reveal only the data necessary to generate the analyses necessary for approval. It felt to him as if Intercept assessed the least risky way to refute each point in the CRL, and then did only the analyses necessary to refute points successfully. In essence, Roger describes the analysis as a way to de-risk the drug and believes they appear to have done so effectively. At this point, Stephen shifts direction. He gives Intercept "accolades...they didn't give up. They persevered. They continued to drive forward and they added three different adjudication committees." And while he believes there is more analysis to be done, he describes the contents of the press release as "a very, very positive implication for the field" and "give[s] it two thumbs up." After Roger concurs, Stephen goes back to Louise's questions about pruritus and notes that the methodology for evaluating pruritus might have produced overstated results. In essence, the investigator asked patients whether they were experiencing pruritus at every visit, an approach Stephen and Jörn believe was likely to produce an overstatement on itching. Stephen continues this line of thinking to note that investigators were forced to discontinue therapy under certain pruritus reports. As the conversation ends, he notes that he is far more interested in hepatic effects.
On July 7, Intercept Pharmaceuticals released new results from the continuation of the REGENERATE trial and announced their intent to file a new NDA for obeticholic acid (OCA) in NASH fibrosis. In this conversation, Stephen Harrison leads Jörn Schattenberg, Louise Campbell and Roger Green in examining the new efficacy analysis and exploring what it means for obeticholic acid, both in terms of the drug's performance and its revised prospects for FDA approval.After Stephen lists the four major bullet points from Intercept's press release, this conversation focuses on the first point: "The 25mg dose of obeticholic acid met the agreed primary endpoint of improvement in liver fibrosis without worsening of NASH at 18 months." The data behind this bullet point stem from a new interim analysis of the original 931 cases. In the re-analysis, the treatment effect remained constant but the placebo effect dropped slightly. The different results from a different method of analyzing histopathology, one that relied on consensus panel reads instead of an individual histopathologist's interpretation (as was done in the original analysis). Stephen goes on to note that there is a similar small change in the NASH resolution percentages, but, like the original analysis, these do not reach statistical significance. He notes that this submission relied on hitting one of the primary endpoints, not both of them. He then asks the group two questions: "Does this change our perception of OCA in NASH?" and "Does this change our perception of this drug as a driver of the field in drug development for NASH?"Roger answers first. Taking a narrow focus on the question, he answers that we still see OCA as an effective anti-fibrotic at the same level we did three years ago. If there is a change, it is that if obeticholic acid had a three-year lead on the market, it would have focused a significant amount of research on FXR agonists -- both in terms of developing more FXRs and in considering them the backbone in NASH pharmacotherapy. In 2022, with another very different agent appearing to be fairly close to market, he felt these results would not dramatically change the other directions in which research is heading.Jörn Schattenberg goes back to the original 2019 paper, which he describes as "groundbreaking" and, quoting Zobair Younossi, "a watershed moment." He notes that the reading method seems more consistent with what FDA wants and says that while others may comment on the small effect size (11%), his view is that this is a positive achievement as the first paper to demonstrate significant effect against fibrosis.Louise Campbell echoes her colleagues' comments about the successful efficacy results but notes that patients who could have benefitted from OCA's approval two years ago have gone two more years without the benefit of medication.Stephen concludes the conversation by agreeing with Jörn that this is a watershed moment. He notes how many observers have said that proving efficacy was essentially impossible due to the complexity of the disease and regulators "moving the goalposts." This study, he says, proves that it can be done.
On July 7, Intercept Pharmaceuticals released new results from the continuation of the REGENERATE trial and announced their intent to file a new NDA for obeticholic acid (OCA) in NASH fibrosis. In this conversation, Stephen Harrison leads Jörn Schattenberg, Louise Campbell and Roger Green in examining the new efficacy analysis and exploring what it means for obeticholic acid, both in terms of the drug's performance and its revised prospects for FDA approval.After reviewing the four key points from Intercept's press release, Stephen Harrison kicks off this conversation by looking at a broader efficacy picture than mere regression of fibrosis, to ask what percentage of patients experienced no further progression of fibrosis compared to the placebo group. Stephen notes that the clinical value of simply halting fibrosis progression in an F3 patient is tremendously important because it allows an asymptomatic patient to continue life at its current level of quality. He adds, "we can manage co-morbidities" separately. He goes on to wonder why Intercept did not expand the analysis to include the large number of patients who made it past the 18-month biopsy time point but were not part of the original 2019 efficacy cohort.At this point, Stephen takes a step back from the actual data to describe how the consensus approach worked on histological reads and to praise the approach for providing clear, simple answers. Jörn Schattenberg picks up the conversation by agreeing with Stephen's assessment of the consensus approach, which he describes as emulating how colleagues assess challenging cases or histopathology reports in actual practice. Roger joins the conversation to wonder why the consensus reading process would have the effect of reducing the percentage of patients who improve in the placebo group on one reading but not elsewhere. More important to him, he goes on to agree with the idea that if this agent regresses fibrosis in some cases but halts progression in most or all, it might become a valuable part of a combination therapy that includes other agents with a stronger effect against steatosis than fibrosis. Thinking from a patient perspective, Louise notes that consensus reads should give the patient greater confidence in the results. In terms of confidence and border reads, Stephen points out that some of the presentations at the recent ILC2022 meeting that drugs that have an impact on NASH might also affect liver volume. (He notes that the open-label cirrhotic cohort of the resmetirom trial MAESTRO-NAFLD 1 also showed spleen volume reduction and an inverse effect on platelet count.) Setting aside the cirrhosis results, he notes that if we start to measure liver volume when conducting biopsies, we can correct estimates of the impact of fibrosis to account for changes in "what we see" based on changes in liver volume. As the conversation ends, he notes that this might be a fruitful topic for future research that can translate into patient treatment.
On July 7, Intercept Pharmaceuticals released new results from the continuation of the REGENERATE trial and announced their intent to file a new NDA for obeticholic acid (OCA) in NASH fibrosis. In this conversation, Stephen Harrison leads Jörn Schattenberg, Louise Campbell and Roger Green in examining how the larger sample and longer time patients were on therapy changed the safety and tolerability profile from the initial analysis.After reviewing the four key points from Intercept's press release, Stephen Harrison kicks off this conversation by discussing the safety evaluation, which included a far larger population with significantly longer exposure to study drug. After describing the enriched population, he quotes from the press release, "Emergent adverse events treatment, emergent serious adverse events, and deaths were generally balanced across the OTC and placebo treatment groups." He goes on to cite the considerable differences in pruritus across groups (22% in placebo, 33% in 10mg and 55% in 25mg), share the comment that most discontinuation stemmed from pruritus, note that gall bladder-related events occurred in less than 3% of patients and, finally, that OCA 25mg had a higher rate of biliary events. He then asked the rest of the group for comments.Jörn commented first, noting that this was mostly "recapitulated" data, but with a much broader set of subjects. Because risk:benefit ratio was perceived as the pivotal issue around the time of the original Complete Response Letter (CRL), he describes the data as improved "by a lot."Louise describes as "reassuring" the idea that the NASH dose could be so much higher than the approved PBC dose (25mg vs. 5 or 10mg) but not demonstrate additional safety concerns. She goes on to declare that practices planning to use OCA should be "planning pathways into delivery" in anticipation that the high level of pruritus will lead to a significant set of discontinuation with a careful approach to patient orientation and management. Roger shared his recollection that increases in LDL levels and the implicit associated cardiovascular risk were major issues in the negative risk:benefit assessment, but that this analysis appears to report that levels returned to normal within the first year of treatment. This might increase chances for approval.At this point, Stephen reads the press release carefully to identify potential safety hazards that are not addressed directly in the document, although, as he notes, one can fit only so much into a press release. As the conversation ends, Stephen asks Jörn if he has "ongoing lingering questions". Jörn notes that he wondered how the reads were done and that he also looked for LDL data. He makes a few other points, but suspects that they may have been covered in the 2019 paper.
On July 7, Intercept Pharmaceuticals released new results from the continuation of the REGENERATE trial and announced their intent to file a new NDA for obeticholic acid (OCA) in NASH fibrosis. In this episode, Stephen Harrison leads the Surfers through a discussion of the new REGENERATE results and the Surfers discuss what they find compelling in the new data, discuss the possibility of approval, and ask (and answer) what an approval might mean for the Fatty Liver community.The basic structure of this episode is: Stephen Harrison walks the group through issues, opportunities and considerations raised in the July 7 press release and the rest of the panel responds with comments and questions as appropriate. He starts by noting that in a recent episode, the Surfers identified the release of updated REGENERATE data and subsequent OCA approval in NASH fibrosis as a potentially transformational event in the Fatty Liver community and proceeds to read the four bullet points that Intercept Pharmaceuticals highlighted:1. The 25mg dose of OCA met the agreed primary endpoint of improvement in liver fibrosis without worsening of NASH at 18 months. 2. The 25mg dose of OCA doubled the fibrosis response rate vs. placebo.3. This data set includes larger and more robust safety database of 2477 patients with nearly 1000 on study drug for four years. 4. Intercept will refile an NDA in liver fibrosis due to NASH, starting with a pre-submission meeting with the FDA later this month. From there, Stephen dives into the data, starting with the efficacy results. He notes that the results for reduction of fibrosis without worsening of NASH are comparable to the initial REGENERATE results statistically: highly significant improvement in the 25mg dose vs. placebo, but not in the 10 mg dose. He also notes a small but statistically insignificant numerical difference in NASH resolution without worsening of fibrosis. The 25mg score is roughly the same as in the earlier trial, but the placebo score dropped, possibly due to a change in the methodology for reading histology slides . In the previous analysis, two histopathologists each read half the slides independently. This time, two teams of three histopathologists read slides in a design that forced consensus on each slide included in the final data. In discussing efficacy data, Jörn describes this study as "groundbreaking" and Louise notes the impact of a two-years-later approval in terms of patients who did not receive drug benefit over that time. In agreeing with Jörn, Stephen notes that this study proves that we can get a fibrosis drug "over the finish line" by meeting FDA efficacy criteria.The group moves on to discuss safety criteria. Stephen notes that pruritus is still the most common side effect and reason for discontinuation, while Roger comments that LDL and cardiovascular issues, which were implicated as the major risk issue in the earlier data, appear to resolve over time and not present as much risk this time. Jörn and Louise both praise the increased robustness of safety data based on sample size and duration of therapy, after which Stephen notes the questions that the press release does not answer (but, presumably, the full data release will). The rest of the discussion focuses on some decisions Intercept made about how to present data and the overall implications of this trial. Stephen and Roger praise Intercept for their continued commitment to OCA in the face of FDA's 2019 Complete Response Letter and the group agrees that this data is more likely to gain approval. When Roger asks for a prediction of what the world might look like 1-2 years from now, the group considers that we might have two approved agents (with resmetirom) as early as the end of 2023.
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). The first three days of the program focused on a range of issues, with specific emphasis on non-invasive tests (NITs) and their role at different stages in diagnosis and treatment. This conversation touches on two issues: the use of AI to better understand the meaning of liver volume and elements of morphology and, relatedly, how much more sophisticated a view we take of NAFLD and NASH than we did even five years ago.The issues around AI and liver morphology arise from Jörn Schattenberg's comment that consistent with Stephen Harrison's "KISS" (Keep It Simple, Stupid!) principle, researchers are starting to explore the meaning of changes in liver volume. Ultimately, Jörn notes, pairing these kinds of measures with AI-supported histopathology can yield tremendous benefits. Roger comments on a breakfast he attended that morning that suggested that AI and NITs each provide different, important information on individual liver health: NITs can address collagen burden but not structure, while AI can identify changes in structure but not link them to the impact on the patient. Zobair ends this part of the conversation by noting that companies are starting to use AI in these ways.The second part of this conversation stems from Roger's observation that we know far more about the disease than we did 3-4 years ago. He goes on to describe how the environment is more collaborative and open-minded than it might have been if, in fact, we saw drug approvals at that time. Zobair takes this observation to a different plane, noting that 5-10 years ago, "some very important experts" believed that we all understood the etiology of Fatty Liver disease, so why spend more time? He goes on, "we could not have been more wrong," observing that what we have learned about progression and regression in placebo arms suggests a far more complex disease than something that progresses linearly, or even constantly in one direction. He goes on to add that the multiple drug trial failures is that targeting drugs to a single solution based on animal models is likely to fail because this is a multiple mode of action disease. His third point: the "source" of the disease is visceral obesity and insulin resistance, which all viable solutions must address. This identifies two targets for treatment, while simultaneously demonstrating that therapy will be chronic, lifelong and with behavioral elements. The rest of the conversation addresses the challenges with shaping this kind of lifelong, multitarget therapy in the US today.
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.
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.
Thursday, June 9, marked #NASHDay 2022, the 5th annual celebration of International NASH Day by the world's largest liver patient advocacy organization, the Global Liver Institute. To celebrate the occasion, Stephen Harrison joined Jörn Schattenberg, Louise Campbell and Roger Green to celebrate the event and comment on one crucial trend or event most signified what the last year has meant in the Fatty Liver community.This conversation includes three sections:• First, Roger discusses the Law of Unintended Consequences in the context of the FDA Complete Response Letter to Intercept Pharmaceuticals over obeticholic acid, an event that many feared would bring all momentum around Fatty Liver disease to a standstill but, two years later, has driven real bursts of creative energy and innovative problem solving centered around the disease rather than a drug.• Second, Stephen's and Jörn's impassioned statements that the providers will never give up on addressing the challenges of NASH, both because, as Stephen describes, it is not in their character and because, as Jörn describes, “this disease is not going away.” As long as people are dying too young from the effects of NASH and HCC, he contends, the fight will continue.• Finally, Roger asked the panelists for bold predictions about what will have changed before we come together a year from now to celebrate the 6th International NASH Day.
Thursday, June 9, marked #NASHDay 2022, the 5th annual celebration of International NASH Day by the world's largest liver patient advocacy organization, the Global Liver Institute. To celebrate the occasion, Stephen Harrison joined Jörn Schattenberg, Louise Campbell and Roger Green to celebrate the event and comment on one crucial trend or event most signified what the last year has meant in the Fatty Liver community.This conversation consists mostly of reactions from Jörn Schattenberg, Louise Campbell and Roger Green to Stephen's initial statement, followed by other thoughts from Stephen. The other Surfers are all impressed by the trial design. In response to a comment from Roger, Stephen comments enthusiastically on the unprecedented collaboration between sponsors, academics, regulators – the entire range of stakeholders – to resolve this issue. He goes on to note other questions – for example, the name of the disease – where the community is demonstrating unparalleled collaboration. All of this, he says, is leading to a proliferation of new research so vast that no one can keep up with all of it. There are three more points in this conversation:• Jörn raises Quentin Anstee's comments from Episode 26 that we need to develop a standard set of NITs to use in the evaluation process as another area where collaboration will be key• Stephen points out that we may see our first drug approval in 2023, which will add new levels of energy and resourcing to the development and education processes• Jörn begins to discuss his issue, which is the convergence between conferences to cover a range of issues that look past simple drug development to improve key questions from drug evaluation to clinical care pathways and inter-specialty collaboration to treat patients
Thursday, June 9, marked #NASHDay 2022, the 5th annual celebration of International NASH Day by the world's largest liver patient advocacy organization, the Global Liver Institute. To celebrate the occasion, Stephen Harrison joined Jörn Schattenberg, Louise Campbell and Roger Green to celebrate the event and comment on one crucial trend or event most signified what the last year has meant in the Fatty Liver community.This conversation is about collaboration. It starts with Jörn Schattenberg noting the increasing momentum for groups to work together and proceeds to explore two observations from Louise Campbell:• One about the rapidly expanding rate of change in the development of key products with particular emphasis on NITs• A second on the increasing momentum behind broad approaches to the NAFLD pandemic, including the expansion of patient advocacy organizations around the world to the increasing energy all the various stakeholders and medical specialties to collaborate in an integrated attack on NAFLD and NASH. She notes that this energy needs to translate to a global set of local conversations sensitive to how healthcare operates in countries and regions.From there, Jörn notes how Louise's prior work in Hepatitis C gives her an experience the NASH physicians will not have and Stephen lists big items with tremendous progress, momentum and potential to a crescendo.
Thursday, June 9, marked #NASHDay 2022, the 5th annual celebration of International NASH Day by the world's largest liver patient advocacy organization, the Global Liver Institute. To celebrate the occasion, Stephen Harrison joined Jörn Schattenberg, Louise Campbell and Roger Green to celebrate the event and comment on one crucial trend or event most signified what the last year has meant in the Fatty Liver community.Roger's first question was for each panelist to describe a major event that took place since the 4th International NASH Day last June. Stephen Harrison answers first by discussing major advances in clinical trial design. This conversation consists of his answer.Stephen Harrison describes two related areas where we have made what he describes as “real, granular progress in drug development” in terms of rethinking the design of Phase 3 clinical trials and endpoint assessment related to this redesign. Historically, sponsors conducted a single, very large, very long trial that sought first to achieve conditional approval based on sub-part H endpoints in fibrosis and then to achieve full approval based on outcomes developed as the initial trial group progresses to cirrhosis. The new idea is to conduct the fibrosis and cirrhosis elements in parallel, thus shortening the time to approval, simplifying endpoints and reducing the cost of the overall trial process. It is a vision of breathtaking scope…and, Stephen reports, it's almost ready to launch.
Thursday, June 9, marks #NASHDay 2022, the 5th annual celebration of International NASH Day by the world's largest liver patient advocacy organization, the Global Liver Institute. With over 200 affiliated organizations and sponsors, many holding their own events, International NASH Day is not only a major day for education and communication, but also in a sense NASH's "New Year's Day," a moment to take stock of the last year and make resolutions for the future.To celebrate the occasion, Stephen Harrison joined Jörn Schattenberg, Louise Campbell and Roger Green to celebrate the event and comment on one crucial trend or event most signified what the last year has meant in the Fatty Liver community.Stephen went first, focusing on a pivotal change in Phase 3 trial design. Unti now, corporate sponsors have conducted one large Phase 3 trial with F2 and F3 NASH patients. The initial phase of the trial would include 1,000 - 1,200 patients with the goal of achieving sub-part H approval based on conditional endpoints. This trial would keep enrolling patients until there were enough patients in the trial for 4-7 years to prove an outcome-based endpoint and achieve full approval. In the new design, two trials transpire in parallel: the original trial with F2 and F3 patients and a trial with well-compensated cirrhotic patients focused solely on achieving an outcome. This design should prove easier to recruit, less expensive, and more likely to achieve outcome-based endpoints more quickly. Also, it allows the sponsor to evaluate "co-endpoints," as Stephen puts it, instead of needing to achieve dual endpoints. This way, the sponsor can succeed by achieving fibrosis improvement with only a stable NAS score or a decline in NAS score with no worsening of cirrhosis. All three panelists expressed admiration and appreciation for the benefits of this approach. Stephen noted how many people needed to collaborate for this to come to fruition and how much more collaboration is taking place in the community.Jörn went next, focusing on the extraordinary breadth in focus and content of pivotal conferences during the year. He mentioned the fireside chat with regulators at NASH-TAG and the broad discussions in Barcelona exploring how best to serve patients after we have a drug. Louise focused on systems thinking, mostly related to diagnostics, focused on how best to use non-invasive methods to screen, diagnose and stage patients. What she found striking is that these discussions are taking place before drugs are approved, which suggests the possibility that shorter after we have drugs to prescribe, we will have systems and protocols to get the drugs to the patients that need them most. Louise contrasted thought development in NASH to Hep C, where the drugs came along before we knew how to find the patients. Rounding out the group, Roger talks about the Law of Unintended Consequences and the Intercept Complete Response Letter from FDA. He recalled the initial thoughts that the failure to approve obeticholic acid would signal a perilous downturn in interest in Fatty Liver disease. Instead, he suggested, the passion of the community coupled with lack of funds led stakeholders to ask better questions and focus on more practical issues, which has led to the convergence we are seeing today.As the conversation wound down, Stephen and Jörn noted that providers will not tolerate "No" for an answer, recalling patients who suffered from HCC and died too young. In the end, Roger asked the group to make a bold predictions about what will happen next year, when the group gets together on the eve of International NASH Day once again to survey the past year. The predictions were bold and optimistic. You will need to listen to or view the episode to learn what they were.
This conversation starts with Quentin Anstee complimenting Stephen Harrison for his observation that when we analyze NASH Biomarkers, we should consider the value of sustained response separate from early OR late response.From here, the group moves to the concept of "stacked" tests -- confirmatory results from different NITs as a way to assess efficacy in an individual clinical trial subject. The conversation takes some twists and turns, but the core concept is unique, challenging and a significant step forward in the broader discussion of how to analyze biomarkers.
Quentin Anstee joins Stephen Harrison, Jörn Schattenberg, Louise Campbell and Roger Green to share recently developed insights about NITs and what the clinical trial best practices around them should be. Quentin started by offer five key takeaways from his recent talks at The Liver Forum and ICFL in Vienna:(1) As we have discussed on this podcast and elsewhere, trial endpoints around balloon hepatocytes are, in Quentin's words, "not sufficiently robust." (2) Rapidly attaining response from a given test (ALT, for example) is not necessarily a guarantee of early efficacy. (3) "Simple indirect biomarker panels like FIB-4" need to be interpreted with caution. (4) Since we do not have a single perfect gold standard test (neither histological nor non-invasive), we should consider a standard for clinical trial assessment that is a composite of multiple different types of tests, perhaps one liquid, one physical (MRE?) and one histological. (5) We need to develop a battery of NITs that are both applied and reported in all cases, instead of running large numbers of NITs and only reporting the ones that support the targeted medication. This stimulating set of opening comments motivates the group to dive deeply into the entire issue of how we deploy and analyze NITs. One key question is longitudinal. Quentin points out that early response to a composite test (like FIB-4) might not suggest endpoint efficacy over time. Similar to this, it also suggests that a positive 26-week result in a composite or liquid test might not mean much if the drop comes in the first couple of weeks and then maintains the lower level the next few months. This leads Stephen to suggest that researchers evaluate change at three levels: early change, late change, sustained change. It also leads to a discussion of "stacking" tests so that a respondent would need to achieve multiple successful test scores for the researcher to be confident that the patient's response is positive. These are only a few insights from a far larger set that emerges during this discussion. Dive in for yourself to see what you find most intriguing.
This conversation is part of a broader overview of NASH drug development in 2022, led by Stephen Harrison and Jörn Schattenberg.Stephen starts this conversation by noting that the mechanics of the drug development pathway, which we discussed earlier this year in the context of NASH-TAG and strategies on how to shift away from traditional metrics, remain what they have been: same conditional endpoints (fibrosis improvement without worsening NASH or NASH resolution without worsening fibrosis, or improving both) and the same need for biopsy read as is has been. In this context, Stephen explains the difference between dual primary endpoints and co-primary endpoints in the context of a recent announcement from Madrigal. From there, he goes on to list the various drugs and modes of action in different stages of development, starting with the five agents in Phase 3, then working his way back through the Phase 2b studies to discuss some of the more significant or interesting agents earlier in development. This episode and all its conversations are sponsored by Madrigal Pharmaceuticals. Conversations 25.5 and 25.6 are a two-part summary of Madrigal's disease-focused presentation at the recent CLDF LiverConnect meeting.
This conversation is part of a broader overview of NASH drug development in 2022, led by Stephen Harrison and Jörn Schattenberg.It starts with Louise Campbell asking whether design and management of the ongoing trials will provide sufficient granularity on matching patient types to medications or drug classes. Stephen Harrison notes that we have not paid sufficient attention to this issue historically. In fact, he notes a range of key variables we do not explore at baseline: genotype disease markers like PNPLA3, microbiome and non-Caucasian population segments, to name three. He also notes that some promising drugs have been killed because of trial design issues. In the end, he returns to core positive concepts: combination therapies, looking for agents with multiple positive metabolic effects and safety.At this point in the conversation, Stephen's transmission starts to fail. Eventually, he leaves the conversation and focus shifts to cirrhosis. This episode and all its conversations are sponsored by Madrigal Pharmaceuticals. Conversations 25.5 and 25.6 are a two-part summary of Madrigal's disease-focused presentation at the recent CLDF LiverConnect meeting.
This conversation is part of a broader overview of NASH drug development in 2022, led by Stephen Harrison and Jörn Schattenberg.It starts with Jörn commenting on the exceptional scope of opportunities for deep data dives and new learning, which becomes a lead-in for him to ask Stephen about the scope of data available from Intercept. From there, the group explores a range of issues the data might address. Among the key points: safety and tolerability are extremely important to FDA, the idea that the optimal NASH drug will also have an impact on the range of metabolic disease issues, and the long-term importance of combination therapy.This episode and all its conversations are sponsored by Madrigal Pharmaceuticals. Conversations 25.5 and 25.6 are a two-part summary of Madrigal's disease-focused presentation at the recent CLDF LiverConnect meeting.
This week, NASH Tsunami responds to listeners who have asked "Where are the episodes on drug development?" by asking Stephen Harrison to lead a review of the NASH pipeline.Stephen starts by noting that the mechanics of the drug development pathway, which we discussed earlier this year in the context of NASH-TAG and strategies on how to shift away from traditional metrics, remain what they have been: same conditional endpoints (fibrosis improvement without worsening NASH or NASH resolution without worsening fibrosis, or improving both) and the same need for biopsy read as is has been. Stephen explains the difference between dual primary endpoints and co-primary endpoints in the context of a recent announcement from Madrigal. From there, he goes on to list the various drugs and modes of action in different stages of development, starting with the five agents in Phase 3, then working his way back through the Phase 2b studies to discuss some of the more significant or interesting agents earlier in development. One interesting point Stephen raises is that clinical development for obeticholic acid, the Intercept drug that FDA failed to approve, continues. By now, he notes we have data on over 2,000 patients and a significant number of patients that have been studied for over four years. Jörn Schattenberg registers his excitement at the size of this population and the wealth of data they offer researchers. Throughout this discussion of ongoing research, including not only Intercept but the length of some of the resmetirom studies, Stephen notes that NASH drug development is very much a work in process. Led by Stephen, the group goes on to consider what our failures to date have taught us about doing drug development better, a phenomenon that Stephen, Jörn and Louise all note makes them hopeful for the future. Stephen specifically notes that drug developers and researchers alike have broadened their ambitions from simply reducing fibrosis and liver fat to being part of a total metabolic solution that includes diabetes, obesity and cardiovascular health along with liver. Before leaving the conversation, Stephen notes the critical need to improvement diversity of clinical trial populations and notes that while it may take some years, he sees the future of patient treatment as lying in combination therapy. After Stephen leaves, the discussion shifts slightly, with more focus on cirrhosis, the reasons for drug development and increasing optimism that the drug development community is on the right path. Toward the end, the discussion turns to consider quality of life, which if affected negatively by Fatty Liver disease. Jörn notes that it could serve as the third leg of a stool or tripod to pull NASH drugs over the line. Roger suggests the possibility that a lot of antidepressants are being prescribed for patients who would feel better with less fatty livers. On that optimistic note, the group provides final answers about the most striking part of the episode and departs to live another week.This episode is sponsored by Madrigal Pharmaceuticals. Today's extra-sode is a summary of Madrigal's disease-focused presentation at the recent CLDF LiverConnect meeting.
Stephen Harrison predictive asset condition monitoring in the field Stephen has over 30 years experience in the field of systems analysis, development, integration and business intelligence. Most recently Stephen has been heavily involved in systems relating to programme / project management, Asset Management and Monitoring, information capture and analysis often working directly on client sites alongside their own resources. Show notes: https://cliffnotespodcast.com/podcasts/47/
This conversation on NAFLD Care Delivery and NASH practices comes from Episode 20, our introductory conversation with newly designated full-time co-host Jörn Schattenberg. Most of the conversation focused on Jörn's background and research interests, but this section explores ways we can provide better diagnosis, coaching and care for Fatty Liver patients in Germany, the UK and the US.The conversation stems from an observation Louise makes about how much she appreciates Jörn's focus on integrating primary care into screening and diagnosis. Jörn picks up on this to mention his work with LiverScreen, an EU-funded consortium that screens for Fatty Liver in primary care offices. This has brought him in contact with a significant number of primary care physicians and opened discussions about primary care's role in NAFLD and NASH. Jörn notes how the phenomenon Stephen Harrison has described as "greet 'em and street 'em" leaves primary care physicians short of the time to screen and support patients.Roger Green asks if the improvising liquid biopsies will help address this problem, which leads Jörn to note that in general, German physicians do not draw blood, which makes liquid biopsies less valuable. This will be particularly true if the blood test is the one shot at diagnosis and the test is FIB-4 or something else with low cost but also low overall predictive ability.Roger asks about the role of AI in this process, which leads Jörn and, after him, Louise to discuss the value of AI in risk identification, although not diagnosis. This brings the discussion back to the question of pathways, testing and the idea that in the German system, physicians have the latitude to ignore an abnormal liver test and many do so...all of which highlights the importance of physician education, which, as Jörn notes, is a focus of NASH Tsunami and becoming increasing important to the new company, SurfingNASH.com.
SurfingNASH.com has produced this special, single-interview episode to give listeners a chance to learn about Jörn Schattenberg in a different way as he becomes the permanent Key Opinion Leader on Surfing the NASH Tsunami.Surfing the NASH Tsunami's "Seasons" start with the calendar year, but our first episode posted on April 15, 2020. As we begin our third year, we wanted to give listeners a chance to get to know Jörn Schattenberg a bit differently than you would just from listening to episodes. Jörn discusses how he decided to become a hepatologist, why Stephen Harrison's phrase "Greet 'em and Street 'em" has such resonance, the basic science work his laboratory in Maïnz does, and where he sees the podcast fitting into the future of Fatty Liver disease. Louise Campbell and Roger Green ask questions and share viewpoints in this fast-moving conversation.
This conversation starts with Stephen Harrison discussing the scope of current NITs in the context of what NAIL-NIT needs to achieve. "We don't need to reinvent the wheel, " he says, "only to make it run smoother." After Naim Alkhouri and Mazen Noureddin discuss the Phase I facilities they are building for future research, the group closes the conversation by focusing on the medical, commercial, financial and patient-centric imperatives that make it so imperative to develop appropriate NIT-based solutions for drug development, diagnosisis and patient management within the next five years.This week marks the 2nd anniversary of Surfing the NASH Tsunami! Thank you for being part of the process that has brought us this far: 126 episodes and 335 separate podcast postings and over 58,000 downloads by individuals in over 105 different countries! We promise you this: the best of NASH Tsunami lies ahead of us.
This week marks the 2nd anniversary for Surfing the NASH Tsunami! This conversation celebrates our anniversary and brings news about the formation of a new company dedicated to using podcasts and related media to put big dent in Fatty Liver disease and changing roles for co-founder Stephen Harrison and "fifth Beatle" Jörn Schattenberg.Before you listen, you might want to join us in the "Stephen Harrison Drinking Game." Get a cup or glass of coffee (hot or iced, as you prefer), feel free to add a non-dairy milk and low-glycemic index sweetener if you need to. Then write down a "Harrisonism" (a distinctive phrase commonly associated with Stephen). Then listen to this conversation to see whether any of our panelists (Stephen, Jörn, Louise Campbell, Mazen Noureddin, Naim Alkhouri and Roger Green) select the same phrase you did.
In this brief conversation, Stephen Harrison discusses the exciting goal and ambitious research plan for NAIL-NIT, after which Mazen Noureddin describes the patient-focused issues and conference conversations that motivated Stephen and Mazen to form and recruit members for this consortium. It is a short but rich listen that will help you understand exactly what NAIL-NIT is driving to accomplish. This week marks the 2nd anniversary of Surfing the NASH Tsunami! Thank you for being part of the process that has brought us this far: 126 episodes and 335 separate podcast postings and over 58,000 downloads by individuals in over 105 different countries! We promise you this: the best of NASH Tsunami lies ahead of us.
This 2nd Anniversary episode focuses on what the retrospective analysis from the NAIL-NIT consortium can achieve in terms of driving the shift beyond the biopsy in NASH diagnostics while simultaneously celebrating Stephen Harrison's contribution to the podcast while announcing that Jörn Schattenberg will become our weekly Key Opinion Leader (other commitments will force Stephen Harrison miss roughly half the episodes).The first part of the discussion focuses on Stephen's role in the podcast, culminating in what SurfingNASH's audio engineer, MiC Wilson, has dubbed "The Stephen Harrison Drinking Game." (Listen to learn about it.)Stephen begins discussion of NAIL-NIT by describing what triggered this effort - a chance to "break down stovepipes" (Harrisonism) to create a multi-study data set that can address some of the biggest issues we face today around NITs. "We want to find the right tests for the right situation at the right time to answer the right question" whether that's diagnosis, monitoring for therapeutic efficacy or prognosis." Stephen then describes a two-step process: (i) Analysis of retrospective data from completed and existing clinical trials, which should provide guidance, followed by (ii) a prospective study that can "nail" the right NIT for each situation within the next 5-6 years.Mazen discusses the patient perspective: what happens for the patient (and physician) who clearly has NASH (maybe even F3) but cannot get into a trial because the biopsy does not reveal presence of ballooning? Over time, casual discussions about this issue with Stephen led them to drive the NAIL-NIT initiative. Mazen goes on to note the valuable work that LITMUS, NIMBLE and the Goldmine project at UCSD have done, but feels that this is the time - and NAIL-NIT is the project - to pull all this together into a focused, eventually conclusive effort. After Naim and Jörn discuss their motivation to participate, Mazen shifts the tone of the conversation by asking each of them to describe his "passionate first project." Naim's answer focuses on thresholds that correspond to histological responses for the different NITs. Jörn focuses on questions of effect size, particularly related to varying placebo responses across different trials.Naim then goes on to quote Nassim Taleb, author of the recent book, "Skin in the Game," on a concept he describes as "IYI", "intellectual yet idiot". Naim provides two examples of IYI in NASH trials. Example 1: an F3 patient cannot be enrolled in a trial due to lack of balloon hepatocytes. As Naim notes, F3 is "aggressive disease," so, he asks, "what else do you need to know?" Example 2: a 0 score on ballooning is required to describe a patient's NASH as having reached resolution. Mazen notes that in a future with 10-15 Phase 3 trials, we will never generate the requisite sample sizes if trials are tethered to biopsy and ballooning. Stephen cites the English author Rupert Sheldrake on the concept of "morphic resonance." Here, it means that you can know something is NASH even if specific metrics do not prove it. After Jörn discusses the project's ability to shape the prospective trial, Louise asks whether the group plans to analyze presenting symptoms. She points out that a goal of research should be to develop a questionnaire a primary care physician can administer to the patient that will point those at higher risk toward additional evaluation.From there, the discussion focuses on other implications of the trial on drug development and patient diagnosis and care. There is not enough room to describe all of it. Listen on to learn why a 5-year timeline to get the answer both makes sense and might be imperative.Make sure to allow the energy and "get it done" (another Harrisonism) tone of the conversation to sink in...
Professors Scott Friedman and Neil Henderson join the Surfers (including the returning Stephen Harrison) to discuss some truly exciting advances in the basic science and technology of defining, diagnosing and treating NAFLD and NASH. This conversation focuses largely on the spatial transcriptomics: its history, what it can tell us today, and how it might improve even further over time. All this places focus on the need for healthy hepatic cells researchers can use with this technology, which may already suggest that cells we once considered "good enough" are not today.Neil starts this conversation by describing the value of spatial transcriptomics today by using what Scott describes as the "blender analogy" developed by Neil's colleague Prakash Ramachandran. This starts with days where we would "mash up" tissue together and redo RNA analysis (in this metaphor, like blending fruit in a blender into a smoothie and trying to taste for the flavors) to a next stage where you can tell what the individual fruits are to spatial transcriptomics today, which is like looking at a fruit tart in three dimensions, seeing where each piece sits in the fruit and the size and nature of spaces between them. As Neil points out, this allows the technology to barcode the spots so the informatics people can work out individual gene expressions.Roger asks Neil to walk the audience back through the history of how we came to this place technologically. He starts with the early days of single cell genomics and proceeds through high throughput droplet-based systems to cDNA libraries that enable informaticians to indicate exactly which gene is expressed in which individual cell.Beyond that, Neil discusses the power of single nuclei sequencing, which provides rich data from frozen tissue and thereby provides greater space for global collaboration and examining tissue that might have been stored for years. In the liver, this has allowed for hepatocyte sequencing, which was not viable previously...and there are more advances yet to come.At this point, the conversation shifts toward what's current and tangible as Jörn Schattenberg asks how much variability in tissue samples can be attributed to human differences. Neil describes his group as "nicely quite surprised at how congruent some of the data has been."The rest of this conversation centers mostly on sources of tissue on how "healthy" that tissue actually is. In Edinburgh, Neil notes, much of his tissue comes from distal liver sites in patients with colorectal cancer. The sites may be free from cancer but may have effects from earlier chemotherapy and other systemic challenges. Scott wraps up this conversation with the story of a patient where pathologists captured tissue "far away" from the site of a neuroendocrine tumor. Pathologists believed the tissue was healthy, but single cell sequencing revealed a "hugh neuroendocrine cell population." Such is the value of the new technologies and the challenges they face for researchers to improve other elements of the process.
Professors Scott Friedman and Neil Henderson join the Surfers (including the returning Stephen Harrison) to discuss some truly exciting advances in the basic science and technology of defining, diagnosing and treating NAFLD and NASH. This conversation focuses largely on questions of how hepatic cells regenerate and what more we can learn about this phenomenon over time as technology improves.Unlike the first three conversations, whose pace ranged from "rapid-fire" to "hold on, we're racing", this conversation goes at a slightly slower pace. It starts with Stephen signing off by discussing how helpful this kind of disucssion is for someone focusing primarily on drug development today and congratulating Scott once more on his recent award.Louise Campbell asks a cautionary question: what if when we replicate the liver's ability to regenerate tissue, it doesn't stop but generates more tissue than the liver needs, thereby creating hyperplasia? Scott responds by noting that his concern is not hyperplasia in itself, but that the regenerating liver will grow more cancer cells. He describes the need to "walk a tightrope" where we regenerate healthy cells but "do not overexcite them to the point where they turn into a cancer," particularly since some of the same processes inherent in regeneration are also found in cancer cell proliferation. Neil agrees, but also comments on the remarkable plasticity of the liver that you can find a "bad" liver scar, clear the scar and have tissue evolve into functional liver tissue once more. It is conceivable, Neil notes, that we could attain the "Holy Grail" of clearing bad fibrosis and having the liver regenerate itself to normal function.On the last round of questions, each remaining participant (Stephen having departed) found something truly valuable and/or profoundly interesting in this discussion. Scott describes the general goal as "developing the right treatment for the right cell at the right time in the history of the disease." He goes on to note that these technologies have helped us learn that the right treatment for a cell in earlier stage disease might differ from later stage, and similarly, the right treatments for two cells at any stage in disease might not be the same. Neil agrees on the issue and goes on to note the challenge of getting through the voluminous amounts of data being created "but boy, is it fun!" Jörn looks from the drug development perspective to note that "individualized pathophysiology" may be necessary to learn why a given drug will work in one patient and not another, but that these tools may enable us to analyze at that level. Louise looks toward these techniques as a way to diagnose earlier when disease burden is lower on the patient and therapies are less costly and intensive. Neil raised the hypothetical prospect of complex molecular diagnostics that can answer these questions using non-invasive modalities, which sounds like a dream but, at the end of a recent conversation with imaging colleagues, "doesn't seem like Saturn." Finally, Roger talks about the idea that this information challenges and simultaneously enriches the concept of longitudinal combination therapy. From this conversation, it seems likely that an F2 patient who has regressed from cirrhosis has differences in cellular structure compared to a newly diagnosed patient with F2 disease. These tools will provide the richness to treat each in the most effective way. Scott wrapped up the discussion by citing work suggesting that when the liver regresses and doesn't need active stellate cells to make scar, some die...but others simply inactivate. Using Roger's example, he asks whether F2 therapy after patients regress should focus on inactivated cells or cells that have never activated in the first place, "and we know they are different."And with that, an exceptionally energizing and intellectually stimulating episode came to an end.
Cullen and Mason chat with Stephen Harrison who is the former guitarist for The Chariot and the current guitarist for Fever 333 and Cancer Bats. They chat about his time in The Chariot and Fever 333 and why he is proud to be a black musician in the heavy music scene.Check out Fever 333: fever333.comCheck out our partner HM Magazine: hmmagazine.comFollow us on Instagram: instagram.com/theblacksheeppodcast