elafibranor

During the 2023 American Association for the Study of Liver Diseases conference, exciting and important results from many primary biliary cholangitis (PBC) clinical trials were reported, including 3 late-breaking studies on the PPAR-δ agonist seladelpar, the dual PPAR agonist elafibranor, and the combination of the FXR agonist obeticholic acid and a fibrate.

In this episode, Kris V. Kowdley MD, FAASLD, FACP, FACG, discusses topline results from several of these studies and more, including: 

• A combination of 3 studies—HEROES, COBALT, and COBALT EC—that evaluated the real-world effectiveness and safety of second-line therapy in PBC where OCA was added to the treatment regimen of people with PBC with an incomplete response to ursodeoxycholic acid 
• Lessons learned from a long-term outcomes study of people with PBC
• Results from 2 phase II studies of obeticholic acid plus bezafibrate in people with PBC who did not respond to or were intolerant of ursodeoxycholic acid

Presenter:

Kris V. Kowdley MD, FAASLD, FACP, FACG
Professor, Elson S. Floyd College of Medicine
Washington State University
Director, Liver Institute Northwest
Seattle, Washington      

Link to reviews of other PBC studies from AASLD 2023: 
https://bit.ly/3RvXXEI

During the 2023 American Association of the Study of Liver Diseases (AASLD) conference, exciting and important results from many primary biliary cholangitis (PBC) clinical trials were reported, including 3 late-breaking studies on the PPAR-delta agonist seladelpar, the dual PPAR agonist elafibranor, and the combination of the FXR agonist obeticholic acid and a fibrate.

In this episode, Stuart C. Gordon, MD, FAASLD, discusses topline results from one of these late-breaking studies and more, including: 

• A phase III study of an investigational PPAR-delta agonist (seladelpar) in people with PBC who had failed to respond to ursodeoxycholic acid
• A study that explored racial differences as they relate to the presentation and diagnosis of PBC

Presenter: 
Stuart C. Gordon, MD, FAASLD
Director of Hepatology
Henry Ford Health System
Professor of Medicine
Wayne State University School of Medicine
Detroit, Michigan

Link to commentary:
https://bit.ly/3GzRMt2

Link to reviews of other PBC studies from AASLD 2023:
https://bit.ly/3RvXXEI

During the 2023 American Association of the Study of Liver Diseases (AASLD) conference, exciting and important results from many primary biliary cholangitis (PBC) clinical trials were reported, including 3 late-breaking studies on the PPAR-delta agonist seladelpar, the dual PPAR agonist elafibranor, and the combination of the FXR agonist obeticholic acid and a fibrate.

In this episode, Marlyn J. Mayo, MD, discusses topline results from several of these studies and more, including: 

• A phase III study of an investigational dual PPAR α/δ agonist (elafibranor) in people with PBC who did not respond to or were intolerant of ursodeoxycholic acid (UDCA)
• A study that evaluated the effectiveness and safety of second-line therapy in PBC where obeticholic acid with or without a fibrate was added to the treatment regimen of people with PBC with an incomplete response to UDCA
• A retrospective review of the rates of hyperlipidemia, atherosclerosis, and/or hepatic steatosis in patients with PBC

Presenter: 

Marlyn J. Mayo, MD
Professor of Internal Medicine
Division of Digestive & Liver Diseases
UT Southwestern Medical Center
Dallas, Texas

Link to commentary:
https://bit.ly/47PmGdc

Link to reviews of other PBC studies from AASLD 2023: 
https://bit.ly/3RvXXEI

This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers what the panelists found exciting, important or striking about the presentations of clinical trial results at TLM2023.  

Instead of focusing immediately on MASH drugs, Scott suggested we should not overlook the idea that elafibranor is preparing to come to market in the US as a novel medication for PBC with good efficacy and safety from patients who do not respond well to ursodiol or obeticholic acid. I note that elafibranor is only one of two PPARs speeding toward market in PBC with exciting data given what we all heard in the late-breaker presentation on seladelpar. Scott also mentions to integrin antagonist from Pliant in PSC, a disease with no available solutions today. Laurent agrees with Scott that the rare disease drug advances were more exciting than the advances in more common liver diseases.

I bring up papers addressing the value of FGF-21 and FGF-19 agents in cirrhosis, which showed some promise for compensated cirrhotic patients. Scott politely disagrees, feeling that while these agents might hold disease steady, they do not address the challenges and mechanisms necessary to meaningfully regress disease. We agree there is a benefit to any agent that slows or reverses the course of disease even slightly in that this buys the patient more time to be treated with more exciting medications still in the pipeline. 

Scott notes that for Hepatitis C, a far simpler disease it took 25 years from discovery to cure on a path of incremental process. Scott notes that drug development successes are keeping investors interested, which is encouraging in a challenging environment for investment. 

Laurent returns to the issue of cirrhosis, noting that there are multiple challenges and concomitant bad behaviors like alcohol consumption. He points out that where good studies exist, these are short studies with small samples. Scott points out that MASH is less like hepatitis and more like inflammatory diseases like IBD, where causes of underlying disease are difficult to determine and there is no single pathway in drug development. He buttresses this by noting that in clinical trials, resmetirom provided benefit to only 25% of patients. 

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

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

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

Manal Abdelmalek, Jörn Schattenberg and Ian Rowe join regulars Stephen Harrison, Louise Campbell and Roger Green to recap this week's just-concluded TLMdX 2021, the AASLD annual liver meeting. 

When AASLD announced that the 2021 TLMdX would be held as a purely virtual meeting, attendees and observers feared a loss of focus and the kind of amplifying energy that comes from being with colleagues. That did not happen. Instead, the breadth, quality and novelty of the meeting's presentations generated exceptional positive energy despite the virtual setting. 

4:10 - Roger starts by saluting Manal for giving the NAFLD Wrap-up Talk at TLMdX 2021, then introduces other panelists
6:58 - Icebreaker question: Where did this meeting "make the biggest dent" in Fatty Liver disease?
12:21 - Manal discusses how she organized and prepared for talk and describes "somewhat surreal" feeling of seeing semi-quantitative histology fail in trials where so many non-invasive markers suggested proof of efficacy
16:13 - Jörn points out the inherent tension between needed accelerated endpoints and being tied to a severely flawed "gold standard" of biopsy
17:15 - Stephen's simplest solution: capitalize on existing study results to link MRE, fibrosis and outcomes
18:56 - Manal counters: this assumes  biopsy is the gold standard, when we know it is seriously flawed
21:02 - Stephen: it's time to "reach a common ground on what it takes to achieve replacement of histology with an NIT"
24:02 - Ian suggests that the FALCON trial history will strengthen FDA's attachment to biopsy
26:13 - Stephen's key to moving beyond biopsy: strengthening the data that supports credibility of NITs
28:13 - Jörn: having a combination of NITs that each reflect different elements of the disease makes effort easier and more credible
28:45 - Ian: controlled cirrhosis studies might allow quick validation and acceptance
29:35 - Manal: we know how to design better trials now,  cites story of ALPINE 2/3 as proof
32:17 - Stephen: the path to the data-driven future explodes when the first drug is approved
33:32 - Lars Johansson (Antaros Medical)  joins from audience to ask Stephen whether we can reanalyze spleen volumes from old trials  and reanalyze imaging data possibly with AI
34:52 - Stephen salutes Lars's "very good insight" about the potential to reanalyze the "huge" bodies of data from older trials
35:54 - Jörn agrees, but cautions that we need to keep primary focus on getting a drug approved
38:41 - Lars returns to audience
39:25 - Manal returns to Louise's  thought that one thing coming from meeting has to do with genomics, citing Million Veteran database
40:16 - Manal describes how single cell RNA data will shape the future of diagnostics and treatment in Fatty Liver diseases
41:10 - Louise refers back to various talks involving the patient-treatment impact of genomics and others implicating genetics as a possible reason for high variability in placebo response between trials.
43:42 - Stephen raises the diversity inherent in microbiome data as playing a role in making Fatty Liver so complex to characterize and treat
45:10 - Jörn points out that any drug that can "elevate above all these thresholds" and complexities will have to be "quite robust"
46:23 - Stephen envisions the day when drugs are approved based on MRE and the scarcity of MREs around the world creates a new set of challenges
47:37 - Manal observes that "precision medicine has been hot and heavy," which spurs Roger to note that all the key advances mentioned in the meeting are tied to advances in computing and modeling power
48:12 - Closing question: The biggest story a year from now? Stephen, Manal and Ian focus on "Phase 3 results." Jörn, Louise and Roger focus on ways patient empowerment will focus attention on better patient solutions.
57:05 - Business section

Profs. Scott Friedman and Michelle Long, Dr. Naim Alkhouri and Global Liver Institute DIrector of Global NASH Programs Jeff McIntyre join Louise Campbell and Roger Green to review some of the most important and exciting presentations from the first three days of the 2021 TLMdX, the annual meeting from AASLD.

Description: Each panelist chose 1-2 presentations or posters from the 2021 TLMdX from AASLD that they thought conveyed a major topic or question in the meeting.  The group discussed each paper, sometimes moving far afield the original topic. As usual with SurfingNASH, conversations were interspersed with challenging insights and comments, debate and laugher.

Highlights include:
5:27 - Introducing tonight's panelists
15:27 - Naim Alkhouri discusses "The Prevalence of Alcoholic and Nonalcoholic Fatty Liver Disease in Adolescents and Young Adults in the US" (Parallel 5)
20:33 - Group discussion
28:56 - Louise Campbell discusses "An advanced practice provider (APP) pathway achieves more effective weight loss in NAFLD patients compared to standards of care" (Parallel 2)
37:40 - Group discussion
46:28 - Scott Friedman discusses "The influence of host genetics on liver microbiome composition in patients with NAFLD" (Poster #`1654)
48:39 - Scott transitions to "The influence of host genetics on liver microbiome composition in patients with NAFLD" (Poster #1781)
50:31 - Scott ties these two results together in addressing the importance and complexity of microbiome: "I say that ...in part based on the work of Marty Blazer...an infectious disease doctor, who's sort of convinced me that epidemiologically it's very hard to explain how a disease showed up on our radar screens in a 20 to 30 year period, uh, that didn't exist before...Certainly our genes haven't changed over hundreds, if not thousands of years, to any extent. And so something external has changed. It comes back to the environment," and dietary changes.
52:53 - Group discussion
58:48 - Michelle Long discusses "Longitudinal association between MRE and liver-related events and CV events in NAFLD" (Sunday Presidential Plenary session)
1:07:56 - Group discussion
1:09:08 - Group discussion shifts toward the question of whether and when FDA might move away from biopsy as the requisite endpoint in drug trials
1:15:03 - Roger shares audience question on probiotics and NAFLD. Scott provides primary answer
1:16:37 - Jeff discusses Donna Cryer's talk on "Grit, Grace, Gratitutde and Resilience: What You Wish Your Doctors Knew about You" (Sunday Patient Forum)
1:22:53 - Group discussion starts by considering the best word to describe the optimal provider:patient interaction ("partnership" emerges as preferred choice)
1:28:23 - Roger discusses "Topline Results from the Alpine 2/3 Study," a Phase 2b trial evaluating 3 doses of the FGF19 Analogue Aldafermin,(Sunday Presidential Plenary session) and "Efficacy and Safety of Pegbelfermin in Patient with NASH and Stage 3 Fibrosis: Results from the Phase 2b FALCON 1 study." He connects these results by saying "What was striking is that if all you were doing was scoring the balls and strikes, then you'd say that those were both the same thing because neither one of them was going to point to a commercial success in launch." However, he continues, "the differences between the two vastly outweigh the similarities" in that pegbelfermin demonstrated minimal ability to differentiate from placebo while aldafermin clearly differentiated from placebo but might not have presented a strong enough commercial profile given other drugs in development.
1:33:07 - Group discussion
1:36:25 - Scott adds one comment on the importance of digital pathology if we are to continue relying on biopsy.
1:37:04 - Final question: "What's the one thing that you hope that the part of the community that you touch most directly is going to take out of this meeting?"

The entire panel enters a discussion around histopathology's shortcomings, ranging from the fact that the NAFLD Activity score does not correlate with liver function to inconsistencies in reading all elements of biopsy.

This conversation revolves around the challenges posed by histopathology's flaws. Scott Friedman reminds us that NAFLD Activity scores do not correlate with outcomes, Roger Green reminds us that coder reliability scores would not be accepted in marketing research and Stephen Harrison describes the impact of these flaws on investors and drug/device companies. In the end, Scott provides a peak at some of the topics his lab is exploring and the entire panel discusses what they consider key takeaways from this engrossing episode.

Scott Friedman, the "Father of Fibrosis", and Jörn Schattenberg join the Surfers to discuss Scott's recent Paris NASH and National Liver Congress talks on Precision Medicine, imaging and liver function.

Scott Friedman's Paris NASH talk on Precision Medicine made a strong impression on Stephen and Jörn, along with our listeners. The conversation summary of that talk and Lars Johansson's (S2 E46.2) is the largest conversation and third largest post in the history of the podcast.

Scott joined us to discuss precision medicine, imaging, stellate cells and an array of additional topics. Highlights include:

4:08 – Scott Friedman discusses his career in studying fibrosis, stellate cells and a range of other liver function issues
9:13 – Session icebreakers: Scott’s fun fact and everyone’s good thing from the past week
12:46 – Stephen Harrison introduces Scott by discussing what he learned at Paris NASH
16:00 – Scott begins his remarks and goes on to discuss Precision Medicine in the context of liver disease
19:02 – Why it means so much that precision medicine includes precision of therapies
19:39 – How the stellate cell got its name
21:04 –The power of technologies lies in single cell sequencing and analyses, and what it means for “us stellate cell geeks”
23:49 – The importance of senescent stellate cells
24:45 – An exciting future for CAR-T cells
25:40 – Jörn Schattenberg asks whether and how we can target drug therapies to specific patients
26:38 – Scott: Pharmacogenomics are the “known” part of how precision might affect prescribing and drug selection in the future
27:46 – The importance of endophenotypes: liver samples look the same under the microscope may reflect quite different causes of disease
28:50 – The ambitious effort to develop software that takes the mass of patient information and distills it into a clear picture and simple recommendation
30:02 – Stephen: do we know enough to target therapies to specific types of patients
31:14 – Scott: What we know about PNPLA3 cells, their variants and patient diagnosis and treatment is a good example of what we can learn over time
32:08 – Does part of the solution lie in pinpointing how a cell signals distress?
33:16 – The significant role imaging can play in improving precision
34:25 – Implications of precision medicine for drug development, and how being “yoked to biopsy” and the NAFLD Activity Score hold us back
38:18 – Should we focus our endpoints more on liver function?
39:38 – Is biopsy the “Premarin of diagnostics” – so highly and unreliably variable that we cannot replicate results?
41:04 – Getting beyond the biopsy: the imperative, the path and the two major challenges
44:02 – Putting existing tissue samples to better use: availability of sample, past discussions, potential solutions, practical considerations
48:06 – “Very cool” research “cooking” in Scott’s lab
49:02 – The importance of mentorship
49:24 – “Final question” to wrap up session
52:52 – Scott: there are good reasons for optimism in our history
55:21 – Business section

Roger Green narrates a series of interviews, conversations and viewpoints about NGM Biopharmaceuticals discontinuing its F2/F3 aldafermin program

The SurfingNASH team weaves interviews, conversations and text notes from 9 stakeholders, including US and EU KOLs, program heads, treating physicians, patient advocates and NASH patients into a narrative addressing key issues. Was the ALPINE 2/3 trial a clinical failure? What commercial considerations might have played into NGM BIo's decision? What lessons can we learn about clinical development strategies? NITs vs. biopsy? When to trust headlines and when not. There is a great deal to unpack in a 25-minute episode.

The Surfers and guests Vlad Ratziu and Mazen Noureddin discuss key lessons learned in 2020 about Drugs and Diagnostics.

Vlad Ratziu and Mazen Noureddin join the Surfers to explore some of the key lessons learned and issues uncovered in 2020. Vlad Ratziu provides a 10-minute overview of a fast-paced year of successes (and occasional failures) in clinical trials and novel diagnostics. Mazen Noureddin discusses the expanding role of non-invasive liver tests in diagnosis, patient treatment and monitoring and drug development. Stephen Harrison updates our knowledge about the use of clinical endpoints in obtaining conditional drug approvals. Finally, Roger Green places the entire year in a systems context with an eye toward the Law of Unintended Consequences and why the obeticholic acid Complete Response Letter was not the death knell many observers feared.

Prof.  Vlad Ratziu, MD, and Prof. Dr. Jörn M. Schattenberg join the Surfers to wrap up our conversation about this year's AASLD meeting.

Prof. Dr. Jörn M. Schattenberg erg and Prof.  Vlad Ratziu, MD join the Surfers for our wrap-up episode for TLMdX 2020. Joern focuses on a diabetes poster demonstrating the path of drug efficacy over a three-year period, while Vlad focuses on the successful Phase 2 trial of the pan-PPAR lanifibranor. The group also asks why placebo response varies so much between studies and whether the ratio of F2:F3 patients may be a factor. Finally, the Surfers focuses on what they consider the biggest lessons emerging from the meeting.