pemvidutide

This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers a pivotal session on the new MASLD nomenclature, plus what the panelists found exciting and important about the developing class of triple agonists, at TLM 2023. 

This conversation starts with Roger stepping gently into the topic of the new MASLD nomenclature by discussing a Saturday morning session chaired by Maru Rinella and Meena Bansal. The session took a broad, fairly detailed view of progress in knowledge and implementation of this nomenclature. Roger's point: two of the three obvious potential downsides to the new nomenclature are now rendered resolved. First, George Makar of FDA stated that the agency now uses the terms “MASH” and “NASH” or “MASLD” and “NAFLD” interchangeably, which means that the nomenclature will cause no delays or rework around drug and device clinical trials. Second, Quentin Anstee and Arun Sanyal reported from the LITMUS and NIMBLE databases that the patient overlap when mapping against the two definitions was 95-98%, which means there should be no dispute around the impact on how we define patient populations. In this regard, Roger notes that Gregory Gores, editor-in-chief of Hepatology, said the journal believes this issue is over and will not accept more publications on the subject. 

The third item is the perceived stigma around the word “fat.” Roger quotes NASH kNOWledge founder and patient advocate Tony Villiotti, who points out that while we may describe a specific medical event as a myocardial infarction, the doctor still tells the patient "You had a heart attack." Similarly, the concept of “fat on the liver” will be essentially to explain what is going on to the patient, whatever the nomenclature says. This leads Laurent to discuss the paper on stigma presented at the conference which suggests that "fatty liver" is far less stigmatizing in general than "obesity" or "diabetes," and some specific nuances of the paper. When he is done, Scott and Roger comment on vastly different moments in history and regions in the world where obesity was actually considered a sign of something positive. 

This entire discussion leads Scott to remember a presentation on Eli Lilly's triple agonist retatrutide and the remarkable impact this class of drugs is likely to have on how we manage obesity, diabetes and liver disease. Roger notes that Altimmune and Merck/Hanmi have similar agents in development. He goes on to note that these drugs demonstrate levels of weight loss found with bariatric surgery and asks Laurent and Scott whether they believe the drugs will have impact similar  to surgery. Both say it is too early to tell. Louise follows this by mentioning a study showing that allied health professionals are proficient at motivating patients to lose weight, maintain that loss, and do so in healthy ways.

Roger's wrap-up question asks what will be different at TLM2024 next year in San Diego. You’ll have to listen to hear the answers.

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. 

Surfing the NASH Tsunami covered the 5th Global NASH Congress. Louise Campbell and Rachel Zayas conducted speaker interviews with executives from Madrigal Pharmaceuticals, Altimmune, Antaros Medical and Julius Clinical, and the Surfers shared reflections on meeting topics and other key Fatty Liver-related issues.

This episode blends conversations between the Surfers and "Surfer-for-a-day" and Aged Diagnostics CEO Rachel Zayas with interviews with four of the 5th Global NASH Congress attendees: Madrigal Pharmaceuticals Founder, Chief Medical Officer and President of R&D Rebecca Taub, Altimmune Chief Medical Officer Scott Harris, Julius Clinical Chief Scientific Officer Diederick Grobbe and Antaros Medical Vice President of Global Business Development Caleb Roberts. 

The interviews covered a range of topics, including: (i) the need to identify Fatty Liver patients at the primary care level; (ii) the critical role patient advocates can and must play in the product development and treatment pathway processes; (iii) the relevance of advanced imaging to understanding the multiple effects of Fatty Liver Disease and drugs that treat it on renal, cardiovascular and other non-hepatic systems in the body; (iv) the importance of liver volume independent of liver fat levels in evaluating patients and therapies; and (v) prospects that future bariatric medicines might deliver long-term weight loss at levels comparable to what we expect from bariatric surgery. 

The Surfers' conversations covered these topics as well, along with a review of the two keynote presentations. In one keynote, Sven Franque expanded on a topic he covered at the #INCBCN conference in Barcelona: the ability of small amounts of liver fat to cause structural changes in the liver (removing fat will reverse these). In the other, William Alawazi discussed some clinical trial design artifacts that might obfuscate or even confound trial results.

The 5th Global NASH Congress will take place in London (in person only) on May 27 and 28. Louise Campbell and scientist/entrepreneur Rachel Zayas, who will cover the Congress for NASH Tsunami, join Ian Rowe and regulars Jörn Schattenberg and Roger Green to discuss some key papers and issues covered there. This conversation starts with Ian Rowe and Jörn Schattenberg sharing their perspectives on how much of the emerging genetics and omics of Fatty Liver disease clinicians need to understand. This transitions into a discussion of the drug development presentations in the meeting and what we stand to learn from these.