Surfing the MASH Tsunami

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This conversation focuses on two issues: (i) identifying the right target MASH patients for Rezdiffra, and (ii) the extensive Madrigal patient support program for Rezdiffra.

It starts with Roger Green asking the group how the current set of target patients is defined. Jeff McIntyre points out that these are the patients currently treated for F2 or F3 MASH in the US healthcare system. Roger asks if this is analogous to the idea of “warehoused” patients observed in Hepatitis C. Jeff suggests these are quite different from warehoused patients in that warehoused patients are not being treated at all, whereas all the target MASH patients are engaged in some form of treatment. 

Next ,Roger notes that Wayne Eskridge published a long post earlier in the day about the extensiveness of the Madrigal patient support program. Wayne discusses the program in some detail, in the process explaining why this process appears likely to be more engaged, interactive and helpful than the typical patient portal program.

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Last Thursday, March 14, Rezdiffra (resmetirom) became the first drug approved in the US for MASH. Five leading North American MASLD patient advocates join the Surfers to discuss their feelings about this approval along with the opportunities and challenges that lie ahead.

00:00:00 - Surf's Up: Season 5 Episode 7
Opening introduction from an excited, enthusiastic panel, including brief quotes taken directly from the episode discussion.

00:05:55 - Groundbreakers
Each panelist shares one piece of good news from the previous week.

00:11:19 - Advocates recall March 14
As March 14 progressed, advocates' attitudes moved from excited anticipation to anxiety to deep happiness.

00:17:41 - Advocates describe their feelings as patients
None of these advocates are Rezdiffra candidates themselves, but each reflected on their personal experiences with MASLD and what the future holds for patients who are or will be candidates for Rezdiffra.

00:22:33 - Identifying target patients
This conversation starts with Roger Green asking the group to describe where the number "315,000 target patients" came from. After the group replies, Jeff McIntyre and Louise Campbell explain how this is different from a "warehoused" patient population, and Wayne Eskridge discusses the exciting, progressive Madrigal patient support program.

00:29:53 - The advocate's role today
Jeff begins this discussion by emphasizing the role GLI has shepherded and advocates have played in informing FDA about patients' key concerns for the label. He describes how these are reflected in the approval decision and label, with biopsy being the most obvious example. The other advocates agree, with Mike Betel emphasizing how closely the leading advocates co-ordinate with GLI and each other. Louise suggests it will be a "game changer" if FDA takes a similar view to labels for other metabolic diseases. Roger points to Madrigal's discussion of medical exception as proof of their commitment.

00:37:10 - The advocate's role tomorrow
Advocates agree that this approval creates new, broader opportunities for education and outreach. To Jeff, the approval will allow advocates to ask bigger questions on emerging needs. He offers treatment for cirrhosis and drug reimbursement as two such areas.

00:41:22 - Slowing the patient flow
Roger asks what steps advocates can take to slow the flow of patients through the progressive stages of MASLD. Tony Villiotti notes that this is the primary goal of NASH kNOWledge, starting with childhood education. Jenn Jones states that publicity about Rezdiffra may lead patients with MetALD or ALD to explore how they can protect their own livers and seek early detection.

00:46:15 - Overwhelming the system
Louise describes herself as "slightly fed up" at individuals who  fear "overwhelming the system." Instead, she says, systems should build capacity to reflect the scale of the disease. Roger notes this may be harder to execute in the US than in countries where governments control their healthcare systems. Jeff points to the US Veterans Administration as a possible model for ways to build capacity. 

00:52:21 - Emerging role of primary care
Louise states that much treatment will shift to primary care over the next 5-7 years.  Roger agrees and seconds Jeff's comments about the role the VA can play.

00:54:55 - Closing question
Roger asks each panelist to identify a healthcare stakeholder group that needs to take a lesson from the issues discussed today. Answers vary widely.

01:02:06 - Question of the Week
The question asks what good ideas listeners have for other stakeholder groups in the aftermath of Rezdiffra's approval.

01:02:54 - Business report
This week's news on audience metrics, future episodes and why there will be no Vault conversation again this week

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As the conversation wound down, Roger Green offered panelists to address any issue pertaining to Rezdiffra, the first MASH drug, that had not come up in the hour-long conversation. 

The seven panelists raised eleven exceptionally diverse issues between them. Rather than provide a simple list of issues, the co-hosts invite you to listen to this short conversation to gain a fuller appreciation of each point.

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This conversation revolves around one question: "What lessons should the BioPharma industry take from the launch of Rezdiffra?" Answers revolve largely around clinical trial design and, generally, taking a broad, long-term view of what the trial must accomplish to optimize drug adoption.

More specifically, Roger Green starts this conversation by noting that much of the SurfingMASH audience works in pharma or biotech. He asks what lessons they should take from this experience. Zobair Younossi responds first, commending Madrigal for “doing the right thing” and being persistent for years, even when it appeared that Rezdiffra would come to market years after the anticipated first drug. To Zobair, "the right thing" includes conducting multiple trials at different diseases and targets, including large samples in each trial, and introducing NITs as endpoints.

Jeff McIntyre also feels that using NIT markers to parallel biopsy in clinical trials has created a major bridge to an all-NIT, post-biopsy initial diagnosis plan. Louise Campbell asks what impact the two-day NIT workshop the FDA conducted last autumn had on any of this. Zobair, who works closely with the FDA, suggests that the agency is taking time to process this information collaboratively. He believes the agency is moving in the right direction, if more slowly than we might like.

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One pivotal question surrounding the launch of Rezdiffra is "Which MASH patients are the correct targets for the first MASH drug?" This conversation focuses on the tools and education the health system will need to locate these patients and have them treated by the appropriate prescribers. 

 The conversation starts by considering educational goals. Zobair Younossi asks what is practical and proceeds to answer his own question.  He starts by pointing out that most early patients will be found in GI practices. This presents a challenge. While hepatologists and their advanced providers have the knowledge they need to identify patients and prescribe, most of the target patients are being treated in gastroenterology practices, and this group is not as knowledgeable about the disease, screening, staging and treatment. For 2024, he says, educating this group must be the primary focus of education. Zobair notes that other specialty organizations are aligned with the need to screen, stage and treat, but the lay practitioners in these specialties also will need education. 

Jeff McIntyre agrees strongly with Zobair’s assessment. Jeff asks: education to what points or outcome? Jeff views education as needing to address two issues: proper prescribing and use of the drug, but also proper identification of patients. To Jeff, these are the key needs in educating gastroenterologists and their advanced providers, but also key issues for educating patients so they can advocate effectively for themselves. 

Jörn Schattenberg states that Rezdifra’s safety profile is a critical benefit. It alleviates some concern that a well-meaning provider might prescribe for a patient with compensated cirrhosis due to a lack of precision with current tests. 

Roger Green notes that the excellent Rezdiffra safety profile will resolve a dilemma physicians have with most first-in-class drugs: how to do no harm while getting the drug to the right patient. This safety profile makes the dilemma less profound, although it is no less important to keep in mind. 

Returning to education, Laurent Castera closes this conversation by noting that he works at a “liver clinic inside a diabetes clinic,” and that the diabetes screening protocol—an annual FibroScan for every patient with suspected advanced liver disease, followed by referral to a hepatologist—is working well. 

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This conversation focuses on the necessity of using NITs to screen and identify Rezdiffra patients, while at the same time acknowledging the shortcomings of current tests. Panelists suggest some different NIT testing strategies while commenting on upsides and potential challenges for each MASH NIT.

Laurent Castera joins the conversation at the beginning, which is helpful given his extensive research and knowledge of the surrounding communities. Laurent points out that distinguishing F3 patients from F4 will be a difficult challenge to solve, in part because we used categorical scores for fibrosis instead of recognizing that it is, in fact, a continuum where, in Laurent's words, "you are not 1.2 or 1.5. You're F1, 2, 3 or 4." Having a drug will facilitate a shift from the old-school categorical view to a more linear one.  

Laurent goes on to comment that it is not clear exactly how we will use NITs, but that liver stiffness will certainly be one key metric, one he describes as "a prediction scale." He also comments on the problems caused by relatively low arbitrary cutoffs here, 12.25) and the need for (a) repeat measures and (b) use of at least two tests. He mentions platelet counts as one important example.  

Jörn Schattenberg discusses the importance of clinical observation and judgment. Zobair Younossi takes that point further to stress the importance of conservative judgment in assessing for cirrhosis. Laurent suggests that a second, "more specialized test" that is "not related" to VCTE will tremendously improve accuracy. 

I comment that one important issue is that individual prescribers will now start treating with Rezdiffra and will derive opinions about the drug based on their experiences with the first few patients for whom they prescribe. I suggest that similar patterns may be true for NITs and ask how panelists anticipate providers will receive education on NITs. 

Louise Campbell talks about the roadmap that Madrigal showed of what they're going to have their reps and MSL trained doctors on and believes that will be exceptionally helpful. She also feels it is vital that practitioners early in the patient visit change also be well-educated on this topic. She notes that many of the people focusing on this topic, including former panelist Suneil Hosmane, now at Madrigal, are first-rate. 

Jeff McIntyre closes the conversation by suggesting there will be a "huge patient role," because patients are people who can demand, or at least ask questions of doctors that will lead the doctor to do things they might not otherwise and to get more informed on related issues. Jeff notes that we have not come up with an adequately specific answer to the question, "What's the best NIT?" which mandates that we keep educating and speaking out.

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FDA approval of the first MASH drug, Rezdiffra, on March 14 marked what co-host and Key Opinion Leader Jörn Schattenberg describes as a "watershed moment" for hepatology. This opening discussion covers how panelists heard the news of Rezdiffra's approval, how they reacted, and their initial thoughts about appropriate patient targets.

As the conversation starts, the various panelists describe their moves throughout the day on March 14th and their reactions when word of the FDA's approval came. They all describe having felt various degrees of trepidation as the day progressed. Jeff McIntyre describes him and his friends as "constantly refreshing our screens" throughout the day. Zobair Younossi probably felt less anxiety than others, while some of the Europeans described feeling more.

This was replaced by excitement and joy at the final announcement. Jörn Schattenberg describes the day as a "watershed moment," that, in Zobair's words, "energiz[ed] for the entire field."

Panelists go on to describe the patients they expect to prescribe Rezdiffra for at launch (now for the US, whatever comes available on the EMR). Jörn intends to prescribe initially for F3 patients but realizes he might not know exactly how to distinguish them from early-stage cirrhosis. Zobair points to prescribing for F2 and F3 patients as indicated in the label. 

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Last Thursday, March 14, Rezdiffra (resmetirom) became the first MASH drug approved in the US. A global panel of Key Opinion Leaders convenes to discuss their excitement about this approval, the opportunities it will create and some of the (largely manageable) challenges it might present.

00:00:00 - Surf's Up: Season 5 Episode 6
Opening introduction from an excited, enthusiastic panel, including brief quotes taken directly from the episode discussion.

00:05:02 - Groundbreakers
Each panelist shares one piece of good news from the previous week.

00:08:15 - Waiting for news and initial reactions
Panelists  describe their moods throughout the day on March 14 and reactions when word of the approval came from FDA. They describe feeling varying degrees of trepidation as the day progressed without word from the agency, replaced by excitement and joy at the final announcement.

00:14:30 - Specific patients to target or avoid
Panelists describe the patients they expect to prescribe Rezdiffra for first (now for the US, when it becomes available for EMA).  The group aligns on the benefits for F3 and F2 patients (the two groups listed on the label) but shares concerns about accurate identification of F3 vs. compensated cirrhosis.

00:17:07 - Impact on explaining lifestyle interventions
Zobair Younossi notes the historical difficulty of getting patients to view lifestyle modification as a specific prescription to be followed. He, Roger and Jeff all makes points to suggest  that  the combination of drug + lifestyle modification will be easier to explain to patients.

00:26:32 - Staging and screening patients using NITs
Laurent Castera joins the conversation as the topic switches to proper use of NITs.  Previously, Jörn Schattenberg and Ian Rowe touched on challenges in deciding which patients have F3 fibrosis vs. early stage cirrhosis. Now the group explores the relative value of different strategies for qualifying patients. One key: while FIB-4 is an efficient screening test in largely negative populations, it produced a high level of false positives in specialty practices.

00:33:50 - How to educate providers
Roger points out that individual providers will conduct individual "clinical trials" in their own practices. This makes provider education on proper use critical to launch success. Louise Campbell commends Madrigal for the education pathway they laid out during the webcast. Jeff discusses the important role patients must play.

00:39:06 - Finding the initial patients
Apropos of education, Zobair points out that most early patients will be found in GI practices. Jeff points out that these patients are already in the system and can be easily identified.

00:43:12 - Why Rezdiffra's strong safety profile matters so much
Panelists agree that Rezdiffra's safety profile alleviates some concern that a well-meaning provider might prescribe for a patient with compensated cirrhosis due to inadequacy of current tests.

00:48:39 - Suggested takeaways for industry
Panelists suggest that industry learn from the large sample sizes and thoughtful use of NITs found in the Rezdiffra trial protocols.

00:52:20 - FDA and NITs
Louise asks how important FDA's two-day NIT workshop last year was in the agency not requiring biopsy prior to prescribing. Zobair says agency officials are moving slowly down a path toward greater acceptance.

00:53:53 - Closing Thoughts
Each panelist shares a closing thought. The topics vary widely.

01:01:06 - Question of the Week
The question is what impact Rezdiffra's approval will have on individuals' day-to-day work.

01:01:47 - Business report
News on audience metrics, future episodes and why there will be no Vault conversation this week

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This conversation comes from our first look at MASEF, last September, when lead author Mazen Noureddin joined the Surfers to discuss his recent breakthrough paper on this new NIT.  The original conversation had a robust write-up:

Mazen Noureddin joins co-hosts Jörn Schattenberg, Louise Campbell and Roger Green to discuss serum identification of at-risk MASH and the Metabolomics-Advanced Steatohepatitis Fibrosis Score (MASEF). In late July, Mazen co-authored a paper on the subject which was published in Hepatology.

This conversation begins with Louise’s initial response around the setting of application for MASEF. She poses a question that leads the group to explore possible pros and cons of different approaches and the potential impact each might have in terms of cost effectiveness. For example, Jörn wonders how feasible it will be for non-experts to administer. Mazen suggests that its application will be relatively easy before explaining how to navigate the caveat of a gray zone similar to that of VCTE. After a few more comments on sequential pairing with FIB-4, Mazen next teases the possibility of demonstrating therapeutic efficacy in the drug development space. 

Louise returns to a question around cohorts and asks whether variables like age or sex has an impact on the test’s capabilities. She then asks whether this sort of work has the potential to inform retrospective cardiac studies. After Mazen and Louise go back and forth with a few ideas in response, Roger makes the comment that he is struck by the wide breadth of application and describes the platform as “elegant.” As the conversation winds down, the group discusses a few comparisons between different blood-based markers. 

If you have questions or comments around MASEF, metabolomics or any other ideas considered in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected]. The Surfing the NASH Tsunami will be back next week with more original content.