Surfing the MASH Tsunami

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This week, Surfing the NASH Tsunami returns to a subject we have explored from time to time over the past two years: helping patients with cirrhosis. While the immediate stimulus for doing so was the semaglutide late-breaker at #ILC2022, our more general interest is that many patients with cirrhosis will start to decompensate and decline in a fairly short period of time. This first conversation begins to look at the importance of identifying cirrhotic patients as early in the disease process as possible and the diagnostic tests that are most helpful in coming to a diagnosis. (Ideally, patients will be diagnosed long before they become cirrhotic, but many patients are never diagnosed with or treated for NASH before progressing to cirrhosis.)

Roger Green starts this conversation by discussing NASH Tsunami's history of cirrhosis episodes and the issues we have focused on. At that point, he turns to Jörn Schattenberg to discuss the importance of diagnosis and the tools available to do so.

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Surfing the NASH Tsunami has explored issues of NASH cirrhosis since our earliest episodes in 2020. This episode integrates panelists with three different perspectives to consider the most important challenges in treating patients with NASH cirrhosis today. Jörn Schattenberg was an author of the #ILC2022 late-breaker presentation discussing semaglutide in NASH cirrhosis. Antaros Medical co-founder and Chief Scientific Officer Lars Johansson has discussed and published on different ways to evaluate the impact of medications on cirrhosis. Louise Campbell's career in nursing and subsequent work at Tawazun Health has focused on providing patients with the information and support they need to improve their own conditions.

Roger Green starts the dialog by recounting the cirrhosis discussions over the life of the podcast, starting with discussions about using older medicines (statins, metformin) that might benefit patients, a significant number of which might decline relatively quickly. Jörn Schattenberg picks up this line of discussion, then goes on the describe the semaglutide late-breaker at ILC2022. Jörn notes that while the study failed to achieve fibrosis regression in 48 weeks, it improved a range of metabolic markers while demonstrating a strong safety profile in this population. Jörn goes on to note the importance of early (okay, earlier) diagnosis in these patients and notes that ELF is indicated in the US and EU to confirm a diagnosis of cirrhosis. 

Lars Johansson joins the conversation to ask Jörn whether he believes 48 weeks is enough time to expect fibrotic regression in cirrhotic patients. After Jörn concurs, Lars comments that effects seen with sema in this population (20-30% reduction in spleen volume and early signs of portal pressure changes) suggest we are "doing something good" even if the drug did not regress fibrosis within the study period. 

Lars goes on to discuss triggers that tell him how well (or poorly) the liver and overall metabolic system are working in a target patient. When evaluating other diseases (heart, kidney), he points out, we look directly at organ function. With liver, he notes, we look at biopsies.

At this point, Roger asks the group where the next breakthrough in cirrhosis therapy is likely to occur. Louise points to the need to improve patient communications, given how many patients do not learn they have ANY liver disease until their initial cirrhosis diagnoses. Jorn states that a key to improving communications and educating front-line physicians is to create simple, automated measures that will allow the patient's risk status to appear on an electronic medical record. Lars foresees a major breakthrough when we can study imaging results along with circulating biomarkers in order to identify a single biomarker (or a small group of them) that can predict advanced disease. 

Louise returns to the point that without improved communications, we will fail to keep patients engaged in their own therapy, which will have severe consequences. This leads Roger to describe the next stage as a "pincer movement," with high-tech diagnostics and new drugs on one end and better human systems engineering and electronic communication on the other. 

Next, Roger asks Lars where he believes what he is learning will translate  into improved diagnostics. Lars and Jörn agree that the best strategy is a first stage of inexpensive screening to rule out patients without disease, and then probably a CT-based evaluation to appreciate the status of the liver and impact on related organ systems. 

As the conversation wraps up, Roger asks where each panelist sees the greatest potential for growth in the next 1-2 year. Louise and Jörn focus on improved patient communication and simple screening, while Lars talks with excitement about starting to garner large amounts of data from some of the large, long-term outcome studi

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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.

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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.

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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.

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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.

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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.

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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.

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Last month, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022.) On Thursday afternoon, Scott Friedman chaired an abstract session discussing advances in the basic liver science of researching and understanding mechanisms surrounding fibrosis and stellate cells. Later, he described it as "one of the most exciting groups of presentations I've seen in many years." After this extremely rich and engaging discussion of advances in research processes and the findings the group discussed, Roger Green asked the group with the impact of advances like these will be over the next "year, three years, five years."

The answers vary significantly from one panelist to another, in each case reflecting where the panel members touch the healthcare system and product industries. Scott discusses the ability of research to create completely new classes of therapies with previously unimaginable impact on disease, citing CAR-T as one example that is already in use. Louise Campbell makes a vastly different but very important point: it will work better for everyone if we can create more tissue samples, and the ability to generate these kinds of advances will make it easier for providers to ask patients to provide tissue samples and will increase the number of patients who say, "Yes." Scott and Neil both note how good and important a point this is, with Neil stating that the growth in data we can produce from tissue is "exponential," and that this data is key to creating better disease understanding, diagnostics and drugs. Rachel discusses two key areas where the cost of research is decreasing: the availability of open-source data sets and the cost of actual sequencing. Jörn suggests that having a richer understanding of disease will reduce the number of drug failures, partly because we will know how to capitalize on what we are learning and partly because we may not rush into major drug trials where we lack elements of basic understanding. Roger closes with two summary points: (i) that the technologies the group discussed will be applicable not only for NASH but an array of other liver diseases, and (ii) that over the past three years, the field has created a vastly larger number of data points which is starting to look less like scattered points and more like connected dots making an actual picture.

With these final notes of optimism and energy, the group closed the discussion.

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Last month, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022.) On Thursday afternoon, Scott Friedman chaired an abstract session discussing advances in the basic science of researching and understanding mechanisms surrounding fibrosis and stellate cells. Later, he described it as "one of the most exciting groups of presentations I've seen in many years." The conversation starts with Roger Green asking the panel how to pay this research off in terms of commercial benefit. Most of the conversation consists of their answers.

Scott Friedman answers Roger's question first. He notes that these advanced techniques will allow us to focus on not only the right type of cell but the right subtype(s). Hitting the right target dead-on will improve the efficacy of drugs and the accuracy of diagnostics. Also important (perhaps more so): we can avoid what Scott calls "off-target effects", which commercial executives might think of as safety, tolerability and side effect issues. 

Consistent with other themes NASH Tsunami visits regularly, Jörn notes that the future of therapy is likely to be individualized, multi-element, and probably multi-phase. The more this basic research can teach us about the disease process stages and how they vary by patient, the better job drug developers can do in developing medicines that resolve specific patients' needs. 

Scott notes that if we can hypothesize which patients will respond best to a specific intervention, we can streamline clinical trials, possibly reduce sample sizes, separate respondents from non-responders better and/or shorten trial durations. All these possible outcomes stem from the increasingly demonstrable reality that NAFLD or NASH is actually a set of related diseases rather than a single, uniform disease process.

As the session begins to wind down, Roger invites Scott to discuss any other topics that emerged from the abstract session. Scott mentions the last paper in the session, where researchers from Heidelberg explored a specific receptor whose acronym is RAGE (Receptor for Advanced Glycation End-products). RAGE drives what Scott terms "a very important response," seen both in NASH and cholestatic disease, in which bile ducts proliferate. This is called a ductular reaction. As Scott notes, both the cause of this reaction and its relationship to fibrosis have been "a bit hazy." Now, this group has identified some players that might be involved in this process...and identified them in such a way that therapeutics are being developed against RAGE. This will benefit NASH and, even more clearly, cholestatic diseases.

As the last question before wrapping up, Roger asks the rest of the panel if they have comments about the meeting aside from this session. Neil points to the optimism and energy caused not only by the new methods but also by the sharing of knowledge AND larger data sets, all of which can lead to molecular pathology-based approaches that will help us define the multiple diseases in the NAFLD galaxy better. Jörn goes almost to the other extreme, commenting on presentations demonstrating the value of FIB-4 as a first-line screening tool and others challenging FIB-4 the same way. To Jörn, this identifies the need for a better first-line screening test, which the kinds of research covered in this session might produce. Roger closes the conversation by noting that the two outstanding benefits of FIB-4 are its low cost and wide availability, which suggests the next steps we are more likely to see is a staged approach to diagnosis and screening.