Surfing the MASH Tsunami

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Amidst a shifting diagnostic pathway, the UK’s National Institute for Health and Care Excellence (NICE) reconsiders its position on vibration controlled transient elastography (VCTE) in the community. In this episode, Roger Green and Louise Campbell are joined by Dr Kathryn Jack and Professors Ian Rowe and William Alazawi to discuss the dynamic challenges of using FibroScan and other noninvasive tests (NITs) for best practice. 

Louise opens the conversation by reflecting on the second public meeting around considering access to FibroScan for primary care. She notes a shift from analyzing costs per test to a broader focus around how these tests are administered and to whom. The group agrees that FibroScan does not necessarily fit well within the traditional framework of NICE. Analytical challenges and out-of-system data obscure answers to critical questions such as what is the cost effectiveness of FibroScan in primary versus secondary care. 

Kate highlights the value of developing an early screening pathway. She notes that when scanning patients, cirrhosis presents in those who have never been diagnosed with Fatty Liver. This is a pivotal opportunity to deliver a targeted intervention and support for the unwittingly cirrhotic population. 

Ian challenges the practicality behind the idea that every patient in primary care should receive FibroScan. He instead suggests non-invasive fibrosis testing in selected patients in the community. “It's important to bear in mind what NICE was asked and then to try and understand how we use FibroScan as part of the wider pathways.” Roger notes the difference between how this process is approached in the US versus the UK. He asks the group whether there is a developed paradigm for how to adopt technology in places where the data is arriving in real time. Ian describes ways the NHS can manage uncertainty and evidence for emerging technologies, citing an example from the cancer space. The conversation shifts toward how the liver can be politicized to arrive at a quicker, better decision. 

Midway through the episode, Will makes his debut after being locked out of the recording session due to technical difficulties. In true breakthrough fashion, he introduces spiky ideas linking socioeconomic strata with liver outcomes. His thought: the more marginalized the patient, the more likely they are to encounter complications of liver disease. The group then proposes a range of factors contributing to inequity. 

Kate steers discussion back to questions around administration of FibroScan and the challenges that oppose nurses and other healthcare professionals. Ian expands these questions and challenges in the context of delivering clear messaging. Settling on a simple, communicable metric may be more difficult and expensive for liver testing than other more recognized health indicators such as reading blood pressure. 

At the bottom of the hour, Roger asks the panelists for one thing in this system worth improving. Ian calls for a clear pathway capable of efficient decision making. Louise hopes for NICE to take action on liver health to drive accessibility in primary care. Kate extends this sentiment to address inequities across communities. Will is looking for stronger signaling to answer patients' concerns: how bad is their Fatty Liver or fibrosis? Finally, Roger offers his US-centric response: if we can appropriately identify the liver’s place in multi-metabolic life, the field moves closer to acknowledgement as a big ticket item. 

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In Season 3, Episode 6, Roger Green assembles audio clips from Surfing the NASH Tsunami’s coverage of NASH-TAG 2022 to reveal an evolving view of the role combination therapies will play in the treatment and management of NASH patients. Discussion about “combination therapies” typically focuses on the idea of multiple agents prescribed concurrently to address a medical condition when monotherapy will not achieve desired goals. At NASH-TAG 2022, the concept of combination therapies took some interesting directions:

1. Longitudinal drug combinations — initial intervention designed to cause a fast reversal of fibrosis or defatting of the liver, followed by a longer-term therapy (mono or combination, but not with the first-round agent) designed to provide longer-term, more complete metabolic benefits in a regimen that is safer, more tolerable, less expensive, or some combination of these.
2. Longitudinal diagnostics — an early, inexpensive “rule out” test like FIB-4, followed by a liquid or machine-based test that provides more accurate disease staging.
3. Logical combinations — so far, most drug combination trials have resulted from a manufacturer trying to resuscitate a developmental agent that missed endpoints in monotherapy trials. It would be more logical to design combinations based on complementary modes of action.

This episode explores these and other combination therapy issues using quotes from the NASH-TAG 2022 coverage and Roger’s commentary.

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A recent string of press releases presaged some of the most exciting, promising data of the last decade in NASH drug development. This conversation explores the single unsuccessful trial result accompanying the spate of positive reports. Intercept’s REVERSE study focuses on evaluating the safety and efficacy of obeticholic acid (OCA) in patients with compensated cirrhosis. Stephen Harrison outlines the Phase 3 results which, ultimately, did not meet its primary endpoint. Stephen notes the analysis of the F3 REGENERATE trial continues and data from REVERSE may provide support for the REGENERATE safety story. 

Louise Campbell takes optimistic interest in this study. She notes, given a cirrhotic population, an F1 improvement may be a difficult, if not unrealistic endpoint. There is value in stabilizing disease. She suggests a focus on improving outcomes and quality of life and halting progression in this most at risk population.

Mazen Noureddin suggests this drug be reserved for combination therapy. Provided the positive data in the preceding press releases, the bar is now much higher. Roger Green adds that ultimately, the results are not statistically significant for this trial. 

Jörn Schattenberg is hopeful to glean learning beyond negative results. This is the largest cirrhosis study to date and it remains a challenge worthwhile to regress cirrhosis in compensated patients. 

The conversation concludes differently than any other previous Surfing the NASH Tsunami episode. Surf on to discover more. 

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A recent string of press releases presaged some of the most exciting, promising data of the last decade in NASH drug development. In this conversation, the panel continues exploring oral drugs (specifically PXL-065) before reviewing positive interim data from the Phase 2b EMMPACT study by Axcella. 

Roger Green notes that introducing multiple modes of action to the market will create the energy and investment to drive a dynamic explosion of education and exploration in Fatty Liver diseases. Stephen Harrison adds final thoughts on why PXL-065 may be a good choice in combination and/or long-term maintenance therapy. The discussion shifts to Axcella’s EMMPACT study, an ongoing global Phase 2b randomized, double-blind, placebo-controlled, dose ranging study to evaluate the safety, tolerability, and efficacy of AXA1125 for the treatment of NASH. The dose form comes in a unique liquid comparable to Tang drink mix. Stephen elucidates on the science behind using multi-targeted endogenous metabolic modulator (EMM) compositions. He presents the pre-planned interim analysis which offers promising findings regarding the effects of AXA1125 administration on selected outcome measures after 12- and 24-weeks of treatment. As the conversation ends, he contextualizes the results and comments on the broad activity of this drug in addition to its well-tolerated profile and safety.

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A recent string of press releases presaged some of the most exciting, promising data of the last decade in NASH drug development. In this conversation, Stephen Harrison continues his review of Phase 2B results from Akero’s HARMONY Trial before introducing more positive Phase 2B results from a study by Poxel. Mazen Noureddin, Jörn Schattenberg, Louise Campbell and Roger Green share impressions.  

Mazen asked whether the future must rely on combination therapies. The question leads Roger back to a comment Akero Chief Development Officer, Kitty Yale, made in a January 2021 podcast. She stated that Akero believes the future of NASH therapy might not hinge on combination therapies. Stephen suggests it prudent to continue following these results as it might be premature to discuss how this drug will be applied. The uncertainty stems from questions around the drug’s modes of action and delivery, potential for tolerability issues or possible reduction of effect over time. Roger asks whether this drug, like BMS’s pegbelfermin, might wear off over time. Stephen suggests that differences in the chemical structure of these two FGF-21 agents points that EFX might not do so. He explains how a drug like EFX could serve as induction therapy followed by a lower cost, better tolerated oral agent. 

The conversation shifts to the next set of data produced by Poxel. The DESTINY-1 study reports positive histology results for PXL065, a novel, proprietary deuterium-stabilized R-stereoisomer of pioglitazone. Stephen elucidates on the science of this drug and the mechanics of deuterium as a stabilizer. The study design consists of 117 subjects across four cohorts: three different doses versus placebo. The trial met its primary efficacy endpoint for liver fat content reduction at 36 weeks for all doses. Louise emphasizes the positives associated with delivering an oral mechanism.

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A recent string of press releases presaged some of the most exciting, promising data of the last decade in NASH drug development. In this conversation, Principal Investigator Stephen Harrison reviews Phase 2b results from Akero’s HARMONY Trial. Special guest Mazen Noureddin joins Jörn Schattenberg, Louise Campbell and Roger Green to share impressions. 

This conversation starts with Stephen returning to his discussion of Altimmune’s dual GLP-1/glucagon agonist, pemvidutide. He comments that stock analysts appear to have punished Altimmune because pemvidutide did not demonstrate greater weight loss. He considers this an inaccurate read. He notes that the 12 week weight loss results of pemvidutide are comparable with 24 weeks with efruxifermin (EFX) in the extremely successful HARMONY Trial. Stephen then segues to detail HARMONY, a 24-week study evaluating the efficacy and safety of the FGF-21 agonist EFX in patients with clinically relevant NASH (F2-F3). The topline results:

• The study met its primary endpoint for both the 50mg and 28mg EFX dose groups. 
• Respectively, 41% and 39% of EFX-treated patients experienced at least a one-stage improvement in liver fibrosis with no worsening of NASH by week 24 (compared with 20% for the placebo arm). 

Stephen notes the presence of key secondary endpoints and important demographics of the patients. He also describes the program for histological analysis and goes on to highlight some extremely positive - perhaps eye-opening - results. Mazen and Jörn react by describing these two results as a Wow! episode. Louise adds comments on the potential for the NIT analysis to speed the transition beyond the biopsy.

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A recent string of press releases presaged some of the most exciting, promising data of the last decade in NASH drug development. In this conversation, Principal Investigator Stephen Harrison reviews the top-line results of Altimmune’s 12 week Phase 1B study of pemvidutide, a GLP-1/glucagon dual receptor agonist.

Stephen describes the effects of pemvidutide on the liver’s fat creation and processing. “It's like taking a drug that both induces weight loss and increases exercise without actually having to diet or get out and exercise. So just think of this drug physiologically working in that particular manner.” 

He goes on to outline the study design, patient qualification and restrictions, and an attention-grabbing set of trial results:

• All 3 pemvidutide dosing groups (1.2 mg, 1.8 mg, 2.4 mg) achieved the primary endpoint of relative and absolute reductions in liver fat, with a 68.5% relative reduction in liver fat content in subjects receiving 1.8 mg dose at 12 weeks of treatment
• Mean weight loss of 4.9% (placebo-adjusted 4.7%) in subjects without diabetes receiving 1.8 mg dose at 12 weeks of treatment

These results are accompanied by a relatively strong safety and tolerability profile. 

When Stephen finishes, Jörn Schattenberg observes that unlike single GLP-1 agonists, this drug has a direct liver effect through its glucagon mechanism. Mazen Noureddin points out that liver fat reduction with pemvidutide is greater than what is typically seen in a drug with 4.3% weight loss. He suggests that the drug's positive impact on other metabolic parameters reflects a "whole body approach" more consistent with the multi-metabolic disease vision we often discuss on this podcast.

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A recent string of press releases has presaged some of the most exciting, promising data of the last decade in NASH drug development. In this episode,  Stephen Harrison reviews recent press releases from Altimmune, Akero, Poxel, Axcella and Intercept, while Jörn Schattenberg, Louise Campbell, special guest Mazen Noureddin and Roger Green share questions and impressions. 

Last month, Altimmune presented its top-line results of a 12 week Phase 1B study of pemvidutide, a GLP-1/glucagon dual receptor agonist. After outlining the study design, Stephen summarizes the positive results of liver fat content reduction. Jörn takes interest in extending the spectrum of GLP-1s by targeting the liver directly with a glucagon agonist. Mazen notes liver fat reduction as disproportionately higher than what is typically seen in a 4.3% weight loss scenario. He expresses optimism that drug's positive impact on other metabolic parameters suggests a "whole body approach." The three then contextualize overall weight loss and liver fat content reductions.

The conversation shifts to Phase 2b results from Akero’s HARMONY Trial.  HARMONY met its primary endpoint for both the 50mg and 28mg EFX dose groups, with 41% and 39% of EFX-treated patients experiencing at least a one-stage improvement in liver fibrosis with no worsening of NASH at week 24, (vs. 20% for the placebo arm). This leads Mazen to ask whether the future must rely on combination therapies.  This leads Roger to recall a similar suggestion from Akero Chief Development Officer on a January 2021 episode. Stephen points out that future therapy might look not only at point-in-time combinations but also sequences of induction and maintenance therapies, as with many cancers.

The next set of data comes from DESTINY-1, a paired liver biopsy Phase 2B trial from Poxel. This study reports positive histology results for PXL065, a novel, proprietary deuterium-stabilized R-stereoisomer of pioglitazone. Stephen elucidates on the science of this drug and the mechanics of deuterium as a stabilizer. The study design consists of 117 subjects across four cohorts: three different doses versus placebo. The trial met its primary efficacy endpoint for liver fat content reduction at 36 weeks for all doses. Louise emphasizes the positives associated with delivering an oral mechanism. Roger expresses enthusiasm that introducing multiple modes of action to the market will create the energy and investment to drive a dynamic explosion of education and exploration in Fatty Liver diseases.

The panel continues exploring oral drugs by reviewing positive interim data from the Phase 2b EMMPACT Study by Axcella. They discuss the broad activity of this drug in addition to its well-tolerated profile and safety.

On a less optimistic note, Stephen outlines the Phase 3 results of the REVERSE trial by Intercept. This study focuses on evaluating the safety and efficacy of OCA in patients with compensated cirrhosis and, ultimately, did not meet its primary endpoint.

Dubbed a Wow! episode by the panelists, there are plenty more observations and supporting data points to be explored in this discussion. Surf on for the full report.

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In this episode From the Vault, Surfers Roger Green and Louise Campbell are joined by Professor Ian Rowe to discuss the implications of the FDA approval of the ELF test.

For Ian, the ELF approval was the most important story of summer 2021. The test promises a brighter future for non-invasive tests and, eventually, decreased reliance on biopsy. Ian points out that transitioning from the ordinal results that biopsy generates (fibrosis score level) provide limited, unrealistic guidance in determining the probability of a downstream negative event (transplant, cancer, death). He contrasts this to continuous test results, including blood-based and device-driven tests, which provide clearer guidance about downstream risks. Louise Campbell adds her own reflections about the importance of inexpensive, blood-based tests to address the emerging NASH pandemic in poorer Third World Countries.

This conversation comes from Season 2, Episode 47. The discussion serves as an example of how people can view the value of a technological or analytical advance from vastly different perspectives. It also illustrates how the robust range of issues provides energy and new inquiries as fields progress. All of which contribute to the exciting prospect of heading into another year characterized by increasing innovation. Stay tuned and surf on.

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After a month of major Fatty Liver medical meetings, Jörn Schattenberg, Louise Campbell and Roger Green explore emerging stories that will shape the next 6-12 months in Fatty Liver disease. In this final conversation, the group discusses the importance of combination NIT biomarkers in developing a viable system for treating patients. The key is that NITs provide a viable strategy for widespread patient screening and staging, whereas biopsy does not.

Roger also asks about several other issues that will come to the fore in the next year. The first item is the Nomenclature conference. Jörn describes it as a moving target with a clear split between the hemispheres. Asia is moving toward a concept more like metabolic-associated disease, however, Europe and North America are not. He notes that an ongoing process of consensus leaves him hopeful. Roger suggests that redefining the disease itself might lead regulators to disregard the vast amounts of research accomplished. Unfortunately, this has the potential to set the field back several years. Jörn agrees that it is imperative that any solutions do not push back drug or diagnostic approvals. The existing data and procedures around patient enrolment in trials remain clear.

The final question returns to the issue of what changes might take place over the next year. Each answer differs and continues themes found in the earlier conversations. Surf on for the group’s predictions.