Post-conference Q&A - AASLD: The Digital Liver Meeting Experience

Date
December 2, 2020
Topics
Pharma, AASLD
Authors
Dr. Andrea Dennis, Marija Mavar, Jack Vidani

With AASLD 2020: The Liver Meeting Digital Experience (TLMdX) having come to a close, we spent some time with catch-up Marija Mavar, co-lead of our Pharma Solutions business unit, and Dr. Andrea Dennis, Head of Biomarker Science, to hear their thoughts. In this Q&A, we take a deep dive into their experience at this year’s digital conference and take a closer look at their perspectives on some of the key research presented by Perspectum.

Q: How did you find the AASLD 2020: The Digital Liver Meeting Experience (TLMdX) compared to the usual in-person conference, and did you feel this year’s digital conference format enhanced or hampered attendees’ ability to connect with others and explore new research?

Andrea: It certainly was a different experience and probably a slightly more relaxed one. I actually really enjoyed it! I thought the open chat during the science sessions seemed to encourage more questions that you might not ordinarily get. Being able to watch at one’s own pace made it easier to take more in as well.

Marija: I liked the digital format a lot. At this point, we are all used to attending virtual meetings and talks from the comfort of our home, which is now being extended to conferences as well. The thing I liked most is how easy it was to attend all the talks I wanted to, even when they were in different sessions taking place at the same time — no more running from one part of the venue to the other!

 

Q: Which work presented at the conference did you feel was most impactful/interesting?  

Andrea: I really enjoyed hearing about some of the innovative approaches to characterizing and utilizing information from genetic sequencing, which is ultimately at the heart of precision medicine. The session on prognostic and diagnostic methods in NAFLD and NASH, in which we were also presenting, had three talks on the various methods of extracting genetic information to better characterize and predict outcomes in NAFLD. It also sparked some interesting questions about feasibility in the clinic. This session had a brilliant talk by Joern Schattenberg who used machine learning on clinical information from electronic health records to identify fast progressors among patients with NASH. While not all were convinced about the findings that diabetes was not a feature of fast progressors, one viewer commented that this was a ’tour de force’ on how machine learning can be used in clinical medicine, to which I would agree.

Marija: The Liver Meeting is always an exciting event when it comes to the announcement of results from clinical trials. This year I particularly liked the presentation on Akero’s Phase IIa NASH study where 50/80 subjects saw a ≥ 30% reduction in liver fat measured by IDEAL-PDFF. You rarely see 0% of change in the placebo arm! I also enjoyed the NAFLD Special Interest Group Symposium which discussed clinical management of NAFLD/NASH in 2020 and the future of NASH diagnostics and therapy. A number of biomarkers were discussed in the context of their usefulness for diagnosis and monitoring of NASH, especially for when the NASH drug becomes available. In context of clinical trials, compounds were assessed according to their success in NASH resolution and fibrosis improvement; I really liked this systematic overview. Finally, I was glad to see the results from two clinical trials on primary biliary cholangitis (PBC) presented in the late breaking session. While patients with rare diseases are often disadvantaged, the scientific and medical community spearheaded by AASLD remains determined to advance our understanding of rare liver disease. I am hopeful there will be more successful clinical research results presented on Primary Sclerosing Cholangitis (PSC) in the near future too.  

 

Q: What type of research did you see that related the severity of developing severe COVID-19 symptoms with NAFLD/NASH and/or other liver disease?

Andrea: Our very own Adriana Roca presented findings from our UKBB analysis in Parallel Session 15: COVID-19 and the Liver, which was a fascinating introduction to some impressive real-world studies. It sparked some interesting questions from the moderator about whether those with chronic liver disease should be prioritized for a vaccine when one becomes available.

Marija:  It was great seeing COVID-19 and its explored effect on the liver disease in the spotlight this year. Right before the conference Moderna announced the first interim analysis of their Phase 3 trial, and Pfizer and Bio-N-Tech have already presented positive results from their phase 3 trial. This now allows us to hope with cautious optimism that by the end of this year we could have an approved vaccine for COVID-19. As clearly outlined in Adriana Roca’s oral presentation, NAFLD/NASH patients are at higher risk of developing symptomatic COVID-19 infection, similar or more than other demographic and clinical factors. Any help with determining patients to be prioritized to receive the vaccine first as well as reducing risk factors will be much appreciated.

 

Q: Did you have a chance to watch Dr. Anthony Fauci’s talk and what did you think about his views on COVID-19?

Andrea: Yes, I did.  I really enjoyed hearing the recognizable and reassuring voice of Dr Fauci as he summarized the virology behind the virus and the current therapeutics and candidate vaccines. It was certainly very topical and accessible for scientists and non-scientists alike. This was followed by a fabulous talk by Dr Elizabeth Verner who explored the hepatic manifestations of the virus in more detail. She confirmed some of the findings we have seen with our own analysis in the UKBB data and from our own COVERSCAN study into multi-organ involvement in COVID-19 by showing the hospitalization rate and mortality were both increased in those with chronic liver disease as well as in those with diabetes, hypertension, cardiovascular disease and obesity. She also showed cases of high rates of steatosis in the absence of such traditional risk factors possibly suggesting a direct effect of the virus on the liver. It is very hard to establish causality in the studies of those after the virus when we don’t know what their baseline was, but it is clear that the liver is vulnerable with this virus.

Marija: I enjoyed Dr Fauci’s talk outlining the current state of therapeutic efforts towards finding a vaccine. It is pretty incredible how fast pharmaceutical companies designed and started the trials! In addition, Dr Fauci touched on the topic of ‘Long COVID’ and its effects on multiple organs. In Perspectum, we are running COVERSCAN, the largest global imaging study on ‘Long COVID’, which enrolled 500 participants who were considered healthy participants before contracting and recovering from COVID-19. Preliminary results show that these patients suffer more long-term organ damage than we expected. Almost 70% of participants had damage to one or more organs, including the heart and lungs.

 

Let’s move on to discussing Perspectum’s abstracts in more detail.

Abstract #1528 “META ANALYSIS OF COMPLICATIONS FROM LIVER BIOPSY: A 2010-2020 UPDATE FOR CHRONIC LIVER DISEASE” 

Q: Given the known complications of liver biopsy outlined in this abstract, do you think it should continue to be the gold standard for the diagnosis and monitoring of chronic liver disease?

Andrea: I think the limitations around liver biopsy as a good standard for NASH is fairly well accepted, for a host of reasons, including not only the complications, but also the lack of agreement between readers and the cost! There is a huge emphasis on finding either non-invasive or minimally invasive alternatives in this space. So, I think it is more a matter of time before the guidelines adjust to perhaps have biopsy used as a confirmatory test only when absolutely necessary.

Marija: Biopsy has been the gold standard test for liver disease for a while despite its inherent limitations — largely due to historic lack of reliable biomarkers. This is now changing, and, with the rise of the liver disease, it is clear that that validated non-invasive tests (NITs) are desperately needed. Late phase clinical trials, such as the REGENERATE trial, are collecting large amounts of biopsy paired NIT data which will help validate new technologies. With the expectation of a NASH drug coming to market in the near future, all eyes will be on biomarkers for identifying patients to be treated as this will simply not be possible with biopsy.

 

Abstract # 1495: “Comparative cost-effectiveness of multiparametric magnetic resonance imaging for detection of high-risk nonalcoholic steatohepatitis” 

Abstract # 1496: “Comparative performance of Non-invasive imaging modalities for the Diagnosis of NASH in a Japanese NAFLD Population”

Abstract #1498: ‘Comparison Between PDFF And CAP as Indicators of Hepatic Steatosis in a Pooled NASH Cohort”

Q: Perspectum presented 3 abstracts (listed above) analyzing and comparing various non-invasive technologies. What do you think the future holds for non-invasive technologies (NITs) being used in clinical trials for chronic liver disease?

Andrea: The future is bright! There is general agreement among regulators and sponsors alike to move towards using non-invasive tests in liver trials. We are constantly learning more about all the different evolving metrics, what contributes to and confounds their signal, and how to interpret that change. All this puts sponsors in an even better position to select the right metrics for their hypothesized mechanisms of action specifically. With the support and encouragement for continued development, it is an exciting time to be developing technologies in this space. In terms of adoption in clinical pathways, Abstract # 1495 is a great piece of work from our collaborators at Value Analytics Lab and MGH demonstrating that LiverMultiScan is cost-effective as a test to identify patients who may be suitable to go onto a NASH drug when one finally becomes available. This essentially means that paying for a LiverMultiScan instead of a biopsy is better value when judged against the impact of quality of life for the patient. Following the question above about biopsies, the scale of need to identify patients suitable for treatment is going to be huge and well validated, non-invasive biomarkers will certainly be needed.

Marija: NITs are undoubtedly the future of NASH in both clinical diagnostics and pharmaceutical trials. At this year’s meeting, several sessions and numerous abstracts focused on comparison of different non-invasive tests and their performance in detecting high-risk NASH as well as monitoring the disease. In a clinical trial setting, it is important that a biomarker has excellent diagnostic accuracy for enhanced enrichment of patient population at screening in addition to being robust and reproducible enough to reliably monitor those patients throughout the trial. Abstract #1496 shows that LiverMultiScan has the best diagnostic performance in identifying NASH in NAFLD population when compared to competitor technologies. It demonstrates positive predictive value of 0.9, making it a perfect biomarker for screening and lowering of screen fail rates and overall cost of the study. High correlation with the underlying disease (abstract #1598) and low variability rates (high reproducibility) of these biomarkers allow for detecting small changes in disease activity and monitoring treatment response. Finally, as seen in the abstract #1495, LiverMultiScan has superior cost-effectiveness in detecting of high-risk NASH when compared to the biopsy and and other imaging modalities. This makes it a diagnostic test of choice for treatment initiation with emerging NASH therapies.

 

Abstract #599 Liver Volume Diurnal Variation in UK Biobank 

Q: Given the marked change in liver volume throughout the day demonstrated by this study, how does this affect how sponsors should write their study protocols?

Andrea: That’s a good question. I think, as with any measure, it is very important to know the sources of variation and noise in the measure in order to be able to interpret it. It is not unusual to see variations in physiological measurement with, for example, the time of day or following meals; blood tests are often done after a 12-hour fast for that very reason. So, aiming for repeat scans at the same time of day is always a good idea. I think it would also be worth considering adjusting organ volumes for body size as well, especially if exploring cross-sectional relationships.

Marija: In comparison to the clinical setting, for clinical trials it is even more important for biomarkers to get the environment right as well as reduce noise from any external factors and other variables. This allows for best possible longitudinal comparison, which leads to the most objective assessment of the compound’s effectiveness. For all of Perspectum’s MRI scans, a minimum of 4-hour fasting is required. It is recommended that all scans are done at the same time of the day in order to reduce noise caused by natural fluctuations in physical parameters. The study presented in this abstract shows how valuable large population studies are; big data allows us to measure relatively small changes with high significance and confidence.

 

Abstract #1524 “Interactions with FDA and EMA: The Litmus Experience from Qualification Advice on Biomarkers in NASH”

Q: Qualification of a biomarkers requires in-depth knowledge of the different needs of EMA and FDA. How can Perspectum aid sponsors in the qualification of biomarkers for clinical trials?

Andrea: Perspectum's own imaging derived biomarker, cT1, has been submitted to the FDA and reviewed by the EMA as a diagnostic enrichment biomarker that can be used in conjunction with clinical risk factors to identify participants who are more likely to have NASH with fibrosis. Following encouraging feedback from both regulators we were invited by the FDA to submit a full qualification plan for the submission, which is currently under review. Having now also had the opportunity to work as part of the LITMUS consortium in this space, we certainly are beginning to know the landscape here!

Marija: LITMUS (EU) and NIMBLE (USA) are two excellent platforms for validation of non-invasive biomarkers for use in clinical trials and we are glad to be participating in advancing the field in this space. Separately, in Perspectum, we now have experience with biomarker qualification of both proprietary (cT1) and non-proprietary (PDFF) biomarkers, which makes us the perfect biomarker partner for sponsors who are either looking to use validated state-of-the-art biomarkers or to develop novel markers of the disease.

 

Oral presentation #55: “Diagnostic accuracy of MRI biomarkers cT1 and fat for high-risk non-alcoholic steatohepatitis”

Q: Are composite biomarker the future of accurate NASH diagnosis? Why do you think the combination of cT1, IDEAL-PDFF, Glucose, and AST performed as well as they did?

Andrea: It is now well accepted in NASH that no single available biomarker is perfect by itself as evidenced by the wealth of emerging research into combined biomarkers (e.g. steatoTest, FibroMax, FAST, APAPT, NIS4). In fact, the LITMUS consortium concluded that combined panels appeared to be more accurate than single biomarkers, demonstrating that harnessing the increased information made available by combining imaging and circulating biomarkers appears to build a more accurate profile of underlying liver disease than when used in isolation. The promise of such approaches may not only match the prognostic performance of liver biopsy but likely one day surpass it by forming a basis for precision medicine. What many of the composite markers have in common is the inclusion of a circulating markers related to inflammation and organs damage (e.g. AST) and in many cases commonly used markers of insulin sensitivity or metabolic syndrome (HOMA-IR, fasting glucose, diabetes status), which have also been independently linked to fibrosis in NASH. The inclusion of genetic markers, like in the NIS-4 panel, is a smart move in precision medicine and certainly an area that is gaining momentum across many fields of medicine. An important consideration, however, when selecting the most appropriate composite for a study is if the biomarker is also likely to be a good endpoint for the clinical trial. The technical stability of a measurement, in terms of test-retest, is a critical feature in order to use the measurement for reliable detection of meaningful changes over the course of an investigative trial. Additionally, it is equally important that the measurement is specific to the organ of interest, accessible and affordable. Imaged derived biomarkers for MR are big contenders in this space, but the pursuit of the ‘perfect’ NASH biomarker continues!

Marija: I do believe composite biomarkers are the future of accurate chronic liver disease diagnosis. Not only in NASH, but in other therapeutic areas as well such as PSC, a complex and rare disease combining parenchymal fibro-inflammation with pathologic changes in biliary tree. For both diagnosis and monitoring, it is important to measure all components of the disease. This is why the FDA guidance recommends composite endpoints as surrogates of actual response to treatment. Similarly, in NASH, there are different facets of the disease, involving steatosis, fibrosis, and inflammation. It makes sense to combine biomarkers to measure underlying pathology, especially in different stages of the disease.

 

Abstract #104: “Non-alcoholic fatty liver disease (NAFLD) associates with higher risk of developing symptomatic COVID19 infection - Initial UK Biobank Observations”

Q: If NAFLD patients are at a higher risk of suffering severe complications due to COVID-19, what does this mean for policy makers and the importance of driving forward NAFLD diagnosis and drug development?

Andrea: In the first instance, I think the more we learn about those more likely to develop severe forms of the virus, the better placed we will be to prioritize vaccines and provide healthy policy makers with information to guide their advice on self-isolation strategies. In the long-term, diagnosis of metabolic fatty liver disease (“MAFLD”) will become more important for the general public, who can often be asymptotic, and thus oblivious of their risk level, and may be a powerful motivator for lifestyle choices

Marija: I agree with Andrea, in addition to the importance of knowing the higher risk of these patients for developing symptomatic COVID-19, it is becoming increasingly clear how NAFLD — or MAFLD as it is more commonly being referred to now — is a silent epidemic that needs a cure, whether it be lifestyle change, medicine, or both.

 

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