Front Line Genomics brought together thought leaders from around the world to discuss New Approaches to the Old Hunt for NASH Therapies, available to watch on-demand. The conversation was moderated by Donna Cryer, the President and CEO of the Global Liver Institute. The panel discussed why there has been limited progress in therapies for nonalcoholic steatohepatitis (NASH) and possible approaches for the future.

Panel experts included:

  • Robert Lumsden, PhD, Clinical Programme Manager, Genomics Medicine Ireland
  • Jeffrey Gulcher, MD, PhD, Chief Scientific Officer & Co-founder, WuXi NextCODE
  • Sean Muthian, PhD, BS, MBA, Executive Director, External Science Innovations, Allergan
  • James Trevaskis, PhD, Director, Cell Biology – Fibrosis/NASH Group, Gilead Sciences
  • Matthews O. Bradley, PhD, Chairman, President, & Founder, SAJE Pharma LLC

NASH is the most severe form of non-alcoholic fatty liver disease (NAFLD). The global prevalence of NAFLD is as high as one billion and is the most common cause of chronic liver disease, affecting between 80 and 100 million in the U.S., among whom nearly 25% progress to NASH. NASH is characterised by the presence of an abnormal accumulation of fat in the liver. As NASH evolves, over time it can result in fibrosis in the liver, potentially leading to cirrhosis or cancer. Even 35 years after its formal description, no treatments have been shown to be universally effective, and even those which work partially have serious side effects.

The panel discussed why there has been limited progress and so many recent drug failures in the NASH field. The panellists pointed to the limited understanding of the underlying biology of NASH and stated that a ‘back to basics’ approach was needed. As NASH is a ‘complicated multi-factorial disease’ governed by multiple biological pathways, it was stressed that a one-target approach may not be that effective, highlighting the weakness in current therapies which are mainly repurposed diabetes and anti-inflammatory drugs with limited effectiveness.

Many researchers are looking at fibrosis as the most important factor, yet there was clear scepticism on the panel whether or not that approach will produce fruit. According to Matthews O. Bradley, SAJE Pharma, “I wonder with NASH whether the fibrosis is really the thing that is most important rather than what’s going before it. … I wonder if there’s a possibility that we end fibrosis and … it really doesn’t have that much effect on the disease itself.”

James Trevaskis, Gilead Sciences, added to this idea, “We don’t really understand what drives fibrosis progression or NASH development [so we must] do those deeper dives into the biology to try to understand what constitutes the right pathways to target in NASH.”

Pointing to a population-scale approach as a potential solution was Robert Lumsden, Genomics Medicine Ireland (GMI). “We need to do larger-scale studies, and we need to look at a DNA level down to a tissue level … really trying to do multi-omics,” Dr. Lumsden said. “In Ireland we’re going to [use] thousands of patients and do germline DNA and we’re going to use tissue, … and looking at RNA-seq, DNA methylation, epigenetics, things like that, and then single-cell sequencing, looking at the individual cell types again, and … we might be able to find new trends and new protein clusters that perhaps we haven’t seen before because we haven’t done something of that size before.”

WuXi NextCODE’s Jeffrey Gucher is working with GMI to make the NASH cohort data available to their partners, as well as developing similar population-scale cohorts elsewhere. According to Gulcher, “one of the collaborations we set up on NASH target discovery is with George Goh with SingHealth in Singapore, … because in that Asian population, the traditional risk factors – diabetes and obesity – are much lower … yet the prevalence of NASH itself is out of proportion to the prevalence of those risk factors. So we think maybe there’s a chance there’s a stronger genetic or genomic component to it. Also there’s less potential contamination from alcohol use.”

What was clear from the panel is that improving understanding of the underlying biology of the progression of NASH in humans is an important part of future R&D. Sean Muthian, Allergan emphasized this point when asked what excites him most about the future of NASH R&D: “what Dr. Gulcher and Dr. Lumsden are working on is in translational sciences from the human context, and then working a little backwards, versus traditionally what we’ve done is animal models and then working towards humans – I think that’s really exciting.”

NASH is also difficult to study in the clinic. There is a shortage of effective biological models for the disease, as rodents display fibrosis differently from humans. As NASH is a long-term and slow-progressing disease, it is difficult to design effective clinical trials. Current tests to see how patients are progressing are highly invasive, which makes it difficult to monitor the disease. Early detection is key for effective NASH treatment, but many patients present at the fibrosis stage. Robert Lumsden, Genomics Medicine Ireland emphasized that “the earlier we intervene, the easier it’ll be. When fibrosis gets [severe], it’s just such a difficult thing to reverse.”

However, it is clear progress has been made in NASH research. Biomarkers provide a mechanism for monitoring NASH progression, meaning patients can be stratified into clinical trials depending on their disease severity. Advances in genetic research will enable researchers to study why some patients progress to fatty liver disease whilst others don’t, which could give indications of possible targets. Artificial intelligence enables researchers to search effectively for relevant gene clusters. The panel was pleased that in a short period NASH ‘has got into the large public domain’ (Dr. Muthian) enabling greater public understanding of the disease and patient engagement.

The panel discussed priority areas for future research. A multi-disciplinary approach is needed across genetics, immunology and artificial intelligence to understand the biology of NASH. James Trevaskis, Gilead Sciences said he is “excited about the advances in technology that hopefully will help us build better pre-clinical packages for prospective targets and therapies, and by that I mean not just single-cell sequencing and advances in understanding what’s going on with the human disease through that kind of analyses, but organ on the chip, bioprinting, utilization of human cells and tissue, to really prosecute compounds or drug development programs through that, hopefully it’ll be faster and more relevant than some of the animal models, which do have some limitations.”

Non-invasive technologies need to be developed to enable monitoring and early diagnosis of NASH. More research is also needed at the pre-fibrosis stage to identify the mechanism through which fatty liver disease occurs, with studies on the epigenetics and RNA involved in the process key to understanding it. In the clinic, more patient input is needed to inform understanding of the disease and dose optimisation, and to ensure the treatment benefits are balanced against side-effect risks. The panel also stressed the importance of clinical trials that were representative of different ethnicities and populations. They concluded that ‘more data, both at the clinical and cell level, is needed to inform new therapies.’

Lastly, they discussed potential therapies and treatments. The panel raised the possibility of combination therapies, although there are concerns that this could lead to synergistic toxicity. Targets that had genomic evidence backing their use were much more successful in getting past stage 1 of clinical trials than those that did not. One panellist cited a potential target which regulated an enzyme involved in inflammation and oxidative stress, which had shown promise in reversing fibrosis. The panel concluded that the multiple targets being explored ‘will lead to impact for clinically meaningful therapies within the next few years.’

If you are interested in finding out more, you can now watch the full webinar on demand here.

We’d like to thank our partner WuXi NextCODE who helped make this webinar possible.

Developing therapies for NASH will require understanding the genetic and biological drivers of its progression from NAFL. WuXi NextCODE is building a patient cohort to answer these questions and are inviting partners to join. To learn more, download the NASH program overview.

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