The Take Home

Take Home from NASH-TAG: On the precipice of the fatty liver pipeline

Michael Charlton, MD
Michael Charlton

by Michael Charlton, MD

Four years ago, as Vlad Ratziu, MD, and I spent some time together, we reflected on the emerging field of non-alcoholic steatohepatitis, realizing it was starting down the same path that hepatitis C forged just years prior. Looking around, we realized we needed a meeting much like HEP-DART, a meeting dedicated to the development of therapeutic agents for viral hepatitis, and we seized the opportunity to start NASH-TAG.

We developed this meeting to fill what we felt was a gap in the NASH landscape. There are a lot of meetings on fatty liver disease, but we wanted one that was very focused on therapeutic agent development, hence the TAG (Therapeutic AGent) acronym. We wanted to have key opinion leaders, lead investigators and the most eminent scientists in the field in the same room as people in the pharmaceutical industry who are designing clinical trials through all their phases –preclinical, phases 1, 2 and 3. We wanted the meeting to be characterized by having the best speakers, by facilitating discussion and being a catalyst for advancing the therapeutic agent development field.

That was the goal and one that I believe we have achieved and will continue to achieve.

This year was our third year and we had a record number of attendees. In fact, this year we were unable to take further registrants. We had clinicians and scientists from Europe and the United States, panelists from the guidelines for AASLD and EASL, as well as lead investigators from the major clinical trials and medical directors from the many companies that are engaged in the NASH space.

2018: A year of lessons

From the current review of the major presentations and clinical trial results from 2018, the emerging theme is that the agents in phase 2B and those that have moved forward into phase 3 studies (there are six underway), have shown modest results at best. The idea forming from those results is that monotherapy is unlikely to endure as the best therapy, again hearkening back to the days of HCV. Combination studies are needed in NASH.

We discussed that those combination studies may include GLP-1 agonists, as these already-approved agents enhance weight loss and have shown front runner efficacy for histological endpoints in phase 2 clinical trials of NASH. GLP-1 agonists can routinely achieve greater than 5% weight loss at a frequency of up to 80% or more. If you take weight loss as a NASH therapy, the histological endpoints associated with greater than 5% weight loss are equal to or better than essentially any of the agents currently in phase 2B or phase 3 studies.

Weight loss, probably facilitated by GLP-1 agonists or other weight loss agents, is an emerging standard of care or at least therapy of choice and it will be the benchmark by which the phase 2 or phase 3 agents in the NASH field will be judged.

Those therapies in phase 3 trials – selonsertib (Gilead), elafibranor (Genfit), obeticholic acid (OCA; Intercept), cenicriviroc (Allergan) – have various relative efficacy, depending on the comparative placebo and endpoint.

For example, if you take fibrosis reduction by at least one stage and compare efficacy to that achieved by a standard placebo, the most efficacious therapy in advanced clinical trials appears to be selonsertib. On the other hand, if you took reduction in fat, you have a completely different relative efficacy, with the FGF-19 agonist, NGM-282 (NGM Bio), achieving the greatest margin over a standard placebo and if you took NASH resolution, a totally different order again. It’s very dependent on the endpoints and to which placebo response rate the agent is considered.

Standardizing the placebo response rate and changing endpoints had a dramatically different effect on apparent relative efficacy. These studies are not conducted head-to-head, but the field is interested in being able to estimate relative efficacy and potency of these agents. That was a key discussion in the first part of the meeting.

The standard placebo we took in the comparison across treatments was the efficacy achieved with less than 5% weight loss, a widely used minimal goal of diet and exercise, based on a paired biopsy-controlled study conducted by Vilar-Gomez. In that study, Vilar-Gomez and colleagues showed that more than 5% weight loss produced improved NASH scores and a frequency of resolution of NASH at significantly greater rates than observed in patients who loss less than 5% weight. In lieu of standard placebo response rate, we feel that histological endpoints achieved by patients who lose less than 5% weight with diet and exercise is a low bar for the sake of a standard placebo effect.

Another emerging idea out of NASH-TAG was that it has become a standard in clinical trials to report the reduction in liver fat measured by 5% reduction or more of absolute proton density fat fraction (PDFF) or a greater than or equal to 30% relative reduction. Yet, if you held the four agents currently in phase 3 studies to that standard, none of them would have been advanced to phase 3.

Relative and absolute reduction in fat as measured by PDFF is certainly an important parameter to consider and obviously it is predictive of de-lipidation of the liver and likelihood of NASH resolution, but it would not have identified any of these agents currently in phase 3 as being efficacious. While we believe it is important to have a broad set of benchmarks and biomarkers, nothing currently available has enabled us to move away from histology. For the time being, histology is still the gold standard for measuring efficacy in NASH treatments. Importantly, data were presented suggesting that the sensitivity of histology itself appears to be enhanced by digital technologies, such as second harmonic generation.

MRE or liver stiffness is clearly affected by things other than fibrosis and is subject to a timeframe in which MRE becomes interpretable. That timeframe is more than 16 weeks, something we learned that from the fibrosis growth factor studies with the FGF19 and FGF21 agonists.

In addition to standardizing the endpoints used, a standardized comparator or placebo arm is sorely needed. Phase 2 studies tend to be reported against tremendously variable placebo response rates across all the endpoints that are currently being assessed. Studies reported in 2018 re-affirmed that a standard placebo response rate is a key unmet need in the field.

Screening, diagnosis

There was a deep discussion about screening approaches and surveillance for fatty liver disease during our meeting. Because there are already 80 million people in the U.S. with fatty liver, and we do not have an FDA approved therapy, no one is yet recommending routine screening for fatty liver disease. That said, screening in high-risk groups should be considered; people with metabolic syndrome, type 2 diabetes, people with testosterone deficiency or growth hormone deficiency should be considered for screening

When measuring fatty liver, it’s hard to beat the NAFLD Fibrosis Score (FS; MDCalc), which is a free test you can perform using an online calculator. There are emerging comparators like the Enhanced Liver Fibrosis (ELF; Siemens) tool, which is currently under review by the FDA.

In terms of imaging as a screening tool, we feel vibration controlled transient elastography, currently marketed with Fibroscan (Echosens), has emerged as an excellent tool for screening because of its point of care availability and the increasing availability of the device itself.

We discussed other emerging technologies such as magnetic resonance elastography, cT1 and emerging biomarkers that are relatively earlier in the development, as well.

Looking ahead

In looking ahead to 2019, we anticipate readouts on at least two of the phase 3 studies. OCA and selonsertib will have full data sets imminently and could submit them to the FDA this year. It’s feasible that the FDA could be making decisions on those treatments in 2020.

There are also emerging data to suggest that digital image analysis may make histological endpoints more reproducible and reliable. Specifically, I am looking forward to new insight into second harmonic generation analysis of fibrosis as well as ballooning and steatosis.

Then there are some totally new approaches in terms of targets and therapeutic agents in development. It is a long list, but there are some exciting agents ranging from antifibrotics – integrin inhibitors – to combined PPAR agonists in addition to oral GLP-1 agonists. There is a tremendous pick up in the pace of therapeutic agent development and endpoint assessment.

I’m also looking forward to combination studies. These are just beginning to get close to data sets that we can consider. It’s likely that combination studies with a GLP-1 agonist and direct-acting NASH agent are likely to begin in the next year or so.

That’s a new idea that’s emerged from this meeting as well as a host of collaborations between smaller biotechs and larger companies. I am most excited that the field is becoming increasingly collaborative in therapeutic agent development.

NASH-TAG has filled a tremendous gap in that regard. I’m looking forward to next year. We’ve received tremendous feedback from attendees and participants about how much they enjoyed and learned so we are very satisfied with the meeting’s progress and position in the field.

We are at the beginning of the direct-acting agent era in NASH. There are differences between HCV and NASH, of course, but there are also similarities in drug development. There are similarities between the early era of DAAs in HCV and the current era for NASH, so we anticipate a quick change in our treatment options as we saw with HCV.

Planning for 2020

NASH-TAG is a wonderful meeting that I hope many more will attend in the coming years. It’s extremely good for networking and learning about the field and we hope to attract even more academic and pharmaceutical industry leaders. In 2020, we will be moving to a bigger space but staying in Deer Valley, roughly the same time and same place.

One of the features of most medical conferences in general – especially for NASH – is that despite having a meeting focused on a disease that is somewhat based on lifestyle, these meetings are held in places where it is hard to be healthy. One of the characteristics of NASH-TAG is that we hold it in a healthy place.

We are on a mountain and although we are a hard-core academic meeting, we do make time in the middle of the day to exercise and enjoy the mountain. We maintain a good total number of hours by starting early and finishing late with the break in the middle of the day. We will maintain the location as it has become a hallmark of the meeting.

Watch www.nash-tag.org for updates on our 2020 meeting.

Disclosures: Charlton reports acting on advisory committees or review panels for Gilead; consulting for AbbVie, Enterome, Gilead, Intercept, Metacrine, NGM Bio and Novartis; and receiving grant or research support from Conatus, Galectin and Gilead.

References:

Vilar-Gomez E, et al. Gastroenterology. 2015; doi: 10.1053/j.gastro.2015.04.005.

Michael Charlton, MD
Michael Charlton

by Michael Charlton, MD

Four years ago, as Vlad Ratziu, MD, and I spent some time together, we reflected on the emerging field of non-alcoholic steatohepatitis, realizing it was starting down the same path that hepatitis C forged just years prior. Looking around, we realized we needed a meeting much like HEP-DART, a meeting dedicated to the development of therapeutic agents for viral hepatitis, and we seized the opportunity to start NASH-TAG.

We developed this meeting to fill what we felt was a gap in the NASH landscape. There are a lot of meetings on fatty liver disease, but we wanted one that was very focused on therapeutic agent development, hence the TAG (Therapeutic AGent) acronym. We wanted to have key opinion leaders, lead investigators and the most eminent scientists in the field in the same room as people in the pharmaceutical industry who are designing clinical trials through all their phases –preclinical, phases 1, 2 and 3. We wanted the meeting to be characterized by having the best speakers, by facilitating discussion and being a catalyst for advancing the therapeutic agent development field.

That was the goal and one that I believe we have achieved and will continue to achieve.

This year was our third year and we had a record number of attendees. In fact, this year we were unable to take further registrants. We had clinicians and scientists from Europe and the United States, panelists from the guidelines for AASLD and EASL, as well as lead investigators from the major clinical trials and medical directors from the many companies that are engaged in the NASH space.

2018: A year of lessons

From the current review of the major presentations and clinical trial results from 2018, the emerging theme is that the agents in phase 2B and those that have moved forward into phase 3 studies (there are six underway), have shown modest results at best. The idea forming from those results is that monotherapy is unlikely to endure as the best therapy, again hearkening back to the days of HCV. Combination studies are needed in NASH.

We discussed that those combination studies may include GLP-1 agonists, as these already-approved agents enhance weight loss and have shown front runner efficacy for histological endpoints in phase 2 clinical trials of NASH. GLP-1 agonists can routinely achieve greater than 5% weight loss at a frequency of up to 80% or more. If you take weight loss as a NASH therapy, the histological endpoints associated with greater than 5% weight loss are equal to or better than essentially any of the agents currently in phase 2B or phase 3 studies.

PAGE BREAK

Weight loss, probably facilitated by GLP-1 agonists or other weight loss agents, is an emerging standard of care or at least therapy of choice and it will be the benchmark by which the phase 2 or phase 3 agents in the NASH field will be judged.

Those therapies in phase 3 trials – selonsertib (Gilead), elafibranor (Genfit), obeticholic acid (OCA; Intercept), cenicriviroc (Allergan) – have various relative efficacy, depending on the comparative placebo and endpoint.

For example, if you take fibrosis reduction by at least one stage and compare efficacy to that achieved by a standard placebo, the most efficacious therapy in advanced clinical trials appears to be selonsertib. On the other hand, if you took reduction in fat, you have a completely different relative efficacy, with the FGF-19 agonist, NGM-282 (NGM Bio), achieving the greatest margin over a standard placebo and if you took NASH resolution, a totally different order again. It’s very dependent on the endpoints and to which placebo response rate the agent is considered.

Standardizing the placebo response rate and changing endpoints had a dramatically different effect on apparent relative efficacy. These studies are not conducted head-to-head, but the field is interested in being able to estimate relative efficacy and potency of these agents. That was a key discussion in the first part of the meeting.

The standard placebo we took in the comparison across treatments was the efficacy achieved with less than 5% weight loss, a widely used minimal goal of diet and exercise, based on a paired biopsy-controlled study conducted by Vilar-Gomez. In that study, Vilar-Gomez and colleagues showed that more than 5% weight loss produced improved NASH scores and a frequency of resolution of NASH at significantly greater rates than observed in patients who loss less than 5% weight. In lieu of standard placebo response rate, we feel that histological endpoints achieved by patients who lose less than 5% weight with diet and exercise is a low bar for the sake of a standard placebo effect.

Another emerging idea out of NASH-TAG was that it has become a standard in clinical trials to report the reduction in liver fat measured by 5% reduction or more of absolute proton density fat fraction (PDFF) or a greater than or equal to 30% relative reduction. Yet, if you held the four agents currently in phase 3 studies to that standard, none of them would have been advanced to phase 3.

PAGE BREAK

Relative and absolute reduction in fat as measured by PDFF is certainly an important parameter to consider and obviously it is predictive of de-lipidation of the liver and likelihood of NASH resolution, but it would not have identified any of these agents currently in phase 3 as being efficacious. While we believe it is important to have a broad set of benchmarks and biomarkers, nothing currently available has enabled us to move away from histology. For the time being, histology is still the gold standard for measuring efficacy in NASH treatments. Importantly, data were presented suggesting that the sensitivity of histology itself appears to be enhanced by digital technologies, such as second harmonic generation.

MRE or liver stiffness is clearly affected by things other than fibrosis and is subject to a timeframe in which MRE becomes interpretable. That timeframe is more than 16 weeks, something we learned that from the fibrosis growth factor studies with the FGF19 and FGF21 agonists.

In addition to standardizing the endpoints used, a standardized comparator or placebo arm is sorely needed. Phase 2 studies tend to be reported against tremendously variable placebo response rates across all the endpoints that are currently being assessed. Studies reported in 2018 re-affirmed that a standard placebo response rate is a key unmet need in the field.

Screening, diagnosis

There was a deep discussion about screening approaches and surveillance for fatty liver disease during our meeting. Because there are already 80 million people in the U.S. with fatty liver, and we do not have an FDA approved therapy, no one is yet recommending routine screening for fatty liver disease. That said, screening in high-risk groups should be considered; people with metabolic syndrome, type 2 diabetes, people with testosterone deficiency or growth hormone deficiency should be considered for screening

When measuring fatty liver, it’s hard to beat the NAFLD Fibrosis Score (FS; MDCalc), which is a free test you can perform using an online calculator. There are emerging comparators like the Enhanced Liver Fibrosis (ELF; Siemens) tool, which is currently under review by the FDA.

In terms of imaging as a screening tool, we feel vibration controlled transient elastography, currently marketed with Fibroscan (Echosens), has emerged as an excellent tool for screening because of its point of care availability and the increasing availability of the device itself.

We discussed other emerging technologies such as magnetic resonance elastography, cT1 and emerging biomarkers that are relatively earlier in the development, as well.

PAGE BREAK

Looking ahead

In looking ahead to 2019, we anticipate readouts on at least two of the phase 3 studies. OCA and selonsertib will have full data sets imminently and could submit them to the FDA this year. It’s feasible that the FDA could be making decisions on those treatments in 2020.

There are also emerging data to suggest that digital image analysis may make histological endpoints more reproducible and reliable. Specifically, I am looking forward to new insight into second harmonic generation analysis of fibrosis as well as ballooning and steatosis.

Then there are some totally new approaches in terms of targets and therapeutic agents in development. It is a long list, but there are some exciting agents ranging from antifibrotics – integrin inhibitors – to combined PPAR agonists in addition to oral GLP-1 agonists. There is a tremendous pick up in the pace of therapeutic agent development and endpoint assessment.

I’m also looking forward to combination studies. These are just beginning to get close to data sets that we can consider. It’s likely that combination studies with a GLP-1 agonist and direct-acting NASH agent are likely to begin in the next year or so.

That’s a new idea that’s emerged from this meeting as well as a host of collaborations between smaller biotechs and larger companies. I am most excited that the field is becoming increasingly collaborative in therapeutic agent development.

NASH-TAG has filled a tremendous gap in that regard. I’m looking forward to next year. We’ve received tremendous feedback from attendees and participants about how much they enjoyed and learned so we are very satisfied with the meeting’s progress and position in the field.

We are at the beginning of the direct-acting agent era in NASH. There are differences between HCV and NASH, of course, but there are also similarities in drug development. There are similarities between the early era of DAAs in HCV and the current era for NASH, so we anticipate a quick change in our treatment options as we saw with HCV.

Planning for 2020

NASH-TAG is a wonderful meeting that I hope many more will attend in the coming years. It’s extremely good for networking and learning about the field and we hope to attract even more academic and pharmaceutical industry leaders. In 2020, we will be moving to a bigger space but staying in Deer Valley, roughly the same time and same place.

One of the features of most medical conferences in general – especially for NASH – is that despite having a meeting focused on a disease that is somewhat based on lifestyle, these meetings are held in places where it is hard to be healthy. One of the characteristics of NASH-TAG is that we hold it in a healthy place.

We are on a mountain and although we are a hard-core academic meeting, we do make time in the middle of the day to exercise and enjoy the mountain. We maintain a good total number of hours by starting early and finishing late with the break in the middle of the day. We will maintain the location as it has become a hallmark of the meeting.

Watch www.nash-tag.org for updates on our 2020 meeting.

Disclosures: Charlton reports acting on advisory committees or review panels for Gilead; consulting for AbbVie, Enterome, Gilead, Intercept, Metacrine, NGM Bio and Novartis; and receiving grant or research support from Conatus, Galectin and Gilead.

References:

Vilar-Gomez E, et al. Gastroenterology. 2015; doi: 10.1053/j.gastro.2015.04.005.