NASH Summit

April 4-6, 2017; Boston, MA; Full Report – Draft

Executive Highlights

We’re back from the first-ever NASH Summit, which took place in the beautiful city of Boston! The goal of the three-day conference was to gather players from all corner of the growing NASH field to “help drug developers meet the unique challenges of developing a NASH drug,” but the agenda also featured many useful talks to bring attendees up to speed on the pathophysiology of the disease, areas of pressing need, and progress in drug development. Following this meeting, we have a new appreciation for just how challenging NASH drug development is from a preclinical, clinical, and commercial perspective:

- The preclinical challenge: There are no good animal models or biomarkers for NASH

- The clinical challenge: NASH diagnosis currently requires a liver biopsy, which makes screening and clinical trial recruitment very difficult

- The commercial challenge: How big is the addressable NASH market? NASH prevalence is great, but the disease is asymptomatic for many years, making it unclear when treatment should begin

Dr. Christian Weyer, President of ProSciento (Chula Vista, CA), summed up the evolving NASH field with the following observation: “we are currently flying the plane while building it.” His apt description underscored the challenge inherent in the development of new drugs for a disease we are still working to understand. This metaphor captured the state of the NASH field so aptly that speakers who followed him quoted him in their own talks. 

Below we outline our top five takeaways from this enlightening meeting, plus detailed summaries of the talks we found most notable.

Top Five Highlights

1. Affecting a staggering 16-64 million people in the US with no currently FDA-approved therapy, NASH may constitute the “next big global epidemic.” First line therapy is lifestyle modification and last line therapy is liver transplantation, leaving a massive need for pharmacotherapy as a mid-stage treatment option: the market for pharmacotherapy for severe forms of NASH is estimated at >$18 billion in the US alone.

2. A bright spot in the challenging NASH arena is the growing size of the competitive landscape, which includes five candidates in phase 3, 37 in phase 2, 23 in phase 1, and 109 in preclinical development. Particular optimism surrounds two phase 3 candidates: Genfit’s dual PPAR alpha/gamma agonist elafibranor and Intercept’s FXR agonist obeticholic acid.

3.  NASH is an incredibly complex disease state, with numerous challenges from a clinical standpoint (it is asymptomatic in early stages, with no known biomarkers) as well as scientific standpoint (the natural history of the disease is not yet understood, and no accurate animal models exist).

4. Ongoing efforts in NASH drug development are taking place alongside research into the pathophysiology of this poorly-understood disease. In two  informative talks, Dr. Wielin Xie (Celgene, Summit, NJ) brought us up to speed on researchers’ current thinking on NASH pathogenesis and Drs. David Lomb and Brent Osborne (Defined Health, Florham Park, NJ) overviewed NASH disease progression and prevalence.

5. Collaboration is key! Nearly every speaker stressed the need for collaboration across industry and academia to surmount the present challenges in NASH drug development.

Top Five Highlights

1. NASH: An Area of Massive Unmet Need (and Opportunity)

NASH affects a staggering 16-64 million people in the US, but there are currently no FDA-approved drugs for its treatment. This, according to Dr. Manal Abdelmalek (Duke University, Durham, NC), may constitute the “next big global epidemic.”

  • First line therapy is lifestyle modification and last line therapy is liver transplantation, leaving a massive need for pharmacotherapy as a mid-stage treatment option. NASH exists along a spectrum: non-alcoholic fatty liver disease (NAFLD) gives rise to non-alcoholic hepatosteatosis (NASH), followed by fibrosis and ultimately cirrhosis. As we learned from Drs. David Lomb and Brent Osborne (Defined Health, Florham Park, NJ), NASH itself is asymptomatic until it progresses to fibrosis and beyond – which it does in 25-40% of cases. Fibrosis is independently associated with long-term overall mortality, liver transplantation, and hepatocellular carcinoma (HCC). Accordingly, drug development efforts have aspired toward therapies that reverse or arrest the progression of fibrosis. This is made challenging, however, by our current inability to predict which patients will progress to the symptomatic fibrosis and cirrhosis stages.
  • Besides being an area of unmet need, NASH is also an area of massive opportunity: the market for treatment targeting only NASH patients with significant (F2) to advanced (F3) fibrosis is estimated at over $18 billion in the US alone. The excitement surrounding this as-of-yet untapped market is reflected in the increasing size of the NASH/NAFLD competitive landscape.

2. The NASH Competitive Landscape: Particular Promise for Genfit’s elfibranor and Intercept’s obeticholic acid

A bright spot in the challenging NASH arena is the growing size of the competitive landscape, which includes five candidates in phase 3, 37 in phase 2, 23 in phase 1, and 109 in preclinical development. (Our competitive landscape outlines several of these in detail.) Particular optimism surrounds two phase 3 candidates: Genfit’s dual PPAR alpha/gamma agonist elafibranor and Intercept’s FXR agonist obeticholic acid, and Dr. Brent Osborne (Defined Health, Florham Park, NJ) predicted that at least one of these candidates will eventually be approved. He warned, however, that both elafibranor and obeticholic acid will likely be priced far above what he calls the “willingness-to-pay threshold.” The predicted cost for elafibranor is $68,000 per year, versus $12,500 to $33,00 per year for obeticholic acid. Dr. Osborne forecasted that unless these drugs have dramatic effect on NASH or a much lower list price, payers are not likely to position these agents favorably on their formularies.  it is very likely that payers will greatly restrict access.

  • We heard from Dr. Sophie Mégnien, CMO of Genfit, on the company’s development program for elafibranor, which holds a Fast Track designation from the FDA.  In the phase 2b GOLDEN-505 trial,  elafibranor was demonstrated to be safe and well-tolerated and led to dose-dependent increase in the primary endpoint, “resolution of NASH without worsening of fibrosis” (p=0.027), as well as significant improvements in other secondary cardiometabolic endpoints over the course of one year in participants across various levels of NAFLD, NASH, and fibrosis (n=275). A multi-center phase 3 trial called RESOLVE-IT is currently ongoing, focused on NASH patients with significant (F2) to advanced (F3) fibrosis (n=2000). The estimated primary completion date is December 2021 according to ClinicalTrials.gov – a lengthy timeline because of Genfit’s suspicions that the timecourse of NASH is so prolonged that even a very effective drug may not show an observable effect until several years have passed.
  • Intercept’s phase 3 REGENERATE trial for obeticholic acid is also ongoing in participants with NASH and stage 2 or 3 fibrosis. Participants are randomized to receive 10 mg or 25 mg obeticholic acid or placebo. Co-primary endpoints of proportion of patients achieving at least one stage of liver fibrosis improvement with no worsening of NASH and the proportion of patients achieving NASH resolution with no worsening of fibrosis after 18 months, and the time to first occurrence of adjudicated liver-related clinical outcomes (death, end-stage liver disease, liver transplant, HCC, progression to cirrhosis, etc.) after six years. The study is expected to complete in October 2021, right on schedule with Genfit’s phase 3 trial. A previous phase 2 study investigated dosing and effectiveness of obeticholic acid at 10, 20, and 40 mg, showing a dose-dependent increase in the percentage of drug-treated subjects compared to placebo who experienced a decrease in NASH severity with no worsening of fibrosis. Notably the results did not reach statistical significance (p=0.053).
  • Allergan is another major player in the NASH arena. The company is developing multiple contenders for a NASH indication, including the phase 2 CCR2/CCR5 inhibitor cenicriviroc (CVC) and phase 1 DPP-4 inhibitor evogliptin (acquired from Tobira Therapeutics) and the preclinical FXR agonist AKN-083 (acquired from Akarna Therapeutics, along with other FXR agonists at earlier stages of development). These acquisitions came within just days of one another this past September, and this seems to signal the company’s commitment to innovation in NASH as well as a very strong vote of confidence in the market potential of NASH therapies.
  • NASH expert Dr. Weilin Xie (Celgene, San Diego, CA) predicts that combination drug therapy is likely to be the most successful in treating this heterogeneous disease.  He highlighted two important histological features of NASH for potential drug targeting: inflammation and fibrosis. Many drugs in development for NASH act on single potential disease-causing mechanism outside inflammation and fibrosis but so far few  can impact multiple such as both inflammation and fibrosis – thus it seems likely that combination therapy will be essential to treat both features of NASH. That said, the timing of different components of combination therapy is also important; Dr. Xie emphasized that anti-inflammatory therapies are likely to slow or arrest the progression of NASH at earlier stages of the disease, but more difficult at the later stages at which NASH is typically diagnosed.
    • Given the sheer diversity of drug classes represented on the NASH competitive landscape, we are optimistic that the future of NASH treatment will be rich with potential combination therapy options. Besides the aforementioned FXR agonists, PPAR alpha/gamma agonists, CCR2/CCR5 inhibitors, and DPP-4 inhibitors, the ever-evolving competitive landscape also includes familiar classes such as GLP-1 agonists and SGLT-2 inhibitors, in addition to ASK-1 inhibitors, a fatty-acid/bile-acid conjugate, capase inhibitors, a leucine/PDE5 inhibitor/metformin coformulation,  thyroid beta receptor agonists, FGF19 agonists, ACC inhibitors, DGAT-2 inhibitors, thyroid hormone receptor-beta (THR-beta) agonists, MetAP2 inhibitors, KLB-FGFR1c receptor complex agonists, LOXL2 antibodies, polysaccharide polymers, and even an oral immunotherapy that targets the gut bacteria. See the full landscape for a much deeper dive.

3. Challenges in NASH Drug Development

NASH is an incredibly complex disease state, with numerous challenges from a clinical as well as scientific standpoint. Some of the most pressing difficulties include:

  • There are no known non-invasive biomarkers to diagnose NASH or assess its progression. The current gold standard for diagnosis is the liver biopsy, an invasive and rare surgery, hence low rates of NASH diagnoses and a severe shortage of clinical trial subjects. Some clinicians use liver enzyme tests as a less-invasive alternative to diagnosis liver diseases, particularly in cardiovascular patients, but enzyme level is not actually associated with the absence or presence of NASH or the severity of its progression.
  • The natural history of the disease is largely unknown. This means that drug developers must use incomplete information as they try to develop a treatment – like “flying the plane while building it,” as articulated by Dr. Christian Weyer (ProSciento, Chula Vista, CA).
  • There is no animal model that can reproduce the clinical features of human NASH. This slows down early-stage drug development and generates extra costs in the long run; drugs often fail in human trials after producing a false positive in the less-than-ideal mouse model.
  • NASH is a slow-developing disease and therefore requires long clinical trials. In the majority of cases, NASH is asymptomatic for decades until it progresses to fibrosis. This slow natural history necessitates long (and therefore costly) clinical trials investigate the effectiveness of any drug.
  • The asymptomatic nature of early-stage NAFLD/NASH makes early intervention nearly impossible. This also dissuades patients and providers regarding liver biopsies for NASH diagnostic screening.

4. NASH Natural History

Ongoing efforts in NASH drug development are taking place alongside research into the pathophysiology of this poorly-understood disease. In an informative talk, Dr. Weilin Xie (Celgene, San Diego, CA) brought us up to speed on the two dominant models of NASH pathogenesis, the “two hit” model and the “multiple parallel hits” model. According to the ” two hit” model, an initial ‘hit’ of triglyceride accumulation in the liver makes the organ more susceptible to injury from second hits such as inflammation, mitochondrial dysfunction, or oxidative stress, which in turn lead to steatohepatitis and then fibrosis. The other theory – which Dr. Xie favors –  is the “multiple parallel hits” model, which contends that there are many parallel events that lead to the development of the disease. The fact that the majority of NASH patients have ‘multiple hits’ in the form of type 2 diabetes, insulin resistance, and obesity adds credence to this theory. As explained in a preconference crash course in NASH led by Defined Health’s (Florham Park, NJ) Drs. David Lomb and Brent Osborne, NAFLD gives rise to NASH, followed by fibrosis and ultimately cirrhosis. It is estimated that 30% of people with NAFLD will progress to NASH and 25-40% of people with NASH will develop significant liver fibrosis. A separate speaker pointed out that a steep 20% of people with NAFLD are “fast progressors,” developing NASH and ultimately cirrhosis in only 10 years.

  • NASH is highly comorbid with type 2 diabetes and obesity. Although consensus has yet to emerge in the literature, it is estimated that between 69-87% of people with type 2 diabetes have NAFLD while 22% have NASH. Furthermore 37% of people with a BMI >40 kg/m2 have NASH, though notably this number is probably larger in individuals of Hispanic or Asian descent, who tend to develop NASH at lower BMI thresholds.

5. Collaboration is Key!

Nearly every speaker stressed the need for collaboration across industry and academia to surmount the present challenges in NASH drug development. Dr. Manu Chakravarthy, VP and Global Head of External R&D in Diabetes and Cardiovascular Disease at Lilly, gave a particularly interesting perspective on this, highlighting the Innovative Medicine Initiative (IMI) consortium, which facilitates collaboration between universities, pharmaceutical companies, patient organizations, and regulatory agencies to speed the drug development process. The consortium will launch a NASH initiative in 3Q17, spearheaded by Dr. Chakravarthy and colleagues, with the primary goal of validating a non-invasive biomarker for all levels of the NAFLD spectrum. Another consortium beginning to become involved in the NASH field is the FNIH Biomarkers Consortium. Formed in 1996 this program of the Foundation for the National Institutes of Health focuses on advancing research into disease biomarkers broadly, and has a program specifically dedicated to advancing the production of a biomarker to NASH, complementary to IMI’s coming work. We are excited to see these unique opportunities for collaboration and hopefully great advances!

  • All aspects of NASH research (or biomedical research in general!) could benefit from this kind of collaborative approach, but in our view, it is no surprise that these pioneering NASH collaborations have focused their efforts on the search for a NASH biomarker. A non-invasive biomarker for NASH is critically important for diagnosis and the assessment of experimental NASH interventions, and at present there are no known biomarkers for NASH. This forces physicians and researchers to rely on a liver biopsy to see if treatment is needed or successful – a major reason why NASH is rarely diagnosed.

Detailed Discussion and Commentary

Review of non-alcoholic steatohepatitis and the new disease liver landscape

David Lomb, PhD & Brent Osborne, PhD (Defined Health, Florham Park, NJ)

Drs. David Lomb and Brent Osborne kicked off the summit with a crash course in NASH physiology. Although, we do not currently have a clear understanding of the pathogenesis or natural history of NASH, there is a clear pattern of disease progression: NAFLD gives rise to NASH, followed by fibrosis and perhaps ultimately cirrhosis, each category characterized in further degrees. Of course, not all patients progress all the way to cirrhosis. It is estimated that 30% of people with NAFLD will progress to NASH and 25-40% of people with NASH will develop significant liver fibrosis. This fibrosis stage, and no other histologic feature of NASH, is independently associated with long-term overall mortality, liver transplantation, and other liver-related events including hepatocellular carcinoma (HCC). Because of this, Drs. Lomb and Osborne recommended focusing drug development efforts on therapies that treat fibrosis. They saw this as not only the most effective way to improve patient outcomes but also as the most strategic way to control the burden of NASH on the healthcare system. Anywhere from 16-64 million Americans has NASH, and understanding which patients will progress to the symptomatic fibrosis and cirrhosis stages is vitally important.

Further, Drs. Lomb and Osborne briefly summarized the state of drug development for NASH. Notably, there are currently no drugs approved for the treatment of NASH: first line treatment is lifestyle modification and last line treatment is liver transplant, with no available pharmacotherapies in between. That said, excitement surrounds two phase 3 candidates in the NAFLD/NASH competitive landscape: Genfit’s dual PPAR alpha/gamma agonist elafibranor and Intercept’s FXR agonist obeticholic acid. Dr. Osborne predicted that at least one of these candidates will eventually be approved, though he warned that both elafibranor and obeticholic acid will likely be priced far above what he calls the “willingness-to-pay threshold.” The predicted cost for elafibranor is $68,000 per year, versus  $12,500 to $33,00 per year for obeticholic acid. Dr. Osborne forecasted that unless these drugs have dramatic effect on NASH or a much lower list price, payers are not likely to position these agents favorably on their formularies.  

The duo also presented some little-known statistics on NASH epidemiology:

  • NASH is currently the third leading indication for liver transplant but it is expected to become the number one leading cause in the next 10 to 20 years.
  • It is estimated that 37% of people with a BMI >40 kg/m2 have NASH. Between 69-87% of people with type 2 diabetes have NAFLD while 22% have NASH.
  • 20% of people with NAFLD are “fast progressors,” developing NASH and ultimately cirrhosis in only 10 years.
  • The primary determinant for severe NASH and cirrhosis is well-established diabetes and being older than 50 years of age.
  • Hispanic and Asian populations tend to develop NASH at lower BMIs than other racial groups.

Dash to treat nash: Overview of non-alcoholic steatohepatitis drug development

Weilin Xie, PhD (Celgene, San Diego, CA)

Dr. Weilin Xie overviewed the natural history of NASH to explain why he believes combination therapy will be essential to treat this incredibly heterogeneous disease. He highlighted two histological features that provide  important information on NASH pathogenesis: inflammation and fibrosis. Many drugs in development for NASH act on either inflammation or fibrosis but so far none can impact both – thus it seems likely that combination therapy will be essential to treat both features of NASH. That said, the timing of therapeutic intervention is also important; Dr. Xie emphasized that anti-inflammatory therapies are likely to slow or arrest the progression of NASH at earlier stages of the disease, but unlikely at the later stages at which NASH is typically diagnosed. Our understanding of NASH is still evolving, and Dr. Xie explained the two dominant models of NASH pathogenesis. According to the ” two hit” model, an initial ‘hit’ of triglyceride accumulation in the liver makes the organ more susceptible to injury from second hits such as inflammation, mitochondrial dysfunction, or oxidative stress, which in turn lead to steatohepatitis and then fibrosis. The other theory – which Dr. Xie favors –  is the “multiple parallel hits” model, which contends that there are many parallel events that lead to the development of the disease. The fact that the majority of NASH patients have ‘multiple hits’ in the form of type 2 diabetes, insulin resistance, and obesity adds credence to this theory. Dr. Xie concluded with a discussion of the currently-available treatment options for NASH. Lifestyle changes have been shown to produce improvements in some NASH histological parameters and bariatric surgery may be helpful as well, though the effect of bariatric surgery on liver fibrosis is the subject of some debate among researchers, reflecting just how much we have left to understand  about this complex disease.

Keynote: paradigms in NASH Disease Progression and Drug Discovery

Sophie Mégnien, MD (Genfit, Lille, France)

Dr. Sophie Mégnien, CMO of Genfit, overviewed the company’s development program for the dual PPAR alpha/gamma agonist elafibranor, one of the leading candidates in the NASH/NAFLD competitive landscape, with Fast Track designation from the FDA.  In the phase 2b GOLDEN-505 trial,  elafibranor was demonstrated to be safe and well-tolerated and led to dose-dependent increase in the primary endpoint, “resolution of NASH without worsening of fibrosis” (p=0.027), as well as significant improvements in other secondary cardiometabolic endpoints over the course of one year in participants across various levels of NAFLD, NASH, and fibrosis (n=275). A multi-center phase 3 trial called RESOLVE-IT is currently ongoing, focused on NASH patients with significant (F2) to advanced (F3) fibrosis (n=2000). The estimated primary completion date is December 2021 according to ClinicalTrials.gov – a lengthy timeline because of Genfit’s suspicions that the timecourse of NASH is so prolonged that even a very effective drug may not show an observable effect until several years have passed.

  • Genfit’s clinical trial program for elafibranor was amongst the trailblazers that helped establish the newly accepted NASH clinical trial endpoint of “resolution of NASH without worsening of fibrosis.” The other FDA accepted endpoint is “improvement of fibrosis by one stage with no worsening of NASH.”  Dr. Mégnien had an interesting take this; though the majority of speakers throughout the summit emphasized the importance of preventing fibrosis, she underscored that NASH resolution itself is likely to lead to improvement in fibrosis, as well as all-cause mortality. She also emphasized that any new drugs for NASH must be at least neutral and ideally positive for cardiovascular diseases for the FDA to approve.  This is in recognition of the fact that cardiovascular disease remains the leading cause of death in NASH patients, whereas liver-related mortalities are a distant third.

Industry and Academia: Crossing the Divide to Move the Needle in Non-Invasive Biomarkers for NASH

Manu Chakravarthy, MD (Lilly, Indianapolis, IN)

Dr. Manu Chakravarthy, VP and Global Head of External R&D in Diabetes and Cardiovascular Disease at Lilly, emphasized the potential of partnerships across industry and academia to surmount the present challenges in NASH drug development. In particular, Dr. Chakravarthy highlighted the Innovative Medicine Initiative (IMI) consortium, which facilitates collaboration between universities, pharmaceutical companies, patient organizations, and regulatory agencies to speed the drug development process. The consortium will launch a NASH initiative in 3Q17, spearheaded by Dr. Chakravarthy and colleagues, with the primary goal of validating a non-invasive biomarker for all levels of the NAFLD spectrum. Another consortium beginning to become involved in the NASH field is the FNIH Biomarkers Consortium. Formed in 1996 this program of the Foundation for the National Institutes of Health focuses on advancing research into disease biomarkers broadly, and has a program specifically dedicated to advancing the production of a biomarker to NASH, complementary to IMI’s coming work. We are excited to see this unique opportunity for collaboration and hopefully great advances!

  • All aspects of NASH research (or biomedical research in general!) could benefit from this kind of collaborative approach, but in our view it is no surprise that these pioneering NASH collaborations have focused their efforts on the search for a NASH biomarker. A non-invasive biomarker for NASH is critically important for diagnosis and the assessment of experimental NASH interventions, and at present there are no known biomarkers for NASH. This forces physicians and researchers to rely on a liver biopsy to see if treatment is needed or successful – a major reason why NASH is rarely diagnosed.

--by Jacqueline Anders, Abigail Dove, Kelly Close