October 10-12, 2017; Frankfurt, Germany; Full Report – Draft

Executive Highlights

We’re back from the inaugural NASH Summit Europe, and though we may have said Auf Wiedersehen to Frankfurt, our team still has plenty to digest on this complex and challenging disease state. This intimate, ~50 person meeting packed a mighty punch, and our full report contains detailed summaries of the sessions we found most notable. Read on for learnings from a pre-conference crash course on the foremost challenges in the NASH arena, exciting clinical updates from several phase 1 and 2 players in the ever-expanding NASH competitive landscape, and basic science galore from the world of preclinical NASH drug development. We are already looking forward to next year!

Detailed Discussion and Commentary

Pre-Conference Workshop

Effectively Build Entry Strategies into the European NASH Market

George O’Rourke (Managing Director, GO Biotech Consulting, Versailles, France)

The conference kicked off with an informative pre-conference workshop that provided an instructive lay of the land in terms of the enormous economic and clinical burdens of NASH, the drivers of NASH progression, and the complexities of bringing drugs to market in the NASH arena in particular. Below we detail our top pearls of insight from this informative session, ranging from updated NASH prevalence estimates to a discussion of current “trailblazers” in the ever-expanding NASH competitive landscape to a hypothetical glimpse into the pharmaco-economic factors that could determine NASH drug pricing once candidates (hopefully) reach the market.

• The workshop began with a clinical overview of basic NASH pathophysiology, describing the spectrum of non-alcoholic fatty liver disease (NAFLD) giving rise to non-alcoholic hepatosteatosis (NASH), followed by fibrosis and ultimately cirrhosis. With each stage, individuals develop progressively greater risk of hepatocyte carcinoma, liver transplantation, or premature death – though, quite challengingly, the disease is largely asymptomatic until this point. NASH’s easier-to-measure precursor, NAFLD, is estimated to affect a staggering 25% of the global adult population, ranging from 13% in Africa to 31% and 32% in South America and the Middle East, with intermediate prevalence in Europe (24%), North America (24%), and Asia (28%). Estimating conservatively, approximately 10% of people with existing NAFLD also have overt NASH, and within this 10% have advanced fibrosis (defined as a fibrosis score of F3 or F4). To contextualize these statistics, this translates to 62.5 million Europeans with NAFLD, six million of whom have NASH, and 600,00 of whom have advanced fibrosis. In the US, NASH with advanced fibrosis is estimated to affect 1.3 million people (0.4% of the general population), a figure which is estimated to grow to 3.5 million people (1% of the general population) by 2030. Due to the difficulty of formally diagnosing NASH (more on this below!), it is important to bear in mind that these numbers are tentative estimates. That said, all in all this is a tremendous patient population, and one that, given rising obesity statistics, we imagine will only increase.
  
  • A metabolic disease itself, NASH is highly comorbid with a number of chronic metabolic conditions, including obesity (82%), type 2 diabetes (44%), hyperlipidemia and dyslipidemia (72%), hypertriglyceridemia (83%), hypertension (68%), and metabolic syndrome (71%).
  • Cardiovascular disease is the most common cause of death in people with NASH, accounting for an estimated 38% of mortality. This is followed by death due to non-liver cancer (19%), complications of liver cirrhosis (8%), infections (8%), hepatocyte carcinoma (1%), and complications of liver transplantation (<1%). The remaining 26% of mortality is due to unknown (8%) or other (18%) causes.
• The current gold standard for NASH diagnosis is a liver biopsy – an invasive and rare surgical procedure, hence low rates of NASH diagnoses and a severe shortage of clinical trial subjects. This is one of the foremost challenges in the NASH arena from both a clinical and a drug development perspective. Presently NAFLD is detectable with non-invasive imaging techniques such as ultrasound, CT scans, and MRI, but confirmation of progression to NASH requires an additional assay to detect inflammation and fibrosis, which only a liver biopsy can do. Toward the ultimate goal of a non-invasive NASH diagnostic tool, a great deal of research is directed towards supplementing imaging technology with biomarkers that would confirm whether NAFLD (as revealed with traditional imaging technology) has progressed to NASH. Until then, the unfortunate reality is that NASH remains a “diagnosis of exclusion” after physicians painstakingly rule out other liver conditions such as alcohol-related cirrhosis, hepatitis C, autoimmune hepatitis, primary biliary cholangitis, or Wilson’s disease (a rare genetic condition that involves excessive copper buildup in the liver) – an arduous process in general, but an especially difficult proposition for a disease with no symptoms and few possible treatment options at present.
  
  • One participant provocatively described liver biopsy, to date the best NASH diagnostic tool, as a “tarnished gold standard” since it imprecisely samples only a small fraction of the liver and could therefore misrepresent the true degree of fibrosis and inflammation. Thus, innovative diagnostic technology for NASH is an area of intense interest and competition – perhaps rivaling that seen on the drug development side!
• How will NASH be defined in the future? This is a fundamental question as more NASH candidates approach late-stage development, and one that has important ramifications for the early pricing strategies of approved drugs. For the first generation of NASH therapies, it remains unclear whether regulatory agencies will gravitate toward narrow (stage 3 or 4 fibrosis confirmed by biopsy) or broad (suspected NASH based on liver imaging) indications.  At an even more basic level, will NASH drugs will be prescribed for chronic use (like diabetes therapies) or only until they reduce fibrosis to a certain, more manageable level? Another open question is whether NASH drugs could be indicated for the prevention of NASH in people with NAFLD, given the progressive nature of the disease. For all of these questions, time will tell. The breadth of the labels for future NASH drugs will be the key in setting initial list prices. For a broader label with a larger eligible patient population, drugs would likely be priced at a comparatively low level (on the order of ~$5/day) whereas for a narrower indication encompassing a smaller patient population, drugs would likely be priced at a premium in order to be profitable (on the order of ~$25/day – roughly comparable to recently-launched next-generation GLP-1 agonist/insulin coformulations for diabetes). Looking at Europe alone, the consensus among workshop attendees was that early NASH drug pricing strategies will go the latter more-expensive route, given that regulatory agencies tend to be fairly conservative for therapies in new disease states, gravitating toward indications that encompass strictly the population studied in the agent’s clinical trial program (a narrow group of patients with NASH and late-stage fibrosis for most ongoing phase 3 studies). We were disheartened to hear this, given the access issues that persist in the adjacent diabetes and obesity arenas. In the long-term we know that a future awaits where NASH drugs are well-reimbursed and widely accessible (and eventually generic), but in the short-term it seems sadly likely that unmet need in NASH will persist for many patients, despite the existence of pharmacotherapies that could help. That said, this issue of pricing is complex and multifactorial, and companies’ strategies when it comes to setting list prices will be difficult to predict – especially since the timescale for this is years away, around 2020 at the earliest. On a hopeful note, the workshop also covered a growth model that predicted that the increased prescription volume that would result from a low $5/day list price would produce approximately $2.3 billion/year NASH market in Europe, vs. only $1.5 billion/year with a $25/day list price and fewer total prescriptions – a prudent argument for a lower pricing strategy down the line, provided these agents can eventually acquire wider indications.
  
  • Another important “pharmaco-economic” factor influencing NASH drug pricing is the ability of these agents to offer cost savings by preventing or delaying NASH complications like CVD, cancer, and liver transplant. At present no studies in NASH are long enough to confidently assess long-term outcomes, but eventually data will reveal the ability of these agents to prevent common but comparatively less expensive conditions like CVD, as well as rare but exceedingly expensive conditions like liver cancer or liver transplant ($750,000 per procedure in the US). Cost savings of this kind could be a very compelling argument for better reimbursement of future NASH drugs, but this is a far-off hope due to the length and expense of the outcomes trials that would be required. The irony is profound from our view since although the trials are expensive, it is miniscule overall compared to the spending that could one day be prevented with effective therapies.
• Particular optimism surrounds three phase 3 NASH candidates: Genfit’s elafibranor, Intercept’s obeticholic acid, and Novartis/Allergan’s cenicriviroc. These candidates – which the workshop framed as “trailblazers” – are currently very influential in establishing what will likely become the standard in NASH clinical trial design and endpoint selection and, following approval, could set the pace for NASH drug pricing strategies.
  
  • Genfit’s dual PPAR alpha/gama agonist elafibranor, which holds a Fast Track designation from the FDA, is currently under investigation in the phase 3 RESOLVE-IT trial. The study (n=2,000) includes NASH patients with significant (F2) to advanced (F3) fibrosis. The estimated primary completion date is December 2021 according to ClinicalTrials.gov – a lengthy timeline reflecting the widely held conviction that the course of NASH is so prolonged that even a very effective drug may not show an observable effect for several years. The study’s primary outcomes are the proportion of patients achieving resolution of NASH without worsening of fibrosis, and a composite long-term outcome composed of all-cause mortality, cirrhosis, and liver-related clinical outcomes. 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 of 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).
  • Intercept’s phase 3 REGENERATE trial for the FXR agonist obeticholic acid is also ongoing in participants with NASH and stage 2 or 3 fibrosis. Participants (n=2,000) 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. According to ClinicalTrials.gov, the study is expected to complete in October 2021, with an interim analysis before the end of this year. 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).
  • Novartis/Allergan launched the phase 3 AURORA trial for its CCR2/CCR5 inhibitor cenicriviroc in April 2017. Like RESOLVE-IT and REGENERATE, the trial seeks to enroll 2,000 participants with NASH and stage 2 or 3 liver fibrosis. Primary outcomes include improvements in a liver histology panel and a composite endpoint encompassing histopathologic progression to cirrhosis, liver-related clinical outcomes, and all-cause mortality. Improvement in fibrosis by at least one stage without worsening of steatohepatitis is a secondary outcome (in contrast to RESOLVE-IT and REGENERATE, where this is a primary outcome). The study is estimated to complete in October 2024, with primary completion in July 2019 according to ClinicalTrials.gov. Notably the phase 2 CENTAUR study of cenicriviroc is also ongoing, with completion expected sometime this month.
  • These represent just three players on the increasingly crowded NASH competitive landscape. Amidst this perhaps overwhelming array, Mr. O’Rourke noted that a useful conceptual division is candidates that act on inflammation vs. fibrosis vs. general metabolic modulation (though these categories are not necessarily exclusive). Prominent anti-inflammatory candidates include Galectin’s polysaccharide polymer GR-MD-02, Novartis/Conatus’ pan-capase inhibitor emricasan, Immuron’s gut bacteria-targeting immunotherapy IMM 124E, and the “trailblazer” Novartis/Allergan’s CVC/FXR agonist cenicriviroc. Prominent anti-fibrotic candidates include Gilead’s now-discontinued LOXL2 monoclonal antibody simtuzumab in addition to some already-mentioned anti-inflammatory agents, namely cenicriviroc and GR-MD-02. Prominent candidates that act as metabolic modulators include two “trailblazers,” Intercept’s FXR agonist obeticholic acid and Genfit’s dual PPAR alpha/gamma agonist elafibranor, as well as Galmed’s fatty-acid/bile-acid conjugate aramchol, Bristol Meyer Squib’s FGF21 analog BMS-986036, NGM BioPharm’s FXF19 agonist NGM282, Gilead’s ACC inhibitor GS-0976, AZ/Regulus’ anti-microRNA RG-125, and Viking’s liver-selective thyroid beta receptor agonist VK5211.
  • The size of the NASH competitive landscape, as well as the multitude of drug classes represented, foreshadows great potential for combination therapy to treat this heterogeneous disease. From our view, it seems particularly strategic to combine agents from across these rough categories of anti-inflammatory agents, anti-fibrotic agents, and metabolic modulating agents. That said, the timing of different components of combination therapy is also important; we learned from Celgene’s Dr. Weilin Xie at this spring’s Boston NASH Summit 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.
• Another key theme of the workshop was the importance of pharmaceutical companies investing in patient and provider education programs and public health campaigns to promote greater awareness of NASH. Although NASH is “bread and butter” for liver specialists, awareness is low among PCPs, and almost non-existent among patients. Raising awareness is of course a crucial strategy for activating the eligible patient population and increasing the number of prescribing physicians and for any new therapy, but this is particularly important for NASH which, due to its asymptomatic nature, is unlikely to otherwise catalyze discussion between patients and their providers. The matter is made more difficult by the fact that many providers don’t consider NASH a full-fledged “disease” in its own right, though this mindset may shift once dedicated NASH therapies become available. Although generating awareness of a largely unknown (and asymptomatic, and difficult to diagnose) disease sounds like a very difficult proposition, this challenge is not unprecedented. A workshop participant noted to this end that first therapies for depression and erectile dysfunction – two very commercially successful areas -- were not considered addressable conditions only a few decades ago. The same can be said for pre-diabetes and even to some extent type 2 diabetes today. While we certainly hope NASH follows the same fate as depression, we know from other crises like pre-diabetes that the challenges are enormous.

Winning the Dash for NASH: Harnessing Recent Advances to Accelerate Drug Development

Keynote: How is the Field Conquering this Global Health Crisis?

Sophie Megnien, MD (CMO, Genfit, Paris, France)

The summit’s official agenda kicked off with a compelling keynote address from Genfit CMO Dr. Sophie Megnien who set an urgent tone for the meeting with a discussion of NASH as a global health crisis. We don’t often hear NASH characterized as a fully-fledged health crisis in the way that type 2 diabetes and obesity are, but the numbers are quite shocking – the NASH precursor NAFLD affects ~25% of the global population (13% in Africa, 24% in Europe and North America, 28% in Asia, 31% in South America and 32% in the Middle East) and approximately 10% of these people have overt NASH, estimating conservatively. Framed in different terms, NASH affects at least 12% of people with type 2 diabetes – a statistic that gave us particular pause. As for natural history, Dr. Megnien explained that NASH typically progresses at the rate of one worsened fibrosis score per seven years; this translates to 40-50% of NASH patients eventually developing severe fibrosis, and 15-20% developing cirrhosis. Approximately 20% of people with NASH are “fast progressors” who develop cirrhosis in only 10 years. The essential questions going forward in NASH drug development, according to Dr. Megnien, is finding a way to identify fast progressors and patients with fibrosis – clearly these are the people who stand to benefit most from NASH drugs, and it is essential that candidates in development are efficacious in these severe forms of the disease. 

• Though one major emphasis of Dr. Megnien’s talk was a discussion of the impressive clinical profile of Genfit’s leading phase 3 dual PPAR alpha/gamma agonist elafibranor (a definitive “trailblazer” in the NASH arena, as we heard yesterday), an even more prominent theme was the promise of an eventual combination therapy approach to NASH, given its complex underlying pathophysiology of steatosis, inflammation, and fibrosis – three processes that are unlikely to be addressable with a single drug. We haven’t yet heard of any specific examples of NASH studies assessing multiple agents, and it’s our sense that these efforts remain mostly theoretical (or incredibly early-stage and not yet public). That said, combination therapy is surely a promising avenue for this heterogeneous and multifactorial disease, and we see this as a particularly compelling option from given the excitement that surrounds already-approved diabetes agents (GLP-1 agonists, DPP-4 inhibitors, and pioglitazone) for NASH, which would be easier from a regulatory perspective to study in combination with a novel agent than the alternative of studying two novel agents in combination.
• “We’re making a mistake if we stop at drug development.” Dr. Megnien unveiled Genfit’s recently-launched NASH Education Program, a campaign designed to raise more awareness of the disease. As was underscored in an earlier pre-conference workshop, generating awareness is a crucial strategy for activating the eligible patient population and increasing the number of prescribing physicians and for any new therapy, but becomes an issue of particular importance in NASH which, due to its asymptomatic nature, is unlikely to otherwise catalyze discussion between patients and their providers. On the patient side, Genfit’s campaign features TV and newspaper reports as well as educational videos about the disease online and on social media.  This is complemented by KOL videos on the provider side, plus educational symposia on NASH at international meetings. At present the campaign is launched only in France (as of March 2017), but could be expanded more broadly if it proves impactful.

Identify & Validate “Druggable” and Clinically Relevant NASH Mechanisms

Exploring Key Regulators in NASH

Marie Wikström Lindholm, PhD (Roche Innovation Center, Copenhagen, Denmark)

On the basic science front, Roche Innovation Center’s Dr. Marie Wikström Lindholm discussed her pioneering work developing mRNA-based therapeutics for NASH. As a key mediator of the process by which genes are translated into active proteins, mRNA transcripts represent a promisingly selective drug target that could theoretically prevent the expression of a specific disease-generating protein of interest. Dr. Lindholm designs agents that do precisely this. Her work involves chemically piecing together a string of nucleotides capped with “locked nucleic acids” (LNA) on either end; when administered, these LNA oligonucleotide strings will bind to a specific protein of interest’s mRNA transcript, targeting it for degradation so the corresponding disease-associated protein is never synthesized. In soon-to-be-published data, Dr. Lindholm overviewed promising preclinical work with an LNA oligonucleotide (SPC4467) that targets MtGPAT1, a mitochondrial protein involved in orchestrating fat synthesis in the liver and known to be associated with the development of NAFLD. Obese mice treated with SPC4467 showed dose-dependent reductions in mRNA transcripts for MtGPAT1 (confirming that the LNA oligonucleotide indeed targeted this for degradation) as well as up to 70% reductions in liver fat. As an unexpected bonus, the drug additionally reduced liver expression of the atherosclerosis and CVD-associated ApoB by up to 40%. Notably these results only reflect the drug’s ability to reduce steatosis and say nothing of the drug’s effect on the inflammation and fibrosis that also characterizes NASH. That said, these data certainly merit further investigation of the candidate, and we look very forward to seeing this creative new therapy progress further in development. Illustrating the viability of this creative class of mRNA-targeting agents, a separate LNA oligonucleotide therapy is already in phase 2a development for hepatitis C. We certainly hope that SPC4467 eventually follows suit, and are extremely intrigued by this exciting new science – which has broad implications for any disease whose pathophysiology is well-understood enough to identify known disease-associated proteins.

Targeting Multiple Fibrogenic Pathways with the NOX 1/4 Inhibitor GKT831

Elias Papatheodorou (CEO, GenKyoTex, Geneva, Switzerland)

GenKyoTex CEO Mr. Elias Papatheodorou underscored the importance of NASH fibrosis as a “disease within a disease,” highlighting to this end his company’s work with the preclinical NOX-1/4 inhibitor GKT831 which shows early signs of reducing both fibrosis and inflammation in mouse models of NASH. Despite this promising preclinical profile, Mr. Papatheodorou noted that the company will not yet launch an in-human monotherapy trial of GKT831, instead emphasizing that “NASH is going to be a combination therapy game” and as such GenKyoTex is deliberating possible metabolic modulating compounds that would be complementary to GKT831 in an initial combination therapy trial. (The logic being that this would cover all three pathophysiological signatures of NASH: inflammation, fibrosis, and metabolic dysfunction [i.e. fat accumulation and steatosis]). Notably, GKT831 is already in development for diabetic kidney disease and data from this phase 2 program foreshadows the drug’s hopeful efficacy in NASH. In a type 2 diabetes trial, the drug failed to meet its primary renal endpoint but performed well on a number of secondary endpoints, demonstrating a statistically significant reduction in liver enzymes (p<0.05), a strong trend for reduction in triglycerides (p=0.066), and signs of dampening levels of markers of inflammation such as hsCRP (p<0.05), serum amyloid protein A (p<0.08), and IL-6 (p=0.2). A second phase 2 study in type 1 diabetes is slated to begin before the end of 2017, funded by the JDRF. Indeed a great deal of excitement surrounds the NOX-1/4 inhibitor class in both the DKD (this discussed only days ago at CMHC) and NASH arenas. Our eyes will be pealed for updates on a dedicated NASH trial for GKT831, potentially ushering in a new era of combination therapy studies.

Analyze Recent Progress in Targeting NASH Fibrosis – Novel Inhibitors of Galectin-3

Hans Schambye, MD (CEO, Galecto Biotech, Lund, Sweden)

Dr. Hans Schambye, CEO of Galecto Biotech, highlighted the anti-fibrotic power of galectin-3 (Gal-3) inhibitors – an emerging class of agents that could be particularly promising for the treatment of NASH. Galectin plays a fundamental role in the fibrosis cascade, activating macrophages, mediating their formation of fibroblasts, and then catalyzing fibroblasts’ formation of collagen fibrosis. Turning to the liver specifically, Dr. Schambye described early stage research showing elevated levels of Gal-3 in fibrotic tissue, and further noted that knockout mice lacking the gene for galectin-3 are resistant to developing NASH when fed a typically NASH-inducing high fat, high sugar diet. Excitingly, Galecto has developed an orally-available Gal-3 inhibitor (Gal-YY) and plans to advance it into clinical trials for a NASH indication within the next 12-15 months. Dr. Schambye specified that this will first involve initial safety and bioavailability studies in healthy volunteers, subsequently moving quickly into safety and tolerability studies in people with NASH. Galecto has already completed phase 1b/2a trials for the inhaled Gal-3 inhibitor TD139 for idiopathic pulmonary fibrosis, and the company’s pipeline also includes several oral Gal-3 inhibitors for lung fibrosis, renal fibrosis, cardiac fibrosis, and ocular fibrosis associated with diabetic retinopathy – indeed an impressive testament to the versatility of this class of agents. Session moderator Dr. Peter Traber enthusiastically echoed this sentiment: “The number of potential indications for an oral galectin-3 inhibitor will blow your mind! This is an important achievement, and I think in the future big companies might rue the day they didn’t pay attention to this class.” Of course this work is very, very early stage, but we look forward to closely tracking Gal-YY’s progress as it enters its first in-human study.

Better Recapitulate Human NASH Preclinically and Effectively Translate into Clinical Development

Modeling Progressive Liver Disease Using 3D Bioprinted Human Liver Tissue

Alice Chen, MD (R&D Director, Organovo, San Diego, CA)

Dr. Alice Chen, R&D Director at Organovo, highlighted the company’s ExVive Human Liver Tissue, a bioprinted 3D model of the human liver that can be induced into a NASH-like state when exposed to lipids and high glucose. This technology could be a game-changer for screening lead preclinical NASH compounds, given the scarcity and heterogeneity of human NASH tissue available for study, and the challenge that human liver tissue is only viable in vitro for a few days. ExVive Human Liver Tissue is generated from healthy liver cells (primary human hepatocytes, stellate cells, endothelial cells, and Kupffer cells) which are 3D printed in a precise arrangement to create a 2mm x 2mm x 0.5 mm tissue sample that retains metabolic competence and liver-specific functions for up to four weeks – far longer than a sample taken directly from a human liver would ever last. Approximately 21 days after induction with exposure to lipids, high glucose, and inflammatory stimuli (to essentially mimic what a human liver would experience after a lifetime of the Western diet), the ExVive tissue shows a very similar profile to native NASH tissue samples: lipid accumulation, excessive fibrosis, cellular ballooning, and the release of the pro-inflammatory cytokines TNFα and IL-1β, both known to play early roles in NASH progression. As a longer-lasting and more controlled alternative to direct NASH tissue samples, Dr. Chen underscored the potential of this bioprinted tissue as an ideal testing ground for new NASH candidate drugs. That said, the technology is still being refined to increase the speed at which the NASH phenotype is induced (the newest iteration takes only one week) and to confirm that ExVive tissue indeed recapitulates the distinct stages of NASH fibrosis and has a similar histological, proteomic, and metabolomics profile as direct NASH tissue samples. If the engaged Q&A session was any indication, this technology appears to be a very promising emerging tool to accelerate future early-stage NASH research. When prompted whether they would use this technology in their own preclinical studies, members of the biotech-heavy audience agreed that they would be very compelled if studies confirm that existing NASH candidate drugs show identical effects in ExVive tissue as previously demonstrated in direct NASH tissue.

Confidently Diagnose and Stratify NASH Patient Populations

Identification of Biomarkers for the Diagnosis of NASH

Dean Hum, MD (CSO, Genfit, Paris, France)

Dr. Dean Hum, Chief Science Officer of Genfit (a leader in NASH with phase 3 elafibranor), discussed the company’s exciting work on a NASH Dx Test, a recently FDA-cleared and CE-marked blood-based diagnostic test for NASH that is expected to launch in 2020 or 2021. The lack of reliable biomarkers for NASH is one of the most challenging issues facing the field: At present, NASH diagnosis requires an invasive liver biopsy, a barrier that has resulted in very low rates of diagnosis and consequently a small pool of clinical trial participants (once NASH drugs reach the market, this will translate into a small pool of potential prescriptions). Enter the NASH Dx Test, which involves only a blood sample – a complete game changer with the potential to make NASH screening a routine practice in endocrinology and primary care clinics. Genfit’s new method could also provide an easy way of measuring disease progress and the efficacy of an ongoing NASH treatment regimen. The test does not involve a single biomarker, but rather a complex signature of biological measurements, including levels of the mitochondrial mRNA miR34a, alpha2-macroglobulin (a protein byproduct of fibrosis), CH3L1 (a marker of inflammation), and A1c – factors Genfit chose based on biostatistical techniques demonstrating high correlation with the outcome of liver biopsies. We see it as no coincidence that the 2020/2021 timeline for the launch of NASH Dx Test aligns precisely with the phase 3 readout of Genfit’s RESOLVE-IT trial for elafibranor. If this trailblazing drug is eventually approved as the first NASH therapy, its uptake will depend on a larger population of people with official NASH diagnoses, not to mention a way of determining whether individuals are responding to the therapy. Gilead is also working on ways to improve NASH screening and diagnosis, and we’re pleased to see a more comprehensive focus from companies investing in NASH, since no drug – no matter how powerful – will bring down population-level prevalence unless a solid infrastructure for screening is in place.

The Importance of High Precision Imaging Biomarkers in NASH Drug Development

Lars Johansson, PhD (CSO, Antaros Medical, Gothenburg, Sweden)

Imaging biomarkers could be an excellent complement to biochemical biomarkers, and to this end, Antaros Medical is developing new MRI/PET imaging techniques that can detect liver fat and fibrosis non-invasively. CEO Dr. Lars Johansson elaborated that this technology is not intended as a diagnostic, but as a way of monitoring therapy and disease progression with more granularity than would be achieved with biochemical analysis alone. He noted that Antaros is actively working on expanding this technique to also assess liver glycogen, and great interest surrounds integrating these liver imaging assessments with CV endpoints (myocardial function and strain, myocardial metabolism, pulse wave velocity, vascular inflammation, etc.), given NASH’s elevation of CV risk. We’re overwhelmed by the amount of data this could generate, and the value of Antaros’ technology is clear from a research and clinical trial perspective. We would love to see this kind of imaging work eventually enter clinical care settings, though of course this may be a longer road given the high cost of MRI/PET scanning. All this said, the new assortment of advanced and complementary imaging and biochemical techniques marks critical progress in NASH and we hope and expect, as the era of the liver biopsy draws to a close, to see increased awareness and a larger, formally-diagnosed addressable population.

Enhance NASH Compound Preclinical Development Strategy

Prosecuting Metabolic Modulators as NASH Therapeutics

James Trevaskis, PhD (MedImmune, Washington, DC)

Interest abounds in combination approaches to NASH to target multiple mechanisms underlying this multifactorial disease, and Dr. James Trevaskis of AZ’s MedImmune highlighted promising data on GLP-1 agonists + glucagon receptor agonists + FXR agonists. Oxyntomodulin is an endogenous dual agonist of both the GLP-1 receptor (concentrated in the brain, pancreas, and gut) and the glucagon receptor (concentrated in adipose tissue and the liver). Dr. Trevaskis led the audience through recent animal data showing additional benefits to the oxyntomodulin analog G49 (with dual action) vs. GLP-1 agonist liraglutide (Novo Nordisk’s Victoza). Although G49 and liraglutide reduced body weight to the same extent in a mouse model of NASH, G49 had a markedly more pronounced effect on clearing liver fat and reducing liver fibrosis, supporting the potential advantage to this GLP-1/glucagon dual agonist in NASH. There is indeed a great deal of enthusiasm surrounding GLP-1/glucagon dual agonists for type 2 diabetes, obesity, and NASH alike (see our GLP-1/glucagon dual agonist competitive landscape for an overview of this area). AZ has another oxyntomodulin analog in phase 2 for type 2 diabetes and obesity, and we heard similar enthusiasm for this combination approach from MedImmune’s Dr. Christina Rondinone at EASD 2017 – we’re pleased to note confidence from AZ in these next-gen candidates, however early-stage they may be (G49 is presumably preclinical).

• Another NASH strategy involves the combination of GLP-1 agonists with FXR agonists (one of the most well-represented drug classes on the NASH competitive landscape). To this end, a MedImmune animal study (in press with Molecular Metabolism) found modest metabolic benefits with the combination of Intercept’s phase 3 FXR agonist obeticholic acid and exenatide vs. either agent as monotherapy. The addition of obeticholic acid added no additional weight loss compared to exenatide alone, but did produce trends toward reduced steatosis, lower levels of the liver enzyme ALT, and lower post-prandial glucose excursions vs. both monotherapies. Most impressively, the combination therapy showed a significant reduction in liver fat vs. either monotherapy, suggesting that this pairing of agents has a synergistic benefit in these aspects of NASH resolution. In all cases, the effects of the obeticholic acid/exenatide combination was not fully additive compared to both monotherapies, possibly indicating some redundancies in the mechanisms of action for GLP-1 agonists and FXR agonists (consistent with the fact that both are metabolic drugs). We would certainly be interested to see further combination studies pairing GLP-1 agonists with primarily anti-fibrotic or anti-inflammatory agents (or, better yet, the emerging class of agents with both anti-fibrotic and anti-inflammatory properties, like Novartis/Allergan’s CVC/FXR dual agonist cenicriviroc) to see if even greater efficacy could be achieved with these more distinct modes of action.

Explore Developments in Clinical Trial Design for Improved Patient Enrollment

The Anti-Fibrogenic and Liver Protective Effects of Namodenoson (CF102): From Preclinical to Human Studies

Pnina Fishman, PhD (CEO and CSO, Can-Fite, Tel Aviv, Israel)

Can-Fite CEO and CSO Dr. Pnina Fishman highlighted the company’s phase 2-ready A3-adenosine receptor (A3AR) agonist namodenoson, which shows early signs of potent anti-inflammatory and liver-protective effects. Formerly known as CF102, the drug is currently in phase 2 development for advanced hepatocyte carcinoma (HCC), with FDA/EMA orphan drug designation and Fast Track status from the FDA. As reflected in namodenoson’s potential utility as an oncology drug, its applicability to NASH comes primarily from its anti-inflammatory properties, but preclinical animal studies indicate that the candidate also has a number of beneficial effects on liver function, including minimizing liver fibrosis, preventing apoptosis of liver cells, and even accelerating liver regeneration following hepatectomy. Given the drug’s strong safety/tolerability profile in the HCC phase 1/2 program, Can-Fite is advancing namodenoson straight into phase 2 for NASH/NAFLD. Enrollment for this exploratory 12-week phase 2 study, which hopes to include 60 participants, is slated to begin as soon as 4Q17 (a slight delay from the February 2017 start date listed on ClinicalTrials.gov). The study will assess two doses of namodenoson (12.5 mg and 25 mg) vs. placebo, using change in liver triglyceride concentration as the primary endpoint, with additional secondary endpoints of change in body weight, serum cholesterol levels, A1c, and degree of insulin resistance. We are certainly interested to follow namodenoson’s progress, especially given its differentiated mechanism of action as the lone A3AR agonist in the NASH competitive landscape. With anti-inflammatory action and putative anti-fibrotic action, namodenoson is quite compelling for its ability to work on two of the three main pathophysiological signatures of NASH, and we see this as an ideal agent for eventual combination with a metabolic drug in order to target all three.

IVA337: Effectively Targeting NASH

Pierre Broqua, PhD (CSO, Inventiva, Dijon, France)

Inventiva Chief Science Officer Dr. Pierre Broqua provided an informative overview of the company’s phase 2 lanifibranor (IVA337), a next-generation “pan-PPAR” agonist that targets the alpha, gamma, and delta isoforms of PPAR, a protein critical in metabolic regulation. Strategies to enhance PPAR signaling are of great interest in NASH, and Dr. Broqua underscored that lanifibranor’s triple agonism increases its potency relative to other PPAR-targeting agents like Genfit’s phase 3 PPAR alpha/gamma dual agonist elafibranor or the generic TZD pioglitazone (often prescribed off-label for NASH in the absence of any FDA-approved treatments). In preclinical animal studies, lanifibranor showed compelling reductions in liver steatosis, inflammation, ballooning, and fibrosis – notably, this encompasses the three main pathophysiological defects in NASH (steatosis, fibrosis, and inflammation). The ongoing phase 2b NATIVE study (n=225) will provide insight into whether these benefits apply to humans. Launched in December 2016, the study is assessing two doses of lanifibranor (800 mg and 1,200 mg) vs. placebo, with the primary outcome of a two-point decrease in the SAF steatosis score without worsening of fibrosis. Primary completion is expected June 2018 with full study completion expected in October 2018 (per ClinicalTrials.gov), and Dr. Broqua noted that the company plans to launch a phase 3 program in mid-2019 on the heels of the phase 2 readout. We see this as a candidate to watch closely for its differentiated multiple mechanisms of PPAR-targeting action, and we’ll be keeping our eyes peeled for future updates.

Looking Towards 2018: Advance Understanding of How the Field Will Evolve

Panel Discussion: What Does the Next 12 Months Hold for NASH Therapeutic Development?

In a conversation on the state of the NASH field, conference participants spanning basic science research, the biotech industry, and large pharmaceutical companies converged on one especially difficult challenge: anticipating regulatory behavior. As the NASH field heats up and as more drug candidates advance into late-stage clinical development, companies are especially attentive to designing clinical trials with regulatory agencies’ positions in mind. This is a difficult proposition, however, because no real consensus between different agencies exists, and most advice is asset-specific without pertaining to NASH drug development as a whole.  One participant astutely contextualized this by noting that the FDA and EMA are “wrestling with the same questions that we are” when it comes to what stage of fibrosis constitutes a “treatable” NASH patient, whether NASH drugs will be chronic treatments, how to define the efficacy of a NASH candidate drug, and the list goes on. “NASH is a rapidly-evolving area. Imaging, biomarkers, endpoints – it’s all moving at once,” added conference moderator Dr. Peter Traber. This makes clinical trial design an enormous challenge, and it is not uncommon for a trial’s primary endpoint to shift from “important to not-important” from a regulatory standpoint before its completion date. Once NASH therapies reach the market, this uncertainty will likely spill over to the payer landscape. To this end, another participant pointed out that “virtually every patient population in NASH has outcomes in terms of decades” – indeed, without hard data from long-term outcomes trials in NASH, it may be an uphill battle to convince payers that these likely pricey drugs would be cost-saving for the healthcare system in the long run (see our coverage of an earlier discussion on the pharmaco-economic complexities of NASH here). The complexity here is certainly great, and we view this as an invitation for greater conversation and collaboration between basic science researchers, drug developers, regulators, payers, and of course, patients to foster more communication and eventually standardization at every level – from identifying gold-standard mouse models for preclinical research to agreeing on a set of NASH outcomes to defining which classes of NASH patients these drugs will be geared toward. 

-- by Abigail Dove, Payal Marathe, and Kelly Close