NASH Summit 2018

April 23-25, 2018; Boston, MA; Full Report – Draft

Executive Highlights

The second ever NASH Summit took place April 23-25 2018 in Boston, MA. The gathering, focused exclusively on this still poorly characterized disease, spanned everything from drug discovery (encompassing NASH pathophysiology and potential novel drug targets), drug development (encompassing preclinical NASH work), and clinical management (encompassing the challenges of NASH diagnosis and trial recruitment, and ongoing clinical trials). Read on in the full report below!

Table of Contents 

Detailed Discussion and Commentary

Pre-Conference Workshop

Evaluating the Key Challenges to the Successful Commercialization of Drugs for NASH

Amama Sadiq, MD (Clarion Healthcare, Boston, MA)

NASH Summit 2018 kicked off a discussion of the challenges to commercializing NASH drugs: (i) disease understanding, (ii) economics, and (iii) clinical care paradigms. Clarion Healthcare’s Medical Director Dr. Amama Sadiq led attendees in identifying specific challenges and brainstorming solutions, ultimately concluding that significant collaboration across biopharma, regulators, academia, and the clinical community will be necessary to successfully bring NASH therapies to market and to improve patient outcomes.

  • Disease Understanding: Dr. Sadiq outlined the three main categories of NASH candidates – anti-lipid, anti-inflammatory, and anti-fibrotic – as well as secondary targets of glucose, insulin resistance, apoptosis, and oxidative stress. It became readily apparent to everyone in the room that NASH as a disease is still not fully characterized, which explains this diversity of therapeutic targetsand growing interest in combination approaches. The field lacks validated diagnostic methods beyond invasive (and expensive) liver biopsy, and animal models of NASH also stand to be improved. To round things out, emerging data suggest that only 10%-20% of NASH patients will develop major complications in 10-15 years, and even patients with fibrosis are extremely heterogeneous in terms of time to progression. Attendees felt that longitudinal studies, reminiscent of the Framingham heart study, would go a long way in answering questions about biomarkers, progressors vs. non-progressors, disease etiology and phenotype, and which endpoints are the most clinically-meaningful.

  • Economics: Pricing and reimbursement are enormous uncertainties in the NASH landscape, and many aspects of the disease are reminiscent of diabetes. As Dr. Sadiq explained, NASH is chronic and highly prevalent, but also responds well to lifestyle modification, is slow progressing, and is asymptomatic; only a small number will develop serious complications. That said, even NAFLD itself is costly and NASH is projected to become the leading cause of liver transplants and hepatocellular carcinoma in the near future – two very costly complications. Dr. Sadiq emphasized that it’s becoming ever more critical for drugs to demonstrate health economic value, and she mapped out various pricing scenarios. On one end, NASH therapy could be priced like diabetes therapy (somewhat ironically, the low end of this spectrum) given the disease’s chronicity. On the other, it could be given specialty pricing (like Hepatitis C therapy) given the long-term morbidity – but that scenario hinges on NASH treatment being a cure. What’s more, payers can push back with generic therapies that are already in use, as well as bariatric surgery. We expect manufacturers, payers, and PBMs will grapple with these questions for years to come, and phase 3 readouts should have a big impact on pricing strategy.

  • Clinical Care Paradigms: One enduring challenge in NASH has been a lack of awareness among patients as well as provider communities, which has contributed to clinical trial delays due to low enrollment. Dr. Sadiq cited that there are only ~600 trained hepatologists in the country, invoking the importance of PCP training on NASH (as well as training for other specialists, including gastroenterologists and endocrinologists). The endocrine system is certainly implicated in NASH, perhaps even creating some confusion about where the disease falls. Attendees pointed to a potential role of interdisciplinary care and the need to educate specialty care providers about NASH as a health crisis; they suggested that pharma companies could play a role in supporting such initiatives. Notably, the NASH Education Program launched last month in the US with the explicit goal of increasing awareness and enhancing medical education around this disease – this spun out of GENFIT’s NASH awareness campaign, ongoing since March 2017 in France.

Keynote Addresses

Latest Advancements in NASH Drug Development

Jason Campagna, MD, PhD (Intercept Pharmaceuticals, New York, NY)

In a morning keynote, Intercept Pharmaceuticals’ Dr. Jason Campagna contextualized the landscape of phase 3 NASH trials in terms of two separate waves,  arguing that the newer generation of trials is shifting toward shorter, smaller scale study designs that take a narrower clinical scope. Dr. Campagna placed six phase 3 trials in the “first wave” group: Intercept’s REGENERATE and REVERSE (for FXR agonist obeticholic acid in F1-F3 fibrosis and cirrhosis, respectively), Genfit’s RESOLVE-IT (dual PPAR alpha/gamma agonist elafibranor in F1-F3 fibrosis), Allergan’s AURORA (CCR2/CCR5 inhibitor cenicriviroc in F2-F3 fibrosis), Gilead’s STELLAR 3 and STELLAR 4 (ASK-1 inhibitor selonsertib in F3 fibrosis and cirrhosis, respectively). Each of these trials has a long duration (ranging from 48 to 78 weeks), with even longer follow-up in some cases; they’re also very involved, including paired biopsies at the start and end of the trial. However, in Dr. Campagna’s words, “You’ll never see studies like this again” – their size, scope, and scale aren’t financially sustainable on a repeated basis, nor are they practical for patient participants and their providers. To this end, he described a series of newer “second wave” trials, characterized by swift and efficient proof of concept demonstration. Many of these trials are being conducted by Gilead, which is known for its early and aggressive pursuit of NASH combination therapy with three in-house NASH candidates (phase 3 ASK-1 inhibitor selonsertib, plus phase 2 ACC inhibitor GS-0976 and FXR agonist GS-9674). The company recently presented positive topline results from the first phase 2 combination trial and will also initiate a second, larger combination study in 2Q18, as specified in Gilead’s 4Q17 update. Dr. Campagna further highlighted Madrigal’s paired use of non-invasive and biopsy measures of NASH in a 36 week timeframe, plus NGM’s strikingly successful demonstration of histological benefit at 12 weeks. Dr. Campagna also identified a movement toward smaller and faster trials leaning on composite endpoints and utilizing non-invasive diagnostic technology, though in the current regulatory environment companies still need biopsy data (“at least”) to reach phase 3.  While much is yet to be determined regarding a regulatory pathway in NASH, Dr. Campagna signaled that the involvement of so many high-caliber, experienced companies in the arena lends weight to the unfolding changes in trial design, toward swifter and more practical trials. That said, the first generation of phase 3 NASH trials is not yet complete, so it remains very difficult to predict how regulatory norms in this arena will evolve.

  • Reminding us again of just how new the NASH field is, Dr. Campagna emphasized a dearth of understanding surrounding the preferences, motivation, and life situations of people with NASH. Indeed, with such low rates of diagnosis, it’s difficult to even glean basic characteristics of the population affected by NASH. As Dr. Campagna noted, patient experience is as important as safety and efficacy, a principle we’ve seen play out in diabetes. In our view, enabling patient engagement by making the patient experience as painless as possible is crucial to long-term outcomes, especially for a chronic disease like NASH. At the most basic level, the field still has to figure out what it means to have a sustainable, chronic treatment regimen in this disease; to this end, Dr. Campagna noted to our surprise that a significant number of patients who receive a liver transplant go on to develop NASH again within a year.

  • Dr. Campagna also shared that Gilead’s STELLAR 3 trial of phase 3 ASK-1 inhibitor selonsertib has completed enrollment. As of Gilead’s 4Q17 update, STELLAR 4 was fully enrolled, but STELLAR 3 was expected to fill during 2Q18. This discrepancy was attributed to the fact that STELLAR 4 enrolled patients with F4 cirrhosis due to NASH, a more severe phenotype with fewer treatment options and less competition from other clinical trials. We’re glad to see STELLAR 3 stay on track (though it’s still listed as recruiting on ClinicalTrials.gov). Gilead has projected that they could be the first company to launch a NASH therapy, with selonsertib on the market as early as 2020.

Exploring the Latest Regulatory Requirements for Developing NASH Therapeutics

Sophie Mégnien, MD (Genfit, Cambridge, MA)

Genfit CEO Dr. Sophie Megnien gave a valuable take on the current regulatory specifics for NASH candidates, emphasizing the importance of being able to demonstrate long-term impact on hard clinical outcomes for definitive approval. If and when the first NASH therapy is approved, in all likelihood the approval will come under the FDA’s Subpart H, which allows for the accelerated marketing approval for a new drug based on a surrogate endpoint “reasonably likely” to predict clinical benefit. This approval comes with the caveat that the sponsor will further study the drug to verify clinical benefit (in the EMA, this is called conditional marketing authorization). Because of the unmet need in NASH, the trial duration that would be necessary to demonstrate clinical benefit, and the lack of an already-established NASH surrogate endpoint, any NASH submission in the near future is expected to occur under Subpart H. Drawing a key distinction between NASH as the underlying cause of fibrosis, and fibrosis as a measure of progression to cirrhosis, Dr. Megnien explained that development programs are actually split between those focused on NASH and those focused on fibrosis. NASH-focused programs include Genfit’s elafibranor and a variety of other phase 2 candidates, while fibrosis-focused programs include the later-stage candidates of Gilead’s selonsertib, Allergan’s cenicriviroc, and Intercept’s obeticholic acid. This distinction has important regulatory consequences: In NASH-focused programs, NASH resolution without worsening of fibrosis is the valid surrogate endpoint for registration and accelerated approval; in fibrosis programs, the surrogate is fibrosis improvement without worsening of NASH. In both cases, however, a long-term endpoint of progression to cirrhosis, mortality, and liver-related outcomes (transplant) is necessary for definitive registration; Dr. Megnien notes that progression to cirrhosis is expected to comprise the majority of events. Moreover, while non-invasive tests have been widely used in early-phase studies, all programs currently need to show efficacy on a surrogate endpoint via histology for conditional approval under Subpart H, meaning liver biopsies are sticking around for a while. In accordance, the rationale of NASH trials so far has occurred within a unique progression: Phase 2a trials are proof-of-concept stage and used to demonstrate biological action via inflammatory markers or MRI for the anti-NASH drugs, or fibrosis improvement via the FibroTest or Enhanced Liver Fibrosis (ELF) blood tests. Then, phase 2b is used to demonstrate histological efficacy (which can be reasonably expected after phase 2a), while phase 3 is meant to demonstrate histological efficacy specifically on the approvable endpoint. With the first NASH therapy expected on the market as early as 2020, these regulations will soon come to a boiling point, and we’re optimistic that FDA is equally eager to improve treatment options for patients with NASH.

Advancing In Vivo Models to Better Represent Human Physiology in the Clinic

Targeting Fructose Metabolism for NASH – KHK Inhibitor Update from Pfizer

Kendra Bence, PhD (Pfizer, New York, NY)

Pfizer’s Dr. Kendra Bence offered a compelling clinical update on one of the company’s three NASH candidates, KHK (ketohexokinase, or hepatic fructokinase) inhibitor PF-06835919. She presented preliminary results from the first phase 1 trial of the candidate (completed July 2017), demonstrating the agent’s robust, dose-dependent engagement with the KHK receptor in healthy participants. In order to assess receptor engagement, the study measured the AUEC (area under the effect curve) of plasma fructose exposure after oral fructose administration in the presence of various doses of PF-06835919 (ranging from 15 mg to 330 mg). All doses over 130 mg gave at least a five-fold increase in plasma fructose AUEC over 24 hours, indicating blockage of hepatic fructose metabolism (excess fructose is lost in urine). As we noted earlier this year, Pfizer advanced PF-06835919 into phase 2 for NASH during 4Q17, and completion of the first phase 2 study of this candidate has been moved up to this month (April 2018) from an initial date of June 2018 (though the six-week study is still technically listed as “recruiting” on ClinicalTrials.gov). If anything, NASH trials have generally been delayed by recruitment challenges, so ahead-of-schedule completion would certainly be impressive – we’re looking forward to a readout in patients with NASH.

  • Within the wider NASH competitive landscape, this KHK inhibitor has a particularly unique, first-in-class mechanism. Inhibiting KHK prevents metabolism of fructose in the liver, which has actually been shown to be potently lipogenic. Indeed, Dr. Bence explained that fructose is actually far worse than glucose in terms of both de novo lipogenesis (triglycerides, LDL cholesterol) and insulin resistance. This is bad news in light of the Western diet, as “added sugar” in food is typically fructose, since it’s sweeter than glucose. In addition to increasing inflammation, then, fructose also promotes steatosis. Mechanistically, fructose is thought to promote expression of the transcription factor ChREBP-beta, which has already been implicated in metabolic syndrome and lipogenesis, and is activated to a lesser extent by glucose. The good news is that, in a matter of days, isocalorically reducing fructose consumption suppresses hepatic lipogenesis and reduces steatosis in children with obesity. With PF-06835919, then, Pfizer is trying to cut off these lipogenic and inflammatory downstream effects at the first step of fructose metabolism, hopefully reducing steatosis and inflammation-mediated fibrosis. Extensive studies in rat models indicate dose-dependent suppression of novo lipogenesis, triglycerides, and fasting insulin levels, as well as reversal of steatosis; now we’re looking forward to data in human NASH. On safety, Pfizer is hopeful that there will be minimal adverse events associated with blocking fructose metabolism with KHK inhibition. To this end, even the rare genetic condition essential fructosuria (characterized by KHK deficiency) is typically asymptomatic and usually only incidentally discovered.

New Use of Niacin for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD): Combinational Therapy with Drugs in Development.

Moti Kashyap, MD (Aasta Pharmaceuticals, Los Angeles, CA)

Co-founder of Aasta Pharmaceuticals Dr. Moti Kashyap introduced a new preclinical player in the NAFLD/NASH arena: Niacin (vitamin B3), a therapy that may also lower CV risk. While all the evidence for niacin in NASH is preclinical, Dr. Kashyap presented data demonstrating that, in rats on a high fat diet niacin significantly reduced liver triglycerides, with histology also supporting a reduction in hepatic steatosis after six weeks on a high-fat diet. Moreover, evidence in human hepatocytes from donors with and without NASH indicates positive effects on collagen concentration, indicating potential for regression of fibrosis with niacin. Additionally, there is preliminary evidence outside of NASH that niacin may be responsible for reducing liver fat in humans with hyperlipidemia. Dr. Kashyap outlined a likely two-part mechanism for niacin’s effect on liver steatosis: Significant inhibition of DGAT2 mRNA expression to block triglyceride synthesis, plus significant reduction of inflammation (and fibrosis) through a reduction in oxidative stress. Both of these have been identified in human hepatocytes, and the first has been shown in rats on a high-fat diet. We find this two-fold mechanism exciting, though we note it is very early stage.

  • A particularly compelling reason to further investigate niacin in NASH is the agents known utility in lowering lipids and CV risk. For all of its associated morbidity, NASH is not the leading cause of death in those patients: 38% of patients with NASH die from CV disease, the leading cause of mortality in this population, and treating both simultaneously is quite compelling. Moreover, there are well-studied and safe generic formulations of extended-release niacin available, which is great for patients. Combining niacin with another agent, Dr. Kashyap argued, could more effectively target the inflammation, steatosis, and fibrosis that comprise the trio of NASH pathophysiology. On balance, Dr. Kashyap’s keenness on combination therapy leads us to postulate that he thinks niacin may not be an effective therapy on its own – though this is pure conjecture, and the NASH field as a whole is also increasingly keen on combination therapy. As a note, Aasta Pharmaceuticals has patented the use of niacin in NASH and is looking for partners with whom to investigate combination therapy.

Advances in Development of Non-Invasive Diagnostics in NASH Clinical Trials: From Biopsy to Biomarker

Panel Discussion: Non-Invasive Biomarkers – How Near Are We?

Sudha Shankar, MD, PhD (NGM Biopharmaceuticals, South San Francisco, CA), Peter Traber, MD (Galectin Therapeutics, Norcross, GA), Jonathan Riek, PhD (BioTelemetry Research, Rockville, MD), Lars Johansson, PhD (Antaros Medical, Mölndal, Sweden)

A fascinating panel discussion focusing on how close the field is to non-invasive biomarkers was punctuated by a single question: “How close to what?” Moderator Dr. Peter Traber (Galectin Therapeutics, Norcross, GA) opened by reflecting on the explosion in information surrounding NASH over the last five years, with relevant progress happening in serum biomarkers and proteomics as well as imaging and analysis. For example, Dr. Jonathan Riek (BioTel Research, Rockville, MD) explained that imaging can now measure steatosis “probably more accurately than with a biopsy,” but those are measures of different things and steatosis does not necessarily equal NASH. Dr. Riek underscored that while imaging is nearing registration endpoint-level quality, importantly, that endpoint would have to be reducing fat in the liver, not treating NASH. The MRI-PDRR (proton density fat fraction) technology used in liver imaging is not nearly as precise on non-steatosis dimensions of NASH such as fibrosis and inflammation, though FibroScan is coming close on the former. Moreover, Dr. Traber said, while some are starting to put together algorithms to identify patients with NAFLD and NASH, the real endgame is validation of a registration endpoint that does not include liver biopsy – and there’s a lot more work to be done before regulatory agencies will accept that. As Dr. Lars Johansson (Antaros Medical, Gothenburg, Sweden) put it, there is a need to differentiate between diagnostics vs. therapy monitoring procedures: The latter demands a connection to outcomes, and a single technology could work for one and not the other. He thinks a diagnostic tool is much closer, and imaging more so than serum biomarkers, but he also made a particularly interesting point: If you, for example, decrease fat, the concentration of everything else changes in proportion, so you might detect increased stiffness in the short term. Further considering biomarkers, Mr. Stephen Rossi (NGM Biopharmaceuticals, South San Francisco, CA) added that no drug yet has given a strong enough signal to see a correlation in a large population, but as more efficacious combination therapies are tested, researchers should see stronger signals. He cautioned against “throwing away” any markers yet, also arguing that more emphasis needs to be placed on monitoring. A potential monitoring tool, he added, will require large clinical utility studies beyond outcomes and be amendable to both drug development and commercial use. A further challenge was raised during Q&A, when one attendee noted that many serum biomarkers – for example, biomarkers of inflammation – are elevated in any number of disease states, and particularly so in patients with diabetes and/or obesity: How can you tell if something directly relates to the liver? Similarly on endpoint validation, Dr. Traber argued that well-conducted clinical trials with multiple endpoints alongside biopsy will be needed to validate a less invasive endpoint, but he also warned the audience against underestimating a regulatory focus on outcomes: “We may be sanguine about what we think is linked to outcomes, but regulators are more skeptical, even to the point of questioning whether reversal of cirrhosis is associated with hard outcomes.” Linking data to outcomes that regulators care about will prove another nuanced challenge in the NASH arena, and Dr. Traber called for the field to start considering liver function, citing how disciplines like cardiology and nephrology have use cardiac output and GFR, for example. The name of the game will be demonstrating how liver function relates to clinical outcomes.

Evaluating the Rationale & Potential for Combinational Therapies in the Treatment of NASH

Panel Discussion: Combinational Therapies in the Treatment of NASH

Michael Crackower, PhD (Celgene, Cambridge, MA), Robert Walczak, PhD (Genfit, Cambridge, MA), Nikolai Naoumov, MD, PhD (Novartis, Basel, Switzerland), Sean Muthian, PhD (Allergan, Boston, MA)

A Wednesday morning panel discussed combination therapy for NASH, emphasizing how unique it is for the field to already be so focused on the idea. We appreciated the extra context from Celgene’s Dr. Michael Crackower, who explained that it’s unusually early to already see combination therapy trials in NASH, before a single agent arm has demonstrated efficacy in phase 3. In his words, “outside of oncology and infectious disease, this is unprecedented; you have to ask if we’re putting the cart before the horse, but we’re facing the challenge that the horse is out of the barn.” Dr. Crackower acknowledged that he isn’t sure how to embark on preclinical work for NASH combination therapy: While it is reasonable to expect combinations to have better efficacy and potentially synergistic actions, one shouldn’t underestimate the complexity of and mystery surrounding the mechanisms of NASH drugs and how difficult it is to predict a clinical response (as illustrated by the commonality of phase 2 failures across all therapeutic areas). With the multifactorial mechanisms and broad actions of NASH candidates, combinations of these therapies may come with a higher risk of adverse drug-drug interactions. At some point, according to Dr. Crackower, it’s more of a strategic than a scientific question, and there’s always going to be some degree of “just going for it.” Allergan’s Dr. Sean Muthian pointed to another challenge in studying combo therapies: The placebo response in NASH trials is quite noisy and getting a signal through the noise has proven difficult enough with a single therapy. With a combination, what signal is one even trying to detect? Is it additive? And how do you determine the right dose balance between mechanisms?

  • Dr. Muthian also addressed issues of pricing and reimbursement (far downstream, for now), noting that combination therapy in areas such as HIV has not been priced additively, but instead has been based on the economic value that the combination generates. Novartis’ Dr. Nikolai Naoumov added that the need to demonstrate additional benefit should not deter companies from developing combination therapies: “Let’s get results first and then worry about the payer aspect,” because clinical benefit should translate to a clear benefit from a health economic point of view.

  • We were intrigued by an attendee’s suggestion that weight loss agents, specifically GLP-1 agonists, might be an effective backdrop to a more specific liver-targeted NASH therapy. See Dr. Coghlan’s talk above for more on this. While Dr. Muthian agreed that data suggest weight loss leads to better outcomes in NASH, he drew the distinction between protecting organs from further damage (i.e. with NASH therapy) and allowing the system to recover by reducing pressure on it (i.e. with weight loss). To this end, Dr. Crackower offered that weight isn’t necessarily a metabolic driver and Dr. Naoumov added the important point that obesity does not equal NASH, and NASH does frequently occur outside of overweight/obesity. In our view, this all points back to the importance of a precision medicine approach to NASH.

  • Dr. Naoumov argued that the heterogeneity among NASH patients and complex three-fold pathophysiology of the disease (involving steatosis, inflammation, and fibrosis) demands a combination approach. In his view, the modest effects observed thus far could reflect the fact that multiple processes are contributing to the NASH phenotype, in different levels among different patients. By using two or more therapies at once, you can engage multiple physiological targets, but you can also tailor treatment according to an individual’s underlying cause, stage of disease, and any comorbidities – though vastly more work is also needed on defining and targeting this heterogeneity. Dr. Naoumov believes this precision medicine approach should both steer drug development and provide better results for patients. As an analogy, Dr. Naoumov cited that NASH therapies under investigation have only been effective in ~one-third of patients – a rate that would never be acceptable in, for example, lowering cholesterol. He established that these monotherapy results are encouraging but suboptimal. The good news is that candidates under development are fairly diverse in their mechanism of action: Among only phase 3 candidates, Intercept’s obeticholic acid and Genfit’s elafibranor target lipid metabolism, Allergan’s cenicriviroc targets inflammation, and Gilead’s selonsertib targets cell death. To be sure, Novartis is a leader in the search for NASH combination therapy, and Dr. Naoumov shared that the planned study of cenicriviroc + an FXR agonist will start imminently.

Clinical Stream: Harnessing Clinical Lessons Learned to Advance Clinical Trial Design

Exploring the Potential of GLP1 Agonists for the Treatment of NASH

Matthew Coghlan, PhD (Novo Nordisk, Copenhagen, Denmark)

Novo Nordisk’s Dr. Matthew Coghlan presented data showing a potential role for GLP-1 agonists in treating NASH, not only through the impressive weight loss associated with these agents, but also through apparent effects on inflammation, glucose metabolism, insulin resistance, and lipids. According to Dr. Coghlan, Novo Nordisk is foraying into NASH with once-daily injectable semaglutide: A phase 2 study (n=288) is ongoing, comparing 0.1 mg, 0.2 mg, and 0.4 mg doses of semaglutide vs. placebo on a primary endpoint of NASH resolution without worsening of fibrosis after 72 weeks. The trial is expected to complete in July 2020, per CT.gov. Moreover, Dr. Coghlan clarified that the company is positioning the next-gen GLP-1 agonist (available for type 2 diabetes as Ozempic) as a “base control” for NASH. While not all patients with NASH have obesity or diabetes, the comorbidity of these conditions is quite high (roughly 80% and 25%-50%, respectively), and we imagine prediabetes is also quite prevalent in people with NASH. We are particularly keen on the idea of a therapy with demonstrated efficacy in all of these cardiometabolic disease areas, and as Dr. Coghlan emphasized, GLP-1 agonists could be this “base control.” He showed how both of Novo Nordisk’s GLP-1 agents, liraglutide and semaglutide, have demonstrated CV benefit in people with type 2 diabetes in the LEADER and SUSTAIN 6 CVOTs. CV disease remains the leading cause of death in the NASH patient population as well as the diabetes patient population, so cardioprotection certainly adds another attractive component to GLP-1 agonists, even if it hasn’t yet been evaluated outside of patients with diabetes (later this year, Novo Nordisk will launch the SELECT CVOT investigating semaglutide in obesity). We also think the fact that GLP-1s are already relatively established in diabetes and increasingly so in cardiology could be a huge plus commercially, if/when GLP-1 products are approved for NASH. Novo Nordisk has explicitly named NASH as an R&D priority, first on the company’s 3Q16 earnings call (when management announced a new R&D strategy expanding into diabetes-adjacent indications) and later when CSO Dr. Mads Thomsen was interviewed by the Wall Street Journal. So far, semaglutide is the only candidate targeting a NASH indication in Novo Nordisk’s public pipeline – we’re eager to see phase 2 data and further clinical progress on this front, and we’ll be curious to note any NASH pipeline additions as well.

  • The most apparent mechanism by which GLP-1 agonists might help NASH is weight loss. Independent studies have shown that weight loss via lifestyle intervention improves fibrosis, with greater benefit at higher levels of weight loss. In one study (n=293), 81% of participants experienced fibrosis regression when they lost ≥10% of body weight – but only 16 participants were able to lose that much weight. According to Dr. Coghlan, Novo Nordisk believes GLP-1 agonists could be a population-level solution for weight loss leading to NASH regression, fitting on a spectrum between lifestyle modification and bariatric surgery. In 2015, the phase 2 LEAN trial of liraglutide (n=52) in NASH delivered proof-of-concept of this, demonstrating resolution of NASH in 39% of patients on liraglutide vs. 9% of patients on placebo (p=0.019), alongside 5.3% and 0.6% mean reductions in body weight, respectively. Even greater optimism surrounds next-gen semaglutide, which is widely regarded as a uniquely potent glucose- and weight-lowering molecule among GLP-1 agonists and most other developed diabetes therapies. Last month at ENDO 2018, full data from a phase 2 dose-ranging study (n=957) of once-daily semaglutide in obesity without diabetes was presented: The highest-dose of semaglutide (0.4 mg) resulted in a mean 14% weight loss vs. only 2% weight loss with placebo (p<0.0001), and 27% of patients on that dose even experienced ≥20% weight loss, which to-date is unheard of for a pharmacotherapy.

    • We’re intrigued by the prospect of GLP-1 agonists as a population intervention for weight loss and NASH, though we note cost-effectiveness data presented by Dr. John Buse at WCPD 2016 suggested this might not be economically feasible (at least at the 2016 list price of GLP-1s). Of course, liraglutide should go generic around 2022/2023.

  • What’s more, the potential beneficial effects of GLP-1s extend beyond weight loss, into inflammation, lipids, and glucose control. After 52 weeks, high-dose semaglutide was associated with significant reductions in free fatty acids, triglycerides, and VLDL cholesterol; all doses trended in the right direction on all lipid measures. The 0.4 mg dose also gave a significant drop in C-reactive protein, a marker of inflammation (estimated treatment ratio=0.66, 95% CI: 0.52-0.83).

Objectively Assessing the Relationship of NASH with Other Diseases

Keynote: Clinical Trials & Endpoints in NASH Cirrhosis

Peter Traber, MD (Galectin Therapeutics, Norcross, GA)

Galectin CEO Dr. Peter Traber detailed the critical but rarely-considered distinction between compensated and decompensated NASH cirrhosis, describing pathophysiological and regulatory nuances between the two. Whether driven by NASH, hepatitis, alcohol, or another cause, there is a distinct transition from compensated to decompensated cirrhosis with the development of variceal bleeding, ascites, encephalopathy, and jaundice/liver failure. That transition is associated with a severe worsening in prognosis: Median survival in compensated cirrhosis is over 12 years but drops to ~2 years once decompensated, and the transition itself can take up to a decade. The transition involves accumulation of even more fibrosis than is accumulated from stage 1 to 4. On this basis, Dr. Traber explained that it’s crucial to consider the two areas separately. Moreover, he underscored that there’s serious clinical benefit to preventing decompensation. Dr. Traber clarified that portal vein hypertension is the main driver of decompensation, rather than the fibrosis and nodules used to define cirrhosis. When a patient develops cirrhosis, portal pressure rises over time due to increased intrahepatic resistance, which has both structural (scar tissue, regenerative nodules) and nonstructural (endothelial dysfunction) components; the former drives ~70% of the change in portal pressure, but Dr. Traber explained that the other ~30% is also clinically-meaningful, making either drivers valid targets of a cirrhosis therapy.

  • Dr. Traber additionally highlighted esophageal varices (varicose veins) as a particularly morbid complication of cirrhosis, arguing for the use of “progression to esophageal varices” as an accepted registration endpoint. He elaborated that while varices themselves are not a decompensation event, bleeding varices are, and they account for ~one-third of deaths among those with cirrhosis. Thus far, FDA has agreed to NASH clinical trial endpoints of (i) liver biopsy (reversal of cirrhosis or reduction in percent of collagen) or (ii) patient outcomes (decompensation events, transplant, death, hepatocellular carcinoma, and possibly patient-reported quality of life). Dr. Traber shared that FDA has also viewed portal pressure as a potential endpoint, but it’s unclear if the measure should be in the form of a threshold, percent change, or something else. Furthermore, measuring portal pressure is fairly invasive (through the jugular vein).

  • Dr. Traber also called for development of liver function tests, ideally non-invasive ones, which would have broad applicability across NASH progression. This would allow for better study of an important question: If you reverse fibrosis, does the liver return to normal? Some evidence from Hepatitis C patients suggests yes, according to Dr. Traber, but this is still very much an open question.

  • Overall, we hope to see further investment in NASH cirrhosis in the future: Anywhere from three to five million people in the US have compensated or decompensated cirrhosis – a relatively small number compared to those living with NAFLD/NASH, but the morbidity and mortality are significantly higher. Currently, Gilead’s STELLAR 4 trial of ASK-1 inhibitor selonsertib and Intercept’s REVERSE trial of FXR agonist obeticholic acid are the only phase 3 investigations of a NASH candidate in patients with cirrhosis. All other phase 3 trials involve participants with F1-F3 fibrosis; see our coverage of the landscape of phase 3 NASH trials from day #2 of the summit for more on this.

Keynote: Overview on NASH Heterogeneity & Relationships as a Sequel of CVM Disease

Aimo Kannt, PhD (Sanofi, Frankfurt, Germany)

Sanofi’s Dr. Aimo Kannt positioned the value proposition of addressing NASH within the framework of improved cardiometabolic outcomes and a longer, healthier life. The all-too-common view, he explained, is that treating NASH is like treating a liver disease that one doesn’t even know they have – and this flawed view underestimates the importance of addressing NASH as a medical condition and as a public health problem. Dr. Kannt suggested that combination therapy or agents with mechanisms that address multiple metabolic risk factors will likely lead to better NASH outcomes, alongside better cardiometabolic outcomes. This shift toward more holistic thinking mirrors one we’ve recently observed in diabetes, where the advent of cardioprotective diabetes therapies has compelled many thought leaders to shift focus toward lowering CV risk, in parallel with the longstanding emphasis on glucose-lowering. To support this thinking, Dr. Kannt presented data demonstrating that obesity, type 2 diabetes, CV disease, and hypertension are all associated with higher NAFLD incidence and a higher risk of NAFLD progression to NASH and fibrosis. What’s more, the relationship actually seems to go both ways: NAFLD has been identified as a risk factor for developing type 2 diabetes, hypertension, CV disease, and cancer. Among patients with NAFLD and NASH, it has been estimated that 51% and 82% have obesity, 23% and 44% have type 2 diabetes, 69% and 83% have dyslipidemia, 41% and 83% have hypertriglyceridemia, and 39% and 68% have hypertension. Importantly, these are not causal associations, and there is a distinct possibility that the same risk factor is giving rise to all of these metabolic dysfunctions (e.g. visceral adiposity). To this end, Dr. Kannt added that therapies that improve fibrosis or NASH but cause an increase in LDL or triglycerides likely have a suboptimal risk/benefit profile: Considering the high overlap between CV risk and NASH, one might question whether these candidates should be pursued at all. Further, he raised some interesting questions, reflecting the need for better understanding of how these different pathophysiologies interact: Would controlling glucose, blood pressure, and lipids resolve NASH? We think this is an important distinction: The primary endpoints for NASH therapies are steatosis and fibrosis, and many are focused on inflammation, but are these drug candidates too focused on the symptoms over the underlying cause of disease? As Dr. Kannt pointed out, weight loss has been shown to resolve NASH and reverse fibrosis, whether through lifestyle therapy, bariatric surgery, or pharmacotherapy. Similarly, we add that substantial weight loss gives a high rate of diabetes remission, as shown in the DiRECT trial, and weight loss also has positive effects on lipids and blood pressure. Thus, in our view, therapies giving substantial weight loss are becoming an ever-more-attractive treatment option, particularly for earlier-stage NAFLD.

 

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