We may have said Auf Wiedersehen to Frankfurt, but we still have one more installment of highlights from the inaugural NASH Summit Europe. The meeting’s last day provided a clinical-facing view on NASH, with exciting updates on Genfit’s FDA-cleared and CE-marked blood-based diagnostic test to replace liver biopsies (launch expected by 2021), compelling data from two phase 2 drug candidates (with a preclinical nod toward the possibility of GLP-1 agonist combination therapies), and a candid discussion on the difficulty of strategizing clinical trial design and defining NASH outcomes in light of limited guidance from major regulatory agencies. Scroll down for detailed summaries on our top insights from this informative session.
In case you missed it, check out our coverage of day #1, featuring an information-rich pre-conference workshop that served as a crash course on the foremost challenges in this complex disease state, and day #2, packed with basic science updates from the world of preclinical NASH drug development.
Top Five Highlights
1. 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. This could revolutionize screening for NASH, which is currently cumbersome and costly, leading to under-diagnosis (and possibly a gross underestimate of the scale of the problem).
2. 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.
3. Inventiva CSO Dr. Pierre Broqua provided an informative overview of the company’s phase 2 lanifibranor (formerly IVA337), a next-generation “pan-PPAR” agonist that targets the alpha, gamma, and delta isoforms of PPAR. He 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 TZDs (often prescribed off-label for NASH in the absence of any FDA-approved treatments).
4. 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 hepato-protective effects. Already in phase 2 development for HCC, an exploratory phase 2 NASH study for namodenoson is slated to begin enrollment as soon as 4Q17.
5. 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. 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. Against this backdrop, everything from animal research to clinical trial design becomes incredibly challenging to strategize.
Top Five Highlights
1. Genfit’s Game-Changing Blood-Based NASH Diagnostic Test on Track to Launch in 2020/2021, Offering a Non-Invasive Alternative to Liver Biopsies
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.
- 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.
2. Enthusiasm Surrounds GLP-1 Agonist Combination Strategies in NASH
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.
3. Update on Inventiva’s Phase 2 PPAR Alpha/Gamma/Delta Triple Agonist Lanifibranor
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.
4. Phase 2 Enrollment for Can-Fite’s Anti-Inflammatory A3AR Namodenoson to Begin Before Year-End
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.
5. NASH Next Challenge: Navigating the Regulatory Arena
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