https://orcid.org/0000-0002-4224-4703
1. Can you tell us about yourself and what led you to work in the field of NAFLD and NASH?
I am the Director of the Metabolic Liver Research Center and Professor of Medicine at the University Medical Center Mainz, Germany. I started to work on NASH in 2002 during my postdoctoral education at the Albert-Einstein College of Medicine, Bronx, NY. Back then, I studied signaling pathways that contributed to liver injury and metabolic abnormalities in animal models. When I returned to Germany for my clinical training in Medicine, GI & Hepatology, I was confronted with an increasing number of patients with metabolic liver disease. Most of them were very worried about their condition but still fairly asymptomatic. The absence of adequate noninvasive diagnostics was a major obstacle in their management. Additionally, no standardized approach for treatment was available. This was when I realized this large unmet need and subsequently founded the Metabolic Liver Research Program at the University Medical Center in Mainz. Today we are offering modern diagnostics and innovative treatments to patients living with NASH; this ranges from supervised, web-based life-style interventions and nutritional counseling to novel drugs under investigation in clinical trials. Even after several years of intensive research in this field, many aspects of the disease are incompletely understood and the number of patients reaching pre-cirrhotic or cirrhotic stages will increase over the next 10 years. Therefore, I see an urgent need to expand the existing efforts to study NASH.
2. How are NASH, liver fibrosis and hepatocellular carcinoma linked?
The disease is a continuous spectrum that is linked through the underlying driver of metabolically defined hepatic inflammation. Inflammation leads to disease progression with increasing amounts of hepatic fibrosis resulting from regeneration and repair of the liver. Problems arise when liver injury persists over time – NASH related to ongoing metabolic stress – and thus, fibrosis is not degraded anymore. The continued injury promotes a ‘toxic’ environment in which HCC and complete scarring of the liver (cirrhosis) can arise. Importantly, hepatic fibrosis can regress, if the liver injury is resolved. So this is not a ‘one-way street.’
3. Looking at the translational gap: despite the strong association between dietary factors and NAFLD and NASH, no dietary animal model has reflected the metabolic and histological phenotype. What are the hurdles to developing animal models?
There are some principal differences related to the initiation and progression of the disease when comparing men and mice. Thus it has been difficult to translate all findings from animal models. Nonetheless, animal models have been very important for informing research and developing novel biomarker and therapeutics. One major difference is related to the time span in which the disease develops and the impact of comorbidities. In humans, NASH is a slowly progressive disease. Metabolic risk factors build up over time and interact to promote the full phenotype. This is not fully captured in most animal models. Therefore, some models use toxins to expedite and augment the phenotype – in particular fibrosis progression. While this can allow for more robust exploration of fibrogenesis, the results are not directly related to fibrosis progression in humans and thus must be interpreted cautiously. As a matter of fact, some recent drug failures have come as a surprise because the preclinical data, e.g. related to Ask-1 inhibition, have been supported by a fairly large data set derived from animal models.
These hurdles can be partly overcome by validation of preclinical findings in well-characterized human samples and translational studies. Thus, by combining animal results with human data is a very powerful approach to define novel targets.
4. Preclinical models are necessary to analyze and understand NASH pathophysiology and assess mechanism‐based treatments. Which requirements should investigators and drug companies consider for the optimization of translational value?
It is critically to replicate and confirm data from animal models in human samples and studies. Robust early data is needed, before a novel compound should be explored in patients. This will allow minimization of the risk posed to patients from an ineffective or potentially unsafe treatment and will help to avoid investments in ineffective compounds.
Optimization of these translational efforts are at the heart of two large biomarker and natural history consortia that have been prospectively built and which will support the validation of findings from animal models at a large scale – these two are the NIMBLE in the US and LITMUS in Europe.
5. What are the key challenges for translating surrogate outcomes of clinical trials to clinical outcomes for patients?
Chronic liver disease develops slowly, therefore surrogate endpoints are required to allow for drug development in this space. A good surrogate marker is tightly linked to the pathogenesis and allows dynamic assessment of disease activity. An accepted surrogate needs to be validated for the specific condition. In the case of NASH, hepatic fibrosis has been shown to predict patient mortality. The challenge in NASH is the influence of metabolic cofactors that impact on hepatic fibrosis and, for example, cardiovascular disease. In the future, we will see dynamic blood-based markers that are currently being validated in the above-named research consortia – both in the US and the EU. By moving away from liver histology, the drug development process will be expedited and standardized.
6. Can you briefly update us on advancements in therapeutic target discovery and which targets are emerging as the most promising?
We are seeing a wide variety of targets that are being explored. I like to think of them in three categories based on their MoA distinguishing drugs that (1) improve the hepatic metabolism, (2) are anti–inflammatory and (3) anti-fibrotic. The most advanced study programs are currently in phase 3 and include the FXR-agonist obeticholic acid. Here actually, a preplanned interim analysis reported a positive endpoint with a significant improvement of fibrosis regression vs. placebo at 18 months. Additional phase 3 trials that will be reporting data soon include the RESOLVE-IT study (NCT02704403) exploring the PPAR a/d agonist Elafibranor, the Auroa study with the CCR2/5 agonist Cenicriviroc, the Armor trial using the synthetic fatty-acid/bile-acid conjugate aramchol and the MAESTRO study (NCT03900429) employing the selective thyroid hormone receptor beta agonist resmetirom.
7. If co-morbidities exclude patients with diabetes and cardiovascular disease from clinical trials, how can these trials reflect real-life scenarios and how can clinical trials be adapted to overcome this?
The real-life scenario is very different from clinical trials. For the pivotal trials, it’s important that potential drugs are being explored in metabolically stable patients. Only then, the additional value on top of current standard of care can be determined. Therefore, any patients with uncontrolled cardiovascular disease (CVD) or diabetes should not be enrolled in clinical trials. The additional benefit for these patients will be established after drug approval in phase IV registers.
8. What does the clinical trial paradigm look like going forward? Clinical development programs have evaluated mostly single agents for NASH therapy, but new treatment paradigms may involve combination approaches. Can you elaborate on why this approach is key to advancement and what the challenges might be?
The combination of compounds is very appealing to me. When considering that hepatic inflammation and fibrogenesis are closely interrelated, the additional benefit of inhibiting both seems obvious. If additionally, a metabolic benefit can be achieved through for example life-style changes or drugs, I am convinced that NASH can resolve more effectively compared to a situation where only one pathway is hit. The benefit might even be exponential considering that the mechanisms of action (MoA) are amplifying themselves. On the other side, the regulatory barriers for combination therapy are high and these trials require more comparators – using the single agent vs placebo and the combination – resulting in more study arms and in the end larger trials.
9. There is an association between NASH and cardiovascular disease and cancer, so off-target adverse effects may present problems in clinical trials and in the real world. How will researchers tackle this issue?
This is an interesting aspect in the pathophysiology of NASH. There is some early evidence that metabolic inflammation, that partly arises in the liver, can promote cardiovascular disease. Additionally, the association with certain types of cancer is supported by large observational studies. In clinical trials, thorough drug vigilance is required, so that potentially detrimental off-targets effects can be identified early. However, I am carefully optimistic, that a drug that improves steatohepatitis will even exert beneficial effects in terms of the CVD risk.
10. Which interventions may reduce the placebo response and improve trial design of NASH trials?
That is an interesting question. I think we will see a lot more of placebo-controlled trials based on the requirements of the regulatory agencies. However, in phase 2 and combination approaches, some drug developers have omitted placebo from their trial design. I could also see a placebo lead-in a seamless design. Overall adaptive trials design will expedite drug development in this area. We have also learned that enrolling patients with more advanced disease and stringent definition of endpoints results in lower placebo response rates. In the end, it will depend on the population you intend to study and the endpoint you define – these are critical for defining the placebo response.
11. How can noninvasive biomarkers substitute for the liver biopsy? Noninvasive tests (nits) for staging, prognosis and monitoring in patients with NASH and advanced fibrosis are crucial. Can you briefly discuss the most promising approaches?
Based on the ongoing biomarker research, we will be able to determine the value and accuracy of blood-based markers that are directly linked to disease activity and clinical outcome. It will be through the scientific work within the ongoing, large clinical consortia where blood-based biomarker, histology and outcome will eventually substitute liver histology. To me, the most prominent approaches are direct fibrosis- and imaging biomarker. These can assess hepatic fibrosis with the highest accuracy. We have learned that the degree of hepatic fibrosis is most strongly correlated to clinical outcomes. It is less likely that markers that are linked to inflammation or fat deposition will be capable of performing at the same level.
Additionally, I do see value in assessing patient-reported outcomes and some well-defined tools have been developed in the field of NASH. Despite all limitations that arise from their use in a multimorbid population – they key here is to study them in metabolically – and otherwise stable – patients and participants.
12. Novel biomarkers are urgently needed for effective NASH therapy, monitoring & prevention. Has there been notable progress in this area?
Yes, definitely. On the one side, major advances have been made in terms of refining established indirect surrogate scores that predict or rule-out advanced fibrosis. Here we have seen a trend in combining these with novel techniques using direct fibrosis markers or an imaging technique (such as elastography) and coming up with a combination surrogate score in order to increase diagnostic accuracy. Also, the development of novel stand-alone biomarkers has progressed. Blood-based markers assessing fibrogenesis and fibrosis-resolution have been presented and will advance the field. In terms of standalone imaging biomarkers, I do see ultrasound and elastography techniques as a strong advancement in the space of monitoring and screening. For Europe, the use of MRI will not be so important, but I do see higher imaging capacities in the US and therefore these techniques, in particular magnetic resonance enterography (MRE), could even be used outside of clinical trials.
13. What are your hopes for the diagnosis, prevention and treatment of patients with NASH over the next decade?
I am optimistic that we will see drugs being approved for this indication based on the positive interim results that have been presented. In the future, I do see blood-based biomarkers substituting liver biopsy. This will also allow us to screen high-risk populations and to counsel them in order to reduce the number of patients reaching end-stage liver disease. Beyond this, we will see a large degree of individualization based on precision medicine approaches that can capitalize on the advances that are currently made in the realm of noninvasive biomarkers. In the end, we will be capable of assigning the drug with the highest response rates based on individual risk profile.
Disclaimer
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Taylor & Francis.
Declaration of interest
J Schattenberg has acted as consultant to Genfit, Gilead Sciences, Intercept Pharmaceuticals, IQVIA, Madrigal, Pfizer, Novartis, Roche, Siemens Healthineers and has received research funding from Gilead Sciences.