The regulatory state of nonalcoholic steatohepatitis and metabolism

With nearly 100 million people affected in the United States with nonalcoholic fatty liver disease (NAFLD) and projections for the advanced stages of NAFLD to soon become the leading indication for liver transplantation, nonalcoholic steatohepatitis (NASH) remains a significant area of unmet medical need. Therapeutic options for NASH are a critical priority for clinicians, drug developers and regulatory authorities. The epidemic proportions have led to a surge in the development of novel drugs aimed at the complex pathogenesis of NASH and in regulatory submissions. There are currently no approved drugs in the United States for the treatment of adult or paediatric NASH. Potential therapeutic targets include steatosis, glucose metabolism, lipogenesis, oxidative stress, apoptosis, fibrosis and immunomodulation, all intended to alter the pathophysiology of NASH and remedy its associated complications. While over 50 candidate drugs are currently under development in the United States, it has yet to be determined the extent to which single agents will be impactful on the multifactorial aetiology of NASH based on publicly available preliminary data.1 The primary challenges in NASH drug development have included the appropriateness of biopsy-based end-points and related statistical handling, drug development for cirrhosis, a cure-based focus (ie only a handful of programmes evaluating symptom-based indications such as ascites, hepatic encephalopathy and variceal bleeding) and paediatric drug development. In addition to the possible role for combination therapies, novel approaches are likely needed within discovery and regulatory science to actualize health solutions for NASH patients across the globe. Such solutions should include further exploration of the relationship between NASH and other metabolic diseases of energy homeostasis such as obesity, dyslipidaemia and type 2 diabetes mellitus (T2DM). This article will discuss the current regulatory landscape for NASH and examines the overlap of the regulatory perspectives between NASH and other metabolic diseases.


E D I T O R I A L
The regulatory state of nonalcoholic steatohepatitis and metabolism BACKG  While over 50 candidate drugs are currently under development in the United States, it has yet to be determined the extent to which single agents will be impactful on the multifactorial aetiology of NASH based on publicly available preliminary data. 1 The primary challenges in NASH drug development have included the appropriateness of biopsy-based end-points and related statistical handling, drug development for cirrhosis, a cure-based focus (ie only a handful of programmes evaluating symptom-based indications such as ascites, hepatic encephalopathy and variceal bleeding) and paediatric drug development. In addition to the possible role for combination therapies, novel approaches are likely needed within discovery and regulatory science to actualize health solutions for NASH patients across the globe. Such solutions should include further exploration of the relationship between NASH and other metabolic diseases of energy homeostasis such as obesity, dyslipidaemia and type 2 diabetes mellitus (T2DM). This article will discuss the current regulatory landscape for NASH and examines the overlap of the regulatory perspectives between NASH and other metabolic diseases.

FDA APPROVAL PATHWAYS
The FDA currently supports commercial drug development in NASH with advanced stage fibrosis as these patients are at a higher risk for liver-related adverse clinical outcomes. There are two types of regulatory approval pathways: traditional (also known as regular or "full") and accelerated approval. Traditional approval relies on clinical benefit end-points which directly measure how a patient feels, functions and survives (eg morbidity and mortality) and would require durations in the order of decades for trials in precirrhotic NASH patients.

FDA DR AF T NON CIRRHOTIC NA S H WITH LIVER FIB ROS IS G U IDAN CE-EFFI C AC Y AND SAFE T Y CONS IDER ATIONS
FDA draft guidance regarding drug development in noncirrhotic NASH with liver fibrosis was published in 2018 3 with primary aims to facilitate clinical development of drugs for the treatment of noncirrhotic NASH patients with liver fibrosis who are at risk for liverrelated adverse outcomes.
The target population for these trials should have a histological diagnosis of NASH with liver fibrosis based on a NAFLD activity score (NAS) equal to or >4 with at least 1 point each in inflammation and ballooning in addition to a NASH Clinical Research Network fibrosis score of stage 2 or 3 prior to enrolment. Currently, there is no specific weight criterion for enrolment, but weight should be stable for at least 3 months prior to enrolment. Patients with T2DM can also be enrolled in NASH clinical trials if at least moderately controlled and on stable doses of anti-diabetic medications for at least 3 months. Concomitant medications with the potential to confound the interpretation of efficacy or safety, for example by contributing to the therapeutic effect of a drug for NASH (eg Vitamin E or pioglitazone), should either be discontinued or have been on a stable dose for at least 6-12 months.
Biopsy-based end-points of (a) resolution of steatohepatitis on overall histopathologic interpretation and no worsening of fibrosis, an imperfect reference standard for NASH diagnosis and monitoring because its use is accompanied by drawbacks including the invasiveness of liver biopsies (particularly in paediatric patients), sampling error due to at most 1/50 000th of the entire liver sampled, intraand interobserver variability, costs and a low but observable risk of serious complications. While it is not yet known whether the effect of any particular drug will be precisely and comprehensively characterized by the inflammatory and fibrotic components of NASH injury as assessed by the histological method or whether the current 12-18 months duration of clinical trials will be sufficiently long to allow detection of treatment effects, what is known is that the fibrosis component of the NASH pattern of injury is the strongest predictor for adverse outcomes in patients. 5 The early failed trials in NASH, 6  For clinical outcome trials, there may be drivers of the clinical benefit end-point (eg progression to cirrhosis component may contribute a greater number of events as it will occur more frequently than other components comprising the composite end-point); while this may allow earlier completion of trials in a shorter duration, it may not evaluate all aspects of the disease and this will need to be factored into the data review and analysis to ensure that a positive treatment response is not an isolated effect. The primary safety conundrum for NASH drug development is that investigational agents intended to treat liver disease can also result in liver injury. 21 For this reason, early hepatic impairment studies are encouraged to better characterize the study drug prior to studies in higher risk populations (eg cirrhosis) and because patients may progress to cirrhosis during the conduct of clinical trials.

FDA DR AF T NA S H WITH COMPEN SATED CIRRHOS IS G U IDAN CE-EFFIC AC Y AND SAFE T Y CONS IDER ATIONS
Detailed drug-induced liver injury (DILI) evaluation and management algorithms in addition to close monitoring as per the DILI guidance 22 are recommended in the setting of suspected DILI. While the DILI guidance may not be fully applicable to patients with underlying liver disease and elevated liver biochemical baselines, it remains the cornerstone for liver safety monitoring in clinical trials. The Agency is aware of this knowledge gap and is engaged globally in collaborative discussions 23,24 to address the need for guidelines specific to patients with pre-existing liver disease.

NA S H IN THE REG UL ATORY CONTE X T OF OB E S IT Y AND OTHER ME TABOLIC DISE A SE S
It has been estimated that as many as 75% of patients with obesity have NAFLD and 20% have NASH. 25,26 Obesity, insulin resistance, T2DM and dyslipidaemia increase the risk of progression from nonalcoholic fatty liver (NAFL) to NASH. 27,28 The treatment of obesity provides an opportunity to simultaneously address co-existing metabolic diseases, including NASH. Likewise, weight loss strategiesincluding lifestyle and surgical interventions-have the potential to improve outcomes in NASH patients by normalizing liver enzymes, inducing regression in hepatic pathology, and mitigating cardiovascular risk factors. 5,29 There are limited data to suggest whether drug-induced weight loss can directly mediate these effects; however, therapies that could effectively treat obesity, its related comorbidities and NASH are highly desirable.
The most recently updated FDA draft guidance for weight management was published in 2007. 28  as it has been associated with improvements in cardiometabolic biomarkers, such as blood pressure, lipids and fasting glucose. 30 There are currently 5 drugs that are FDA-approved for chronic weight management in patients with obesity: orlistat (gastrointestinal lipase inhibitor), lorcaserin (serotonin 2C receptor agonist), phentermine/topiramate (combination of a sympathomimetic anorectic and an antiepileptic drug), bupropion/naltrexone (combination of an aminoketone antidepressant and an opioid antagonist) and liraglutide (GLP-1 receptor agonist). One-year placebo-subtracted weight loss from baseline body weight as described in the prescribing information ranges from 3% to 9% and depends to a large extent on the patient population, background lifestyle intervention, treatment adherence, study discontinuation rate and the statistical methods used to address missing data. The labelled prescribing information for these drugs includes changes in weight-related secondary endpoints, such as blood pressure and lipids, but currently does not include liver-related efficacy end-points, or claims related to the reduction of cardiovascular morbidity and mortality or improvement in quality of life. To date, no obesity drug has demonstrated cardiovascular risk reduction in a dedicated trial.

PAEDIATRIC CONS IDER ATIONS
Obesity and severe obesity in children and adolescents ages 2 and above are often defined as a BMI at or above the 95th percentile of sex-specific BMI-for-age and BMI at or above 120% of the 95th percentile, respectively. 31 With the rise in paediatric obesity over the last several decades, the prevalence of associated metabolic diseases including NAFL and NASH is also increasing. [32][33][34] As with adults with obesity or NASH, the mainstay of treatment of children and adolescents is lifestyle modification, with the hope and expectation that effective diet and physical activity interventions can prevent or delay many of the associated co-morbidities.
Currently, there are limited pharmacological treatment options in children and adolescents with obesity, with only one drug, orlistat, labelled for long-term weight management in patients ages 12 and above. The assessment of certain drugs and biologics in children is required under the Pediatric Research Equity Act, 35  Paediatric studies in NASH are few and, as with adults, there are no FDA-approved drugs. While several drug manufacturers have identified the need for paediatric studies in NASH as early as possible in their initial paediatric study plans, the path forward is less clear because of the differences in adult and paediatric NASH histopathologic features making it impracticable to extrapolate efficacy from adult data to children, lack of natural history information to define feasible end-points, ethical and regulatory requirements that enrolment of children in drug intervention trials be adequately justified through demonstration of prospect of direct benefit 36 to the subject and the need for age-appropriate formulations. Notably, the pressing need for end-points with acceptable invasiveness that can be assessed in a timely manner and will predict clinical outcomes cannot be overstated. There has been some suggestion that assessing delays in the time to onset or prevention of NASH co-morbidities may be possible end-points; however, the sample size and trial duration needed for such paediatric studies as well as the clinical relevance or likelihood that these would predict direct clinical benefit for NASH may still be limiting factors. with NASH could be specifically targeted in obesity and other metabolic drug programmes to enrich for cardiometabolic risk factors, or to evaluate NASH end-points as part of the efficacy assessments to support obesity drug approval. However, equating benefit from one metabolic disorder to the next may be more complicated than foreseen even if it were possible to attribute relatedness of differential outcomes (ie improvement of metabolic derangements equals an improvement in NASH). As this is a fairly novel approach in already complex pathophysiology, drug manufacturers and investigators are encouraged to discuss such study proposals with the Agency.

ARE A S OF E XPLOR ATORY OPP ORTUNITIE S
Examples of overlapping drug classes or mechanisms in the pipeline for NASH and other metabolic diseases include glucagon-like peptide-1 receptor agonists, peroxisome proliferator-activated receptor agonists, sodium glucose cotransporter-2 inhibitors, fibroblast growth factor-21 analogs, and others. 1 Complementary targets and mechanisms create opportunities for approved drugs and investigational agents for other metabolic indications to be reconsidered or used as part of combination therapies, to potentially expand the armamentarium for NASH. Combination drug development programmes will need to address the fixed combination rule, which states that " [t] wo or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labelling for the drug". 38

CO N FLI C T O F I NTE R E S T
The authors declared no conflict of interest.

AUTH O R CO NTR I B UTI O N S
SOO conceived the concept for the manuscript and is the primary author. JKG authored sections on drugs to treat obesity and other metabolic diseases. Both authors contributed to the preparation and revision of the manuscript.

E TH I C A L S TATEM ENT
The authors declare that the manuscript is original and has not been submitted for publication elsewhere. No specific ethical approval or informed consent was required for this editorial.