Structure of proof of concept studies that precede a nonalcoholic steatohepatitis development program

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Nonalcoholic steatohepatitis (NASH) is approaching epidemic proportions with a high prevalence in obese, insulin‐resistant subjects, and patients with type 2 diabetes mellitus. In the United States, the prevalence of NASH among patients with nonalcoholic fatty liver disease, as determined with imaging techniques, has been reported to be ∼60%, with similar or higher rates in Europe and Japan (the prevalence of nonalcoholic fatty liver disease being ∼24% of the population).1 The features of NASH include fat accumulation in the liver, inflammation, and various degrees of cellular damage and fibrosis, leading to liver‐related outcomes and mortality. Diagnosis and disease staging of NASH requires liver biopsies and expert pathological review. Currently, there are no drugs approved for the treatment of NASH although the multiple pathogenic steps implicated in the development of NASH provide a broad spectrum of potential, and differing, pharmacological targets.2 For example, targets already being investigated in clinical trials include such mechanistically diverse pathways as proliferator‐activated receptor‐related signaling, galectin inhibition, and farnesoid receptor activation. With at least two drugs in phase III development, we can expect to see continued interest in the development of drugs to treat NASH, and continued interest for assessing the value of various phase II proof‐of‐concept (POC) study designs for this complex metabolic disease.
Definitive phase II POC studies in NASH often require a sufficient duration (≥48 weeks) to demonstrate liver improvements through the evaluation of tissue biopsies. From a drug development perspective there are many disadvantages for stakeholders when conducting such long POC studies involving an invasive procedure, such as a liver biopsy: (1) patients might be exposed to ineffective investigational drugs with potentially unknown side effects for relatively long periods of time; (2) enrollment challenges from reluctance by patients and caregivers to participate due to repeated liver biopsies; and (3) long‐term POC studies incur substantive cost burdens on the sponsor. These issues become magnified when considering dose response studies with inclusion of several experimental arms, or when the sponsor is considering exploring the pharmacological activity of several potentially effective drugs within their portfolio.
To establish a more streamlined and affordable approach for drug development in NASH, we and others have considered an alternative strategy of utilizing early phase II POC noninvasive study designs lasting ≤28 weeks. These short‐term phase II POC studies provide composite biomarker endpoints that incorporate a variety of noninvasive measures. Although noninvasive measures have not been clinically validated for use in NASH, they can provide a degree of confidence strong enough for all stakeholders to further invest in the development of the product, patients, sponsors, and regulators. Such noninvasive measures include scanning technologies (e.g., magnetic resonance imaging, magnetic resonance elastography) and various biochemical markers (e.g., markers of insulin resistance, liver inflammation, and fibrosis).3 Although none of these biomarkers taken in isolation can fully replace a liver biopsy in terms of NASH progression, they do provide information about pathogenic factors associated with NASH as well as drug‐induced changes in morphology and liver function. Furthermore, based upon the mechanism of action of the drug, specific biomarkers can be preselected based on the mechanism of action of a new drug to best determine if an experimental agent is having the positive impact expected on histological outcomes. Given these short‐term noninvasive studies can offer a signal of pharmacological activity, and at less cost than biopsy‐driven studies, they can offer a more attractive option for patients, and certainly provide a more sustainable financial model for drugs in early clinical development (Table1).

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