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Development considerations for pioneering a NASH clinical program

The National Institute of Diabetes and Digestive and Kidney Diseases considers nonalcoholic fatty liver disease (NAFLD) as a condition wherein the liver stores excess fat and nonalcoholic steatohepatitis (NASH) as one type of NAFLD. Individuals with obesity and type 2 diabetes appear to be at greater risk of developing NAFLD. Many innovative and scientifically intriguing therapeutic options are emerging as of the time of this blog. There are a few clinical pharmacology considerations that must be accounted for when developing treatments for these disorders. They are as follows.

Ensuring bench to bed translation

Preclinical models of NASH are fraught with design and validation challenges and adequate replication of human disease (1). Moreover, the necessity of liver histology predisposes the experiments to longer term readouts, which makes translating from animals to humans that much harder. Invariably, even shorter-term human experiments and translating to patient disease state is also a challenge. While there are multiple biomarkers and endpoints accepted and negotiated for NASH between clinical and regulatory scientists alike, early human experiments should include biomarker rich sampling to understand the mechanism of action (target specific biomarkers) and to understand the extent and nature to which the molecule engages with the target and in doing so, for how long. Longer trials in later phases of development are limited by timings of liver biopsies. So, it becomes helpful if thought and action are built in to ensure sufficient translatability from early human to late human experiments. The increased emphasis on prevention of cirrhosis in NASH has fueled translational models that address the decline in progression as a measurable target. Designing clinical trials that ensure an acceptable battery of endpoints are prudently used and supplementing them with a cohesive model-informed development plan can strengthen your translational objectives and reduce uncertainty in asset development.

Designing an appropriate hepatic impairment trial

Because small molecules are routinely metabolized by the liver, a hepatic impairment study is typically considered a clinical pharmacology best practice. However, in the case of NASH, there is one other complicating feature. If NASH results in cirrhosis and subsequently, hepatic failure, then the consequences of such a disease progression to survival becomes critical. The role of the hepatic impairment study is then a safety assessment as well. For this reason, the design of a hepatic impairment study in the program must be carefully considered and designed to meet not only the pharmacokinetic objectives but also for safety reasons. A multiple dose hepatic impairment study is not an uncommon scenario in this regard. Explore the work of Edwards et al (2) that persuasively explores these aspects (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351006/).

Ensuring sufficient data rigor to assess longer term exposure/response and exposure/safety

Because NASH exhibits slow disease progression (3), the disease state predisposing to pharmacokinetics could change from start of treatment to later in the maintenance phase, 6 months, or a year and longer. In addition, the added emphasis on drug-related liver injury adds an additional consideration for NASH. For this reason, it is prudent to set up the PK and pharmacodynamic (PD) sampling schedule in pivotal studies that addresses both short term and long-term objectives. This would entail collection of PK sampling in all subjects enrolled in a trial. Oftentimes, such sampling comes at a small logistical overhead. However, the value gained from PK sampling all subjects is invaluable. There are model-based solutions in ensuring there is an optimal balance between trial objectives and sampling, such as a balance between rich PK sampling in some subjects and sparse sampling in others. Common statistical methods can ensure that this balance is right. As trials are designed with adaptive components (whether dose and/or sample size), incorporation of smart PK sampling choices can assist in dose optimization for later phase trials and/or the drug label.

Building a physiologically significant pharmacokinetic model

Very likely, there is a subtle interplay between the target tissue concentrations and those commonly sampled from the systemic central compartment. In many cases, systemic concentrations are sufficient to explain compartmental pharmacokinetics. In some other cases however, systemic concentrations could in fact be misleading. A careful consideration on this aspect is helpful early in the clinical program. An example of this approach is borrowed from the work of Edwards et al (2). Their landmark work is significant because they showed that while moderate and severe hepatic impairment significantly increased the systemic exposure of obeticholic acid, predicted liver concentrations did not. Because the liver is the site of pharmacological activity, liver concentrations are more likely to be meaningful in this regard rather than plasma concentrations. Importantly, their results confirmed the belief system that the liver‐to‐plasma ratio differs between healthy volunteers and those that are hepatically impaired.

In summary, drug development for NASH is in a captivating phase of scientific innovation. The challenges in translatability presents creative opportunities to bootstrap the clinical program with rational choice of biomarkers and PK/PD approaches to ensure the principal considerations of dose, dosing regimen, and target engagement are all appropriately considered. The regulatory frameworks in major markets present interesting opportunities for the drug developer, as seen in a recent webcast (4).

Certara’s experts can assist you in building a strong model-informed clinical pharmacology program for NASH and other liver diseases.

To learn how pharmacokinetic modeling was used to support the approval of a treatment for a rare liver disease, read this case study.


  1. Hansen HH, Feigh M, Veidal SS, et al. Mouse models of nonalcoholic steatohepatitis in preclinical drug development. Drug Discov Today. 2017;22:1707–18.
  2. Edwards JE et al. Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage. Clin Trans Sci. 2016 Dec;9(6):328-336.
  3. Fazel Y, Koenig AB, Sayiner M, et al. Epidemiology and natural history of non-alcoholic fatty liver disease. Metabolism. 2016;65:1017–25.
  4. Regulatory Perspectives for Development of Drugs for Treatment of NASH. Jan 2021
    (URL: https://www.fda.gov/drugs/news-events-human-drugs/regulatory-perspectives-development-drugs-treatment-nash-01292021-01292021).

About the author

By: Rajesh Krishna
Rajesh Krishna, PhD is a Senior Director in Integrated Drug Development at Certara Strategic Consulting.  Rajesh came to Certara after a rich 20+ years of pharmaceutical industry experience in translational and clinical development at Merck, Sanofi (legacy Aventis), and Bristol-Myers Squibb.  He has contributed to 40+ INDs, more than 200 Phase 1/1b studies; and to the worldwide registration of 9 new molecular entities.

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