The future R&amp;D landscape in non-alcoholic steatohepatitis (NASH)

Black, Darcey; Brockbank, Sarah; Cruwys, Simon; Goldenstein, Kim; Hein, Peter; Humphries, Bob

doi:10.1016/j.drudis.2018.09.020

Cited by 8 publications

(6 citation statements)

References 34 publications

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“…NASH is a multifactorial disease with a complex pathophysiology and a steadily growing global health and economic burden [5,[9][10][11][12]. Despite significant research efforts, there are no approved therapies available to date specifically to treat NASH.…”

Section: Discussionmentioning

confidence: 99%

“…Nonalcoholic steatohepatitis (NASH), the severe form of NAFLD [4], is characterized by hepatic ballooning, steatosis and inflammation and can progress to advanced fibrosis/cirrhosis and/or hepatocellular carcinoma leading to liver transplantation or death [5,6]. So far, there are no approved therapies specifically for NASH [7,8] because of the potential key challenge of the development of effective pharmacotherapies that target multiple cellular pathways involved in NASH [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial

Pedrosa

Seyedkazemi

Francque

et al. 2020

Contemporary Clinical Trials

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial

Pedrosa

Seyedkazemi

Francque

et al. 2020

Contemporary Clinical Trials

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“…Among the experimental drugs, a plethora of pathways and target mechanisms are being tested, such as metabolic dysfunction, glucose homeostasis, lipid metabolism, or bile acid signalling. 12 In this scenario, it has been hypothesised that the presence of a NAFLD-related comorbidities could influence response rates depending on the mechanism of action.…”

Section: Impact Of Comorbidities and Lifestyle On Treatment Responsementioning

confidence: 99%

Stratification of patients in NASH clinical trials: A pitfall for trial success

Ampuero

Romero–Gómez

2020

JHEP Reports

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Identifying the most effective therapeutic intervention in patients with NAFLD is challenging. Precise stratification in clinical trials is key to ensuring the inclusion of patients who will benefit (and not those who will be harmed) and/or in whom the natural history can be improved. Clinical trials in NAFLD can provide useful information about the individual components that underlie this complex metabolic disorder and the concomitant medications that could interfere with responses to an experimental intervention. However, to date, clinical trial reporting for NAFLD has been suboptimal, limiting our understanding. Frequently dysmetabolic comorbidities and/or daily habits are not reported or adequately accounted for. Herein, we suggest new strategies to integrate the spectra of comorbidities usually present in patients with NAFLD, accounting for the impact of lifestyle, to develop personalised therapeutic approaches. First, the mechanism of action of the drug being explored should be considered. Second, the same proportion of patients with relevant metabolic comorbidities should be maintained from phase II to III clinical trials, if such comorbidities are expected to impact on the treatment response. Third, innovative trial designs, such as the adaptative, umbrella or basket strategies, could be used to increase the efficiency of clinical trials, potentially benefiting patients while reducing costs and enhancing the likelihood of finding a real benefit of the therapy being studied. Finally, alcohol intake and daily exercise should be assessed objectively not only in the screening period but also during follow-up.

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“…Although NAFLD is of increasing concern since it is highly prevalent, potentially aggressive, and progressing, no therapy has been approved. Targeting intrahepatic lipid accumulation is considered as the primary therapeutic strategy for NAFLD 6 . The peroxisome proliferator-activated receptors (PPARs), including PPAR α , β / δ , and γ , are a family of nuclear receptors that have been well-characterized to be master regulators in lipid transport, fatty acid oxidation, and inflammation 7 .…”

Section: Introductionmentioning

confidence: 99%

Integrative lipidomic and transcriptomic study unravels the therapeutic effects of saikosaponins A and D on non-alcoholic fatty liver disease

Cai

et al. 2021

Acta Pharmaceutica Sinica B

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Nonalcoholic fatty liver disease (NAFLD) has become one of the most prominent causes of chronic liver diseases and malignancies. However, few therapy has been approved. Radix Bupleuri (RB) is the most frequently used herbal medicine for the treatment of liver diseases. In the current study, we aim to systemically evaluate the therapeutic effects of saikosaponin A (SSa) and saikosaponin D (SSd), the major bioactive monomers in RB, against NAFLD and to investigate the underlying mechanisms. Our results demonstrated that both SSa and SSd improved diet-induced NAFLD. Integrative lipidomic and transcriptomic analysis revealed that SSa and SSd modulated glycerolipid metabolism by regulating related genes, like Lipe and Lipg . SSd profoundly suppressed the fatty acid biosynthesis by downregulating Fasn and Acaca expression and promoted fatty acid degradation by inducing Acox1 and Cpt1a expression. Bioinformatic analysis further predicted the implication of master transcription factors, including peroxisome proliferator-activated receptor alpha (PPAR α ), in the protective effects of SSa and SSd. These results were further confirmed in vitro in mouse primary hepatocytes. In summary, our study uncoded the complicated mechanisms underlying the promising anti-steatosis activities of saikosaponins (SSs), and provided critical evidence inspiring the discovery of innovative therapies based on SSa and SSd for the treatment of NAFLD and related complications.

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The future R&D landscape in non-alcoholic steatohepatitis (NASH)

Cited by 8 publications

References 34 publications

A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial

A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial

Stratification of patients in NASH clinical trials: A pitfall for trial success

Integrative lipidomic and transcriptomic study unravels the therapeutic effects of saikosaponins A and D on non-alcoholic fatty liver disease

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