Cenicriviroc treatment for adults with non-alcoholic steatohepatitis: Year 2 analysis of the Phase 2b CENTAUR study

Ratziu, Vlad; Sanyal, A.; Francque, S.; Sun, Wenjing; Wong, Vincent Wai‐Sun; Loomba, Rohit; Goodman, Z.; Lefebvre, E.; Aithal, Guruprasad P.; Harrison, S.; Abdelmalek, M.; Friedman, Scott L.; Tacke, Frank

doi:10.1016/s0168-8278(18)30221-6

Cited by 15 publications

(13 citation statements)

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“…Thus, histological fibrosis improvement by one stage has been reported in about 20% (15% to 35%) of patients with placebo . In a study with subsequent biopsies, patients with initial fibrosis improvement on placebo after 1 year were highly likely (80%) to worsen between year 1 and year 2 . With advanced fibrosis (stage F3‐F4), outcomes become more predictable, with exemplified by a dramatic increase in the risk of progression to “hard outcomes” (i.e., decompensation of liver disease, liver transplantation, death).…”

Section: Nafld Natural History and Subtypesmentioning

confidence: 99%

“…Lifestyle changes that produce even modest results (for example, sustained weight loss of no more than 5% of initial body weight can reduce steatosis, liver enzymes, and metabolic parameters, and is sometimes used as secondary endpoints in NAFLD clinical trials). In addition, dietary composition itself (e.g., Mediterranean versus Western‐style diet) is a factor affecting hepatic outcomes, regardless of weight loss . Fibrosis is less susceptible to minor changes in weight or dietary composition, but regresses in patients achieving sustainably greater than 10% weight loss .…”

Section: Placebo Response: a Critical Determinant Of Trial Successmentioning

confidence: 99%

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Report on the AASLD/EASL Joint Workshop on Clinical Trial Endpoints in NAFLD

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) is a global public health concern. Its natural history, the development of nonalcoholic steatohepatitis (NASH) and fibrosis, is highly variable, prone to endogenous (e.g., genetics, microbiota) and exogenous (e.g., nutrition, alcohol, physical activity) disease modifiers, and can fluctuate over time. The complexity of its pathophysiology is reflected by the multitude of pharmacological targets in development. NASH clinical trials have provided valuable insight that is applicable to future trial design. Endpoints for NASH have evolved over the past decade and will continue to be refined. Currently accepted endpoints for conditional approval include resolution of NASH without worsening of fibrosis and/or improvement in fibrosis without worsening of NASH by standardized evaluation of paired liver histology. In pediatric NASH, practical obstacles, pubertal hormonal changes, and stringent safety requirements mandate adaptations in trial design. In adult patients with NASH‐related cirrhosis, clinical events (e.g. decompensation, hepatocellular carcinoma, transplantation, death) are more prevalent and thereby are viable primary endpoints. Consideration of the natural fluctuation of disease, the clinical implication of the chosen primary endpoint, and factors that may affect placebo response will facilitate an accurate determination of efficacy of emerging therapeutics for NASH. Conclusion: The June 2018 American Association for the Study of Liver Diseases and European Association for the Study of the Liver joint workshop on NAFLD endpoints summarized important findings from ongoing and completed trials, defined the scientific evidence supporting distinct endpoints, and provided guidance for future trial design.

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Section: Nafld Natural History and Subtypesmentioning

confidence: 99%

Section: Placebo Response: a Critical Determinant Of Trial Successmentioning

confidence: 99%

Report on the AASLD/EASL Joint Workshop on Clinical Trial Endpoints in NAFLD

et al. 2019

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“…Indeed, although initials trials yielded promising results, the chemokine receptor (CCR) 2/5 inhibitor cenicriviroc and the ASK1 inhibitor selonsertib did not significantly improve liver fibrosis as compared to placebo, and their possible efficacy was not directly correlated with inhibition of inflammation. 59,60 Furthermore, administration of JKB-121, an antagonist of Toll-like receptor 4, a key pattern recognition receptor involved in NASH development in experimental studies, paradoxically led to worsening of liver damage, which was associated with more severe hepatic fat accumulation. 61 Concerning pure antifibrotic drugs, the lysyl oxidase like 2 (LOXL2) inhibitor simtuzumab did not improve fibrosis nor portal hypertension.…”

Section: Ther Apeuti C Trial Smentioning

confidence: 99%

Hepatic fat as clinical outcome and therapeutic target for nonalcoholic fatty liver disease

Pelusi

Valenti

2018

Liver International

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Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the leading cause of advanced liver disease in Western countries. NAFLD is defined in the presence of increased hepatic fat content, which is mainly stored under the form of neutral lipids within intracellular droplets and is not explained by at risk alcohol intake. In order to understand the pathogenesis, monitor the progression and find novel treatments for this condition, previous research efforts mainly addressed the role of inflammation. However, very recent data seem to suggest that hepatic lipid accumulation may be involved in NAFLD pathogenesis by driving secondary inflammation and fibrosis progression. Here, we will briefly review the novel results derived from natural history, genetics, imaging studies and therapeutic trials that support the notion that hepatic fat accumulation may represent a major clinical outcome and therapeutic target for NAFLD. Indeed, prospective and genetic data are consistent with hepatic fat being a driver of NAFLD progression. Furthermore, new technologies will render possible to monitor hepatic fat content without the need of invasive assessment, thereby allowing to identify patients at higher risk, and to monitor the response to drugs that act by decreasing hepatic lipid accumulation.

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“…4 In a study with subsequent biopsies, patients with initial fibrosis improvement on placebo after 1 year were highly likely (80%) to worsen between year 1 and year 2. 19 With advanced fibrosis (stage F3-F4), outcomes become more predictable, as exemplified by a dramatic increase in the risk of progression to ''hard outcomes" (i.e., decompensation of liver disease, liver transplantation, death). Preventing progression, or inducing regression, of advanced fibrosis is therefore a clear priority.…”

Section: Nafld Natural History and Subtypesmentioning

confidence: 99%

“…In addition, dietary composition itself (e.g., Mediter-ranean versus Western-style diet) is a factor affecting hepatic outcomes, regardless of weight loss. 19 Fibrosis is less susceptible to minor changes in weight or dietary composition, but regresses in patients achieving sustainably greater than 10% weight loss. 31 Thus, data capture is recommended for diet (caloric intake, composition, and as discussed previously, alcohol consumption), physical activity, and anthropometric measures (e.g., weight, body mass index, waist circumference, visceral adipose tissue, abdominal fat).…”

Section: Placebo Response: a Critical Determinant Of Trial Successmentioning

confidence: 99%