The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial

@article{Loomba2017TheAI,
  title={The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial},
  author={Rohit S. Loomba and Eric Lawitz and Parvez Mantry and Saumya Jayakumar and Stephen Hugh Caldwell and Hays L. Arnold and Anna Mae Diehl and Constantine S Djedjos and Ling Han and Robert P. Myers and Gangadharan Mani Subramanian and John McHutchison and Zachary Goodman and Nezam H. Afdhal and Michael R. Charlton},
  journal={Hepatology (Baltimore, Md.)},
  year={2017},
  volume={67},
  pages={549 - 559}
}
Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. [] Key Method In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone.

Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis.

TLDR
In two phase 2b trials of patients with bridging fibrosis or compensated cirrhosis associated with nonalcoholic steatohepatitis, simtuzumab was ineffective in decreasing hepatic collagen content or hepatic venous pressure gradient, respectively.

Current and new pharmacotherapy options for non-alcoholic steatohepatitis

TLDR
Farnesoid X receptor (FXR) agonist (obeticholic acid [OCA]) significantly ameliorated hepatic fibrosis in NASH stage 2/3 fibrosisIn an interim analysis of phase 3 trial, and the combination of GLP-RA/glucagon receptor agonist and GLP/gastrointestinal peptide agonist are promising future options.

NGM282 Improves Liver Fibrosis and Histology in 12 Weeks in Patients With Nonalcoholic Steatohepatitis

TLDR
In this open‐label study, NGM282 improved the histological features of NASH in 12 weeks with significant reductions in NAS and fibrosis scores, accompanied by improvements in noninvasive imaging and serum markers.

Effects of Selonsertib in Patients with Diabetic Kidney Disease.

TLDR
Although the trial did not meet its primary endpoint, exploratory post hoc analyses suggest that selonsertib may slow diabetic kidney disease progression.

Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects

TLDR
Selonsertib exhibited a favorable PK profile amenable to once-daily dosing without regard to food, and PD data suggest pharmacologically relevant exposures were achieved in the dose range evaluated.

Future Pharmacotherapy for Non-alcoholic Steatohepatitis (NASH): Review of Phase 2 and 3 Trials

TLDR
The major targets and mechanisms of action by class, results from completed pivotal phase 2 studies, and a detailed outline of key active studies with trial data for drugs in development are provided, including obeticholic acid, elafibranor, cenicriviroc and selonsertib.

New Drugs on the Block—Emerging Treatments for Nonalcoholic Steatohepatitis

TLDR
Drugs target almost all steps in the pathogenesis of NASH to improve insulin sensitivity, glucose and lipid metabolism, to inhibit de novo lipogenesis and delivery of lipids to the liver, and to influence apoptosis, inflammation and fibrogenesis.

Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis

TLDR
Givinostat is efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for the treatment of human NASH.
...

References

SHOWING 1-10 OF 53 REFERENCES

Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates

TLDR
Findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.

The therapeutic landscape of non‐alcoholic steatohepatitis

  • H. PerazzoJ. Dufour
  • Medicine
    Liver international : official journal of the International Association for the Study of the Liver
  • 2017
TLDR
Diversity in possible treatments for NASH calls for a better understanding of NASH in order to enrich trial populations with patients more susceptible to progress and to respond.

Ezetimibe for the Treatment of Nonalcoholic Steatohepatitis: Assessment by Novel Magnetic Resonance Imaging and Magnetic Resonance Elastography in a Randomized Trial (MOZART Trial)

TLDR
This trial demonstrates the application of colocalization of MRI‐PDFF‐derived fat maps and magnetic resonance elastography‐derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH.

Novel Pharmacotherapy Options for NASH

  • V. Ratziu
  • Medicine
    Digestive Diseases and Sciences
  • 2016
TLDR
The need for specific pharmacotherapy is now acknowledged by practitioners, the pharmaceutical industry, and regulators and is largely expected by patients, and there is a clear move away from products developed second hand for NASH or from generic, non-specific hepatoprotectors toward molecules developed and tested specifically forNASH.

Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial.

Effect of Colesevelam on Liver Fat Quantified by Magnetic Resonance in Nonalcoholic Steatohepatitis: A Randomized Controlled Trial

TLDR
MRI and MRS may be better than histology to detect longitudinal changes in hepatic fat in NASH as assessed by MRI as well as MRS without significant changes seen on histology.

Pathologic criteria for nonalcoholic steatohepatitis: Interprotocol agreement and ability to predict liver‐related mortality

TLDR
A diagnosis of NASH by the original criteria for NAFLD subtypes and the current study's criteria for NASH were in almost perfect agreement, but their level of agreement with the NAS and Brunt criteria was lower.

Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH): treatment.

Current efforts and trends in the treatment of NASH.

...