NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD),
NON-ALCOHOLIC STEATOSIS HEPATIS (NASH)

NAFLD and NASH: a challenge for clinical research that CRS is actively addressing

NAFLD increases overall mortality by up to 60 percent

The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to have passed 25 percent in adults. In obese or type 2 diabetic subjects, the prevalence even rises to 70-80 percent. NAFLD increases overall mortality by up to 60 percent, mainly driven by liver related mortality or cardiovascular complications.

In case of an exacerbation of hepatic inflammation and fibrosis, 30-40 percent of the NAFLD-cases progress to non-alcoholic steatosis hepatis (NASH); this further increases the risk of liver cirrhosis or the development of hepatic cellular carcinoma (HCC).

Thus, NAFLD and NASH have become the leading cause of hepatic morbidity and mortality. In western countries, sedentary lifestyle, obesity, adipose tissue dysfunction, insulin resistance, and type 2 diabetes have been identified as the major risk factors associated with the development of NAFLD.

NAFLD is also understood as the hepatic component of the metabolic syndrome. Not only is the development of NAFLD more common in subjects with metabolic syndrome, but progression to NASH with aggravating inflammation and fibrosis becomes more likely. Adipose tissue dysfunction, lipotoxicity, inflammation, and the release of hepatokines, adipokines, and inflammatory cytokines are considered to play a crucial role in the progression from NAFLD to NASH.

NAFLD/NASH prevention and treatment: promising candidates but no approved drug yet

In recent years, tremendous research efforts have been made to explore the underlying pathophysiology of NAFLD and to develop intervention strategies to prevent or treat NAFLD/NASH. Although lifestyle intervention was found to be highly effective in clinical trials, it is incredibly challenging to achieve reliable and sustainable lifestyle changes in a real world setting over time.

Up to now, no pharmacological treatment of NAFLD/NASH has been approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Even though Vitamin E or PPAR-gamma (peroxisom proliferator-activated receptor gamma) agonists have shown some promising results in a few smaller clinical trials, their role in the treatment of NAFLD/NASH is negligible.

Meanwhile, vigorous basic research has identified several molecular signaling pathways, which appear promising for pharmacological interventions in the development or treatment of NAFLD or NASH.
Incretin based treatments or SGLT-2 (sodium-glucose transport protein 2) inhibitors, as yet approved for the treatment of diabetes mellitus type 2, have shown some beneficial effects in obese type 2 diabetic patients with NAFLD/NASH.

New drugs are under clinical evaluation, e.g., dual or pan peroxisom proliferator-activated receptor (PPAR) agonists, apoptosis signal-regulating kinase 1 (ASK1), fibroblast growth factor 21 analogs (FGF21), C-C chemokine ligand types 2 and 5 agonists (CCR2/CCR5), farnesoid X receptor (FXR) agonists, acetyl-CoA carboxylase inhibitors, modification of intestinal microbiome, and others.

CRS in collaboration with others has initiated multiple activities to combat NAFLD/NASH

CRS is fully aware of the clinical relevance of these metabolic disorders. That is why CRS has initiated multiple activities to combat NAFLD/NASH in collaboration with the University of Heidelberg and the University of Göttingen.

Thus, we at CRS continuously expand our patient’s database as part of an epidemiological survey for the categorization of obese or diabetic subjects regarding several hepatic biomarkers for NAFLD/NASH.

In several clinical trials and together with our partner clinical and laboratory sites we have established various diagnostic tools and biomarkers for the evaluation of NAFLD/NASH, e.g.:

• Transient liver elastography (FibroScan®)
• Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF)
• Liver Biopsy – Liver Histology
• Laboratory Biomarkers
• Cytokeratin 18 (CK 18)
• Soluble CD 163 (sCD 163)
• Adipokines
• Cytokines
• NAFLD/NASH Scores
  • BARD-Score
  • NAFLD-Score
  • Fibrosis 4 Score
  • Fatty Liver Index
• Metabolomic and proteomic analysis
• RNA, micro-RNA epigenetic factors

With CRS, your clinical trial is in best hands

The constant care of a powerful CRS proprietary database of volunteers and patients together with a solid network of collaborating medical specialists and office-based family doctors are the key of our highly effective recruitment of healthy volunteers or patients with cardiovascular disease.

CRS-owned excellent equipped and carefully quality controlled Early Phase Clinical Trial Units are a reliable guarantee for CRS-customers for a conduct of the trial complying with all regulatory requirements of the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

Together with carefully selected external clinical centers of excellence we at CRS can provide a wide range of studies bridging from preclinical evidence to the proof of concept in healthy humans or patients with cardiovascular disease.

CRS’ experienced scientists, statisticians and medical writers can provide essential support in creating powerful study outlines or writing the study protocols in preparation of a study, as well as in finalizing study reports and drafting manuscripts for publication in scientific journals after completion of the clinical trial.

A large number of scientific papers published in international peer-reviewed journals are proof of our outstanding expertise in this therapeutic area.

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