Although a fatty liver can be considered a benign condition in itself, it predisposes people to the development of diabetes and cardiovascular disease on the one hand, and progressive liver disease (liver inflammation and fibrosis, liver cirrhosis, liver failure, hepatocellular carcinoma) on the other. This is why there is a wide consensus about a high need for specific drugs that effectively interfere already with the early stages of NAFLD by reducing the amount of liver fat and/or resolving ongoing liver fibrosis. Indeed NAFLD is considered to be the dominant disease indication for the development of anti-fibrotic drugs (Trautwein et al., 2016).
Profil has the capacity to effectively support the early phases of clinical drug development addressing NAFLD. Clinical trials in NAFLD could focus on fatty liver (first hit) resolution – aiming at decreasing the hepatic susceptibility to a „second hit“. Clinical trials in NAFLD could also focus on the resolution of liver fibrosis – aiming to stop the progression of chronic liver disease.
In order to economise clinical trial conduct and to control sample size, proof-of concept trials in NAFLD require a careful patient stratification based on presence of a fatty liver, signs of the metabolic syndrome, and surrogates of hepatic inflammation. For the assessment of liver fibrosis-related endpoints (aiming at documenting a stop of progression or reversal of liver fibrosis) patients with an intermediate stage of fibrosis should be pre-identified.
Transient elastography (TE) with controlled attenuation parameter (CAP) has been well acknowledged for simultaneously addressing liver fat and liver fibrosis in patients with NAFLD (Mikolasevic et al., 2016; Festi et al., 2015; Wong et al., 2013). Profil uses the FibroScan® medical device (Echosens, Paris) for a non-invasive and cost-effective staging of liver fibrosis and liver fat. Here a piston-like probe is applied to the trial participant positioned perpendicular to the skin surface in one of the intercostal spaces adjacent to the right lobe of the liver to initially cause a slow-moving shear wave of low frequency (50 Hz). This is followed by the emission of fast ultrasound waves according to a pulse-echo scheme. This enables for a determination of the propagation of the shear wave front over time which can be used to output Liver Stiffness Measurements (LSM, ranges from about 1.5 kPa to 75 kPa with lower values indicating a more elastic liver). Simultaneously the CAP value which reflects the ultrasonic attenuation in the liver can be captured (ranges from about 100 – 400 dB/m with higher values indicating higher amounts of liver fat).
There are multiple advantages of TE with CAP over MR-based methods and liver biopsy analyses. This non-invasive investigation is painless, rapid, and cost-effective. LSM and CAP are simultaneously calculated from the same volume of liver parenchyma.
Although analysing liver biopsies is sometimes considered the gold standard for staging of fatty liver and liver fibrosis, the limitations related to invasiveness of sampling, high sampling variability, and not indicating early changes in fibrogenic and fibrolytic activity are increasingly a subject of debate (Trautwein et al., 2016).
Compared with liver biopsy TE captures a region of interest which is about a hundred times larger. Invalid measurements are automatically rejected by the device. TE with CAP can be combined with the assessment of serum marker panels in order to further substantiate the staging of liver disease.
We recommend the use of TE with CAP (optionally combined with the assessment of surrogates such as the Fatty Liver Index or signs of the metabolic syndrome) for a frequent longitudinal assessment of liver fat and fibrosis related endpoints, and for pre-selecting potential trial participants before performing more cost-intensive MRI or MRS-based methods.
TE with CAP also helps to pre-stratify patient populations for the presence of fatty liver and/or liver fibrosis in order to better control the pharmacodynamic effect size and thereby the required number of trial participants. Profil has both the M- and the obese-specific XL-probe for the assessment of LSM and CAP available.
In collaboration with academic centres in Frankfurt/Main (Liver Center at the Johann Wolfgang Goethe University), Aachen (RWTH, Clinic for Diagnostic and Interventional Radiology) and Düsseldorf (German Diabetes Research Center) we also have the option to take advantage from MR elastography (MRE – permits assessment of the whole liver) and MRI-derived proton density fat fraction imaging (MRI-PDFF).