PHARMACEUTICALS
loss , glucose metabolism , energy expenditure and suppression of inflammation . Due to the number of signalling receptor that bile acids hit , they are considered metabolic regulators and nutrient sensors of great importance , to the extent that dysregulation in bile acid homeostasis by high-fat diets , drugs and circadian disruption have been linked with conditions such as cholestatic liver diseases , inflammatory bowel diseases , Type 2 diabetes , obesity and non-alcoholic fatty liver diseases . Bile acids are now shown to act on a number of other NRs and GCPRs , including VDR , PXR , CAR , M3R and S1PR2 . It is thus becoming clear that bile acid signalling properties are complex and extend beyond that of FXR and TGR5 , where most of current bile acid research has been conducted .
Figure 3 – Selected bile acids in clinical development
UDCA
UDCA is a well-established and safe product and , as the scientific community continues to better understand its properties , it is being repurposed for other indications . As a result of this UDCA is currently in multiple clinical trials . Researchers have also designed novel bile acids molecules resulting in growth in the number of bile acids in clinical development over the past ten years ( Figure 3 ) There is growing evidence between the link in susceptibility of neurodegenerative conditions such as Alzheimer ’ s ( AD ) and Parkinson ’ s disease ( PD ) with Type 2 diabetes and obesity . BA regulation is disrupted in obese and Type 2 diabetic patients , altering bile acid NR and GCPR signalling pathways as well as causing changes to the gut microbiome that alter gut-liver-brain signalling .
These disruptions may well be part of the complex pathways leading to neurodegenerative conditions and bile acids are now being considered as potential markers for prodromal diagnosis of both AD and PD . For example , in 2014 UDCA was shown to restore mitochondria function in PD patients ’ fibroblast cells and may represent an approach to treat this disease . It is anticipated that the rescue of mitochondria ( the powerhouse of the cell ) will restore bioenergetics to the diseased neurones and will allow these cells to start to function again . There is also a protective effect of restoring mitochondria , as when these are in a dysfunctional state , they can trigger apoptosis which is the driving factor of neurodegenerative conditions such as PD . Mitochondria are now considered a target for many neurodegenerative diseases and UDCA is currently in Phase II clinical studies for AD , ALS and PD . The data from the Amylyx Phase IIb ALS study ( Centaur ) was so compelling that they are submitting an NDA to the FDA and are also seeking approval in other territories , including Canada and the EU .
Outlook
ICE Group is a niche API and speciality ingredients maker , which is focused on the development and manufacture of bile acid derivatives and is one of the main UCDA suppliers in the world . We have developed a novel library of many hundreds of bile acid compounds and we are exploring novel analogues as next generation bile acids for possible neurodegenerative and metabolic disease intervention . •
Roger Viney
CCO
ICE GROUP k + 44 7827 672091 J r . viney @ iceitaly . com j www . iceitaly . com
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