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  • Writer's pictureBenin Joseph

Lessons from NASH RWE that Pre-Clinical Programs should incorporate

Updated: Jun 5, 2023

Real word Data points to directions away from monotherapies.

From lessons learned, the risk of severe side effects of ppar agonism, such as weight gain, fluid retention, congestive heart failure and similar scenarios with other NASH targets have been a barrier to employing monotherapies in NASH. Pre-Clinical success stories are struggling to be translated in field clinical trials enrolling patients.


It's has been hard to find significance in patient data

While promising targets also cause an increase in LDL, with OCA treatment that needs statins to overcome and a similar path with FXR agonist showing elevated LDL, slowing down the journey to patients. A host of combinatorial therapies could work ! but, how do we manage weight gain and cancer? as seen with Acetyl‐CoA carboxylase (ACC) and Stearoyl‐CoA desaturase 1 and CCR specifically.


"Targets are difficult to modulate without dysregulation of the cell's homeostasis - when treatment goes by the law of average in a patient population"


Or safer NASH therapies could lie in only reduction of circulating fatty acids and a gradually increase in metabolism without over stimulation of β-oxidation or production of ketones and let time play out.


The journey is hazy as mist and hence intelligent Pre-clinical programs could help here.


Long term patient response could get better with small animal phenotype studies. The data can always be cross verified with a host of AI tools.


Zebrafish larvae serum can tell if NASH therapies are offsetting Free Fatty Acids (FFAs). We are looking at how many pools post treatment that got low FFAs vs high FFAs irrespective of liver resolution. Such assays can secure your market path.


The components of drug discovery should be carefully selected to identify market focused candidates !


Write to me if you find this interesting @ ben@pentagrit.com





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