FXR AGONISTS, POTENTIAL INDUCED HCC HIGHLIGHTED


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Actions of FXR agonists could be different in human and mouse, and potential tumorigenicity effect on human should be monitored despite no tumorigenicity effects noticed on mouses.


Scientific publication puts the finger on a possible liver cancer risk for FXR agonists


A publication published in January in Journal of Hepatology (http://dx.doi.org/10.1016/j.jhep.2017.01.027) has gone almost unnoticed, but its conclusions are clear on the carcinogenic risk of FXR agonists.

Now these molecules are very present in the list of drug candidates against NASH!

The best known is OCALIVA from Intercept Pharmaceutical, but one can also notice Novartis LJN 452, Gilead GS 9674, Intercept Pharmaceutical INT 767 and Enanta EDP 305.

These molecules were already under surveillance due to their systemic effect on LDL increase and HDL reduction, but this very comprehensive study points to a significant metabolic difference between the murine model, used to evaluate the potential carcinogenesis of these molecules, and human metabolism.

To summarize, the FXR agonists would induce the production of close, but different, hormones in mice and humans.

In mice, the hormone stimulated by FXR agonists would be Fibroblast Growth Factor 15 (FGF15) whereas in humans it would be Fibroblast Growth Factor 19 (FGF19).

If the two hormones act on the synthesis of bile acids, they have different effects.

FGF15, contrary to FGF19, would not reduce glycated hemoglobin nor would it have a protective effect on β-cells, which would limit its action on diabetes. But above all, it would not induce hepatocellular carcinomas as found for FGF19.

Indeed, in humans, FGF19 is amplified in about 15% of liver tumors and is associated with worsening prognosis in patients with liver cancer.

The authors of the article therefore question the relevance of the tests carried out on mice with FXR agonists and stress the need for follow-up of patients treated with FXR agonists, due to the increased risk of liver cancer Induced by FGF19 whose production is stimulated by these molecules.

This is not a very good news for these drug candidates against NASH.

Careful attention should be paid to the rate of liver cancer reported in future clinical studies, although the expected duration (18 months of treatment) of trial for accelerated agreement - Subpart H -  is probably not sufficient for the possible increase in cancers to be noticeable.

In the face of an identified risk like that, health regulatory agencies may take a cautious stance and postpone the marketing authorization of FXR agonists to the overall results at the end of Phase 3 (36 At 48 months).

To follow ..






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