Replies to post #188317 on Biotech Values

[biomaven0]

I think the challenge with FXR agonists is generally going to be toxicity rather than potency. Lots of potential landmines I suspect.

A mouse model of chronic FXR activation produced some unexpected results:

Chronic activation of FXR in transgenic mice caused
perinatal toxicity and sensitized mice to cholesterol
toxicity

http://press.endocrine.org/doi/pdf/10.1210/me.2014-1337

This article is a good review by a proponent

Recent advances in the development of farnesoid X receptor agonists

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293481/

[DewDiligence]

ICPT starts phase-1 trial of dual-acting INT-767:

http://finance.yahoo.com/news/intercept-pharmaceuticals-initiates-phase-1-210500000.html

Intercept Pharmaceuticals…today announced the initiation of a Phase 1 study of INT-767, a dual farnesoid X receptor (FXR) and TGR5 agonist, in healthy volunteers.

INT-767 is Intercept's second bile acid analog to enter clinical development, and is a three-fold more potent FXR agonist than obeticholic acid (OCA), Intercept's lead product candidate. INT-767 also activates TGR5, a second bile acid receptor. TGR5 has been shown to affect energy metabolism, glucose homeostasis, bile composition/secretion, and inflammation. INT-767 has potentially promising preclinical activity in both preventing and reversing organ damage due to fibrosis.

The dual MoA may be an advantage, but having 3x the FXR potency of OCA is not in itself something to crow about (#msg-111502128).

[DewDiligence]

ENTA starts phase-1 trial of NASH compound, EDP-305:

http://finance.yahoo.com/news/enanta-pharmaceuticals-initiates-phase-1-201200159.html

EDP-305 is an FXR agonist—the same drug class as ICPT's OCA and GILD's GS-9674 (acquired from PFNX in 2015: #msg-109653984).

ENTA has asserted that EDP-305 is substantially more potent than ICPT's OCA—see slides 24, 26, &27 at http://jpmorgan.metameetings.com/confbook/healthcare16/stash/slides/19782/confbook_slideshow.php .