Conclusions
In general, initial biased assays are measures designed to identify
molecules that appear to stabilize a unique receptor active state;
however, subsequent experiments further measuring nuances and textures
in bias may identify molecules less sensitive to pharmacologic
environment and physiological conditions and thus identify ‘robust’
biased signaling. Beyond that these assays should not be seen as
guarantees against lack of bias translation in vivo . Considering
the myriad of possible variation in the bias translation process toin vivo therapy, the best approach may be to identify exemplar
biased molecules and then compare them head-to-head in the
therapeutically relevant system as soon as possible. However,
considering the case of TRV027, the in vivo testing conditions
also should be considered carefully as the initial clinical test will
color the future testing of a biased molecule thereafter, i.e. would
TRV027 have shown valuable activity in another set of patients (higher
renin-angiotensin elevated activity) or under another set of conditions?
In this case, TRV027 was a molecule designed to enhance cardiac
remodeling over many months yet the trial was short term (48-96 hr
infusion) with endpoints that would not detect the possible beneficial
effects of this molecule. The risk with inadequate tertiary testing of
biased molecules is the possibility of ‘throwing out the baby with the
bathwater’ and losing a potentially valuable entity through poorly
devised tests.
Further dissection of bias in experiments may discover texture in bias
that may be useful should the candidate molecule fail in vivo,i.e. to eliminate further study with similarly textured biased
molecules. In any case, the increasing tide of biased molecules coming
into development will be a positive force in assessing the value of this
pharmacologic effect for therapy.
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