The Therapeutic Impact of Biased Signaling:
In general, prior art suggests that identifying agonists that stabilize
unique receptor states is not a difficult task. However, the linking of
these exemplar molecules to attainable biased signaling states of
benefit in therapy is a more formidable challenge. As a preface to
considering this, it is useful to review the current impact of bias on
drug therapy.
Retrospective Analyses of Known Drugs: Over the past
years, literature reports have linked favorable therapeutic profiles of
drugs retrospectively with identified bias. An example of this is the
drug carvedilol, an inverse agonist for Gαs-mediated cAMP production in
heart failure where beneficial effects have been attributed to
β-arrestin–mediated partial agonist activity for activation of ERK1/2
(Wisler et al, 2007; Kim et al, 2008). This shared profile also has been
cited for the useful responses to propranolol (Azzi et al, 2003; Baker
et al, 2003), nebivolol (Erickson et al, 2013), and alprenolol (Baker et
al, 2003). Further, the reduced respiratory depression potential of the
opioid analgesic levorphanol (over morphine) has been attributed to its
biased signaling profile (lack of β-arrestin2 recruitment) (Le Rouzic et
al, 2019). Interestingly, the dependence liability of oxycodone,
hydrocodone/paracetamol, and hydromorphone has been attributed to biased
signaling to G protein over β-arrestin (Johnson et al, 2017). Other
reportedly unique biased profiles for established drugs have been
reported for the adenosine 2b receptor agonist capadenoson
(cardioprotective and cardiac fibrosis–modulating properties through
biased cAMP activity; Baltos et al, 2017) and the
β2-adreoceptor agonist fenoterol (biased activation of
Gαs protein over nonspecific dual Gαs and Gαi activation (Jozwiak et al,
2010). While it is not clear whether the noted biased signaling for
these molecules is the discerning property in their beneficial
therapeutic effects, it is notable that beneficial profiles are
associated with biased profiles in these drugs. These drugs were
developed before bias was considered a viable drug property; since then,
molecules consciously have been developed with known biased signaling
properties in attempts to improve therapeutic profiles.
Current Biased Molecules: As mentioned previously, the
first biased molecule designed to enter the therapeutic arena was TRV027
for congestive heart failure. This molecule has a unique lack of
efficacy for angiotensin-mediated vasoconstriction (via Gαq protein) and
a residual and measurable efficacy for angiotensin receptor-mediated
β-arrestin activation. Notably,
an acute randomized double-blind placebo-controlled Phase IIB
dose-ranging trial (BLAST-AHF) did not show superior efficacy for TRV027
illustrating the difficulties in bias translation from the in
vitro to in vivo arena; in this case, the trial design could
have been the reason for failure. Specifically, a molecule such as
TRV027 would be expected to enhance beneficial cardiac remodeling over
many months. In contrast, the trial design was a short term 24-28 hr
infusion of TRV 027 followed by a 30 day endpoint of symptoms and
survival which really would not detect the possible beneficial effects
of this molecule. In addition , a possible lack of activation of the
renin-angiotensin system in the heart failure patients could have caused
a negative background for this molecule coupled with shortcomings in
study design and duration of treatment (Pang et al, 2017; Sugihara et
al, 2017).
Data from early experiments with morphine and other opioids had
suggested that bias away from β-arrestin could be beneficial (Raehal and
Bohn, 2011; Raehal et al, 2005; Bohn et al, 2003; Urs and Caron, 2014)
and this led to continued research into biased opioid agonists for pain
management (Le Rouzic et al, 2019; Conibear et al, 2019). This is a very
active area of research and presently there is a viable biased agonist
opioid agonist (TRV130) approved for moderate to severe pain (Lambert et
al, 2020; Viscusi et al, 2019).
A recent and very active research into biased signaling is in the field
of incretin agonists for metabolic diseases such as obesity and
diabetes. Several peptides are under development for GLP-1R and either
the glucagon receptor (GCGR) and/or glucose-dependent insulinotropic
peptide receptor (GIPR) as dual- or tri peptide agonists. It has been
shown that many novel peptides have distinct biased agonism profiles
relative to either natural agonists or each other (Darbalaei et al,
2020). Examples of this are biased signaling for GIP mono-agonists
(Pro3GIP, Lys3GIP) towards ERK1/2 phosphorylation (pERK1/2) relative to
cAMP accumulation at GIPR, the dual GIPR/GLP-1R agonist, LY3298176,
biased towards pERK1/2 relative to cAMP accumulation at both GIPR and
GLP-1R (vs endogenous ligands), and the triple agonist GLP-1R/GCGR/GIPR
tirzepatide biased towards pERK1/2 relative to β-arrestin2 recruitment.
In addition, studies have shown reduced β-arrestin recruitment for
tirzepatide leading to less GLP-1 receptor desensitisation and
downregulation (Yuliantie et al, 2020). While there is an abundance of
data on the biased signaling for these agonists, it is not yet clear to
what extent the bias contributes to their beneficial action vs dual and
tripartide agonism (Jones, 2021).