Discussion and Conclusion
A clear understanding of drug
exposure at the site of action, target binding and functional
pharmacological activity is key for optimal design of phase II clinical
trials. (Morgan et al., 2012) MR309, a selective σ1R antagonist, was
well tolerated in early clinical trials at a daily dose of 400 mg and
signals of preliminary efficacy for acute CIPN were observed in patients
with colorectal cancer receiving an oxaliplatin-containing regimen
(Abadias, Escriche, Vaque, Sust & Encina, 2013; Bruna et al., 2018) and
in patients with chronic PSNP lasting for >6 months. (EU
Clinical Trials Register (EudraCT 2012-000402-30)) Here, we confirm the
occupancy of brain σ1R by MR309 following administration of clinically
meaningful doses, and demonstrate a quantitative relationship between
plasma concentration of MR309 and target occupancy, enabling optimised
dose selection in future studies.
The PK study demonstrated that BID dosing of MR309 offers the
opportunity to lower fluctuation of drug plasma levels compared with QD
dosing. At steady state lower peak and higher trough concentrations of
MR309 were observed with BID compared with QD dosing: geometric mean
[CV, %] Cmaxss (4143 [17.2] ng/mL vs 5222 [18.3] ng/mL);
Cminss (1915 [29.8] ng/mL vs 1764 [29.9] ng/mL). Consequently,
it is feasible that BID dosing of MR309 may be better tolerated than QD
dosing, with the potential to reduce the incidence and/or severity of
AEs associated with high peak plasma concentrations; this may have
particular relevance as MR309 is a CNS active compound. Indeed, in this
study treatment-emergent AEs (56.3% vs 37.5%) and treatment-related
AEs (43.8 vs 18.8%) were more frequent with MR309 400 mg QD compared
with 200 mg BID. Based on these PK findings, BID dosing of MR309 was
recommended for evaluation in future studies.
In the second study, the relationship between plasma concentrations of
MR309 and σ1R occupancy in the human brain was estimated successfully.
Modelling the relationship between MR309 plasma concentration and σ1R
occupancy indicated that for MR309 200 mg BID dose, which produces
steady state plasma concentrations of approximately 2000–4000 ng/mL,
brain σ1R occupancy will be in the range of 59–74%. The data suggest
that meaningful levels of σ1R occupancy can be achieved with steady
state dosing of 400 mg MR309 daily dose. Further, the signs of clinical
efficacy in the CIPN and in the PSNP studies seen with 400 mg daily
dosing could be interpreted as further support for the mechanism of
action. It is apparent that higher σ1R occupancy rates will need to be
investigated to explore the full potential of σ1R in neuropathic pain.
Notably, nonclinical data suggest that a higher degree of brain σ1R
occupancy may be required to elicit a maximal effect. When MR309 was
administered to animal models of neuropathic pain, ex vivobinding in brain section autoradiograms using3H-pentazocine and analysis of dose–response curves
indicated maximal antinociception was achieved at brain σ1R occupancy
levels >75%. (Romero et al., 2012)
In addition to achieving higher brain σ1R occupancy, it is also
important to elucidate the clinical impact of 59–74% brain σ1R
occupancy by a selective σ1R antagonist. Plasma steady-state was
previously reported after 8 days of MR309 QD (based on no significant
difference in Cmin values on days 6, 7 and 8; p<0.05)
(Abadias, Escriche, Vaque, Sust & Encina, 2013). Consequently, the
5-day dosing regimen for MR309 utilized in the Phase II study of CIPN
study is anticipated to result in σ1R occupancy below 59–74%. Further
studies are warranted to fully explore the potential of MR309 to
mitigate signs of oxaliplatin-induced acute sensory and motor
neurotoxicity, and reduce the frequency and severity of chronic sensory
neuropathy. These would require higher dosing of MR309 or a pre-dosing
regimen in order to achieve steady state levels resulting in σ1R
occupancy >75%.
Investigation of σ1R occupancy by MR309 in peripheral nerves is also
warranted, as it is feasible that receptor occupancies may differ
between the peripheral and central nervous systems, given that
concentrations of MR309 were approximately 2-fold greater in brain
compared with plasma in animal studies. (Romero et al., 2012) To our
knowledge, the only PET study analysing σ1R in peripheral tissue was a
case report of a patient with chronic knee pain. Using18F-FTC-146 σ1R radioligand, σ1 receptor upregulation
was reported in a subject with an inflamed intra-articular synovial
lipoma. Removal of the lipoma resulted in cessation of pain. (Cipriano
et al., 2018)
It is noteworthy that MR309 was well tolerated by the healthy volunteers
participating in the present two studies. AEs were mild in severity,
with dizziness being the most frequently reported event. Orthostatic
pulse rate changes were also reported by some individuals in the PK
study, although were not correlated with plasma concentrations of MR309
and were not consistent with postural orthostatic tachycardia syndrome.
(Stewart, 2004) While dizziness was also a common side effect reported
by healthy volunteers in a prior Phase I study of MR309, it was reported
less frequently by patients with colorectal cancer in the Phase II study
of MR309 compared with the present study. (Abadias, Escriche, Vaque,
Sust & Encina, 2013; Bruna et al., 2018) Variations in the reported
safety profile may relate in part to the different characteristics of
the study participants, including underlying disease and chemotherapy.
The reported studies are associated with some limitations. Both studies
were exploratory and the PK– σ1R model fitting did not account for
potential variation in the precision with which individual data points
were determined, or that the data set comprised multiple points for each
participant rather than independent samples. Consequently, while the
choice of model used in the present study had only a modest effect on
EC50 estimates (ranged from 1268–1380 ng/mL), it is
feasible that more sophisticated model fitting may have produced a
different EC50 estimate. Also, based on data that were
available at the time the PK study was designed, 9 days of dosing with
MR309 was considered sufficient to achieve steady-state PK. However, in
the present study small increases in trough concentrations of MR309 were
observed prior to Day 10, when full PK sampling was obtained (data not
shown). This was not anticipated, given the previously reported
half-life of MR309 was approximately 18 hours. (Abadias, Escriche,
Vaque, Sust & Encina, 2013) As trough concentrations were not formally
compared to establish whether steady-state had been achieved in the
present study, further evaluation of the time to establish steady state
is recommended in future studies of MR309. With regard to the PET study,
an underestimation of receptor occupancy achieved with MR309 may occur
if SA4503 had limited selectivity for the σ1R. SA4503 has been reported
to have σ2R / σ1R ratio of approximately 100-fold, with no significant
affinity to 36 other receptors, transporters or channels. (Kawamura et
al., 2000; Matsuno, Nakazawa, Okamoto, Kawashima & Mita, 1996) However,
using masking protocols with selective ligands, the σ2R / σ1R ratio was
reported to be 14-fold in guinea pig brain membranes, although such
masking protocols were shown to carry their own challenges and these
data should be treated with caution. (Abbas, Borde, Willars, Ferry &
Safrany, 2020; Lever, Gustafson, Xu, Allmon & Lever, 2006). The
magnitude of the PET signal is proportional to the ratio of target
density and affinity (Bmax/Kd). The σ2R,
a transmembrane ER-resident regulator of the Nieman-Pick-Carrier
protein, (Alon, Schmidt, Wood, Sahn, Martin & Kruse, 2017) contributed
to the PET signals obtained in this study. While sigma receptor
expression is qualitatively similar between various animal species and
man, there are notable species-dependent differences in expression
levels. For example, Bmax for σ1R in cerebellum differs between s mouse
strains and is lower for Rhesus compared with guinea pig and mice.
(Brust, Deuther-Conrad, Lehmkuhl, Jia & Wunsch, 2014) While human data
on brain σ1R binding has not been published, σ2R expression was found to
be much lower in human cortical membranes than in rat brain. (Brust,
Deuther-Conrad, Lehmkuhl, Jia & Wunsch, 2014) Data so far suggest
comparable expression levels of σ1R and σ2R. Based on the assumption of
comparable σ1R and σ2R expression levels and using the lowest reported
σ2R / σ1R selectivity of 14, the contribution of non- σ1R component to
the total [11C]SA4503 will be at most ~7%. Assuming
that MR309 has no affinity for σ2R, and use this estimate to adjust for
the potential bias in the estimation of σ1R occupancy, we find a minor
effect with the expected EC50 at σ1R being 1225 ng/mL and a range of
62-77% receptor occupancy expected in the plasma concentration range of
2000-4000 ng/mL.
In conclusion, our data indicate MR309 200 mg BID dosing facilitates
less fluctuation of plasma levels of this selective σ1R antagonist
compared with 400 mg QD dosing. However, PK– σ1R occupancy modelling
indicated that at steady state a daily dose of MR309 200 mg BID would be
associated with a level of brain σ1R occupancy <75%, which
may be insufficient to elicit maximal efficacy in neuropathic pain.
Furthermore, the 5-day MR309 regimen utilized in the previous study of
CIPN would likely be associated with lower brain σ1R occupancy compared
to that observed in the present study of healthy volunteers. (Bruna et
al., 2018) Consequently, further
clinical studies of MR309 in
neuropathic pain indications are needed to inform efficacy and
tolerability across a broad range of brain σ1R occupancy levels in order
to establish the optimal dose ranges in different patient populations.