Background/Purpose: Mirogabalin (DS-5565) is a
preferentially selective a2d-1 ligand intended for treatment of pain
associated with fibromyalgia and neuropathic pain. We evaluated the safety,
tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of mirogabalin
after multiple doses in healthy elderly subjects to guide dose selection for
further clinical development.

Methods: A randomized, double-blind, placebo- and
active-controlled, multiple ascending-dose study was conducted in healthy
subjects aged 55─75 years inclusive. Subjects were randomly
assigned (6:2:2) to receive multiple oral doses of mirogabalin (5, 10, 15, 20,
and 25 mg BID [25 mg QD followed by 25 mg BID]), pregabalin (75 mg followed by
150 mg BID), or placebo for 14 days. PK samples (blood and urine) were collected
after each treatment, and PD assessments evaluated sedation, attention,
dizziness, and ataxia. Safety was based on treatment-emergent adverse events (TEAEs),
clinical laboratory evaluations, vital signs, suicidality, and physical examinations.

Results: In total, 48 subjects participated (6
subjects each received mirogabalin 5, 10, 15, 20, or 25 mg BID, 8 received
pregabalin, and 10 received placebo). Mean mirogabalin concentrations increased
with increasing doses (Figure), though exposure appeared to increase in a
slightly less than proportional manner. Mean clearance and volume of
distribution were comparable across all mirogabalin dose levels. Half-life of
mirogabalin ranged from 3.6─7.5 h. There was no significant plasma
accumulation of mirogabalin on day 14. Mirogabalin did not appear to increase
sedation or decrease attention; however, subjects receiving 15, 20, or 25 mg BID
reported increases in dizziness and ataxia from day 3; highest rates were in
the 20 mg BID cohort. Mirogabalin 5, 10, and 15 mg BID doses were generally
well tolerated, though 15 mg BID was associated with a higher incidence of
dizziness/somnolence. Mirogabalin 20 and 25 mg BID doses were not well
tolerated. One subject in the mirogabalin 10 mg BID group discontinued on day 8
due to a mild TEAE of elevated hepatic transaminases that subsequently
resolved. Most common TEAEs after mirogabalin administration were somnolence (47%),
constipation (33%), headache (27%), and dizziness (27%). Somnolence and
dizziness tended to resolve within 4 days. Pregabalin PK and PD parameters were
comparable to those previously reported for healthy subjects.

Conclusion: Mirogabalin plasma concentrations
increased with increasing doses, with no significant accumulation over 14 days
of dosing. Doses up to 15 mg BID were well tolerated. Based on these data, 15 mg
BID was selected as the highest target dose for clinical development. Somnolence
and dizziness observed with mirogabalin were expected based on the mechanism of
action but tended to resolve spontaneously, suggesting possible development of
tolerance after repeated dosing.