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Effects of Selective Sphingosine-1-Phosphate Receptor 1 Agonist, TRV045, on Evoked Pain Tests: An Exploratory,
Wouter A Bakker1, P Eijsvogel1,2, Erica S Klaassen1
1Centre for Human Drug Research, Leiden, the Netherlands.
Introduction:
Preclinical evidence suggests that dysregulation of the ceramide-sphingosine-1-phosphate (S1P) axis may have analgesic properties. However, currently approved S1PR1 modulators such as fingolimod are hindered for this indication as they induce lymphopenia. The aim of the current study was to evaluate whether the novel, selective S1PR1 agonist TRV045 has analgesic effects in a validated evoked pain test battery in healthy volunteers.
Methods:
In this randomized, double-blind, double-dummy, placebo-controlled, four-way cross-over study, 25 male or female healthy volunteers were randomized to receive either placebo or TRV045 50, 150 or 300 mg at separate occasions. The primary endpoint was heat pain detection threshold on UVB-induced inflammatory pain. Secondary endpoints included analgesic reduction of capsaicin-induced allodynia and pain detection and tolerance thresholds to evoked cold, electrical, pressure and heat pain. Furthermore, safety, tolerability and pharmacokinetics were monitored throughout the study. Data analyses included a repeated-measures mixed-effects model.
Results:
TRV045 was well tolerated, without serious adverse events. Compared to placebo, TRV045 did not reduce heat pain detection thresholds on UVB-exposed skin, but significantly reduced the secondary area of capsaicin-induced pain for the higher dose levels: 150 mg: -304.10 mm2 (95% CI: -494.78 to -113.43, p = 0.002); 300 mg: -298.51 mm2 (-486.83 to -110.20, p = 0.002). No effects on peripheral lymphocyte count were observed.
Conclusion:
TRV045 is a well-tolerated S1PR1 modulator with analgesic properties in healthy volunteers as measured by the capsaicin-induced pain model, which provides initial clinical evidence that selective S1PR1 modulation may be an appropriate novel target for the treatment of neuropathic pain.
Significance Statement:
Selective S1PR1 modulation produced analgesic effects in a validated human experimental pain model. This study provides clinical proof-of-concept for S1PR1 as a promising therapeutic target for neuropathic pain.
