Treatment of Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker.
Mutations in the SCN9A gene leading to deficiency of its protein product, Na(v)1.7, cause congenital indifference to pain (CIP). CIP is characterized by the absence of the ability to sense pain associated with noxious stimuli. In contrast, the opposite phenotype to CIP, inherited erythromelalgia (IEM), is a disorder of spontaneous pain caused by missense mutations resulting in gain-of-function in Na(v)1.7 that promote neuronal hyperexcitability. The primary aim of this study was to demonstrate that Na(v)1.7 antagonism could alleviate the pain of IEM, thereby demonstrating the utility of this opposite phenotype model as a tool for rapid proof-of-concept for novel analgesics. An exploratory, randomized, double-blind, 2-period crossover study was conducted in 4 SCN9A mutation-proven IEM patients. In each treatment period (2days), separated by a 2-day washout period, patients were orally administered XEN402 (400mg twice daily) or matching placebo. In 3 patients, pain was induced by heat or exercise during each treatment arm. A fourth patient, in constant severe pain, required no induction. Patient-reported outcomes of pain intensity and/or relief were recorded, and the time taken to induce pain was measured. The ability to induce pain in IEM patients was significantly attenuated by XEN402 compared with placebo. XEN402 increased the time to maximal pain induction and significantly reduced the amount of pain (42% less) after induction (P=.014). This pilot study showed that XEN402 blocks Na(v)1.7-mediated pain associated with IEM, thereby demonstrating target engagement in humans and underscoring the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept.
Xenon Pharmaceuticals Inc., Burnaby, British Columbia, Canada Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands Strength in Numbers Mathematical and Statistical Services, Vancouver, British Columbia, Canada University of British Columbia, Department of Medical Genetics, Center for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada.
Yigal Paul
YP
Goldberg
Nicola
N
Price
Rostam
R
Namdari
Charles Jay
CJ
Cohen
Mieke H
MH
Lamers
Conrad
C
Winters
James
J
Price
Clint E
CE
Young
Henry
H
Verschoof
Robin
R
Sherrington
Simon Neil
SN
Pimstone
Michael Reuben
MR
Hayden
D000328:Adult; D004311:Double-Blind Method; D004916:Erythromelalgia / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010147:Pain Measurement; D010865:Pilot Projects; D026941:Sodium Channel Blockers / Q000627:therapeutic use*; D015222:Sodium Channels / Q000235:genetics*; D016896:Treatment Outcome
D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels