Treatment of Nav1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker

Abstract

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.

Voltage gated sodium channels as drug discovery targets

“…Results from an oral Phase II study with XEN402 (16) suggested positive effects in patients suffering from primary erythromelalgia. 30 Xenon recently partnered XEN402 (TV-45070, 16) with Teva and have been granted orphan drug designation by the FDA for the treatment of erythromelalgia. Pfizer have advanced a Na V 1.7 compound PF-05089771 into Phase II clinical trials of third molar extraction and primary inherited erythromelalgia.…”

Ion channel therapeutics for pain

“…A number of these compounds have now entered clinical trials for pain (Fig. 3), including the proline derivative 5 from GSK/Convergence, 11 a spiro-oxindole compound from Xenon (series exemplified by 6 XEN402, now known as TV-45070) 12 and an aminoheterocycle sulphonamide series from a Pfizer-Icagen collaboration (series exemplified by 7). 13 To-date, Xenon have reported efficacy treating pain in patients with congenital erythromelalgia, but no efficacy was seen in a study of postherpatic neuralgia.…”

The Role of Sodium Channels in Painful Diabetic and Idiopathic Neuropathy

“…SCN9A mutations were found to produce different effects on the channel functions, which include enhanced activation (in PE) and impaired inactivation (in PEPD), giving some insight into the features of pain [46]. New compounds under development have been shown to engage Nav1.7 [50], suggesting that in the future, it will be possible to develop tailored treatments that target sodium channels.…”