Safety and Tolerability of Lacosamide in Patients With Gain-of-function Nav1.7 Mutations Related Small Fiber Neuropathy

Overview

Lacosamide is a functionalized amino acid with antinociceptive properties in inflammatory and neuropathic pain, and displays a unique mechanism: it enhances slow inactivation of Nav1.3, Nav1.7, and Nav1.8. Nav1.7 is expressed predominantly in nociceptive and sympathetic neurons. Gain-of-function mutations have been described in Nav1.7 that result in extreme pain disorders such as SCN9A-associated small fiber neuropathy. In the disease states genetically linked to a gain-of-function of Nav1.7, the sodium channel is mutated to increase the sodium influx resulting in a hyperexcitable sensory neuron, and a resultant sensation of pain. The objective of the study is to determine the efficacy and safety of lacosamide, a sodium channel blocker, in patients with pain due to SCN9A-associated small fiber neuropathy.

Indication Lacosamide is a functionalized amino acid with antinociceptive properties in inflammatory and neuropathic pain, and displays a unique mechanism: it enhances slow inactivation of Nav1.3, Nav1.7, and Nav1.8. Rationale A significant body of evidence implicates sodium channels in mediating the pathophysiological components of both neuropathic and nociceptive pain. This is supported by clinical evidence suggesting that local anaesthetics, anticonvulsants and tricyclic compounds that block voltage-gated sodium channels may act as useful therapeutics for managing and treating pain. The use of these sodium channel blockers has, however, been limited by the lack of selectivity for different sodium channel subtypes with often additional central nervous system (CNS) and cardiovascular side effects. Therefore, a key to improvement on the limitations of most existing sodium channel blockers is to selectively target those that are involved in pain mechanisms whilst sparing those channels involved in cardiovascular function. Nav1.7 is expressed predominantly in nociceptive and sympathetic neurons. The role of this channel in nociceptive neurons has been characterized by human genetics, which indicates an essential and non-redundant role in pain transduction and conduction following noxious stimuli. Gain-of-function mutations have been described in Nav1.7 that result in extreme pain disorders such as inherited erythromelalgia (IEM), paroxysmal extreme pain disorder (PEPD) and SCN9A-associated small fiber neuropathy. In the disease states genetically linked to a gain-of-function of Nav1.7, the channel is mutated to increase the sodium influx resulting in a hyperexcitable sensory neuron, and a resultant sensation of pain. Lacosamide is a functionalized aminoacid that was synthesized during the development of anticonvulsant drug candidates and has displayed antinociceptive properties in inflammatory and neuropathic pain. Lacosamide displays a unique mechanism of action in that it seemingly selectively stabilizes channels into the slow- inactivated state. Lacosamide inhibited currents from Nav1.3, Nav1.7, and Nav1.8, but only after prolonged depolarizations, consistent with an enhancement in slow-inactivation with no effect on fast inactivation. Furthermore, lacosamide was better able to discriminate between resting and inactivated channels compared to lidocaine or carbamazepine, thus likely allowing for improved selectivity over neurons with a depolarized membrane potential, with little tonic block. Small fiber neuropathy (SFN) is a relatively common disorder of peripheral nerves, primarily affecting small somatic fibers, autonomic fibers, or both. In a proportion of patients with SFN, no underlying cause can be identified; these cases are termed idiopathic SFN. Gain-of-function mutations in SCN9A have recently been reported to be present in 28% of patients with idiopathic SFN, suggesting an underlying genetic basis for a proportion of patients with this disease. Electrophysiological analysis demonstrated multiple gain-of-function changes in the mutant channels with each of the mutations resulting in hyperexcitability in dorsal root ganglion (DRG) neurons. Moreover, most of these mutations showed impaired slow inactivation of Nav1.7, a finding that provides a rationale to evaluate the possible pain reduction potential of lacosamide in this condition. Study Rationale and Objectives The objective of the study is to determine the efficacy and safety of lacosamide, a sodium channel blocker, in patients with pain due to SCN9A-associated SFN. The proposed study plans to recruit patients with clinically diagnosed SFN, where a mutation in SCN9A has been confirmed genetically, and where possible, has been demonstrated on functional testing, to cause hyperexcitability of DRG neurons. This small, precision medicine population provides an opportunity to evaluate the efficacy and safety of lacosamide in treatment of pain due to SCN9A-associated SFN.