Safety and Tolerability of Lacosamide in Patients With Gain-of-function Nav1.7 Mutations Related Small Fiber Neuropathy
Condition: Small Fiber Neuropathy
MeSH terms: Peripheral Nervous System Diseases; Small Fiber Neuropathy
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Lacosamide; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): comparison between lacosamide 200mg twice daily and microcrystalline cellulose (placebo) 200mg twice daily.; comparison between microcrystalline cellulose (placebo) 200mg twice daily and lacosamide 200mg twice daily.
Other intervention name(s): Vimpat; Microcrystalline cellulose
Intervention MeSH terms: Lacosamide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Small Fiber Neuropathy; Painful Neuropathy; NAV1.7 Voltage-Gated Sodium Channel; SCN9A