Efficacy, safety and tolerability of lacosamide in patients with gain-of-function Nav1.7 mutations related small fiber neuropathy: a randomized, double-blind, placebo controlled, crossover trial

Indication
Lacosamide is a functionalized amino acid with antinociceptive properties in
inflammatory and neuropathic pain, 1-6 and displays a unique mechanism: it
enhances slow inactivation of Nav1.3, Nav1.7, and Nav1.8. 7 8
Rationale
A significant body of evidence implicates sodium channels in mediating the
pathophysiological components of both neuropathic and nociceptive pain. 9 10
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.11 The
use of these sodium channel blockers has, however, been limited by the lack of
selectivity for different sodium channel subtypes with often additional 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.12
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.13-15 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.1-6 Lacosamide displays a
unique mechanism of action in that it seemingly selectively stabilizes channels
into the slow- inactivated state.7 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.8
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.16
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,15 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.15
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.

Objectives
Primary Objective
* The primary objective of this study is to evaluate the efficacy of lacosamide
versus placebo in subjects with SCN9A-associated SFN.
Secondary Objectives
* To evaluate effect on maximum pain of subjects treated with lacosamide versus
placebo.
* To evaluate effect on neuropathic pain quality in subjects treated with
lacosamide versus *placebo.
* To evaluate subject * reported sleep interference due to pain in subjects
treated with lacosamide versus placebo.
* To evaluate subject*s global impression of change in subjects treated with
lacosamide versus placebo.
* To determine the effect of lacosamide versus placebo on autonomic symptoms in
SCN9A-associated SFN.
* To determine the effect of lacosamide versus placebo on health-related
quality of life (HQoL).
* To evaluate the safety and tolerability of lacosamide in subjects with
SCN9A-associated SFN.

Study Design and Study Treatments
This is a randomized, double-blind, placebo-controlled, 2 period crossover
study to evaluate the efficacy, safety, and tolerability of lacosamide compared
to placebo in subjects with SCN9A-associated SFN. Subjects meeting eligibility
criteria, aged 18 yrs to 80 yrs will be enrolled in the study. Both males and
females will be eligible for this study. Subjects will receive 200 mg
lacosamide BID or equivalent placebo for 8 weeks during the study, after a
titration period of 3 weeks (for lacosamide: 1st week: 50 mg BID, 2nd week: 100
mg BID, 3rd week: 150 mg BID). As part of the informed consent process,
subjects will be informed that they will receive active treatment for 8 weeks
(excluding titration and tapering period) during during the 1st or 2nd
treatment period, but neither they, nor the study personnel will know when
active treatment will be administered. This study does not require subjects to
undergo a washout period to discontinue current pain medications in order to be
suitable to participate in the study and undergo randomization.

The burden for the patient exists of visits and telephone calls, a total of
approximatly 16 hours, during the 33 weeks of the trial.
There is no invasive treatment, there are no special risks for the patient,
there is possibility of side effects from medication.