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

 1. Male and/or female subjects between the ages of 18 and 80 years.

 2. Presence of a clinical diagnosis of Small Fiber Neuropathy (SFN), with at least 2 of
 the following clinical symptoms:

 -  Burning feet.

 -  Allodynia.

 -  Diminished pain and/or temperature sensation.

 -  Dry eyes or mouth.

 -  Orthostatic dizziness.

 -  Bowel disturbances (constipation, diarrhea, gastroparesis).

 -  Urinary disturbances.

 -  Sweat changes (hyper-/hypohidrosis).

 -  Visual accommodation problems and/or blurred vision.

 -  Hot flashes/palpitations.

 -  Impotence, diminished ejaculation or lubrication.

 3. In addition to the clinical diagnosis of SFN, presence of confirmed abnormality on
 intra-epidermal nerve fiber density evaluation (IENFD) and/or Quantitative Sensory
 Testing (QST) and a mutation in the SCN9A gene, confirmed by sequencing. Where
 possible, in vitro confirmation of the functionality of the mutation should have been
 performed and documented.

 4. Presence of pain due to SFN for at least 3 months prior to Screening and an average
 self-reported pain score of at least 3 during this time.

 5. If on analgesic medication to manage pain due to SFN, subject must have stable
 analgesic medication for a minimum of 30 days prior to the start of the study and
 should continue with the same regimen throughout the study.

 6. Evidence of a personally signed and dated informed consent document indicating that
 the subject (or a legal representative) has been informed of all pertinent aspects of
 the study.

 7. Subjects who are willing and able to comply with scheduled visits, treatment plan,
 laboratory tests, and other study procedures.

 Exclusion Criteria:

 1. Subjects with predominantly signs of large nerve fiber involvement, clinically
 significant abnormal nerve conduction studies.

 2. History or presence of illnesses known to cause SFN (excluding diabetes mellitus).

 3. Subjects with other severe pain conditions which may impair the self-assessment of
 pain due to SFN.

 4. Any condition possibly affecting drug intake and absorption.

 5. History of known alcohol, analgesic or illicit drug abuse within 12 months of
 Screening.

 6. Subjects taking medications with activity at sodium channels. These medications are
 prohibited until the end of the study period and require a washout period of at least
 5 half lives (90 days for capsaicin patches) prior to the Screening visit.

 7. 12-lead ECG demonstrating QTcF (Fridericia's correction) >450 or a QRS interval >120
 msec at Screening. If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should
 be repeated two more times and the average of the three QTcF values should be used to
 determine the subject's eligibility.

 8. Severe renal impairment (creatinine clearance ≤ 30 mL/min).

 9. Treatment with an investigational drug within 30 days or 5 half-lives preceding the
 first dose of study medication.

 10. Participation in other studies during the period of current study participation, or
 has planned surgery during the course of the study.

 11. Pregnant females; breastfeeding females; females of childbearing potential not using
 effective contraception or not agreeing to continue effective contraception for at
 least 28 days after the last dose of investigational product.

 12. Other clinically significant or unstable, or severe acute or chronic medical or
 psychiatric/psychological condition or laboratory abnormality that may increase the
 risk associated with study participation or investigational product administration or
 may interfere with the interpretation of study results and, in the judgment of the
 Investigator, would make the subject inappropriate for entry into this study.

 13. In the case of incidental findings the patient and his/her treating physician will be
 informed and asked to undertake action if necessary. If a patient does not want to be
 informed about possible incidental findings, nor wants his treating physician to be
 informed, he or she cannot participate in this study.