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What are Nav1.7 inhibitors and how are they used in the treatment of neuropathic pain?

Ask the Expert July/August 2017

Nav1.7 is a voltage-gated sodium channel isoform encoded by the SCN9A gene. Voltage-gated sodium channels are composed of α and β subunits. The α subunit consists of 4 homologous domains (DI-DIV), each of which contains 6 membrane-spanning segments (S1-S6). Segments S1-S4 comprise the voltage-sensing domain (VSD). The Nav1.7 channel is normally expressed in the dorsal root ganglion neurons, trigeminal neurons, and their small-diameter peripheral axons.1

Mutations in these isoforms have been associated with several pain disorders, including erythromelalgia, paroxysmal extreme pain disorder (PEPD), congenital insensitivity to pain (CIP), and painful peripheral neuropathy. Erythromelalgia is a rare condition causing intense burning and redness to patients’ extremities.2

Gain-of-function mutations (genetic changes that result in a new, dominant or semidominant molecular function) may result from any of these pain disorders. Loss-of-function mutations, which have been associated with CIP, may also occur.2

What are Nav1.7 inhibitors and how are they used in the treatment of neuropathic pain?

In peripheral neuropathy, these mutations have led to hyperexcitable dorsal root ganglion neurons, which can result in spontaneous action potentials and abnormal firing of neurons.2 Inhibitors selective for the Nav1.7 isoform are small molecular compounds that alter VSD function and improve specificity and selectivity over current drug therapy.1

The high selectivity provides desired pain treatment without blocking activity of other voltage-gated sodium channels and causing undesired adverse events involving heart activity, muscle contraction, and CNS neurotransmission.3

Trails for Diabetic Peripheral Neuropathy

In the US, there are currently 3 Nav1.7 inhibitors in phase II development or higher with an indication for pain treatment. Only one, PF-05089771, has completed a phase II trial for the treatment of diabetic neuropathy, with results presented.4 PF-05089771 is a low nanomolar-potency, state-dependent Nav inhibitor that binds to the VSD of DIV on the α subunit. This interaction inhibits depolarized human Nav1.7 channels at a slow rate, thereby stabilizing the channel in a non-conducting conformation.1

The phase II trial evaluated the use of PF-05089771 alone or as add-on therapy to pregabalin for treatment of diabetic peripheral neuropathy. The study included men and women, ranging from 18 to 80 years old, with a diagnosis of type 2 diabetes (T2D) and a hemoglobin A1c level of ≤ 11%. All patients were on a stable antidiabetic medication regimen and had ongoing pain due to diabetic peripheral neuropathy for at least 6 months.4

This randomized, double-blind placebo, active-controlled study had 4 treatment arms,4 followed for 4 weeks:

  • PF-05089771 (150 mg twice daily)
  • Placebo and pregabalin (300 mg)
  • Pregabalin (300 mg)
  • PF-05089771 (150 mg twice daily) and pregabalin (300 mg)

The primary outcome of this trial was to evaluate the average pain score at endpoint. The mean score at baseline for all groups was about 6. This was calculated using the mean pain scores based on a report derived from daily pain diaries over the last 7 days of treatment.

The results of PF-05089771 vs. placebo following 4 weeks of treatment showed a mean difference of -0.41 (90% CI; -1.00 to 0.17), which was not statistically significant. No results were reported for the comparison between PF-05089771 and pregabalin.4 Several secondary outcomes were assessed, including response rate, neuropathic pain symptoms, patients’ global impression of change score, and the amount of rescue medication per week.

Results from the usual pain thresholds—30% and 50%—had responder rates between PF-05089771 vs. placebo with an odds ratio of 1.91 (90% CI; 0.78 to 4.69) and 1.25 (90% CI; 0.33 to 4.74), respectively. Fasting total cholesterol and LDL (reported as % change from baseline) showed a mean difference in PF-05089771 vs. placebo of 7.99 (90% CI, 2.98 to 13.01) for total cholesterol and in LDL of 11.55 (90% CI, 2.94 to 20.17).4 The short duration of therapy, limited efficacy data, and small sample size are limitations to be considered in future research.

Limited Research for Other Nav1.7 Inhibitors

Raxatrigine, another Nav1.7 inhibitor under phase II development, is being studied for the treatment of inherited erythromelalgia. Additional indications in early stages of investigation include neuropathic pain and trigeminal neuralgia.5

Funapide, also known as TV-45070 or XEN-402, is in phase II development as a topical formulation for the treatment of postherpetic neuralgia and knee pain associated with primary osteoarthritis. No reports on its use for diabetic peripheral neuropathy are known.6

Preclinical research on the 3 Nav1.7 inhibitors mentioned above, and other inhibitors were initiated for indications such as musculoskeletal pain, dental pain, and osteoarthritis; however, one trial was discontinued for undisclosed reasons.4-6

Currently, clinical research is in the early stages of investigation for the use of Nav1.7 inhibitors for pain management. The limited clinical evidence lacks clear benefit and may result in undesirable adverse drug effects. However, there is a need for further research to fully assess the efficacy and safety of these inhibitors for pain relief.

Last updated on: August 21, 2017
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