Na _v 1.7 target modulation and efficacy can be measured in nonhuman primate assays

Abstract

Humans with loss-of-function mutations in the Nav1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Nav1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Nav1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC50 values derived from electrophysiological studies to calculate anticipated human doses. To increase the chance of clinical success, we developed rhesus macaque models of action potential propagation, nociception, and olfaction, to measure Nav1.7 target modulation in vivo. The potent and selective Nav1.7 inhibitors SSCI-1 and SSCI-2 dose-dependently blocked C-fiber nociceptor conduction in microneurography studies and inhibited withdrawal responses to noxious heat in rhesus monkeys. Pharmacological Nav1.7 inhibition also reduced odor-induced activation of the olfactory bulb (OB), measured by functional magnetic resonance imaging (fMRI) studies consistent with the anosmia reported in Nav1.7 loss-of-function patients. These data demonstrate that it is possible to measure Nav1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays used, it is anticipated that they can be also used in phase 1 clinical studies to measure target modulation and aid in the interpretation of phase 1 clinical data.

Examination of the contribution of Nav1.7 to axonal propagation in nociceptors

“…Our finding that many nociceptors depend on Na v 1.7 for propagation is consistent with that of a report in Na v 1.7 KO mice 18 and a pharmacological study in nonhuman primates. 28 However, these findings seem to contradict an in vivo imaging study that suggested peripheral excitability of nociceptors in Na v 1.7 KO mice was largely unaffected by the loss of channel function. 30 Using pharmacological tools to assess protein function in neurons permits a "before and after" comparison, whereas a KO approach only allows for this when sampling from a global population.…”

Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents

“…Poor design of trials [for example, failure to recognize that heterogeneity of sensory phenotypes of patients may hint at different underlying mechanisms ( 65 , 66 ) or lack of target modulation assays to enable clinical interpretation of NaV1.7 inhibitors, but see ( 67 )] has likely led to faltering of NaV1.7-targeted drugs at the doorstep of the clinical stage ( 68 ). Future clinical trials for CRMP2 SUMOylation inhibitors should stratify patients with chronic pain based on the presence of SUMOylated CRMP2 in skin biopsies; increased amount of SUMOylated CRMP2 are present in the skin, spinal cord, and sciatic nerves in preclinical models of neuropathic pain ( 30 ).…”

Translational Pharmacokinetic–Pharmacodynamic Modeling of NaV1.7 Inhibitor MK-2075 to Inform Human Efficacious Dose

“…In vivo antinociceptive potency of MK-2075 was determined preclinically in the rhesus thermode heat withdrawal study based on treatment-mediated decrease in magnitude of behavioral response to a thermal stimulus on the forearm. Rhesus thermode heat withdrawal was measured by brief application of heat delivered to the forearm of rhesus macaque as described by Vardigan et al (2018) and Kraus et al (2021). Briefly, four test temperatures: 44 °C, 46 °C, 48 °C, and 50 °C were delivered randomly and repeated six times per session.…”

“…Humans with genetic mutations leading to a loss of function (LOF) of the NaV1.7 channel have a congenital indifference to pain and anosmia while a gain of function mutations can result in pain syndromes such as primary erythromelalgia (Dib-Hajj et al, 2007;Weiss et al, 2011). Pharmacological inhibition of NaV1.7 channels in nonhuman primates has demonstrated a similar phenotype to humans with a genetic loss of NaV1.7 function, including hyposmia and analgesia (Kraus et al, 2021). While drugs with sodium channel-blocking activity such as carbamazepine have demonstrated some utility in pain treatment, their nonselective nature contributes to dose-limiting adverse effects (Tanelian and Victory, 1995;Dick et al, 2007;Moulin et al, 2014).…”