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Papers of the Week

Papers: 15 May 2021 - 21 May 2021

Human Studies, Pharmacology/Drug Development

2021 May 19

Sci Transl Med



Na1.7 target modulation and efficacy can be measured in nonhuman primate assays.


Kraus RL, Zhao F, Pall PS, Zhou D, Vardigan JD, Danziger A, Li Y, Daley C, Ballard JE, Clements MK, Klein RM, Holahan MA, Greshock TJ, Kim RM, Layton ME, Burgey CS, Serra J, Henze DA, Houghton AK
Sci Transl Med. 2021 May 19; 13(594).
PMID: 34011626.


Humans with loss-of-function mutations in the Na1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Na1.7 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 Na1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC 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 Na1.7 target modulation in vivo. The potent and selective Na1.7 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 Na1.7 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 Na1.7 loss-of-function patients. These data demonstrate that it is possible to measure Na1.7 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.