Lack of Detection of the Analgesic Properties of PF‐05089771, a Selective Na_v1.7 Inhibitor, Using a Battery of Pain Models in Healthy Subjects

Abstract

Sodium channel blockers are used for the treatment of pain, but this is limited by the lack of selectivity for different sodium channel subtypes, which can result in central nervous system and cardiovascular side effects. As such, there is special interest in the Nav1.7 subtype, which is expressed predominantly in nociceptive and sympathetic neurons. The aim was to demonstrate analgesic properties of a potent selective Nav1.7 sodium channel blocker, PF‐05089771, alone and concomitantly with pregabalin in healthy subjects using a battery of human evoked pain models. This was a double‐blind, double‐dummy, randomized, placebo‐controlled, five‐period cross‐over study with PF‐05089771 alone and PF‐05089771 concomitantly with pregabalin as treatment arms with pregabalin, ibuprofen, and placebo as control arms (NCT02349607). A battery of human evoked pain models was used to investigate analgesic properties of PF‐05089771. Twenty‐five subjects were enrolled in the study of which 23 subjects completed all five periods. PF‐05089771 alone did not differ from placebo on the primary pain end points. The same holds when comparing PF‐05089771 concomitantly with pregabalin and pregabalin alone. Pregabalin showed significant effects relative to placebo on thermal pain on the normal skin and UVB skin (least squares means with 90% confidence interval: 0.63 (0.32–0.93) and 0.53 (0.11–0.96)), pressure stimulation (1.10 (1.04–1.18)), and cold pressor (1.22 (1.14–1.32)). Ibuprofen demonstrated significant effects on thermal pain UVB skin (1.26 (0.82–1.70)) and pressure stimulation assessment (1.08 (1.01–1.15)), consistent with historical results. This study did not demonstrate analgesic properties of PF‐05089771 alone or concomitantly with pregabalin in a battery of pain models.

Overexpressed NaV1.7 Channels Confer Hyperexcitability to in vitro Trigeminal Sensory Neurons of CaV2.1 Mutant Hemiplegic Migraine Mice

“…While the low-threshold T-type Ca 2+ current has kinetics similar to Na V 1.7 current, this conductance is mostly inactivated at the resting membrane potential (−60 to −70 mV), and requires significant hyperpolarization to remove voltage-dependent channel inactivation ( Lovinger and White, 1989 ; Yoshida and Oka, 1998 ; Seo et al, 2013 ) making it an unlikely contributor to firing modulation in our mouse model. Our results accord with previous studies ( Shields et al, 2018 ; Wu et al, 2019 ; Neff et al, 2020 ; Siebenga et al, 2020 ) reporting pharmacological evidence that Na v 1.7 inhibition by its blockers may be involved in relieving pain.…”

Studies on CRMP2 SUMOylation–deficient transgenic mice identify sex-specific Nav1.7 regulation in the pathogenesis of chronic neuropathic pain

“…Some reasons (among those disclosed) for why these NaV1.7-targeting drugs failed include issues with central nervous system penetration [1; 2; 64], lack of selectivity (e.g. of Biogen's Vixotrigine [1]), inadequacy of pain models [64], and inadequate degree of block leading to a lack of action potential inhibition [20]. Global or nociceptor-specific deletion of NaV1.7 abolished thermal nociception as well as pain behaviors, notably in inflammatory (formalin) and post-surgical pain models [26; 56; 63].…”

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

“…Similarly, in people with erythromelalgia, only a subset of patients obtained clinically meaningful relief from evoked pain after a single administration of 1600 mg of PF-05089771 (41). Furthermore, PF-05089771 (300 mg) alone or concomitantly with pregabalin did not demonstrate analgesic properties in a battery of pain models in healthy subjects (47). These data have led some to conclude that inhibition of Na v 1.7 channels by a small-molecule inhibitor is insufficient to provide adequate pain relief in patients (45).…”