Pre-clinical validation of a novel CNS-sparing histamine-binding drug, Votucalis, for chronic neuropathic pain

Paul Chazot¹, Ilona Obara², Miles Nunn^3
1Durham University, ²Newcastle University, ³Akari therapeutics

Introduction/Background & aims Current medications prescribed for chronic neuropathic pain have limited efficacy, and display significant safety concerns. NICE recommendations have recently advocated the limitation of prescription for opioid and gabapentinoid class drugs in primary care for chronic pain. One of the major common features of these drug classes is access to the CNS, leading tolerance, dependence and serious side-effects, particularly when used in polypharmacy. The histaminergic system is a promising target for management of both chronic pruritis and neuropathic pain. A natural product centrally-sparing high-affinity histamine binding protein, votucalis (derived from tick saliva), was explored as a novel anti-pruritic and analgesic strategy in mice.

Method/Summary of work Adult male mice were subjected to histaminergic itch induced by intradermal injection of compound 48/80 (100 μg) or peripheral neuropathy induced by sciatic nerve chronic constriction injury (CCI). Votucalis was injected 30 min before pruritogen, to determine local peripheral effects of votucalis on histaminergic and non-histaminergic itch. Behavioural responses were recorded for 40 min after votucalis and/or H₁R, H₂R and H₄R antagonist injection. In the neuropathic pain model, the peripheral effect of votucalis on mechanical and heat hypersensitivity was determined 0.5-24 h after votucalis administrations (4 injections every 24 h for 4 days) using von Frey filaments and Hargreaves tests, respectively.

Results/Discussion Bouts of scratching induced by the histamine-dependent pruritogenic compound 48/80 were significantly reduced by s.c. pre-treatment with votucalis (1mg/kg, P<0.0001). The anti-pruritic effect produced by votucalis was potentiated by peripheral (s.c.) administration of mepyramine, ranitidine, and systemic (i.p.) injection of JNJ7777120. In the neuropathic pain model, votucalis (1mg/kg i.pl.), produced a potent dose-dependent analgesic effect (mechanical hypersensitivity) (P<0.0001); with a weak effect on heat hypersensitivity, only through systemic (i.p.) administration (P=0.03). Importantly, votucalis did not affect the pain threshold, measured in sham animals or when assessed on the uninjured paw (P>0.05).

Conclusion(s) We provide the first evidence for targeting the peripheral histamine system by votucalis, as a novel strategy for the treatment of pruritis and chronic pain. Votucalis has already been tested in the clinic for other indications, with a good safety record. Based on our successful pre-clinical studies, votucalis has recently entered the pipeline for Akari Therapeutics (UK) for chronic neuropathic pain and dermatological diseases (https://www.akaritx.com/2021/02/01/akari-therapeutics-adds-histamine-inhibitor-votucalis-to-pipeline-to-treat-neuropathic-pain-and-dermatological-disease/).

Reference(s)

Obara I, Telezhkin V, Alrashdi I, Chazot PL. Histamine, histamine receptors, and neuropathic pain relief. Br J Pharmacol. 2020 Feb;177(3):580-599.