BLU-5937 is a potent P2X3 receptor antagonist that is currently in Phase 2 clinical trial for the treatment of chronic cough. It is hypothesized that sensitization of the afferent neurons expressing P2X3 receptors may be involved in chronic itch (CI) and that a P2X3 antagonist could be effective in the treatment of pruritus. 

Electrophysiology studies using mouse DRG neurons were performed to determine if pruritogens (β alanine, chloroquine, serotonin and histamine) can cause sensitization of sensory neurons expressing P2X3 and whether this sensitization is enhanced by P2X3 agonists (ATP or α,βmeATP) and blocked by BLU-5937. In addition, the inhibitory effect of BLU-5937 on scratching was studied in a chloroquine (CQ) + α,βmeATP-induced acute itch (AI) mouse model.  Finally, we evaluated the effect of BLU-5937 in CI mouse models of dry skin (DS w/acetone-ether-water), allergic contact dermatitis (ACD w/ dinitrofluorobenzene) and atopic dermatitis (AD w/calcipotriol) along with changes in P2X3 mRNA in DRG and changes of P2X3 fiber density in the skin.

All pruritogens induced sensitization of the DRG neurons and presence of a P2X3 agonist induced a synergistic effect.  The increase of excitability was blocked by BLU-5937. In AI, α,βmeATP did not trigger itch by itself, but caused a dose-dependent increase of scratching behaviour with CQ, which was inhibited by BLU-5937. Finally, BLU-5937 inhibited scratching in DS and AD models, while no effect was observed in ACD with either BLU-5937 or the positive control.  Although P2X3 transcription levels in DRG were not affected in CI, the density of P2X3 fiber in the skin was increased in DS and AD, but not in ACD, which may explain the anti-pruritic effects of BLU-5937 in DS and AD.

We present, for the first time, evidence that the ATP-induced hypersensitization mediated by P2X3 receptors in cutaneous C-fibers plays a role in chronic itch and that BLU-5937 may represent a novel treatment modality for chronic pruritus.

BLU-5937, A Potent and Selective P2X3 Antagonist, For the Treatment of Chronic Itch: Evidence from Pre-Clinical Studies