Effects of a topical treatment with spleen tyrosine kinase (SYK) inhibitor in healthy subjects and patients with cold urticaria or chronic spontaneous urticaria: results of a Phase 1a/b randomised double-blind placebo-controlled study.

AIM To explore the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of GSK2646264 using skin challenge models. METHODS Healthy volunteers (HV) with a positive allergen skin prick test received GSK2646264 (0.5% or 1% ww) and placebo creams on up to 10% body surface area (BSA). Cold (ColdU) or chronic spontaneous (CSU) urticaria patients received 1% GSK2646264 or placebo on up to 10% BSA. PD assessments included weal characteristics post skin allergen challenge (SAC), critical temperature threshold (CTT) in ColdU patients, and defined area urticaria activity score (UAS7DA ) in CSU patients. RESULTS 34 patients were randomised (17 HV, 12 ColdU, 5 CSU). Topical application of GSK2646264 and placebo was well tolerated. Systemic PK (AUC [0-24] h*ng/mL) was similar between HVs (Geomean 97.9 [%CV 37]) and ColdU patients (Geomean 68.2 [%CV 14] [3.5% BSA] or 167 [%CV 120] [10% BSA]). Whilst in HVs a similar reduction in SAC weal area was observed following 3 applications of GSK2646264 and placebo, a trend towards a greater reduction was seen in ColdU with GSK2646264 compared to placebo. A clinically meaningful reduction in CTT, in ColdU patients treated with GSK2646264, was observed in four of nine patients, who demonstrated either a complete inhibition of ColdU to ≤ 40 C (n=2) or partial response (reduction by >40 C, n=2). Due to the small number of CSU patients recruited, no meaningful conclusions could be drawn from the UAS7DA PD endpoint. CONCLUSION This Phase 1/1b study confirms that GSK2646264 cream applied topically penetrates the skin and some reduction in CTT was observed.