Rationale: Janus kinases have a key role in cytokine signalling in
asthma. VR588 is a potent, balanced and selective pan-JAK inhibitor.
This study investigates the pharmacokinetics (PK) of inhaled VR588
and its in-vivo efficacy in an asthma model.
A-22 POSTER ABSTRACTS
Methods: Murine lung and plasma VR588 PK were measured for 24
hours following intranasal (i.n) delivery (1.5 to 50 mg/kg; n¼6 per group).
HDM extract (25 lg) was given i.n 5 days/week for 3 weeks with i.n
VR588 doses (1.5 to 7.5 mg/kg) given 1 hour prior; another group received
i.n VR588 7.5 mg/kg during only the last week of HDM exposure
(n¼8). Oral tofacitinib (T)(15 mg/kg) and i.n fluticasone propionate
(FP)(1.5 mg/kg) were controls. Airway hyperresponsiveness (AHR) was
assessed 24 hours after the last HDM; bronchoalveolar lavage fluid (BAL)
was assessed for differential cell count, STAT activation and cytokines.
Results: VR588 i.n rapidly (5 mins) achieved dose related lung
levels which stayed at relevant levels for 24 hours; plasma levels were
1000-fold less. VR588 resulted in significant AHR reduction, at least
equal to FP. All VR588 doses significantly reduced BAL total cell
count with some doses inhibiting cell differentials. VR588 attenuated
cytokine release (IL-4, IL-5, IL-17) compared with saline control and
activation of STAT 3 at 24 hrs comparable to FP and T.
Conclusions: VR588 i.n has a PK profile suited to inhaled delivery.
Attenuation of HDM inflammation suggests that inhaled VR588 may
represent a novel treatment for asthma.