First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3Kδ inhibitor for the treatment of immune and inflammatory diseases.
OBJECTIVE
PI3Ks are potential therapeutic targets in immune-inflammatory diseases. These studies aimed to investigate the safety, tolerability and PK profile of seletalisib, a selective inhibitor of PI3Kδ in humans.


METHODS
These phase I, randomised, double-blind, placebo-controlled, single-centre studies (NCT02303509, NCT02207595) evaluated single and multiple oral doses of seletalisib (5-90 mg QD and 30 mg BID) in healthy adults and subjects with mild-to-moderate psoriasis (Study-1). Pharmacodynamic effects on markers of inflammation were assessed via changes in ex vivo basophil degranulation and histological assessment of psoriatic skin biopsies.


RESULTS
Seletalisib was well tolerated at doses ≤15 mg (Study-1) and ≤45 mg QD (Study-2) for 14 days. No safety concerns or dose-limiting toxicities were identified (Study-1). Incidence of gastrointestinal-related AEs was not dose related but higher incidences of rash AEs were associated with higher-dose seletalisib (Study-2 rash AEs: 18 in 12 seletalisib-treated subjects versus 1 in 1 placebo-treated subject). Mean seletalisib plasma concentration-time profiles increased with increasing doses after single and multiple dosing, with no major deviations from dose-proportionality. There was no unexpected accumulation or loss of exposure after multiple dosing (time-independent pharmacokinetic profile). Apparent t1/2values were supportive of once-daily dosing (geometric mean t1/2: Study-1, 17.7-21.1 h; Study-2, 18.1-22.4 h). No clinically significant food effect was observed (Study-1). Pharmacodynamic findings demonstrated ex vivo inhibition of basophil degranulation, improvements in histological assessment of skin biopsies and other markers of psoriatic biology and preliminary evidence of target engagement in psoriatic skin tissue.


CONCLUSIONS
Seletalisib safety, tolerability and pharmacokinetic/pharmacodynamic profiles support its continued clinical development in immune-inflammatory diseases.
UCB Pharma, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK. Eric.Helmer@ucb.com.
Eric
E
Helmer
TranScrip Partners LLP, Reading, UK.
Mark
M
Watling
Veramed Limited, Twickenham, UK.
Emma
E
Jones
UCB Pharma, Braine l'Alleud, Belgium.|Clinical Pharmacokinetics/Pharmacometrics, Sanofi-Aventis, Deutschland GmbH, Frankfurt am Main, Germany.
Dominique
D
Tytgat
UCB Pharma, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK.
Mark
M
Jones
UCB Pharma, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK.
Rodger
R
Allen
UCB Pharma, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK.
Andrew
A
Payne
PAREXEL, Harrow, UK.
Annelize
A
Koch
Dermatopharmacology, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Eugene
E
Healy
D000284:Administration, Oral; D001682:Biological Availability; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010919:Placebos; D011565:Psoriasis / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D011804:Quinolines / Q000008:administration & dosage / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010919:Placebos; D011725:Pyridines; D011804:Quinolines; C000620182:seletalisib
Inflammatory; PI3Kδ; Pharmacodynamic; Pharmacokinetic; Phase I; Seletalisib