First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3Kδ inhibitor for the treatment of immune and inflammatory diseases

Purpose: 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 t 1/2 values 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

Shade and leaf loss affect establishment of grove-forming ectomycorrhizal rain forest tree species

The poor regeneration of Microberlinia bisulcata in groves in Korup, Central Africa was investigated in the forest to highlight factors that interact with light. Survival and growth of nursery‐grown seedlings of M. bisulcata with four other species in each of two 1‐yr trials were recorded after transplantation into quadrats differing in PAR. Total mass was predicted for PAR treatments in nursery trials reported separately. Plant mass was strongly dependent on PAR for all species. At low PAR, across species, plant mass was positively related to seed mass. Forest : nursery mass ratios decreased with increasing PAR; M. bisulcata had the lowest ratios of all species at high PAR. Leaf weight ratio declined more steeply with increasing PAR in the forest than in the nursery and this was particularly marked for M. bisulcata. Herbivory was the most probable cause of leaf loss. Forest : nursery ratios were negatively correlated with species’ abundances in the forest. Besides its small seed size and shade intolerance, M. bisulcata is highly susceptible to leaf loss when illuminated. Opportunities for seedling release are thus very low