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

First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3Kδ inhibitor for the treatment of immune and inflammatory diseases
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.
0031-6970
Watling, Mark
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Jones, Emma
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Tytgat, Dominique
de7a8c61-a26f-4dd1-b600-8ffbc419101b
Jones, Mark
c63a3b33-b43b-46a9-afe7-3ca67a8191c7
Allen, Rodger
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Payne, Andrew
b158f374-d4ff-460d-ade6-f411ac487ab7
Koch, Annelize
beb80449-f721-4846-b36e-a1fb482012c6
Healy, Eugene
400fc04d-f81a-474a-ae25-7ff894be0ebd
Watling, Mark
6affdc83-6163-404d-aa88-c09bb72af36b
Jones, Emma
f9404c2f-0b14-478c-9be9-b43b003dc93a
Tytgat, Dominique
de7a8c61-a26f-4dd1-b600-8ffbc419101b
Jones, Mark
c63a3b33-b43b-46a9-afe7-3ca67a8191c7
Allen, Rodger
61c5e0a7-c0e3-4a16-a338-f4b35a55815f
Payne, Andrew
b158f374-d4ff-460d-ade6-f411ac487ab7
Koch, Annelize
beb80449-f721-4846-b36e-a1fb482012c6
Healy, Eugene
400fc04d-f81a-474a-ae25-7ff894be0ebd

Watling, Mark, Jones, Emma, Tytgat, Dominique, Jones, Mark, Allen, Rodger, Payne, Andrew, Koch, Annelize and Healy, Eugene (2017) First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3Kδ inhibitor for the treatment of immune and inflammatory diseases. European Journal of Clinical Pharmacology. (doi:10.1007/s00228-017-2205-7).

Record type: Article

Abstract

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.

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Accepted/In Press date: 17 January 2017
e-pub ahead of print date: 4 February 2017
Organisations: Clinical & Experimental Sciences

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Local EPrints ID: 406144
URI: https://eprints.soton.ac.uk/id/eprint/406144
ISSN: 0031-6970
PURE UUID: bd4f6945-88ad-4e0f-a10f-04a978197ae7

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Date deposited: 10 Mar 2017 10:40
Last modified: 09 Dec 2019 18:58

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