Delving into the Latest Updates on Seletalisib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

PI3Kδ

Mechanism

PI3Kδ inhibitors(Phosphatidylinositol 3 kinase delta inhibitors)

Therapeutic Areas

Immune System DiseasesCongenital DisordersOther Diseases+ [4]

Active Indication-

Inactive Indication

Activated PI3K-delta SyndromeArthritis, PsoriaticPlaque psoriasis+ [2]

Originator Organization

UCB SA

Active Organization-

Inactive Organization

UCB Celltech

UCB SA

UCB Pharma GmbH

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

RegulationOrphan Drug (EU)

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Structure

Molecular FormulaC23H14ClF3N6O

InChIKeyLNLJHGXOFYUARS-OAQYLSRUSA-N

CAS Registry1362850-20-1

AbstractPI3K pathway plays a crucial role in dendritic cells (DCs) functions, as it regulates different cellular processes, such as maturation and cytokines production. However, the specific role of PI3K p110δ isoform in human DCs has not been thoroughly addressed. In this study, we analyze the effects of seletalisib, a potent and specific inhibitor of PI3K p110δ, on phenotype and antigen-presenting functions of monocyte-derived DCs undergone maturation via LPS. Seletalisib treatment reduced membrane HLA-DR as well as CD83 and CD40 costimulatory molecules, whereas CD80 and CD86 expression was only partially affected. Additionally, DCs cultures showed reduced TNF-α, IL-10, and IL-12 and increased IL-23 secretion levels. This resulted in a reduced capacity of DCs to prime allogeneic T cells, with a strong decrease of Th1 differentiation. On the other hand, PI3K p110δ inhibitor seletalisib increased CXCR4 and CCR7 expression and augmented the DCs migration toward CCL19 and CXCL12 ligands. At molecular level, inhibition of PI3K p110δ isoform by seletalisib significantly down-regulated the phosphorylation of AKT and other downstream signaling molecules, such as ribosomal protein S6, 4E-BP1, and NF-κB p65. In contrast, seletalisib did not affect p38 MAP kinase phosphorylation or TLR-associated adapter molecule TIRAP in DCs. Our results indicate that PI3K p110δ can serve as an important regulatory signal for DCs, and selective inhibition of PI3K p110δ isoform by seletalisib could be used for the prevention of exaggerated and harmful immune responses occurring in pathologic conditions, such as autoimmune disorders.

02 Mar 2021·RheumatologyQ2 · MEDICINE

A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren’s syndrome

Q2 · MEDICINE

Article

Author: Gottenberg, Jacques-Eric ; Sánchez Bursón, Juan ; Nayar, Saba ; Helmer, Eric ; Giacomelli, Roberto ; Payne, Andrew ; Rosas, José ; Guggino, Giuliana ; Cain, Dionne ; Fisher, Benjamin A ; Johnston, Geoffrey I ; Mariette, Xavier ; Bowman, Simon J ; Devauchelle-Pensec, Valerie ; Ng, Wan Fai ; Barone, Francesca ; Diaz, Nieves ; Juarez, Maria ; Triolo, Giovanni ; Williams, Paulette ; Kvarnström, Marika

AbstractObjectivesThis phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kδ inhibitor, in patients with moderate-to-severe primary Sjögren’s syndrome (PSS).MethodsAdults with PSS were randomized 1:1 to seletalisib 45 mg/day or placebo, in addition to current PSS therapy. Primary end points were safety and tolerability and change from baseline in EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score and histological features in salivary gland biopsies.ResultsTwenty-seven patients were randomized (seletalisib n = 13, placebo n = 14); 20 completed the study. Enrolment challenges led to early study termination with loss of statistical power (36% vs 80% planned). Nonetheless, a trend for improvement in ESSDAI and ESSPRI [difference vs placebo: –2.59 (95% CI: –7.30, 2.11; P=0.266) and –1.55 (95% CI: –3.39, 0.28), respectively] was observed at week 12. No significant changes were seen in saliva and tear flow. Serious adverse events (AEs) were reported in 3/13 of patients receiving seletalisib vs 1/14 for placebo and 5/13 vs 1/14 discontinued due to AEs, respectively. Serum IgM and IgG concentrations decreased in the seletalisib group vs placebo. Seletalisib demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo.ConclusionDespite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS. Histological analyses demonstrated encouraging effects of seletalisib on salivary gland inflammation and organisation.Trial registrationhttps://clinicaltrials.gov, NCT02610543.

01 Dec 2020·The Journal of ImmunologyQ2 · MEDICINE

Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies

Q2 · MEDICINE

Article

Author: Juarez, Maria ; Moshous, Despina ; Helmer, Eric ; Simonetti, Alessandra ; Martín-Nalda, Andrea ; Heeg, Maximilian ; Mann, Joanne ; Cancrini, Caterina ; Garcia-Prat, Marina ; Cavazzana, Marina ; Cain, Dionne ; Soler-Palacín, Pere ; Johnston, Geoffrey I. ; Conti, Francesca ; Martínez-Gallo, Mónica ; Payne, Andrew ; Ehl, Stephan ; Diaz, Nieves ; Santilli, Veronica ; Maccari, Maria Elena ; Di Cesare, Silvia ; Kracker, Sven ; Semeraro, Michaela ; Yuill, Daisy ; Suarez, Felipe

AbstractMutations in two genes can result in activated PI3Kδ syndrome (APDS), a rare immunodeficiency disease with limited therapeutic options. Seletalisib, a potent, selective PI3Kδ inhibitor, was evaluated in patients with APDS1 and APDS2. In the phase 1b study (European Clinical Trials Database 2015-002900-10) patients with genetic and clinical confirmation of APDS1 or APDS2 received 15–25 mg/d seletalisib for 12 wk. Patients could enter an extension study (European Clinical Trials Database 2015-005541). Primary endpoints were safety and tolerability, with exploratory efficacy and immunology endpoints. Seven patients (median age 15 years; APDS1 n = 3; APDS2 n = 4) received seletalisib; five completed the phase 1b study. For the extension study, four patients entered, one withdrew consent (week 24), three completed ≥84 wk of treatment. In the phase 1b study, patients had improved peripheral lymphadenopathy (n = 2), lung function (n = 1), thrombocyte counts (n = 1), and chronic enteropathy (n = 1). Overall, effects were maintained in the extension. In the phase 1b study, percentages of transitional B cells decreased, naive B cells increased, and senescent CD8 T cells decreased (human cells); effects were generally maintained in the extension. Seletalisib-related adverse events occurred in four of seven patients (phase 1b study: hepatic enzyme increased, dizziness, aphthous ulcer, arthralgia, arthritis, increased appetite, increased weight, restlessness, tendon disorder, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (aphthous ulcer). Serious adverse events occurred in three of seven patients (phase 1b study: hospitalization, colitis, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (stomatitis). Patients with APDS receiving seletalisib had improvements in variable clinical and immunological features, and a favorable risk–benefit profile was maintained for ≤96 wk.

100 Deals associated with Seletalisib

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12706

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Activated PI3K-delta Syndrome	Phase 3	FR	UCB SA	08 Jun 2016
Primary Sjögren's syndrome	Phase 3	SE	UCB Celltech	01 Oct 2015
Primary Sjögren's syndrome	Phase 3	ES	UCB Celltech	01 Oct 2015
Primary Sjögren's syndrome	Phase 3	IT	UCB Celltech	01 Oct 2015
Primary Sjögren's syndrome	Phase 3	FR	UCB Celltech	01 Oct 2015
Primary Sjögren's syndrome	Phase 3	GB	UCB Celltech	01 Oct 2015
Arthritis, Psoriatic	Phase 3	GB	UCB Pharma GmbH	01 Aug 2013
Plaque psoriasis	Phase 3	GB	UCB SA	-
Sjogren's Syndrome	Phase 3	GR	UCB SA	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02610543 (Pubmed \| Rheumatology (Oxford)) Manual	Phase 2	Primary Sjögren's syndrome	27	seletalisib	(rkoophxetu): Difference = -2.59 (95% CI, 2.11 - 7.30), P-Value = 0.266 View more	Positive	02 Mar 2021
				Placebo
NCT02610543 (Phase II, EULAR2019)	Phase 2	Primary Sjögren's syndrome EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI)	27	Seletalisib	(jwbwgpfrag) = ierezxtugx wpiaralxtl (fpmnphaddv, 1.7) View more	Positive	12 Jun 2019
				Placebo	(jwbwgpfrag) = utxlcqvrzr wpiaralxtl (fpmnphaddv, 1.5) View more
NCT02207595 \| NCT02303509 (Pubmed \| Eur J Clin Pharmacol) Manual	Phase 1	Inflammation \| Immune System Diseases	-	seletalisib (90 mg QD)	(jdrztoxtdw) = nbhafdhfvz bmcdjbveeb (crezlkmjzl )	Positive	01 May 2017
				seletalisib (30 mg BID)	(jdrztoxtdw) = tocdqbqrnt bmcdjbveeb (crezlkmjzl )