seletalisib (UCB5857) / UCB - LARVOL DELTA

Effectiveness of biological drugs in the treatment of xerostomia and salivary hypofunction in patients with Sjögren disease. (PubMed, J Am Dent Assoc) - "RTX, iscalimab, and IFN-α have potential benefits in management of salivary gland dysfunction in SjD. Adequate methodological trials are needed to clarify the role of these agents in SjD. The research protocol was planned and registered with PROSPERO, an international systematic review registry (CRD42024596176), and it was not modified throughout the study."

Clinical • Journal • Review • Dental Disorders • Sjogren's Syndrome • Xerostomia • IFNA1

Molecular Insight into Drug Resistance Mechanism Conferred by Aberrant PIK3CD Splice Variant in African American Prostate Cancer. (PubMed, Cancers (Basel)) - "Compared with PCa expressing the full-length PI3Kδ-L, PCa expressing PI3Kδ-S exhibits enhanced drug resistance properties, including a higher cell viability, more antiapoptotic and invasive capacities, and constitutively activated PI3K/AKT signaling, in the presence of PI3Kδ/PI3K inhibitors (Idelalisib, Seletalisib, Wortmannin, and Dactolisib). Additionally, SRSF2 has been identified as a critical splicing factor mediating exon 20 skipping in PIK3CD pre-mRNA. The inhibition of the SRSF2 activity by SRPIN340 successfully sensitizes AA PCa cells to PI3Kδ inhibitors, suggesting a novel therapeutic option for Idelalisib-resistant tumors."

Journal • Genito-urinary Cancer • Prostate Cancer • Solid Tumor • PIK3CD • SRSF2

The phosphoinositide-3-kinase (PI3K)-delta inhibitor seletalisib impairs monocyte-derived dendritic cells maturation, APC function, and promotes their migration to CCR7 and CXCR4 ligands. (PubMed, J Leukoc Biol) - "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."

IO biomarker • Journal • Immune Modulation • Immunology • Inflammation • CCL19 • CCR7 • CD40 • CD86 • CXCL12 • CXCR4 • EIF4EBP1 • IL10 • IL12A • IL23A • RELA • TNFA

PI3Kδ Sustains Keratinocyte Hyperproliferation and Epithelial Inflammation: Implications for a Topically Druggable Target in Psoriasis. (PubMed, Cells) - "It is worth mentioning that PI3Kδ inhibition by seletalisib attenuates the severity of psoriasiform phenotype induced in the Imiquimod-induced mouse model of psoriasis by restoring the physiological proliferation and differentiation programs in epidermal keratinocytes and contrasting the cutaneous inflammatory responses. Therefore, we suggest PI3Kδ as a potential topically druggable target in psoriasis and skin diseases characterized by epidermal hyperproliferation and skin inflammation."

Journal • Dermatitis • Dermatology • Immunology • Inflammation • Psoriasis • IL22 • PDPK1 • PIK3CA • PIK3CD • TNFA

Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies. (PubMed, J Immunol) - P1 | "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."

Clinical • Journal • P1 data • Dental Disorders • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Liver Failure • Musculoskeletal Pain • Rheumatology • Stomatitis • CD8

A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren's syndrome. (PubMed, Rheumatology (Oxford)) - P2 | "Despite 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."

Clinical • Journal • P2 data • Immunology • Inflammation • Sjogren's Syndrome

Role of P-glycoprotein in the brain disposition of seletalisib: Evaluation of the potential for drug-drug interactions. (PubMed, Eur J Pharm Sci) - "The observed data were found aligned with those predicted by in vitro-in vivo extrapolation. Based on the same extrapolation method combined with literature data, only very few P-gp inhibitors (i.e. CsA, quinine, quinidine) were predicted to increase the brain disposition of seletalisib in the clinical setting (maximal 3-fold changes)."

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Selective targeting of PI3Kδ suppresses human IL-17-producing T cells and innate-like lymphocytes and may be therapeutic for IL-17-mediated diseases. (PubMed, J Autoimmun) - "Using in vitro studies with primary human cells and ex vivo studies with inflamed target tissues, we assessed if seletalisib, a selective PI3Kδ inhibitor, suppresses cytokine production by T cells and innate-like lymphocytes, and if seletalisib modulates the inflammatory responses in stromal cell populations in psoriasis (human dermal fibroblasts (HDF)) and SpA (fibroblast-like synoviocytes (FLS))...Collectively, inhibition of PI3Kδ reduces the production of pro-inflammatory cytokines from IL-17-producing adaptive and innate-like lymphocytes and thereby inhibits downstream inflammatory and tissue remodeling responses. PI3Kδ-targeting may therefore represent a novel therapeutic avenue for the treatment of IL-17-mediated chronic inflammatory diseases such as psoriasis and SpA."

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Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjögren's syndrome. (PubMed, Ann Rheum Dis) - "These data demonstrate activation of PI3Kδ pathway within the glands of patients with pSS and its contribution to disease pathogenesis in a model of disease, supporting the exploration of the therapeutic potential of PI3Kδ pathway inhibition in this condition."

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A PHASE II RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PROOF OF CONCEPT STUDY OF ORAL SELETALISIB IN PATIENTS WITH PRIMARY SJÖGREN’S SYNDROME (PSS) (EULAR 2019) - P2; "Although this Phase II PSS study was terminated early due to slow recruitment, seletalisib demonstrated a trend to clinical improvement in patients with PSS and acceptable safety and tolerability. Histological analyses demonstrated encouraging effects of seletalisib on the organisation and extent of salivary gland lymphocytic infiltration in patients with PSS."

Clinical • P2 data

Expression of PI3K signalling associated with T cells in psoriasis is inhibited by seletalisib, a PI3Kδ inhibitor, and is required for functional activity. (PubMed, J Invest Dermatol) - No abstract available.

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