GLPG3970 / Lakefront Biotherapeutics, Gilead - LARVOL DELTA

Bridging preclinical and clinical efficacy of SIK2/SIK3 inhibition in inflammatory bowel disease through integrated murine, patient-derived models, and phase 2a trial-based analyses. (PubMed, J Crohns Colitis) - P2 | "Integrated analyses across murine, patient-derived, and clinical trial datasets demonstrate conserved immune-epithelial responses to SIK2/SIK3 inhibition by GLPG3970. These findings support the value of patient-relevant experimental platforms to assess target engagement and therapeutic activity prior to clinical testing, strengthening translational alignment in IBD drug development."

Journal • P2a data • Preclinical • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • CD4 • IL2RA

Inhibition of Salt-Inducible Kinases 2 and 3 reduces inflammatory signature in Psoriasis. (PubMed, J Invest Dermatol) - "Bulk RNA sequencing of lesional psoriasis biopsies treated ex vivo with GLPG3970 and of biopsies received from responders vs. placebo-treated patients of the clinical trial showed downregulation of inflammatory pathways with suppression of IL1B, CXCL1, CXCL8, CEBPB, CD177, and CLEC5A in both settings. In summary, this study suggests that specific inhibition of SIK2/SIK3 reduces acute phase immunity and neutrophil recruitment in psoriasis."

Journal • Dermatology • Immunology • Inflammation • Psoriasis • CD177 • CEBPB • CLEC5A • CXCL1 • CXCL10 • CXCL8 • IFNG • IL1B • IL6 • SIK1

Targeting hypothalamic SIK3 to promote weight loss and improve glycemic control in mice. (PubMed, Nat Commun) - "Pharmacological inhibition of SIK3 with the inhibitor GLPG3970 in diet-induced obese mice led to significant reductions in body weight and adiposity, primarily due to decreased energy intake, with notable improvements in metabolic health. These effects are linked to enhanced central leptin and insulin signaling, and the dephosphorylation and nuclear translocation of key transcriptional metabolic regulators, CRTC1 and HDAC5. These findings reveal a previously unidentified SIK3-mediated pathway that promotes positive energy balance and suggests SIK3 inhibition may offer therapeutic potential for treating obesity and metabolic disorders."

Journal • Preclinical • Genetic Disorders • Metabolic Disorders • Obesity • CRTC1 • HDAC5 • LEP

Bio-experienced state drives differential responses towards GLPG3970 in ex vivo biopsies from patients with ulcerative colitis. (BWG 2026) - P2 | "Aim: Building on our previous ex vivo comparison of GLPG3970 with approved UC therapy tofacitinib,(6) this study aimed to elucidate the mechanistic effects of GLPG3970 and delineate response patterns in bio- naive and bio-experienced patients. GLPG3970 effectively suppressed inflammatory signaling in UC ex vivo biopsies. Network analysis showed enhanced extracellular remodeling in bio-experienced patients, with GLPG3970 reversing connective tissue-related processes in this group. These findings emphasize the importance of considering prior treatment exposure in patient stratification and preclinical study design."

Biopsy • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IFNG • MMP9 • TGFB1 • TNFA

Differential ex vivo responses to GLPG3970 in bio-naive and bio-experienced biopsies from patients with UC (ECCO-IBD 2026) - "2-5 Building on our previous ex vivo comparison of GLPG3970 with approved UC therapy tofacitinib, 6 this study aimed to elucidate the mechanistic effects of GLPG3970 and delineate response patterns in bio-naive and bio-experienced patients. Network analysis showed enhanced extracellular remodelling in bio-experienced patients, with GLPG3970 reversing connective tissue-related processes in this group. These findings emphasize the importance of considering prior treatment exposure in patient stratification and preclinical study design."

Biopsy • Preclinical • Inflammatory Bowel Disease • Ulcerative Colitis • IFNG • MMP9 • TGFB1 • TNFA

Selective SIK2/SIK3 inhibition reprograms pro- and antiinflammatory pathways in myeloid cells, improving autoimmune disease outcomes. (PubMed, JCI Insight) - "We investigated whether selective inhibition of SIK2 and SIK3 with GLPG3970 could reprogram monocytes, macrophages, and dendritic cells, and we assessed pharmacological effects on activated T and B cells...These findings suggest that myeloid cell dysfunction and impaired myeloid phenotype switching contribute to chronic inflammation in autoimmune diseases and that therapeutic targeting of SIK2/SIK3 holds the potential to restore immune balance by converting proinflammatory into regulatory pathways. Collectively, this work supports SIK2/SIK3 inhibition as a potential treatment strategy for myeloid cell-driven chronic inflammatory conditions."

Journal • Dermatology • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Arthritis • Inflammatory Bowel Disease • Psoriasis • Rheumatoid Arthritis • Rheumatology • Ulcerative Colitis

Structure-Activity Relationship Guided Scaffold Hopping Resulted in the Identification of GLPG4970, a Highly Potent Dual SIK2/SIK3 Inhibitor. (PubMed, J Med Chem) - "Overlay of 7 with GLPG3970 (6) within the SIK3 protein structure inspired the design of pyridine derivatives, leading to the identification of GLPG4970 (8). Compound 8 was negative in genotoxicity screening assays and demonstrated potent SIK2/SIK3 inhibition, for which isoform selectivity was determined in a cellular context. Compound 8 displayed improved potency compared with previously reported SIK inhibitors in biochemical and phenotypic cellular assays, and showed dose-dependent activity in disease relevant mouse pharmacological models of colitis."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • SIK1

Effects of GLPG3970 on Sulfasalazine and Methotrexate Pharmacokinetics in Healthy Adults: Two Open-Label, Phase I, Drug-Drug Interaction Studies. (PubMed, Clin Pharmacol Ther) - P1 | "Therefore, the strong in vitro BCRP inhibition was not confirmed in vivo. No safety concerns were observed when GLPG3970 was coadministered with SSZ or MTX."

Journal • PK/PD data • Breast Cancer • Oncology • Solid Tumor

ACUTE EXPOSURE OF EX VIVO INFLAMED UC AND CD BIOPSIES TO THE SELECTIVE SIK2/SIK3 INHIBITOR GLPG3970 RESULTS IN A STRONG REDUCTION OF PRO-INFLAMMATORY RESPONSES (UEGW 2024) - "Acute exposure of GLPG3970 to ex vivo inflamed tissue biopsies from patients with UC and CD showed a strong reduction in the release of pro-inflammatory mediators. Transcriptomic analysis further confirmed GLPG3970’s robust activity in reducing inflammatory NF-κB-mediated pathways while modulating TGF-β-related immunoregulatory pathways versus tofacitinib. Our findings support the dual mechanism of GLPG3970 in relevant pathogenic pathways in IBD and confirm the therapeutic potential of SIK2/SIK3 inhibition in treating patients with either UC or CD."

Biopsy • Preclinical • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • CXCL10 • CXCL11 • IFNA1 • IFNG • IL1R1 • IL2 • IL22 • IL23A • IL9 • MMP9 • MX1 • SOCS3 • TGFB1 • TNFA

EXPOSURE OF THE SELECTIVE SIK2/SIK3 INHIBITOR GLPG3970 TO ORGANOIDS DERIVED FROM ULCERATIVE COLITIS PATIENTS INDUCES UPREGULATION OF MUCUS EXPRESSION AND TARGET-SPECIFIC MARKERS (UEGW 2024) - "SIK2/SIK3 inhibition by GLPG3970 showed a significant upregulation of target engagement markers as measured by the CREB activation genes NR4A1/2/3 in UC patient-derived colon epithelial cells, whereas no direct downregulation of inflammatory markers was observed. Exposure of UC patient-derived colonic organoids to GLPG3970 20 μM resulted in a signature of enhanced mucus secretion, both in the presence and absence of inflammation. Overall, these data indicate a direct impact of SIK2/SIK3 inhibition in intestinal epithelial cells with potential benefit in promoting barrier reinforcement via goblet cell mucus production in patients with active UC."

Biomarker • Clinical • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • AGR2 • CREB1 • CXCL8 • IL1B • MUC2 • MUC5AC • NR4A1 • NR4A2 • NR4A3 • TNFA

Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases. (PubMed, J Med Chem) - "The dual activity of 32 in modulating the pro-inflammatory cytokine TNFα and the immunoregulatory cytokine IL-10 is demonstrated in vitro in human primary myeloid cells and human whole blood, and in vivo in mice stimulated with lipopolysaccharide. Compound 32 shows dose-dependent activity in disease-relevant mouse pharmacological models."

Journal • Immunology • Inflammation • AMPK • IL10 • SIK1 • TNFA

Discovery of novel and selective SIK2 inhibitors by the application of AlphaFold structures and generative models. (PubMed, Bioorg Med Chem) - "In this paper, based on the binding pose of the reported compound (GLPG-3970, 3) with AlphaFold protein structure, a series of hinge cores were generated via AI-generative models (Chemistry42)...Furthermore, 8g also demonstrated excellent selectivity over other AMPK kinases, favorable in vitro ADMET profiles and decent cellular activities. This work provides an alternative approach to the discovery of novel and selective kinase inhibitors."

Journal • Oncology • AMPK

Discovery of GLPG3970, a first-in-class SIK2/SIK3 inhibitor evaluated in clinical trials for the treatment of autoimmune and inflammatory diseases (ACS-Fall 2022) - "GLPG3970 is the first SIK2/SIK3 inhibitor evaluated in patients. An overview of the clinical studies exploring different indications with GLPG3970 will be shown."

Clinical • Immunology • Inflammation

GLIDER: A Study Evaluating the Effects of GLPG3970 Given as an Oral Treatment for 12 Weeks in Adults With Active Primary Sjögren's Syndrome (clinicaltrials.gov) - P2 | N=31 | Terminated | Sponsor: Galapagos NV | Active, not recruiting ➔ Terminated | Trial primary completion date: Mar 2022 ➔ Oct 2021; Study was terminated based on Sponsor decision

Trial primary completion date • Trial termination • Sjogren's Syndrome

GLIDER: A Study Evaluating the Effects of GLPG3970 Given as an Oral Treatment for 12 Weeks in Adults With Active Primary Sjögren's Syndrome (clinicaltrials.gov) - P2; N=31; Active, not recruiting; Sponsor: Galapagos NV; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Sjogren's Syndrome

[VIRTUAL] Preclinical Investigation of the First-in-Class SIK2/SIK3 Inhibitor GLPG3970 in Models of Arthritis (ACR-CONVERGENCE 2021) - P2 | "Efficacy of GLPG3970 treatment from day 32–47 was compared with an anti-TNF agent (Enbrel®) and evaluated by clinical score analysis and bone erosion (Larsen score after X-ray imaging). This study associates the underlying mechanism of SIK2/SIK3 inhibition with RA and highlights the therapeutic activity of GLPG3970 in murine arthritis models, supporting GLPG3970 as a promising novel approach for the treatment of arthritis. GLPG3970 is being tested in a phase 2a study in patients with RA (NCT04577781)."

Preclinical • Immunology • Inflammatory Arthritis • Psoriatic Arthritis • Rheumatoid Arthritis • Rheumatology • Seronegative Spondyloarthropathies • IL10

TAPINOMA: A Study Evaluating the Effects of GLPG3970 Given as Oral Treatment for 12 Weeks in Adults With Systemic Lupus Erythematosus (clinicaltrials.gov) - P1; N=11; Terminated; Sponsor: Galapagos NV; N=30 ➔ 11; Trial completion date: Mar 2022 ➔ Oct 2021; Recruiting ➔ Terminated; Trial primary completion date: Mar 2022 ➔ Oct 2021; Study stopped on business grounds

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

[VIRTUAL] PRECLINICAL MECHANISTIC INVESTIGATION OF THE FIRST-IN-CLASS SIK2/SIK3 INHIBITOR GLPG3970 IN AN EXPERIMENTAL MODEL OF IBD: Discussion (UEGW 2021) - No abstract available

Preclinical

[VIRTUAL] PRECLINICAL MECHANISTIC INVESTIGATION OF THE FIRST-IN-CLASS SIK2/SIK3 INHIBITOR GLPG3970 IN AN EXPERIMENTAL MODEL OF IBD (UEGW 2021) - "Our preclinical investigations demonstrate the efficacy of GLPG3970 in the murine T-cell transfer colitis model and support the dual mechanism of SIK2/SIK3 inhibition in local inflamed intestinal tissues underpinning its potential to restore intestinal homeostasis. These data support GLPG3970 as an attractive novel potential therapeutic option for the treatment of chronic IBD."

Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IL10 • IL22 • MUC2

[VIRTUAL] PRECLINICAL IN VITRO AND IN VIVO INVESTIGATION OF THE FIRST-IN-CLASS SELECTIVE SIK2/SIK3 INHIBITOR GLPG3970 IN EXPERIMENTAL MODELS OF IBD: Discussion (UEGW 2021) - No abstract available

Preclinical

[VIRTUAL] PRECLINICAL IN VITRO AND IN VIVO INVESTIGATION OF THE FIRST-IN-CLASS SELECTIVE SIK2/SIK3 INHIBITOR GLPG3970 IN EXPERIMENTAL MODELS OF IBD (UEGW 2021) - P2 | "Our preclinical investigations demonstrate the dual activity of selective SIK2/SIK3 inhibition in inflammatory conditions and highlight the therapeutic activity of GLPG3970 in 3 different experimental models of colitis. GLPG3970’s mechanism of action represents a promising novel approach for the treatment of IBD and supports its investigation in a phase 2a proof-of-concept study in patients with ulcerative colitis (NCT04577794)."

Preclinical • Gastroenterology • Gastrointestinal Disorder • Immune Modulation • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • ABCB1 • IL10 • TNFA

Evaluation of Mass Balance and Absolute Bioavailability of GLPG3970 (clinicaltrials.gov) - P1; N=6; Completed; Sponsor: Galapagos NV; Recruiting ➔ Completed

Trial completion

Galapagos demonstrates early clinical activity with SIK2/3 inhibition in inflammation (GlobeNewswire) - P2, N=31; SEA TURTLE (NCT04577794); P1, N=100; CALOSOMA (NCT04106297); Sponsor: Galapagos NV; "Galapagos NV (Euronext & Nasdaq: GLPG) reports topline results with GLPG3970 in three patient studies...CALOSOMA study: Phase 1b trial in psoriasis...At Week 6, four out of 13 patients on GLPG3970 had a PASI 50 response, defined as at least a 50% improvement of baseline PASI, compared to none on placebo...SEA TURTLE study: Phase 2a trial in UC...At Week 6, positive signals were observed in patients on GLPG3970 on objective parameters such as endoscopy, histology, and fecal calprotectin...Galapagos intends to submit study outcomes with GLPG3970 for publication at scientific conferences and in peer-reviewed medical journals."

P1 data • P2a data • Immunology • Inflammatory Bowel Disease • Psoriasis • Ulcerative Colitis

Drug-drug Interaction Study With GLPG3970 and Sulfasalazine in Adult, Healthy Subjects (clinicaltrials.gov) - P1; N=8; Completed; Sponsor: Galapagos NV; Recruiting ➔ Completed; N=12 ➔ 8

Clinical • Enrollment change • Trial completion

SEA TURTLE: A Study Evaluating the Effects of GLPG3970 Given as an Oral Treatment for 6 Weeks in Adults With Ulcerative Colitis (clinicaltrials.gov) - P2; N=31; Completed; Sponsor: Galapagos NV; Active, not recruiting ➔ Completed

Clinical • Trial completion • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • TNFA