olamkicept (FE999301) / Ferring, NovaBridge Biosciences, Conaris - LARVOL DELTA

Safety and Pharmacokinetics of Olamkicept Doses up to 2400 mg in Healthy Japanese Men: Phase I, Randomized, Placebo-Controlled, and Double-Blind Trial. (PubMed, Clin Transl Sci) - P1 | "In conclusion, single doses of olamkicept up to 2400 mg have a favorable safety profile and dose proportional PK in healthy Japanese men. Trial Registration: ClinicalTrials.gov identifier: NCT06515834."

Clinical • Journal • PK/PD data • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Inflammation • IL6

IL-6 trans-signaling regulates CXCL12 expression in mesenchymal stromal cells and plasma cell niche in rejecting lung allografts. (PubMed, bioRxiv) - "IL-6 trans-signaling/STAT3 signaling axis was shown to upregulate CXCL12 secretion in human MCs, and Olamkicept-mediated neutralization of IL-6 trans-signaling in murine RAS attenuates CXCL12 expression, intra-graft ASC population, and fibrogenesis. Our findings represent the first delineation of specialized CXCL12-expressing mesenchymal stromal cells in adult lungs and the contribution of IL-6 trans-signaling driven CXCL12 expression to sustaining intra-graft ASC niches and allograft fibrogenesis. We characterize CXCL12-expressing mesenchymal cells and their role in a pro-survival niche for antibody-secreting cells in rejecting lung allografts."

Journal • Transplantation • CXCL12 • GLI1 • IL6 • PRDM1

Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Olamkicept up to 2400 mg in Healthy Men: Phase I, Randomized, Placebo-Controlled, and Double-Blind Trial. (PubMed, Clin Transl Sci) - "New anti-olamkicept antibodies were identified in 4/18 participants (22.2%) across all dose levels in the MAD part. SAD and MAD administration of up to 2400 mg olamkicept were well tolerated by healthy men and demonstrated dose-proportional increases in exposure."

Clinical • Journal • PK/PD data • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • IL6

Selective Inhibition of IL6 Trans-Signaling by Olamkicept Mitigates Humoral Immune Response and Fibrosis in Restrictive Allograft Syndrome Post-Lung Transplantation (ATS 2026) - No abstract available

Fibrosis • Immunology • Transplantation • IL6

Extraocular Muscle-Myokine-Scleral Remodeling Axis: IL-6 Trans-Signaling as a Novel Mechanism in Myopia Development. (PubMed, Exp Eye Res) - "This study establishes an "extraocular muscle-myokine-scleral remodeling" axis, providing experimental evidence for an endogenous inflammatory mechanism in myopia. It underscores IL-6 trans-signaling as a potential therapeutic target and offers new insights for myopia prevention and control."

Journal • Ocular Inflammation • Ophthalmology • IL1R1 • IL6 • IL6R • IL6ST • ITGB3 • MMP2 • SERPINH1

IL-6 Signaling in Immunopathology: From Basic Biology to Selective Therapeutic Intervention. (PubMed, Immunotargets Ther) - "Consequently, antibodies that block either IL-6 itself or the IL-6R are in clinical use and have been approved for different inflammatory diseases, including rheumatoid arthritis (RA). This review gives an overview about the complex biology of this important cytokine, summarizes the current usage of anti-IL-6 therapeutics in clinical use and highlights the pre-clinical and clinical development of novel therapeutic agents that specifically block only the trans-signaling pathway of IL-6."

Journal • Review • Immunology • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology • IL6 • IL6R

Assessment of IL-6 Pathway Inhibition in Gastrointestinal Behçet's Disease from Immunological and Clinical Perspectives. (PubMed, Biomedicines) - "Given the current paucity of data, we reflected on the potential of IL-6 inhibitors such as tocilizumab and olamkicept based on immunopathogenic considerations and available clinical data in patients with inflammatory bowel disease (IBD), in whom clinical response or remission was induced. Still, the benefits of IL-6 inhibitors for patients with GIBD need to be evaluated in appropriate proof-of-concept studies. The clinical outcomes of IL-6 inhibitors in IBD are promising and may suggest their potential relevance in GIBD."

Journal • Review • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Rare Diseases • Vasculitis • IL6 • TNFA

Investigating the Safety, Tolerability, Immunogenicity and Pharmacokinetics of Olamkicept in Healthy Japanese Persons (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Ferring Pharmaceuticals | Recruiting ➔ Completed

Trial completion • Gastroenterology • CRP

A Study Investigating the Safety, Tolerability, Immunogenicity and Pharmacokinetics of Olamkicept in Healthy Persons (clinicaltrials.gov) - P1 | N=49 | Completed | Sponsor: Ferring Pharmaceuticals | Recruiting ➔ Completed

Trial completion • Gastroenterology • Gastrointestinal Disorder • Inflammatory Bowel Disease • CRP

Obesity Arrhythmias: Role of IL-6 Trans-Signaling. (PubMed, Int J Mol Sci) - "The first selective inhibitor of IL-6 trans-signaling, olamkicept, has shown encouraging results in phase II clinical studies for inflammatory bowel disease. Nevertheless, the connection between IL-6 trans-signaling and obesity-linked ventricular arrhythmias remains unexplored. Therefore, understanding how IL-6 trans-signaling elicits a cellular pro-arrhythmic phenotype and its use as an anti-arrhythmic target in a model of obesity remain unmet clinical needs."

Journal • Review • Atrial Fibrillation • Cardiovascular • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Heart Failure • Immunology • Inflammation • Inflammatory Bowel Disease • Obesity • IL6

Investigating the Safety, Tolerability, Immunogenicity and Pharmacokinetics of Olamkicept in Healthy Japanese Persons (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Ferring Pharmaceuticals

New P1 trial • Gastroenterology • CRP

Longitudinal single-cell data informs deterministic modelling of inflammatory bowel disease. (PubMed, NPJ Syst Biol Appl) - "Finally, we tested the translational relevance of the mathematical model by deconvolution of longitudinal bulk mRNA-sequencing data from a cohort of human IBD patients treated with olamkicept. We found that neutrophil depletion may contribute to IBD patients entering remission. The predictive power of IBD deterministic modelling highlights its potential to advance our understanding of immune dynamics in health and disease."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease

Safety, tolerability, and pharmacokinetics of single- and multiple-ascending doses of olamkicept: Results from randomized, placebo-controlled, first-in-human phase I trials. (PubMed, Clin Transl Sci) - "Complete target engagement (inhibition of phosphorylation of signal transducer and activator of transcription-3) was achieved in blood around or above olamkicept serum concentrations of 1-5 μg/mL. Overall, these results suggest that olamkicept is safe and well-tolerated in healthy subjects and patients with CD after single intravenous/SC and multiple intravenous administrations."

Clinical • Journal • P1 data • P1 data • PK/PD data • Cough • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • Musculoskeletal Pain • Pain • Respiratory Diseases • IL6

A Study Investigating the Safety, Tolerability, Immunogenicity and Pharmacokinetics of Olamkicept in Healthy Persons (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Ferring Pharmaceuticals

New P1 trial • Gastroenterology • Gastrointestinal Disorder • Inflammatory Bowel Disease • CRP

Nonspecific Inhibition of IL6 Family Cytokine Signalling by Soluble gp130. (PubMed, Int J Mol Sci) - "These data show that sgp130Fc does not exclusively block IL6 trans-signalling and reveal instead that broad inhibition of gp130 signalling likely underlies its therapeutic effects. This proposes global or modular inhibition of gp130 as a therapeutic approach for treating human disease."

Journal • Oncology • ADAM10 • IL6 • IL6R • OSMR

Differential Roles of Interleukin-6 in Severe Acute Respiratory Syndrome-Coronavirus-2 Infection and Cardiometabolic Diseases. (PubMed, Cardiol Discov) - "However, the efficacy of inhibition of IL-6 signaling in metabolic diseases, such as obesity and diabetes, may depend in part on cell type-dependent actions of IL-6 in controlling lipid metabolism, glucose uptake, and insulin sensitivity owing to complexities that remain to be elucidated. The present review sought to summarize and discuss the current understanding of how and whether targeting IL-6 signaling ameliorates outcomes following SARS-CoV-2 infection and associated clinical complications, focusing predominantly on metabolic and cardiovascular diseases."

Journal • Cardiovascular • Diabetes • Genetic Disorders • Infectious Disease • Metabolic Disorders • Novel Coronavirus Disease • Obesity • Respiratory Diseases • IL6

An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma. (PubMed, Respir Res) - "sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. Higher local airway IL-6 + sIL-6Rα signaling is observed in asthma patients with low sputum eosinophils."

Gene Signature • Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • IL6

DISCRIMINATION OF THE DIFFERENTIAL EFFECTS OF SELECTIVE SUPPRESSION OF IL-6 TRANS-SIGNALING BY OLAMKICEPT IN MODERATE-TO-SEVERE ULCERATIVE COLITIS (UEGW 2023) - P2 | "In the developed in silico model of colonic inflammation, inhibition of IL-6 signaling was associated with attenuation of Th17 mediated inflammation in the gut. Pan-inhibition of IL-6 signaling was associated with impaired tissue healing, however this was not observed for olamkicept, where homeostatic, classical IL-6 signaling was preserved.This study provides quantitative support to therapeutic strategies targeting IL-6 trans-signaling in UC to reduce the cytokine's undesirable effects while preserving its beneficial functions."

Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • CD4 • CRP • IL6

SIL-6Rα amplified IL-6 signaling in bronchial epithelial cells defines a subgroup of asthma patients low in sputum eosinophils (ERS 2023) - " Human airway epithelial cells were stimulated with different combinations of IL-6, sIL-6Rα, sgp130 (Olamkicept), and anti-IL6 (Tocilizumab) to assess their effect on signaling pathway activation, epithelial barrier integrity, and gene expression. sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. We find evidence for higher local airway IL-6/sIL-6Rα signaling in asthma patients with low sputum eosinophils. These findings provide a rationale for the evaluation of olamkicept as a potential drug to be repositioned for patients with non-eosinophilic IL-6 high asthma.; Endoscopy and interventional pulmonology; Imaging; Pulmonary function testing; Pulmonary rehabilitation; Transplantation; General respiratory patient care; Physiology; Cell and molecular biology"

Clinical • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • Transplantation • IL6

Blockade of IL-11 Trans-Signaling or JAK2/STAT3 Signaling Ameliorates the Profibrotic Effect of IL-11. (PubMed, Immunol Invest) - "Besides, IL-11 and ADAM10 were also elevated in the skin and pulmonary of bleomycin-induced SSc mouse. Fibroblasts co-stimulated with IL-11 and ionomycin showed increased expression of COL3 and phosphorylation of STAT3, which could be inhibited by TJ301 or WP1066...IL-11 induces fibrosis in SSc by regulating the trans-signaling pathway. Blockage of sgp130Fc or inhibition of the JAK2/STAT3 pathway could ameliorate the profibrotic effect of IL-11."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immune Modulation • Immunology • Respiratory Diseases • Rheumatology • Scleroderma • Systemic Sclerosis • ADAM10 • ADAM17 • CD163

Dissecting Interleukin-6 Classic and Trans-signaling in Inflammation and Cancer. (PubMed, Methods Mol Biol) - "This protein under the WHO name Olamkicept has successfully undergone phase II clinical trials in patients with autoimmune diseases. Here, in this chapter, we describe several molecular tools to differentiate between IL-6 classic and trans-signaling and to analyze the consequences of cellular IL-6 signaling in vivo."

Journal • Immunology • Oncology • IL6 • IL6R

Worldwide attention for the therapy for chronic intestinal inflammation developed in Kiel [Google translation] (University Hospital Schleswig-Holstein) - "'The successful phase II study in JAMA now gives many patients with inflammatory diseases new hope. The path from the discovery of a new biochemical principle to clinical application follows our mission statement of sustainability in medical research. This success is a milestone in precision medicine. Stefan Schreiber....Prof. Dr. Stefan Schreiber...and his team made significant progress in developing the active ingredient."

Media quote

Olamkicept induces clinical response in nearly 60% of patients with active UC (Healio) - "Olamkicept represents a novel mechanism of action for the treatment of ulcerative colitis. This is a first-in-class, selective inhibitor of the s-interleukin-6R/IL-6 complex that is being studied for UC....we move closer to a precision-medicine approach to the treatment of IBD patients and the administration of medications based on a patient's molecular profile."

Media quote

Targeting IL-6 trans-signalling: past, present and future prospects. (PubMed, Nat Rev Immunol) - "The first selective inhibitor of IL-6 trans-signalling, sgp130, has shown therapeutic potential in various preclinical models of disease and olamkicept, a sgp130Fc variant, had promising results in phase II clinical studies for inflammatory bowel disease. Technological developments have already led to next-generation sgp130 variants with increased affinity and selectivity towards IL-6 trans-signalling, along with indirect strategies to block IL-6 trans-signalling. Here, we summarize our current understanding of the biological outcomes of IL-6-mediated signalling and the potential for targeting this pathway in the clinic."

Journal • Review • Gastroenterology • Gastrointestinal Disorder • Immune Modulation • Immunology • Inflammatory Bowel Disease • Oncology • IL6

Effect of Induction Therapy With Olamkicept vs Placebo on Clinical Response in Patients With Active Ulcerative Colitis: A Randomized Clinical Trial. (PubMed, JAMA) - P2 | "Further research is needed for replication and to assess longer-term efficacy and safety. ClinicalTrials.gov Identifier: NCT03235752."

Clinical • Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • IL6