Yeliva (opaganib) / RedHill, Apogee Biotech - LARVOL DELTA

DARO-LIPID (ANZUP2205): A randomised phase 2 study of sphingosine kinase inhibitor (opaganib) with darolutamide in poor prognostic metastatic castration resistant prostate cancer based on a circulating lipid biomarker, PCPro (ESMO 2026) - No abstract available

Biomarker • Clinical • Metastases • P2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Farnesol mitigates post-infarction ventricular remodeling via pharmacological modulation of the SPHK2/S1P/SMAD3 axis. (PubMed, Eur J Pharmacol) - "In vivo target validation was achieved through pharmacological blockade of sphingosine kinase 2 (SPHK2) using opaganib...These findings suggest that farnesol confers cardioprotection against post-MI remodeling, an effect closely associated with the pharmacological upregulation of the SPHK2/S1P axis and the subsequent attenuation of TGF-β/SMAD3-mediated fibrogenesis. Together, these findings highlight crosstalk between the mevalonate and sphingolipid pathways, supporting modulation of SPHK2 as a potential therapeutic strategy for the clinical management of post-MI heart failure."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Metabolic Disorders • Myocardial Infarction • SMAD3 • SPHK2 • TGFB1

Opaganib Protects Against High-Fat Diet-Induced Hypercholesterolemia and NAFLD (MASLD) (OBESITY WEEK 2026) - No abstract available

Dyslipidemia • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease

Response to the Letter to the editor regarding conflicting reports of opaganib efficacy against high-fat diet-induced obesity. (PubMed, Life Sci) - No abstract available

Journal • Genetic Disorders • Obesity

Letter to the editor regarding conflicting reports of opaganib efficacy against high-fat diet-induced obesity. (PubMed, Life Sci) - "We argue herein that those studies were flawed because of the use of an unusually low opaganib dose, as well as a route and schedule of administration that do not provide sufficient blood levels for opaganib efficacy. We are concerned that these limitations provide a misleading representation of opaganib efficacy in this model of obesity and type 2 diabetes."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Oncology • Type 2 Diabetes Mellitus

Sphingosine Kinase 2 (SPHK2) Inhibition as A Therapeutic Strategy for Adrenocortical Carcinoma (ACC) (ENDO 2026) - "Opaganib (ABC294640), a selective SPHK2 inhibitor, reduced cell viability across all three cell lines to a similar extent as mitotane. SPHK2 inhibition, already in phase II clinical trials for other cancers, may present an alternative/adjunctive therapy in ACC. Further work is ongoing to characterise the biological pathways disrupted by SPHK2 inhibition and delineate how they differ from those targeted by mitotane."

Adrenal Cortex Carcinoma • Endocrine Disorders • Genito-urinary Cancer • Metabolic Disorders • Nephrology • Oncology • Renal Disease • Solid Tumor • MUC1 • SPHK2

RedHill Biopharma Ltd…announced that the U.S. Food and Drug Administration (FDA) has granted rare pediatric disease (RPD) designation to opaganib for treatment of neuroblastoma (NB). (PRNewswire)

FDA event • Neuroblastoma

Therapeutic potential of the sphingosine kinase 2 inhibitor opaganib. (PubMed, Pharm Sci Adv) - "This study reviews the role and mechanisms of opaganib effects as anticancer, anti-inflammatory, and antiviral agent. The latest research directions for opaganib are described as gastrointestinal acute radiation syndrome (GI-ARS), chemical exposure indications, and COVID-19, Ebola, and other viruses, providing new therapeutic ideas and considerations for future research and clinical trials."

Journal • Review • Ebola Virus Disease • Infectious Disease • Novel Coronavirus Disease • Oncology • SPHK2

Sphingosine-1-Phosphate Promotes FOS Activation in Osteosarcoma Under Tumor Acidosis. (PubMed, Acta Physiol (Oxf)) - "We identified a novel mechanism where acidosis stimulates both nuclear sphingosine kinase 2 to synthesize sphingosine-1-phosphate and histone H3 acetylation, ultimately leading to FOS transcription. Targeting this axis decreased clonogenesis, underscoring its therapeutic potential in osteosarcoma and potentially other acid-adapted cancers."

Journal • Metabolic Disorders • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • LAMP2 • SPHK2

The SPHK2 inhibitor opaganib potentiates tumor-intrinsic STING activation in triple-negative breast cancer in vitro (AACR 2026) - "Upregulated pathways in cells treated with the opaganib-diABZI combination compared to cells treated with diABZI alone or opaganib alone included cytokine signaling in immune system and responses to cytokine stimulus. In summary, we show that malignancy-associated production of S1P blunts tumor-intrinsic STING activity and suggest that targeting the SPHK2-S1P axis with opaganib may augment anti-tumor immunity in TNBC."

IO biomarker • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • SPHK1 • SPHK2 • STING

RedHill's Opaganib Enhances Efficacy of Neuroblastoma Chemo Combination and Augment Anti-Tumor Immunity in Triple-Negative Breast Cancer in Preclinical Studies - New Data Presented at AACR 2026 (PRNewswire) - "The data showed that opaganib directly destabilized n-Myc, a key oncogenic driver of neuroblastoma and other solid tumors, regulating cell proliferation, differentiation, and apoptosis during embryonic development, a critical factor driving poor outcomes....A second poster from the University of Kansas' Colette Worcester describes in vitro model data showing that pre-treatment with opaganib, followed by low-dose diABZI treatment, potentiated the downstream STING-mediated effects and may augment anti-tumor immunity in TNBC, which has the poorest prognosis of the breast cancer subtypes."

Preclinical • Neuroblastoma • Triple Negative Breast Cancer

Opaganib in combination with oxaliplatin and doxorubicin as a novel salvage therapy for relapsed/refractory high-risk neuroblastoma (AACR 2026) - "Opaganib has been extensively tested in adult COVID patient populations with a favorable toxicity profile. Clinical testing of this novel three-drug combination in NB patients is under evaluation by the Beat Childhood Cancer Research Consortium."

Combination therapy • Neuroblastoma • Oncology • Solid Tumor • CASP3 • CD68 • MCL1 • MYC • MYCN • SPHK1 • SPHK2

Phase II Trial of Opaganib Addition in Metastatic Castration-Resistant Prostate Cancer After Disease Progression on Abiraterone or Enzalutamide. (PubMed, Cancer Med) - P2 | "The trial did not meet its primary objective of demonstrating 30% disease control at 113 days. However, subjects who experienced a PSA response or stabilization warrant further exploration for biomarkers of response."

Journal • P2 data • Cardiovascular • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hematological Disorders • Hypertension • Metabolic Disorders • Musculoskeletal Diseases • Oncology • Prostate Cancer • Solid Tumor • SPHK2

Reduction in NSCLC tumorigenesis by targeting sphingosine kinase 2 (AACR 2024) - "We hypothesize that inhibiting/downregulating SphK2 could reduce tumorigenicity and overcome ER (Erlotinib) and OR (Osimertinib) resistance...H3255OR cells were also bioprinted with GelMA hydrogel using an R-Gen 200 bioprinter to mimic the physiological tumor environment and treated with SphK2 siRNA or ABC294640 (SphK2i)...These results suggest that targeting SphK2 could be a valuable approach for treating lung cancer.[A.K. and B.D. contributed equally to this work.]"

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KLK2 • SPHK2

SPHK2 modulates the tumor-intrinsic response to STING agonism in triple-negative breast cancer cells (AACR 2025) - "The FDA-approved SPHK2 inhibitor opaganib was able to augment diABZI-stimulated ISRE transcriptional activity in a dose-dependent manner. These data suggest that malignancy-associated SPHK2 overexpression may attenuate STING activation in TNBC, and that SPHK2 inhibition may be a therapeutically relevant and viable approach to augment anti-tumor immunity. The interactions between SPHK2 and the STING-interferon pathway warrants further study to develop potential therapeutic combinations to benefit patients with TNBC."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • SPHK2 • STING

Investigating the role of sphingosine kinase 2 and p53 in bioprinted head and neck cancer 3D models (AACR 2025) - "Combined inhibition of SK2 activity by Opaganib and p53 aggregation by ReACp53 (Soragni et al, 2016) decreased organoid size, ATP levels, and p53 aggregation...Our studies highlight a complex interplay between SK2 and p53 in HNSCC, resulting in more aggressive disease. Combinatorial targeting of these proteins could offer a potential therapeutic strategy for HNSCC.Funding: CAPES, CNPQ and FAPESP Grant n.2023/15046-8"

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • SPHK2

Danggui-Shaoyao-San modulates sphingolipid metabolism to promote oligodendrocyte differentiation and maturation in vascular dementia rats. (PubMed, Chin Med) - "DSS improved VaD cognitive impairment by modulating sphingolipid metabolism and promote myelin regeneration via activating the SPHK2/S1P/S1PR5 signaling pathway. This study provides important experimental evidence for the clinical application of DSS in VaD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Metabolic Disorders • Solid Tumor • S1PR5 • SPHK2

RedHill Biopharma's Positive Opaganib Results Indicate Reduction in Venetoclax Resistant Cells (PRNewswire) - "Studies show that sphingosine kinase 2 (SPHK2) is overexpressed in venetoclax-resistant cancer cells and that SPHK2 inhibition may reduce T-cell-induced activation and proliferation of venetoclax-resistant CLL cancer cells and resensitize previously resistant CLL cells; ew in vivo study shows adding opaganib, a potent SPHK2 inhibitor, to venetoclax reduces CLL cell (CD19⁺, CD5⁺) counts by 50% compared to controls and lowered CD3+, CD4+ and CD8+ T cell counts compared to controls with lowered PD1 expression (CD8+)"

Preclinical • Chronic Lymphocytic Leukemia

Mechanisms and potential therapeutic targets of SphK1 and SphK2 in hepatocellular carcinoma. (PubMed, Front Med (Lausanne)) - "It also maintains telomere activity via mitochondrial S1P, which promotes tumor survival and facilitates resistance to regorafenib. In targeted therapy, SphK1 inhibitors (e.g., PF-543) and SphK2 inhibitors (e.g., ABC294640) have shown significant anti-tumor effects in preclinical models...This paper systematically summarizes the mechanisms of action and therapeutic progress of SphK1/SphK2 in HCC. It provides an important theoretical basis for the clinical translation of precision therapy strategies in HCC."

Journal • Review • Hepatocellular Cancer • Oncology • Solid Tumor • SPHK1 • SPHK2

Inhibition of Sphingosine Kinase 2 Enhances Immunotherapy in Mouse Model of Multiple Myeloma (ASH 2023) - "Our study demonstrated that inhibition of SK2 enhances anti-tumor immunity by promoting CD8 T cell activation likely through IL-36gamma and KLK1B22. These studies provide rationale for clinical trials investigating the combination of opaganib with CAR T therapy or other immunotherapy in cancer treatment."

IO biomarker • Preclinical • Brain Cancer • CNS Tumor • Genito-urinary Cancer • Glioma • Hematological Malignancies • Melanoma • Metabolic Disorders • Multiple Myeloma • Oncology • Prostate Cancer • Solid Tumor • CCL2 • CD69 • CD8 • GZMB • HAVCR2 • IFNG • IL10 • IL12A • IL6 • LAG3 • MCL1 • MYC • PD-1 • SPHK2 • TIGIT • TNFA

Sphingosine Kinase 2 Inhibition Ameliorates Neuroinflammation in Diet-Induced Obese Mice. (PubMed, Aging Dis) - "After 7 weeks, mice received the SphK2 inhibitor ABC294640 (SphK2i; 5 mg/kg, s.c.) or vehicle every other day for two weeks...SphK2 was undetectable in cortical microglia, while hippocampal microglia were SphK2-positive. Despite regional specificities of HFD-induced S1P/S1PR1 alterations, pharmacological SphK2 inhibition reduced microglial activation across regions, highlighting its potential relevance for obesity-associated neuroinflammation in a brain region-specific manner."

Journal • Preclinical • Cognitive Disorders • Genetic Disorders • Inflammation • Obesity • S1PR1 • SPHK1 • SPHK2

Subcutaneous administration of the sphingosine kinase 2 inhibitor ABC294640 has no metabolic benefits in high fat diet-induced obesity in male mice. (PubMed, Life Sci) - "Contrary to prior studies, our findings reveal no therapeutic benefit of SphK2 inhibition in diet-induced obesity. These results underscore the importance of tissue and context specificity in targeting the sphingosine kinase pathway and caution against broadly applying SphK2 inhibition as a strategy for treating obesity-associated metabolic dysfunction."

Journal • Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • SPHK1 • SPHK2

Advanced Computational Approaches to Evaluate the Potential of New-Generation Adamantane-Based Drugs as Viroporin Inhibitors: A Case Study on SARS-CoV-2. (PubMed, J Phys Chem B) - "Our results predict that the adamantane-based drugs opaganib, artefenomel, and its regioisomer RLA-3107 exhibit strong affinity and significant inhibitory potential in blocking ion channels, thereby preventing the passage of cations into the host cytoplasm. Our analysis reveals that hydrophobic interactions between the adamantane cage and key Leu residues drive channel closure. The detailed mechanism of these drugs against SARS-CoV-2 viroporin serves as a case study to guide future research on other viroporins."

Journal • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases

A study of opaganib in addition to darolutamide in participants with metastatic hormone resistant prostate cancer, selected for the presence of a specific biomarker. (ANZCTR) - P2 | N=60 | Recruiting | Sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group | Not yet recruiting ➔ Recruiting | Initiation date: Jun 2025

Biomarker • Enrollment open • Trial initiation date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

RedHill Biopharma Announces Recruitment Initiated into Expanded Phase 2 Opaganib/Darolutamide Combination Study in Advanced Prostate Cancer (PRNewswire) - "RedHill Biopharma...announced the initiation of patient recruitment into the Phase 2 study evaluating the efficacy of opaganib in combination with darolutamide in men with metastatic castrate-resistant prostate cancer (mCRPC), sponsored by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Ltd. (ANZUP) in Australia, and supported by Bayer (ETR: BAYN) and Ramsay Hospital Research Foundation. The Company also announced the study will recruit people across at least 10 sites across Australia and New Zealand....The unique study will utilize a companion lipid biomarker test (PCPro) to select mCRPC patients who have poor prognosis to standard of care treatment, and who may benefit from an opaganib + darolutamide combination approach to treatment."

Trial status • Castration-Resistant Prostate Cancer