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

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

Sphingosine‐1‐Phosphate Links ER Stress to NOD1/2-Mediated Inflammation in Response to Brucella abortus Infection (ASM Microbe 2025) - "Pharmacological inhibition of SPHK1/2 (using SKI-II and ABC294640) reduced proinflammatory cytokines production in Brucella-infected BMDMs...In conclusion, B. abortus-induced ER stress promotes S1P accumulation via SPHK1/2, linking cellular stress to inflammation and NOD1/2 activation. These findings highlight S1P as a key mediator of immune signaling during bacterial infections and position SPHK1/2 as potential therapeutic targets for managing inflammation in Brucella infections and other ER stress-associated conditions."

Infectious Disease • Inflammation • SPHK1

SPHK2 inhibition alleviates chronic intermittent hypoxia-induced inflammation in adipose tissue by decreasing endoplasmic reticulum stress. (PubMed, Eur J Pharmacol) - "Administration of the SPHK2 inhibitor ABC294640, opaganib, attenuated these effects, reducing ERS activation and restoring lipid homeostasis...In contrast, ERS activation by thapsigargin reversed the protective effects of SPHK2 inhibition, exacerbating metabolic and inflammatory dysregulation. In summary, our findings highlight the critical role of SPHK2 and ERS in CIH-induced adipose tissue inflammation and lipid metabolic disturbances. Pharmacological inhibition of SPHK2 represents a promising therapeutic approach for mitigating OSA-related lipid metabolic disturbances."

Journal • Cardiovascular • Dyslipidemia • Inflammation • Metabolic Disorders • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder • ATF4 • NLRP3 • 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

Opaganib Promotes Weight Loss and Suppresses High-Fat Diet-Induced Obesity and Glucose Intolerance. (PubMed, Diabetes Metab Syndr Obes) - "Opaganib administered either concurrently with semaglutide or as a single drug following cessation of semaglutide treatment eliminated weight rebound. Overall, the data indicate that opaganib effectively suppresses the loss of metabolic control in mice on HFD, suggesting that opaganib may be useful alone or in combination with existing therapies for weight management and improve conditions associated with obesity and diabetes."

Journal • Diabetes • Genetic Disorders • Infectious Disease • Metabolic Disorders • Novel Coronavirus Disease • Obesity • Oncology • SPHK2

RedHill Biopharma's Positive Opaganib Weight Loss & Diabetes Data Published: Signals Potential $100B Market Disruption (PRNewswire) - "The data indicates that opaganib effectively suppresses the loss of metabolic control in mice on a HFD, suggesting that opaganib, alone and in combination with semaglutide, is associated with improved glucose tolerance, decreased deposition of fat, weight loss and the prevention of weight gain rebound after removal of semaglutide."

Preclinical • Obesity

Discovery of Sphingosine Kinase Inhibition by Modified Quinoline-5,8-Diones. (PubMed, Pharmaceuticals (Basel)) - "SphK inhibition has been an attractive target for anticancer drug development for the past decade, with SphK inhibitors such as PF-543 and opaganib exhibiting clinical antitumour effects. Molecular modelling on the pyrrolidine quinoline-5,8-dione construct revealed favourable docking, low binding energies and opportunities for further improvement. Although the screening of anticancer activity was inconclusive, low micromolar dual SphK1/2 inhibition with the quinoline-5,8-dione framework has been identified for the first time, and a plausible new binding mode has been identified."

Journal • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • SPHK1 • SPHK2

RedHill Announces Initiation of Phase 2 Study of Opaganib and Darolutamide in Advanced Prostate Cancer (PRNewswire) - "RedHill Biopharma Ltd...announced the initiation of a Phase 2 clinical study to evaluate the efficacy of opaganib in combination with darolutamide in men with metastatic castrate-resistant prostate cancer (mCRPC). Financially supported by Bayer (ETR: BAYN) and the Ramsay Hospital Research Foundation, the 80-patient placebo-controlled randomized study is designed to test the potentially enhancing effect of opaganib in overcoming resistance to standard of care androgen receptor pathway inhibition (ARPI) treatment."

Trial status • Castration-Resistant Prostate Cancer

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 | Not yet recruiting | Sponsor: Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Biomarker • Metastases • New P2 trial • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

S1P/S1PRs-TRPV4 axis is a novel therapeutic target for persistent pain and itch in chronic dermatitis. (PubMed, Br J Pharmacol) - "Our results indicate that, in CD, increased S1P induces chronic pain and itch partly through TRPV4. Inhibition of S1P synthesis or the S1P/S1P receptor-TRPV4 pathway are promising treatment strategies for CD-associated pain and itch."

Journal • Dermatitis • Dermatology • Immunology • Metabolic Disorders • Pain • SPHK2

Addition of Opaganib to Androgen Antagonists in Patients With mCRPC (clinicaltrials.gov) - P2 | N=69 | Completed | Sponsor: Medical University of South Carolina | Active, not recruiting ➔ Completed

Trial completion • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Effect of Opaganib on Supplemental Oxygen and Mortality in Patients with Severe SARS-CoV-2 Based upon FIO2 Requirements. (PubMed, Microorganisms) - P2/3 | "While the primary analyses were not statistically significant, post-hoc analysis suggests opaganib benefit for patients with severe COVID-19 requiring supplemental oxygen with an FIO2 of ≤60%. Further studies are warranted to prospectively confirm opaganib benefit in this subpopulation."

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

Targeting SNAI1-Mediated Colorectal Cancer Chemoresistance and Stemness by Sphingosine Kinase 2 Inhibition. (PubMed, World J Oncol) - "CRC cell lines with or without ectopic expression of SNAI1 were used to study the role of S1P signaling as mediators of cancer stemness and 5-fluorouracil (5FU) chemoresistance. SNAI1/SPHK2 signaling mediates cancer stemness and 5FU resistance, implicating S1P as a therapeutic target for CRC. The S1P inhibitor ABC294640 holds potential as a therapeutic agent to target CSCs in therapy refractory CRC."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • SNAI1 • SPHK2

The sphingosine kinase 2 inhibitors ABC294640 and K145 elevate (dihydro)sphingosine 1-phosphate levels in various cells. (PubMed, J Lipid Res) - "We have now investigated the effects of seven commonly used SphK inhibitors (5c, ABC294640 (opaganib), DMS, K145, PF-543, SLM6031434 and SKI-II) on profiles of selected sphingolipids in Chang, HepG2 and HUVEC cells. We found that both compounds affect sphingolipid de novo synthesis, with 3-ketodihydrosphingosine reductase and DEGS as their targets. Our study emphasizes the urgency of monitoring cellular sphingolipid profiles when SphK inhibitors are used in mechanistic investigations, as none of the seven SphK inhibitors tested was free of unexpected on-target and/or off-target effects."

Journal • Infectious Disease • Metabolic Disorders • Novel Coronavirus Disease • Oncology • SPHK1 • SPHK2

RedHill's Opaganib Granted Orphan Drug Designation by the FDA for Childhood Cancer, Neuroblastoma (PRNewswire) - "RedHill Biopharma Ltd...announced that the U.S. Food and Drug Administration (FDA) has granted orphan-drug designation to opaganib for treatment of neuroblastoma, a type of childhood cancer that develops from immature nerve cells and accounts for 15% of all pediatric cancer-related deaths."

Orphan drug • Brain Cancer • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor

Orphan Designation: Treatment of neuroblastoma (FDA) - Date Designated: 08/21/2024

Orphan drug • Neuroblastoma

5-Fluorouracil resistance due to sphingosine kinase 2 overexpression in colorectal cancer is associated with myeloid-derived suppressor cell-mediated immunosuppressive effects. (PubMed, BMC Cancer) - "Our findings suggest that 5-FU treatment combined with simultaneous Spkh2 inhibition by ABC294640 has anti-tumor synergistic effects by influencing multiple effects on tumor cells, T cells, and MDSCs, potentially improving the poor prognosis of colorectal cancer patients."

Journal • Myeloid-derived suppressor cells • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD4 • CD8 • IL6 • SPHK2 • STAT3

DUAL TARGETING OF MCL-1 AND SPHINGOLIPID METABOLISM: CAN IT BE A NOVEL APPROACH FOR AN EFFECTIVE TREATMENT OF ACUTE MYELOID LEUKEMIA? (EHA 2024) - "Specifically, we aimed to investigate the effects of combining S63845, an Mcl-1inhibitor, with either Fingolimod (S1PR antagonist), ABC294640 (Opaganib, SPHK2 inhibitor), or Carmofur(ASAH1 inhibitor) regarding the cell proliferation, cell death, and, notably, on the lipidome via shotgunlipidomics in MV4-11, KG1 and HL60 human AML cell lines. Shotgun lipidomics results showed that S63845 + Opaganib combination altered the lipidome more than theother drug combinations, confirming the data from the cell proliferation and combination index analyses. Overall, our results suggest that dual targeting of Mcl-1 and SPHK2 might be an effective approach in AMLtreatment."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Mantle Cell Lymphoma • Metabolic Disorders • Oncology • ASAH1 • BCL2 • CASP3 • IL6 • SPHK1 • SPHK2 • TGFB1 • TNFA