senicapoc (ICA-17043) / EMD Serono - LARVOL DELTA

SENIPERA: Senicapoc and Perampanel for Newly Diagnosed Glioblastoma (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: Aarhus University Hospital | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Early-stage clinical trial investigating the individual and combined effect of two drugs, senicapoc and perampanel, as part of the treatment for newly diagnosed glioblastoma, which is an aggressive brain tumor (clinicaltrialsregister.eu) - P1 | N=36 | Not yet recruiting | Sponsor: Region Midtjylland

New P1 trial • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Senicapoc in Alzheimer's Disease (clinicaltrials.gov) - P2 | N=55 | Recruiting | Sponsor: University of California, Davis | Trial primary completion date: Dec 2025 ➔ Jun 2026

Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

SENIPERA: Senicapoc and Perampanel for Newly Diagnosed Glioblastoma (clinicaltrials.gov) - P1 | N=36 | Not yet recruiting | Sponsor: Aarhus University Hospital

New P1 trial • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

RESCUE: Efficacy and Safety of SIL-8301 for Control of Hemolysis in a Uniform Sickle Cell Disease Endotype (clinicaltrials.gov) - P2 | N=105 | Not yet recruiting | Sponsor: Biossil Inc.

New P2 trial • Anemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Biologic Assessment of RBC Biology and Neutrophil Activation: Correlation with Sickle Cell Disease Activity (ASH 2023) - "A subset of samples were examined for RBC reactive oxygen species (ROS) content and adhesivity to laminin with and without stimulation by epinephrine...Interestingly, we also found that RBC [ATP] was lower in the RBCs of patients with higher total Hb, while it was higher in individuals with higher retic counts, suggesting that more long-lived RBCs have diminished [ATP], despite the fact that both [ATP] and total Hb have been reported to rise substantially after treatment with pyruvate kinase activators etavopivat and mitapivat...Similarly, senicapoc, which also reduces hemolysis, although by a different mechanism, failed to lessen VOE frequency...Anti-adhesive agents (crizanlizumab, rivipansel, sevuparin) have thus far failed to yield marked improvements in VOE frequency, but our results suggest that, in order to decrease the frequency of VOEs, it is not sufficient to reduce sickling and hemolysis. On the other hand, higher HbF levels were associated with lower admission..."

Cardiovascular • Genetic Disorders • Hematological Disorders • Pulmonary Arterial Hypertension • Pulmonary Disease • Renal Disease • Respiratory Diseases • Sickle Cell Disease • MMP9

Validation of Townes As Mice As a Model of Chronic Kidney Disease and Venous Thrombosis Associated with Sickle Cell Trait (ASH 2023) - "Senicapoc, an oral Gardos channel inhibitor, was administered twice daily (20mg/kg, bid) for 2 weeks to prevent AS RBC dehydration and subsequent sickling...In aggregate, our data demonstrate that Townes AS murine nephropathy closely mimics the renal abnormalities (impaired urinary concentration and albuminuria with later onset loss of GFR) described in humans with SCT. Furthermore, we have established a mouse model of the venous thrombotic complications associated with SCT and have demonstrated that hypoxia-induced sickling of RBCs may contribute to enhanced VT observed in AS mice."

Preclinical • Cardiovascular • Chronic Kidney Disease • Fibrosis • Genetic Disorders • Glomerulonephritis • Hematological Disorders • Immunology • Metabolic Disorders • Nephrology • Renal Disease • Sickle Cell Disease • Thrombosis • KIM1

Targeting Gardos Channel to Regulate Lipid Scrambling in Red Blood Cells (ASH 2024) - "Although Gardos inhibition is a promising strategy to decouple PIEZO1-TMEM16F interaction and prevent PS exposure, Senicapoc is not a suitable Gardos inhibitor for this purpose due to its unknown off-target effect. More specific Gardos inhibitors are needed to prevent PS exposure in red cell disorders."

Anemia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Sickle Cell Disease • ANO6

Kcnn4/KCa3.1 inhibition blunts polycystic kidney disease progression in mouse models. (PubMed, JCI Insight) - "Importantly, senicapoc treatment of Pkd1 mouse models phenocopied most effects of Kcnn4 inactivation. This first study on the efficacy of KCa3.1 inhibition in PKD progression recommends senicapoc as a clinical trial candidate for ADPKD."

Journal • Preclinical • Autosomal Dominant Polycystic Kidney Disease • Fibrosis • Gene Therapies • Genetic Disorders • Immunology • Nephrology • Polycystic Kidney Disease • Renal Disease • KCNN4 • PKD1 • PRKD1

Targeting GluN2B-containing NMDA receptors to interact with stress pathways and Ca2+-regulated K+ channels in murine islets of Langerhans. (PubMed, Eur J Pharmacol) - "KCa3.1 and KCa1.1 channels were identified as main constituents of the NMDA-induced K+ current by specific inhibition with senicapoc or paxilline...The latter was partially mimicked by the ER-stress chaperon and mitochondrial stabilizer tauroursodeoxycholic acid but not by solely scavenging mitoROS or unselective inhibition of NADPH oxidases. In summary, prolonged stimulation of GluN2B-containing NMDA receptors mediates β-cell dysfunction on the level of ion channel coupling and multiple stress responses. Targeting this subunit protects against most of these islet-cell damaging effects and could be an additional option for the treatment of type 2 diabetes."

Journal • Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • GRIN2A • GRIN2B

Visualization of KCa3.1 Channels in Tumor Cells by Optimized Senicapoc-Bodipy Conjugates. (PubMed, ACS Pharmacol Transl Sci) - "MD simulations showed weaker interactions of the amide moiety of 16 with Thr250, explaining the lower channel inhibition of the open-pore blocker 16 compared to senicapoc (1). Due to their optimal imaging properties, high specificity, balanced lipophilicity/hydrophilicity, and sufficient water solubility, senicapoc-bodipy conjugates 7a and 16 represent innovative diagnostic tools to image KCa3.1 channels."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

FIBROPOC: Senicapoc in Patients With Worsening Fibrotic Interstitial Lung Disease (clinicaltrials.gov) - P2 | N=140 | Recruiting | Sponsor: Vejle Hospital | Not yet recruiting ➔ Recruiting

Enrollment open • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases

Red blood cells sickling contributes to the enhanced venous thrombosis in sickle cell trait mice (ISTH 2025) - "We previously demonstrated that enhanced VT formation in humanized SCT mice was attenuated by the Gardos channel inhibitor, Senicapoc (SEN)...Treatment with SEN (green line) decreased the PoS and increased the Elmax demonstrating that SEN improved ION-induced AS RBC dehydration and rendering them less prone to sickling (Fig2B). Table or Figure Upload"

Preclinical • Cardiovascular • Hematological Disorders • Thrombosis

Dehydrated Hereditary Stomatocytosis (DHS): A Rare Inherited Hemolytic Disorder With Unusual Hypochromic Microcytic Anemia. (PubMed, Cureus) - "Senicapoc has been used recently to treat DHS as it showed activity against RBC dehydration in vitro; however, its clinical outcome is not established. In this study, we report an unusual case of a 10-year-old male child who was misdiagnosed with iron deficiency anemia (IDA) for three years, despite persistent anemia and unresponsiveness to iron therapy. The diagnosis was done using whole exome sequencing (WES)."

Journal • Anemia • Hematological Disorders

KCa3.1 Contributes to Neuroinflammation and Nigral Dopaminergic Neurodegeneration in Experimental models of Parkinson's Disease. (PubMed, bioRxiv) - "Pharmacological inhibition of KCa3.1 via senicapoc or TRAM-34 inhibits KCa3.1 channel activity and the associated reactive microglial phenotype in response to aggregated αSyn, as well as ameliorates of PD like pathology in diverse PD mouse models...Moreover, reduced neuroinflammation and subsequent PD-like neuropathology were observed in SYN AAV inoculated KCa3.1 knockout mice. Together, these findings suggest that KCa3.1 inhibition represents a novel therapeutic strategy for treating patients with PD and related α-synucleinopathies."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Inflammation • Lewy Body Disease • Movement Disorders • Parkinson's Disease • STAT1

FIBROPOC: Senicapoc in Patients With Worsening Fibrotic Interstitial Lung Disease (clinicaltrials.gov) - P2 | N=140 | Not yet recruiting | Sponsor: Vejle Hospital | Initiation date: Jan 2025 ➔ May 2025

Trial initiation date • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases

Administration of the KCa channel activator SKA-31 improves endothelial function in the aorta of atherosclerosis-prone mice. (PubMed, Front Pharmacol) - "Treatment of Apoe-/- HFD mice with SKA-31, but not senicapoc, restored maximal relaxation to the WT level. Phenylephrine-evoked contraction was similar in WT and vehicle/drug treated Apoe-/- mice, as was the maximal relaxation induced by the endothelium-independent vasodilator sodium nitroprusside...Fatty plaque formation, tissue collagen, α-smooth muscle actin and resident macrophages in the aortic sinus were also unaltered by either treatment vs. vehicle treated Apoe-/- HFD mice. Our data show that prolonged administration of the KCa channel activator SKA-31 improved endothelial function without modifying fatty plaque formation in the aorta of Apoe-/- mice."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • APOE • KCNN4 • NOS3

TGFβ1 generates a pro-fibrotic proteome in human lung parenchyma that is sensitive to pharmacological intervention. (PubMed, Eur J Pharmacol) - "A pro-fibrotic proteome is induced in human lung parenchyma exposed to TGFβ1, sensitive to pharmacological intervention. This approach has the potential to enhance therapeutic drug screening for IPF treatment."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • TGFB1

Fluorescent Probes to Image the KCa3.1 Channel in Tumor Cells. (PubMed, Pharmaceutics) - "It was hypothesized that the antibody binds selectively at the closed channel (58.5%), whereas the senicapoc-bodipy conjugate 10b binds selectively at the open channel (41.5%). The ratio 58.5:41.5 reflects the ratio of the ion channel in closed and open conformations."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

The potential of Senicapoc, a KCNN4 inhibitor, for the prevention and treatment of breast cancer. (LCC 2025) - "The mode of action is postulated to be via macrophages as we see changes in their numbers, polarization and function as determined by scRNAseq, flow cytometric analysis and functional ex-vivo analysis. These results provide a rationale for clinical testing of Senicapoc (and other macrophage modulators) for treating triple negative breast cancers."

Anemia • Asthma • Breast Cancer • Genetic Disorders • Hematological Disorders • Immunology • Oncology • Respiratory Diseases • Sickle Cell Disease • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • KCNN4

KCa3.1 modulation as a potential therapeutic target for the prevention of vein graft disease following coronary artery bypass grafting (AHA 2024) - "The expression of KCa3.1 is upregulated in LSV following acute arterial haemodynamics and targeting KCa3.1 using senicapoc can reduce VGD by modulating inflammation and EndMT."

Fibrosis • Immunology • Inflammation • CCL2 • CXCL8 • IL1B • IL6 • KCNN4 • TGFB1 • TNFA

FIBROPOC: Senicapoc in Patients With Worsening Fibrotic Interstitial Lung Disease (clinicaltrials.gov) - P2 | N=140 | Not yet recruiting | Sponsor: Vejle Hospital

New P2 trial • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases

Potassium dynamics in sickle cell anemia: clinical implications and pathophysiological insights. (PubMed, Ann Med Surg (Lond)) - "Inhibitors of the Gardos channel, such as senicapoc, have demonstrated potential in reducing sickling and hemolysis. Additionally, hydration therapy plays a crucial role in maintaining electrolyte balance and preventing RBC dehydration. A comprehensive approach that includes monitoring and correcting electrolyte imbalances, along with standard treatments like hydroxyurea and blood transfusions, is essential for effective disease management."

Journal • Review • Anemia • Cardiovascular • Genetic Disorders • Hematological Disorders • Pain • Sickle Cell Disease

Senicapoc in Alzheimer's Disease (clinicaltrials.gov) - P2 | N=55 | Recruiting | Sponsor: University of California, Davis | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • CRP • IL10 • IL1B • IL6 • TNFA

Prothrombotic mechanisms associated with enhanced venous thrombosis in sickle cell trait (ISTH 2024) - "We previously demonstrated that sickling of SCT red blood cells (RBCs) contributes to enhanced VT in humanized SCT mice that was attenuated by Senicapoc, an anti-sickling agent... As shown in Figure 1A-C, sickled SCT RBCs express phosphatidylserine distributed over the cell surface. This is associated with shortening of the Russell Viper Venom time, indicative of phosphatidylserine-dependent prothrombinase activity (Figure 1D). The weight of thrombi formed 24 hours after IVC stasis was significantly increased (p < 0.01) in AS mice (n=8) compared to AA controls (n=7)."

Cardiovascular • Hematological Disorders • Thrombosis • Venous Thromboembolism