Xiflam (tonabersat) / Sawai Pharma, InflammX - LARVOL DELTA

Influence of tear fluid properties on physicochemical, mucoadhesion and ocular penetration characteristics of transfersomes. (PubMed, Eur J Pharm Biopharm) - "Specifically, the effect of tear fluid pH and osmolarity on vesicle size, polydispersibility index (PDI) and zeta potential (ZP) of unloaded as well as curcumin- and tonabersat-loaded TFS were studied...Deeper tissue penetration was observed for curcumin TFS suspended in water compared to TFS suspended in healthy tears, with significantly less penetration for TFS mixed with DED tears. This study confirmed that tear fluid properties significantly influence TFS characteristics and thus their penetration ability, highlighting the importance of evaluating ocular drug delivery systems under physiological conditions that reflect the disease state."

Journal • Dry Eye Disease • Ophthalmology

Evaluation of ocular tolerability and bioavailability of tonabersat transfersomes ex vivo. (PubMed, Drug Deliv Transl Res) - "Overall, this study demonstrates that TFS are well tolerated on the ocular surface and have the potential for sustained and targeted drug delivery to ocular tissues. Thus, they present a promising alternative for safe and effective ocular drug delivery."

Journal • Preclinical

Formulation and Characterization of Transfersomes for Ocular Delivery of Tonabersat. (PubMed, Pharm Dev Technol) - "Drug penetration between different ocular tissues was compared, shedding light on the penetration mechanism of TFS into the eye. Overall, this study demonstrates that TFS provide a promising alternative for the ocular delivery of tonabersat."

Journal

Targeted Cx43 therapeutics reduce NLRP3 inflammasome activation in rat burn injury. (PubMed, Burns) - "This study used a deep partial thickness rat burn model to evaluate the effect of Cx43 antisense oligodeoxynucleotides (Cx43asODN) or the Cx43 hemichannel blocker Tonabersat for the inhibition of inflammasome activation and their use as potential treatments for burn injury...Collectively, our findings suggest a possible involvement of the Cx43-mediated NLRP3 inflammasome pathway via P2X7 activation in early burn wound healing. This indicates that targeting Cx43 may have a potential therapeutic effect to improve healing outcomes."

Journal • Preclinical • Fibrosis • Immunology • Inflammation • Thermal Injury • NLRP3

AN: Evaluation of Tonabersat for DME (clinicaltrials.gov) - P2 | N=128 | Active, not recruiting | Sponsor: Jaeb Center for Health Research | Recruiting ➔ Active, not recruiting | Trial completion date: May 2025 ➔ Nov 2025 | Trial primary completion date: Nov 2024 ➔ Jun 2025

Enrollment closed • Trial completion date • Trial primary completion date • Diabetic Macular Edema • Ophthalmology

Tonabersat enhances temozolomide-mediated cytotoxicity in glioblastoma by disrupting intercellular connectivity through connexin 43 inhibition. (PubMed, Mol Oncol) - "In conclusion, TO disrupts TM-based network connectivity via GJ inhibition and renders glioblastoma cells more susceptible to cytotoxic therapy. Given its previous use in clinical trials for migraine therapy, TO might harbor the potential of bridging the idea of a GJ-targeted therapeutic approach from bench to bedside."

Journal • Brain Cancer • CNS Disorders • CNS Tumor • Glioblastoma • Migraine • Oncology • Pain • Solid Tumor

Development and validation of stability-indicating HPLC method for assay of tonabersat in pharmaceutical formulations. (PubMed, Methods) - "No chemical degradation was observed in either formulation on storage. Thus, the method was sensitive, specific, and suitable for stability testing of tonabersat in pharmaceutical formulations."

Journal

Tonabersat suppresses priming/activation of the NOD-like receptor protein-3 (NLRP3) inflammasome and decreases renal tubular epithelial-to-macrophage crosstalk in a model of diabetic kidney disease. (PubMed, Cell Commun Signal) - "Using a model of DKD, we report for the first time that high glucose and inflammatory cytokines trigger aberrant Cx43 hemichannel activity, events that instigate NLRP3-induced inflammation in RPTECs and epithelial-to-macrophage crosstalk. Recapitulating observations previously reported in diabetic retinopathy, these data suggest that Cx43 hemichannel blockers (i.e., Tonabersat) may dampen multi-system damage observed in secondary complications of diabetes."

Journal • Diabetes • Diabetic Nephropathy • Diabetic Retinopathy • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • Retinal Disorders • GJA1 • NLRP3

Featured Presentation: Historical Perspective on Migraine Treatment* (AHS 2024) - "Knowledge of regional cerebral blood flow changes suggesting cortical spreading depression led to tonabersat with prophylactic effect in migraine with- but not without aura (not marketed). The invention of a human migraine provocation model showed possibilities in the nitric oxide triggered cascade (not yet exploited) and strongly supported the development of CGRP antagonistic drugs. The same model has suggested many novel targets for drug development in migraine, most notably PACAP(validated) and potassium channels"

CNS Disorders • Depression • Migraine • Pain • Psychiatry • ADCYAP1

Study of Xiflam™ Treatment in Patients Post COVID-19 Infection Suffering From What is Known as Long COVID (LC) (clinicaltrials.gov) - P2 | N=15 | Recruiting | Sponsor: Inflammx Therapeutics Inc

New P2 trial • Infectious Disease • Novel Coronavirus Disease

Integrating and optimizing tonabersat in standard glioblastoma therapy: A preclinical study. (PubMed, PLoS One) - "Glioblastoma (GB), a highly aggressive primary brain tumor, presents a poor prognosis despite the current standard therapy, including radiotherapy and temozolomide (TMZ) chemotherapy. The study suggests tonabersat's potential to reduce tumor invasiveness, providing a new avenue for GB treatment. In conclusion, this preclinical investigation highlights tonabersat's potential as an effective adjuvant treatment for GB, and its established safety profile from clinical trials in migraine treatment presents a promising foundation for further exploration."

Journal • Preclinical • Brain Cancer • CNS Disorders • CNS Tumor • Glioblastoma • Glioma • Migraine • Oncology • Pain • Solid Tumor

Inhibition of intercellular communication via gap junctions renders medulloblastoma cells more susceptible for cytotoxic therapy (DKK 2024) - "Meclofenamate and Tonabersat were used as clinically-feasible pharmacological GJ-blockers. Inhibition of intercellular GJ renders MB cells more susceptible for lomustine-mediated cytotoxicity. GJ-targeted approaches might constitute a novel treatment strategy for MB."

Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • TERC

Tonabersat enhances temozolomide-mediated cytotoxicity in glioblastoma by disrupting intercellular connectivity through connexin 43 inhibition (DKK 2024) - "TO demolishes TM-based network connectivity and renders glioblastoma cells more susceptible for cytotoxic therapies. Given its previous use in clinical trials for migraine therapy, TO might harbor the potential of bridging the idea of a gap junction-targeted therapeutic approach from bench to bedside."

Brain Cancer • CNS Disorders • CNS Tumor • Glioblastoma • Migraine • Oncology • Pain • Solid Tumor

Tonabersat Significantly Reduces Disease Progression in an Experimental Mouse Model of Multiple Sclerosis. (PubMed, Int J Mol Sci) - "MOG EAE mice showed clinical signs of MS, but MOG EAE mice treated with tonabersat retained behavior closer to normal. These data suggest that clinical trial phase IIb-ready tonabersat may merit further investigation as a promising candidate for MS treatment."

Journal • Preclinical • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • Solid Tumor • GFAP • MBP • NLRP3

Blockade of connexin hemichannels with tonabersat protects against mild hypoxic ischemic brain injury in neonatal rats. (PubMed, Exp Neurol) - "Blockade of connexin hemichannels with tonabersat significantly reduced mild HI injury in the hippocampus and white matter, without causing hypothermia."

Journal • Preclinical • Cardiovascular • CNS Disorders • Solid Tumor • Vascular Neurology • CA3

AN: Evaluation of Tonabersat for DME (clinicaltrials.gov) - P2 | N=128 | Recruiting | Sponsor: Jaeb Center for Health Research | Not yet recruiting ➔ Recruiting

Enrollment open • Diabetic Macular Edema • Ophthalmology

Orally Delivered Connexin43 Hemichannel Blocker, Tonabersat, Inhibits Vascular Breakdown and Inflammasome Activation in a Mouse Model of Diabetic Retinopathy. (PubMed, Int J Mol Sci) - "However, the tonabersat treatment in the inflammatory NOD mice significantly reduced macrovascular abnormalities, hyperreflective foci, sub-retinal fluid accumulation, vascular leak, inflammation, and inflammasome activation. These findings suggest that tonabersat may be a safe and effective treatment for DR."

Journal • Preclinical • Diabetes • Diabetic Retinopathy • Immunology • Inflammation • Metabolic Disorders • Obesity • Ocular Inflammation • Oncology • Retinal Disorders • IL1B • NLRP3

AN: A Phase 2 Evaluation of Tonabersat for DME (clinicaltrials.gov) - P2 | N=128 | Not yet recruiting | Sponsor: Jaeb Center for Health Research

New P2 trial • Diabetic Macular Edema • Ophthalmology

Blocking connexin-43 hemichannel-mediated ATP release reduces communication within and between tubular epithelial cells and medullary fibroblasts in a model of diabetic nephropathy. (PubMed, Diabet Med) - "Tonabersat-sensitive hemichannel-mediated ATP release enhances TGFβ1-driven heterotypic cell-cell interaction and favours myofibroblast activation. The data supports the potential benefit of Cx43 inhibition in reducing tubulointerstitial fibrosis in late-stage diabetic nephropathy."

Journal • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Nephrology • Renal Disease • TGFB1

Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS. (PubMed, Proc Natl Acad Sci U S A) - "SignificanceOur results demonstrate that connexin 43 hemichannels are the conduits for amyotrophic lateral sclerosis (ALS) astrocyte-mediated motor neuron toxicity and disease spread, acting as a common mechanism that can target both familial ALS and sporadic ALS populations. Furthermore, our present work provides proof of principle that tonabersat, as a drug already studied in clinical trials for other indications, could serve as a potential ALS therapeutic."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

Blocking connexin43 hemichannels prevents TGF-β2 upregulation and epithelial-mesenchymal transition in retinal pigment epithelial cells. (PubMed, Cell Biol Int) - "To determine whether open Cx43 hemichannels may enable EMT of RPE cells and thus result in BRB breakdown, ARPE-19 cells were either challenged with high glucose plus the inflammatory cytokines IL-1β and TNFα (HG + Cyt) to simulate DR or treated with the Cx43 hemichannel blocker tonabersat alongside the HG + Cyt challenge...All of these changes were significantly reduced with tonabersat treatment, which also prevented HG + Cyt-induced TGF-?2 release. In conclusion, Cx43 hemichannel block with tonabersat attenuated both TGF-?2 release and RPE EMT under disease-mimicking conditions, offering the potential to ameliorate the progression of EMT-associated retinal diseases."

Journal • Diabetes • Diabetic Retinopathy • Ophthalmology • Retinal Disorders • IL1B • TGFB1 • TNFA

Differential Action of Connexin Hemichannel and Pannexin Channel Therapeutics for Potential Treatment of Retinal Diseases. (PubMed, Int J Mol Sci) - "The analysis showed that treatment with tonabersat alone was better than probenecid alone at restoring retinal function in the light-damaged retina model. The results assist in the interpretation of the differential action of connexin hemichannel and pannexin channel therapeutics for potential treatment of retinal diseases."

Journal • Immunology • Inflammation • Ocular Inflammation • Ophthalmology • Retinal Disorders • GFAP

Tonabersat Inhibits Connexin43 Hemichannel Opening and Inflammasome Activation in an In Vitro Retinal Epithelial Cell Model of Diabetic Retinopathy. (PubMed, Int J Mol Sci) - "It also prevented the release of proinflammatory cytokines IL-1β, VEGF, and IL-6. Tonabersat therefore has the potential to reduce inflammasome-mediated inflammation in diabetic retinopathy."

Journal • Preclinical • Diabetes • Diabetic Retinopathy • Immunology • Inflammation • Retinal Disorders • IL18 • IL1B • IL6 • NLRP1 • TNFA

Gap junctions contribute to anchorage-independent clustering of breast cancer cells (AACR 2018) - "...We next show that pharmacological inhibition of GJIC using Tonabersat and Meclofenamate both reduces calcein transfer and delays clustering of MCF7 cells... Our results demonstrate that GJIC are involved at the earliest stages of the anchorage-independent clustering process. They shed new light on the regulatory mechanisms that could modulate the formation of clusters of circulating tumor cells."

Breast Cancer

Connexin43 hemichannel block inhibits NLRP3 inflammasome activation in a human retinal explant model of diabetic retinopathy. (PubMed, Exp Eye Res) - "Furthermore, we showed that by blocking connexin43 hemichannels with the hemichannel modulator, tonabersat we were able to prevent NLRP3 inflammasome complex aggregation, Müller cell activation, as well as release of pro-inflammatory cytokines and VEGF. This further supports the possible use of connexin43 hemichannel blockers as potential new therapies for DR."

Journal • Diabetes • Diabetic Retinopathy • Immunology • Inflammation • Metabolic Disorders • Retinal Disorders • IL1B