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

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

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

Connexin therapeutics: blocking connexin hemichannel pores is distinct from blocking pannexin channels or gap junctions. (PubMed, Neural Regen Res) - "Blocking the different channel types has distinct physiological and pathological implications and this review describes current knowledge of connexin and pannexin protein channels, their function as channels and possible mechanisms of the channel block effect for the latest therapeutic compounds. We summarize the evidence implicating pannexins and connexins in disease, considering their homeostatic versus pathological roles, their contribution to excesive ATP release linked to disease onset and progression."

Journal • Review

Upsher-Smith launches online community resource program for patients living with seizure clusters (Multivu) - “Upsher-Smith Laboratories…announced a new educational program created for patients living with seizure clusters, as well as their families and friends. The initiative—called Seizure Clusters Connect™—uses traditional and social media to offer patients and their caregivers a community for learning and support….Upsher-Smith's central nervous system (CNS) pipeline includes a number of investigational drug programs for various indications within epilepsy, including USL255, USL260, and USL261.”

eHealth • Epilepsy

Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. (PubMed) - Nature - "As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis."

Journal • Biosimilar • Triple Negative Breast Cancer

Gap junctions contribute to anchorage-independent clustering of breast cancer cells. (PubMed, BMC Cancer) - "Our results demonstrate that GJIC are involved from the earliest stages of anchorage-independent cancer cell aggregation. They also give insights into the regulatory mechanisms that could modulate the formation of clusters of circulating tumor cells."

Journal • Biosimilar • Breast Cancer • Oncology • Solid Tumor

Additive effect of tonabersat on standard medical treatment in glioblastoma: preliminary results (EANO 2018) - "Currently, standard medical treatment consists of maximal surgical resection followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Evaluation of tumor growth showed a trend towards longer stagnation of the tumor volume in the connexin modulator group compared to the standard medical treatment group, which may indicate the possible additive effect of tonabersat."

Biosimilar • Brain Cancer • Oncology • Solid Tumor

Adjuvant therapeutic potential of tonabersat in the standard treatment of glioblastoma: A preclinical F98 glioblastoma rat model study. (PubMed, PLoS One) - "Our results demonstrate a therapeutic potential of tonabersat for the treatment of GB when used in combination with radiotherapy and temozolomide chemotherapy."

Journal

Targeting connexin hemichannels to control the inflammasome: the correlation between connexin43 and NLRP3 expression in chronic eye disease. (PubMed, Expert Opin Ther Targets) - "Expert Opinion: In over 25 different animal models of disease, connexin hemichannel regulation has shown therapeutic benefit, and at least one oral connexin hemichannel blocker, tonabersat (Xiflam), is Phase II ready with safety evidence in over 1000 patients. Regulating the connexin hemichannel provides a means to move quickly into clinical trials designed to ameliorate the progression of devastating chronic diseases of the eye, but also elsewhere in the body."

Journal

Connexin Hemichannel Block Using Orally Delivered Tonabersat Improves Outcomes in Animal Models of Retinal Disease. (PubMed, Neurotherapeutics) - "Inflammation was also reduced and retinal electrical function restored. Tonabersat regulates assembly of the inflammasome (NLRP3) through Connexin43 hemichannel block, with the potential to reduce inflammation, restore vascular integrity and improve anatomical along with some functional outcomes in retinal disease."

Journal • Preclinical