Tyvalzi (sovateltide) / Pharmazz, Sun Pharma, Assertio - LARVOL DELTA

Intranasal treatment targeting the brain endothelin system attenuates cognitive decline in diabetic rats after ischemic injury (ISC 2025) - "and either a modified Bederson score 10% on Day 3) were randomized to ETA antagonist BQ-123 (3 µg/100 µl PBS), ETB agonist Sovateltide (5 µg/kg), or vehicle intranasal treatment for 3 days per week until 8 weeks post-stroke (n=6-8)... These results suggest that intranasal stimulation of brain ETB receptors or ETA receptor inhibition can prevent the development of progressive cognitive decline after stroke. While further studies are required to better understand how the brain ET system impacts stroke recovery in diabetes, our findings provide novel insights into potential neuroprotective therapies for VCID."

Preclinical • Alzheimer's Disease • Cardiovascular • CNS Disorders • Cognitive Disorders • Dementia • Diabetes • Ischemic stroke • Metabolic Disorders

Discovery and development of sovateltide, an endothelin-B receptor agonist to treat cerebral stroke patients (ISC 2025) - "The number of patients with NIHSS of 0-5 at 90 days was 67.95% in control and 85.00% in the sovateltide groups (p=0.0114). The ordinal shift in mRS from 0-1 showed an absolute increase of 8% in the favorable outcome of sovateltide compared to the control group, while a shift in mRS from 0-2 showed an absolute increase of 22% in the favorable outcome of sovateltide compared to the control group.Pharmacologically targeting ET-B receptors with sovateltide is safe and effective in improving neurological outcomes in cerebral ischemic stroke patients."

Clinical • Cardiovascular • Ischemic stroke

Updated results from the multicentric, randomized study of sovateltide (Tycamzzi™) in acute cerebral ischemic stroke patients (ISC 2025) - "Sovateltide produced significant improvement in neurological outcomes at 90 days post-treatment in acute cerebral ischemic stroke patients and suggests imminent efficacy trials."

Clinical • Late-breaking abstract • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Diabetes • Hematological Disorders • Hypertension • Ischemic stroke • Metabolic Disorders • EDN1

Developing Topics. (PubMed, Alzheimers Dement) - "These findings suggest that sovateltide treatment promotes regeneration while simultaneously decreasing the pathology associated with Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • Metabolic Disorders • CASP3 • MFN2 • Napsin A • NEUROD1 • SYP

Microglial cell proliferation is regulated, in part, by reactive astrocyte ETBR signaling after ischemic stroke. (PubMed, Exp Neurol) - "In experiments with primary adult astrocytes stimulated by IRL1620, a specific ETBR agonist, we found that ERK1/2 and NFkB mediated the effects of ET on Ang-2 production...In transgenic GFAP-CreER™-EDNRB-fl/fl mice with stroke, conditional knockout of astroglial ETBR significantly decreased the number of proliferating cells in the peri-infarct area with a microglial phenotype (Ki67+/CD11b+). Our results indicate that Ang-2, and possibly other paracrine effectors functioning downstream of astroglial ETBR signaling, are important mediators of microglial cell dynamics after stroke."

Journal • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke • Vascular Neurology • CX3CR1 • EDNRB • GFAP • ITGAM

Efficacy and Safety of Sovateltide in Patients with Acute Cerebral Ischaemic Stroke: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase III Clinical Trial. (PubMed, Drugs) - P3 | "The sovateltide group had a greater number of cerebral ischaemic stroke patients with lower mRS and NIHSS scores at 90 days post-treatment than the control group. This trial supported the regulatory approval of sovateltide in India, but a multinational RESPECT-ETB trial will be conducted for US approval."

Journal • P3 data • Cardiovascular • Cerebral Hemorrhage • Ischemic stroke

Endothelin-1 potentiated constriction in preeclampsia placental veins: Role of ETAR/ETBR/CaV1.2/CALD1. (PubMed, Placenta) - "The present study firstly demonstrated ET-1 induced greater contraction in preeclampsia placental chorionic plate veins via ETAR/ETBR, instead of via weaker CaV1.2. In utero hypoxia promoted plasma ET-1 in fetal lambs and ewe, similar to that in preeclampsia. ET-1, binding with ETAR/ETBR increased CALD1, which was associated with stronger contraction in preeclampsia. The data provided important information in preeclampsia onset."

Journal • Gynecology • CALD • EDN1

SOVATELTIDE DID NOT INFLUENCE THE THROMBOLYTIC ACTIVITY OF T-PA WHEN USED TO TREAT ACUTE ISCHEMIC STROKE (WSC 2024) - "While t-PA by itself or in combination with sovateltide demonstrated 50% clot lysis within 1-2 hours of incubation, the maximum concentration of sovateltide demonstrated less than 5% clot lysis even after 5 hours of incubation. Conclusions The thrombolytic effect of t-PA is not affected by sovateltide, nor does it possess any thrombolytic activity."

Cardiovascular • Ischemic stroke

A NOVEL PHARMACOLOGICAL APPROACH TO TREAT CEREBRAL STROKE (WSC 2024) - "An absolute increase in the favorable outcome of 22% was observed with sovateltide in patients with mRS of 0 to 2. Conclusions Pharmacologically targeting ET-B receptors with sovateltide is safe and effective in improving neurological outcomes in cerebral ischemic stroke patients."

Cardiovascular • Ischemic stroke

RESULTS FROM THE MULTICENTER RANDOMIZED TRIAL TO DETERMINE THE EFFICACY OF SOVATELTIDE IN ACUTE CEREBRAL ISCHEMIC STROKE PATIENTS WITH MISSING VALUES IMPUTED (WSC 2024) - "On day 6, the number of patients with NIHSS scores of 0-5 was 37.18% (29/78) in control and 57.50% (46/80) in the sovateltide group (p=0.0105). Conclusions Sovateltide is efficacious in improving neurological outcomes in ACIS patients."

Clinical • Cardiovascular • Ischemic stroke

SOVATELTIDE REGENERATES AND REPAIRS ISCHEMIC STROKED BRAIN (WSC 2024) - "Conclusions The study demonstrates a unique mechanism of action of sovateltide involving the differentiation of NPCs into neuronal cells and promoting neural cell survival through upregulating specific neuronal markers. Overall, this study provides evidence for the effectiveness of sovateltide in neuronal regeneration and repair in the brain affected by ischemic stroke."

Cardiovascular • Ischemic stroke • MFN2 • NEUROD1

Sovateltide (IRL-1620) enhances motor function and reduces hyperalgesia in a rodent model of spinal cord injury. (EAN 2024) - No abstract available

Preclinical • CNS Disorders • Orthopedics

Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke (clinicaltrials.gov) - P3 | N=514 | Not yet recruiting | Sponsor: Pharmazz, Inc. | Trial completion date: Nov 2025 ➔ Nov 2026 | Trial primary completion date: Aug 2025 ➔ Aug 2026

Trial completion date • Trial primary completion date • Cardiovascular • Ischemic stroke

The Effects of IRL-1620 in Post-ischemic Brain Injury: A Systematic Review and Meta-analysis of Experimental Studies. (PubMed, Neurocrit Care) - "According to the above, in animal MCAO models, IRL-1620 enhanced neurogenesis and neuroprotection and improved outcome. Future studies are needed to expand our understanding of its effects in human study participants with acute ischemic stroke as well as in other common causes of cerebral ischemia including cardiac arrest."

Journal • Retrospective data • Review • Cardiovascular • CNS Disorders • Ischemic stroke • Vascular Neurology

Study to Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke (clinicaltrials.gov) - P4 | N=160 | Recruiting | Sponsor: Pharmazz, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Ischemic stroke

Sovateltide (ILR-1620) Improves Motor Function and Reduces Hyperalgesia in a Rat Model of Spinal Cord Injury. (PubMed, Neurocrit Care) - "This study suggests that sovateltide may offer neuroprotective effects, enhancing neurogenesis and angiogenesis. Furthermore, it may possess anti-inflammatory and antinociceptive properties. Future clinical trials are needed to validate these findings, but sovateltide shows promise as a potential therapeutic strategy to improve functional outcomes in SCI. Sovateltide, an endothelin B receptor agonist, exhibits neuroprotective properties, enhancing motor recovery and ameliorating hyperalgesia in a rat SCI model. These findings could pave the way for innovative pharmacological interventions for SCI in clinical settings."

Journal • Preclinical • CNS Disorders • Orthopedics

To evaluate the effect of endothelin receptor agonist IRL-1620 alone and in combination with donepezil in modulating neurodegeneration elicited by amyloid-β in rats. (PubMed, Exp Neurol) - "The combination treatment exhibited enhanced effects compared to monotherapy, highlighting its potential promising therapeutic approach. Additional research is required to understand the mechanisms behind these synergistic benefits and to establish the ideal dosage and duration of therapy for therapeutic applications."

Combination therapy • Journal • Preclinical • Alzheimer's Disease • CNS Disorders

Advances in Therapies to Treat Neonatal Hypoxic-Ischemic Encephalopathy. (PubMed, J Clin Med) - "Understanding the cellular and molecular aspects of the different phases of HIE is crucial for developing new interventions and therapeutics. This review aims to discuss the pathophysiology of HIE, therapeutic hypothermia (TH), the only approved therapy for HIE, ongoing developments of adjuvants for TH, and potential future drugs for HIE."

Journal • Review • Cardiovascular • Cerebral Palsy • CNS Disorders • Inflammation • Vascular Neurology

Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke (clinicaltrials.gov) - P3 | N=444 | Not yet recruiting | Sponsor: Pharmazz, Inc. | Initiation date: Aug 2023 ➔ Nov 2023

Trial initiation date • Cardiovascular • Ischemic stroke

Gestational intermittent hypoxia induces endothelial dysfunction and hypertension in pregnant rats: role of endothelin type B receptor†. (PubMed, Biol Reprod) - "However, mIH and sIH rats exhibited impaired endothelium-dependent vasorelaxation responses to ETBR agonist IRL-1620 and acetylcholine compared to controls...This was associated with elevated circulating NOx levels, enhanced ETBR expression, increased eNOS activation, and improved vasodilation responses. Our data suggested that IH exposure during gestation increases BP in pregnant rats by suppressing ETBR-mediated signaling, providing a molecular mechanism linking IH and gestational hypertension."

Journal • Preclinical • Cardiovascular • Hypertension • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder • EDN1 • NOS3

Pharmazz Inc. and Sun Pharma enter into licensing agreement for introducing Tyvalzi (Sovateltide) in India (GlobeNewswire) - "Pharmazz, Inc...announced that it has entered into a license agreement with Sun Pharmaceutical Industries Limited...to commercialise a first-in-class innovative drug, Tyvalzi™ (Sovateltide) in India. Developed by Pharmazz for potential global use, Sovateltide is indicated for treating cerebral ischemic stroke....As per agreement terms, Sun Pharma is granted rights for marketing Sovateltide in India under the brand name Tyvalzi™ (Sovateltide). Pharmazz will be entitled to upfront and milestone payments, including royalties."

Licensing / partnership • Cardiovascular • CNS Disorders • Ischemic stroke

Endothelin B Receptor Agonist, Sovateltide, Promotes Neural Regeneration by Improving Mitochondria Function in a Neonatal Rat Model of Hypoxic-Ischemic Encephalopathy (AHA 2022) - "Stimulation of ETBR by sovateltide promotes neural regeneration via maintaining mitochondrial dynamics, indicating a potential neuroprotective effect and may, therefore, offer a legitimate therapeutic target for the treatment of neonatal HI brain injury."

Preclinical • Cardiovascular • CNS Disorders • Metabolic Disorders • Vascular Neurology • MFN2 • NEUROD1 • NEUROD1

Sovateltide: First Approval. (PubMed, Drugs) - "In May 2023, sovateltide was approved in India for the treatment of cerebral ischemic stroke within 24 h of stroke onset. This article summarizes the milestones in the development of sovateltide leading to this first approval for use in patients with ACIS."

Journal • Review • Alzheimer's Disease • Cardiovascular • CNS Disorders • Ischemic stroke • Musculoskeletal Diseases • Orthopedics • EDN1

Sovateltide prevents loss of spatial memory retention and reduces neuroinflammation in a transgenic mouse model of Alzheimer's disease (AAIC 2023) - "Altogether, our work suggests a novel strategy by improving memory deficits and reducing Aβ plaque load and neuroinflammation by targeting ETBR and suggests that sovateltide could be an effective therapeutic option to treat AD."

Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation • IL10 • IL2 • IL4 • IL6

Sovateltide prevents loss of spatial memory retention and reduces neuroinflammation in a transgenic mouse model of Alzheimer's disease (AAIC 2023) - "Altogether, our work suggests a novel strategy by improving memory deficits and reducing Aβ plaque load and neuroinflammation by targeting ETBR and suggests that sovateltide could be an effective therapeutic option to treat AD."

Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation • IL10 • IL2 • IL4 • IL6