A Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Clinical Study to Assess the Efficacy and Safety of Sovateltide in Patients With Traumatic Brain Injury
| Registry | NCT07861126, acronym RESTORE-TBI |
|---|---|
| Status | Not yet recruiting |
| Phase | Phase 3 |
| Study type | Interventional; randomized, parallel, masking: quadruple, treatment |
| Enrollment | 214 (Estimated) |
| Sponsor | Pharmazz, Inc. (Industry) |
| Conditions | Traumatic Brain Injury |
| Interventions | Placebo, Sovateltide (Drug) |
| Dates | start 2026-12-01 (estimated), primary completion 2028-02-01 (estimated), completion 2028-03-01 (estimated), first posted 2026-10-06, last updated 2026-10-13 |
Related Papers Related Patents Related Grants Related Experts
All trials for Traumatic Brain Injury All trials of Placebo All trials of Sovateltide
Traumatic brain injury (TBI) remains a leading cause of global disability, yet current clinical management is limited to supportive care and pressure stabilization using hyperosmolar therapies like mannitol and hypertonic saline. These strategies fail to address the destructive cellular cascades that persist long after the initial impact, leaving 66.3% of severe TBI patients with permanent cognitive and neurological deficits. To bridge this critical unmet medical need, the therapeutic focus must shift toward neuroprotective and neuroregenerative agents that actively block secondary injury cascades such as excitotoxicity, apoptosis, and chronic neuroinflammation.
Sovateltide is a selective endothelin-B receptor agonist. It was previously reported to reduce apoptosis, stimulate neurogenesis, and improve functional recovery. Unlike most TBI candidates restricted to preclinical phases, sovateltide possesses a robust human safety and tolerability profile established across Phase I, II, III, and IV ischemic stroke trials.
We conducted a preclinical study in Wistar rats with induced TBI and showed that sovateltide effectively preserved BBB integrity, a critical determinant of post-injury outcomes, and significantly reduced neuronal apoptosis, as evidenced by decreased expression of caspase-3 and caspase-6, key markers of programmed cell death. Treated animals also exhibited notable improvements in neurobehavioral performance, reflecting functional recovery likely attributable to the drug's antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. These results align with earlier evidence showing that ETB receptor activation enhances angiogenesis, neurogenesis, and synaptic remodeling, processes essential for neural repair following brain injury.
The present study has been designed to advance sovateltide (IRL-1620) into a pivotal Phase III clinical trial for acute traumatic brain injury (TBI). With millions affected annually and zero approved neuroprotective pharmacotherapies available, this milestone marks a critical step forward in addressing one of modern medicine's greatest unmet needs. By harnessing our proprietary neural repair discovery platform, sovateltide targets the cascade of secondary cell death while stimulating neurogenesis and angiogenesis. Building on the strong momentum of our ongoing global Phase III RESPECT-ETB study in acute ischemic stroke, this study will further validate the broad therapeutic potential of our endothelin-B receptor platform across severe acute neurovascular conditions.
A traumatic brain injury (TBI) is a form of brain damage that results from an external mechanical force impacting the head or body, such as a sudden blow, jolt, or wound. The injuries could be penetrating (open) ones - commonly seen in motor vehicle accidents, falls, sports injuries, and explosive blasts in which an object such as a bullet, shrapnel, or bone fragment breaches the skull and directly damages brain tissue, or non-penetrating (closed or blunt) ones, which result from rapid acceleration, deceleration, or rotational forces that cause the brain to move within the skull. Based on the timing of the impact and damage, these injuries are categorized as primary or secondary. Primary injuries, such as contusions, lacerations, or hemorrhage, occur at the moment of impact and involve immediate damage. Secondary injury develops over time through complex biochemical and physiological processes such as increased intracranial pressure, cerebral edema, ischemia, excitotoxicity, oxidative stress, and neuroinflammation, which can worsen neurological outcomes later.
According to the Global Burden of Diseases database in 2021, there were 20.84 million incident cases and 37.93 million prevalent cases of TBI worldwide. Between 1990 and 2021, the global number of TBI incidents and prevalent cases increased by 22.6% and 53.3%, respectively; however, the age-standardized incidence rate declined by 0.11%. These rates generally increased with age and were higher in males than in females. The highest age-standardized prevalence and years lived with disability rates were observed in Eastern and Central Europe. Globally, falls were the leading cause of TBI in 2021, followed by road injuries, violence, and exposure to mechanical forces.
Currently, no therapeutic agent is approved for TBI because of the injury's biological complexity, heterogeneity in patient presentation, and limited translation of preclinical success into human trials. Hence, future progress likely depends on developing drugs or combination therapies with multimodal mechanisms of action that support neural cell protection, regeneration, repair, and functional restoration. Moreover, TBI pathophysiology is complex, involving vascular damage, inflammation, apoptosis, and other processes that trigger neuronal damage and death. A thorough understanding of TBI pathophysiology is essential for developing novel therapeutic agents that provide neuroprotection by curbing inflammation, enhancing angiogenesis, reducing hypoxic episodes, excitotoxicity, and apoptosis, and promoting neuroregeneration in injured brain tissue. Endothelin signaling regulates these pathophysiological events in the mammalian neurovascular system; therefore, the endothelin system could be a potent drug-development target in TBI.
Sovateltide (TycamzziTM, IRL-1620, PMZ-1620) is a first-in-class ETB receptor agonist approved in India for treating acute ischemic stroke (AIS), promoting neuroprotection and regeneration via neuron and blood vessel growth. We evaluated the neuroprotective potential of sovateltide in the Marmarou weight-drop rat model of traumatic brain injury (TBI). TBI onset in rats damaged blood-brain barrier (BBB) and increased brain water content, inflammation and oxidative stress. Neuronal damage in the prefrontal cortex and hippocampal subfields (CA1-CA3 and dentate gyrus) was seen on day 1 post-injury. A marked increase in Neurobehavioral Severity Score-Revised (NSS-R), indicating neurological impairment, was also observed. Rats were either treated with sovateltide (5μg/kg) or mannitol (20% w/v) or Normal Saline (5ml/kg) administered three times a day on 1st, 3rd and 6th day after induction of TBI. Animals treated with sovateltide or mannitol showed progressive functional recovery with a significantly reduced NSS-R score compared to untreated TBI rats by day 7. These animals also showed a clear trend toward behavioral improvement; however, anxiety levels and locomotor activity remained comparable. Damage to the BBB, reflected by elevated Evans Blue Dye elution, was substantially reduced in sovateltide-treated rats. Sovateltide exhibited antioxidant activities and reduced malondialdehyde (MDA) levels, restoring superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels to near-normal. Sovateltide-treated rats had decreased inflammatory indicators/mediators (e.g., NF-κB, IL-6, and TNF-α) compared with untreated and mannitol-treated animals. At the tissue level, sovateltide-treated animals had better-preserved neural tissue architecture, like sham animals, than control and mannitol-treated animals. Apoptotic markers caspase-3 and caspase-6 were significantly reduced in sovateltide animals, along with attenuation of astrocytic activation indicated by decreased GFAP in cortical and hippocampal regions. Thus, sovateltide confers multimodal neuroprotection by alleviating oxidative stress, suppressing neuroinflammation, preserving BBB integrity and neuronal morphology, and inhibiting apoptosis following TBI.
A TBI study in Wistar rats found that sovateltide preserved BBB integrity and reduced apoptosis, as evidenced by decreased caspase-3 and caspase-6 expression and improved neurobehavioral outcomes, likely due to its antioxidant and anti-apoptotic properties. Overall, studies show that the endothelin system, particularly ETB receptor signaling, represents a promising therapeutic axis that can address TBI heterogeneity by integrating vascular protection, anti-inflammatory effects, and neural regeneration. Unlike traditional monotherapies that target isolated pathways, ETB activation through sovateltide would offer a multimodal approach to target the full spectrum of TBI, from acute neuroprotection to long-term neural repair.
* Sovateltide stimulates ETB receptors, which are highly expressed during neural development. Research indicates that activating these receptors in the adult brain enhances NPC proliferation and differentiation into mature, functional neurons.
* Effective neurogenesis requires a robust blood supply. Sovateltide promotes the formation of new micro-vessels (angiogenesis) by increasing levels of Vascular Endothelial Growth Factor (VEGF) and Nerve Growth Factor (NGF). This ensures that the "new" brain tissue has the oxygen and nutrient support needed to survive and integrate.
* Sovateltide has been shown to inhibit the pathways that lead to delayed neuronal death. Protecting existing neurons in the "penumbra" (the area surrounding the core injury) limits the eventual size of the brain lesion.
* Research suggests that Sovateltide enhances mitochondrial biogenesis and maintains mitochondrial membrane potential. Since TBI causes massive metabolic failure, stabilizing the cell's "powerhouse" is critical for preventing further tissue loss.
* Stimulation of ETB receptors on the vascular endothelium triggers the release of nitric oxide, leading to vasodilation and improved perfusion to the injured regions.
The pathophysiological similarities between stroke and TBI-specifically the roles of ischemia, inflammation, and the need for remodeling-provide a strong "proof of concept" for the application of sovateltide in TBI.
| Arm | Type | Interventions | Description |
|---|---|---|---|
| The reference product is a matching placebo for sovateltide | Placebo comparator | Drug: Placebo | |
| The test product is sovateltide | Active comparator | Drug: Sovateltide |
Sex: All, ages: 18 Years to 90 Years
Inclusion Criteria: A participant will be eligible for inclusion in the study if the participant fulfills the following criteria: 1. Adult male or female aged 18-90 years 2. Consent must be obtained prior to any study-specific procedure from the participant or, if the participant lacks capacity to provide informed consent, from the participant's Legally Authorized Representative (LAR), in accordance with applicable law and IRB requirements. 3. Clinical diagnosis of closed traumatic brain injury (TBI), classified as moderate to severe, with a post-resuscitation Glasgow Coma Scale (GCS) score of 5 to 13, inclusive, at screening (moderate TBI: GCS 9-13; eligible severe TBI range: GCS 5-8). 4. Radiological confirmation of TBI on neuroimaging (diffuse injury II-V, Marshall's CT Classification). 5. At least one reactive pupil (pinpoint pupils due to opioid pain treatment are considered reactive). 6. The participant is <48 hours from the time of TBI onset when the first dose of sovateltide is administered. The time of TBI onset is when the injury occurred. 7. Reasonable expectation of availability to receive the full sovateltide course of therapy and to be available for subsequent follow-up visits. Exclusion Criteria: A participant will not be considered eligible for inclusion in this study if the participant meets any of the following exclusion criteria: 1. TBI caused by penetrating injury (e.g., gunshot wound) rather than blunt trauma. 2. Isolated epidural hematoma. 3. Suspected or confirmed spinal cord injury. 4. Severe cardiac or hemodynamic instability prior to randomization. 5. Life expectancy of less than 72 hours as determined by the Investigator. 6. Pregnant or lactating women. 7. Known medical history of neurological (other than current TBI) or psychiatric condition that, in the investigator's opinion, would confound the neurological and functional evaluations, lead to further deterioration of neurological status, or interfere with participation in this study. 8. Evidence of any other major life-threatening or serious medical condition, such as severe renal, hepatic, and cardiovascular disease, which would prevent completion of the study protocol, impair the assessment of outcome, or in which sovateltide therapy would be contraindicated or might cause harm to the participant. 9. Concurrent participation in any other therapeutic clinical trial.