Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke

A Multicentric, Randomized, Double-blind, Parallel, Placebo-controlled Phase III Study to Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke.

Extensive research is being conducted in search of neuroprotective agents for possible use in the acute phase of stroke and agents that can be used for neurorepair in later stages of stroke. Several trials have been conducted and are in progress using different pharmacological agents, but none of the studies involve the stimulation of ETB receptors to treat cerebral ischemic stroke. Sovateltide (IRL-1620, PMZ-1620) has been effective in animal models of cerebral ischemic stroke. Its safety and tolerability have been demonstrated in a human phase I study with 7 subjects. Clinical phase II and III results indicate that sovateltide is a novel, first-in-class, highly effective drug candidate for treating cerebral ischemic stroke. Safety and significant efficacy in improving the National Institutes of Health Stroke Scale (NIHSS), Modified Rankin scale (mRS), and Barthel index (BI) obtained in phase II and III studies in patients with cerebral ischemic stroke in India are convincing and encouraged us to investigate its safety and efficacy in cerebral ischemic stroke patients in the United States. Therefore, the plan is to conduct a phase III clinical study to evaluate the safety and efficacy of sovateltide therapy along with standard of care in patients of acute ischemic stroke.

A stroke is a syndrome defined as an abrupt neurological outburst due to impaired blood flow to part of the brain. There are two types of stroke: hemorrhagic stroke and ischemic stroke. A hemorrhagic stroke follows the rupture of a weakened blood vessel in the brain causing accumulation of blood and compression of the surrounding brain tissue. An ischemic stroke follows a blocked blood vessel by a thrombus (blood clot) or embolism. In both types of strokes, the specific region of the brain supplied by the affected blood vessel is deprived of oxygenated blood, causing local hypoxia that damages the brain tissue and cells. Both types of stroke are very serious, however ischemic stroke is more common. The global burden of ischemic stroke is nearly 4-fold greater than hemorrhagic stroke with close to 87% of the total incidence of stroke attributed to acute cerebral ischemic stroke (ACIS). ACIS is a critical care emergency caused by a significant reduction in blood flow to the brain by a blood clot or embolism. This nearly halts cerebral blood flow to the affected region leading to neuronal death. Neuronal cell death is followed by plasma membrane disruption, swelling of organelles, leaking of cell contents into extracellular space, and loss of neuronal function. Other events that take place include inflammation, excitotoxicity, free radical mediated toxicity, cytokine mediated cytotoxicity, impaired blood-brain-barrier, and oxidative stress. Therapeutic management of ACIS is a multidisciplinary approach with a primary goal of revascularization and limiting neuronal injury. A stroke team consists of emergency medicine physicians, neurologists/neurosurgeons, radiologists, nurses and advanced care providers, clinical pharmacists, therapists, technicians, and laboratory personnel. Currently, the only FDA-approved pharmacological agent for ischemic stroke is tissue plasminogen activator (t-PA). It is a thrombolytic agent which restores blood flow by breaking down a clot. However, timing is crucial in administration of t-PA as the therapeutic time window is very narrow and the patient must receive it within 4.5 hours of onset of stroke symptoms. Therapeutic administration after this timeframe can result in hemorrhagic transformation, leading to additional brain damage. Nevertheless, even upon timely administration of t-PA in ACIS, only about 30% of patients obtain stroke resolution having minimal or no disability at the 90-day mark. Sovateltide (PMZ-1620, IRL-1620) is a highly selective ETB receptor agonist and a synthetic analog of ET-1. Studies conducted to determine the effects brought about by sovateltide upon its interaction with neural ETB receptors and have found that it enhances angiogenesis and neurogenesis as well as promotes neural repair and regeneration. In a rat model of ischemic stroke, sovateltide was found to be neuroprotective as well as enhance angiogenic and neurogenic remodeling. Sovateltide significantly improved survival, reduced neurological and motor function deficit, while effectively decreasing infarct volume, edema, and oxidative stress. Sovateltide was also found to be safe and well tolerated in healthy human volunteers in a phase I clinical trial (CTRI/2016/11/007509). A phase II study was also conducted in patients with acute ischemic stroke where sovateltide demonstrated significant improvement when compared to standard of care (CTRI/2017/11/010654, NCT04046484). A recent phase III study conducted in patients of acute ischemic stroke demonstrated improved favorable functional and neurological outcome at 3 months compared to standard of care (CTRI/2019/09/021373, NCT04047563). Clinical phase II and III results indicate that sovateltide is a first-in-class neuronal progenitor cell therapeutic that promotes quick recovery and significantly improves neurological outcomes in cerebral ischemic stroke patients. With this convincing evidence, the plan is to conduct a multicentric, randomized, double-blind, parallel, placebo-controlled phase III clinical study in the United States, Canada, United Kingdom and Europe (the demographics and standard of treatment being similar in these countries) to further assess the safety and efficacy of sovateltide in patients with acute cerebral ischemic stroke.

This is a multi-centric, randomized, double-blind, placebo-controlled phase-III clinical study to assess the safety and efficacy of sovateltide in patients with acute cerebral ischemic stroke.

In this double-blind study, the subject and all relevant personnel involved with the conduct and interpretation of the study (including investigator, investigational site personnel, and the sponsor or designee's staff) will remain blinded to the identity of the Investigational Product (IP) assigned and the randomization codes. The final randomization list will be kept strictly confidential, filed securely by the independent biostatistician, and accessible only to authorized persons as per the sponsor's standard operating procedures until the completion of the study.

Normal saline will be used as a comparator. It will be available in a 5.0 mL vial. Three doses will be administered as an IV bolus over one minute every 3 hours ± 1 hour on day 1. The dose will be repeated on days 3 and 6 post randomization. The study drug will be administered as an IV bolus dose over 1 minute within 24 hours of the stroke onset.

The test product is sovateltide. It is available as a lyophilized injection containing 30 µg of sovateltide in a 5.0 mL vial. Three doses of 0.3 μg/kg will be administered as an IV bolus over one minute every 3 hours ± 1 hour on day 1. The dose will be repeated on days 3 and 6 post randomization. The study drug will be administered as an IV bolus dose over 1 minute within 24 hours of the stroke onset.

Normal saline to be used as vehicle in the phase-III study to assess efficacy of sovateltide in patients with acute cerebral ischemic stroke.

To determine the efficacy of sovateltide in patients with acute cerebral ischemic stroke assessed by modified Rankin Scale (mRS) score at day 90 post randomization

The proportion of acute cerebral ischemic stroke patients having a good outcome with modified Rankin Scale score of 0-2 on day 90 post randomization

To determine excellent outcome of sovateltide in patients with acute cerebral ischemic stroke as assessed by modified Rankin Scale (mRS) score at day 90 post randomization

The proportion of acute cerebral ischemic stroke patients having an excellent functional outcome with modified Rankin Scale score of 0-1 on day 90 post randomization

Increase in the proportion of acute cerebral ischemic stroke patients with National Institute of Health Stroke Scale (NIHSS) score < 6, mRS ≤ 2, Barthel Index (BI) score > 60 on day 6, day 30, and day 90 post-randomization

Proportion of cerebral ischemic stroke patients with NIHSS score ≥ 6, mRS > 2, and BI score ≤ 60 on day 6, day 30, and day 90 post-randomization

Improvement in the functional outcome of cerebral ischemic stroke patients as assessed by NIHSS, mRS, and BI scores at day 6, day 30, and day 90 post-randomization

Change in NIHSS score ≥ 6, mRS score > 2, and BI score ≥ 40 from baseline to day 6, day 30, and day 90 post-randomization

Improvement in the overall clinical outcome as assessed by the global statistical test of mRS, NIHSS, and BI scores at day 6, day 30, and day 90 post-randomization.

Proportion of patients with overall clinical outcome as assessed by the global statistical test of NIHSS, mRS, and BI scores at day 6, day 30, and day 90 post-randomization

Change in Quality-of-life (QoL) as assessed by EuroQol-EQ-5D and by Stroke-Specific Quality of Life (SSQOL) at day 30, day 60, and day 90 post- randomization

Change in QoL as assessed by EuroQol-EQ-5D and by SSQOL from baseline to day 30, day 60, and day 90 post-randomization

Incidence of recurrent cerebral ischemic stroke within day 30 and day 90 post-randomization, as assessed by Questionnaire to Validate Stroke-Free Status (QVSFS)

Proportion of patients with recurrent ischemic stroke within day 30 and day 90 post-randomization as assessed by Questionnaire to Validate Stroke-Free Status (QVSFS)

Incidence of radiographic or symptomatic Intra Cerebral Hemorrhage (ICH) within 24 (± 6) hours of randomization

Inclusion Criteria: A patient will be eligible for inclusion in the study if he/she fulfils the following criteria: Adult males or females aged 18 - 80 years of age Patient or Legally Acceptable Representative (LAR) willing to give informed consent before study procedure Stroke is ischemic in origin and radiologically confirmed Computed Tomography (CT) scan or diagnostic magnetic resonance imaging (MRI) prior to enrolment. No hemorrhage as proved by cerebral CT/MRI scan. Cerebral ischemic stroke patients presenting within 24 hours after onset of symptoms with NIHSS score of ≥ 8 and < 20 as well as NIHSS Level of Consciousness (1A) score < 2 at the time of screening. This includes cerebral ischemic stroke patients who completely recovered from earlier episodes before having a new or fresh stroke. The patient is < 24 hours from time of stroke onset when the first dose of sovateltide is administered. Time of onset is when symptoms began; for stroke that occurred during sleep, time of onset is when the patient was last seen or was self- reported to be normal Reasonable expectation of availability to receive the full sovateltide course of therapy, and to be available for subsequent follow-up visits Exclusion Criteria: A patient will not be eligible for inclusion in this study if they meet any of the following exclusion criteria: Patients receiving endovascular therapy or is a candidate for any surgical intervention for the treatment of stroke, which may include but not limited to endovascular techniques. Patients classified as comatose are defined as a patient who requires repeated stimulation to attend or is obtunded and requires strong or painful stimulation to make movements (NIHSS Level of Consciousness (1A) score ≥ 2) Evidence of intracranial hemorrhage (intracerebral hematoma, intraventricular hemorrhage, subarachnoid hemorrhage (SAH), epidural hemorrhage, acute or chronic subdural hematoma (SDH) on the baseline CT or MRI scan Known pregnancy and lactating women Confounding pre-existing neurological or psychiatric disease Concurrent participation in any other therapeutic clinical trial Evidence of any other major life-threatening or serious medical condition that 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 patient

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