Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized Controlled Clinical Trial in Patients with Acute Cerebral Ischemic Stroke

Abstract

Background Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, has been previously shown to increase cerebral blood flow, have anti-apoptotic activity and produce neurovascular remodeling when administered intravenously following acute cerebral ischemic stroke in rats. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509). Objective Our objective was to determine the safety, tolerability and efficacy of sovateltide as an addition to standard of care (SOC) in patients with acute cerebral ischemic stroke. Methods A prospective, multicentric, randomized, double-blind, placebo-controlled study was conducted to compare the safety (primary objective) and efficacy (secondary objective) of sovateltide in patients with acute cerebral ischemic stroke. Adult males or females aged 18–70 years who had experienced a radiologically confirmed ischemic stroke within the last 24 h were included in the study. Patients with intracranial hemorrhage and those receiving endovascular therapy were excluded. Patients randomized to the sovateltide group received three doses of sovateltide (each dose 0.3 µg/kg) administered as an intravenous bolus over 1 min at an interval of 3 ± 1 h on day 1, day 3 and day 6 (total dose of 0.9 µg/kg/day). Patients randomized to the placebo group received an equal volume of saline. Every patient in both groups received SOC for stroke. Efficacy was evaluated using neurological outcomes based on National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) scores from day 1 through day 90. Quality of life was measured using the EuroQoL-5 Dimensions (EQ-5D) and Stroke-Specific Quality of Life (SSQoL) at 60 and 90 days of follow-up. Results A total of 40 patients with acute cerebral ischemic stroke were enrolled in this study, of whom 36 completed the 90-day follow-up. Patients received saline ( n = 18; 11 male and 7 female) or sovateltide ( n = 18; 15 male and 3 female) within 24 h of onset of stroke. The number of patients receiving investigational drug within 20 h of onset of stroke was 14/18 in the saline group and 10/18 in the sovateltide group. The baseline characteristics and SOC in both cohorts was similar. Sovateltide was well-tolerated, and all patients received complete treatment with no incidence of drug-related adverse events. Hemodynamic, biochemical or hematological parameters were not affected by sovateltide. Sovateltide treatment resulted in improved mRS and BI scores on day 6 compared with day 1 ( p < 0.0001), an effect not seen in the saline group. Sovateltide increased the frequency of favorable outcomes at 3 months. An improvement of ≥ 2 points on the mRS was observed in 60 and 40% of patients in the sovateltide and saline groups, respectively ( p = 0.0519; odds ratio [OR] 5.25). An impro...

Targeting Pro-Oxidant Iron with Deferoxamine as a Treatment for Ischemic Stroke: Safety and Optimal Dose Selection in a Randomized Clinical Trial

“…In this subpopulation in which baseline scores are similar, DFO induced a larger percent reduction of neurological impairment at 90 days ( Figure 3 B), and the proportion of good outcome patients (mRS ≤ 2) increased with the dose of DFO at 7 and at 90 days. The mRS, that has been used to assess neurological status mostly at 90 days to evaluate long-term outcomes, has been reported in recent papers to be informative in the evaluation of short-term outcomes as well [ 53 , 54 ]. Although this is a post hoc analysis based on a relatively small number of patients, our observations support that DFO, at doses capable of reducing systemic iron and TSAT, seem to be a promising therapy increasing the proportion of patients showing better functional outcome.…”

Sovateltide Mediated Endothelin B Receptors Agonism and Curbing Neurological Disorders

“…All the patients received saline or sovateltide between 8 and 24 h after the onset of stroke; however, the number of patients receiving investigational drug within 20 hrs of onset of stroke was 14/18 in the saline group and 10/18 in the sovateltide group. The baseline characteristics and SOC in both cohorts were similar [65]. and electromyography (EMG).…”

Structural and Functional Diversity of Animal Toxins Interacting With GPCRs

“…In the face of this unappealing clinical picture, the unique indication for which an endothelin agonist has emerged with a positive outcome is stroke treatment. Indeed, IRL-1620 (Sovateltide), currently in phase III clinical trials, has yielded better recovery from acute cerebral ischemic stroke (Gulati et al, 2021;Pharmazz, Inc. 2021). IRL-1620 is a linear, truncated, modifier ET/SRTX family peptide that acts as a selective and potent ETB agonist.…”