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Cerebral Ischemic Stroke

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Stroke is an important cause of serious long-lasting disability. Ischemic stroke caused by arterial occlusion is responsible for most strokes. Limitations of time, risk of bleeding and involvement of larger blood vessels for thrombectomy restricts current treatment only to a handful (about 5%) of patients. Development of new effective drugs for acute cerebral ischemic stroke to alleviate neurological deficit and repair the cerebral damage is urgently required.

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.

A phase II trial was conducted to evaluate safety, tolerability and efficacy of sovateltide in patients with acute cerebral ischemic stroke. It was found to be safe and well tolerated. No adverse event was reported in patients.

A significantly greater number of patients in the sovateltide group had an improvement of BI of ≥40 points at 90 days of treatment (64% compared to 36% in the control group). The number of patients showing a favorable improvement in mRS (change of ≥2 points vs baseline) and NIHSS (change of ≥ 6 points vs baseline) at 90 days was numerically greater in the sovateltide group (60% compared to 40% in the control group; and 56% compared to 43% in the control group, respectively).

Sovateltide is likely to offer significant advantages over existing products because it has been found to have anti-apoptotic, anti-inflammatory, and antioxidant activity thereby limiting the death of brain cells. It also promotes the formation of new neurons (neurogenesis) and new blood vessels (angiogenesis).

Promising results of this study have led to an efficacy study in a larger cohort of ischemic stroke patients and sovateltide is currently being tested in a multicentric, randomized, blinded, controlled efficacy clinical trial phase III.

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Status of Cerebral Ischemic Stroke

Product Pre-Clinical Clinical Market
Phase 1 Phase 2 Phase 3
Cerebral Ischemic Stroke (Sovateltide)
Publications
# Publication List
background Gulati A, Agrawal N, Vibha D, Misra UK, Paul B, Jain D, Pandian J, Borgohain R. Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized Controlled Clinical Trial in Patients with Acute Cerebral Ischemic Stroke. CNS Drugs. 2021 Jan;35(1):85-104. doi: 10.1007/s40263-020-00783-9. Epub 2021 Jan 11. PMID: 33428177; PMCID: PMC7872992.
background Ranjan AK, Briyal S, Khandekar D, Gulati A. Sovateltide (IRL-1620) affects neuronal progenitors and prevents cerebral tissue damage after ischemic stroke. Can J Physiol Pharmacol. 2020 Sep;98(9):659-666. doi: 10.1139/cjpp-2020-0164. Epub 2020 Jun 23. PMID: 32574518.
background Briyal S, Ranjan AK, Hornick MG, Puppala AK, Luu T, Gulati A. Author Correction: Anti-apoptotic activity of ETB receptor agonist, IRL-1620, protects neural cells in rats with cerebral ischemia. Sci Rep. 2020 Feb 14;10(1):2992. doi: 10.1038/s41598-020-60114-2. Erratum for: Sci Rep. 2019 Jul 18;9(1):10439. PMID: 32054963; PMCID: PMC7018771.
background Ranjan AK, Briyal S, Gulati A. Sovateltide (IRL-1620) activates neuronal differentiation and prevents mitochondrial dysfunction in adult mammalian brains following stroke. Sci Rep. 2020 Jul 29;10(1):12737. doi: 10.1038/s41598-020-69673-w. PMID: 32728189; PMCID: PMC7391684.
background Briyal S, Ranjan AK, Hornick MG, Puppala AK, Luu T, Gulati A. Anti-apoptotic activity of ETB receptor agonist, IRL-1620, protects neural cells in rats with cerebral ischemia. Sci Rep. 2019 Jul 18;9(1):10439. doi: 10.1038/s41598-019-46203-x. Erratum in: Sci Rep. 2020 Feb 14;10(1):2992. PMID: 31320660; PMCID: PMC6639304.
background Gulati A, Agrawal NR, Vibha D, Misra UK, Paul BS, Kumar R, Pandian JD, Lavhale MS. Efficacy of Sovateltide (PMZ-1620), a First-in-Class Neuronal Progenitor Cell Therapeutics, in Patients With Cerebral Ischemic Stroke. Circulation. 2019 Nov 19;140(Suppl_1):A14683-.
background Gulati A, Agrawal N, Vibha D, Misra UK, Paul B, Pandian J, Rupam B, Reddy G. 5: Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke. Critical Care Medicine. 2021 Jan 1;49(1):3.
background Ranjan AK, Briyal S, Khandekar D, Gulati A. Sovateltide (IRL-1620) affects neuronal progenitors and prevents cerebral tissue damage after ischemic stroke. Canadian Journal of Physiology and Pharmacology. 2020;98(9):659-66.
background Ranjan AK, Briyal S, Gulati A. Sovateltide (IRL-1620) activates neuronal differentiation and prevents mitochondrial dysfunction in adult mammalian brains following stroke. Scientific reports. 2020 Jul 29;10(1):1-7.
background Briyal S, Ranjan AK, Hornick MG, Puppala AK, Luu T, Gulati A. Anti-apoptotic activity of ET B receptor agonist, IRL-1620, protects neural cells in rats with cerebral ischemia. Scientific reports. 2019 Jul 18;9(1):1-3.
background Gulati, A., Hornick, M. G., Briyal, S., and Lavhale, M. S. (2018) A novel neuroregenerative approach using ET(B) receptor agonist, IRL-1620, to treat CNS disorders. Physiol Res 67, S95-S113
background Joshi, M. D., Oesterling, B. M., Wu, C., Gwizdz, N., Pais, G., Briyal, S., and Gulati, A. (2016) Evaluation of liposomal nanocarriers loaded with ETB receptor agonist, IRL-1620, using cell-based assays. Neuroscience 312, 141-152
background Gulati, A. (2016) Endothelin Receptors, Mitochondria and Neurogenesis in Cerebral Ischemia. Curr Neuropharmacol 14, 619-626
background Bhalla, S., Leonard, M. G., Briyal, S., and Gulati, A. (2016) Distinct Alteration in Brain Endothelin A and B Receptor Characteristics Following Focal Cerebral Ischemia in Rats. Drug Res (Stuttg) 66, 189-195
background Puppala, B., Awan, I., Briyal, S., Mbachu, O., Leonard, M., and Gulati, A. (2015) Ontogeny of endothelin receptors in the brain, heart, and kidneys of neonatal rats. Brain Dev 37, 206-215
background Leonard, M. G., Prazad, P., Puppala, B., and Gulati, A. (2015) Selective Endothelin-B Receptor Stimulation Increases Vascular Endothelial Growth Factor in the Rat Brain during Postnatal Development. Drug Res (Stuttg) 65, 607-613
background Gulati, A. (2015) Understanding neurogenesis in the adult human brain. Indian J Pharmacol 47, 583-584
background Leonard, M. G., and Gulati, A. (2013) Endothelin B receptor agonist, IRL-1620, enhances angiogenesis and neurogenesis following cerebral ischemia in rats. Brain Res 1528, 28-41
background Leonard, M. G., Briyal, S., and Gulati, A. (2012) Endothelin B receptor agonist, IRL-1620, provides long-term neuroprotection in cerebral ischemia in rats. Brain Res 1464, 14-23
background Leonard, M. G., Briyal, S., and Gulati, A. (2011) Endothelin B receptor agonist, IRL-1620, reduces neurological damage following permanent middle cerebral artery occlusion in rats. Brain Res 1420, 48-58
background Briyal, S., Gulati, A., and Gupta, Y. K. (2007) Effect of combination of endothelin receptor antagonist (TAK-044) and aspirin in middle cerebral artery occlusion model of acute ischemic stroke in rats. Methods Find Exp Clin Pharmacol 29, 257-263
background Gupta, Y. K., Briyal, S., Sharma, U., Jagannathan, N. R., and Gulati, A. (2005) Effect of endothelin antagonist (TAK-044) on cerebral ischemic volume, oxidative stress markers and neurobehavioral parameters in the middle cerebral artery occlusion model of stroke in rats. Life Sci 77, 15-27