Presenter of 3 Presentations
SOVATELTIDE (TYCAMZZI™) INDUCES NEURONAL REGENERATION IN THE ADULT MAMMALIAN CEREBRAL ISCHEMIC BRAIN BY STIMULATING ENDOTHELIN B RECEPTORS
SOVATELTIDE (TYCAMZZI™) INDUCES NEURONAL REGENERATION IN THE ADULT MAMMALIAN CEREBRAL ISCHEMIC BRAIN BY STIMULATING ENDOTHELIN B RECEPTORS
Abstract
Background and Aims
We have demonstrated that sovateltide, an endothelin B Receptors (ETBRs) agonist, effectively treats cerebral ischemic stroke, and its potential to develop as a novel drug for acute cerebral ischemic stroke (ACIS) is being evaluated (NCT04046484). In the present study, we have assessed the effect of sovateltide on neuronal regeneration and repair after ACIS.
Methods
We investigated the effect of sovateltide in permanent middle cerebral artery occluded (MCAO) adult rats. MCAO rats were treated with either sovateltide (5 µg/kg body wt.) or saline (equal volume) through tail vein injection and were assessed at 24 hrs or day 7 post-MCAO.
Results
We observed upregulation of neuronal differentiation markers Doublecortin (DCX) (p=0.00011), HuC/HuD (p=0.0037) along with NeuroD1 (p=0.00002) at 24 hrs post MCAO. Decreased infarct volume and DNA damage in the sovateltide group on day 7 post MCAO was observed. Downregulation of mitochondrial fission marker, DRP1 (p<0.001), increase in fusion marker, MFN2 (p<0.0001), and increase in cross-sectional area x number as well as mitochondrial/tissue area (p<0.05) at 24 hrs and day 7 post MCAO were seen. Increased mitochondrial DNA (MT ATP8; p=0.0418) was observed, indicating better mitochondrial biogenesis at day 7 post MCAO. Sovateltide treated rats had better neurological outcomes and motor functions at day 7 post MCAO. In vitro testing of sovateltide mediated differentiation in cultured rat NPCs demonstrated higher survival and expression of NeuroD1 and NeuN (a mature neuronal marker) after 24 hrs.
Conclusions
Sovateltide promotes differentiation of NPCs and mitochondrial fusion and biogenesis and helps in neuronal regeneration and function restoration following ACIS.
A RANDOMIZED MULTICENTER STUDY TO DETERMINE THE EFFICACY OF SOVATELTIDE (TYCAMZZI™) IN PATIENTS WITH CEREBRAL ISCHEMIC STROKE
Abstract
Background and Aims
Sovateltide (Tycamzzi™) in animal models of acute cerebral ischemic stroke (ACIS) increased cerebral blood flow, had anti-apoptotic activity, and produced neurovascular remodeling when administered intravenously. In addition, it was safe and well-tolerated in healthy human volunteers, and it improved neurological outcomes in patients with ACIS 90 days post-treatment (NCT04046484).
Methods
A phase III study fully enrolled 158 patients with ACIS, of which 138 completed 90-day follow-up. All patients received standard treatment and were randomly assigned to either control (saline; n=70) or sovateltide cohort (n=68). The inclusion and exclusion criteria are at NCT04047563. Clinical outcome parameters NIHSS and mRS for ACIS were determined. Standard treatment and care were provided to all the patients. Sovateltide or normal saline was administered in three doses, each 0.3 μg/kg, as an intravenous bolus over 1 min at an interval of 3 ± 1 h on day 1, day 3, and day 6 post-randomization.
Results
Patient demographics and baseline characteristics were comparable between the two groups, including baseline NIHSS (saline 10.82 ± 0.41; sovateltide 9.79 ± 0.34) scores. The number of patients having a reduction of 2 or more in mRS was 52.86% in control and 72.06% in the sovateltide group (p=0.0199). mRS in the group treated with sovateltide compared to the comparator group at 90 days after treatment was significantly lower (p=0.0081). NIHSS showed similar improvement in the sovateltide group (p=0.0028) compared to the control group at 90 days of treatment.
Conclusions
Sovateltide significantly improved neurological outcomes in patients with acute cerebral ischemic stroke.