Neonatal encephalopathy due to perinatal asphyxia is known as hypoxic-ischemic
encephalopathy (HIE). HIE is a serious neurological complication affecting premature and
full-term neonates, resulting from oxygen deprivation and reduced blood flow to the
neonatal brain, leading to neuronal and white matter injury. Currently, no
well-established therapies are considered effective for neonatal HIE. The standard of
care at present includes supportive management to maintain cerebral perfusion, metabolic
balance, and seizure detection and treatment. Currently, the only neuroprotective
treatment for HIE is therapeutic hypothermia. However, improvement in patient outcomes
following therapy has been moderate, with only 1 in 6 infants benefitting from
therapeutic hypothermia.
Additionally, therapeutic hypothermia is time-sensitive, having a narrow therapeutic
window wherein therapy must be initiated within 6 hours of delivery to be effective.
Timely initiation is also restricted to those neonatal units having adequate equipment
and trained staff for therapeutic hypothermia. Death or disability is reported to occur
in 55% of infants receiving therapeutic hypothermia. To the best of our knowledge, there
is no pharmacotherapy available for the treatment of HIE. Hence, there is a significant
unmet medical need.
ETB receptors located widely throughout the CNS are a necessary component of the
developing nervous system and also promote neurorestorative processes involving
neurogenesis and synaptogenesis. There was an increased expression of neural progenitor
markers, NeuroD1 and Double Cortin, and neural markers for mature neurons, NeuN was
observed in the sovateltide group compared to vehicle. In addition, Sovateltide increased
the expression of presynaptic markers (synapsin1 and synaptophysin) and post-synaptic
marker (Postsynaptic Density-95) compared to vehicle. Our results suggest that
sovateltide treatment helps recruit and differentiate neural progenitor cells and
augments synaptogenesis and endogenous neurorestorative processes.
Sovateltide is a synthetic analog of ET-1 synthesized in 1992 and is a highly specific
ETB receptor agonist. We and others have conducted studies to determine the effects of
sovateltide upon its interaction with neural ETB receptors and have found that it
enhances angiogenesis and neurogenesis and promotes repair and regeneration. This is
indicated by neuronal cell proliferation, alleviation of oxidative stress, improvement of
neurological and motor functions, and increase in anti-apoptotic markers. In our
preclinical study, sovateltide was shown to have neuroprotective effects by promoting
repair and regeneration in the brain in a neonatal rat model of HIE. The study showed
that sovateltide treatment alone or in combination with hypothermia significantly
(p<0.01) increased ETB receptor expression compared to vehicle-treated rat pups. In
addition, enhanced VEGF and NGF expression were observed in rat pups treated with
Sovateltide alone or in combination with hypothermia compared to vehicle-treated rat pups
(p<0.0001, p<0.0001). Sovateltide alone and in combination with hypothermia also
demonstrated a significantly reduced number of apoptotic cells compared to the control
group. Furthermore, oxidative stress markers, including malondialdehyde, reduced
glutathione, and superoxide dismutase was, significantly improved (p<0.0001, p<0.0001,
p<0.0001) in those rat pups treated with sovateltide.
Sovateltide was safe and well-tolerated in a Phase I trial (CTRI/2016/11/007509) in
healthy human volunteers. In addition, we conducted human studies in patients with
cerebral ischemic stroke (NCT04046484, CTRI/2017/11/010654; NCT04047563,
CTRI/2019/09/021373), Alzheimer's disease (NCT04052737, CTRI/2017/12/016394), and acute
spinal cord injury (NCT04054414, CTRI/2018/12/016667) patients. In summary, about 300
patients have been treated with sovateltide, and no drug-related adverse event has been
reported to date.
We plan to conduct a phase II clinical study to evaluate the safety and efficacy of
sovateltide therapy along with supportive management in neonates with perinatal asphyxia
(HIE). The dose of sovateltide proposed for this phase II study is 0.3µg/kg same as used
in the phase II study in ischemic stroke.