- Exposure to the Nerve Agent Surrogate Pilocarpine Causes Prolonged Seizures (Status Epilepticus) that Result in Significant
Oxidative Stress - Status Epilepticus Induced Oxidative Stress Causes Brain Damage, Cognitive Impairment, and Additional Mortality
in Initial Survivors of Nerve Agent Exposure - Adding AEOL 10150 to Standard Therapy After Pilocarpine Exposure Improved Survival
from 69 to 100 Percent - Mechanistic Data Demonstrates Adding AEOL 10150 to Standard Therapy Significantly Reduces Oxidative
Stress, Brain Damage, and Neuro-Inflammation Resulting from Status Epilepticus
MISSION VIEJO, CA / ACCESSWIRE / September 20, 2017 / Aeolus Pharmaceuticals, Inc. (OTCQB: AOLS), a biotechnology company
developing compounds to protect against fibrosis, inflammation, brain damage, and infection, announced today the publication of a
study titled, "Oxidative Stress Contributes to Status Epilepticus Associated Mortality," in the journal Neurochem Research,
demonstrating that AEOL 10150 improves survival and protects against brain damage and oxidative stress caused by seizures (status
epilepticus, or "SE") after pilocarpine exposure. In studies conducted by researchers, led by Manisha Patel, PhD, at the University
of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medial Campus rats receiving AEOL 10150 and atropine
plus diazepam, the current standard of care ("SOC"), after exposure to the nerve agent surrogate pilocarpine, had statistically
significant higher rates of survival and lower levels of brain damage caused by oxidative damage and associated inflammation than
animals receiving the SOC alone. The studies were conducted under a grant from the National Institutes of Health Countermeasures
Against Chemical Threats ("NIH CounterACT") group.
"While the current standard of care improves survival after nerve agent exposure, treated survivors experience neuronal damage
and associated cognitive decline and additional mortality is seen," stated Manisha Patel, PhD, of the University of Colorado
Anschutz Medical Campus. "In this and previous publications, we have noted that the addition of AEOL 10150 to the standard of care
provides significant protection to susceptible brain areas, reduces associated cognitive impairment and further improves survival
outcomes in this rat model. Together with our previous work, this represents a very promising addition to standard care to address
the cognitive damage and improve treatment outcomes."
"AEOL 10150 has demonstrated efficacy in improving survival against radiation, chemical vesicant and nerve agent exposure and
has been safe and well tolerated in 49 patients. Its broad spectrum utility as a medical countermeasure and dual use potential in
pulmonary and neurological conditions such as IPF, non-small cell lung cancer and neurodegenerative disorders make it unique among
products under development by the US Government and are a testimony to the vision and commitment of the National Institutes of
Health to bring novel products to FDA approval by leveraging public-private partnerships to address high priority threats and
provide new therapies to meet major, unmet medical needs," said John McManus, President and Chief Executive Officer of Aeolus. "We
are grateful to the National Institutes of Health for its recognition of AEOL 10150's efficacy and safety as a broad spectrum
medical countermeasure against radiological and chemical threats and its commitment and continued funding to achieve FDA approval
of AEOL 10150 to address very real threats to the citizens of our country."
Improving the Current Standard of Care for Nerve Agent Exposure
After nerve agent exposure, scopolamine and atropine are currently administered to reduce SE-associated damage and mortality by
reducing SE duration and intensity. Treatment with benzodiazepines improves mortality in much the same way, further reducing SE
duration and intensity. Duration of SE is a significant predictor of morbidity and mortality therefore quick treatment with
atropine or scopolamine and diazepam has been shown to improve mortality and secondary consequences. However, while these
treatments have been shown to mitigate direct toxicity, seizure activity and its consequences, such as neuronal damage and
neuro-inflammation remain major unmet needs. Therefore, individuals who survive the initial exposure are at risk for secondary
damage, and typically experience cognitive dysfunction.
In the studies performed by Dr. Patel, the addition of AEOL 10150 to the SOC improved survival and provided significant
protection of neurons and reduction of microgliosis in the hippocampus. Without treatment, pilocarpine exposure resulted in
SE-induced mortality of 57%. Treatment with the SOC reduced mortality to 31%, while treatment with AEOL 10150 alone reduced
mortality to 20% (p<0.05). Adding AEOL 10150 to the SOC completely prevented SE-induced mortality. Neuronal loss and
microgliosis were evaluated by immunofluorescence in hippocampal areas CA3 and hilus 24 hours after treatment with SOC and SOC plus
AEOL 10150. The addition of AEOL10150 to treatment starting 90 minutes after pilocarpine exposure significantly reduced SE-induced
neuronal loss in the CA3 (p < 0.05), but not in the hilar region of the hippocampus (p > 0.05). Microgliosis was
significantly attenuated by AEOL10150 treatment in the hilar region (p < 0.05) but not the CA3 region.
Defining the Mechanism of Damage from Status Epilepticus
Oxidative stress can cause free-radical induced damage to proteins, lipids, and DNA, as well as inflammation and neurotoxicity.
This is particularly the case when levels of reduced glutathione ("GSH") are altered, as it functions as one of the primary
antioxidants responsible for free-radical detoxification. One important consequence of altered GSH levels is activation of cell
death cascades. Alterations in glutathione redox status are quantifiable and specific indicators of oxidative stress and contribute
to SE-induced neuronal loss. Nitration of tyrosine (ratio of "3-NT/tyrosine") is a quantifiable and specific indicator of
nitrosative stress, as well as an indicator of cell damage and inflammation. Both can be used to determine whether
pilocarpine-induced SE results in oxidative stress.
Data from these studies showed that pilocarpine depletes levels of GSH, increases oxidized glutathione (GSSG) and decreases the
glutathione redox status (ratio of GSH:GSSG). It increases 3-NT/tyrosine in the hippocampus at 24 and 48 hours after exposure
(p<0.001 for all measures) in rats receiving the SOC for nerve agent exposure. The changes in the ratio of GSH:GSSG and
increased protein nitration indicate that pilocarpine-induced SE results in oxidative stress.
AEOL 10150 Mechanism of Action in Improving Survival and Clinical Outcomes
To determine if treatment with the SOC plus AEOL10150 offered protection from SE-induced oxidative stress, glutathione redox
status and protein nitration was assessed after pilocarpine exposure. Treatment with the SOC significantly improved levels of GSH
versus no treatment (p < 0.05), and adding AEOL10150 treatment every 4 hours further improved GSH levels (p < 0.001). While
neither treatment regiments were able to prevent accumulation of GSSG, treatment with the SOC plus AEOL10150 was able to
significantly improve the SE-induced depletion of the ratio of GSH:GSSG compared to the SOC alone. Both SOC and SOC plus AEOL10150
treatment regiments were able to significantly reduce SE-induced protein nitration (p < 0.001).
Targeting oxidative stress with AEOL 10150 significantly reduces mortality associated with SE produced by pilocarpine, a nerve
agent surrogate. The greatest reduction in pilocarpine-associated mortality was observed when AEOL10150 was used in conjunction
with the current SOC. SOC plus AEOL 10150 also resulted in the greatest reduction in oxidative stress and improvements in neuronal
loss and microgliosis in the hippocampus. AEOL10150 alone did not have any direct effects on the intensity or duration of SE.
Therefore, the reduction of oxidative stress (shown by improvement in the glutathione redox status) provides a rationale as to why
mortality was completely prevented when AEOL 10150 was added to the SOC. The data suggest oxidative stress is an important target
to reduce mortality and improve neurological outcomes associated with nerve agent induced-SE.
About Nerve Agent Exposure and Status Epilepticus
Status epilepticus (SE) is a period of prolonged seizure activity, and is considered a neurological emergency associated with
significant morbidity and mortality. SE can occur in people that have experienced brain trauma, metabolic insults or that have been
exposed to toxic chemicals including organophosphorus compounds and nerve agents even after treatment with the current standard of
care. SE is associated with oxidative stress in the brain as indicated by significant alterations in the glutathione redox status
and increased protein nitration following nerve agent or organophosphate exposure. SE induced by these compounds is also sufficient
to increase markers of oxidative stress suggesting that SE and not the inciting compound is responsible for increased oxidative
stress in the brain. Cholinergic agonists such as pilocarpine and organophosphates are also considered surrogate nerve agents due
to their effects on the cholinergic system resulting in SE. Studies have shown that SE-induced mortality occurs up to 30 days after
exposure and glutathione redox status alterations and mitochondrial dysfunction persist up to 3 months after SE. Prolonged SE
results in neuronal injury, epilepsy, and cognitive impairment and mortality in approximately 20% of patients.
About AEOL 10150
AEOL 10150 protects tissue from damage and increases survival in animal models of lung damage after exposure to radiation, toxic
chemicals and disease and neurological models of nerve agents and disease by mitigating and/or preventing cell death and
inflammation through its action on oxidative stress and regulation of growth factors and chemokines, as well as impacting
subsequent signaling pathways of reactive oxygen species production, apoptosis and fibrosis. We are developing 10150 as a MCM for
national defense and for use in oncology and treating lung fibrosis and neuro-degenerative disorders.
AEOL 10150 has performed well in preclinical and non-clinical studies, demonstrating statistically significant survival efficacy
in an acute radiation-induced lung injury model, and was well-tolerated by 49 patients in two human clinical trials in ALS
patients, and a phase 1 study in healthy subjects. The Company believes that AEOL 10150 could have a profound beneficial impact on
people who have been exposed, or are about to be exposed, to high-doses of radiation, whether from cancer therapy or a nuclear
event, and potentially reduce lung damage in patients with idiopathic pulmonary fibrosis and people who inhale chemical vesicants,
such as sulfur mustard gas. We also believe that AEOL 10150 could have a profound beneficial impact on people who have been exposed
to nerve agents, and potentially reduce neuro-degeneration in patients with ALS, and other neurological disorders based on the
drug's demonstrated ability to protect nerve cells and cognitive ability. AEOL 10150 has received Fast Track and Orphan Drug
designation and is at Technology Readiness Level ("TRL") 7 for Lung ARS, TRL 6A for sulfur mustard gas and nerve agent exposure,
and TRL 6/5 for chlorine and phosgene gas exposure. AEOL 10150 has received Orphan Drug Designation for Idiopathic Pulmonary
Fibrosis and Amyotrophic Lateral Sclerosis ("ALS"), and is phase 2 ready for the ALS indication.
About Aeolus Pharmaceuticals
Aeolus Pharmaceuticals is developing a platform of novel compounds for use in biodefense, fibrosis, oncology, infectious
diseases, and diseases of the central nervous system. Its most advanced compound, AEOL 10150, is being developed, with funding from
the US Department of Health and Human Services, as a medical countermeasure against chemical and radiological weapons, where its
initial target indications are as a protective agent against the pulmonary effects of acute radiation exposure, sulfur mustard gas
and nerve agent exposure. Aeolus' strategy is to leverage the substantial investment in toxicology, manufacturing, and preclinical
and clinical studies made by US Government agencies to efficiently develop compounds for use in commercial indications. For more
information, please visit Aeolus's corporate website at www.aolsrx.com.
Forward-Looking Statements
The statements in this press release that are not purely statements of historical fact are forward-looking statements. Such
statements include, but are not limited to, those relating to Aeolus' product candidates the effects of the Notification, the
Company's proprietary technologies and research programs, and the Company's initiation of a phase 1 multiple dose study in healthy
volunteers and/or potential initiation of a clinical study in pulmonary fibrosis patients. Such forward-looking statements involve
known and unknown risks, uncertainties and other factors that may cause Aeolus' actual results to be materially different from
historical results or from any results expressed or implied by such forward-looking statements. Important factors that could cause
results to differ include risks associated with uncertainties concerning BARDA and ASPR, uncertainties of progress and timing of
clinical trials, scientific research and product development activities; difficulties or delays in development, testing and
obtaining regulatory approval; the need to obtain funding for pre-clinical and clinical trials and operations; the scope and
validity of intellectual property protection for Aeolus' product candidates, proprietary technologies and their uses; competition
from other biopharmaceutical companies; and whether BARDA is ultimately able to exercise one or more additional options under its
contract with Aeolus. Certain of these factors and others are more fully described in Aeolus' filings with the Securities and
Exchange Commission, including, but not limited to, Aeolus' Annual Report on Form 10-K for the year ended September 30, 2016.
Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof.
Contact:
John McManus President and Chief Executive Officer Aeolus Pharmaceuticals, Inc. 1-(949) 481-9820
SOURCE: Aeolus Pharmaceuticals, Inc.