- AEOL 10150 treatment once per day for 60 days beginning 24 hours post-exposure:
- significantly improved survival at 180 Days
- delayed onset of lethal effects by 90 days
- Increased mean survival at 360 days
- Data presented at the American College of Clinical Pharmacology annual meeting in San Diego
MISSION VIEJO, CA / ACCESSWIRE / September 22, 2017 / Aeolus Pharmaceuticals, Inc. (OTCQB: AOLS), a biotechnology company developing compounds to protect against fibrosis, inflammation, nerve damage and infection announced today presentation of pharmacometric-based analysis confirming the optimal dosing schedule for AEOL 10150 in the treatment of the pulmonary effects of acute radiation syndrome ("Lung ARS"). The analysis, performed by Jogarao Gobburu, PhD, Vijay Ivaturi, PhD and Hechuan Wang, MS with the Center for Translational Medicine, School of Pharmacy at the University of Maryland and funded by Aeolus' Lung ARS development contract with the Biomedical Advanced Research and Development Authority ("BARDA") confirmed that the significant improvement in survival and underlying pathophysiology seen in non-human primate ("NHP") efficacy studies was also seen in mouse studies. The conclusion of the analysis is that the optimal dose schedule based on results from studies in both species is AEOL 10150 administered for 60 days beginning 24 hours after exposure to lethal levels of radiation. The results of the analysis, "Dose and Regimen Determination Study of AEOL10150 as a Mitigator of Radiation-Induced Lung Injury in C57L/J Mice," were presented at the American College of Clinical Pharmacology annual meeting in San Diego.
"The pharmacometric modeling of AEOL 10150's effects in treating the pulmonary effects of acute radiation exposure is compelling and our modeling and analysis of the data from multiple studies conducted in the mouse and NHP models clearly shows that treatment for 60 days beginning 24 hours after exposure produces optimal and statistically significant survival benefits," stated Jogarao Gobburu, PhD, Executive Director of the Center for Translational Medicine, Schools of Pharmacy and Medicine at the University of Maryland. "In addition to the statistically significant survival seen for the primary endpoint of 180 day survival, treatment with AEOL 10150 for 60 days delays the onset of lethal effects of radiation exposure in mice by 3 months, which might allow for other interventions and treatments to produce additional benefits to victims."
"AEOL 10150 has consistently demonstrated efficacy in mouse, rat and NHP models of lung radiation, and this pharmacometric-based analysis provides further confirmation that treatment for 60 days beginning 24 hours post exposure significantly improves survival in the species and animal models developed under the BARDA Lung ARS contract, which the FDA has concurred are appropriate for this indication," said John McManus, President and Chief Executive Officer of Aeolus. "Based on the confirmatory findings of this analysis and the consistent, significant efficacy demonstrated after 60 days of treatment with AEOL 10150, we will request a special protocol assessment from the FDA Division of Medical Imaging Products to reach a consensus on the design of an 'adequate and well controlled study' in the NHP."
The pharmacometric-based analysis was performed on a study conducted by Isabel L. Jackson, Ph.D. and Zeljko Vujaskovic, MD, Ph.D. Division of Translational Radiation Sciences, Department of Radiation Oncology at the University of Maryland, School of Medicine and funded by Aeolus' Lung ARS development contract with BARDA. The underlying study was conducted in 260 C57L/J mice and compared survival to control for animals treated for 28, 60 and 90 days with a single daily dose of 25 mg/kg of AEOL 10150 beginning 1 day, 7 days, 4 weeks and 10 weeks post-exposure. Kaplan-Meier plot analysis showed that initiation of treatment 24 hours post exposure yields the most significant improvement in 180 days survival versus control, across various durations of treatment. Of the various durations of treatment initiated 24 hours post exposure, the best results were obtained with treatment for 60 days, where 100 percent of animals survived, compared to 75 percent in the control arm. The 60 days treatment arm initiating at 24 hours post exposure also had a longer mean survival time and a higher 360 days survival rate and mean survival time compared to control and the other treatment arms.
Pharmacometric-based analysis of the study was performed to model the various treatment initiation and duration combinations to determine optimal timing and duration and estimate a Human Equivalent Dose to inform the design of phase 1 safety studies. Fisher's exact test was used to compare the proportion of survivors at 180 days, the primary endpoint in the study, in the treatment groups vs. control group. The proportion of survivors in the 60-day treatment arm is significantly different from the proportion of responders in control arm (p=0.020), as well as in the 28-day and 90-day treatment arms. In addition, the log-rank test showed that the survival distribution in 60 days arm is significantly different from the survival distribution in the control group (p=0.018), and the 28-day and 90-day treatment arms. Piecewise parametric survival analysis results further confirmed the significance of the 60-day arm in improving survival at 180 days compared to the control arm and 28-day and 90 day treatment arms, and showed that AEOL 10150 treatment for 60 days delays the onset of lethal effect by 90 days - from 93 days in the control arm to 183 days.
About Pharmacometrics
Pharmacometrics is the science that quantifies drug, disease and trial information to aid efficient drug development and/or regulatory decisions. Pharmacometric drug models describe the relationship between exposure (pharmacokinetics) and response (pharmacodynamics) for both desired and undesired effects. Pharmacometric disease models describe the relationship between biomarkers and clinical outcomes and the time course of disease progression. The key strength of pharmacometric analyses is its ability to integrate knowledge gained across a drug development program.
About Acute Radiation Syndrome (ARS) and the Delayed Effects of ARS
AEOL 10150 is currently the only treatment in advanced development for Lung ARS. Statistically significant improvement in survival in both NHP and mouse models of Lung ARS have been demonstrated at HED's that have been safe and well tolerated in human safety studies. In June 2017, AEOL 10150 was granted Fast Track designation for Lung ARS by the FDA, and a special protocol assessment to reach agreement on the design of a pivotal ("adequate and well designed") study in the NHP will be submitted to the FDA shortly.
Ionizing radiation exposure through accidental release or detonation of a nuclear bomb leads to organ and tissue damage that may take months to manifest symptomatically. Direct or indirect damage to vital cellular macromolecules such as DNA, proteins, and lipids results in complex changes to molecular pathways leading to endothelial dysfunction, extravasation of plasma proteins, increased vascular contractility, vascular smooth muscle cell growth and apoptosis, monocyte migration, lipid peroxidation, inflammation, angiogenesis, epithelial-mesenchymal transition, and fibrosis in tissues. It is well documented that generation of free radicals leading to oxidative/nitroxidative modification of key intracellular signaling pathways facilitates the processes leading to radiation induced toxicity.
The short-term clinical presentation of these cellular insults is known as Acute Radiation Syndrome or ARS, which occurs following whole- or partial-body exposure to high doses of radiation. Depending on the dose and anatomic region of exposure, the result can be acute damage to the hematopoietic system and/or gastrointestinal (GI) tract or delayed effects on the lung and kidney. Severe damage to these organ systems may lead to morbidity and mortality among the exposed population, due to immunosuppression, malabsorption, hemorrhage, infection, respiratory failure, or a combination of these injuries.
Hematopoietic ARS (H-ARS) and GI-ARS are the primary syndromes responsible for early‑onset morbidity and mortality following acute total-body irradiation. The US Government has acquired products such as Neupogen®, Neulasta®, and Leukine® to treat H-ARS and antibiotics to treat GI-ARS. Radiation accident victims, treated with these types of products and supportive care, have survived both H-ARS and GI-ARS; however, they have then succumbed to delayed effects of acute radiation exposure, including lung injury presenting as pneumonitis and/or fibrosis. This has also been seen in mouse and non-human primate animal studies of the acute and delayed effects of total and partial body irradiation.
About AEOL 10150
AEOL 10150 protects tissue from damage and increases survival in animal models of lung damage after exposure to radiation, toxic chemicals, disease and trauma by mitigating and/or preventing cell death, inflammation and fibrosis 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 AEOL 10150 as a MCM for national defense and for use in oncology and treating lung fibrosis.
AEOL 10150 has performed well in pre-clinical and non-clinical studies, demonstrating statistically significant survival efficacy in an acute radiation-induced lung injury model, and was well-tolerated in two human clinical trials in ALS patients, and is currently being tested in 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, based on the drug's demonstrated ability to protect nerve cells and cognitive ability. AEOL 10150 has received Fast Track designation and is at Technology Readiness Level 7 for lung radiation, and is at Technology Readiness Levels 5 and 6 for sulfur mustard, chlorine and phosgene gas and nerve agent exposure.
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 by 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 effects of acute radiation syndrome and delayed effects of acute radiation 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 multiple dose phase 1 study in healthy volunteers and/or potential initiation of a phase 1 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.
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