- AEOL 10150 Treatment Once Per Day for 60 Days Beginning 24 Hours Post-Exposure Reduced Mortality by 50 Percent
- AEOL 10150 Is The Only Drug in Advanced Development by The US Government to Address the Delayed Effects of Radiation
- Stockpiled Therapies Such as Neupogen®, Neulasta® And Leukine® Enhance Short Term Survival, But Also Increase the Need for and Value of Treatments to Reduce Suffering and Mortality Expected from Delayed Effects in Acute Survivors
- Data Presented at The American College of Clinical Pharmacology Annual Meeting in San Diego
MISSION VIEJO, CA / ACCESSWIRE / September 26, 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 at the University of Maryland School of Pharmacy and funded by Aeolus' Lung ARS development contract with the Biomedical Advanced Research and Development Authority ("BARDA") confirmed the statistical significance of the improvement in survival and underlying pathophysiology seen after treatment with AEOL 10150 in NHP efficacy studies conducted by and previously reported by Thomas MacVittie, PhD at the University of Maryland School of Medicine ("UMSOM"). Dr. Gobburu's analysis of data from NHP and mouse efficacy studies, performed under the BARDA contract, concluded that administration of AEOL 10150 for 60 days beginning 24 hours after exposure to lethal radiation provided the best survival benefit and that this level of efficacy demonstrated in an "adequate and well designed" study would likely produce a dose modification factor supporting approval under the Animal Rule. The results of the analysis, titled AEOL 10150 Improves 180-day Survival of Lethally Irradiated Rhesus Macaques, were presented at the American College of Clinical Pharmacology annual meeting in San Diego.
"Our pharmocometric-based modeling results show that AEOL 10150 treatment for 60 days at a dose of 5 mg/kg/day provides statistically significant survival benefits over the control arm at the level of alpha=0.1 and results in reduced clinical, histopathological and anatomic evidence of radiation-induced lung injury," stated Jogarao Gobburu, PhD, professor of pharmacy practice and science and executive director of the Center for Translational Medicine at the University of Maryland School of Pharmacy. "This dosing regimen should be carried forward to clinical study in humans to satisfy safety requirements and used to inform the design of an "adequate and well-controlled" study in the NHP to meet the efficacy requirements under the FDA Animal Rule."
"We appreciate the funding provided by BARDA to bring the development of AEOL 10150 as a medical countermeasure to Technology Readiness Level 7 and are encouraged that the National Institutes of Health-National Institute of Allergy and Infectious Disease is working with us to help fund the remaining work required for approval under the Animal Rule," stated John L. McManus, President and Chief Executive Officer of Aeolus Pharmaceuticals, Inc. "BARDA research and procurement activity over the past few years has been focused on developing new animal models and acquiring proven therapies to treat the acute effects of radiation. Given the potential for radiation exposure that our country faces, it is critical that more funding be focused on treating the delayed effects, which, if left untreated, will lead to suffering and mortality due to lung and other organ system damage and will place a tremendous burden on hospitals and medical providers in affected areas."
"We are grateful to Dr. MacVittie and his lab for the development of the Lung ARS NHP animal model and subsequent studies testing the efficacy of AEOL 10150 and to Dr. Gobburu and his team for their analysis, which cumulatively have demonstrated the significant efficacy of AEOL 10150 against the lethal, pulmonary, late effects of radiation exposure," continued Mr. McManus. "The University of Maryland School of Medicine, Division of Translational Radiation Sciences has been a critical partner in the successful development of AEOL 10150 as a radiation countermeasure, and has been instrumental in transitioning our pre-clinical healthy tissue protection studies into clinical programs in Idiopathic Pulmonary Fibrosis and for patients receiving radiation therapy for cancer."
The pharmacometric-based analysis was performed on data from a study conducted by Tom MacVittie, Ph.D., a professor at UMSOM, and Anne Farese, MS, an assistant professor at UMSOM, and funded by Aeolus' Lung ARS development contract with BARDA. The full results of the NHP Efficacy study titled, "AEOL 10150 Mitigates Radiation-Induced Lung Injury in the Non-human Primate: Morbidity and Mortality are Administration Schedule-Dependent," were published in the journal Radiation Research earlier this year. The underlying study was conducted in 80 non-human primates and compared survival to control for animals treated for 28 days, 60 days and days 1-28 then days 60-88 after exposure with a single daily dose of 5 mg/kg of AEOL 10150 beginning 24 hours post-exposure to 10.74 Gy of Whole Thorax Lung Irradiation (LD75/180). Kaplan-Meier plot analysis showed that initiation of treatment 24 hours post exposure for 60 days yielded the most significant improvement in 180-day survival versus control (p<.05). The MacVittie study demonstrated that 60-day treatment with AEOL 10150 doubled survival at 180 days to 50 percent compared to 25 percent survival in untreated, control animals. The 60-day administration also increased the mean survival time of decedents, diminished lung injury and improved non-sedated respiratory rate.
Pharmacometric-based analysis was performed by Dr. Gobburu's team at the University of Maryland School of Pharmacy to model the various treatment durations and to inform the design of an adequate and well controlled animal efficacy and human phase 1 safety studies. Based on cox-proportional hazard analysis, 60-day treatment significantly decreased the chance of death by 51% compared to control arm (p=0.08; alpha = 0.1). The hazard ratio between treatment arms and the control arm was estimated to be 0.90, 0.49 and 1.09 for the 28 days, 60 days and 1-28 & 60-88 days treatment arms. In addition, comparison of the 60-day treatment arm vs control produced a statistically significant difference in hazard (p=0.0458). In the pneumonitis phase (42-180 days in observed data), the hazard ratio between treatment arms and control arm was estimated to be 0.91, 0.51 and 1.09 for the 28 days, 60 days and 1-28 & 60-88 days treatment arms, and the results from cox-proportional analysis and parametric survival analysis were found to be consistent, demonstrating that NHP's treated for 60 days died 50% less frequently per unit time (day) than control animals during the pneumonitis phase.
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 facilitate the processes leading to radiation induced toxicity across organ systems.
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 lungs, heart, kidneys, central nervous system, and other organ systems. Severe damage to these organ systems may lead to morbidity and mortality among the exposed population, due to immunosuppression, malabsorption, hemorrhage, infection, pneumonitis, pulmonary or myocardial fibrosis, respiratory failure, vascular damage, cerebrovascular injury, systemic or neuro-inflammation 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 neutropenia and antibiotics to treat an infection. Radiation accident victims, treated with these types of products and supportive care, have survived the acute effects of 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 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 by the US Department of Health and Human Services, as a broad spectrum medical countermeasure against chemical and radiological threats, where its initial target indications are as a protective agent against pulmonary injury from radiation or sulfur mustard exposure and brain injury from nerve agent exposure, with dual use in commercial indications involving pulmonary fibrosis, radiation therapy, and neuro-degeneration. 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 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.