Aeolus Pharmaceuticals

Development Plan

Cancer Radiation Therapy

We plan to leverage the substantial investment made by various government agencies in the development of AEOL 10150 as a potential medical countermeasure against the effects of Lung-ARS, chlorine gas and GI-ARS to develop AEOL 10150 in oncology, where it will be used in combination with radiation therapy.  We believe we would be able to use many of the non-clinical studies as support for efficacy and safety as support of a new drug application (“NDA”) filing for oncology indications.

We expect to begin a Phase I/II study in non-small cell lung cancer (“NSCLC”), where AEOL 10150 will be used in combination with radiation therapy, in the first half of 2011.  Later in 2011 we are expecting to begin a Phase I/II study in Mesothelioma, where approximately 30% of the patients succumb to the effects of the radiation therapy.

If we are awarded the contract with BARDA to develop AEOL 10150 for Lung-ARS, we believe that substantially all of the costs associated with the preclinical, chemistry, manufacturing, and controls (“CMC”) and toxicology necessary for the oncology indications, plus a large safety database in humans, will be covered by the contract. We plan on funding the clinical efficacy development of AEOL 10150 in oncology using internally generated funds.

Acute Radiation Syndrome

Lung

Aeolus’ objective is to develop AEOL 10150 as a MCM against ARS pulmonary effects, via the FDA’s “Animal Rule”.  This development pathway requires demonstration of the key study efficacy parameter of AEOL 10150 treatment in two animal models relevant to the human radiation response and its treatment, demonstration of safety in humans, demonstration of relevant dosing and administration in humans, and clear identification of the mechanism of radiation-induced damage to the lung and its amelioration by the drug candidate.

AEOL 10150 has several distinct advantages as a MCM, including the following:

  • Demonstrated survival increase in animal studies when administered 2 hours after exposure (P<0.05),
  • Demonstrated reduction in lung fibrosis in animal studies up to 24 hours post exposure (P<0.05),
  •  Demonstrated histological improvement in lung tissue post-radiation exposure,
  • Addresses an unmet medical need as a MCM to lung ARS,
  • Established safety profile in both clinical and pre-clinical studies,
  • Subcutaneous self-administration possible by exposed individuals during emergency,
  • Rapid administration, allowing large numbers of patients to be treated quickly,
  • Stable for up to 4½ years at 0–8°C and 1 year at room temperature,
  • Requires no non-standard storage conditions (i.e., not photosensitive),
  • Currently in development in oncology, to be used in combination with radiation therapy; if approved will provide a pre-existing distribution and stockpile resource at oncology centers in the event of a radiological emergency,
  • Demonstrated potential as both a therapeutic and prophylactic,
  • Demonstrated potential to address multiple sub-syndromes of ARS,
  • Demonstrated potential to address sulfur mustard gas and chlorine gas exposure, and
  • Potential dual use as an adjunct treatment for cancer patients receiving radiation therapy.

We believe in order to file an NDA for ARS with the FDA, we will need to demonstrate efficacy in Animal Models and demonstrate product safety which is based upon the FDA’s “Animal Rule”.    We also plan on pursuing an Orphan Drug designation and Fast Track submission status for this indication, enabling priority review and enabling rolling NDA submission if accepted by the FDA.

The FDA “Animal Rule” enumerates criteria whereby the FDA can rely on animal efficacy data when “evidence is needed to demonstrate efficacy of new drugs against lethal or permanently disabling toxic substances when efficacy studies in humans, ethically cannot be conducted.  The criteria are as follows:

  • Knowledge of the mechanism of radiation-induced damage to the lung and its amelioration by the candidate drug.
  • Pharmacokinetic and pharmacodynamic analysis to provide information on relevant dose and administration schedule.
  • Direct correlation of key study parameters (e.g., survival or major morbidity) with the desired clinical benefit in humans.
  • Collection of efficacy data in two species relevant to the human radiation response and its treatment unless otherwise justified under GLP-compliant conditions.
  • A Phase 1 safety trial using the same product and formulation as used in the pivotal trial(s) required.

Demonstrate Efficacy in Animal Models

Our efficacy plan is designed to accomplish two key goals: the validation of two animal models for acute radiation-induced lung injury and the generation of pivotal efficacy data in these species. The efficacy data produced in pivotal studies using these validated models will provide the data required to demonstrate efficacy of AEOL 10150 at the dose and schedule proposed for licensure. A second criterion of the “Animal Rule” is that the models must be reflective of “real world” conditions to which a human is likely to be exposed. The proposed models have been designed to reflect these real world conditions. Initial studies have been conducted with whole thorax exposure models to irradiate the total lung parenchym, and will be followed by studies with Total Body Irradiation (“TBI”) with shielding of roughly 5 percent of bone marrow. This study design mimics real world conditions in which it is anticipated that many of those exposed to radiation will benefit from some shielding (e.g., from cars, buildings, etc.), which will protect some bone marrow and allow for survival without a bone marrow transplant. This shielding approach has been used to develop both murine and NHP models for GI ARS and in the NHP for radiation-induced lung injury.

Demonstrate Product Safety

For product approval under the Animal Rule, we will also demonstrate product safety using the same product and formulation used in the animal efficacy trials and proposed for use in humans. Demonstration of safety includes preclinical demonstration of safety via the standard pre-clinical studies and analyses methods and Phase I safety trials sufficient to demonstrate product safety in the target patient population.  We believe our safety studies completed as a therapy for ALS may be utilized to demonstrate safety for this indication.  As a result, we believe it may only be necessary to conduct mutagenicity and teratogenicity studies for completion of the pre-clinical package required for NDA filing and product licensure.  We also plan to conduct two additional Phase I clinical safety studies in patients receiving radiation therapy.  This will provide safety data in a population similar to that for which the final product indication will be targeted (i.e., patients receiving high radiation doses sufficient to cause radiation-related lung damage) for a longer period of treatment with our compound. A secondary benefit of using this population is that prophylactic effects of the product can also be demonstrated; efficacy measures toward achieving this end will be incorporated into the study design.

Gastrointestinal (GI)

In collaboration with the NIH NIAID, we are planning additional studies to confirm the efficacy results demonstrated in the study described above.  During the first quarter of fiscal year 2011, the Company expects NIH-NIAID to initiate a third study of AEOL 10150 in mice.  This study will examine the effects of radiation doses from 9 to 11 Gy on the GI tract, as well as the effect that AEOL 10150 has in mitigating these effects.  Studies examining the effects of 9 to 11 Gy of radiation on the GI tract in non-human primates are expected to begin during the second quarter of fiscal year 2011.   We also expect to perform additional studies which could be funded by NIH, NIAID to optimize dose and duration of delivery, and to evaluate the window of opportunity for treatment after exposure.

Upon completion of these studies we would need to demonstrate efficacy in Animal Models and demonstrate product safety based upon the FDA’s “Animal Rule”.    We also plan on pursuing Fast Track submission status for this indication, enabling priority review and enabling rolling NDA submission if accepted by the FDA.  Under the ‘Animal Rule’, we would need to complete pivotal studies in two species relevant to the human radiation response and its treatment.  We believe that these studies can be completed using existing validated models for both murine and NHP.  This study design would also mimic real world conditions in which it is anticipated that many of those exposed to radiation will benefit from some shielding (e.g., from cars, buildings, etc.), which will protect some bone marrow and allow for survival without a bone marrow transplant.

We will also demonstrate product safety using the same product and formulation used in the animal efficacy trials and proposed for use in humans. Demonstration of safety includes preclinical demonstration of safety via the standard pre-clinical studies and analyses methods and Phase I safety trials sufficient to demonstrate product safety in the target patient population.  We believe our safety studies completed as a therapy for ALS may be utilized to demonstrate safety for this indication.  As a result, we believe it may only be necessary to conduct mutagenicity and teratogenicity studies for completion of the pre-clinical package required for NDA filing and product licensure.  We also plan to conduct two additional Phase I clinical safety studies in patients receiving radiation therapy.  This will provide safety data in a population similar to that for which the final product indication will be targeted (i.e., patients receiving high radiation doses sufficient to cause radiation-related lung damage) for a longer period of treatment with our compound. A secondary benefit of using this population is that prophylactic effects of the product can also be demonstrated; efficacy measures toward achieving this end will be incorporated into the study design.