Research Project
9132197
? DESCRIPTION (provided by applicant): New treatment options are needed for inner ear disorders including Meniere's disease, sensorineural hearing loss, autoimmune inner ear disease, and tinnitus. In the absence of FDA-approved drugs, physicians use improvised treatments, including the administration of off-label steroids, which lack safety and efficacy data These ad hoc approaches often fail to achieve the desired outcomes; a result potentially attributable to insufficient and variable drug exposure in the inner ear. Orbis Biosciences's extended-release inner ear drug delivery platform, Unison, has the potential to significantly improve treatment for a wide-range of otic disorders by maintaining precise and therapeutic drug levels in the inner ear for more than thirty (30) days after a single, cost-effective intratympanic injection. The Unison platform is a composite of: (1) drug-loaded microspheres - produced using Orbis' patented Precision Particle Fabrication technology - that allow for precise control of drug release, and (2) a novel Fast Film- forming Agent (FFA) that severs as both a diluent for microsphere injection and a film that holds the microspheres to the Round Window Membrane (RWM), allowing the microspheres to continuously deliver their drug payload to the inner ear for over a month. The first product to use the Unison platform is ORB-202, an extended release betamethasone for the treatment of steroid-responsive otic disorders. Upon successful FDA approval, ORB-202 will replace the current clinical practice of multiple intratympanic injections of aqueous suspensions spaced over the course of several weeks, a treatment that is painful, inconvenient, and often ineffective. Under SBIR Phase I, Orbis successfully developed a prototype of Unison and ORB-202. Orbis used its patented Precision Particle Fabrication technology to successfully encapsulate and control the in vitro release of betamethasone, a potent, glucocorticoid steroid. Concurrently, Orbis developed a FFA capable of affixing microspheres in the RWM for over thirty (30) days and demonstrated that this novel FFA was non-toxic in mice. The objective of this SBIR Phase II proposal is to demonstrate the safety and efficacy of ORB-202 in preclinical models for both small and large animals and to hold a pre-IND meeting with the FDA in preparation for an IND-filing during Phase III of this SBIR program. Orbis will first establish the in vitro-in vivo correlation of ORB-202 in guinea pigs along with shelf stability testing of the ORB-202 components (Aim 1). Subsequently, Orbis will characterize the safety, pharmacology, and toxicology of ORB-202 in guinea pigs using an acute ototoxicity model (Aim 2). Finally, Orbis will establish the dose-response curve of ORB-202 in a large animal, sheep model (Aim 3), to characterize the dose requirements in an animal with inner ear fluid volume near the size of the human. At the completion of this Phase II SBIR program, Orbis will have established the safety and efficacy of ORB-202 to achieve steady concentration of steroid in the inner ear for a minimum of thirty (30) days in both small and large animal models, thereby positioning the resultant formulation for IND-enabling preclinical trials.
