SBIR-STTR Award

Current approaches to treat sudden sensorineural hearing loss (SSNHL) do not maintain inner ear drug concentrations within an appropriate therapeutic window for sufficient lengths of time to achieve therapeutic effect. A novel delivery system for long-term, controlled release of glucocorticoid steroids to the inner ear would constitute a dramatic improvement in SSNHL treatment options. Our proposed strategy uses Precision Particle Fabrication (PPF) to create betamethasone-loaded microspheres for transtympanic injection, round window membrane (RWM) localization, and sustained-release to the inner ear. The central advantage of our approach is that PPF technology allows for precise control of particle size, shape, material, and release rates. Our long-term goal is for transtympanic delivery of PPF-enabled betamethasone-loaded microspheres to be the standard-of-care for people who suffer from SSNHL. We hypothesize that microspheres can be retained on the RWM for two weeks and that betamethasone release can be maintained within 25% of a therapeutic dose (~55 ng/day). We expect that this novel approach will enable sustained levels of therapeutic concentrations of betamethasone to the inner ear that will dramatically improve the safety and efficacy of SSNHL treatments over currently available options. Our research team will first develop and characterize the relationship between the microsphere size and betamethasone release profiles to establish the feasibility of achieving long-term, controlled release to the inner ear (Aim 1). We will then determine the optimal microsphere immobilization strategy to enable RWM localization for a minimum of 14 days with minimal toxicity (Aim 2). The result will be microspheres that sustain a precise betamethasone dose and adhere to the RWM for sufficient time. After establishing the feasibility of this approach, we will, in Phase II, demonstrate our ability to precisely control the pharmacokinetic profile of inner ear betamethasone concentrations in small (mouse) and large (sheep) animal models. This PPF- enabled drug-delivery strategy addresses issues of dosage accuracy and long-term release. In addition, PPF- based encapsulation is highly adaptable and can serve as a transtympanic delivery platform for multiple drug classes. This unique strategy has significant potential to become the standard-of-care for treatment of SSNHL.

Public Health Relevance:
Current approaches to treat sudden sensorineural hearing loss (SSNHL) do not maintain inner ear drug concentrations within an appropriate therapeutic window for sufficient lengths of time to achieve therapeutic effect. A novel delivery system for long-term, controlled release of glucocorticoid steroids to the inner ear would constitute a dramatic improvement in SSNHL treatment options. Our proposed strategy uses Precision Particle Fabrication (PPF) to engineer glucocorticoid-loaded microspheres that are designed to remain localized to the round-window membrane of the inner ear and provide controlled and sustained release of the therapeutic throughout the treatment period.

Public Health Relevance Statement:
Current approaches to treat sudden sensorineural hearing loss (SSNHL) do not maintain inner ear drug concentrations within an appropriate therapeutic window for sufficient lengths of time to achieve therapeutic effect. A novel delivery system for long-term, controlled release of glucocorticoid steroids to the inner ear would constitute a dramatic improvement in SSNHL treatment options. Our proposed strategy uses Precision Particle Fabrication (PPF) to engineer glucocorticoid-loaded microspheres that are designed to remain localized to the round-window membrane of the inner ear and provide controlled and sustained release of the therapeutic throughout the treatment period.

NIH Spending Category:
Biotechnology; Neurosciences

Project Terms:
Address; Adhesives; American; Animal Model; Animals; Anti-inflammatory; Anti-Inflammatory Agents; base; Betamethasone; Biocompatible; Biotechnology; Caliber; Caring; Clinical; clinical practice; Clinical Trials; Complete Hearing Loss; controlled release; Data; design; Diffuse; Disease; dosage; Dose; Drug Controls; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Engineering; Ensure; experience; Film; Glucocorticoids; Goals; Histology; Human; Immobilization; improved; In Vitro; Injection of therapeutic agent; Kansas; Kinetics; Labyrinth; Length; Marketing; Measures; Medical; Membrane; Microspheres; middle ear; Modeling; mouse model; Mus; Needles; novel; novel strategies; Oranges; particle; Particle Size; Pharmaceutical Preparations; Phase; Positioning Attribute; Principal Investigator; professor; Research; Safety; safety study; Scientist; Sensorineural Hearing Loss; Shapes; Sheep; Steroids; Structure of cochlear window; success; Surface; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Effect; Therapeutic Index; Time; Toxic effect; treatment duration; treatment strategy; Universities; Work

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.

Public Health Relevance Statement:


Public Health Relevance:
There are no FDA-approved drugs for the treatment of inner ear diseases that afflict millions of Americans ever year. In their place, physicians often prescribe drugs off-label that - whether delivered orally or through local injection to the ear - lack safety data and show widely variable clinical responses. Orbis Biosciences's innovative inner ear drug delivery platform will enable cost-effective, local delivery and extended-release of new and existing drugs, thereby providing physicians and patients new safe and effective treatments for debilitating diseases of the inner ear.

NIH Spending Category:
Biotechnology; Brain Disorders; Neurosciences

Project Terms:
Acute; Adverse effects; Affect; Agreement; Ambulatory Care Facilities; American; Animal Model; Animals; aqueous; Auditory Brainstem Responses; Autoimmune Process; Betamethasone; Capital; Cavia; Characteristics; Clinical; clinical practice; Cochlear structure; cost; cost effective; Data; Development; Dexamethasone; Disease; Disease Progression; dosage; Dose; Drug Controls; Drug Delivery Systems; Drug Exposure; Drug Formulations; Drug Kinetics; Drug Prescriptions; Ear structure; effective therapy; Encapsulated; evidence base; Exposure to; FDA approved; Film; Foundations; Funding; Future; Glucocorticoids; Goals; Grant; Health Personnel; Histology; Human; improved; In Vitro; in vivo; Injection of therapeutic agent; inner ear diseases; innovation; Investments; Label; Labyrinth; Lead; Legal patent; Length; Liquid substance; Marketing; Measures; Medicine; meetings; Membrane; Meniere's Disease; Methods; Microspheres; middle ear; Modeling; Mus; novel; ototoxicity; Outcome; Pain; particle; Patients; Perilymph; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Physicians; Positioning Attribute; Pre-Clinical Model; preclinical study; Preparation; Procedures; programs; prototype; public health relevance; response; Safety; safety testing; Sensorineural Hearing Loss; Serum; Sheep; Small Business Innovation Research Grant; stability testing; Steroids; Structure of cochlear window; Suspension substance; Suspensions; System; Technology; Therapeutic; Time; Tinnitus; Tissues; Toxic effect; Toxicology; United States National Institutes of Health; Variant