Autoimmune inner ear disease (AIED) is the name given to describe a disorder where the ear is the target of an overactive immune system, causing symptoms of progressive hearing loss and/or dizziness. Most cases of AIED are accompanied by hearing loss and tinnitus that occur over a course of a few months1,2 that progresses rapidly to the second ear, indicative of AIED.3 There are currently no FDA-approved medications for the treatment of AIED, or any type of inner ear hearing loss. The use of high dose oral or intratympanic injection corticosteroids to suppress immune function is the most common treatment for AIED. However, the use of high doses of corticosteroids leads to significant side effects. In response to this unmet medical need, O-Ray Pharma has developed a lead formulation of sustained-release fluticasone pellets (OR-102) for the treatment of AIED that will provide a consistent low dose of corticosteroid to the cochlea over a period of three months. The pellet is implanted directly into the cochlea and releases steroid at the affected site to protect against hearing loss. The OR-102 formulation has demonstrated its safety, pharmacokinetics (PK), and efficacy in multiple guinea pig studies. To test the safety and preliminary efficacy of OR-102 in a first-in-human clinical trial in AIED-affected patients, O-Ray Pharma has submitted an IND application to the FDA. The FDA provided tacit approval of the majority of the application save for a request to perform an additional animal study and suggestions for additional Chemistry/Manufacturing/Control (CMC) work. In response, there were no clinical holds pertaining to the clinical protocol and the chemistry/manufacturing/controls procedures. Thus, the IND is on clinical hold pending the completion of a Good Laboratory Practices (GLP) compliant toxicity and pharmacokinetics study. This IND correspondence has provided us with a clear framework towards an IND allowance. The Specific Aims of this Direct to Phase II proposal are, therefore, to complete the following IND-enabling activities: 1) Drug product manufacturing in accordance with current Good Manufacturing Practices (cGMP) for animal and human trials; 2) Performance of a GLP-compliant guinea pig study as guided by FDA feedback, 3) Preparation and submission of an IND response. The milestone for the successful completion of this grant will be the granting of an IND approval. The team of investigators at O-Ray is uniquely qualified to perform the work proposed herein, and has expertise in otology, regulatory affairs, and business development. O-Ray's scientists have successfully developed other therapeutic formulations from concept to FDA approval, including an intraocular sustained- release steroid implant capable of maintaining anti-inflammatory intravitreal drug levels for up to three years from a single implantation. O-Ray's management has previously out-licensed three drug delivery products to larger pharmaceutical companies upon demonstration of proof-of-concept in the target patient populations.
Public Health Relevance Statement: PROJECT NARRATIVE Autoimmune inner ear disease (AIED) is a rare but devastating condition that can result in profound hearing loss. Currently, there is no FDA-approved medication for the treatment of AIED. The use of systemic and/or intratympanic (IT) injection of corticosteroids is the most common AIED treatment and works to suppress immune function. However, there are many complications from long-term steroid use and many AIED patients comment that they would prefer to go deaf and have a cochlear implant than continue the oral high-dose steroids. O-Ray has developed a small pellet (OR-102) that can release a consistent low dose of steroid in the inner ear for 3-6 months. Continued successful development of OR-102 may also lead to broader hearing loss treatments including the protection of hearing loss associated with cochlear implantation.
Project Terms: Adrenal Cortex Hormones; Corticoids; Corticosteroids; Affect; Animals; Anti-Inflammatory Agents; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Chemistry; Ciprofloxacin; Clinical Protocols; Clinical Research; Clinical Study; Clinical Trials; Cochlea; Cochlear Organ; Cochlear Implants; Cochlear Prosthesis; Complication; Dexamethasone; Disease; Disorder; Dizziness; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Ear; Ear Diseases; ear disorder; Environment; Feedback; Goals; Grant; Human; Modern Man; Immune system; allergic/immunologic body system; allergic/immunologic organ system; Kinetics; Labyrinth; Internal Ear; inner ear; Lead; Pb element; heavy metal Pb; heavy metal lead; Methods; Names; middle ear infection; Otitis Media; Patents; Legal patent; Patients; Pharmacokinetics; Drug Kinetics; Investigators; Researchers; Research Personnel; Safety; Steroid Compound; Steroids; Suggestion; Technology; Testing; Ringing-Buzzing-Tinnitus; Tinnitus; Toxicology; Universities; Virginia; Work; fluticasone; Drug Delivery Systems; Drug Delivery; Businesses; Cavia; Guinea Pigs; Guinea Pigs Mammals; Otology; Fluticasone propionate; New Drug Approvals; Investigational New Drug Application; Label; Procedures; Site; Clinical; Residual state; Residual; Phase; Medical; Lifting; Development Plans; Sustainable Development; Comment; Commentary; Editorial Comment; Viewpoint; Published Comment; Letters; Therapeutic; Cochlear Implantation; Cochlear Prosthesis Implantation; Cochlear implant procedure; Scientist; Frequencies; Oral; Protocol; Protocols documentation; Techniques; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Operative Surgical Procedures; meetings; experience; Performance; Animal Models and Related Studies; model of animal; model organism; Animal Model; Hydrogels; Toxicities; Toxic effect; Therapeutic Index; novel; response; Documentation; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; Cellular Immune Function; immune function; Hearing Loss; Hypoacuses; Hypoacusis; dysfunctional hearing; hearing defect; hearing deficit; hearing difficulty; hearing disability; hearing dysfunction; hearing impairment; Address; Dose; Symptoms; Polymer Chemistry; Regulatory Affairs; Preparation; Development; developmental; pre-clinical; preclinical; design; designing; innovation; innovate; innovative; biocompatible polymer; Implant; implantation; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; FDA approved; patient population; common treatment; clinical material; safety testing; stability testing; good laboratory practice; phase 1 study; Phase I Study; phase 2 study; phase II study; phase 3 study; Phase III study; Formulation; preclinical development; pre-clinical development; Injections; first-in-human; first in man; Autoimmune Inner Ear disease; deaf; deafened; profound hearing loss; progressive hearing loss; hearing loss treatment; hearing loss therapy; treatment for hearing loss; side effect; Hearing Protection; protect hearing
