Otonomy is developing a portfolio of locally delivered drug products to treat a broad set of otic disorders including hearing loss, balance problems, tinnitus and otitis media. The topical delivery of antibiotics to treat recurrent or persistent otitis media in patients with a tympanostomy tube has already been widely adopted. More recently, otolaryngologists have demonstrated that the administration of drugs into the middle ear via intratympanic (IT) injection can provide dosing to the inner ear as a treatment for various hearing and balance disorders. The use of IT injections holds great promise for the otology field just as intravitreal injections helped revolutionize the treatment of ophthalmic disorders.
In an IT injection, drug is injected into the middle ear cavity through a small puncture hole in the tympanic membrane. Drug then enters the inner ear compartment via diffusion through the round window membrane (see figure below). This thin membrane is permeable to small and large molecules thereby providing ready access to both the cochlear (hearing) and vestibular (balance) organs. Preclinical and clinical studies have demonstrated that intratympanic injections result in higher inner ear drug levels and lower systemic exposure than either oral or intravenous routes of administration.
Numerous physician-sponsored studies have demonstrated the clinical benefits of intratympanic (IT) drug treatment. The most widely studied treatment involves the use of IT steroids to treat disorders with acute symptom onset such as Ménière’s disease and sudden sensorineural hearing loss. In Ménière’s, Garduno et al.¹ reported an immediate and durable improvement in the frequency of vertigo symptoms experienced by patients treated with IT steroids compared to placebo. And in patients suffering from sudden sensorineural hearing loss, Rauch et al.² have demonstrated that treatment with IT steroids provided comparable hearing improvement to high dose oral steroids.
While these and other favorable clinical results are driving increased use of IT treatment for various hearing and balance disorders, widespread adoption requires an improved delivery system. The critical drawback with solution-based drug formulations used off-label by clinicians today is the rapid elimination of drug down the Eustachian tube as soon as the patient talks, swallows or sits up. To address this problem, physicians often require patients to undergo repeat injections per course of treatment (5 consecutive daily injections in the Garduno study and 4 injections over 2 weeks in the Rauch study) and to remain immobilized for an extended period of time following each injection. Rapid elimination of solutions from the ear increases treatment variability, decreases patient compliance and reduces physician acceptance.
Otonomy has developed a breakthrough proprietary formulation that eliminates the need for multiple IT injections and can be applied to a broad range of therapeutics. The key component of this formulation is a thermosensitive gel which increases residence time in the middle ear thereby enabling higher levels of drug exposure to the inner ear. Preclinical studies confirm the sustained drug delivery profile and advantages over solution-based formulations. Applicability of this technology has been demonstrated across a number of therapeutic classes which are claimed by Otonomy under its broad patent estate. Of the many possible product opportunities, Otonomy has advanced two of its three product candidates into clinical development:
- OTO-104 is a sustained-exposure formulation of the steroid dexamethasone. Based on the current use of oral and IT steroids in the treatment of hearing and balance disorders, the target market for OTO-104 is more than one million patients per year in the U.S. alone. A Phase 1b study of OTO-104 has been completed in patients with Ménière’s disease. Lambert et al3 reported OTO-104 to be safe and well-tolerated. Furthermore, patients treated with OTO-104 experienced clinically meaningful reductions in vertigo frequency and improvements in tinnitus as compared to placebo. A pivotal Phase 2b clinical study is underway and completion of enrollment is anticipated in mid-2014. Top line results are expected to be available during the fourth quarter of 2014. The FDA has granted OTO-104 Fast Track designation. Further studies are being planned.
- OTO-201 is a sustained-exposure formulation of the antibiotic ciprofloxacin designed to treat various middle ear conditions including recurrent or persistent otitis media. A Phase 1b clinical trial has been completed in pediatric patients undergoing tympanostomy tube placement surgery. Study results showed that OTO-201 reduced the risk of treatment failure, as measured by the occurrence of post-operative otorrhea (drainage) or use of rescue antibiotics, by more than 60% versus control (p<0.05). Two Phase 3 clinical trials are underway with OTO-201 in pediatric patients with bilateral middle ear effusion requiring tympanostomy tube replacement. Completion of enrollment is expected during the second quarter of 2014. Additional clinical trials are being planned.
- OTO-311 is a sustained-exposure formulation of the N-Methyl-D-Aspartate (NMDA) receptor antagonist gacyclidine. Emerging clinical data, including pilot studies conducted with gacyclidine, support the use of NMDA antagonists as treatments for tinnitus.
1Garduno MA, De Toledo HC, Hinojosa-Gonzalez R, Pane-Pianese C, Rios-Castaneda LC. Dexamethasone Inner Ear Perfusion by Intratympanic Injection in Unilateral Ménière’s Disease: A Two-year Prosepctive, Placebo-Controlled, Double-blind, Randomized Trial. Otolaryngology-Head and Neck Surgery. 2005;133(2): 285-294.
2Rauch SD et al. Oral vs Intratympanic Corticosteroid Therapy for Idiopathic Sudden Sensorineural Hearing Loss - A Randomized Trial. Journal of the American Medical Association, 2011; 305(2); 2071-2079
3Lambert PR, et al. A Randomized, Double-Blind, Placebo-Controlled Clinical Study to Assess Safety and Clinical Activity of OTO-104 Given as a Single Intratympanic Injection in Patients With Unilateral Ménière's Disease. Otology & Neurology, 2012; 33:1257-1265.