Pipeline

Otonomy is developing a portfolio of locally delivered drug products to treat a broad set of otic disorders including hearing loss, balance problems, 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 injection 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 a thin membrane called the round window membrane (see figure below). This 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.

The clinical benefits of intratympanic (IT) drug treatment have been demonstrated in numerous physician-sponsored studies. 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, Battaglia et al.² have demonstrated a higher response rate following IT steroids than a standard course of 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 3 weekly injections in the Battaglia protocol) 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 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 GRAS-listed 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 product opportunities possible, Otonomy has advanced two candidates into active development:

• OTO-104 is a sustained release 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 roughly 3 million patients per year in the US alone. A clinical trial has been initiated in Ménière’s Disease patients and future studies are being planned for acute hearing loss.
• OTO-203 is a sustained release anti-infective being developed for the treatment of otitis media. Otonomy anticipates filing an IND application for OTO-203 in early 2011.
• Investigations are underway regarding product candidates for other otic disorders including age-related hearing loss, otosclerosis, and 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.
²Battaglia A, Burchette R, Cueva R. Combination Therapy (Intratympanic Dexamethasone + High-Dose Prednisone Taper) for the Treatment of Idiopathic Sudden Sensorineural Hearing Loss. Otology and Neurology. 2008;29(4): 453-60.