PharmTech» What advantages do poloxamers offer?

»LeBel: The value of poloxamers is that one can easily draw them into a syringe while they're in solution. [One] can use a traditional 25–27 gauge, with a 4-inch needle, which is long enough to advance through the ear canal and inject the solution into the tympanic cavity or middle ear. Within seconds of encountering the patient's higher body temperature, the solution transitions to a gel. As a gel, the formulation adheres to the epithelial lining of the middle-ear space, where it can remain in place long enough to deliver the drug for a prolonged period of time to the inner-ear fluids.

One other feature of poloxamers is that you can also adjust the concentrations of the polymers to optimally control a drug's release profile. You can develop short or longer-acting drugs by altering the relative concentrations of the polymers.

»LeBel: In animal studies, the observed duration was as short as three consecutive days and as long as six weeks. But we suspect drug can be retained for two or three months.

PharmTech» How will regulators respond to this formulation?

»LeBel: Several of these components, independently and in mixtures, are already on the US Food and Drug Administration's safe list. In addition, these components are in approved pharmaceutical preparations and are commercially available. We typically purchase poloxamer from BASF [Ludwigshafen, Germany]. We recently held our pre-investigational new drug (IND) filing meeting with FDA. We intend to file an IND later this year for the purpose of testing our first drug candidate in humans, and they seem to concur with our strategy, pending formal FDA review of our IND.

PharmTech» Can you tell me about the indication you'll be filing on and more specifically about the steroid?

»LeBel: We'll be testing the use of the steroid dexamethasone in this formulation to treat Meniere's disease.

PharmTech» How did you choose that active pharmaceutical ingredient (API)?

»LeBel: There have been numerous publications in the medical literature suggesting that steroids injected intratympanically provide clinical benefit in the treatment of Meniere's. Many papers report a reduced frequency in episodes of vertigo. But not everyone is in agreement about the results, and we believe that part of the problem is the issue of limited drug exposure. That is, there's some question about whether the adequate delivery of drugs to the middle ear with adequate exposure to the drug can produce a therapeutic benefit. We're hoping that Otonomy's new formulation will allow physicians to settle that question once and for all.

Our clinical trial, which we project will start early in 2010, will look at the dose/response profile of dexamethasone in Poloxamer 407 versus Poloxamer 407 alone in patients with Meniere's disease. Our goal would be to provide a formulation that allows for sustained steroid exposure for approximately one month.

PharmTech» How do you imagine the drug will be packaged once it reaches commercial release?

»LeBel: Ideally, we'd like to offer it in a prefilled syringe or single-use vial. We don't yet know whether it will be premixed or mixed on injection.