Minipig Model Validation for Hearing Research and Drug and Device Development

Project Summary The field of drug delivery to the inner ear is facing a disaster. Otonomy, the most prominent company that led the field for over 10 years, declared bankruptcy following clinical trial failures of multiple therapeutics. Frequency Therapeutics, a second powerhouse, shut down all ear research after clinical trial failures of their FX322 hearing restoration therapy. In the light of these failures, it has become appreciated that drug delivery to the inner ear faces serious technical challenges. One of the primary tenets in pharmacotherapy is that the applied drug must reach the target tissue to exert therapeutic effects. Many small molecules, which enter the ear easily following local applications, readily leak from perilymph and do not distribute well along the length of the cochlea. The limited distribution has been well characterized in guinea pigs. Computer simulations further suggest that restricted drug distribution becomes a proportionately greater problem for the longer, human cochlea. However, computer simulations alone carry little credence without supporting experimental data. The failure of drugs to reach the intended target tissues needs to be clearly demonstrated by credible measurements. We believe that the recent therapy failures could have been avoided if a well-studied large animal model of the inner ear had been available. For the small molecules used in several formulations (dexamethasone in Otonomy’s Otividex; gacyclidine in Otonomy’s OTO-313; Valproate in Frequency Therapeutic’s FX322) confirmation of the inability to deliver drug to mid and apical regions of the cochlea in a large animal model would have driven searches for alternative therapeutics with more suitable pharmacokinetic properties. Today, we still have many biotech companies (some of which work with Turner Scientific) developing therapeutics for the ear without a large animal model to evaluate the PK properties of their formulations. Drugs that may not distribute along larger cochleas are still being pursued. It is imperative to know when a therapeutic for hearing fails to reach the mid and apical regions of the cochlea. Without supporting or opposing measurements, valuable research resources from both private investments and federal grants will be squandered pursuing the development of “no hope” drugs towards failed clinical trials. Turner Scientific will provide the hearing research community with the minipig as a large animal model for drug pharmacokinetics and for implantable device development of the inner ear. But to accomplish this it needs support collecting the baseline data which are required to establish the model in the field. Standard measures for assessing drug efficacy and safety, including pharmacokinetic measurements, ABRs, DPOAEs, and hair cell quantification will be validated in normal and noise-damaged mini pigs, furthering their utility in preclinical studies. In the long-term, this investment will save years of time and resources, avoiding wasteful research spending and perhaps preventing additional bankruptcies of those companies remaining in the hearing therapy field.