Efficacy and Safety of AM-101 in the Treatment of Acute Inner Ear Tinnitus—A Double-Blind, Randomized, Placebo-Controlled Phase II Study

Tinnitus, the perception of sound without external acoustic stimulation, is a very common disorder. According to some recent estimates, approximately 25% of American adults have experienced tinnitus, with nearly 8% having frequent occurrences (1). European population studies estimate that 7% to 14% of the population has spoken to their physician about tinnitus, whereas potentially disabling tinnitus occurs in 1% to 2.4% of people (2). Tinnitus may seriously impact the ability to sleep or relax or lead to tiredness, irritation, nervousness, despair, frustration, or depression (3,4). Many tinnitus patients are prepared to try a wide variety of treatments in the search for effective relief (5). Although approaches, such as tinnitus retraining therapy (6) or cognitive behavioral therapy (7), may provide relief for certain patients, there exists no universal standard of care for tinnitus or approved tinnitus drug (8), provoking substantial frustration among patients and physicians (9). AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland) is a small molecule noncompetitive NMDA receptor antagonist that is being developed for treatment of acute inner ear tinnitus. Cochlear NMDA receptors are located at the inner hair cell postsynapse (10) and upregulated during neosynaptogenesis after glutamate excitotoxicity (11), which can be triggered, for example, by acoustic trauma or hypoxia (12). In cochlear neosynaptogenesis, glutamate has a neurotrophic role via the activation of NMDA receptors (13). It has been proposed that during this critical process of regrowth and synaptic repair of auditory dendrites, the auditory nerve may be particularly susceptible to (aberrant) excitation via NMDA receptors (14), thus generating “phantom noise.” It has been suggested that the initiation phase of cochlear tinnitus is dependent on NMDA receptor activity in primary auditory neurons similar to memory processes during a consolidation window (15,16). AM-101 aims to treat tinnitus in the acute stage before it becomes centralized or memorized at higher structures of the auditory system and/or brain. It is delivered in a hyaluronic acid gel formulation by intratympanic (I.T.) injection into the middle ear from where the active substance diffuses across the round window membrane into the cochlea. This approach provides for a highly targeted cochlear therapy with only minimal systemic exposure (17,18). Clinical development with AM-101 was initiated with a randomized, double-blind, placebo-controlled phase I/II study, which enrolled 24 patients with acute tinnitus after acute acoustic trauma (AAT) or ISSNHL (19). Single doses of AM-101 were well tolerated up to the maximum tested concentration of 0.81 mg/ml, and only small traces of the active substance and its primary metabolite (<0.3 ng/ml) could be detected in blood plasma, confirming minimal systemic exposure. In addition, gradual improvement in tinnitus was observed over the 60-day observation period. Based on these outcomes, a larger study was designed to evaluate AM-101’s efficacy and safety. The eligible patient population was broadened to include also patients with tinnitus after acute otitis media (OM). Inner ear hearing loss and tinnitus are sometimes sequelae of middle ear inflammation as presumably pathogens migrate from the middle into the inner ear; the proinflammatory cytokine IL-1β has been suggested as a trigger of glutamate excitotoxicity in various neurologic disorders (20). The dose regimen was extended from single to triple injections to address potential variability in drug exposure at the round window membrane, and the observation period was extended to 90 days to capture any continued effects.