Auris Medical Holding AG, a Switzerland-based clinical-stage company developing therapeutics for hearing conditions, announced that articles have been published in two peer-reviewed journals related to AM-101, the company’s drug developed for treating acute inner ear tinnitus. The first article appeared in the April 8, 2015 edition of Audiology & Neurotology and describes the outcomes from TACTT1, the second randomized, placebo-controlled, double-blind phase 2 clinical trial conducted with AM-101 in the treatment of acute inner ear tinnitus. The second article was published in the March 26, 2015 edition of Cellular Physiology and Biochemistry and presents the results of a study of AM-101 in an animal model of tinnitus induced by acute noise trauma.

“We are very pleased to see these important additional pre-clinical and clinical data published on our AM-101 program,” said Thomas Meyer, Auris Medical’s founder, chairman, and CEO. “They add further to our understanding of the pathogenesis of inner ear tinnitus as well as AM-101’s therapeutic effects and potential clinical use.”

According to the announcement from Auris Medical, the primary objective for TACTT1 was the evaluation of appropriate dosing regimens by comparing treatment outcomes between a single intra-tympanic dose of AM-101 and three doses spread over two weeks. The trial showed a consistent trend for superior tinnitus improvement for AM-101 treatments over placebo that was similar for both dose regimens, says the company. The primary endpoint, the change in tinnitus loudness from baseline to the last follow-up visit, did not show a statistically significant difference. The comparison of the primary endpoint effect sizes observed in TACTT1 with the corresponding value in the preceding TACTT0 trial revealed that the best results were achieved with repeated injections over a short treatment cycle.

“The TACTT1 trial provided further evidence of AM-101’s therapeutic benefits in the treatment of acute inner ear tinnitus and additional support for our choice of dose regimen,” said Bettina Stubinski, Auris Medical’s Chief Medical Officer. “The repeated application of AM-101 over a few days is well tolerated and allows for concentrated inhibition of cochlear NMDA receptors, while limiting the procedural impact on the patient.” In the currently ongoing phase 3 trials, AM-101 or placebo are administered three times over 3-5 days.

Auris Medical says the second study article on AM-101 was based on research conducted by Professor Marlies Knipper and colleagues at the Tübingen Hearing Research Center in Germany. The researchers sought to further assess the role of aberrant NMDA receptor activation and related auditory nerve excitation in the generation of tinnitus following traumatic injury to the cochlea. Auris reports that the researchers focused on the damage to inner hair cells (IHCs) and, as well as on the impact on auditory brainstem responses (ABRs). Previous studies had shown that a pattern of severe IHC ribbon loss and reduced ABR wave size after acute noise trauma was linked to high-frequency hearing impairment and tinnitus.

According to the study article, the researchers administered AM-101 to the inner ear of laboratory rats in single or repeated doses several days after exposure to tinnitus-triggering noise trauma. They found in AM-101 treated animals a significant reduction in trauma-induced loss of IHC ribbons and superior preservation of the centrally generated ABR wave amplitudes. While the IHC ribbon synapses and signal transmission in the auditory nerve were conserved, the treatment had no negative effect on hearing thresholds. The authors concluded that round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus by counteracting maladaptive auditory patterns in the ascending auditory pathway.

AM-101: A New Tinnitus Drug in Development

According to Auris Medical, AM-101 is a small molecule N-methyl-D-aspartate (NMDA) receptor antagonist formulated in a biocompatible gel for intratympanic injection. Emerging evidence suggests that NMDA receptors in the cochlea play a major role in the occurrence of tinnitus following inner ear excitotoxicity, which is characterized by excessive synaptic release of glutamate, the principal neurotransmitter in the auditory system. Cochlear excitotoxicity may be triggered by, for example, exposure to excessive noise, neuroinflammation, disturbances in inner ear blood supply (anoxia/ischemia), or the administration of certain ototoxic drugs. It has been proposed that the upregulation of NMDA receptors induced by cochlear excitotoxicity is responsible for aberrant excitation of auditory nerve fibers, which is perceived as tinnitus.

The development of AM-101 is reportedly based on research conducted at the INSERM Institute for Neurosciences of Montpellier, France. The clinical development of AM-101 was initiated by Auris Medical in 2007 and comprises three completed clinical trials to date. Currently, two pivotal trials with AM-101 are ongoing in North America and Europe (TACTT2 and TACTT3). In 2013, Auris Medical reached agreement with the US Food and Drug Administration (FDA) under a Special Protocol Assessment (SPA) for its pivotal TACTT2 study. Patents have been granted in more than 40 countries worldwide so far.

Source: Auris Medical