Date: 2015-04-20
Type of
information: Publication of results in a medical journal
phase: 2
Announcement: publication of results in Audiology & Neurotology reports
Company: Auris Medical (Switzerland)
Product: AM-101
Action
mechanism:
- NMDA receptor antagonist. AM-101 contains a small molecule that selectively blocks N-methyl-D-aspartate (NMDA) receptors. 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, trauma (e.g. exposure to excessive noise), neuroinflammation, disturbances in inner ear blood supply, or the administration of certain ototoxic drugs. It has been hypothesized that the upregulation of NMDA receptors induced by cochlear excitotoxicity is responsible for aberrant excitation of auditory nerve fibres, which is perceived as tinnitus.
The development of AM-101 is 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. Patents have been granted in more than 30 countries worldwide to date.
Disease: acute peripheral tinnitus
Therapeutic
area: Otorhinolaryngology
Country: Belgium, Germany, Poland, USA
Trial
details:
Latest
news:
- • On April 20, 2015, Auris Medical announced publications related to AM-101 in two peer-reviewed specialist journals. The first article appeared in 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 primary objective for TACTT1 was the evaluation of appropriate dosing regimens by comparing treatment outcomes between a single intratympanic dose of AM-101 or 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. 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 second article was published in 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. The study was conducted by Prof. 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. They focused on the damage to inner hair cells (IHCs)and in particular loss of ribbon synapses as correlate for deafferentation as well as on its 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.
- In the present study, 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.
- • On September 9, 2013, Auris Medical has announced positive results from the TACTT11 study, its second phase II clinical trial with AM-101 for the treatment of acute peripheral tinnitus. The study provided further evidence for the safety and efficacy of the treatment and supports the conduct of phase III confirmatory studies. The randomized, placebo-controlled, double-blind study was conducted in the USA, Belgium, Germany and Poland. It enrolled patients suffering from tinnitus following traumatic injury to the cochlea (acute noise trauma, inner ear barotrauma, middle ear surgery) or otitis media up to 3 months after tinnitus onset. A total of 85 patients were randomized to receive AM-101 at 0.81 mg/mL or placebo by way of intratympanic injection either in a single dose (stage 1 of the trial) or in three doses over two weeks (stage 2) by way of intratympanic injection. Following treatment, study participants were observed for 90 days.
- Preliminary results from the TACTT1 study show that both single and triple dose treatments with AM-101 were well tolerated. Occurrence of adverse events or clinically relevant hearing loss overall was low to moderate with no statistically significant differences between treatment groups and dose regimens. As in the previous studies with AM-101, most adverse events were mild or moderate in intensity and represented transient local effects of the injection procedure. At substance and primary metabolite in blood plasma were close to the analytical limits of quantification, thus confirming the minimal systemic exposure offered by the intratympanic approach.
- In addition, the TACTT1 trial showed a clear trend for superior improvement in AM-101 treated study participants over placebo groups with regards to subjective tinnitus loudness, annoyance, sleep difficulties, tinnitus handicap/impact and tinnitus severity. Although the study was not powered to demonstrate statistical significance between treatment groups, the difference between active and placebo groups was significant for several efficacy outcomes. The results were also broadly in line with the trends observed in the previous phase II trial with AM-101. The primary endpoint, the change in tinnitus loudness from baseline to the last follow-up visit, did not show any statistically significant difference between dose regimens.
- • On February 13, 2013, Auris Medical has announced that enrolment has been completed for its TACTT1 study, a phase II clinical trial with AM-101 for the treatment of acute peripheral tinnitus. A total of 85 patients were enrolled in the study to receive either AM-101 at 0.81 mg/mL or placebo. In Stage 1 of the trial, a single dose intratympanic injection was administered, while in Stage 2 each study subject received a total of 3 intratympanic injections over 2 weeks. The study recruited patients suffering from tinnitus following acute noise trauma, inner ear barotrauma, middle ear surgery or otitis media up to 3 months after onset. Results from the TACTT1 study, which is being conducted in the USA, Belgium, Germany and Poland, are expected to become available in summer 2013.
• On August 10, 2012, Auris Medical has announced that enrolment has been completed for the first of two stages in its TACTT1 phase II clinical trial with AM-101 for the treatment of acute inner ear tinnitus. A total of 40 patients were enrolled in the study and received either AM-101 at 0.81 mg/mL or placebo in a single dose intratympanic injection. The study recruited patients suffering from tinnitus following acute noise trauma, otitis media, inner ear barotrauma or middle ear surgery not more than 3 months ago. The purpose of the TACTT1 study is to further evaluate the optimum dosing regimen for AM-101 as well as to generate additional safety and pharmacokinetic data. It is being conducted in the USA, Belgium, Germany and Poland. In the second stage of the study, a dosing regimen comprising 3 intratympanic injections over 2 weeks will be tested. Enrolment for the TACTT1 study is expected to be concluded before the end of the year.
Is
general: Yes
