Clinical Trials

Date: 2014-03-31

Type of information: Publication of results in a medical journal

phase: 2b

Announcement: publication of results in Otology & Neurotology

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 (an-oxia/ischemia), 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. Following proof of concept, confirmatory Phase III clinical trials are currently under preparation. Patents have been granted in more than 30 countries worldwide to date.

Disease: acute inner ear tinnitus

Therapeutic area: Otorhinolaryngology

Country: Germany, Belgium, Poland and the Netherlands

Trial details:

• The double-blind, randomized, placebo-controlled, parallel-dose phase IIb trial with AM-101 was conducted at 28 study sites in Germany, Belgium, Poland and the Netherlands. A total of 248 patients suffering from persistent acute inner ear tinnitus were randomized to receive three i.t. injections of either AM-101 at 0.27 or 0.81 mg/mL or placebo over three consecutive days. Their tinnitus was triggered by acute acoustic trauma, sudden deafness (idiopathic sudden sensorineural hearing loss, ISSNHL) or otitis media and no older than three months. Trial participants were monitored over 90 days.

Latest news:

• • On March 31, 2014, Auris Medical has announced that results from its phase IIb clinical trial with AM-101 in the treatment of acute inner ear tinnitus have been published in the specialist journal Otology & Neurotology. The trial demonstrated that AM-101 was well tolerated and safe and established proof of concept in the treatment of tinnitus arising from traumatic acoustic injury to the cochlea and otitis media. In particular the trial showed persistent, clinically relevant and statistically significant improvement in several patient-reported tinnitus measures. The trial demonstrated a dose-dependent and persistent improvement in several patient reported outcomes (PROs). Patients suffering from unilateral tinnitus following acute acoustic trauma or otitis media who re-ceived AM-101 0.81 mg/mL showed a gradual and statistically significant improvement 90 days post-treatment in tinnitus loudness, annoyance, tinnitus-related sleep difficulties and in overall tinnitus impact (THI-12 questionnaire) compared with placebo.  Treatment effects of AM-101 were somewhat less pronounced in patients with bilateral rather than unilateral tinnitus since only one ear was treated as a precautionary safety measure. Efficacy outcomes with patients suffering from tinnitus related to ISSNHL were not conclusive for that subgroup overall, owing to an unexpectedly large rate of spontaneous recovery and the heterogeneity in tinnitus origin. Psychoacoustic measures such as the minimum masking level turned out to be insufficiently reliable and did not show re-sults that were consistent with PROs.
• Furthermore, AM-101 showed good safety in the phase IIb trial, and the repeated intratympanic injections were well tolerated. Mean hearing thresholds improved slightly in all treatment groups; the frequency of clinically relevant hearing deterioration overall was low and not significantly different between groups. Adverse events were reported by similar proportions of patients across the treatment groups with no appar-ent clinically relevant differences in frequency, intensity, or relationship to the treatment. Local events ac-counted for greater than 50% of reported adverse events and related mostly to anticipated transient changes in tinnitus perception and hearing following the injection procedure. In 93% of cases, the eardrum was already fully closed again five days after the last injection.
• • On May 17, 2013,  Auris Medical has announced that safety results from clinical development of AM-101 were presented at the 7th International TRI Tinnitus Conference in Valencia, Spain. The accumulated data demonstrate that the treatment and the administration procedure are well tolerated and safe even when repeated several times. The clinical development programme with AM-101 so far comprises a total of three double-blind, randomized, placebo-controlled, clinical trials, of which two have been completed, and one is approaching comple-tion. In the first of the three trials, a Phase I/II study involving 24 patients, the safety of a single dose ad-ministration of AM-101 was demonstrated in a dose escalation up to 0.81 mg/mL. It also revealed minimal systemic exposure from the treatment.
• At the TRI Tinnitus Conference, key safety outcomes from the second study, a Phase IIb clinical trial, were presented for the first time. The study enrolled a total of 248 patients who were treated 3 times over 3 con-secutive days either with AM-101 at 0.27 or 0.81 mg/mL or placebo. Study participants were monitored over 90 days. The primary safety endpoint was the occurrence of clinically relevant hearing deterioration from baseline to Day 30, defined as increase in the pure tone hearing threshold ?15 dB in any two contiguous test frequencies.
• The Phase IIb study confirmed the previous results from the Phase I/II trial and provided a wealth of additional safety and local tolerance data. As expected, the occurrence of clinically significant hearing loss was low, and there were no statistically significant differences between treatment groups, neither for the pri-mary endpoint at D30, nor at any of the other study visits or overall. On average, hearing thresholds im-proved slightly over the 90 day observation period.
• There were no statistically significant and/or clinically significant differences in the frequency, intensity or relationship of adverse events between treatment groups in the Phase IIb study. Most adverse events were mild or moderate in intensity, and local rather than systemic. As expected, the majority of them were re-ported for a transient deterioration in hearing and tinnitus perception, which was mostly related to the tympanotomy performed prior to the injection. They usually resolved upon full closure of the eardrum. At D7, just 7% of eardrums were not fully closed, yet. Other procedure-related transient adverse events like vertigo, ear pain or inflammation were observed only rarely. Serious adverse events were also low in num-bers and all considered unrelated or unlikely related.
• • On June 26, 2012, Auris Medical has announced that results from a phase IIb study with AM-101 were presented at the recent 6th International TRI Tinnitus Conference in Bruges, Belgium. The study demonstrated that the treatment was well tolerated and safe and showed a statistically significant reduction in various tinnitus measures as compared to placebo. The safety assessment of AM-101 in the phase IIb study showed no drug-related impact on hearing function. Anticipated adverse events related to the procedure of i.t. injection were of transient nature and occurred in moderate to low numbers. In terms of efficacy, the study demonstrated a dose-dependent improvement in various measures of the tinnitus symptom and its impact. Patients suffering from acute tinnitus with established cochlear origin (i.e. after noise trauma or otitis media) who received AM-101 at 0.81 mg/ml showed a statistically significant improvement.
• • On October 17, 2011, Auris Medical has announced positive results from a phase IIb clinical trial with AM-101. The study demonstrated that the treatment was very well tolerated and showed a statistically significant treatment effect. Preliminary results from the phase IIb study show that the local treatment with AM-101 was very well tolerated, and in particular that it had no negative impact on hearing. In addition, the study demonstrated a dose-dependent improvement in various measures of tinnitus impairment, disability and handicap.
• • On February 28, 2011, Auris Medical has announced that the company is starting enrolment in its first US clinical trial with AM-101. The TACTT1 will enrol a total of 24 patients for further evaluation of the optimum dosing regimen for AM-101 as well as to generate additional pharmacokinetic data. The inclusion criteria require among others that the tinnitus was triggered by an incident of acute noise trauma, sudden deafness, otitis media, inner ear barotrauma or middle ear surgery not more than 3 months ago. Study participants will receive either AM-101 at 0.81 mg/ml or placebo in a single or triple dose intratympanic injection. Recruitment for the TACTT1 study is expected to be completed before the end of this year.
• • On February 3, 2011, Auris Medical has announced that enrolment has been completed for its phase IIb clinical trial with AM-101 for the treatment of acute inner ear tinnitus. A total of 252 patients were enrolled in the study to receive 3 intratympanic injections of either AM-101 at 0.27 or 0.81 mg/ml or placebo. The study recruited patients suffering from persistent inner ear tinnitus due to acute acoustic trauma, sudden deafness or otitis media not more than 3 months from onset.
• AM-101 was clinically evaluated for the first time in a phase I/II study in 2007/08, which showed that the treatment was well tolerated and safe. The trial also provided some first indications of therapeutic efficacy. This was followed by a much larger phase IIb clinical trial that was conducted in Germany, Belgium, Poland and the Netherlands and that involved more than 240 patients. Results from this study are expected to be released in the second half of 2011.  A third study (TACCT1) is about to start in the USA.

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