Auris Medical has acknowledged the second Phase III failure in 19 months for its tinnitus candidate Keyzilen® (AM-101), promising a future update on its plans for the company’s co-lead development program.

Auris said Keyzilen failed the TACTT3 trial (NCT02040194) by missing its primary efficacy endpoint of a statistically significant improvement in the Tinnitus Functional Score from baseline to day 84 in participants treated with the drug compared to those treated with placebo, either in the overall population or in the otitis media subpopulation.

TACTT3, which was conducted in Europe, was designed to assess Keyzilen in acute and postacute inner ear tinnitus following traumatic cochlear injury or otitis media. The trial enrolled a combined 893 participants in the acute tinnitus stage (Stratum A) and the postacute tinnitus stage (Stratum B).

The trial’s status was updated to “completed” as of January 16, the date of TACTT3’s most recent update on

“The Company is investigating the outcomes, including those in the previously conducted sister trial TACTT2, and will provide an update in due course,” Auris stated yesterday in a terse statement.

Auris acknowledged the failure of TACTT2 in August 2016, stating that Keyzilen did not reduce tinnitus loudness and tinnitus burden compared to placebo.  

TACTT2 (NCT01803646) was designed to assess Keyzilen in acute inner ear tinnitus following traumatic cochlear injury or otitis media. The trial was conducted primarily in North America, and 343 patients received either Keyzilen 0.87 mg/mL or placebo. The co-primary endpoints were the improvement in subjective tinnitus loudness from baseline to day 84 and the improvement in tinnitus burden from baseline to day 84.

Co-Primary Endpoint Added

Following the failure of TACTT2, Auris shifted improvement in the Tinnitus Functional Score from a key secondary endpoint to an alternate primary endpoint, began increasing the number of patients recruited, and included in confirmatory testing the subgroups of patients with tinnitus following otitis media and patients with severe or extreme tinnitus.

Keyzilen is a small-molecule N-methyl-D-aspartate (NMDA) receptor. According to the company, evidence suggests that NMDA receptors in the cochlea play a major role in the occurrence of tinnitus following acute injury to the inner ear, such as from exposure to excessive noise, infections, disturbances in inner ear blood supply, or the administration of certain ototoxic drugs.

Persistent overexpression of NMDA receptors may lead to pathologic excitation of auditory nerve fibers, which in the brain is perceived as tinnitus.

In November 2017, Auris disclosed the that its acute inner ear (sensorineural) hearing loss candidate AM-111 (brimapitide) had failed a Phase III trial by missing its primary endpoint in the Phase III HEALOS trial (NCT02561091) of statistically significant improvement in hearing from baseline to day 28 compared to placebo.

The setback that has prompted the company to terminate a second late-stage trial.

According to Auris’ website, the next key milestone for AM-111 is discussion of a regulatory pathway with agencies, expected during the second quarter of this year.

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