Auris Medical is developing AM-111 for the treatment of acute inner ear (sensorineural) hearing loss (ASNHL). AM-111 contains brimapitide, or D-JNKI-1 (D-stereoisomer of c-Jun N-Terminal Kinase Inhibitor 1), an inhibitor of the JNK stress kinase coupled to an intracellular transporter. AM-111 is formulated in a biocompatible and fully biodegradable gel and administered in a single dose intratympanic injection into the middle ear. From there the drug diffuses through the round window membrane into the cochlea.
AM-111 received orphan drug designation from both EMA and FDA for the treatment of ASNHL. AM-111 has the potential to become the first approved pharmaceutical treatment for ASNHL.
JNK is a signal transmitting enzyme that regulates a number of important cellular activities, including activation of genes encoding inflammatory molecules or promoting cell death (apoptosis). JNK is activated following various types of cochlear insults (stress) that may lead to ASNHL. AM-111 enters cells and binds to JNK, thereby inhibiting activation of transcription factors such as c-jun and c-fos. This in turn prevents JNK mediated apoptosis and inflammatory response, which could otherwise result in irreversible loss of hair cells and cochlear neurons. AM-111 supports natural recovery processes and helps to prevent or reduce chronic hearing loss.
AM-111's otoprotective effect has been demonstrated in various animal models of cochlear stress, including acute acoustic trauma, acute labyrinthitis (inflammation), drug ototoxicity (aminoglycosides), bacterial infection, cochlear ischemia and cochlear implantation trauma.
Auris Medical is conducting two pivotal clinical trials with AM-111 in the treatment of ISSNHL: the HEALOS trial ((Efficacy and Safety of AM-111 in the Treatment of Acute Inner Ear Hearing Loss) Europe/Asia, initiated in Q4/2015) and the ASSENT trial (Efficacy and Safety of AM-111 as Acute Sudden Sensorineural Hearing Loss Treatment; North America and South Korea, initiated in Q2/2016).
In a Phase 2 trial, patients with ASNHL following acute acoustic trauma or sudden deafness were enrolled within 48 hours from onset. Patients with severe to profound hearing loss (i.e. hearing thresholds ≥ 60 dB at the three worst affected test frequencies) who were treated with AM-111 0.4 mg/mL showed a clinically revelant improvement in hearing threshold, speech discrimination and a higher rate of complete tinnitus remission compared with placebo. The therapeutic effect was clinically meaningful (more than 10 dB better than placebo) already at Day 3 and continued to do so to Day 30 and Day 90. Improvement in the AM-111 2.0 mg/mL group tended to be lower and failed to reach significance. In patients who were treated more than 24 hours after ASNHL onset the treatment effect was larger as the rate of spontaneous recovery decreased.
No therapeutic benefit was observed in patients with mild to moderate hearing loss as they recovered essentially all of their initial hearing loss naturally, respectively recovered most of it.
AM-111 was safe and well tolerated in the Phase 2 clinical trial. There were no statistically significant differences in the occurrence of clinically relevant hearing deterioration in the treated ear. Also, there were no apparent differences in the frequency of adverse events between placebo and AM-111 treated patients at any time points, no systemic side effects and no negative impact on balance or tinnitus. There were transient procedure related effects such as ear discomfort or pain, incision site complications or middle ear infection in less than 5% of patients.