Drugs in Clinical Pipeline: AM-111

AM-111 (D-JNKI-1 gel for intratympanic injection) is a 31-amino acid cell-permeable peptide, formulated in a biocompatible hyaluronic acid gel that is being developed for topical treatment of acute inner ear (sensorineural) hearing loss (ASNHL). AM-111 contains the synthetic peptide 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. D-JNKI-1 is formulated in a biocompatible and fully biodegradable gel. It is administered by a single dose intratympanic injection into the middle ear. From there the drug diffuses through the round window membrane into the cochlea.

AM-111 contains the synthetic peptide H-D-Asp-D-Gln-D-Ser-D-Arg-D-Pro-D-Val-D-Gln-D-Pro-D-Phe-D-Leu-D-Asn-D-Leu-D-Thr-D-Thr-D-ProD-Arg-D-Lys-D-Pro-D-Arg-D-Pro-D-Pro-D-Arg-D-Arg-D-Arg-D-Gln-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-D-Gly-NH2.

AM-111’s effector domain has been derived from the scaffold protein islet-brain 1, which retains c-Jun N-terminal kinase (JNK) in the cytoplasm; it is coupled to the trans-activator of transcription (TAT) protein transduction domain. JNK is a member of the stressactivated group of mitogen-activated protein kinases involved in apoptosis after extracellular stress insults and inflammation. Its inhibition prevents formation of transcription complexes and further progress along the apoptotic pathway or activation of genes, which are encoding inflammatory molecules.

AM-111 received orphan drug designation from both EMA (June 2005) and US-FDA (April 2006) for the treatment of ASNHL. AM-111 has the potential to become the first approved pharmaceutical treatment for ASNHL.


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. 

Common Name: AM-111

Synonyms: AM-111; AM111; AM 111; D-JNKI-1; XG-102; XG102; XG 102; AM111 peptide; XG102 peptide

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Mechanism of Action: Kinase Inhibitor; JNK Inhibitor; c-Jun N-terminal Kinase Inhibitor

Indication: Treatment of Sensorineural Hearing Loss; Cardiovascular Therapy; Eye disorder Therapy; Neuroprotectants

Development Stage: Phase III

Company: Auris Medical/Xigen

References:
1. Suckfuell, M.; et. al. Efficacy and safety of AM-111 in the treatment of acute sensorineural hearing loss: a double-blind, randomized, placebo-controlled phase II study. Otol Neurotol 2014, 35(8), 1317-1326.