Brimapitide

What is Brimapitide?#

Brimapitide (AM-111, D-JNKI-1) is a synthetic 31-amino acid cell-penetrating peptide designed to inhibit the c-Jun N-terminal kinase (JNK) signaling pathway. It was developed by Auris Medical (now part of Altamira Therapeutics) for the treatment of acute idiopathic sudden sensorineural hearing loss (ISSNHL), a condition characterized by rapid-onset hearing loss of unknown cause.

The drug was administered as a single intratympanic injection in a biocompatible, biodegradable hyaluronic acid gel, allowing sustained local drug delivery to the inner ear without systemic exposure.

Mechanism of Action#

JNK is a mitogen-activated protein kinase (MAPK) that is activated by various forms of cellular stress. In the cochlea, JNK activation following acute injury (noise trauma, ischemia, ototoxic drugs) triggers apoptosis of sensory hair cells and supporting cells, leading to permanent hearing loss.

Brimapitide blocks JNK signaling through a two-component design:

1. TAT domain: A 10-amino acid sequence derived from HIV transactivator of transcription that enables the peptide to cross cell membranes and enter cells
2. IB1/JIP1 effector domain: A 19-amino acid sequence derived from the JNK scaffold protein IB1/JIP1 that competitively blocks JNK binding to its substrates
3. Proline spacers: Two proline residues connecting the two functional domains

The entire peptide is composed of D-amino acids, making it resistant to proteolytic degradation and providing a long intracellular half-life.

Development History#

Important Considerations#

Brimapitide development has been discontinued. While it demonstrated a significant treatment effect in the profound hearing loss subgroup, the failure to meet the primary endpoint in the overall population and early termination of the ASSENT trial led to the end of the program.

Key Research Findings#

Efficacy and Safety of AM-111 in the Treatment of Acute Unilateral Sudden Deafness - A Double-blind, Randomized, Placebo-controlled Phase 3 Study, published in Otology and Neurotology (Staecker H et al., 2019; PMID: 31083077):

Phase 3 HEALOS trial evaluating single-dose intratympanic AM-111 (0.4 mg/mL or 0.8 mg/mL) versus placebo gel in 256 patients with acute unilateral ISSNHL presenting within 72 hours.

• Primary endpoint not met in the overall study population
• Post-hoc analysis showed significant effect in profound ISSNHL subgroup (n=98)
• AM-111 0.4 mg/mL group showed 42.7 dB improvement versus 26.8 dB placebo in profound subgroup (p=0.0176)

Efficacy and safety of AM-111 in the treatment of acute sensorineural hearing loss - a double-blind, randomized, placebo-controlled phase II study, published in Otology and Neurotology (Suckfuell M et al., 2014; PMID: 24979398):

Phase 2 double-blind, randomized, placebo-controlled trial of AM-111 intratympanic injection in patients with acute sensorineural hearing loss.

• Established proof of concept for AM-111 in severe-to-profound hearing loss
• Drug and administration procedure were well-tolerated
• JNK activation appears most relevant in cases with pronounced cochlear injury

Related Reading#

• Brimapitide research studies and evidence
• Brimapitide dosing protocols
• Brimapitide side effects profile
• BPC-157 research guide
• Ziconotide research guide