Brimapitide
Brimapitide (XG-102, AM-111, D-JNKI-1), cell penetrating JNK inhibitor peptide
Written by Aaron CuhaReviewed Sep 2026
Also known as: XG-102, AM-111, D-JNKI-1, KU002
A 31 residue D-amino acid peptide that blocks the stress kinase JNK. Its phase 3 in sudden hearing loss (256 people) did not meet its primary endpoint, and the two phase 3 trials in post-cataract inflammation (648 people) completed in 2016 with no results posted or published.
Overview
Brimapitide is a peptide built from D-amino acids (which resist breakdown) that links a cell penetrating sequence from the HIV TAT protein to a fragment that blocks c-Jun N-terminal kinase, an enzyme that drives programmed cell death after injury. It has had three names in three programmes: D-JNKI-1 in the laboratory, AM-111 at Auris Medical for hearing loss, and XG-102 at Xigen for eye inflammation. More recently it has been called KU002 in an interstitial cystitis programme.
The hearing programme is the one with published results. A phase 2 in 210 people with acute hearing loss (Auris Medical, 2014) did not show a benefit in the whole group, which the authors attributed to strong spontaneous recovery in milder cases, but reported a benefit in the severe to profound subgroup. The phase 3 that followed, in 256 people with severe to profound idiopathic sudden sensorineural hearing loss given a single intratympanic injection, was designed to confirm that: the primary endpoint, hearing improvement to day 28, was not met in the overall population. The authors report a post hoc, nominally significant effect of the lower dose in patients with profound loss. A second phase 3 (NCT02809118) was stopped after 56 participants because of the first trial's result. In the eye programme, a 20 person phase 1b of subconjunctival XG-102 after surgery or trauma was well tolerated, and two phase 3 trials in post-cataract inflammation totalling 648 participants completed in 2015 and 2016; neither has results on the registry or a publication that could be located.
In animals, the peptide protects hearing in guinea pig and rodent models of noise, implant and labyrinthitis injury, and in 5XFAD Alzheimer model mice reduced plaque burden and cognitive deficits at 10 mg/kg intravenously every three weeks. Nothing from the Alzheimer work has been tried in a person. Brimapitide is not approved anywhere.
Mechanism of action
In people, what is established is pharmacokinetic and safety: a single intravenous infusion of 10 to 80 mcg/kg in 24 healthy men gave a half-life of roughly 20 to 40 minutes with mild adverse events not related to dose, and after subconjunctival injection the peptide was undetectable in plasma at doses up to 450 mcg. That the peptide reaches and inhibits JNK in a human cochlea or retina has not been shown directly; it is inferred from the animal work. In animals and cells, the TAT derived sequence carries the peptide across membranes, and a JNK binding fragment (taken from the scaffold protein JIP-1) prevents JNK from phosphorylating c-Jun, interrupting the mitochondrial cell death pathway in hair cells and neurons after noise, drug or ischaemic injury. The hearing trial authors interpret their subgroup result to mean JNK activation only becomes important after large acute injuries, which is a hypothesis to explain a failed primary endpoint, not a demonstrated mechanism in humans.
Human evidence
Roughly 1,200 people have received brimapitide across two hearing loss trials, a terminated third, two eye phase 3 trials, a phase 1b and a phase 1. The one adequately powered trial with a published result, the 256 person hearing phase 3, did not meet its primary endpoint.
- Phase 3, sudden hearing loss (2019): 256 patients, single intratympanic injection, primary endpoint (hearing improvement to day 28) not met overall; post hoc nominally significant effect of 0.4 mg/mL in profound loss. Developer funded.
- Phase 2, acute hearing loss (2014): about 210 patients, no benefit in the whole population; benefit reported in the severe to profound subgroup, which became the phase 3 population. Developer funded.
- NCT02809118: second phase 3, terminated at 56 participants after the first phase 3 reported.
- Post-cataract inflammation: two phase 3 trials, 339 and 309 participants, completed 2015 and 2016, no results posted and no publication located.
- Phase 1b, eye inflammation: 20 patients, single subconjunctival dose, well tolerated, uncontrolled.
- Phase 1, healthy men: 24 participants, intravenous 10 to 80 mcg/kg, well tolerated, half-life under an hour.
- Interstitial cystitis: a 2024 review describes a phase 1/2a exploratory trial of intravesical brimapitide (KU002) with minimal systemic exposure and reported symptom improvement; the trial itself has not been published.
What this does not tell you: The hearing result is a failed primary endpoint with a post hoc subgroup, which is hypothesis generating and nothing more until a prospective trial in profound loss confirms it; the trial designed to do that was stopped. The eye phase 3 trials are unreported, so their outcome is unknown, and a completed trial with no posted result after nearly a decade is itself a finding. There is no human data of any kind for the Alzheimer, colitis or general neuroprotection uses that appear in catalogues. Every human exposure was a single dose by a local route; nothing is known about repeated systemic dosing.
Reading the research record
Brimapitide has been through three sponsors and three indications, and the pattern across them is the same: a mechanism that is convincing in injured animal tissue, and human trials in which the whole treated population does not separate from placebo. Auris Medical funded the hearing programme, and the drift from a phase 2 subgroup to a phase 3 population to a phase 3 post hoc subgroup is worth following closely, because it is how a programme can keep finding a responder group one step ahead of the trial that would test it. The authors' own word for the phase 3 subgroup result is nominally significant, meaning not adjusted for the multiple comparisons that produced it.
Xigen's two post-cataract phase 3 trials enrolled 648 people and completed by early 2016. Ten years on, neither has results on ClinicalTrials.gov and no publication could be located. Sponsors are not obliged to publish, and unreported trials skew the visible record toward whatever did get published. The interstitial cystitis work under the KU002 name is described only in a 2024 review by people involved in the programme, and the underlying trial data have not appeared. None of this says the peptide is inactive. It says that after roughly 1,200 human exposures, the published evidence for a clinical benefit rests on a subgroup analysis.
The evidence, charted
Fig. 1 · evidence composition
6of 7 citations (86%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 5 distinct years, 2014 to 2019, counted from the citation list on this page. The newest citation on file is from 2019, more than five years ago; the published record may have gone quiet.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Key studies & citations
- Human2019
Efficacy and Safety of AM-111 in the Treatment of Acute Unilateral Sudden Deafness: A Double-blind, Randomized, Placebo-controlled Phase 3 Study
256 patients aged 18 to 65 within 72 hours of severe to profound idiopathic sudden sensorineural hearing loss, 51 European and Asian sites, single intratympanic injection of 0.4 or 0.8 mg/mL or placebo. The primary endpoint, hearing improvement to day 28, was not met in the overall population. A post hoc analysis reported a nominally significant effect of 0.4 mg/mL in patients with profound loss. Sponsored by Auris Medical, the developer (NCT02561091).
Otology & Neurotology - Human2014
Efficacy and safety of AM-111 in the treatment of acute sensorineural hearing loss: a double-blind, randomized, placebo-controlled phase II study
About 210 patients within 48 hours of acoustic trauma or idiopathic sudden hearing loss, 25 European sites, 0.4 or 2.0 mg/mL or placebo. No treatment benefit in the whole population, which the authors attribute to spontaneous recovery in milder cases; a benefit was reported in the severe to profound subgroup (threshold 60 dB or worse). Sponsored by Auris Medical (NCT00802425).
Otology & Neurotology - Human2016
Efficacy and Safety of AM-111 as Acute Sudden Sensorineural Hearing Loss Treatment (NCT02809118)
Second phase 3, terminated after 56 of the planned participants. Sponsor's stated reason: availability of relevant new efficacy data from another study, meaning the failed primary endpoint of the first phase 3.
ClinicalTrials.gov, Auris Medical - Human2014
XG-102 administered to healthy male volunteers as a single intravenous infusion: a randomized, double-blind, placebo-controlled, dose-escalating study
24 healthy men, single intravenous doses of 10, 40 or 80 mcg/kg over 60 minutes (6 per dose) or placebo (2 per dose). Adverse events were mild to moderate and not dose related; geometric mean half-life 0.36 to 0.65 hours; exposure rose more than proportionally with dose. Sponsored by Xigen, the developer (NCT01570205).
Pharmacology Research & Perspectives - Human2015
Subconjunctival injection of XG-102, a JNK inhibitor peptide, in patients with intraocular inflammation: a safety and tolerability study
Phase 1b, 20 patients with post-surgical or post-traumatic intraocular inflammation, single subconjunctival dose of 45, 90, 450 or 900 mcg (5 per group). 17 non-serious adverse events judged unrelated to treatment; plasma peptide undetectable in the three lower dose groups. No control group, so the observed fall in inflammation cannot be attributed to the drug. Funding not stated in the abstract.
Journal of Ocular Pharmacology and Therapeutics - Human2014
Efficacy and Safety of XG-102 in Reduction of Post-cataract Surgery Intraocular Inflammation (NCT02235272)
Phase 3, 339 participants, completed December 2015. No results posted and no publication located. A companion phase 3 (NCT02508337, 309 participants, completed January 2016) is in the same position.
ClinicalTrials.gov, Xigen - Animal2018
Brimapitide Reduced Neuronal Stress Markers and Cognitive Deficits in 5XFAD Transgenic Mice
5XFAD mice given 10 mg/kg intravenously every 3 weeks for 3 or 6 months (6 to 9 per group). Plaque burden fell at 3 months but not at 6; cognitive deficits, cell death markers and IL-1beta were reduced at 6 months. Mouse data only.
Journal of Alzheimer's Disease
Frequently asked questions
Did brimapitide work for sudden hearing loss?
The phase 3 in 256 people did not meet its primary endpoint. A post hoc analysis reported a nominally significant benefit of the lower dose in patients with profound hearing loss, and a second phase 3 that might have tested that was terminated after 56 participants. The phase 2 before it had also failed in its whole population.
What happened to the cataract trials?
Two phase 3 trials of XG-102 in post-cataract inflammation enrolled 339 and 309 participants and completed in 2015 and 2016. No results have been posted on ClinicalTrials.gov and no publication could be found as of September 2026.
Is there evidence in Alzheimer's disease?
Only in mice. In 5XFAD transgenic mice, intravenous brimapitide every three weeks reduced plaque burden at three months and cognitive deficits at six. No person with Alzheimer's disease has received it in a trial.
Is brimapitide a nootropic?
Nothing supports that. It is a JNK inhibitor studied for acute tissue injury, given as a single local injection in every human trial. No study has measured cognition in a healthy person taking it.