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Auris Medical Achieves Midpoint for Enrollment in Phase 3 Trial of AM-111 in Sudden Deafness


Dual kinase inhibition affords extended in vitro neuroprotection in Aβ toxicity

Gourmaud et al, Journal of Alzheimer’s Disease, 2016, PMID: 27636848
The present study show that PKR (double-stranded RNA dependent kinase) and c-Jun N-terminal kinase (JNK) pathways are actively activated in Aβ-induced neurotoxicity in neuronal cultures and that the dual inhibition of PKR and JNK (using XG-102 and XG-104) nearly completely blocked neuronal death in vitro.
https://www.ncbi.nlm.nih.gov/pubmed/27636848

Sub-conjunctival injection of XG-102, a JNK inhibitor peptide, in patients with intraocular inflammation: A safety and tolerability study

Beydoun et al, Journal of Ocular Pharmacology and Therapeutics, 2015, PMID: 25347151
In this clinical trial, XG-102 administered as a single subconjunctival injection as adjunct therapy in patients with recent post-surgery or post-trauma intraocular inflammation is safe and well tolerated.
Complete version (PDF, 188 Kb)


XG-102 administered to healthy male volunteers as a single intravenous infusion: a randomized, double-blind, placebo-controlled, dose-escalating study

Deloche et al, Pharmacology Research & Perspectives, 2014, PMID: 25505576
The present clinical trial concluded that XG-102 single IV doses of 10-80 μg/kg administered over 1 h to healthy male subjects were safe and well tolerated.
Complete version (PDF, 832 Kb)

Efficacy and safety of AM-111 in the treatment of acute sensorineural hearing loss: a double-blind, randomized, placebo-controlled phase II study

Suckfuell et al, Otology Neurology, 2014, PMID: 24979398
The clinical study established proof of concept for AM-111 in the treatment of severe-to-profound acute sensorineural hearing loss (ASNHL). Control for spontaneous hearing recovery is essential for ASNHL studies
https://www.ncbi.nlm.nih.gov/pubmed/24979398

Sub-conjunctival injection of XG-102, a c-Jun N-Terminal Kinase inhibitor peptide in the treatment of endotoxin-induced uveitis in rats

El Zaoui et al, Journal of Ocular Pharmacology and Therapeutics, 2014, PMID: 25313830
The study determined optimal XG-102 dose and route of administration in endotoxin-induced uveitis (EIU) in rats with the purpose of clinical study design. The results confirm that XG-102 peptide has potential for treating intraocular inflammation. Sub-conjunctival injection appears as a good compromise to provide a therapeutic effect while limiting side effects.
Complete version (PDF, 499 Kb)

Molecular mechanisms involved in cochlear implantation trauma and the protection of hearing and auditory sensory cells by inhibition of c-Jun-N-terminal kinase signaling

Eshraghi et al, Laryngoscope, 2013, PMID: 23382052
Molecular mechanisms involved in programmed cell death of hair cells [HCs] are different than the ones involved in programmed cell death of supporting cells [SCs]. Local delivery of AM-111 provided a significant level of protection against electrode insertion trauma [EIT]-induced hearing losses, HC losses, and damage to neural elements.

Protection against ischemic cochlear damage by intratympanic administration of AM-111

Omotehara et al, Otology Neurology, 2011, PMID: 22089955
Direct application of AM-111 in gel formulation on the round window was effective in preventing acute hearing loss because of transient cochlear ischemia.  
https://www.ncbi.nlm.nih.gov/pubmed/22089955

Auris Medical secures CHF 47.1 mn Series C financing from Sofinnova Ventures and Sofinnova Partners to advance ground-breaking inner ear therapies through Phase III clinical development


Role of the c-Jun N-terminal kinase pathway in retinal excitotoxicity, and neuroprotection by its inhibition

Bessero et al, Journal of Neurochemistry, 2010, PMID : 20345748
The present study demonstrated the involvement of c-Jun N-terminal kinase (JNK) activation in NMDA-mediated retinal excitotoxicity. The JNK pathway being involved, XG-102 activity was verified in this model.
Complete version (PDF, 695 Kb)

A peptide inhibitor of c-Jun N-terminal kinase for the treatment of endotoxin-induced uveitis

Touchard et al, IOVS, 2010, PMID: 20393119
The efficacy of XG-102 in an endotoxin-induced uveitis (EIU) rat model of ocular inflammation using either intravenous or intravitreous administration was determined as well as the biodistribution in ocular tissues.
Complete version (PDF, 4.7 Mb)

Intratympanic treatment of acute acoustic trauma with a cell-permeable JNK ligand: a prospective randomized phase I/II study

Suckfuell et al, Acta Otolaryngology, 2007, PMID: 17712672
Functional and morphological analysis of the treated ears revealed that AM-111 had an excellent otoprotective effect, even when administered hours after the noise exposure. Blocking the signal pathway with AM-111 is therefore a promising way to protect the morphological integrity and physiological function of the inner ear in various conditions involving acute sensorineural hearing loss.
https://www.ncbi.nlm.nih.gov/pubmed/17712672n

Inhibition of the c-Jun N-Terminal Kinase-Mediated Mitochondrial Cell Death Pathway Restores Auditory Function in Sound-Exposed Animals

Wang et al, Molecular Pharmacology, 2007 PMID: 17132689
Sound-damaged hair cell nuclei show that apoptosis is the predominant mode of cell death after sound trauma. By blocking this signaling pathway with XG-102, we may obtain significant therapeutic value to protect cochlea from the effects of sound trauma.
Complete version (PDF, 1.45 Mb)

Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity

Eshraghi et al, Hearing Research, 2007, PMID: 17098385
Mechanisms of cell death and proposal for blocking of JNK signaling as a therapeutic approach for permanent hearing loss prevention are discussed in this article. XG-102 use in such problematic is also discussed.
https://www.ncbi.nlm.nih.gov/pubmed/17098385

AM-111 Reduces Hearing Loss in a Guinea Pig Model of Acute Labyrinthitis

Barkdull et al, The Laryngoscope, 2007, PMID: 18322422
Acute inflammation within the inner ear may result in sensorineural hearing loss. This study evaluated the safety and the therapeutic potential of AM-111 in acute labyrinthitis (one of the multiple disease processes leading to hearing loss and ranging from acute bacterial labyrinthitis and viral labyrinthitis to meningitis and immune-mediated labyrinthitis).
https://www.ncbi.nlm.nih.gov/pubmed/18322422

AM-111 protects against permanent hearing loss from impulse noise trauma

Coleman et al, Hearing Research, 2007, PMID: 16839720
In our study, the therapeutic window for a treatment with AM-111 after acute acoustic trauma (Impulse noise: high intensity, short-duration sound, represents a particular origin of acute acoustic trauma (AAT), with considerable hazards to hearing capabilities.) was explored with different drug delivery routes.
https://www.ncbi.nlm.nih.gov/pubmed/16839720

The c-Jun N-terminal kinase JNK participates in cytokine and isolation stress-induced rat pancreatic islet apoptosis

Abdelli et al, Diabetologia, 2007, PMID : 17558486
More than 50% of pancreatic islet tissue undergoes apoptosis within a few days after transplantation; inflammatory processes (at least partly involving JNK) may play a role in the destruction of the graft after transplantation. Delivery of a protease-resistant JNK inhibitory peptide (XG-102) was tested for the viability improvement of rat pancreatic islets.
Complete version (PDF, 416 Kb)

D-JNKI-1 treatment prevents the progression of hearing loss in a model of cochlear implantation trauma

Eshraghi et al, Otology Neurology, 2006, PMID: 16791042
Hearing loss caused by cochlear implant electrode insertion trauma in guinea pigs has both acute and delayed components. The delayed component can be prevented by treating the cochlea with D-JNKI-1.
https://www.ncbi.nlm.nih.gov/pubmed/16791042

Use of cell-permeable peptides to prevent neuronal degeneration

Borsello et al, Trends in Molecular Medicine, 2004, PMID: 15121051
Neurodegenerative disorders are often associated with loss of neurons condition arising through apoptotic mechanisms. Here, recent findings on the use of cell-permeable peptide inhibiting JNK in in vivo models of neuronal degeneration following ischemia and its potential are reviewed.
https://www.ncbi.nlm.nih.gov/pubmed/15121051

A Peptide Inhibitor of c-Jun N-Terminal Kinase Protects against Both Aminoglycoside and Acoustic Trauma-Induced Auditory Hair Cell Death and Hearing Loss

Wang et al, The Journal of Neuroscience, 2003, PMID: 13679429
Hearing loss can be caused by a variety of insults, including acoustic trauma and exposure to ototoxins that principally affect the viability of sensory hair cells via c-Jun N-terminal kinase (JNK) activity. XG-102 was evaluated as a peptide possessing JNK-pathway inhibitory functions to demonstrate its possibilities in otoprotective activities.
https://www.ncbi.nlm.nih.gov/pubmed/13679429

A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia

Borsello et al, Nature Medicine, 2003, PMID: 12937412
During ischemic stroke, delayed mechanisms (following energy depletion, excitotoxicity and peri-infarct depolarization) involved both inflammation and apoptosis concerning neuronal death consequences. Targeting these secondary mechanisms was tested using a JNK inhibitor in this ischemia model.
Complete version (PDF, 1.34 Mb)


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