inner ear disorders
Vertigo is the sensation of self-motion when no self-motion is occurring or the sensation of distorted self-motion during an otherwise normal head movement (“illusion of movement”). This movement illusion manifests itself as false spinning sensations (spinning vertigo) and also other false sensations like swaying, tilting, bobbing, bouncing, or sliding (non-spinning vertigo). The illusion of movement in vertigo is often associated with the manifestation of several other clinical symptoms: nausea, vomiting, spatial disorientation, postural instability, falls, nystagmus (spontaneous eye movements). Vertigo persisting for more than three months is considered chronic.
Vertigo is a symptom of vestibular dysfunction. Frequently, it is caused by an imbalance between the left and right peripheral vestibular systems in signaling position and movement to the brain. Both inner ears sense angular and linear movements and relay this information continuously to the central vestibular system, which is processing and integrating this information with input from the eyes and muscles and joints. If this peripheral input is no longer synchronized between the two sides e.g. due to some infection, inflammation, or trauma, the brain may perceive movement and position that is different from reality, i.e. a false sensation.
Vertigo and related balance problems are very common. Their incidence and prevalence increase with age. It has been estimated that slightly more than one third of the US population ≥ 40 years of age experience vestibular dysfunction, and that the lifetime prevalence of vertigo interfering with daily activities is 3-8%.
Histamine acts as a neurotransmitter, amongst others, in the vestibular system. Histamine receptors are localized both within the inner ear as well as in the brain. It has been shown that vestibular stimulations enhance histamine release in the hypothalamus and brainstem, and that histamine enhances microcirculation to the inner ear. Decades ago, histamine was sometimes perfused to patients suffering from vestibular dysfunction; however, this entailed the risk of anaphylactic reactions (allergic reactions). Betahistine, the active substance of AM-125, is a small molecule drug that acts as a partial histamine H1-receptor agonist and a H3-receptor antagonist. Originally, it was developed to improve blood circulation. It was later launched for the treatment of vestibular dysfunction. As betahistine increases inner ear and cerebral blood flow and increases histamine turnover and enhances histamine release in brain, it acts as a vestibular stimulant. Notably, betahistine improves and accelerates vestibular compensation, which is the body’s natural response to a vestibular dysfunction. Vestibular compensation seeks to restore balance based on restoration of the vestibular function, compensation of any remaining deficit through other means (e.g. by giving more importance to visual input) or habituation to the deficit.
AM-125 is applied with a nasal spray. This allows to bypass the effects of first-pass metabolism found with oral delivery of betahistine.
Acoustic trauma and other insults to the inner ear may trigger increased levels of extracellular glutamate, which in turn cause excessive activation of cochlear NMDA (N-Methyl-D-Aspartate) receptors. This process results in damage or killing of sensory cells and is thought to be responsible for abnormal spontaneous "firing" of auditory nerves, which may be perceived as tinnitus. Under normal circumstances, the NMDA receptors are thought to play no role in fast excitatory neurotransmission, respectively normal hearing. Keyzilen® is blocking cochlear NMDA receptors to suppress the aberrant excitation of the auditory nerve that is perceived as tinnitus.
Keyzilen® is formulated in a biocompatible and fully biodegradable gel and administered in three doses over 3-5 days through intratympanic injection into the middle ear. From there the drug diffuses through the round window membrane into the cochlea.
Hearing loss may be either due to insufficient sound conduction from the outer to the inner ear ("conductive hearing loss"), or - much more frequently - to damage to the hair cells and neurons in the cochlea or to the auditory nerve ("sensorineural hearing loss"). In most cases, hearing loss develops over many years, but sometimes it sets in acutely, e.g. following some loud noise, infection, disruption in blood supply or autoimmune disorder.
While sensorineural hearing loss in the chronic stage is irreversible, all or part of it may recover in the acute stage thanks to cochlear repair mechanisms. The more severe the acute hearing loss is, the less likely spontaneous recovery becomes and the higher the risk for permanent damage and chronic hearing loss is. Usually, hearing recovery is most pronounced in the hours and days following the onset of acute hearing loss and tapering off over 4 to 5 weeks. In human beings, loss of cochlear hair cells or neurons is irreversible.
Hearing loss may have serious impacts on professional and personal lives, e.g. through reduced job performance and earning power, impaired memory and ability to learn new tasks or reduced alertness and increased risk to personal safety (loss of monitoring of environmental warning sounds). In the US, more than 66,000 patients are seen annually with sudden sensorineural hearing loss.
JNK is a signal transmitting enzyme that regulates several important cellular activities, including activation of genes encoding inflammatory molecules or promoting cell death (apoptosis). JNK is activated following various types of insults (stress) to the inner ear that tend to result in severe or profound acute hearing loss.
Brimapitide (or D-JNKI-1; D-stereoisomer of c-Jun N-Terminal Kinase Inhibitor 1), the active substance of Sonsuvi® which is coupled to an intracellular transporter, inhibits the JNK stress kinase inside affected sensory cells. It 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. Sonsuvi® supports natural recovery processes and helps to prevent or reduce chronic hearing loss.
Sonsuvi® 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.
Associate Professor of Surgery, Otolaryngology Director of the Hearing and Balance Program Yale School of Medicine, New Haven (CT), USA
David and Mary Zamierowsky Professor, Director Division Otology/Neurotology, Departments of Otolaryngology, Head and Neck Surgery and Speech and Hearing University of Kansas (KS), USA
We are developing Keyzilen® (AM-101) under a world-wide exclusive license from Inserm, Paris, France.