Hearing loss and inner ear disorders: The next frontier for pharmaceutical success?

Disabling hearing loss and other inner ear disorders affect more than 360 million people worldwide, with approximately one billion additional people at risk, according to the World Health Organization. Hearing loss is triggered by many factors, with ageing and noise exposure being two of the most common causes. Other causes include genetic conditions, complications at birth, specific infectious diseases (e.g., meningitis and measles), use of some medications, and chronic ear infections. There are varying levels of hearing loss, ranging from mild to profound, but it is widely accepted that an individual’s quality of life is greatly affected when it difficult to hear the common sounds that most of us take for granted. Not only is this detrimental to patients’ quality of life, it poses a heavy economic burden on the healthcare system in the range of $67 to as much as $107 billion.

The physiology of the inner ear, which contains the sensory organs responsible for both hearing and balance, and the delivery requirements it poses, is one of the major obstacles to overcome in developing new treatments for hearing loss and associated disorders. As the human inner ear is physically inaccessible, studying its normal function and pathology is difficult. .

To hear, soundwaves are channelled by the outer ear towards the bones of the middle ear and transformed into a force that pushes on a membrane (the oval window) in the cochlea. This force causes the fluid in the cochlea to move, thereby stimulating tiny sensory hair cells. Each hair cell corresponds to, and is activated by, specific frequencies.  Signals from the activated hair cells are converted into nerve impulses and sent to the mid-brain, or the cochlear nucleus, via the cochlear portion of the auditory nerve, and then to the hearing portion (auditory cortex) of the brain. These hair cells do not regenerate when damaged. As hair cell populations decline, the ability to perceive certain frequencies diminishes, and hearing ability as a whole is reduced.

The vestibular system is the other part of the inner ear and is responsible for balance. It uses the same kinds of fluids and transducing sensory cells (hair cells) as the cochlea, sending information to the brain about the rotation and linear motion of the head and body.

There is no cure for hearing loss. Currently, patients are mostly treated with various types of assistive hearing technologies. Typical devices include hearing aids, assistive listening devices, cochlear implants and other implantable devices. These existing technologies may help patients to improve their overall ability to hear but do not restore full hearing ability. There are no approved drug treatments for hearing loss, providing a significant untapped market to the pharmaceutical industry.

Delivering drugs to the inner ear, whether local or systemic, is very difficult. The human ear has evolved to have very tight regulation over what can and cannot enter the cochlear and vestibular fluids of the inner ear. The architecture of the outer and middle ear, in addition to the presence of physical and semipermeable barriers, makes it structurally challenging for injection or droplets to reach the inner ear. On the other hand, the blood labyrinth barrier (BLB), separates the inner ear from most systemic circulation, and similar to the blood brain barrier (BBB), imposes significant limitations on the molecular entities that can reach the inner ear tissues. For this reason, it is critical that therapeutic approaches to addressing either vertigo or hearing loss are able to overcome the physical and/or physiological barriers to inner ear delivery.

The regeneration of new hair cell growth in the inner ear is an area of focus for development of both small molecules and gene therapy. Novartis is conducting a clinical study of a gene therapy, CGF166 in Phase 1/2 to deliver atonal gene transcription factor. The atonal gene, during embryonic development, induces differentiation of sensory cells in the inner ear. Meanwhile, Frequency Therapeutics is developing small molecules to restore auditory sensory cells. This approach stimulates inner ear progenitor cells to multiply and create new hair cells. As small molecules, the gene therapy can be formulated for direct injection into the middle ear where it then diffuses into the cochlea.    

Major progress is also being made in the development of improved methods for treating inner ear disorders. Gels, which transition into liquids at body temperature, are being developed to provide sustained drug exposure. Auris Medical’s AM-111 is being evaluated to treat acute inner ear hearing loss in Phase 3 development. AM-111 is formulated in a biodegradable gel, which following a single dose intratympanic injection into the middle ear, diffuses through the round window membrane into the cochlea. In a Phase 3 study, although the primary endpoint was not met, post-hoc analysis of patients with profound acute hearing loss revealed a clinically and statistically significant improvement in the AM-111 treatment group.

A similar approach using a sustained-exposure formulation of the steroid dexamethasone, Otividex, has now completed two Phase 3 studies for treating Meniere’s disease. Developer Otonomy is working with the US Food and Drug Administration to determine next steps needed for regulatory approval. Otonomy is also developing OTO-413, a sustained-exposure formulation of brain-derived neurotropic factor (BDNF). This naturally-occurring protein is involved in neuron growth and repair. The target indication for OTO-413 will be patients with hidden hearing loss, a disorder characterised by speech-in-noise hearing difficulty.

There also is a micropump technology in research that would help target and safely deliver the drug to the inner ear. Draper, in collaboration with Massachusetts Eye and Ear, have developed a device capable of delivering drugs directly to the cochlea. The device, which is still in preclinical studies, may also be used to sample drug concentration in the cochlea, delivering supporting information towards securing FDA approval for potential new treatments for hearing loss.

Targeting the hearing process further downstream, Autifony Therapeutics is focused on improving auditory processing once the sound wave reaches the brainstem. AUT00063 targets potassium Kv3.1 channels in the brain thought to be important in central auditory neural processing. Hearing loss from age, toxic drugs or noise exposure can damage these neural networks so compounds that increase Kv3.1 currents by shifting the voltage-dependent activation to more negative potentials could potentially be useful in the treatment of hearing disorders.

At Sensorion, we have two products in mid-stage clinical development, which were selected for development based on their scientific basis for effectiveness coupled with their ability to reach the inner ear tissues systemically as orally administered candidates. Seliforant is being assessed in a multicenter Phase 2 study for the treatment of acute unilateral vestibulopathy (AUV), a form of extreme, acute vertigo. Seliforant is an H4 receptor antagonist that reduces the imbalance of neural signaling between the two vestibules to reduce severity of vertigo crises. Data are expected in the second half of 2018. To date, seliforant data have been promising, with pharmacokinetics, pharmacodynamics, safety and tolerance evaluated in multiple Phase 1 and preclinical studies. 

A second drug candidate, SENS-401, is being developed for sudden sensorineural hearing loss (SSNHL) and prevention of cisplatin-induced ototoxicity in children. SENS-401 is a 5-HT3 receptor antagonist (setron family) that has shown an ability to significantly reduce hearing loss and enhance survival of outer hair cells of rats exposed to acoustic trauma or cisplatin infusion.  In a Phase 1 trial, SENS-401 showed good tolerance and confirmed pharmacokinetics at higher doses than those usually prescribed with R/S azasetron, a similar product marketed in Asia for chemotherapy-induced nausea and vomiting. The molecule is believed to work by halting the hair cell apoptosis pathway that is initiated by damage to the cell and reducing the loss of synaptic contacts between sensory hair cells and peripheral neurons.

Furthermore, Phase 1 studies have shown that despite the difficulty of delivering systemic, or localised, drugs to the inner ear, SENS-401 had excellent penetration into the site of disease as an orally delivered systemic treatment, compared to penetration of other clinically-tested treatments. A Phase 2 trial for SENS-401 in SSNHL is planned to start in 2018. Sensorion is also working with cancer survivor advocacy groups to highlight the issue of hearing loss related to cancer treatments, especially in children, and to facilitate the design of a more patient-centric trial that will provide the basis for Sensorion to determine if SENS-401 is able to prevent and treat hearing loss in patients that are battling cancer.

Looking to the future, Sensorion and UConn Health have discovered a potential biomarker, called prestin, for hearing loss. Prestin is an outer hair cell protein that is critical to hearing function. This discovery has the potential to be a vital biomarker for diagnosing early stages of hearing loss. Sensorion will use this measurement in clinical trials for SENS-401.

Great strides in developing novel treatments for hearing loss and inner ear disorders have been made in the past several years. The pioneering research being conducted worldwide suggests a great breakthrough could happen soon. Perhaps that breakthrough will even be a cure.

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