Emerging Therapies for Sensorineural Hearing Loss

Abstract

Objective To critically review and evaluate the proposed mechanisms and documented results of the therapeutics currently in active clinical drug trials for the treatment of sensorineural hearing loss. Data Sources U.S. National Institutes of Health (NIH) Clinical Trials registry, MEDLINE/PubMed. Study Selection & Data Extraction A review of the NIH Clinical Trials registry identified candidate hearing loss therapies, and supporting publications were acquired from MEDLINE/PubMed. Proof-of-concept, therapeutic mechanisms, and clinical outcomes were critically appraised. Data Synthesis 22 active clinical drug trials registered in the United States were identified, and six potentially therapeutic molecules were reviewed. Of the six molecules reviewed, four comprised mechanisms pertaining to mitigating oxidative stress pathways that presumably lead to inner ear cell death. One remaining therapy sought to manipulate the cell death cascade, and the last remaining therapy was a novel cell replacement therapy approach to introduce a transcription factor that promotes hair cell regeneration. Conclusion A common theme in recent clinical trials registered in the United States appears to be the targeting of cell death pathways and influence of oxidant stressors on cochlear sensory neuroepithelium. In addition, a virus-delivered cell replacement therapy would be the first of its kind should it prove safe and efficacious. Significant challenges for bringing these bench-to-bedside therapies to market remain. It is never assured that results in non-human animal models translate to effective therapies in the setting of human biology. Moreover, as additional processes are described in association with hearing loss, such as an immune response and loss of synaptic contacts, additional pathways for targeting become available.

Age‐related hearing loss: Unraveling the pieces

“…Given the potential role of oxidative stress in ARHL, there has been significant interest in clinical trials investigating molecules which target oxidative stress pathways, several of which are in Phase III trials. 60 Lifestyle modifications may also have a role in delaying presbycusis. As discussed previously, exercise has been shown to improve both the histologic and functional findings of hearing loss.…”

“…Recent findings may open the door for new pathways for treatment, particularly if earlier detection is possible. Given the potential role of oxidative stress in ARHL, there has been significant interest in clinical trials investigating molecules which target oxidative stress pathways, several of which are in Phase III trials . Lifestyle modifications may also have a role in delaying presbycusis.…”

Emerging Interventions for Elderly Patients—The Promise of Regenerative Medicine

“…This hearing loss is most commonly caused by the degeneration of hair cells caused by a combination of the aging process, along with ototoxic insults, such as noise, drugs, and infections. Several biopharmaceutical companies are developing molecules that act via a variety of mechanisms to protect the ear from known causes of hearing loss, such as chemotherapy and oxidants . AM‐111 is a molecule that acts on the mitogen‐activated protein kinase/c‐Jun N‐terminal kinase signaling pathway.…”

“…AM‐111 is a molecule that acts on the mitogen‐activated protein kinase/c‐Jun N‐terminal kinase signaling pathway. This pathway has been found to be activated after damaging levels of noise trauma or with ototoxic levels of aminoglycosides . Auris Medical AG (Zug, Switzerland) has completed a phase III study of AM‐111 in 256 patients with sudden sensorineural hearing loss of unknown cause (NCT02561091), but the results of this study are not yet published.…”

“…Several biopharmaceutical companies are developing molecules that act via a variety of mechanisms to protect the ear from known causes of hearing loss, such as chemotherapy and oxidants. 52 AM-111 is a molecule that acts on the mitogenactivated protein kinase/c-Jun N-terminal kinase signaling pathway. This pathway has been found to be activated after damaging levels of noise trauma or with ototoxic levels of aminoglycosides.…”