Reading the headline of the following press release [1] from March 2024, you may think the University College of London and its affiliated hospital were announcing a drug to restore hearing:
“World-first trial of regenerative hearing drug is successfully completed. Researchers at UCL and UCLH have successfully completed the first trial of a therapy designed to restore hearing loss.”
Despite the promising headline, it’s important to note that true hearing regeneration is still a work in progress.Hearing regeneration drug development is complex cellular and molecular biochemistry translational medical research focused on regenerating inner ear auditory transduction cells called outer hair cells, or OHC. These cells amplify sound wave energy and convert it into electrical signals. The signals are then passed to inner hair cells (IHC), transported by the auditory nerve into the brain.
Hearing regeneration drug development is conducted within the larger disciplines of tissue engineering and regenerative medicine, hoping to go beyond treatments to find cures for complex, chronic diseases [2]. Hearing regeneration drug development is in its relative infancy. High failure rates are expected.
The research program reported in the press release investigates a gamma secretase inhibitor (GSI) named LY3056480 developed by the pharmaceutical company Eli Lilly. Secretases are cellular enzymes involved in the production of amyloid-beta precursor proteins (APP), which lead to amyloid plaque formation. GSI inhibitor molecules are among those being investigated for their potential role treating Alzhemer’s disease.
A team of researchers and the GSI drug licensee Audion Therapeutics, supported by a European Commission grant, investigated a gamma secretase inhibitor (GSI) drug to treat sensorineural hearing loss by regenerating auditory hair cells [3]. The press release shared findings from two early-stage translational medicine trials that began in 2018. After about two years in peer review, the outcomes were published in 2024 in an open-access academic journal, making them available to anyone with internet access [4].
These small, early-stage clinical trials were designed to “...test the hypothesis that local administration with the GSI LY3056480 restores outer hair cell function and thereby improves the perception of speech-in-noise, which is the primary unsolved problem for people with hearing loss.”
The first study was a 12-month Phase I safety trial of 15 patients with mild to moderate inner ear hearing loss. Three different dosing levels of the drug were injected into the inner ear three times. “In total 174 AEs [adverse events] were reported of which 2 were probably related to the investigational medicinal product (IMP) [the drug] and 52 probably or definitely related to the procedure.” [emphasis added] Five patients dropped out of the trial by the end.
The second was a 12-month Phase II efficacy trial of the same drug. 44 patients were enrolled, 33 completed the trial. “...all patients experienced one or more AEs.... [T]he therapy did not restore hearing across the group of adults with mild to moderate hearing loss. [emphasis added].
Hearing regeneration drugs are a moonshot. The GSI LY3056480 drug is a good example of the challenges. Audion Therapeutics discontinued the program after larger clinical trials failed to deliver evidence of benefit.
Several other drug candidates have encountered the same setbacks.
- Novartis and GenVec collaborated on the drug CGF166, a gene therapy aimed at regenerating cochlear hair cells using the Atoh1 gene as a direct delivery vehicle. Clinical trials did not show significant results. The project was discontinued in 2017.
- Otonomy developed the drug OTO-413, targeting cochlear cell synapse regeneration. The drug failed in clinical trials.
- Frequency Therapeutics developed the drugs FX-322 and FX-345 to treat sensorineural hearing loss (SNHL). Both drug candidates were abandoned following results from a clinical study showing no statistically meaningful differences between the treated and placebo groups.
State of the art and a forecast
A 2023 review article divides clinical trials for treating sensorineural hearing loss (SNHL) into two main types: those aiming to prevent hearing loss and regenerative therapies that seek to repair it, noting that, “Preventing SNHL may be more realistic than regeneration, while the therapeutic time window for regeneration is considerably wider than that for prevention [5].”
In 2018, researchers at Northwestern University disclosed their discovery of a “master gene" named TBX2 that acts as a genetic switch to determine whether a hair cell in the ear develops into an inner hair cell or an outer hair cell (OHC). OHCs are the hearing regeneration drug target. When expressed, TBX2 the cell becomes an inner hair cell when TBX2 is expressed, and becomes an outer hair cell when it is not. At the time of publication, the authors estimated that it might take another dozen years to develop genetic medicines to control TBX2 gene expression [6], followed by years of translational studies.
Additionally, effective delivery of these therapies into the inner ear presents a challenge, as eardrum injections cause adverse events. Cost is also likely to be a barrier. Drug development is expensive. Makers need a return on their investment, and charge accordingly.
References
-
REGAIN consortium, https://cordis.europa.eu/project/id/634893/reporting
-
A phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss, https://pmc.ncbi.nlm.nih.gov/articles/PMC10907343/pdf/41467_2024_Article_45784.pdf
-
Matsunaga M, Nakagawa T. Future Pharmacotherapy for Sensorineural Hearing Loss by Protection and Regeneration of Auditory Hair Cells. Pharmaceutics. 2023 Feb 26;15(3):777. http://doi/10.3390/pharmaceutics15030777 PMID: 36986638; PMCID: PMC10054686.
-
Wiwatpanit, T., Lorenzen, S.M., Cantú, J.A. et al. Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1. Nature 563, 691–695 (2018). https://doi.org/10.1038/s41586-018-0570-8 [Paywall]
