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Audion Therapeutics and the REGAIN Consortium Announce Publication in Nature Communications of Their Phase 1/2a Trial of an Intratympanic Gamma Secretase Inhibitor for the Treatment of Mild to Moderate Sensorineural Hearing Loss

March 4, 2024 – Clinical Trials – Audion Therapeutics, REGAIN Consortium, clinical trials, hearing loss

The phase 1 part of the study (Multiple Ascending Dose of 3 administrations) confirms safety and tolerability of a dose of 250 microgram of Gamma Secretase Inhibitor LY3056480
Pre-defined Primary Endpoints in the phase 2a part were not met. Post-hoc analysis of the data however showed signs of clinical efficacy in a subset of patients across various endpoints up to 12 months post-treatment
These efficacy signals warrant further development of LY3056480 under an optimised study protocol that incorporates the learnings from this trial.

4 March 2024, Amsterdam, the Netherlands — Audion Therapeutics, a clinical stage biopharmaceutical company advancing therapies to treat hearing disorders announced today, together with the REGAIN consortium the publication of the results from a phase 1/2a trial of an intratympanically administered gamma-secretase inhibitor (LY3056480) as a drug treatment for acquired sensorineural hearing loss (ISRCTN number 59733689). The study was conducted by the REGAIN consortium; an international consortium of 7 partners with a unique combination of expertise in hearing loss biology, drug development and clinical expertise in hearing disorders.

The data was published in Nature Communications in a paper entitled ‘A phase 1/2a safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss’ authored by Schilder et al.

Hearing loss is the most common sensory disorder in humans and an area of significant and growing unmet clinical need. Previous work by Audion Therapeutics co-founder Albert Edge PhD, professor of Otolaryngology–Head and Neck Surgery, Harvard Medical School, and others has shown that pharmacological inhibition of Notch signalling with a gamma secretase inhibitor results in partial recovery of hearing in animal models of sensorineural hearing loss. LY3056480 was identified as a drug candidate with an optimal profile and following successful preclinical development a phase 1/2a clinical trial was designed and performed. The paper reports on the results of this trial.

The phase 1 trial including 15 patients in the UK (Multiple Ascending Dose, 3 administrations, one week apart) confirmed tolerability and safety of the highest dose of 250 micrograms.

In the phase 2a trial, the pre-defined primary endpoint (≥10 dB change in the average pure-tone air conduction threshold across 2, 4 and 8 kHz at 12 weeks) was not met. However, post-hoc analysis, as outlined in the supplementary information section of the paper, shows positive changes in predefined secondary pure-tone audiometry and speech perception in noise measures in 20-25% of patients.

“We are very pleased with the results of this clinical trial conducted as part of the REGAIN consortium, as the study has confirmed the safety and tolerability of intratympanic administration of LY3056480, but also that it shows signs of clinically relevant responses on multiple outcome measures in a subset of patients. More specifically, the improvements in the ability to understand speech in a noisy environment that we see in some patients are encouraging as this addresses the primary complaint of many people suffering from hearing loss. Importantly, these improvements continued to be observed during the optional 12 month follow-up period. We believe that this data set is promising and forms an important building block for further development of this experimental regenerative treatment,” said Rolf Jan Rutten, CEO of Audion Therapeutics. “We look forward to continue the development of LY3056480 with an optimised clinical trial design that may lead to a higher number of patients responding to the treatment.”

Prof Anne GM Schilder, coordinating investigator of the REGAIN consortium said, “We are very pleased with this publication, as the project has generated important learnings about the design and delivery of early phase trials of novel hearing approaches. The preclinical work by Audion Therapeutics was solid and promising so it was a privilege for our Consortium to take this to clinic. It took time to analyse and interpret the trial results, because the tests we have available nowadays are developed to study progression of hearing loss instead of reversion. We did not see improvements in hearing across all patients, but we feel that the positive changes in some patients call for further work with this approach. The trial also highlights the demand among patients to participate in hearing loss research. Our team was contacted by more than 5,000 patients with hearing loss requesting to take part, illustrating the huge unmet clinical need for better hearing treatments.”

About Audion Therapeutics
Audion Therapeutics , is a privately held clinical stage biopharmaceutical company dedicated to the development of therapies to treat hearing loss. Audion’s lead program is aimed at regenerating cells and neuronal connections that are lost in patients with acquired Sensorineural Hearing Loss (SNHL), which is the most prevalent form of Hearing Loss. The programme is based on scientific discoveries from the Edge lab at Massachusetts Eye and Ear Infirmary (MEE). Visit: www.audiontherapeutics.com.

About the REGAIN Consortium
An international consortium of 7 partners that was awarded a €5.8m Horizon 2020 (the EU Research and Innovation programme) grant to develop and test a new drug to treat hearing loss. The consortium’s unique combination of expertise in hearing loss biology, drug development and clinical expertise in treating hearing loss has allowed this programme to advance from a preclinical concept to early clinical studies. The consortium consists of 3 academic parties (UCL Ear Institute, UK, University of Tubingen, Germany and the National and Kapodistrian University of Athens, Greece) and 4 companies (Audion Therapeutics, Eli Lilly, Nordic Biosciences and Ttopstart). Visit: www.regainyourhearing.eu.