A phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss

Anne G. M. Schilder, Stephan Wolpert (), Shakeel Saeed, Leonie M. Middelink, Albert S. B. Edge, Helen Blackshaw, Kostas Pastiadis and Athanasios G. Bibas
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Anne G. M. Schilder: National Institute for Health Research University College London Hospitals Biomedical Research Centre
Stephan Wolpert: University of Tübingen
Shakeel Saeed: National Institute for Health Research University College London Hospitals Biomedical Research Centre
Leonie M. Middelink: Middelinc
Albert S. B. Edge: Harvard Medical School
Helen Blackshaw: National Institute for Health Research University College London Hospitals Biomedical Research Centre
Kostas Pastiadis: National & Kapodistrian University of Athens
Athanasios G. Bibas: National & Kapodistrian University of Athens

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: Abstract Inhibition of Notch signalling with a gamma-secretase inhibitor (GSI) induces mammalian hair cell regeneration and partial hearing restoration. In this proof-of-concept Phase I/IIa multiple-ascending dose open-label trial (ISRCTN59733689), adults with mild-moderate sensorineural hearing loss received 3 intratympanic injections of GSI LY3056480, in 1 ear over 2 weeks. Phase I primary outcome was safety and tolerability. Phase lla primary outcome was change from baseline to 12 weeks in average pure-tone air conduction threshold across 2,4,8 kHz. Secondary outcomes included this outcome at 6 weeks and change from baseline to 6 and 12 weeks in pure-tone thresholds at individual frequencies, speech reception thresholds (SRTs), Distortion Product Otoacoustic Emissions (DPOAE) amplitudes, Signal to Noise Ratios (SNRs) and distribution of categories normal, present-abnormal, absent and Hearing Handicap Inventory for Adults/Elderly (HHIA/E). In Phase I (N = 15, 1 site) there were no severe nor serious adverse events. In Phase IIa (N = 44, 3 sites) the average pure-tone threshold across 2,4,8 kHz did not change from baseline to 6 and 12 weeks (estimated change −0.87 dB; 95% CI −2.37 to 0.63; P = 0.252 and −0.46 dB; 95% CI −1.94 to 1.03; P = 0.545, respectively), nor did the means of secondary measures. DPOAE amplitudes, SNRs and distribution of categories did not change from baseline to 6 and 12 weeks, nor did SRTs and HHIA/E scores. Intratympanic delivery of LY3056480 is safe and well-tolerated; the trial’s primary endpoint was not met.

Date: 2024
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DOI: 10.1038/s41467-024-45784-0

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