A phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss
Anne GM Schilder, Stephan Wolpert, Shakeel R. Saeed, Leonie M. Middelink, Albert S.B. Edge, Helen Blackshaw, Anne GM Schilder, Leonie M. Middelink, Albert S.B. Edge, Athanasios Bibas, Elizabeth Arram, Asger Bilhet, Hannah E. Cooper, Ernst Dalhoff, Femke van Diggelen, Rolf Jan Rutten, Helmuth van Es, Karin Hojgaard, Eleftheria Iliadou, Ömürsen Yıldırım, Sherif Khalil, Dimitris Kikidis, Hubert Löwenheim, Nikos Markatos, Marcus Mueller, Thore Schade‐Mann, Fritz Schneider, Katerina Vardonikolaki, A Wilke, Kostas Pastiadis, Athanasios Bibas
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.