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

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.

Fig. 1. Consort diagram phase I and IIa trial.

Patient disposition of phase I trial and phase IIa trial.

Fig. 2. Mean pure-tone air-conduction thresholds in the treated ear of all patients that completed 12 weeks follow-up (N = 42).

Presented timepoints are baseline (black), 6 (blue) and 12 (red) weeks, error bars indicate standard deviations. Pure-tone thresholds are displayed in decibel hearing level (dB HL), frequency in kilohertz (kHz). Source data are provided as “supplementary data 4”.

Fig. 3. Individual pure-tone audiograms (treated ear) of all patients that completed 12 weeks follow-up (N = 42).

Presented timepoints are baseline (black circle), 6 (blue cross) and 12 (red triangles) weeks. Frequencies not shown indicate that thresholds are beyond the maximum output of the audiometer. Pure-tone thresholds are displayed in decibel hearing level (dB HL), frequency in kilohertz (kHz). Source data are provided as “supplementary data 4”.