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

  • Nat Commun. 2024 Mar 1;15(1):1896. doi: 10.1038/s41467-024-45784-0.
Anne G M Schilder  1  2  3 ,  Stephan Wolpert  4 ,  Shakeel Saeed  1  2  3 ,  Leonie M Middelink  5 ,  Albert S B Edge  6 ,  Helen Blackshaw  1  2 ,  REGAIN Consortium ,  Kostas Pastiadis  7 ,  Athanasios G Bibas  7
Affiliations
  • 1. National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, UK.
  • 2. Ear Institute, University College London, London, UK.
  • 3. Royal National ENT and Eastman Dental Hospitals, University College London Hospitals Trust, London, UK.
  • 4. Department of Otolaryngology, Head and Neck Surgery, University of Tübingen, Tübingen, Germany. [email protected].
  • 5. Middelinc, Utrecht, the Netherlands.
  • 6. Department of Otolaryngology, Harvard Medical School, Boston, USA.
  • 7. 1st Department of Otolaryngology, Hippocration Hospital Athens, National & Kapodistrian University of Athens, Athens, Greece.
PMID: 38429256 DOI: 10.1038/s41467-024-45784-0
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.

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