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

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 receive...

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Vydáno v:Nature communications Ročník 15; číslo 1; s. 1896 - 9
Hlavní autoři: Schilder, Anne G. M., Wolpert, Stephan, Saeed, Shakeel, Middelink, Leonie M., Edge, Albert S. B., Blackshaw, Helen, Pastiadis, Kostas, Bibas, Athanasios G.
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 01.03.2024
Nature Publishing Group
Nature Portfolio
Témata:
631/378/1687
631/378/2619/1533
692/308
692/700/565
Adult
Adults
Aged
Amplitudes
Amyloid Precursor Protein Secretases
Animal models
Audiometry, Pure-Tone
Auditory system
Auditory Threshold - physiology
Effectiveness
Hearing
Hearing loss
Hearing Loss, Sensorineural - drug therapy
Humanities and Social Sciences
Humans
Inhibitors
multidisciplinary
Otoacoustic emissions
Otoacoustic Emissions, Spontaneous - physiology
Safety
Science
Science (multidisciplinary)
Secretase
Thresholds
ISSN:2041-1723, 2041-1723
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Shrnutí: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. Pharmacological inhibition of gamma-secretase induced partial recovery of hearing in animal models. Here, the authors present the safety and efficacy results and key learnings of the First in Human Phase I/IIa study of a gamma-secretase inhibitor in patients with acquired Hearing Loss.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-45784-0