Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study

Will J McLean, Ashley S Hinton, Jenna T J Herby, Alec N Salt, Jared J Hartsock, Sam Wilson, David L Lucchino, Thomas Lenarz, Athanasia Warnecke, Nils Prenzler, Heike Schmitt, Susan King, Lance E Jackson, Jeffrey Rosenbloom, George Atiee, Moraye Bear, Christina L Runge, René H Gifford, Steven D Rauch, Daniel J Lee, Robert Langer, Jeffrey M Karp, Christopher Loose, Carl LeBel, Will J McLean, Ashley S Hinton, Jenna T J Herby, Alec N Salt, Jared J Hartsock, Sam Wilson, David L Lucchino, Thomas Lenarz, Athanasia Warnecke, Nils Prenzler, Heike Schmitt, Susan King, Lance E Jackson, Jeffrey Rosenbloom, George Atiee, Moraye Bear, Christina L Runge, René H Gifford, Steven D Rauch, Daniel J Lee, Robert Langer, Jeffrey M Karp, Christopher Loose, Carl LeBel

Abstract

Objectives: There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo. The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL.

Study designs: Middle ear residence, cochlear distribution, and elimination profiles of FX-322 were assessed in guinea pigs. Human perilymph sampling following intratympanic FX-322 dosing was performed in an open-label study in cochlear implant subjects. Unilateral intratympanic FX-322 was assessed in a Phase 1b prospective, randomized, double-blinded, placebo-controlled clinical trial.

Setting: Three private otolaryngology practices in the US.

Patients: Individuals diagnosed with mild to moderately severe chronic SNHL (≤70 dB standard pure-tone average) in one or both ears that was stable for ≥6 months, medical histories consistent with noise-induced or idiopathic sudden SNHL, and no significant vestibular symptoms.

Interventions: Intratympanic FX-322.

Main outcome measures: Pharmacokinetics of FX-322 in perilymph and safety and audiometric effects.

Results: After intratympanic delivery in guinea pigs and humans, FX-322 levels in the cochlear extended high-frequency region were observed and projected to be pharmacologically active in humans. A single dose of FX-322 in SNHL subjects was well tolerated with mild, transient treatment-related adverse events (n = 15 FX-322 vs 8 placebo). Of the six patients treated with FX-322 who had baseline word recognition in quiet scores below 90%, four showed clinically meaningful improvements (absolute word recognition improved 18-42%, exceeding the 95% confidence interval determined by previously published criteria). No significant changes in placebo-injected ears were observed. At the group level, FX-322 subjects outperformed placebo group in word recognition in quiet when averaged across all time points, with a mean improvement from baseline of 18.9% (p = 0.029). For words in noise, the treated group showed a mean 1.3 dB signal-to-noise ratio improvement (p = 0.012) relative to their baseline scores while placebo-treated subjects did not (-0.21 dB, p = 0.71).

Conclusions: Delivery of FX-322 to the extended high-frequency region of the cochlea is well tolerated and enhances speech recognition performance in multiple subjects with stable chronic hearing loss.

Conflict of interest statement

No other authors have conflicts of interest.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.

Figures

FIG. 1
FIG. 1
Population human perilymph measures. Box plot representation of perilymph measures of FX-322 active ingredients CHIR99021 and VPA (n = 7).
FIG. 2
FIG. 2
Modeled pharmacokinetics of FX-322 in the human inner ear. Calculated human cochlear distributions of CHIR99021 and valproic acid (VPA) as a function of cochlear distance and time based on elimination measurements obtained in guinea pig pharmacokinetic studies. Calculations include entry, perilymph kinetic and middle ear kinetic parameters, as summarized in Table S3.
FIG. 3
FIG. 3
Consort diagram. Low volume = 0.05 ml; high volume = 0.2 ml.
FIG. 4
FIG. 4
Hearing improvement in WR and WIN from a single dose of FX-322 in a Phase 1b clinical trial. A, A bivariate plot of Word Recognition in Quiet (WR) scores at Baseline and Day 90. Subjects with significant improvements by falling outside the 95% confidence interval (CI) are numbered by their patient number. Four FX-332-treated subjects and zero placebo-treated subjects fall outside of the 95% CI. B, FX-322 subjects showed increased WR scores across Days 15, 30, 60, and 90 whereas the placebo group did not improve; (2-tailed pairwise comparison of adjusted means between treatment groups averaged across all time periods, SE, p = 0.029). C, Psychometric functions for words-in-noise (WIN) data show no improvement from Baseline to Day 90 for placebo-treated subjects, (D) while FX-322-treated subjects show improvement (mean, 95% CI, p = 0.012). Data presented includes all subjects (n FX322 = 15, n placebo = 8).

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