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

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.

LGR5-Positive Supporting Cells Survive Ototoxic Trauma in the Adult Mouse Cochlea

“…This strongly suggests that the deafened mammalian cochlea retains regenerative potential, and hence therapeutic opportunities targeting the LGR5+ SCs could arise. A pioneering clinical trial has already shown that modulating the Wnt and Notch signaling pathway with a recently commercialized drug (FX322) in patients with sensorineural hearing loss improves speech recognition (both in quiet and in noise) 90 days after treatment ( McLean et al, 2021 ). This report, including only patients with noise-induced or idiopathic sudden SNHL, supports the hypothesis that Wnt-responsive SCs with regeneration potential are present in human, even after deafness.…”

Approaches to Treat Sensorineural Hearing Loss by Hair-Cell Regeneration: The Current State of Therapeutic Developments and Their Potential Impact on Audiological Clinical Practice

“…In a Phase 1b trial, 23 subjects were randomized to treatment with FX-322 via intratympanic injection (n ¼ 15) or placebo (n ¼ 8). 45 There were no notable differences in treatment-related AEs between the FX-322and placebo-treated subjects. No drug-related systemic AEs occurred, and no clinically relevant changes were observed for clinical laboratory values, vital signs, ECG, otoscopy (with the exception of the single perforation), or tympanometry.…”

“…When examining data from the WR in quiet test, McLean et al (2021) 45 showed 13 of 23 participants scored 90% or better (excellent performance) at baseline and due to ceiling effects, could not be assessed for efficacy. 46 The 10 remaining participants (6 FX-322 and 4 placebo) scored less than 90%, allowing for efficacy assessment using Thornton and Raffin's binomial distribution.…”

Hearing loss: The final frontier of pharmacology

“…In its first Phase 1/2 clinical trial, intratympanic FX‐322 showed variable improvement in word recognition scores in a quiet background for a small subset of subjects (5 of 15 patients) with mild to moderately severe hearing loss, and potential improvement in hearing thresholds at a single frequency (8 kHz) in a limited number of patients when administered as a single dose. 39 However, a follow‐on Phase 2a study, which evaluated single and multiple doses of FX‐322 in an attempt to overcome the short duration of cochlear exposure to the drug combination, 39 failed to show any improvement in similar audiologic endpoints. A concurrent open‐label single‐administration FX‐322 study in patients with mild to moderately severe hearing loss showed an improvement in word recognition scores in a subset of patients although a study in age‐related hearing loss showed no evidence of benefit.…”