A First-In-Human Study of OTO-413, an Intratympanic Sustained-Exposure Formulation of BDNF, for the Treatment of Speech-in-Noise Hearing Impairment
Jeffery J. Anderson(1), James Robinson(1), Alice Blaj(1), Ines Hoffmann(1), Alan Foster(1), Justin Gull(2), Peter Volsky(3), David Moore(4), Victoria Sanchez(5);
(1)Otonomy Inc., San Diego, CA, (2)ENT Specialists, Salt Lake City, UT, (3)South Florida ENT Associates, Inc., Miami, FL, (4)Cincinnati Children’s Hospital, Cincinnati, OH (5)University of South Florida, Tampa, FL

Introduction
• Synaptic connections between inner hair cells (IHCs) and type 1 spiral ganglion neurons (SGNs) in the cochlea may be lost after noise exposure and with aging, even without notable hair cell damage.
• Loss of cochlear synapses in the absence of changes in auditory thresholds has been proposed as a mechanism of speech-in-noise (SIN) hearing impairment and may be one of the earliest manifestations of sensorineural hearing loss.

• The neurotrophin brain-derived neurotrophic factor (BDNF) plays a prominent role in establishing afferent connections between SGNs and IHCs during development, and local administration of BDNF protects SGNs and restores IHC ribbon synapses and their function in animal models of cochlear synaptopathy.
• OTO-413 is a thermo-sensitive formulation of BDNF which provides sustained exposure of BDNF to the cochlea after intratympanic (IT) administration.
• This is the first clinical study evaluating BDNF for treatment of patients with hearing loss.

Methods
• The safety, plasma PK, and exploratory efficacy of OTO-413 was assessed in a randomized, double-blind, placebo-controlled Phase 1/2 clinical study in patients with SIN hearing impairment.
• 39 subjects with self-reported difficulty hearing in noisy environments were enrolled after assessment by the Digits-in-Noise test (DIN) and audiometry.
• Four ascending dose-cohorts of at least 8 subjects each received a single IT injection of OTO-413 or placebo in a single ear.
• Safety was evaluated over 12-weeks by vital signs, adverse events (AE), clinical safety labs, otoscopy, tympanometry, audiometry, distortion product otoacoustic emissions (DPOAEs), and assessment of suicidality.
• Hearing assessments included SIN tests (DIN, Words-in-Noise test, and American English Matrix test), electrophysiological measures of cochlear synaptopathy (middle ear muscle reflex, ABR), and self-reported assessments related to hearing (SSQ-12, PGIC).

OTO-413 was well tolerated across all dose cohorts with 52% of OTO-413 subjects versus 70% of placebo subjects reporting ≥ 1 adverse event. There was no apparent impact of dose on AE incidence across OTO-413 cohorts. Most of the OTO-413 reported AEs were mild 28/37 (76%) or moderate 8/37 (22%) in severity. No Serious Adverse Events (SAEs) were reported. One AE of Diarrhea (due to COVID-19) was reported as Grade 3 and was not related to study drug.

AEs of the Ear and Labyrinth Disorders System Organ Class were the most frequently occurring AEs. The occurrence of ear related adverse events between OTO-413 and placebo treated subjects were comparable. One of the 4 tinnitus AEs for the OTO-413 treated subjects was deemed not related to study treatment and occurred in the non-injected ear; the tinnitus for this subject resolved within a day.

There were no clinically significant findings regarding vital signs, clinical safety labs, otoscopy, tympanometry, audiometry, DPOAEs, or the suicidal assessment.

All three SIN tests (DIN, WIN, AEMT) were administered monoaurally at Screening, Baseline (pre-dose), Day 15, Day 29, Day 57 and Day 85 study visits using HDA-300 headphones. The speech reception threshold (SRT) expressed in dB signal to noise ratio (dB SNR), in which the listener recognizes 50% of the digits/words correctly, was measured.

• There were 9 evaluable subjects from the OTO-413 high dose (0.30 mg) cohort (1 subject with no Day 57 visit and 1 early term not related to AE) and 8 placebo subjects pooled from Cohorts 2, 3 and 4 (1 placebo subject did not complete the AEMT at baseline).
• OTO-413 therapeutic activity was demonstrated by subjects achieving a clinically meaningful improvement from baseline across multiple speech-in-noise tests at consecutive timepoints (Days 57 and 85).

A subset of subjects with moderate (41-70 dB) to severe (70-90 dB) high frequency pure tone averages at 8, 10, and 12.5 kHz were evaluated. SIN improvements were observed in 5 of 7 OTO-413 treated subjects with this loss, while none of the 6 placebo subjects meeting these criteria had improvements.

Conclusions
• In this first-in-human study of BDNF for the treatment of hearing loss, OTO-413 was well-tolerated after a single IT injection across all dose cohorts.
• 6 of 9 (67%) of OTO-413 subjects at the highest dose demonstrated a clinically-meaningful improvement on at least one of the three SIN tests at both Days 57 and 85 versus 0 of 8 (0%) placebo subjects.
• Performance on the sentence-based AEMT favored OTO-413, with 4 of 9
(44%) OTO-413 subjects experiencing a clinically meaningful improvement at both Day 57 and 85 compared to 0 of 7 (0%) placebo subjects at any single time point.
• These results demonstrate safety and suggest therapeutic benefit of OTO-413 over placebo. These findings support further clinical development of OTO-413 for the treatment of hearing loss.