Intratympanic Administration of OTO-313 Reduces Tinnitus in Patients With Moderate to Severe, Persistent Tinnitus: A Phase 1/2 Study

Abstract

Objective: To evaluate the safety and exploratory efficacy of intratympanic administration of OTO-313 in patients with tinnitus. Study Design: Single intratympanic injection of OTO-313 evaluated in a randomized, double-blind, placebo-controlled Phase 1/2 clinical study. Setting: Tertiary referral centers. Patients: Patients with unilateral tinnitus (moderate-severe) with tinnitus duration 1 to 6 months. Interventions: Intratympanic OTO-313. Main Outcome Measures: Safety and change from baseline in tinnitus functional index (TFI), daily ratings of tinnitus loudness and annoyance, and patient global impression of change (PGIC). Results: OTO-313 was well-tolerated with lower incidence of adverse events than placebo. Mean TFI reduction from baseline favored OTO-313 at Week 2, 4, and 8. A clinically meaningful, 13-point improvement on the TFI was observed in 43% (6/14) of OTO-313 patients at both Weeks 4 and 8 versus 13% (2/16) of placebo patients (ad hoc responder analysis, p-value < 0.05). Reductions in daily ratings of tinnitus loudness and annoyance favored OTO-313 compared with placebo. In OTO-313 responders, a strong correlation existed between change from baseline in TFI score and changes in tinnitus loudness, tinnitus annoyance, and PGIC. Conclusions: OTO-313 was well-tolerated and demonstrated a higher proportion of responders than placebo across consecutive visits (Weeks 4 and 8) supporting further clinical development of OTO-313 for the treatment of tinnitus.

Hearing loss: The final frontier of pharmacology

“…There are also pharmacological developments in the associated areas of balance disorders 99 and initial proof‐of‐concept data in tinnitus. 16 Local gene therapy for the inner ear is also under investigation as a means to restore hearing function in monogenetic hearing disorders. 100 With the promise of hearing loss therapies now on the horizon, it seems likely that the next decade will yield meaningful inroads into this “final frontier” of pharmacology and provide much needed relief for those suffering from hearing loss.…”

“…The current efforts reviewed here provide hope that effective pharmacological treatments are on the way to ameliorate hearing loss due to cochlear malfunction caused by noise, aging, and ototoxicity. There are also pharmacological developments in the associated areas of balance disorders 99 and initial proof‐of‐concept data in tinnitus 16 . Local gene therapy for the inner ear is also under investigation as a means to restore hearing function in monogenetic hearing disorders 100 .…”

“… 12 This has proved to be a versatile means of minimally invasive, sustained delivery that is amenable to small molecule drugs, biologics, RNA/DNA‐based molecules, and viral vectors, and whose benefits have now been demonstrated in clinical studies involving thousands of patients. 14 , 15 , 16 Additional delivery technologies that make use of other types of hydrogels, nanoparticles, magnetic beads, and oils have also been investigated. 17 For example, a lipid formulation of the NMDA receptor antagonist gacyclidine has demonstrated sustained cochlear exposure following intratympanic administration and initial clinical proof‐of‐concept for the treatment of tinnitus.…”

“… 17 For example, a lipid formulation of the NMDA receptor antagonist gacyclidine has demonstrated sustained cochlear exposure following intratympanic administration and initial clinical proof‐of‐concept for the treatment of tinnitus. 16 …”

“…With intratympanic injection of P407, preclinical studies have shown that therapeutic drug levels can be detected in the perilymph and cochlear tissue for weeks to months after a single injection 12 . This has proved to be a versatile means of minimally invasive, sustained delivery that is amenable to small molecule drugs, biologics, RNA/DNA‐based molecules, and viral vectors, and whose benefits have now been demonstrated in clinical studies involving thousands of patients 14–16 . Additional delivery technologies that make use of other types of hydrogels, nanoparticles, magnetic beads, and oils have also been investigated 17 .…”