EFFICACY OF INTRATYMPANIC OTO-104 FOR THE TREATMENT OF MÉNIÈRE’S DISEASE: THE OUTCOME OF THREE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDIES

Dear Editor We are writing to provide our perspective on the article titled “Efficacy of Intratympanic OTO-104 for the Treatment of Ménière’s Disease: The Outcome of Three Randomized, Double-Blind, Placebo-Controlled Studies” published by Phillips et al. in Otology & Neurotology in July 2023 (1). The research conducted on the efficacy of OTO-104 for the treatment of Ménière’s disease is indeed a valuable contribution to the medical field; at this regard, we would like to provide some comments and insights regarding the study. First, we commend the authors for their rigorous study design, using three randomized, double-blind, placebo-controlled, multicenter phase three studies. Such an approach is essential to ensure the reliability and validity of the findings. Additionally, the inclusion of patients from both the United States and Europe enhances the generalizability of the results, making them relevant to a broader population. However, we would like to draw attention to a few aspects that may warrant further investigation and discussion. One notable finding was the difference in treatment response based on the patients’ history of intratympanic steroid injections. As revealed in the AVERTS-1 study, patients who had previously received intratympanic steroids showed a significant response to placebo compared to OTO-104, raising questions about the potential impact of prior treatment on the outcomes. This observation merits further investigation to better understand its implications for the overall efficacy of OTO-104. Additionally, the results of the AVERTS-2 study, which was terminated early, showed mixed outcomes. Although the main analysis population indicated a statistically significant improvement with OTO-104 treatment, the subgroup analysis of patients who completed the full follow-up period yielded different results. Considering the premature termination of the study and the possible impact it may have had on the results, the interpretation of these findings should be approached with caution. Furthermore, the coronavirus disease 19 (COVID-19) pandemic affected the conduct of the 811 study, and while the authors concluded that it did not impact study data or results, it might be beneficial to explore the potential implications of remote visits and the variability they introduced into the study (2,3). Moving on to the discussion and conclusions of the work, the authors aptly discussed the mechanisms of OTO-104’s sustained exposure and mucoadhesive properties, which provide advantages over traditional intratympanic corticosteroid solutions. The potential benefits of the thermosensitive poloxamer-based formulation in terms of sustained drug diffusion into the inner ear and patient convenience are noteworthy. However, the study’s overall conclusion highlights the challenges faced in determining the efficacy of intratympanic steroids for Ménière’s disease treatment. While the three large, high-quality clinical trials found numerical benefits in OTO-104 treatment, statistical significance was only achieved in one of the studies. The remarkably high placebo response rates observed in all three studies, surpassing those reported in other patient-reported outcome studies, make it difficult to separate the true effects of OTO-104 from the placebo effect. In light of these findings, the authors emphasize the need for continued research in this area. Intratympanic steroids should not be disregarded as a treatment option, considering the safety profile and the potential positive effects, especially in subsets of Ménière’s disease sufferers (4,5). The research community should focus on strategies to effectively manage placebo responses, possibly through subtyping patients based on clinical aspects, radiological features, or inflammatory cytokine profiling. In conclusion, the research on the efficacy of intratympanic OTO-104 for Ménière’s disease presented in the article published by Phillips et al. contributes valuable insights to the field. However, the study findings and discussion highlight the complexities of evaluating intratympanic steroids and emphasize the need for further research to develop evidence-based treatments for patients with Ménière’s disease. Alfonso ScarpaDepartment of Medicine and SurgeryUniversity of SalernoSalerno, Italy[email protected]Mario CarucciDepartment of OtolaryngologyAzienda Ospedaliera Universitaria "San Giovanni di Dio eRuggi d'Aragona", SalernoMassimo RalliDepartment of Sense OrgansSapienza University RomeRome, Italy,[spi_endthyc]Pietro De LucaOtolaryngology DepartmentIsola Tiberina - Gemelli Isola HospitalRome, Italy, [spi_endthyc]Giovanni SalzanoMaxillofacial Surgery UnitUniversity Hospital of Naples “Federico II,” Naples, ItalyPasquale ViolaGiuseppe ChiarellaUnit of AudiologyRegional Centre for Cochlear Implantsand ENT DiseasesDepartment of Experimental and Clinical MedicineMagna Graecia UniversityCatanzaro, Italy [spi_endthyc]Antonio Salzano FrancescoDepartment of Medicine and SurgeryUniversity of SalernoSalerno, Italy