Medical Policy

This document addresses gene therapy for the treatment of profound hearing loss due to variants of the otoferlin (OTOF) gene.

Note: Please see the following related document for additional information:

• CG-SURG-81 Cochlear Implants and Auditory Brainstem Implants

Note: For a high-level overview of this document, please see “Summary for Members and Families” below.

Medically Necessary:

The use of lunsotogene parvec-cwha is considered medically necessary for the treatment of hearing loss in individuals when all of the following criteria are met:

1. Diagnosis of congenital or early-onset sensorineural hearing loss attributed to a biallelic pathogenic or likely pathogenic variant in the otoferlin (OTOF) gene; and
2. For each ear indicated for treatment, all of the following:
   1. Hearing loss is severe-to-profound or profound as defined by audiologic evaluation (that is, average audiometric threshold of greater than 90 decibel hearing level); and
   2. Preserved outer hair cell function confirmed by presence of one of the following (a or b) in the ear(s) to be injected with gene therapy:
      1. Otoacoustic emissions greater than or equal to 6 decibels signal to noise ratio (dBSNR) at greater than or equal to 3 frequencies from 1 to 8 kHz; or
      2. The cochlear microphonic; and
   3. No anatomic contraindications to inner ear administration are present (for example, no indication that preoperative imaging demonstrates that access to the inner ear is not feasible, including in individuals with abnormal mastoid pneumatization or clinically significant anatomic variations of the middle ear and inner ear); and
   4. No history or presence of a cochlear implant in the same proposed treatment ear; and
   5. No prior treatment with gene therapy.

Investigational and Not Medically Necessary:

Gene therapy for the treatment of hearing loss is considered investigational and not medically necessary when the above criteria are not met, and in all other situations.

Repeat administration of gene therapy for the treatment of hearing loss is considered investigational and not medically necessary in all situations.

This document describes clinical studies and expert recommendations and explains when gene therapy for the treatment of profound hearing loss is clinically appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

Gene therapy for profound hearing loss aims to fix a faulty gene called OTOF. OTOF is responsible for the creation of a protein named otoferlin, which is important for transmitting sound signals from the ear to the brain and is needed for hearing. The gene therapy is given as one infusion into the inner ear during surgery with general anesthesia. The goal is to restore hearing by replacing the faulty gene in the ear and helping sound signals travel from the ear to the brain.

What the Studies Show

Early studies found that some children and teens had better hearing after treatment. The U.S. Food and Drug Administration (FDA) gave accelerated approval for this treatment in 2026. Even so, the studies this decision was based on were small and follow-up was limited. Better studies are needed to know how well this treatment improves health over time. The treatment also has risks from surgery and from the treatment itself, so the possible benefits need to be weighed against these risks. The gene therapy is given directly into the cochlea, which is part of the inner ear. This means treatment requires a surgical procedure and anesthesia. Possible harms reported in studies included side effects after treatment, side effects related to surgery, walking instability, and infection-related problems.

The main study that supported FDA approval included 12 children and teens. At 24 weeks, 9 of 12 individuals met the main hearing goal, and 9 of 12 individuals also showed auditory brainstem responses that were not present before treatment. Other early studies also reported hearing improvement in some treated children and young adults. However, these studies had few people, and follow-up was limited. Some trials are still ongoing. Because of these limits, longer follow-up and larger studies are still needed to better understand safety, durability, and how much this treatment improves long-term health outcomes.

When is this Clinically Appropriate?

Lunsotogene parvec-cwha (Otarmeni^™, Regeneron, Tarrytown, NY) may be appropriate in these situations:

• The person has congenital or early-onset sensorineural hearing loss caused by a disease-causing or likely disease-causing change in both copies of the OTOF gene; and
• For each ear planned for treatment, hearing loss is severe-to-profound or profound, with an average hearing threshold greater than 90 decibels; and
• For each ear planned for treatment, outer hair cell function is preserved, shown by otoacoustic emissions of at least 6 decibels signal to noise ratio (dBSNR) at 3 or more frequencies from 1 to 8 kHz, or by the cochlear microphonic; and
• There are no anatomic reasons that would prevent treatment from being given into the inner ear; and
• There is no cochlear implant in the same ear planned for treatment; and
• The person has not had gene therapy before.

When is this not Clinically Appropriate?

Gene therapy for hearing loss is not clinically appropriate when the criteria above are not met and in all other situations. The studies so far are encouraging, but they involved few people and limited follow-up. Better studies are needed to know if this treatment improves health over the long term and to better understand the balance of benefits and risks.

(Return to Description/Scope)

Summary

Published data suggests a single injection of lunsotogene parvec-cwha (Otarmeni) (previously known as DB-OTO) improves hearing for individuals with congenital hearing loss due to biallelic pathogenic otoferlin (OTOF) mutations. While current published literature is limited to small group sizes with short-term follow-up, a 2026 U.S. Food and Drug Administration (FDA) approval indicates Otarmeni is appropriate for certain individuals with sensorineural hearing loss. Clinical trials are still ongoing and longer-term data is necessary to continue to evaluate efficacy and improvement on net health outcomes.

Discussion

Gene therapy is being studied as a treatment for congenital hearing loss. Gene therapy can treat or prevent diseases and involves replacing or correcting a missing or faulty gene with a healthy version of that gene in cells.

Otoferlin is a protein important for the process of transmitting sound signals from the ear to the brain. Otoferlin is produced by the OTOF gene, and mutations in OTOF can cause profound congenital deafness. Despite the profound hearing loss, young children with otoferlin deficiency have intact cellular structures of the inner ear. This suggests that introducing otoferlin protein with adeno-associated virus (AAV)-based gene therapy could restore natural hearing. A dual AAV1 vector using a hair cell-specific promoter has been developed which delivers OTOF to hair cells in the inner ear. The goal of DB-OTO treatment is to enable synaptic transmission between sensory inner hair cells and the cochlear nerve, allowing sound signals to be transmitted from the ear to the brain. DB-OTO is administered into the cochlea as a single infusion, under general anesthesia.

In April 2026, the FDA issued an accelerated approval for lunsotogene parvec-cwha for intracochlear infusion. Otarmeni is an AAV vector-based gene therapy indicated for use in individuals with severe-to-profound and profound sensorineural hearing loss. Sensorineural hearing loss is defined as any frequency > 90 decibels (dB) hearing loss. The FDA label considers Otarmeni for those with confirmed variants in the OTOF gene, preserved outer hair cell function, and no history of a prior cochlear implant in the same ear.

The FDA approval was based on the children/infants with hearing loss due to otoferlin mutations (CHORD) trial (NCT05788536). Published in 2026 by Valayannopoulos, this phase I/II multicenter, open-label, first in-human study investigated individuals with OTOF variants and profound deafness. Part A was the dose escalation portion in which participants received Otarmeni in one ear (the contralateral ear could have a cochlear implant or remain untreated). In part B, participants received Otarmeni in both ears. Safety and efficacy were assessed at 48 weeks following treatment, then annually for 4 years. Participants were between the ages of 10 months and 16 years of age and had biallelic OTOF variants. In this study, profound hearing loss was defined as an average audiometric threshold of > 90 dB hearing loss. The presence of outer hair cell function was confirmed by otoacoustic emissions (defined as ≥6 decibels signal to noise ratio [dBSNR] at ≥3 frequencies from 1-8 kHz in the ear(s) to be injected. Participants were excluded if they had prior gene therapy or had a cochlear implant in the ear receiving the Otarmeni infusion. There were 9 participants who received Otarmeni in 1 ear and either a cochlear implant or no treatment in the contralateral ear. The other 3 participants received Otarmeni in both ears. The primary efficacy endpoint was an average threshold on behavioral pure-tone audiometry at week 24 of 70 dB hearing level or less. At week 24, the primary efficacy endpoint was met in 9 of 12 participants (75%; 95% confidence interval [CI], 43 to 95; p=1.1×10). Of the 3 participants who did not reach the primary efficacy endpoint, 1 showed no improvement, and 2 participants showed improvement with respect to baseline. A secondary endpoint was the presence of an auditory brainstem response at or below 90 dB normalized hearing level at week 24. At baseline, none of the participants had neural responses at a threshold above 90 dB. At week 24, there were 9 of the 12 participants (75%; 95% CI, 43 to 95; p=1.1×10^-13) who had an auditory brain-stem response at or below 90 dB normal hearing level. Of the participants who received Otarmeni treatment in one ear, an auditory brain-stem response was detected in 7 of 9 treated ears compared to 0 of 9 untreated ears. There were 2 participants who received treatment in both ears had an auditory brain-stem response detected. There were 67 adverse events reported. Of those, 17 were considered related to the surgical delivery of Otarmeni. There were 2 serious adverse events; 1 participant with grade 3 mastoiditis associated with the cochlear implant in the ear that had not been treated with Otarmeni and 1 participant with a grade 3 walking instability that developed following treatment. Both events resolved. Follow-up was done in 8 participants for more than 24 weeks. This study has limitations which include the small number of participants and limited duration. The authors note “Longer-term monitoring remains necessary.” However, hearing remained stable or continued to improve. Assessment is planned for 5 years following treatment.

A 2025 single-arm study by Qi reported the efficacy of DB-OTO in 10 participants between the ages of 1.5 years to 23.9 years. There were 7 participants who received a unilateral injection of DB-OTO while the other 3 participants received DB-OTO bilaterally. The primary endpoints of the study were safety and tolerability. No serious adverse events were reported. Of the 162 adverse events that did occur, most frequently noted was decreased neutrophil percentage, increased platelet count, and anemia. The secondary endpoint was efficacy. After receiving a single injection of DB-OTO, all 10 participants were followed for 6 months and all showed hearing improvement in pure-tone-average hearing level from baseline 106 ± 9 (mean ±standard deviation [SD]) to 52 ± 30 dB. At the time of publication, this trial was still ongoing. The study limitations include the small sample size, lack of a control group, and short duration. The authors note “Future studies with a larger and more diverse sample size as well as longer follow-ups are needed to delineate the dosage and biological variable interactions and determine the optimal therapeutic window and strategies.”

A 2024 study by Lv reports on 6 participants with autosomal recessive deafness 9 (DFNB9) due to biallelic pathogenic OTOF mutations and complete hearing loss who received a unilateral injection of DB-OTO. Participants ranged in age from 1.0 to 6.2 years. The primary endpoint was dose-limiting toxicity. Secondary endpoints included efficacy (defined as auditory function and speech perception) and safety. At the 26 week assessment, there were no dose-limiting toxicities reported. A total of 5 of the 6 participants had hearing recovery following treatment. Those with hearing recovery were also found to have improved speech perception. Additional trials with larger group sizes and longer follow-ups are needed. This trial remains ongoing.

Another 2024 study by Wang evaluated the efficacy of an injection of DB-OTO on participants with DFNB9. In this single-arm, single center trial, there were 5 participants ranging in age from 1.2 years to 11.0 years. This interim analysis includes data from the 26-week assessment. The primary endpoint included dose-limiting toxicity. Secondary endpoints included safety and efficacy. With 36 adverse events reported after treatment, none were reported as serious or dose-limiting. Bilateral hearing loss was restored in the 5 participants following treatment. This trial remains ongoing with longer-term follow-ups and more participants.

Hearing impairment is the most frequent sensory deficit in humans. Congenital hearing loss (which is a condition present at birth) is caused by genetic factors. It is estimated to affect approximately 1.7 out of every 1000 children born in the U.S., with half of these cases having a genetic cause (Valayannopoulos, 2026). Current treatment for congenital hearing loss is cochlear implants. Gene therapy is being studied as a treatment for profound genetic hearing loss.

Adeno-associated virus (AAV): A small virus that infects humans and is not known to cause disease. Modified (non-replicating) AAVs are frequently used as viral vectors for gene therapy.

Congenital: A condition or trait that is present at birth.

Gene therapy: A medical treatment that introduces or alters genetic material to replace the function of a missing or dysfunctional gene with the goal of lessening or eliminating a disease process that results from genetic dysfunction.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Lv J, Wang H, Cheng X, et al. AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial. Lancet. 2024; 403(10441):2317-2325.
2. Naso MF, Tomkowicz B, Perry III WL, Strohl WR. Adeno-associated virus (AAV) as a vector for gene therapy. BioDrugs. 2017; 31(4):317-334.
3. Qi J, Zhang L, Lu L, et al. AAV gene therapy for autosomal recessive deafness 9: a single-arm trial. Nat Med. 2025; 31(9):2917-2926.
4. Valayannopoulos V, Bance M, Carvalho DS, et al. DB-OTO gene therapy for inherited deafness. N Engl J Med. 2026; 394(11):1074-1083.
5. Wang H, Chen Y, Lv J, et al. Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Nat Med. 2024; 30(7):1898-1904.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Centers for Disease Control and Prevention (CDC). Early hearing detection and intervention (EHDI) hearing screening & follow-up survey. August 2019. Available at: https://archive.cdc.gov/www_cdc_gov/ncbddd/hearingloss/annual-data-files/2017-Annual-EHDI-Data.pdf Accessed on July 28, 2026.
2. Otarmeni^™ (Product Information), Tarrytown, NY. Regeneron; April 2026: Available at: https://www.fda.gov/media/192098/download. Accessed on July 28, 2026.
3. Regeneron Pharmaceuticals. A study of DB-OTO, an adeno-associated virus (AAV) based gene therapy, in children/infants with hearing loss due to otoferlin mutations (CHORD). NLM Identifier: NCT05788536. Last updated on July 1, 2026. Available at: https://clinicaltrials.gov/study/nct05788536. Accessed on July 28, 2026.

1.  National Institute on Deafness and other Communication Disorders. Available at: https://www.nidcd.nih.gov/ Accessed on July 28, 2026.

Congenital hearing loss
DB-OTO
Gene therapy
Otarmeni

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member’s contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan.

© CPT Only – American Medical Association