Gene Therapy for Congenital Hearing Loss

(CHORD Trial)

Recruiting at 26 trial locations

Overseen By Clinical Trials Administrator

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Regeneron Pharmaceuticals

Disqualifiers: Cochlear implants, Malignancies, Meningitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new gene therapy called DB-OTO to help children with hearing loss caused by changes in the otoferlin gene. Researchers aim to determine if DB-OTO is safe, comfortable for patients, and effective in improving hearing. The trial consists of two parts: one tests the treatment in one ear, and the other tests it in both ears. Eligible children have profound hearing loss due to specific genetic changes and do not have cochlear implants. As a Phase 1, Phase 2 trial, this research focuses on understanding how DB-OTO works in people and measuring its effectiveness in an initial, smaller group, offering participants the chance to be among the first to benefit from this innovative treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications. It is best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that DB-OTO is likely to be safe for humans?

Research shows that DB-OTO is a gene therapy designed to help children with hearing loss caused by changes in the otoferlin gene. Studies have found it generally safe, as most participants did not experience lasting discomfort. No major reports of unexpected medical problems have emerged. Since this study is in its early stages, researchers have initially tested the treatment to ensure it doesn't cause harm, deeming DB-OTO safe enough for further research.

However, like any new treatment, monitoring for side effects is crucial. Participants should report any unusual symptoms to the researchers. Overall, current evidence supports the safety of DB-OTO for use in clinical trials. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about DB-OTO for congenital hearing loss because it offers a novel approach through gene therapy. Unlike current treatments, such as hearing aids or cochlear implants, which only amplify or bypass damaged auditory pathways, DB-OTO aims to address the root cause by delivering a corrective gene directly to the inner ear. This intracochlear delivery method could potentially restore hearing at the cellular level, making it a groundbreaking option for those who do not benefit from conventional devices. By targeting the genetic underpinnings of hearing loss, DB-OTO has the potential to provide a more permanent solution compared to existing options.

What evidence suggests that DB-OTO might be an effective treatment for congenital hearing loss?

Research has shown that DB-OTO, a gene therapy under investigation in this trial, may help treat hearing loss caused by changes in the otoferlin gene. In one study, almost all participants (11 out of 12) experienced significant improvements in their hearing, with three reaching normal hearing levels. Another report noted that ten children with severe genetic hearing loss showed noticeable improvements after receiving DB-OTO. These findings suggest that DB-OTO could effectively restore hearing in children with this specific genetic condition. Participants in this trial will receive either unilateral or bilateral intracochlear dosing of DB-OTO, with the dose determined based on safety and efficacy data. ^{1 3 4 6 7}

Who Is on the Research Team?

Clinical Trial Management

Principal Investigator

Regeneron Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for children under 18 with profound sensorineural hearing loss due to OTOF gene mutations, who meet cochlear implant criteria and have not benefited from ear amplification. They must not have had previous gene therapy or cochlear implants in the affected ear(s), nor other untreatable hearing conditions.

Inclusion Criteria

My child's inner ear function is confirmed normal for DB-OTO treatment.

My child has severe hearing loss diagnosed by tests.

My child's ears can produce sounds in response to a test, and they are 24 months old or younger.

Exclusion Criteria

I have had meningitis before.

I have had cancer before or have it now.

My ear structure allows for the planned surgery based on my scans.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive unilateral intracochlear dosing to evaluate safety and tolerability

4-6 weeks

Dose Expansion

Participants receive bilateral intracochlear dosing using the dose selected based on safety and efficacy data from the Dose Escalation phase

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• DB-OTO

Trial Overview DB-OTO, an AAV based gene therapy, is being tested on pediatric patients with biallelic OTOF mutations. The study has two parts: Part A tests increasing doses in patients, while Part B expands to more participants receiving the treatment bilaterally.

How Is the Trial Designed?

Group I: DB-OTO - Unilateral Dose Escalation Experimental Treatment 1 Intervention

Part A: Unilateral intracochlear dosing

Group II: DB-OTO - Bilateral Dose Expansion Experimental Treatment 1 Intervention

Part B: Bilateral intracochlear dosing using the dose selected based on safety and efficacy data from Part A.

Who Is Running the Clinical Trial?

Regeneron Pharmaceuticals

Lead Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Decibel Therapeutics

Lead Sponsor

Trials

3

Recruited

60+

Published Research Related to This Trial

Gene therapy shows great potential for treating hearing loss, a common sensory disability, by addressing genetic mutations that cause the condition and possibly restoring hearing function.

Recent studies in animal models suggest that gene therapy could not only restore hearing but also promote hair cell regeneration in the cochlea, which is crucial for hearing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for sensorineural hearing loss. Chien, WW., Monzack, EL., McDougald, DS., et al.[2014]

Recent advancements in human genomics have identified defective genes linked to deafness, presenting new potential targets for gene-based therapies.

Successful gene therapies for hearing loss will depend on effective gene carrier systems, with the choice of vector and administration route significantly influencing the success of gene transfer to inner ear cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene transfer in inner ear cells: a challenging race. Sacheli, R., Delacroix, L., Vandenackerveken, P., et al.[2013]

Hearing loss is projected to affect over 900 million people by 2050, highlighting the urgent need for effective treatments, especially given its significant economic impact of $750 billion annually.

Recent research indicates that fetal gene therapy and pharmacotherapy could be promising strategies for treating congenital hearing loss, with mouse models showing success in early intervention that may translate to human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction. Hastings, ML., Brigande, JV.[2021]

A novel gene therapy using a single overloaded adeno-associated virus (AAV) vector successfully delivered the full-length otoferlin gene to about 30% of inner hair cells in deaf otoferlin knock-out mice, showing promise for treating genetic hearing impairments.

This approach demonstrated partial restoration of hearing in the mice, suggesting that using a single AAV vector simplifies the gene transfer process compared to previous dual-AAV methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overloaded Adeno-Associated Virus as a Novel Gene Therapeutic Tool for Otoferlin-Related Deafness. Rankovic, V., Vogl, C., Dörje, NM., et al.[2021]

A dual adeno-associated virus (AAV) approach successfully restored otoferlin expression in the cochlea of deaf mice, demonstrating a potential method for treating DFNB9 congenital deafness.

This method allowed for the reconstitution of the otoferlin gene, leading to a reversal of the deafness phenotype, which suggests promising implications for future gene therapy trials in humans with DFNB9.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. Akil, O., Dyka, F., Calvet, C., et al.[2020]

A novel dual-AAV-mediated gene therapy successfully reversed bilateral deafness in Otof -/- mice with a single injection, demonstrating the potential for treating auditory neuropathy caused by OTOF gene mutations.

The therapy effectively restored hearing to near normal levels for at least 6 months and improved synaptic vesicle release in inner hair cells, indicating a promising approach for future treatments in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hearing of Otof-deficient mice restored by trans-splicing of N- and C-terminal otoferlin. Tang, H., Wang, H., Wang, S., et al.[2023]

Recent advances in understanding the mechanisms behind sensorineural hearing loss have led to gene delivery being recognized as a promising strategy for treating the root causes of this condition.

While there are successful examples of gene delivery in animal models, significant challenges remain before these methods can be effectively applied in human clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances and challenges in adeno-associated viral inner-ear gene therapy for sensorineural hearing loss. Bankoti, K., Generotti, C., Hwa, T., et al.[2021]

Citations

1. investor.regeneron.com investor.regeneron.com/news-releases/news-release-details/db-oto-results-new-england-journal-medicine-showcase-dramatic

DB-OTO Results in the New England Journal of Medicine ... Nearly all participants (11 of 12) experienced clinically meaningful hearing improvements, including three who achieved normal hearing; ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41036103/

Functional, sustained recovery of hearing in Otoferlin- ... These data supported the initiation of an ongoing phase I/II clinical trial of DB-OTO in pediatric patients with OTOF-related hearing loss.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05788536

NCT05788536 | A Study of DB-OTO, an Adeno-Associated ... DB-OTO is a gene therapy that is being developed to treat children who have hearing loss due to changes in the otoferlin gene. The purpose of this study is to:.

4. biopharmadive.com biopharmadive.com/news/regeneron-gene-therapy-hearing-loss-deafness-decibel-otof/802627/

Regeneron, with 'game-changing' new data, to seek ... Study results published in The New England Journal of Medicine show the therapy significantly improved hearing in nearly a dozen children ...

5. ajmc.com ajmc.com/view/genetic-hearing-loss-improves-with-db-oto-gene-therapy-chord-trial

Genetic Hearing Loss Improves With DB-OTO Gene Therapy Ten children who received DB-OTO for profound genetic hearing loss due to variants of the otoferlin gene showed notable improvements in hearing.

6. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/407555

A Study of DB-OTO, an Adeno-Associated Virus (AAV) ... DB-OTO is a gene therapy that is being developed to treat children who have hearing loss due to changes in the otoferlin gene. The purpose of this study is to:

7. synapse.patsnap.com synapse.patsnap.com/drug/d10a5ca3981d405c99348d076dacf6ac

DB-OTO - Drug Targets, Indications, Patents These data supported the initiation of an ongoing phase I/II clinical trial of DB-OTO in pediatric patients with OTOF-related hearing loss.