An Evaluation of the Long Term Safety and Efficacy of AAVAnc80-hOTOF Gene Therapy in Individuals with Sensorineural Hearing Loss due to Otoferlin Gene (OTOF) Mutations - AK-OTOF-LTFU

Start Date-

Sponsor / Collaborator

Akouos, Inc.

NCT05821959 / RecruitingPhase 1/2

A Trial of AAVAnc80-hOTOF Gene Therapy in Individuals with Sensorineural Hearing Loss Due to Otoferlin Gene Mutations

Part A of this trial will evaluate the safety and tolerability of a single unilateral administration of one of two dose levels of AAVAnc80-hOTOF and will evaluate the Akouos delivery device to safely achieve the intended product performance.

Start Date15 Sep 2023

Sponsor / Collaborator

Akouos, Inc.

[+1]

NCT05572073 / RecruitingNot Applicable

A Natural History Study in Individuals With Otoferlin Gene-mediated Hearing Loss

This is a retrospective and prospective longitudinal study in participants with Otoferlin Gene-Mediated Hearing Loss.

Start Date14 Jul 2022

Sponsor / Collaborator

Akouos, Inc.

[+1]

100 Clinical Results associated with AK-OTOF

100 Translational Medicine associated with AK-OTOF

100 Patents (Medical) associated with AK-OTOF

Literatures (Medical) associated with AK-OTOF

01 Mar 2024·Advanced Science

AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness

Article

Author: Tan, Chang ; Zhou, Yinyi ; Zhang, Ziyu ; Chai, Renjie ; Liu, Jiancheng ; Shu, Yilai ; Qi, Jieyu ; Yang, Xuehan ; Zhang, Shanzhong ; Chen, Tian ; Tan, Fangzhi ; Li, Huawei ; Zhang, Liyan ; Lu, Yicheng ; Gao, Xia ; Jiang, Lulu ; Yu, Chaorong ; Xu, Lei ; Sun, Sijie ; Song, Huaien ; Dong, WenXiu ; Wu, Lianqiu ; Lu, Ling ; Qian, Xiaoyun ; Zhai, Yabo

AbstractMutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno‐associated virus (AAV)‐mediated OTOF gene replacement therapy is extensively validated in Otof‐deficient mice. However, the clinical safety and efficacy of AAV‐OTOF is not reported. Here, AAV‐OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non‐human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV‐OTOF is delivered into one cochlea of a 5‐year‐old deaf patient and into the bilateral cochleae of an 8‐year‐old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure‐tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5‐year‐old patient can be restored to the normal range at 1 month after AAV‐OTOF injection, while the 8‐year‐old patient can hear the conversational sounds. Most importantly, the 5‐year‐old patient can hear and recognize speech only through the AAV‐OTOF‐injected ear. This study is the first to demonstrate the safety and efficacy of AAV‐OTOF in patients, expands and optimizes current OTOF‐related gene therapy and provides valuable information for further application of gene therapies for deafness.

01 May 2023·International Journal of Pediatric Otorhinolaryngology

Epidemiology, etiology, genetic variants in non- syndromic hearing loss in Iran: A systematic review and meta‐analysis

Review

Author: Afshari, Mahdi ; Naraghi, Mohsen ; Eslami, Maryam ; Gilani, Sapideh ; Aliazami, Farnoush ; Farhud, Dariush

OBJECTIVESHearing loss is one of the most common heterogeneous complicated disorders worldwide. We previously analyzed the results of published data on non-syndromic hearing loss in the Iranian population systematically. A broad range of genes is a challenge for molecular screening and clinical diagnosis in our populations on the ground of distinct genetics. The aim of this study was to analyze the role and frequency of the variants accountable for non-syndromic hearing loss (NSHL) in the Iranian population. These were identified with different methods including whole exome sequencing (WES), next-generation sequencing (NGS), targeted genomic enrichment and massively parallel sequencing (TGE + MPS), autozygosity mapping, STR markers, linkage analysis, and direct sequencing. This is the comprehensively study focusing on classifying 13 common NSHL genes according to their frequencies. Previous studies have not studied different regions and the Iranian population, and this is the definitive study on the topic.METHODSWe searched Scopus, PubMed, Science Direct databases, and Google Scholar. After a systematic review of the evidence 95 studies were considered then 31 studies were eligible for meta-analysis. In total, 6995 families, 358 variants, and 117 novel variants were included. Statistical analyses were conducted using Stata SE version 11 software. The inverse variance method enjoyed combining data. Heterogeneity of the preliminary results was assessed using Q (Cochrane test), and I square index. Random effects or fixed models were applied to combine the results, relying on the degree of heterogeneity. Point and pooled prevalence of variants acting on different regions were illustrated by forest plots.RESULTSThe total prevalence of at least one variant of GJB2 and SLC26A genes was estimated at 26% and 5%, respectively. Variant c.35delG accounted for 18% of the GJB2 variants while 1% of these variants were novel ones. The next most common variants in the GJB2 gene were c.109G>A at 3.5% and c.-23+1G>A at 2.3%. Moreover, the prevalence of GJB2 gene variants varied on average 0.002% from one region to another in Iran (p=0.849). Our meta-analysis also showed that the frequency of at least one variant of MYO15A varied between 1.2% and 12.5%. Corresponding prevalences for the other variants were as follows: ILDR1 (3.5%-3.7%), CDH23 (2%-10%), PJVK (1.4%-33%), TECTA (1.3%-6.7%), MYO6 (2%-4.8%), TMC1 (1.8%-2%), MYO7A (0.7%-5%), MARVELD2 (0.7-5%), OTOF (0.7%-4%), LRTOMT (0.7%-2.5%). Finally, we did not find any relationship between geographic area and the presence of these variants.CONCLUSIONGJB2 gene variants were the most common cause of NSHL in Iran. Understanding the prevalence of NSHL gene frequency in Iran may be the foundation for future studies in an Iranian population which may lead to future NSHL therapy.

News (Medical) associated with AK-OTOF

08 May 2024

·firstwordpharma.com

Regeneron gene therapy sustains promise in deafness trial

Regeneron Pharmaceuticals announced further encouraging early results for its DB-OTO gene therapy for hearing loss, including 24-week data showing that the first treated patient – a 10-month-old infant – went from profound deafness at baseline to being able to detect sounds in the conversational range.The company also unveiled six-week results from a second patient who was treated at 4 years old and appears to be showing signs of a similar trajectory.The results, presented Wednesday at the American Society of Gene and Cell Therapy (ASGCT) meeting, are from Regeneron's ongoing Phase I/II CHORD trial evaluating DB-OTO as a treatment for profound hearing loss caused by mutations in the otoferlin gene.DB-OTO, a dual AAV1 vector designed for intracochlear delivery, aims to provide a full-length copy of the OTOF gene to hair cells in the inner ear. The therapy is surgically delivered using a well-established approach based on cochlear implantation, allowing direct infusion into the perilymph – the fluid-filled space of the inner ear.Preliminary data from the first patient were reported last October. The infant received a single unilateral dose of 7.2 x 1012 vector genomes of DB-OTO administered in the right ear, while a cochlear implant was placed in the left ear during the same surgical procedure.At the 24-week mark, no serious adverse events related to DB-OTO were reported. Researchers were also concerned with not damaging vestibular organs, which help people keep their balance, during surgical delivery of the therapy in the inner ear. Regeneron says vestibular function has remained normal.Unlocking auditory functionResults also showed progress in hearing ability through week 24 in the ear treated with DB-OTO. Auditory brainstem response (ABR) indicated improvement in hearing at different sound levels ranging from 45 to 85 dB, whereas before treatment, there was no response to sound at 100 dB. Additionally, an audiogram demonstrated improvement in hearing levels to within normal hearing thresholds compared to the beginning of the study, while there was no improvement in hearing intensity observed in the untreated ear with cochlear implant turned off.The first patient "entered the study with profound deafness, a sort of a level at which you couldn't even hear [a] chainsaw," explained Johnathon Whitton, who heads the Auditory Global Program at Regeneron, in an interview with FirstWord. But after treatment, "we saw responses that are in the normal sensitivity range, which is just remarkable."Corroborating the tests, parents also reported improved auditory behaviour and voice quality when the cochlear implant in the untreated ear was turned off.In a second patient, a 4-year-old child who received the same unilateral dose of DB-OTO, preliminary data demonstrated ABR and audiogram improvement through week six in the treated ear compared to baseline. No DB-OTO-related adverse events or vestibular abnormalities were observed here either."It looks very similar basically to what we saw on the first patient at that time point, so I think we're seeing something consistent starting to play out," Whitton commented.End-of-2025 filing targetRegeneron is now engaging with regulators to align on the necessary data requirements and expedite patient enrollment in the ongoing trial, targeting a filing for the end of next year. "We believe and it's a moral obligation to push as aggressively as possible now given…that very promising early efficacy data," Christos Kyratsous, co-head of Regeneron Genetic Medicines, told FirstWord.Regeneron acquired DB-OTO through its purchase of Decibel Therapeutics last year for $109 million or up to approximately $213 million if contingent value right (CVR) milestones are achieved. Alongside DB-OTO, Regeneron is also advancing other gene therapy programmes, including AAV.103 for GJB2-related hearing loss and AAV.104 for stereocilin-related hearing loss.Regeneron's efforts are part of a broader push to develop gene therapies for genetic hearing loss. Eli Lilly earlier this year reported that an 11-year-old boy born with hearing loss due to a mutation in the otoferlin gene was able to hear across all tested frequencies after being treated with a single dose of AK-OTOF, while another group involving Refreshgene Therapeutics posted positive data for the gene therapy AAV1-hOTOF.

AcquisitionClinical ResultGene Therapy

08 May 2024

·www.biospace.com

Regeneron’s Gene Therapy Shows ‘Dramatic’ Hearing Improvement in Deaf Kids

Pictured: Regeneron logo on a light brown building/Shutterstock/Lev Radin Regeneron Pharmaceuticals’ investigational gene therapy DB-OTO improved hearing in two young children with “profound genetic deafness” since birth, according to the company’s Wednesday oral presentation at the 2024 American Society of Gene & Cell Therapy annual meeting in Baltimore. One patient returned to normal hearing levels within 24 of treatment, as measured by auditory brainstem response (ABR) and the gold-standard pure tone audiometry (PTA)—both of which are validated methods of evaluating hearing function. The patient was dosed with DB-OTO at 11 months of age and is “one of the youngest in the world to receive a gene therapy for genetic deafness,” Regeneron said in its news release on Wednesday. At the 24-week assessment mark, the patient showed an average 84-dB improvement from baseline across key speech frequencies. PTA found that one frequency even reached 10 dB in hearing level. The second patient, who was given the gene therapy at four years of age, showed “initial hearing improvements” at the six-week follow-up. The patient demonstrated behavioral responses to loud sounds. The average improvement from baseline across key speech frequencies was 19 dB. Lawrence Lustig, study investigator and chairperson of Columbia University’s Department of Otolaryngology-Head & Neck Surgery, in a statement called these initial results “impressive,” adding that they “showcase the revolutionary promise of DB-OTO as a potential treatment for otoferlin-related deafness.” Wednesday’s initial readout comes from the ongoing Phase I/II CHORD trial, a first-in-human open-label study, which is still currently enrolling patients from sites in the U.S., U.K. and Spain. In addition to efficacy, CHORD also looked at the safety of DB-OTO and found it to be well-tolerated with no treatment-related serious adverse events. Designed to be delivered via a single sear injection, DB-OTO is a cell-selective, AAV-delivered gene therapy that works by delivering a functioning copy of the otoferlin gene, which is mutated and dysfunctional in patients with genetic hearing loss. Affecting nearly 1.7 out of every 1,000 children born in the U.S., congenital hearing loss presents a “significant unmet need,” according to Regeneron. The otoferlin gene is implicated in about half of these cases. With the early results from CHORD, Regeneron follows in the footsteps of Eli Lilly, which in January 2024 revealed that its investigational otoferlin gene therapy AK-OTOF restored the hearing of an 11-year-old boy within 30 days of treatment. A day later, a Chinese research group published results in The Lancet, showing that they were able to restore hearing in five of six children treated with their own otoferlin gene therapy. As in the case of CHORD, the patients in these two studies had profound genetic deafness since birth. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Clinical ResultGene TherapyClinical StudyCell Therapy

08 Apr 2024

·www.pharmaceutical-technology.com

Sensorion raises $16m for gene therapies to treat deafness

Mutations in the otoferlin protein are a frequent cause of deafness in children. Image credit: Shutterstock/CC7. Sensorion has secured €14.8m ($16m) from its investors to advance its gene therapy programmes for the treatment of deafness and hearing loss disorders. The capital raise, via the issuance of 24,574,694 shares to existing shareholders, extends the biotech’s cash runway until the end of next year. The offering is expected to close around 11 April, adding to the private placements of $54m in February 2024 and $38.3m from August 2023 . The France-based biotech stated that the funds will go towards its clinical-stage gene therapy assets indicated for patients with deafness, covering research and development activities through 2025. At the helm of Sensorion’s pipeline is SENS-501, an adeno-associated virus (AAV) gene therapy candidate that was approved to start a European Phase I/II clinical trial in January. See Also: Pluri launches manufacturing division as cell therapy pipeline progresses Navigating post-approval research and reimbursement for orphan therapies The biotech said the funds will support the enrolment of the first two cohorts in the trial. The study, called Audiogene, will assess the safety, tolerability, and efficacy of SENS-501 via intra-cochlear injection in paediatric patients with hearing loss. Sensorion is targeting patients with mutations in the gene coding for otoferlin protein – responsible, amongst other genes, for congenital deafness. A Sensorion spokesperson told Pharmaceutical Technology that the first results from Audiogene are expected in the second half of 2024. Also standing to benefit from the financing is the biotech’s second clinical programme for GJB2-GT, a gene therapy designed to restore hearing in those with mutations in the GJB2 gene. This gene encodes for gap junction beta-2 protein, mutated versions of which can cause childhood deafness. Sensorion expects to submit a clinical trial application for the drug in the first half of 2025. There are currently no approved gene therapies to restore hearing in adults or children, though the research space is ramping up. In January 2024, Eli Lilly subsidiary Akouos reported positive initial data from a Phase I/II trial investigating its gene therapy AK-OTOF for genetic hearing loss. AK-OTOF is also an AAV gene therapy designed to restore hearing in patients with otoferlin gene mutations. In the same month, a study co-led by Harvard Medical School and Fudan University’s Eye & ENT Hospital in China showed promise with a gene therapy in the same patient population. In February, a gene therapy developed at Italy’s TIGEM Telethon Institute of Genetics and Medicine was used to treat a patient with deafness in the US, as reported by Nature Italy. Gene therapies are gaining regulatory traction , with 2023 seeing the highest number of approved treatments in the past decade. The global market value of AAV therapies is expected to reach $22.3bn in 2029, up from $1.5bn in 2023, according to analysis by GlobalData. GlobalData is the parent company of Pharmaceutical Technology. Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva. Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content. Free Whitepaper Cell and gene therapies: Pipe dream to pipeline The cell and gene industry is gaining momentum, with a new wave of therapies promising to transform the way doctors treat, and even cure, disease. In this report, Cytiva and GlobalData have collaborated to explore the rise of the cell and gene therapy industries, the current state of the market, present and future opportunities for advancement, and the challenges that lie ahead. By Cytiva Thematic By downloading this case study, you acknowledge that GlobalData may share your information with Cytiva Thematic and that your personal data will be used as described in their Privacy Policy

Gene TherapyClinical StudyCell Therapy

100 Deals associated with AK-OTOF

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Indication	Highest Phase	Country/Location	Organization	Date
Hearing Loss, Sensorineural	Phase 2	US	Eli Lilly & Co.	15 Sep 2023
Hearing Loss, Sensorineural	Phase 2	GB	Eli Lilly & Co.	15 Sep 2023
Hearing Loss, Sensorineural	Phase 2	TW	Eli Lilly & Co.	15 Sep 2023
Hearing Loss	Phase 2	US	Eli Lilly & Co.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05821959 (AK-OTOF-101, NEWS) Manual	Phase 1/2	Hearing Loss	1	AK-OTOF	(barjzefmcy) = was observed within 30 days of a single administration of AK-OTOF in the initial AK-OTOF-101 study participant, the first to receive gene therapy in the United States for a genetic form of hearing loss. azlmorrzfx (nbkyyviuge ) View more	Positive	23 Jan 2024

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