Two gene therapies for deafness make progress

A long-term clinical trial of a gene therapy for a rare genetic form of deafness has demonstrated sustained hearing restoration, while a separate gene therapy for the same condition has received approval from the Food and Drug Administration (FDA).

Mutations in the OTOF gene cause a form of congenital bilateral deafness by preventing production of otoferlin, a protein needed for transmitting sound signals from the inner ear to the brain. A follow-up Nature study extending earlier trials (see BioNews 1214, 1224 and 1242) reported that a one-off gene therapy improved hearing in 90 percent of patients with OTOF mutations, and continued to show benefits for up to two and a half years. In parallel, the FDA granted accelerated approval for Otarmeni (see BioNews 1212, 1238 and 1279), a separate therapy from Regeneron Pharmaceuticals, Inc. It will be made available at no cost to eligible patients in the USA through a company programme.

'It's remarkable to see patients go from complete deafness to being able to hear,' said Dr Zheng-Yi Chen, co-lead author of the Nature study and associate professor of otolaryngology-head and neck surgery at Harvard Medical School, Boston, Massachusetts. 'For many patients, that also means the ability to develop and use speech.'

The long-term study followed 42 participants carrying OTOF mutations, ranging in age from nine months to 32 years. They were treated with a viral vector delivering a functional OTOF gene into the cochlea. Improvements were rapid in the first months and then stabilised, remaining durable through the full follow-up period. No serious adverse effects were reported, and the participants will continue to be monitored. This study represents the largest patient cohort and the longest follow-up to date for a gene therapy treating congenital deafness.

The second gene therapy, Otarmeni (lunsotogene parvec-cwha, formerly DB-OTO), was granted FDA accelerated approval based on results from the ongoing CHORD trial, which showed improved hearing in 80 percent of participants (20 patients aged ten months to 16 years) lasting up to 48 weeks. Continued approval will depend on confirming results from the next phase of the trial.

Dr George Yancopoulos, board co-chair, president and chief scientific officer of Regeneron, said: 'We are honoured to be in the position to be the first company to ever offer such a gene therapy advance for free to those in the USA.'

Both studies used single-dose gene replacement approaches and reported high rates of hearing improvement. Together, they provide complementary evidence across different patient cohorts and follow-up periods.

'The FDA approval of Otarmeni signals a new era in the treatment of genetic forms of hearing loss, where reinstating 24/7 natural hearing is now possible,' said Dr Eliot Shearer, a CHORD trial investigator at Boston Children's Hospital and Harvard Medical School. However, genetic testing for congenital hearing loss is not included in routine newborn screening in the USA, meaning that some potentially eligible patients may not be identified.

Dr Lawrence Lustig of Columbia University Irving Medical Centre, New York, a clinical investigator on the CHORD trial, has expressed hope that the development of Otarmeni will lead to wider genetic testing for newborns diagnosed with hearing loss in the USA.

Identifying the genetic cause of deafness could enable more targeted treatments. Professor Yilai Shu, co-lead author of the Nature study, based at the Eye and ENT Hospital of Fudan University, Shanghai, China, said: 'The success of OTOF gene therapy marks a paradigm shift in treating hearing loss.' He added that the results from both therapies provide evidence that personalised gene therapy approaches could be developed for congenital deafness caused by different gene mutations.