“Pardon, doctor?”

“I said that hearing loss is part of growing old and there’s nothing we can do about it”

Perhaps this dialogue won’t be necessary for much longer and it will be possible to prescribe drug treatments to patients suffering from hearing loss. The recent report from Action on Hearing Loss (previously RNID) predicts that the first drugs to treat hearing conditions could be available by 2020. The pioneering new treatments will help alleviate some types of tinnitus, reduce hearing loss associated with loud noise exposure, middle ear infections and counter specific anti-cancer drugs that cause hearing loss [1].

Currently, one in six people in the UK has a hearing loss, and the figure is predicted to rise to one in four by 2031. Tinnitus is also a widespread problem with over six million people in the UK suffering its effects. There are no drugs approved for the treatment of either tinnitus or hearing loss.

There can be many causes of defective hearing ranging from genetic predisposition to noise-induced hearing loss (NIHL), and including deafness caused by infection and age-related degradation of hearing. The mechanism of human hearing is very complex but fundamentally it involves the sensory hair cells in the organ of Corti detecting sounds and passing messages via synapses to the spiral ganglion neurones that carry the signal to the brain. 90% of hearing loss is caused by damage to cells within the cochlea, particularly the sensory hair cells, and once these cells are damaged they degenerate and die. Mammals cannot regenerate lost hair cells or auditory neurons so hearing loss can be permanent [1].

However, birds and many non-mammalian species are able to regenerate hair cells after they have been damaged, so the question is: why have mammalian species lost this ability? A better understanding of the mechanisms will help future research.

There are currently a handful of drugs nearing the final stages of testing:

• Sodium thiosulphate (STS – Fennec Pharmaceuticals): This molecule is currently in Phase 3 trials to protect against cisplatin-induced hearing loss. Treatment with the anti-cancer agent cisplatin is a frequent cause of hearing loss. Recent studies have shown that infusion with STS at the same time as the cisplatin treatment avoids clinically significant ototoxicity [2].
• AuriPro™ (Otonomy): This sustained-exposure form of ciprofloxacin that can be used to treat otitis media is currently undergoing Phase 3 trials.
• AM-111 (Auris Medical): This cell-permeable peptide is currently in Phase 3 trials for the treatment of idiopathic sudden sensorineural hearing loss.
• OTO-104 (Otonomy): This sustained-exposure formulation of the steroid dexamethasone in development for the treatment of Ménière’s disease and other inner ear conditions. Successful results from Phase 2b trials were announced in May 2015.
• AM-101 (Auris Medical): This formulation of esketamine hydrochloride, an N-Methyl-D-Aspartate (NMDA) receptor antagonist, is currently undergoing Phase 3 trials for the treatment of tinnitus following traumatic cochlear injury or otitis media.
• D-methionine (Southern Illinois University): This small molecule is being investigated for protection against noise-induced hearing loss and tinnitus and is currently entering Phase 3 trials.

Other potentially valuable therapies are currently in earlier stages of development including OTO-311 (Otonomy), which is a sustained-exposure formulation of gacyclidine, a potent and selective antagonist of the NMDA receptor. Initial clinical studies support the use of NMDA receptor antagonists as a potential treatment for tinnitus. OTO-311 is still in the pre-clinical phase of research [3].

Stem cell research

For over ten years Action on Hearing Loss has been supporting research into the replacement of cells with stem cells to restore hearing.

The long-term project with Professor Marco Rivolta at the University of Sheffield has shown that stem cells can be turned into both hair cells and auditory neurons that have similar electrical properties to their natural counterparts. Animal studies then followed, which showed that transplanted stem cells were able to change into auditory neurons that could reconnect to the sensory hair cells. The results are promising so far with an average 45% recovery in these animal models [1, 4].

Gene therapy

Research into the differences between non-mammalian and mammalian species has identified a gene called Atoh1 which acts as a “switch” to turn on hair cell growth. In mammals the Atoh1 switch is turned off following birth but in birds and amphibians it remains on into adulthood. When Atoh1 is artificially switched on in mammalian cells that support hair cells (called “supporting cells”) it instructs them to divide and form new hair cells.

This discovery has opened the door to a possible gene therapy to treat certain types of profound hearing loss. The key to this kind of gene therapy is to how the gene can be delivered into the target cells. Genvec and Novartis are in the early clinical stages of testing a gene therapy – still known by its research name CGF166 – that uses a harmless virus to “infect” the cells and deliver the therapeutic gene [5]. Results from the study are expected in 2017.

It is a long journey from the first clinical trials to a prescription product, but with several different approaches in the pipeline it is possible that Action on Hearing Loss’s 2020 target might be achievable.

If you would like to comment on any of the issues raised by this article, particularly from your own experience or insight, Healthcare-Arena would welcome your views.

References

1. Action on Hearing Loss. Drugs to prevent hearing loss expected within 5 years – Action On Hearing Loss: RNID [Internet]. [cited 2015 Sep 17]. Available from: http://www.actiononhearingloss.org.uk/news-and-events/all-regions/press-releases/hearing-progress-report-2015.aspx
2. Womack AM, Hayes-Jordan A, Pratihar R, Barringer DA, Hall JH, Gidley PW, et al. Evaluation of ototoxicity in patients treated with hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin and sodium thiosulfate. Ear Hear. 2014 Dec;35(6):e243–7.
3. Otonomy. OTO-311 [Internet]. Otonomy. [cited 2015 Sep 17]. Available from: http://www.otonomy.com/pipeline/oto-311/
4. Rivolta MN. New strategies for the restoration of hearing loss: challenges and opportunities. Br Med Bull. 2013;105:69–84.
5. Action on Hearing Loss. Testing the world’s first gene therapy for hearing loss – Action On Hearing Loss: RNID [Internet]. [cited 2015 Sep 17]. Available from: http://www.actiononhearingloss.org.uk/community/blogs/our-guest-blog/the-first-gene-therapy-trial-for-hearing-loss.aspx