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15th May 2018
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Hear hear

Katrina Megget, 16 May 2018

018 Hearing spread web

Finally, researchers predict that the first drugs to prevent hearing loss are poised to become available within the next five years, Katrina Megget reports.

Roughly 5% of the world’s population – some 360m people – have disabling hearing loss. The World Health Organization (WHO) says this poses an annual global cost of $750bn, while growing noise pollution and an ageing population mean that 900m people will be affected by the condition by 2050. According to UK charity Action on Hearing Loss, ‘we are facing a potential public health crisis’.

Currently, the only way to treat hearing loss is with hearing aids or cochlear implants. Hearing aids work well for patients where volume is a problem, but patients who have problems processing the sound information due to the loss of sensory cells (see Box) are often better served by cochlear implants that can bypass the damage and stimulate the auditory nerve to send electrical signals to the brain. Both devices can be ‘very effective, but they aren’t a substitute for regular hearing’ as they stop short of restoring normal sound perception and hearing function, says Jochen Schacht, professor emeritus at the University of Michigan’s Kresge Hearing Research Institute.

A cure for hearing loss is still some way off, Schacht believes. However, small molecule drugs to prevent damage leading to hearing loss could be on the marketplace ‘within the next five to 10 years,’ he says.

Action on Hearing Loss, which has invested £1.7m in supporting more than 100 research projects around the world, also believes the first drugs to treat the condition could be available by 2020. It estimates such drugs could have a market value of around $2bn. ‘Remarkable progress has been made, bringing us to a point where there are a number of promising new treatments for hearing loss and tinnitus being clinically tested,’ says chief executive Paul Breckell. ‘We’re about to enter a new exciting era where people confronting hearing loss won’t just be limited to hearing aids and cochlear implants – drug treatments are within touching distance.’

But making progress is far from easy. Swiss biopharma company Auris Medical, for example, has already been forced to terminate two late-stage trials of its drug candidate AM-111 for acute inner ear hearing loss. One Phase 3 trial showed the drug was not statistically significant in improving hearing in the overall patient population.

Another problem hampering progress is a lack of knowledge of the molecular targets involved in hearing loss, according to Edwin Rubel, professor emeritus at the Virginia Merrill Bloedel Hearing Research Center at the University of Washington. ‘Most new drugs are developed from knowing the molecular target and developing a drug to bind to that target,’ Rubel says. ‘Easy if you know the target but in hearing loss we don’t know.’

Almost all the candidate drugs currently being tested for hearing loss prevention are repurposed drugs developed for other diseases, he points out, adding: ‘I can name on one hand and one finger the number of new drugs designed from scratch to protect hearing.’

900m
Number of people expected to be affected by hearing loss by 2050

US $2bn
Estimated market value of drugs to prevent hearing loss expected to reach the marketplace by 2020, according to Action on Hearing Loss

>20,000
Number of compounds screened before discovery of a new chemical entity –ORC-13661 – found to completely protect hearing in lab animals exposed to high doses of the aminoglycoside antibiotic amikacin

Most of the candidate drugs currently being tested for hearing loss prevention are repurposed drugs developed for other diseases

Studying what goes on in the inner ear is not easy, because of its location, and there are also limited cell culture models and cell lines of hair cells. In 2015, however, Rubel and his colleague David Raible hit on the idea of using laboratory zebra fish – a common model organism used for drug development – to study the effects of different compounds on hearing loss.

Taking advantage of the easily accessible hair cells found to grow externally in larval zebrafish, the scientists were able to develop a high-throughput screening platform to evaluate drug-like small molecules that might protect the hair cells from chemotoxic damage from certain medications. More than 20,000 compounds were screened, resulting in the discovery of a new chemical entity – ORC-13661 – found to completely protect hearing in lab animals exposed to high doses of the aminoglycoside antibiotic amikacin.

The drug is now licensed to Seattle-based Oricula Therapeutics and in February 2018, the US Food and Drug Administration (FDA) granted approval for a Phase 1 clinical trial in humans to test for safety, tolerability and pharmacokinetics. If the benefits seen in preclinical studies, which suggest a once-a-day oral therapy is possible, can be replicated in humans, ORC-13661 may be the first approved medicine to prevent hearing loss for patients undergoing aminoglycoside treatment. ‘We are now on the precipice of having an important, life-changing impact on the ability of people to communicate,’ Rubel says. ‘I’m enormously excited about the opportunity to begin clinical trials.’

Slightly more advanced along this clinical trial road is a drug candidate being evaluated by French biotech Sensorion. Due to enter Phase 2 trials later in 2018, the drug, SENS-401 (R-azasetron besylate), aims to prevent sudden sensorineural hearing loss and to prevent hearing loss induced by cancer chemotherapy drug cisplatin. It is a first-in-class 5-hydroxytryptamine receptor antagonist (5-HT3), which works on a subtype of serotonin receptors. The drug is an enantiomer of azasetron, which is marketed in Asia under the name Serotone for chemotherapy induced nausea and vomiting.

Nawal Ouzren, chief executive of Sensorion, says SENS-401, which has been granted orphan drug designation, is believed to protect hair cells by disrupting the cellular pathway that signals cell death in response to acoustic trauma, reducing cell death and neurodegeneration. Preclinical studies showed the drug, which is administered orally, has big potential to reduce hearing loss; rats treated with SENS-401 were found to have significantly more surviving outer hair cells and up to 11-fold more hair cells in the ‘basal turn’ region of the cochlea than rats on placebo.

‘For the first time, once impossible-to-treat diseases and conditions are being tackled with some of the most innovative minds, and cures for these ailments are coming close to reality,’ Ouzren says. The company is collaborating with cochlear implants manufacturer Cochlear to study the combination of SENS-401 with the implants, she continues. ‘Our approach speaks volumes towards the potential for revolutionary therapeutics, and we hope that by advancing SENS-401 through clinical trials, Sensorion can bring real clinical benefit to the field and possibly even offer a more permanent fix for patients suffering from these conditions.’

Another company interested in the hearing loss space, meanwhile, is Woburn, Massachusetts-based Frequency Therapeutics. Here, the focus is on regenerating new hair cells through the development of small molecule drugs that activate a type of stem cell known as progenitor cells, prompting them to create new hair cells. ‘The hearing loss space is eager for and in need of a therapeutic that can address hearing loss at the cellular level, by regenerating new cells that allow hearing to occur,’ says Chris Loose, co-founder and chief scientific officer at Frequency Therapeutics.

Frequency’s FX-322, which is a combination of small molecule drugs, was born out of research at Massachusetts Institute of Technology, Brigham and Women’s Hospital, and Massachusetts Eye and Ear teaching hospital. Progenitor cells from a mouse cochlea were grown in the laboratory and exposed to two types of molecules – one that stimulates the cell signalling pathway Wnt to induce cells to multiply, and another that activates a separate signalling pathway known as Notch, which prevents cells from differentiating too soon.

The experiment resulted in 2000 times more hair cell progenitors than previous approaches and about 60 times more mature hair cells than previous techniques using growth factors. When the approach was explored in an intact mouse cochlea removed from the body, the drugs successfully stimulated the progenitors to create new hair cells.

A Phase 1 trial for FX-322, completed in December 2017, demonstrated safety and tolerability, and a Phase 2 trial is expected later in 2018. The drug would be delivered locally by injection into the middle ear, from where it will diffuse into the cochlea. Loose remarks that the intention is to restore natural hearing. ‘As the scientific community continues to discover more about natural biological pathways, thereby uncovering the innate healing abilities of our own bodies, regenerative medicine will play an increasingly significant role in improving hearing,’ he says.

Gene and cell therapy applications are yet another active area of hearing loss research. Drug giant Novartis, for instance, is running a Phase 1/2 gene therapy trial to stimulate the growth of hair cells using the human atonal transcription factor protein, which should be completed in 2019. At the University of Sheffield, meanwhile, researchers reported in 2012 successfully transplanting healthy converted stem cells to replace the damaged cells in the cochlea in deaf gerbils. The gerbils, on average, recovered 46% of their hearing. (Chen, W. et al.; Nature, 2012, 490, 278).

Massachusetts-based biotech Decibel Therapeutics is yet another innovative young company to watch in the hearing loss space. Decibel, which only launched in 2015, has not released details of specific programmes, but is looking at repairing the synapses between neurons in the inner ear, among other approaches. The company joined forces with New York biotech Regeneron at the end of 2017, to develop novel hearing loss therapies

‘The field of hearing research is now reaching a tipping point,’ according to Paula Cobb, Decibel’s executive vice president of corporate development. ‘Over the next five years, we believe that we will see the first regulatory approvals of medications intended to protect, repair or restore hearing. This is an incredibly exciting time for the development of hearing loss therapeutics, which have the potential to transform the lives of millions of people around the globe.’

Hearing loss explained

021 Hearing impaired man with hearing aid webHearing starts with the ears, which picks up sound waves as vibrations. These travel down the ear canal until they reach the eardrum, causing it to vibrate. This movement causes a group of tiny bones behind the eardrum, known as the ossicles, to move, which pushes the sound waves through to the inner ear. The inner ear contains the snail-shaped cochlea, which is filled with fluid and lined with about 15,000 tiny sensory cells called hair cells. The sound waves cause the fluid in the cochlea to ripple, which stimulates the hair cells in such a way that an electrical signal is created. This signal is then carried by the auditory nerve to the brain, which translates it into a recognised sound. Until now, preventing or curing loss has been out of reach. Part of the reason for the slow progress is a lack of understanding the intricacies of hearing loss, which can affect the outer, middle or inner ear. The most common type of hearing loss, responsible for about 90% of cases of impaired hearing, can result from exposure to loud noises, ageing or a chemotoxic response to certain antibiotics and cancer chemotherapy drugs. In this sensorineural hearing loss, the hair cells are damaged and are unable to regenerate, so the hearing loss is permanent.

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