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Healthy hair cells (green) spiraled in a mouse cochlea (left) and in a mouse cochlea with hair cell death (right). When Tom Hirko was diagnosed with small cell lung cancer in May 2012, his oncologist immediately started treating him with a common chemotherapy called cisplatin. When he went to an audiologist for a hearing test, he was told the loss was most likely due to cisplatin, one of several drugs that can damage cells in the inner ear.
Although Hirko knows hearing loss is a fair trade-off for a longer life, it has left him feeling isolated. Hirko is one of 36 million Americans who report some degree of hearing loss, according to the National Institute on Deafness & Other Communication Disorders (NIDCD).
Today, doctors can only offer people like Hirko a hearing aid, a device that can cost anywhere from $500 to $3,500 per ear, with no guarantee of effectiveness. Drug companies find a lot to like about hearing loss: large numbers of patients, a lack of treatments, clinical trials with clear-cut end points, and a small universe of hearing specialists to call on. From a drug discovery perspective, the ear is also like the eye in that therapies can be delivered directly to the source of the problem.
When a sound wave arrives, the tufts move and vibrate, triggering an electrical response inside the cells that causes them to release neurotransmitters.
Because hearing requires both a functioning inner ear and proper processing by the brain, drug development efforts have taken two main paths: preventing or treating damage to the cochlea and modulating how the central nervous system processes sound. Otonomy, which has two treatments in late-stage development, is trying to better deliver drugs that have long been used off-label to treat hearing disorders.
That process is repeated multiple times over the course of two weeks, and yet only small amounts of the drug make it to the inner ear. Otonomy’s solution is to suspend the steroid in a polymer that is liquid at room temperature so it can be injected into the middle ear, but that becomes a gel when it hits body temperature. Several firms are contributing to a stream of drug candidates that aim to prevent or treat hearing disorders. According to NIDCD, up to 10% of the adult population experiences tinnitus for more than three months of the year, yet little can be done about it. Otonomy plans to ask the Food & Drug Administration for permission to start Phase I human tests of the drug, OTO-301, in early 2015. Autifony was spun out of GlaxoSmithKline in 2011 to develop a series of small molecules that modulate Kv3 voltage-gated potassium channels, which allow neurons to fire quickly and precisely.
Autifony’s lead drug candidate is poised to start Phase II studies in age-related hearing loss later this year. In addition to trying to treat hearing loss, the biotech industry wants to prevent it from happening in the first place.
Sound has developed an oral formulation of ebselen, a compound originally developed by a Japanese firm to treat stroke. Sound’s version of the compound, SPI-1005, has completed a Phase II study of protecting against the kind of hearing loss that occurs from listening to a too-loud iPod. Sound is also embarking on a Phase II study of SPI-1005 to prevent the ototoxicity, or drug-induced hearing loss, that affects people like Hirko. As Rubel points out, the good news, from a biological standpoint, is that damage occurs by just a handful of mechanisms. Under the National Institutes of Health’s Blueprint Neurotherapeutics Network, a project that provides funding, contract research services, and industry advisers to academics with a promising drug target, Rubel and several colleagues developed analogs of PR0T01, a small molecule found to protect zebra­fish hair cells exposed to gram-negative antibiotics. Year after year, hearing loss and tinnitus—a perception of sound where there is none—top the list of injuries reported by U.S. In recognition of the growing need and cost, HCE was established in 2009 to coordinate government efforts to prevent, diagnose, and treat hearing loss. One of HCE’s ongoing efforts is to support the burgeoning pipeline of new drugs for hearing disorders.
The group is also creating guidelines for companies developing products that could be useful in combat.
Going forward, HCE wants to help advance the field of genomics as it relates to hearing loss. Those active in the hearing field expect drugs developed to prevent hearing loss or to halt its progression will pave the way for therapies based on even more cutting-edge technology. In the mid-1980s, two research groups showed that chicks were able to regenerate hair cells after damage had occurred. That shift in thinking sparked a quest to understand the restorative mechanism used by birds so it could one day lead to treatments for humans. Progress in identifying targets for hair cell regeneration was slow, but academics eventually formed a consortium to help one another pick through the various pathways implicated in hair cell growth. In studies of human embryonic stem cells, Edge found that blocking Notch, a protein critical to embryonic development, prompts creation of new hair cells. Edge was able to show that giving mice the compound resulted in enough hair cell growth to improve hearing. While some researchers seek to regenerate hair cells using small molecules, others are using gene therapy.

CGF166, the partners’ lead candidate, uses an adenovirus carrying the human atonal gene to convert supporting sensory cells into hair cells that, when administered to inner ears of mice, enabled partial recovery of hearing. As they start the long clinical testing process, Novartis and GenVec can learn a lesson or two from firms such as Auris and Otonomy that potentially are just a few years from commercialization.
Back when Rubel first discovered birds’ ability to regrow hair cells, the idea of treating hearing loss with drugs seemed fanciful.
After the third round of treatment, Hirko started to notice what he described as a “fullness” in his ear. Because Hirko had for years worked as a safety technician at a factory near his hometown of Perry, Ohio, his doctors had a baseline for his hearing ability before he underwent chemotherapy. Worse, Hirko had a tough time understanding his 20-year-old daughter, who has a high-pitched voice and tends to talk fast. The most common cause of hearing loss is simply loud noise, be it a single event, like a firecracker erupting, or chronic exposure to excessive noise, like Hirko’s time in the factory or regular iPod use with the volume cranked up. Although cochlear implants have done wonders for the deaf and those with severe hearing loss, they don’t work for everyone. Efforts are diverse: Some biotechs are working on drugs that target the inner ear, where sound is first perceived, whereas others are focused on the central nervous system, where sound is processed. But the newness means they are starting from scratch when it comes to designing and recruiting for trials.
A handful of products are in the last stage of clinical development, but the overall pipeline is still sparse. The outer and middle ear exist primarily to conduct sound, which is first perceived when it hits the inner ear. Treatments in development range from improvements on known techniques for halting the progression of hearing loss to cutting-edge technology for restoring hearing by regrowing hair cells.
As Otonomy’s Weber explains, that involves asking a patient to lie on a table as the drug is injected into the middle ear. The polymer dissolves over the course of a week, slowly releasing the steroid to the inner ear. As Otonomy learns from its experience delivering sustained-exposure versions of known treatments, it is starting to apply the technology to novel compounds.
Researchers believe one way that tinnitus arises is when damage to the inner ear causes over-activation of NMDA receptors, which play an important role in the transmission of signals in the cochlea. Auris, the Sofinnova-backed firm, is further along in this area, having recently started two Phase III studies of AM-101, an NMDA receptor antagonist.
After all, even if the cochlea can pick up a sound signal, “you can only hear what the brain allows you to hear,” Auti­fony’s Domayne-Hayman notes.
If the studies are successful, Autifony expects to recruit a partner to help fund Phase III trials, Domayne-Hayman says. Sound Pharmaceuticals’ goal is to mimic a cellular defense mechanism the body uses to protect the inner ear from noise- and drug-induced damage.
Ebselen is a small-molecule mimic and inducer of glutathione peroxidase, an anti­oxidant enzyme highly expressed in the cochlea. Taken as a pill twice daily, the drug was shown to be safe and appears effective at preventing noise-induced hearing loss. The trial tests the drug’s ability to protect the hearing of certain patients undergoing treatment with platinum-based chemotherapy.
It set up the Pharmaceutical Interventions for Hearing Loss (PIHL) working group to help create standards for developing drugs to prevent and treat hearing loss. Understanding how a loud noise or explosion affects the cochlea at the molecular level could help pinpoint genes that make a person susceptible to or resilient against hearing loss.
After NIH funding ended last year, Rubel and his colleagues started Oricula Therapeutics to develop a drug to prevent antibiotic-induced hearing loss.
One new approach is treatments that can prevent the loss of, or even regenerate, hair cells. Unlike skin or blood cells, which constantly renew, “hair cells have to last you a lifetime,” explains Albert Edge, a professor of otology and laryngology at Harvard Medical School. The finding was a surprise: Although cold-blooded creatures were known to produce hair cells throughout life, the idea that damaged hair cells could be repaired was not considered possible.
The promise even lured a few big biotech firms, including Amgen and Genentech, to the field.
One advance came last year from the labs of Harvard’s Edge, who focuses on understanding how stem cells differentiate into hair cells and auditory neurons. That discovery led to a search for compounds that might turn off Notch and elicit the same effect in grown animals. The discovery is the scientific basis for Audion Therapeutics, a biotech start-up that recently scored a first round of funding from Lilly. GenVec and Novartis, through a pact forged in 2010, are trying this approach, according to Lloyd Klickstein, head of translational medicine for the new indications discovery unit at Novartis Institutes for BioMedical Research. Klickstein says the therapy could address hearing loss stemming from noise exposure and ototoxicity.

And more generally, the feeling across the field of hearing loss treatment is that prospects are improving now that biotechs, venture capitalists, and big drug companies are all participating.
I'm a musician convinced that I've been losing the taste buds of my sense of hearing through exposure to loud noise at concerts, and I want to experience the complexity and detail of sound again.
He and his wife, understandably more preoccupied by his lung cancer, chalked it up as a minor annoyance that would resolve itself after he completed his course of chemo. Although the noisy work environment had cost him the ability to hear some high-pitched sounds, after chemo his hearing deteriorated to the point where he had trouble following conversations. And the millions of people with milder, but still meaningful, hearing disorders have few good options. Healy’s firm is an investor in Auris Medical, a small company that has some of the most clinically advanced drugs for hearing disorders. The expectation is that treatment of hearing disorders will undergo a similar evolution, shifting from basic devices like hearing aids, to more advanced cochlear implants, and eventually to drugs that can prevent and treat hearing loss.
And whereas companies elsewhere in the drug industry tend to flock to a single promising target, in the hearing disorder arena nearly every firm is taking a different approach.
The inner ear houses the snail-shaped cochlea, which is lined with hair cells, so called because of the tuftlike projections topping each one. Then for 30 minutes the patient must remain perfectly still: no moving, talking, or swallowing. The company’s next drug candidate is a tinnitus treatment based on an antagonist of the glutamate receptor N-methyl-d-aspartate (NMDA). NMDA receptor antagonists dampen this aberrant signaling, thereby reducing the severity of tinnitus symptoms. However, its product must be injected into the inner ear several times over the course of two weeks. Among the many variables interpreted in the nervous system are volume, where a sound is coming from, and what the sound means.
The biotech is currently raising its profile with big pharma companies in anticipation of a future deal.
When the cochlea is exposed to noise, several reactive oxygen species appear with the potential to cause hair cell death. The company plans to begin enrollment later this year on a Phase IIb study, according to Chief Medical Officer Jonathan Kil. Rubel and David Raible, professors at the University of Washington’s Virginia Merrill Bloedel Hearing Research Center, have spent the past decade trying to understand the pathways responsible for chemotherapy- or antibiotic-related hearing loss, while also doing phenotypic, or cell-based, screens for protective small molecules. For example, PIHL is helping establish animal model standards for preclinical studies and guidelines for conducting clinical trials. On the basis of the options in the pipeline that meet those parameters, HCE’s current focus is on drugs that prevent hearing loss, rather than treat acute hearing losses in the field. The firm is operating with a Small Business Innovation Research grant from NIH and money from the University of Washington’s Life Sciences Discovery Fund.
Indeed, the majority of hearing loss results from damage to hair cells or auditory nerve cells.
In fact, it was such a surprise that it took researchers nearly a decade to accept that hair cell regeneration was a possibility, recalls Rubel, whose lab made one of the discoveries.
Lilly also licensed a series of related compounds to the firm, with an option to buy them back after Phase IIa tests. Now, Audion scientists are trying to improve the response to the point where humans could benefit.
You may be laudatory or critical, but please stay on topic and be respectful of the author and your fellow readers. Several of their projects are reaching late-stage development, and big pharma is starting to pay attention.
When processing of the signal goes awry, simple tasks, like picking out words against background noise, become a challenge.
Some of that damage is prevented by antioxidant enzymes called into action to neutralize the free radicals.
Indeed, in fiscal 2010, the Department of Veterans Affairs spent nearly $1.4 billion in compensation for auditory injuries. Moreover, the doses administered in his lab are too toxic for people, and the company needs to develop a way to deliver the compounds to the middle ear. We reserve the right to remove any comments that are profane, obscene, abusive, or otherwise inappropriate. Email addresses are required so that we can verify you are not a robot overlord and in case we need to contact you about your comment privately.

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