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Drug Discovery

Sound Science

Emerging technology and a wide-open market are spurring more companies to pursue drugs to treat or prevent hearing loss

by Lisa M. Jarvis
April 7, 2014 | A version of this story appeared in Volume 92, Issue 14


Confocal microscopy images of two mature mammalian (mouse) cochlear whole-mounts, stained for hair cells (green), nerve fibers (red), and cellular nuclei (blue). The cochlea on left is normal.  Note the row of hair cells that spiral through the organ.  The cochlea on right is from a mouse in which all hair cells were destroyed at 6 weeks 0f age using a new transgenic mouse model.
Credit: Courtesy of Edwin Rubel and Glen MacDonald
Healthy hair cells (green) spiraled in a mouse cochlea (left) and in a mouse cochlea with hair cell death (right).

Jump to Topics:
Animation: How a sound wave travels through the ear
- Hearing Loss By The Numbers
- Firms are contributing to a stream of drug candidates that aim to prevent or treat hearing disorders
- The Military Advances Hearing Loss Efforts

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. After the third round of treatment, Hirko started to notice what he described as a “fullness” in his ear. 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.

Instead, the problem worsened. 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. 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.

Certain sounds, like “ess” and “eff,” eluded him. Worse, Hirko had a tough time understanding his 20-year-old daughter, who has a high-pitched voice and tends to talk fast.

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. As his wife, Lorrie, puts it, it’s “like the world is going on without him.”

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). 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.

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. Although cochlear implants have done wonders for the deaf and those with severe hearing loss, they don’t work for everyone. And the millions of people with milder, but still meaningful, hearing disorders have few good options.

In fact, the ear is largely untouched by the pharmaceutical industry. “If we look at the ear today, the only approved products are antibiotic eardrops,” says David Weber, chief executive officer of the San Diego-based biotech firm Otonomy.

But a handful of small drug firms aim to help those suffering from hearing disorders. 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. Some want to treat damage that has already occurred; others hope to prevent it. Several of their projects are reaching late-stage development, and big pharma is starting to pay attention.


Credit: Yang Ku / Ty Finocchiaro / C&EN


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. But the newness means they are starting from scratch when it comes to designing and recruiting for trials. “The thing about hearing is it is actually pretty much white space,” says Barbara Domayne-Hayman, chief business officer of Autifony Therapeutics, a biotech firm developing treatments for hearing loss. “There are no precedents, no templates. We’re figuring out how to do it as we go along.”

Industry veterans compare hearing loss treatment to ophthalmology 10 years ago. “The eye field really started with simple devices such as contact lenses, and moved to surgical procedures, and ultimately ended up with therapies to treat the front of the eye and injectables to treat the back of the eye,” explains James Healy, general partner at Sofinnova Ventures. Healy’s firm is an investor in Auris Medical, a small company that has some of the most clinically advanced drugs for hearing disorders.

As the eye market’s potential became clear, big pharma got interested. Today, treatments for eye diseases rake in $10 billion in annual sales, Healy says. 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.

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. “You have the possibility of doing local injection of drugs, which can reduce or limit systemic exposure,” points out Clare Ozawa, chief business officer of Inception Sciences, a drug discovery venture that in 2012 formed a hearing loss treatment incubator with Roche and Versant Ventures.

Yet drug discovery for hearing disorders is in its infancy. A handful of products are in the last stage of clinical development, but the overall pipeline is still sparse. 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 diversity of approaches reflects the complexity of the auditory system. The outer and middle ear exist primarily to conduct sound, which is first perceived when it hits the inner ear. The inner ear houses the snail-shaped cochlea, which is lined with hair cells, so called because of the tuftlike projections topping each one.

When a sound wave arrives, the tufts move and vibrate, triggering an electrical response inside the cells that causes them to release neurotransmitters. Signals then travel along the auditory nerve to the brain, where they are interpreted.

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. 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.


Credit: Shutterstock
Graphic of outer, middle, and inner ear shows how sound travels from outside to the brain.
Credit: Shutterstock

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.

When someone suffers from Ménière’s disease, an inner-ear disorder that causes vertigo, hearing loss, and the ringing in the ear known as tinnitus, a doctor’s best course of action is a series of steroid injections. As Otonomy’s Weber explains, that involves asking a patient to lie on a table as the drug is injected into the middle ear. Then for 30 minutes the patient must remain perfectly still: no moving, talking, or swallowing.

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. “Like the eye, the ear is designed to keep things out,” Weber says.

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. The polymer dissolves over the course of a week, slowly releasing the steroid to the inner ear.



Several firms are contributing to a stream of drug candidates that aim to prevent or treat hearing disorders.

Audion/Eli Lilly & Co.
Preclinical small molecules for hair cell regeneration

Auris Medical
AM-101, an N-methyl-d-aspartate (NMDA) receptor antagonist in Phase III studies to treat tinnitus
AM-111, a peptide that inhibits a stress kinase called JNK for the treatment of noise-induced hearing loss

Autifony Therapeutics
AUT00063, a small-molecule modulator of the Kv3 voltage-gated potassium channel, expected to start Phase II studies to treat age-related hearing loss in second-half 2014

CGF166, a gene therapy to restore hair cells; an Investigational New Drug Application (INDA) was filed in early 2014

Preclinical small molecules to treat hearing loss (undisclosed target)

Oricula Pharmaceuticals
Preclinical small molecules to prevent aminoglycoside-driven hearing loss

OTO-201, a sustained-release antibiotic in Phase III studies for children receiving ear tubes; an NDA filing is expected in first-quarter 2015
OTO-104, a sustained-release steroid in Phase IIb studies for treatment of Ménière’s disease
OTO-311, a sustained-exposure formulation of an NMDA receptor antagonist; an INDA is expected in first-quarter 2015

Sound Pharmaceuticals
SP-1005, an oral formulation of ebselen, a small-molecule mimic and inducer of the antioxidant enzyme glutathione peroxidase, approved to start Phase III studies to prevent noise-induced hearing loss
SP-3005, an oral formulation of ebselen, slated to start Phase II studies to prevent noise- and chemotherapy-induced hearing loss

SOURCE: Companies

The technology is being deployed in two drugs that are in late-stage development. As Otonomy learns from its experience delivering sustained-exposure versions of known treatments, it is starting to apply the technology to novel compounds. The company’s next drug candidate is a tinnitus treatment based on an antagonist of the glutamate receptor N-methyl-d-aspartate (NMDA).

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. 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. NMDA receptor antagonists dampen this aberrant signaling, thereby reducing the severity of tinnitus symptoms.

Otonomy plans to ask the Food & Drug Administration for permission to start Phase I human tests of the drug, OTO-301, in early 2015. 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. However, its product must be injected into the inner ear several times over the course of two weeks.

Some companies are focused on modulating the central nervous system to improve hearing. 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. Among the many variables interpreted in the nervous system are volume, where a sound is coming from, and what the sound means. When processing of the signal goes awry, simple tasks, like picking out words against background noise, become a challenge.

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. The biotech’s molecules are designed to positively modulate the channels’ performance, which in animal models has been shown to wane with age.

Autifony’s lead drug candidate is poised to start Phase II studies in age-related hearing loss later this year. If the studies are successful, Autifony expects to recruit a partner to help fund Phase III trials, Domayne-Hayman says. The biotech is currently raising its profile with big pharma companies in anticipation of a future deal.

In addition to trying to treat hearing loss, the biotech industry wants to prevent it from happening in the first place. Sound Pharmaceuticals’ goal is to mimic a cellular defense mechanism the body uses to protect the inner ear from noise- and drug-induced damage. When the cochlea is exposed to noise, several reactive oxygen species appear with the potential to cause hair cell death. Some of that damage is prevented by antioxidant enzymes called into action to neutralize the free radicals.

Sound has developed an oral formulation of ebselen, a compound originally developed by a Japanese firm to treat stroke. Ebselen is a small-molecule mimic and inducer of glutathione peroxidase, an anti­oxidant enzyme highly expressed in the cochlea.

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. Taken as a pill twice daily, the drug was shown to be safe and appears effective at preventing noise-induced hearing loss. The company plans to begin enrollment later this year on a Phase IIb study, according to Chief Medical Officer Jonathan Kil.

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. The trial tests the drug’s ability to protect the hearing of certain patients undergoing treatment with platinum-based chemotherapy.


Another biotech firm recently launched in the ototoxicity space. The labs of Edwin W. 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.

As Rubel points out, the good news, from a biological standpoint, is that damage occurs by just a handful of mechanisms. “We’ve learned so much about cell death in neurons and neuronal-like cells over the past 25 years,” he says. “We know these kinds of cells die using somewhere between two and five different pathways.”

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.



The Military Advances Hearing Loss Efforts

Year after year, hearing loss and tinnitus—a perception of sound where there is none—top the list of injuries reported by U.S. military veterans. “It is consistently, over multiple eras of war and at peacetime, the most prevalent injury,” says Mark Packer, executive director of the Department of Defense’s Hearing Center of Excellence (HCE). Indeed, in fiscal 2010, the Department of Veterans Affairs spent nearly $1.4 billion in compensation for auditory injuries.

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. 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. For example, PIHL is helping establish animal model standards for preclinical studies and guidelines for conducting clinical trials.

The group is also creating guidelines for companies developing products that could be useful in combat. That means educating drug firms on the specific needs of the military. Current treatments for sudden hearing loss—namely steroids used off-label—are administered by injection into the inner ear. That approach simply isn’t practical in a deployed or combat setting.

“We don’t want to give military members anything that is going to degrade their sensorium or give them nausea when they’re supposed to be patrolling and providing safety for their unit,” Packer says. “And they’ve got to carry it in their rucksack,” so a drug needs to be stable at various temperatures and have a long shelf life. 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.

Going forward, HCE wants to help advance the field of genomics as it relates to 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. “I think this is an extremely important and promising field,” Packer says.

That project generated several discovery candidates. After NIH funding ended last year, Rubel and his colleagues started Oricula Therapeutics to develop a drug to prevent antibiotic-induced hearing loss. 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.

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. One new approach is treatments that can prevent the loss of, or even regenerate, hair cells.

At birth, we have about 15,000 hair cells per ear. 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. Indeed, the majority of hearing loss results from damage to hair cells or auditory nerve cells.

In the mid-1980s, two research groups showed that chicks were able to regenerate hair cells after damage had occurred. 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. 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.

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. The promise even lured a few big biotech firms, including Amgen and Genentech, to the field.

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. 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.

In studies of human embryonic stem cells, Edge found that blocking Notch, a protein critical to embryonic development, prompts creation of new hair cells. That discovery led to a search for compounds that might turn off Notch and elicit the same effect in grown animals.

Luckily, the drug industry had plenty of molecules at the ready. It turns out that many inhibitors of γ-secretase, an enzyme companies long pursued for its role in forming the amyloid deposits that are the hallmark of Alzheimer’s disease, also knock out Notch. Using a stem cell screen, Edge landed on a potent γ-secretase inhibitor: Eli Lilly & Co.’s LY411575.

Edge was able to show that giving mice the compound resulted in enough hair cell growth to improve hearing. The discovery is the scientific basis for Audion Therapeutics, a biotech start-up that recently scored a first round of funding from Lilly. Lilly also licensed a series of related compounds to the firm, with an option to buy them back after Phase IIa tests.

Edge cautions that the initial results in mice were modest. “The amount of regeneration we got was fairly low,” he says. Now, Audion scientists are trying to improve the response to the point where humans could benefit. 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.

While some researchers seek to regenerate hair cells using small molecules, others are using gene therapy. 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.

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. Klickstein says the therapy could address hearing loss stemming from noise exposure and ototoxicity. It would not be able to treat some genetic causes of hearing loss or damage from injury.

Novartis has asked FDA to allow it to start a Phase I trial. A patient will need to undergo general anesthesia and surgery to receive a one-time dose of CGF166, “with the aspirational goal that regenerated, functional sensory hair cells would persist for the life of the patient,” Klickstein says.

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. 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.

Back when Rubel first discovered birds’ ability to regrow hair cells, the idea of treating hearing loss with drugs seemed fanciful. Today, researchers are far more hopeful. “It’s not a question of if we will regenerate hair cells in humans but a question of when,” Rubel says. “And that will depend on luck and money.” 


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