Investors are taking notice of the number of people affected by hearing loss, and they're banking on that prevalence adding up to big profits for investigational medications targeting audiological conditions.
About 17 percent of American adults report some degree of hearing loss, and this figure jumps to 47 percent for adults who are at least 75 years old. However, only one of five people who could benefit from a hearing aid actually wears one, according to statisticshttp://www.nidcd.nih.gov/health/statistics/pages/quick.aspx compiled by the National Institute on Deafness and Other Communication Disorders.
“There's a huge unmet need,” said Mark Parker, PhD, director of audiology at St. Elizabeth's Medical Center and assistant professor of otolaryngology at Tufts University School of Medicine.
“Biotech companies are paying more attention, and more and more big companies are investing in hearing treatments.”
For example, Audion Therapeutics announced in February that it received a Series A investment from Eli Lilly and Company to advance Audion programs targeting sensorineural hearing loss. A licensing agreement gives Audion the rights to certain Lilly compounds that potentially can be developed to treat hearing loss through hair cell regeneration.
Nonprofit organizations also recognize the need for hearing loss therapies. The American Tinnitus Association (ATA) recently announced the recipients of its annual grants for research on tinnitus, which affected roughly 10 percent of adults in the United States for at least five minutes in the past year.
The ATA is funding three projects that will explore the role of the cholinergic system in tinnitus, the relationship between tinnitus and tonotopic remapping in auditory regions of the brain, and similarities between tinnitus and hyperacusis (see HJ’s August cover storyhttp://journals.lww.com/thehearingjournal/Fulltext/2014/08000/Help_for_Hyperacusis___Treatments_Turn_Down.1.aspx).
For his part, Dr. Parker is investing his time and energy in gene therapy.
“I've also done work with stem cell regeneration, and there are other biotech firms that are looking into the application of stem cells in hearing loss,” he said.
But it's hard to control the differentiation of stem cells into hair cells, he explained.
“I've moved to gene therapy because I think it's more promising and more clinically feasible, and I think that's going to be the best shot at actually getting a cure for hearing loss.”
Meanwhile, Michael Seidman, MD, director of the Division of Otologic/Neurotologic Surgery at Henry Ford Hospital, is a firm believer in nutritional supplements.
He recognizes the potential pitfalls of developing treatments for hearing conditions, no matter what approach is taken.
“Some people can experience adverse reactions to just about anything,” Dr. Seidman said. “Or it might not work, and you've just invested a lot of resources—a lot of time and money—and you may be barking up the wrong tree.”
At Autifony Therapeutics, CEO Charles Large, PhD, does not believe the company is barking up the wrong tree.
The London-based spin-out from GlaxoSmithKline announced in June that the United Kingdom's innovation agency, the Technology Strategy Board, awarded the company £2.2 million for a Phase 2a clinical trial in tinnitus patients with lead compound AUT00063. This first-in-class Kv3 potassium channel modulator, in the form of a once-per-day oral tablet, is also in development for the treatment of age-related hearing loss.
“From the feedback we received, we believe that the Technology Strategy Board clearly recognizes the very sig-nifi-cant unmet medical need of people suffering from tinnitus,” Dr. Large said.
“They were also very interested in the fact that Autifony's approach is targeting a completely novel mechanism of action, for which we have strong underpinning preclinical data.”
While other companies are targeting the cochlea, Autifony is taking a central nervous system approach, Dr. Large explained. The Kv3 potassium channels targeted by AUT00063 are found in brain regions that process sound.
“We believe there is strong evidence to suggest that while the initial damage that leads to tinnitus may originate in the cochlea—for example, through noise exposure—tinnitus becomes established as a central nervous system phenomenon, so therapies need to focus on targets in the brain, not the cochlea.”
But according to Dr. Parker, the exact causes of this condition are not entirely clear. Tinnitus indicates that something is wrong in the auditory system, which includes the ear, the auditory nerve that connects the inner ear to the brain, and the parts of the brain that process sound.
“No one really knows where tinnitus is caused,” Dr. Parker said. “It's probably caused in different places in different people.
“And there's a lot of evidence that tinnitus is generated all over the brain; it's not just one place. The more we learn about the pathophysiology of these diseases, the better we'll be able to target treatments.”
Dr. Large remains optimistic about AUT00063’s potential.
“We believe that our approach has a strong chance of pioneering a completely new treatment for tinnitus that will greatly reduce the suffering of many people with this problem,” Dr. Large said.
“Of course, tinnitus is a highly complex and heterogeneous condition, arising from many different causes, and it will take time for us to figure out which types of patients will benefit the most from our approach.”
Autifony is also planning a Phase 2a study for age-related hearing loss in the United States.
“The drug's mechanism of action should help restore the rapid and accurate firing of neurons, which is necessary to hear the very rapid transient sounds of speech and tends to decline with age,” Dr. Large said.
“We believe that our Kv3 ion channel-modulating mechanism has the potential to improve hearing for people with age-related hearing loss, particularly in interpreting speech in noisy backgrounds, which is where so many people struggle.”
TREATMENT FOR TRAUMATIC INJURY
One important group who could benefit from increasing investment in treatments for hearing conditions is war veterans with problems like noise-induced hearing loss. This condition can be caused by a one-time exposure to an intense sound, such as an explosion.
“Noise-induced hearing loss and tinnitus constitute some of the most common disabling conditions affecting our military currently,” said Rick Kopke, MD, chief medical officer at Otologic Pharmaceutics and a U.S. Army veteran.
Otologic Pharmaceutics is focusing on advancing the clinical development of an oral medication for acute noise-induced hearing loss, with extensive funding from the U.S. Department of Defense.
The Oklahoma City-based company's lead product, NHPN-1010, is a combination of two antioxidants, HPN-07 and N-acetylcysteine (NAC).
This therapeutic approach, which has been tested in animals, can reduce damage to the entire auditory pathway, including the cochlea, auditory nerve, and the brainstem ( Hear Res 2012;285[1-2]:29-39http://www.sciencedirect.com/science/article/pii/S0378595512000238). As a result, it could potentially enhance recovery from traumatic injury and reduce permanent hearing loss when given before or shortly after acute injury.
“None of the other treatments that I am aware of have addressed hearing loss secondary to blast injury, which is a very prevalent problem in the military, as well as a growing civilian problem,” Dr. Kopke said.
“We are also investigating our drug to see if it will reduce the onset of noise-induced tinnitus. So in theory, for blast, a single pill could be taken that could address hearing loss, tinnitus, and mild to moderate traumatic brain injury.”
Otologic Pharmaceutics is planning Phase 1 clinical trials for noise-induced hearing loss and working to expand the applicability of NHPN-1010 to prevent or reverse hearing loss from other causes, such as the chemotherapy drug cisplatin.
The gold-standard endpoints for demonstrating treatment efficacy have been pure-tone audiometry and threshold shifts, and speech-discrimination measures.
“However, new approaches are needed, and these might include hearing-in-noise tests; measures of afferent auditory nerve function, such as auditory brainstem response wave I amplitude measures; as well as other measures of central hearing performance,” Dr. Kopke said.
Based on preclinical treatment efficacy data combined with toxicology and safety data, Dr. Kopke is very optimistic that NHPN-1010 can be brought to market.
“The pill could be taken shortly after unexpected noise or blast exposure, as soon as someone notes muffled hearing or sustained tinnitus,” Dr. Kopke said.
“Although not meant to be a substitute for hearing protection devices, this pill could help to reduce substantially the permanent hearing loss of large numbers of our own military, as well as military personnel in other countries.”
Potentially, the antioxidant treatment also could treat a wide range of civilians, Dr. Kopke said.
Approximately 30 million workers are exposed to hazardous noise on the job, and noise-induced hearing loss is one of the most common occupational illnesses or injuries, according to the Centers for Disease Control and Preventionhttp://www.cdc.gov/niosh/docs/2001-103/.
“Many work environments in manufacturing, construction, energy, and others also face some of these severe challenges, and this treatment approach would be helpful in these settings,” Dr. Kopke said.
TOO EARLY TO TELL
Auris Medical and Otonomy are jumping on the bandwagon, too. The two companies are actively developing treatments for hearing conditions. In August, Auris announced the closing of its initial public offering (IPO), and Otonomy announced pricing of its IPO.
Auris Medical is developing AM-101 for the treatment of acute inner ear tinnitus following traumatic cochlear injury or middle ear infection.
This gel, which is currently undergoing Phase 3 clinical trials at the Henry Ford Health System and other sites, contains an N-methyl-D-aspartate (NMDA) receptor antagonist called esketamine hydrochloride.
The Swiss biopharmaceutical company is also developing AM-111 for the treatment of acute inner ear hearing loss. The gel works by preventing cell death and inflammatory responses mediated by the c-Jun N-terminal kinase pathway.
Meanwhile, Otonomy, which is based in San Diego, is developing a tinnitus treatment called OTO-311, a sustained-exposure formulation of the NMDA receptor antagonist gacyclidine.
The company is also conducting a Phase 2b clinical trial for OTO-104, a sustained-exposure formulation of the steroid dexamethasone in development for the treatment of inner ear conditions such as Ménière's disease, which can cause severe dizziness, hearing loss, and tinnitus.
“There are a lot of drug companies looking to find better ways of delivering dexamethasone to the cochlea and getting it to stay in the middle ear longer so the patient will get a higher and more effective dose,” Dr. Parker said.
The drug is routinely used in clinics all over the United States to treat sudden sensorineural hearing loss.
“Almost the first thing the EMT will do is put dexamethasone in the middle ear, but the data is pretty ambiguous about whether or not that's effective at all,” Dr. Parker said.
To determine the most effective treatments moving forward, it will be very important to develop better diagnostic tests, he said.
“Right now, our hearing tests are a very crude estimation of what type of damage is actually occurring that leads to the hearing loss.
“The cart is a little bit before the horse here because our treatments are starting to become really advanced, but our assessments of the types of hearing loss aren't. At some point we're going to need better diagnostics in order to pick which treatment is going to be the best treatment to use.”
For the time being, it may be too early to tell if and when any of these treatments will be clinically available.
“Auris Medical and Otonomy and any other company that's working on a novel drug is banking on bringing it to market,” Dr. Seidman said. He predicted that these treatments probably won't be available for at least three to five years.
According to Dr. Parker, treatments for the middle ear may be brought to market the soonest. These therapies are less invasive, and they could be the easiest to get to the clinic.
On the other hand, patients may have to wait a long time for a hair cell regeneration approach, which he thinks will probably become the gold standard for the treatment of hearing loss and deafness.
“I gave up a long time ago predicting when it's going to be in the clinic,” Dr. Parker said. “Hopefully it will happen in my children's lifetime, but I'm sure it will happen in my grandchildren's lifetime.”