Human trials of drug therapy for otology are few and far between. Whether it’s due to competing advances in amplification technology or the difficulty of determining a mechanism of action that could be consistently targeted by medications, pharmaceutical research has taken a back seat to hearing assistance devices.
But that’s all beginning to change.
In just the last year, several phase 2 and 3 clinical trials of drug therapy for tinnitus and hearing loss have started adding patients. In some of the studies, interim results suggest significant advances. Even gene therapy, long talked about in otology circles but mostly a cancer-focused affair, has been tried in a handful of patients.
Thomas Meyer, PhD, chief executive officer of Auris Medical, a Basel, Switzerland-based company that has launched late-stage clinical trials of AM-101 and AM-111, two targeted intratympanic drugs for tinnitus and hearing loss, said the industry is poised for much-needed breakthroughs. “I believe we are now very close to seeing the arrival of what we call rational pharmacotherapy in inner ear disorders,” Dr. Meyer said.
Barbara Domayne-Hayman, DPhil, chief business officer of Autifony Therapeutics, a U.K.-based company that is actively recruiting U.S. patients for the CLARITY-1 study, the first trial of its kind to assess an oral medication for age-related hearing loss (ARHL), agreed that otologic drug research “is definitely headed in the right direction.”
—Thomas Meyer, PhD
The advances, she stressed, are sorely needed, given the limits of amplification technology. “Until now, hearing aids have been the primary focus of research and product development,” she said. “The problem with these devices is that they tend to amplify all sound; they don’t always do a very good job helping you interpret speech against a background of noise.” Indeed, she added, “that is why so many people who have been fitted with expensive hearing aids often leave them in the drawer at home; they don’t find them all that helpful in a noisy restaurant or work environment.”
That’s where the CLARITY-1 trial comes in. The phase 2a placebo-controlled, double-blind study’s goal is to assess changes in ARHL after four weeks of treatment in patients treated with the oral investigational drug AUT00063. The drug targets the Kv3 ion channel, “which is present on neurons throughout the auditory processing system,” Dr. Domayne-Hayman said. As patients age, Kv3 ion channel activity tends to decline (J Neurosci. 2004;24:1936-1940). That age-related decline is thought to contribute to auditory processing disorders, she added. “Our goal with AUT00063 is to enhance Kv3 ion channel firing in patients with age-related hearing loss, so that the brain is better able to process and discriminate sounds from background noise,” she said.
Animal studies underscore the effectiveness of AUT00063. In an abstract presented in 2014 at the Midwinter Meeting of the Association for Research in Otolaryngology in San Diego, an Autifony-sponsored study showed that the drug significantly improved auditory temporal processing in a rat model of ARHL. The results suggest that AUT00063, “via positive modulation of Kv3 channels, has potential in the treatment of age-related hearing impairment,” the investigators concluded.
QUIET-1 Tinnitus Trial
Hearing loss isn’t the only focus of Autifony; the company also is conducting a trial of AUT00063 in patients with tinnitus, known as QUIET-1. The U.K.-based study began in October 2014, according to Dr. Domayne-Hayman, and seeks to improve tinnitus in patients who have experienced symptoms for at least six months, but no more than 18 months, from diagnosis. That is the point in time, she noted, when the condition has shifted from one caused by localized damage to hair cells in the inner ear to a more centralized problem mediated by the central nervous system and brain.
“In the beginning of our research with AUT00063, we only focused on ARHL,” she said. “But given the overlap we were seeing in how important the brain is to both hearing loss and tinnitus and the strong preclinical data we got in tinnitus models, we realized there was an opportunity to study both conditions and potentially have a huge societal impact, given how prevalent they are in our aging population.”
A Focus on Acute Disease
While Autifony continues its focus on patients whose tinnitus has shifted to a chronic, centralized pattern of symptoms, Dr. Meyer and his research team at Auris Medical are focused on the acute stage of the hearing disorder, before it becomes centralized and is no longer amenable to treatment.
Their weapon of choice is AM-101, a drug that targets N-methyl-D-aspartate (NMDA) activity. NMDA receptors, he explained, are located at the post-synapse of inner hair cells and become activated after traumatic injury (Ann N Y Acad Sci. 1999;884:249-254). In some cases, acute hearing loss and tinnitus resolve spontaneously after such injury. In other instances, however, NMDA receptors remain pathologically active and generate the phantom “noise” that typifies tinnitus, Dr. Meyer said.
AM-101 has been shown to be safe and effective in two phase 2 trials. In one of the studies, patients treated with AM-101 reported experiencing significant reductions in tinnitus loudness, annoyance, and tinnitus-related sleep difficulties when compared with the placebo (Otol Neurotol. 2014;35:589-597). The benefits were dose dependent and increased gradually during the 90 days of observation.
Dr. Meyer said he has been involved in researching tinnitus-targeted drug therapy since 2003, when he first launched Auris Medical. During that time, he noted, he has learned that selectivity is one of the keys to successful drug development. In the case of tinnitus, “you not only have to target the right type or etiology, where you fully understand the biology; you also have to be very specific regarding the type of patient you’re treating. For us, our clinical data suggest that patients in the early stages of the disorder—up to three months out, possibly more—will respond best to our approach.”
Dr. Meyer said he is optimistic that a phase 3 trial of acute tinnitus launched in the United States in February 2014, known as TACTT2, will replicate the positive findings of previous trials.
Another Mechanism, Another Hearing Disorder
Auris Medical also has several clinical trials in the works in the United States and Europe that focus on sudden and surgery-induced hearing loss. The drug being evaluated, AM-111, is a stress kinase inhibitor peptide known as D-JNKI-1 that is formulated in a biocompatible and biodegradable gel. By acting on that kinase, AM-111 prevents apoptosis in hair cells and also attenuates the damaging effects of cellular inflammation following acute inner ear injury (Hear Res. 2007;226:168-177).
In a phase 2 clinical trial of AM-111, patients with severe to profound sensorineural hearing loss (PTA thresholds > 60dB) who were treated with 0.4 mg/mL of the drug showed an absolute improvement in hearing loss to day seven of the study (29.9 dB vs. 17.9 dB for place-treated patients; P=0.017) (Otol Neurotol. 2014;35:1317-1326). The drug was well tolerated, with no negative impact on hearing, balance, or tinnitus.
Dr. Meyer said he is excited by the prospect of seeing the first drugs specifically developed for inner ear therapy moving towards broad clinical use. “If all goes well, there will be FDA drugs approved for intratympanic treatments in a few years from now,” he said. “That could have quite an impact on the field of otology.”
Hinrich Staecker, MD, PhD, a professor of otolaryngology and head and neck surgery at the University of Kansas Medical Center in Kansas City, has participated in all three clinical trials involving AM-101. Although “we’re not long enough out” on the phase 3 study, “based on what we’ve seen with prior patients, the prospects for this drug therapy are very promising,” he said.
Gene Therapy Makes a Debut
Dr. Staecker is also the investigational leader of the Novartis-sponsored CGF166 trial, the first to offer gene therapy to adult patients with hearing loss. The protocol was developed by GenVec, a Maryland biotech firm, and involves introducing a gene known as Atoh1 into the inner ear. Atoh1 has been shown in animal models to trigger the formation of inner ear sensory hair cells (PloS One 2014;9:e102077). The hope is that in humans, supporting cells in the inner ear will absorb Atoh1 and transform into functioning hair cells that could mitigate or even reverse hearing loss, Dr. Staecker said.
Although positive anecdotal results have appeared in the lay press, “it’s really too soon to tell” how the four patients who have received the gene therapy at his center ultimately will fare, he said. “We plan on going back to the FDA in the fall with our clinical data, and we anticipate some positive further developments at that time.”
As for the overall direction of otologic drug and gene therapy, Dr. Staecker echoed the importance of pursuing a very focused approach. “Our animal models of tinnitus and hearing loss show that these conditions are extremely heterogeneous and pose very different challenges,” he said. “That’s why we need to develop targeted treatments for different aspects of inner ear disease.”
Disclosure: Dr. Staecker is a member of the surgical advisory board for MedEl Gmbh, and has received grant support from Novartis for animal studies related to gene therapy for inner ear disease.
David Bronstein is a freelance medical journalist based in New Jersey.