What if We Could Cure Hearing Loss? A Clinical Trial Explores the Possibility.

What if we could cure hearing loss? What if those of us who are hard of hearing could put aside the expensive and sometimes frustrating technology we use now? What if we could simply turn a biological switch and hear again, as well as we did before our ears suffered the detrimental effects of noise and age?

Researchers have been working on this problem for decades. They’re optimistic – they’ve always been optimistic. But when you ask when they might have results, the answer has always been, Maybe a decade. That was true when I published my book Shouting Won’t Help, in 2013, and it was true ten years before that.

But there is one big difference between 2013 and 2022 and that is that biotech and pharmaceutical companies have discovered the potential benefits (and potential profits) of restoring hearing, and are putting big money into research. Ten years ago, the researchers who were looking for ways to reverse hearing loss were mostly academics, funded by grants from the National Institutes of Health. The nonprofit Hearing Health Foundation also funded this work, through its Hearing Restoration Project, which fostered communication between researchers. Today large pharmaceutical companies like Novartis are funding research. Biotech companies like Frequency Therapeutics seem to be making significant headway. Competition has replaced collaboration.

Why is hearing so hard to restore? We can fully correct vision loss but fumble when it comes to hearing loss. A $500 pair of glasses corrects a complicated vision loss like mine (myopia plus astigmatism), but my $3,000 hearing aid and $10,000 cochlear implant can only approximate normal hearing.

There is a flip side to this, however, a plus in the ability to restore hearing. We can provide adequate hearing in those with profound loss – and in children and others often more than adequate hearing. A cochlear implant allows people who are functionally deaf to hear. We don’t yet have a similar miracle treatment for profound vision loss. There is no cure for blindness, and no treatment at this point. It’s an interesting paradox, with biology at the core.

Finally, though, there’s a chance for hearing restoration, via the promising field of tissue regeneration. What follows is a detailed description of a trial that is currently recruiting participants. Potential applicants should know the history of this trial so far. Others may not want to read on. It’s long!

One of the leaders in the field,  Frequency Therapeutics, based in Lexington, Mass., is now recruiting for a clinical trial on the efficacy of its patented drug candidate FX-322 to restore hearing in people with sensorineural loss. At the moment it is the only active clinical trial to restore hearing, and it’s an ambitious one. (There are other companies working on helping sensorineural hearing loss, but most are looking at more narrow indications, like a specific disorder. Here are links to a few: Decibel Therapeutics, Otonomy, and Pipeline.)

This new study is the sixth clinical trial Frequency has conducted. Earlier trials tested safety, and to a lesser extent also measured efficacy. These trials were encouraging — with one exception, which I’ll get to.

As the company’s scientific staff explained recently in a webinar hosted by the nonprofit Hearing Loss Association of America, FX-322 is a combination of two molecules that can potentially regenerate cochlear progenitor cells, which, it is hoped, will form new sensory hair cells in the inner ear. Progenitor cells are active in utero, but so far no mechanism exists to reactivate them later in life to restore hearing. (Other species, including birds and reptiles, do have the ability restore their hearing). FX-322 is intended to reactivate these cells through a process called Progenitor Cell Activation, or PCA.

Here’s how it works: An ENT physician injects FX-322 into the middle ear. The liquid injection, a polymer, becomes a gel in the middle ear, which allows prolonged diffusion into the cochlea. Early tests on mice showed favorable changes in those cells, suggesting that they can be successfully reactivated. (If you are interested in knowing more about FX-322 and how it works, see a 2021 article in the journal Otology & Neurotology.)

In Frequency’s first trial of FX-322 on humans, which started in 2018, 23 adult subjects aged 33 to 64 with mild to moderately severe stable sensorineural hearing loss were enrolled in a study mostly to assess safety. Fifteen received FX-322 and 8 received a placebo. The company’s analysis showed statistically significant and clinically meaningful increases in word recognition in four of the 15 subjects treated with FX-322, with some nearly doubling their word scores from baseline. Two others showed improvements that were not statistically significant. FX-322 was observed to be well-tolerated in this trial with no serious adverse events. In the months following, five of the six individuals who had seen improvements in speech perception returned for testing. Three of the subjects continued to show statistically significant improvements in word recognition 13 to 21 months after the study. Several other studies of safety and administration of the drug also showed improved speech perception. It was time to focus on efficacy. Does it actually restore hearing?

But then came the setback. Ninety-five patients with mild to moderately severe hearing loss were enrolled in an efficacy study, with results announced in March 2021. This study, disappointingly, found no improvement in hearing in those treated but, paradoxically, found better hearing in those who received the placebo and in the untreated ear of those who got the drug. That’s the opposite of what one would hope. In a clinical trial you want the drug being tested to work where it’s been administered. If, instead, the drug has no effect on the treated ear, but improves hearing in untreated ears — those receiving the placebo and the untreated ear in those receiving the drug — it likely means that there is something wrong with the test. 

Frequency attributed the troubling findings to design flaws that allowed bias. For example, a single baseline measure resulted in too much variability. Further, tips on how to qualify for the trial were shared by patients on social media. Frequency accepts responsibility for the flaws that let bias into the study. The new study uses more rigorous protocols for baseline measures in addition to more stringent blinding of entry criteria.

Encouraged by favorable results in the other studies, and confident that they could make protocols more rigorous, the company decided to go forward with plans to test efficacy again. In October 2021, Frequency began to recruit participants to the new trial, which will enroll 124 participants, half of whom will receive the drug, half a placebo. Patients will receive a single injection. Prior to receiving the drug or placebo, patient hearing will be tested three times, two weeks apart, to arrive at a single average baseline. The tests will be recorded and monitored. The trial is double blind: no one involved will know who gets the drug and who the placebo. Patients will return to the testing site for hearing tests monthly for six or seven months. There are 26 sites across the country. Recruiting continues through most of this year. (To learn more about the trial, criteria for inclusion, and how to apply to participate, go to ClinicialTrials.gov.)

Part of the preparation for the new investigation was coming to an agreement with the FDA about trial design. What measure should be used to calculate efficacy? The FDA and Frequency agreed on improvement in speech recognition. Speech perception would be tested at baseline and then one, two and three months after. The tests include several standard tests of speech perception, including words-in-noise, words-in-quiet, and sentences-in-noise. Frequency and the FDA also agreed on the inclusion of a questionnaire with multiple parts to be administered to each participant at the beginning and end of the study.

Previous studies of FX-322 in mice and the safety tests in humans showed improvement in high frequency sound, which is at the top end of the area where speech recognition lies (this is mapped as the speech banana on an audiogram). High frequencies are at the opening of the spiral cochlea and thus more easily reached by the injected drug. A future study is planned on a second compound, FX-345, which is expected to penetrate further into the cochlea and thus into lower frequencies.

In agreeing on speech recognition as the measure of efficacy, Frequency and the FDA were guided by practicalities. Other measures of success ideally would have included visual evidence in the hair cells in the cochlea, as was shown in studies in mice. But it’s not possible to study changes in the hair cells in humans (except in an autopsy).

Many steps lie ahead. Carl LeBel, Chief Development Officer at Frequency, estimated a timeline: a year for this trial, ending approximately at the end of 2022. Then the results go to the FDA. If the data is favorable, testing goes into final phases. “We’re looking for an approval of FX-322 sometime in the middle part of this decade,” Dr. LeBel said, acknowledging that he was being deliberately vague.

How permanent would a clinical change be? Early tests suggest that some participants retained their improved scores longer than others. Do people with long-standing hearing loss fare worse than people newly impaired? So far, the data suggest there is no difference. Are the ears still  subject to damage from noise, aging, ototoxins? Probably.

Dr. LeBel cautioned that the researchers expect gains to be slight at first. Someone considering a cochlear implant might be able to continue using a hearing aid instead. Someone with more moderate loss could forgo a hearing aid, at least for a while. Dr. LeBel said he sees the drug as part of a patient’s overall hearing plan. “We see it fitting in and being used in a complementary way with the way devices are used today.”

Frequency’s FX-322 is a work in progress. But the fact that it is in progress, and in humans, is something to be optimistic about. Other trials at other institutions will be testing other methods. The race is on.

In the meantime, the best advice for those with hearing loss is to keep our brains in shape by wearing hearing aids or cochlear implants. That will keep speech pathways from atrophy, which would mean a harder time reviving them if – or when — a drug to reverse hearing loss comes along.

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For more about living with hearing loss, read Smart Hearing, available on paper or as an e-book at Amazon.com, or Shouting Won’t Help, available in both formats at Amazon and other booksellers.

One Potential Way to Cure Hearing Loss

At the end of May (May 30), a few days after Americans honored Veterans on Memorial Day, a New England biotech company announced that it had received a grant from the Department of Defense to research a therapeutic opportunity that may help reverse hearing loss.

Cochlear hair cells_Credit- W. McLean
Cochlear Hair Cells. Credit:W. McLean

A 2015 study of almost 50,000 soldiers showed that peak noise levels in combat can reach 180 dB. Combat veterans have a 63% increased risk for hearing loss. Two and a half million veterans have service-connected hearing disabilities.

Clearly there is a need for treatment.

Frequency Therapeutics based in Woburn, Mass., and Farmington, Ct., announced that it had received a $2 million grant from the Department of Defense to investigate the restoration of hearing after noise-related damage as a result of military service-related injuries.

Frequency’s Progenitor Cell Activation, or PCA Regeneration, technique, uses a combination of small-molecule drugs to stimulate inner ear progenitor cells to multiply and create new hair cells. Hair cell regeneration happens spontaneously in fish and birds, but not in mammals.

Humans are born with only 15,000 hair cells in each ear and do not develop any more after birth. Damage to these hair cells over time results in a loss of hearing. Figuring out how to make regeneration happen in mammals would be a major step towards finding a cure for hearing loss, and this goal is being pursued by others in addition to Frequency.

In December, Frequency announced the completion of the first in-human safety and tolerance study of its proprietary drug combination, FX-322. (You can read more about it here.) The drug is injected into the inner ear using a standard intratympanic injection, with the patient awake.  The Phase 1 trial was conducted at Victoria Eye and Ear Hospital in Melbourne, Australia, on 9 adults with severe to profound sensorineural hearing loss who were scheduled for cochlear implant surgery 24 hours after receiving the injection.

In the press release announcing the DOD grant, Frequency noted that the PCA Regeneration platform targets the root cause of disease without removing stem cells from the body. This avoids issues that can develop with traditional stem cell or gene therapy, which can affect cells other than those targeted. Frequency’s FX-322 awakens the dormant progenitor cells already in the ear, initiating cell division and differentiation to repair the damaged hair cells.

Frequency hopes this technique can be used elsewhere in the body as well, to restore healthy tissue, and it has a number of other programs in development including preclinical research in muscle regeneration and type 1 diabetes. Frequency plans to initiate a Phase 2 trial for hearing regeneration in the U.S. later this year.

This grant applies only to military personnel with service-related hearing loss, although of course if the technique is found to work it would be available to others with sensorineural hearing loss. More than 48 million Americans of all ages have some degree of hearing loss.

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This study is one of many efforts to find a biological cure for hearing loss. I will be writing about others in the coming months. If you are a researcher with relevant information please email me at katherinebouton@gmail.com