Mass Eye and Ear Researchers Make Strides Toward Drug Delivery for Hearing Loss Treatment

Ready for some progress in the search for a cure for hearing loss? Yeah, me too.

I came across an article on how researchers recently used a drug-like cocktail to regenerate hair cells for hearing loss. The findings were published in an April 2023 study in the scientific journal PNAS.

Sounds promising. But as a layperson, it can be hard to understand what that means, and if it’s actual progress.


So I reached out to the study’s principal investigator, Zheng-Yi Chen, DPhil, an associate scientist in the Eaton-Peabody Labs at Mass Eye and Ear in Boston. Dr. Chen graciously replied to my questions about his findings. 


In a nutshell, this study is the first of its kind to show that drugs may one day be able to be used to regenerate hair cells in a clinical setting (i.e. a doctor’s office) — and some of the existing tools researchers already have may help to speed up development. In the future, the drug cocktail may be used to treat noise-induced or age-related hearing loss, or in combination with gene therapy to restore hearing in people with genetic hearing loss.

1. How are your findings different from previous research on potential treatments for hearing loss?

In the previous study, we showed that it is possible to regenerate hair cells in the fully mature mammalian inner ear by genetic manipulation. The current study is to demonstrate that similar hair cell regeneration can be achieved by a combination of drug-like molecules, which is a major step for us to move the work towards the clinic.

This is not to say we have solved all the issues. We now focus on using the new approach to restore hearing in deaf mice, and all the information will be necessary for future clinical development.


2. What most surprised or excited you about the findings in this study?

The most surprising part is that some of the molecules we use to regenerate hair cells have been used in patients (VPA, LiCl) or the technology is mature (for siRNA in humans including Alnylam’s drugs), so we may benefit from the mature technology to speed up our work toward the clinic.


3. What are you hoping these findings will lead to in terms of potential genetic therapies for hearing loss?

If hair cell regeneration ultimately results in the treatment of hearing loss in patients, it potentially could be applied to the largest patient population with hearing loss including people suffering from age-related and noise induced hearing loss.

For genetic hearing loss, while regeneration alone may not be sufficient, it can be combined with gene therapy that is progressing rapidly as treatment. For many forms of genetic hearing loss due to hair cell damage or loss, gene therapy alone will not be sufficient due to the loss of a large number of hair cells. In this situation, we can regenerate hair cells and perform gene therapy at the same time as the treatment. The gene therapy approach is part of the hair cell regeneration in our study in which Atoh1 is delivered by adenovirus.

4. How can people with hearing loss help support hearing loss research like the type you’re doing?

There are many ways for people with hearing loss to support and speed up our work. Patients should first be properly diagonalized so we know what type of hearing loss they have (e.g. genetic, noise-induced, viral infection or age-related). This will serve as an important resource for potential candidates for future clinical trials.

Patients could join different organizations (e.g. the Hearing Loss Association of America) to help themselves and other people with hearing loss.

Of course, making donations is one of the most effective ways to help our work. I cannot emphasize enough how philanthropic support has helped our work enormously and will continue the trajectory till we develop the treatment.

We are truly excited about the future and will do all we can to get there as soon as we can.

Frequency’s FX-322 is discontinued…now what?

I’m a bit behind on sharing this, but just learned that in February, Frequency Therapeutics discontinued their FX-322 program, which had been the company’s flagship offering, and an exciting promise in the quest to cure hearing loss. Frequency also announced they would reduce their headcount by 55 percent, and instead shift their focus to clinical trials of a multiple sclerosis program.

This is a stark change from 4 months prior, when the company was in the midst of a phase 2b study and hoping to achieve Breakthrough Therapy designation from the FDA.

The FX-322 journey was long and cautious. Frequency started phase 1/2 clinical trials back in 2019. Over the years, they were able to show that the drug was safe, and that some participants were able to make gains in their high-frequency hearing threshold and word recognition scores.

However, as the pool of participants in clinical trials increased, FX-322 and FX-345—the next iteration of the drug that went further into the cochlea—failed to show statistically meaningful improvements, according to a press release on Feb. 13.

But according to Cliff Olson, AuD, “this [FX-322] was always going to be a long shot.” There isn’t going to be a hearing restoration drug on the market anytime soon.

For people with hearing loss, this news is incredibly disappointing. Of course, we’re used to disappointment; we live with hearing loss, after all. But it can feel even more frustrating to see the lack of progress when there are breakthroughs in treating other chronic health conditions all the time now.

The only thing I can say, based on the incredibly talented researchers I’ve been able to interview for this blog, is that the path to scientific progress is rarely a straight line. It’s a long process of experimentation. When something doesn’t work, it does help point the way to what may work in the future—but how far in the future is still a mystery.

Thanks to all the researchers at Frequency Therapeutics for their efforts over the years. They are still much appreciated.

Progress and Promise With Frequency Therapeutic’s FX-322 to Treat Acquired Hearing Loss

Frequency Therapeutics is making even more progress with their development of FX-322, a drug candidate in clinical trials to potentially restore acquired sensorineural hearing loss. The company has now completed enrollment of its phase 2b study of the drug candidate, and plans to release study data in the first quarter of 2023.

The large phase 2b study is designed to look at efficacy and safety, and includes a broad number of secondary outcome measures. “The study is powered to detect a statistically significant (p<0.05) difference between FX-322 and placebo subject groups,” Carl LeBel, PhD, Frequency’s Chief Development Officer. P<0.05 means there is less than a 5 percent chance that the changes aren’t real. If this study goes well, the next step is phase 3 trials. “Assuming we have positive data, we would meet again with the FDA and file for Breakthrough Therapy designation,” says Dr. LeBel. Breakthrough Therapy designation is designed to expedite the development and review of drugs that demonstrate substantial improvement over existing therapies. Of course, there are currently no drug therapies available to improve hearing loss, so this would be the first of its kind.

More Participants, More Hearing Gains

The phase 2b study has enrolled 142 individuals at 28 different clinical sites throughout the U.S. The participants are adults between 18-65 years old who have either noise-induced or permanent idiopathic sudden hearing loss, which are considered “acquired” hearing loss. “Our study population are people who’ve had a cochlea that was working well, that stops working well because of some force on it, such as noise or other external factors,” says Kevin Franck, PhD, Senior Vice President of Strategic Marketing and New Product Planning.

Due to what the company has learned from previous trials, the study population is also comprised of people with higher mild to lower severe hearing loss range, as they seem to respond best to the drug candidate. Improvement response is focused on better speech perception. With improved speech perception, individuals may hear words more clearly, a critical unmet need for individuals with hearing loss.

Measuring Improvement of FX-322

First, the study group is divided into people who will get a placebo, and those who will get FX-322. FX-322 participants get a single injection of the drug in their middle ear. Ninety days after, they undergo a speech perception test, which people with hearing loss do routinely when they are examined by an audiologist. A list of 50 words is read out loud, and the person has to repeat them back.

Although a 10 percent improvement is considered clinically meaningful, Frequency is also looking for what is statistically significant. So, while an extra 5 correct words would be a 10 percent improvement, “Some of the differences we’re seeing are actually twenty words out of fifty,” which is quadruple that, says Dr. Franck. To be deemed successful, a statistically significant (p<0.05) percent more of the participants treated with FX-322 have to show clear improvements in their speech perception compared to the placebo group.

The drug also seems to be well-tolerated in participants. “The beauty of doing local delivery to the ear is you don’t have to worry about systemic side effects,” says LeBel. The drug gets straight into the cochlea, and while people who receive it may feel a sense of fullness in their ear, the discomfort is mild and temporary, with no lasting side effects observed. “That’s really important for therapy of this nature,” LeBel adds.

Looking to the Future

The team has learned a lot from their previous trials of the drug, and the possibility that FX-322 will be available on the market in the not-too-distant future draws closer. “We feel confident that we’ve designed a study in the best way possible to be able to demonstrate very clearly that FX-322 can provide a benefit in hearing loss,” says LeBel. “We really can’t wait to see the results.”

More to come in early 2023 when the study results are published.

Frequency Therapeutics: Strides Towards a Disease-Modifying Therapy for Acquired Hearing Loss

Last year was a busy and eventful one for Frequency Therapeutics, the Boston-based biotech company working on FX-322, a drug candidate in clinical trials to potentially restore sensorineural hearing loss. The company has learned some interesting lessons from clinical trials of FX-322 conducted in 2021, and has also introduced a new clinical candidate, FX-345, that they hope will be able to get even deeper into the cochlea – potentially enabling treatment of different populations of patients with acquired hearing loss.

So far, Frequency has run 4 clinical trials of FX-322 in phase 1, which is the first step towards developing a drug approved by the Food and Drug Administration (FDA) to be used to treat a given condition. In phase 1, researchers test for drug safety and the maximum effective dose of a drug in humans. The company has run 5 trials to date and has just begun their largest, a new phase 2b study.

Results of Previous FX-322 Clinical Trials

Frequency has thus far found in three separate studies that hearing improvements can be seen following a single administration of FX-322, when testing participants’ hearing 90 days following dosing to see if their speech perception measures increased. These participants had hearing loss ranging from mild to severe. “Speech perception is important because that’s what people with hearing loss have told us is the critical unmet need. They said, ‘We struggle to hear conversations, particularly in noise,'” says Kevin Franck, PhD, Senior Vice President of Strategic Marketing and New Product Planning.

When tested, some participants showed an increase in word recognition – in a test of 50 words, the highest was an increase of 20 words, or a 40 percent increase in the words recognized. The drug was well-tolerated in people. And in a separate study, the company re-tested the hearing of participants who had received the drug a year or two prior. “Some of those people continued to have that benefit [of increased word recognition], which makes sense, because we believe we’re restoring some of the original biology – and that original keeps working,” Dr. Franck adds.

A Game-Changing Possibility

These results represent potentially a huge advance in the field of hearing restoration. “This is suggesting that the drug could be disease-modifying – so you’re actually correcting the underlying condition,” says Carl LeBel, PhD, Frequency’s Chief Development Officer. “And we can’t think of a single example where you’ve given one dose of an agent, you produce an effect, and that effect lasts for this long.”

So far, the company has had the most success in treating people who have sudden sensorineural hearing loss with no known cause (meaning not caused by trauma or another obvious factor), as well as people with noise-induced hearing loss. Together, these fall into the category of acquired adult sensorineural hearing loss. “Where we have the most confidence about the percentage of responses is in moderate to moderate- severe range due to noise and sudden hearing loss,” Franck says. “And that’s the group that we’re using to study this next clinical trial that’s underway.”

This isn’t to say that the company is ignoring other hearing loss populations, such as those with age-related hearing loss, or those who are given drugs that diminish hearing, such as certain cancer patients. “We’re going to continue to study them,” says Dr. LeBel. “But for us to get the drug approved as quickly as possible, we want to focus in on the populations that have shown the greatest response so far.”

How to Learn More about Frequency’s Current Clinical Trial

Frequency’s current clinical trial is a double-blind, placebo-controlled phase 2b study, in which researchers are studying the drug candidate with a larger group of patients to assess effectiveness and further study safety. The company has expanded testing to 27 different sites around the country. To qualify, you need to have noise-induced hearing loss or sudden hearing loss and be between 18 and 65 years old. To see if there is a testing site near you, visit the study’s ClinicalTrials.gov page. There is also a separate website with a questionnaire to see if you qualify for the study.

FX-345: Another Clinical Trial to Come

The company is also working on a new clinical candidate for hearing restoration, called FX-345, which is designed to go further into the cochlea to potentially activate more progenitors to restore hearing function. FX-345, like FX-322, is a combination of two drugs that Frequency believes are required to activate cells in the cochlea to divide and then form new hair cells. “What we have done is taken one of those drugs, and we’ve swapped in a new drug that goes after the same target, but that new drug is much more potent than the one that’s currently in FX-322,” LeBel says.

Because of the activity of the drug and its concentration, researchers believe that they may be able to restore some of the lower frequencies in the cochlea, not just the high frequencies that are on the outer part. “So the might open up the door that some of the folks that aren’t responding to FX-322 for whatever reason,” LeBel adds. Clinical trials for FX-345 are expected to start in the second half of 2022.

For more information on the current FX-322 trial, check out ClinicalTrials.gov, or visit Frequency Therapeutics.

Society Says Hearing Loss Doesn’t Matter: Part 1

Even though I’ve lived with hearing loss for over 35 years — and our world is supposedly getting more evolved — it’s still surprising to me when I come across evidence of how little regard society has for hearing loss, its ramifications, and for people who suffer from it.

Consider the following example, recently highlighted by the Hearing Health Foundation: In March, the U.S. Preventive Services Task Force (USPSTF) recommended against screening older adults for hearing loss. The organization “concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for hearing in older adults.”

Um, what?! Pun intended.

In the United States, 1 in 2 adults who are 65 years or older have a hearing loss. Not only that, but about 25 percent of those hearing-impaired adults don’t even know they have hearing loss (and others probably know but don’t want to deal with it).

There is a prevailing idea in our society that hearing loss isn’t a big deal; it’s a nuisance for others to have to repeat themselves, or communicate with the hearing-impaired, but little regard is given to how it impacts the person experiencing it. Studies show that untreated and undiagnosed hearing loss is associated with dementia, falls, depression, and social isolation. That’s not even getting into the profound impact it can have on quality of life, employment, relationships, and other critical factors.

The USPSTF’s disregard for hearing screening is indicative of a few things: First, that hearing loss is still not taken seriously. Second, they aren’t recommending screening because the current treatment — hearing aids — isn’t utilized by the majority of people with hearing loss, and it isn’t covered by most insurance, making the cost out-of-reach for many Americans.

It’s not a big secret that health insurance companies aren’t really designed to keep us healthy; they are for-profit companies that have raked in billions in profits, even during the pandemic. I doubt they want to cover hearing screenings in older adults, because then they’d have to start covering hearing aids, too.

When will hearing loss be given the urgent attention it deserves? When will the government, health officials, and insurance executives start to treat hearing impairment like a real issue? Not anytime soon, it seems.

Akouos: A Bold Step Towards Treat Hearing Loss with Genetic Medicines

Last week, Akouos, Inc. (pronounced Ah-KOO-os), a Boston-based biopharmaceutical company, was granted both Orphan Drug Designation (ODD) and Rare Pediatric Disease Designation (RPDD) by the FDA for AK-OTOF, a gene therapy the company is developing to treat hearing loss caused by mutations in the otoferlin (OTOF) gene. The company is expecting to submit an investigational new drug application in the first half of 2022. These events are significant not just because they could lead to the first clinical trial to treat a genetic form of hearing loss, but also because an orphan drug and rare pediatric disease designation could mean that clinical development of the therapy can go faster.

I had the pleasure of learning about Akouos’ work from Manny Simons, PhD, the president and co-founder of the company. While some companies in the hearing research space are focused on treating noise-induced hearing loss or preventing hearing loss caused by ototoxic drugs, Akouos was founded with an initial focus on treating genetic hearing loss. “Genetic hearing loss is underappreciated and under the radar,” says Dr. Simons. “Even in our early fundraising, it was sometimes hard to convince investors of the prevalence of genetic hearing loss.” While hearing loss can be caused by many factors, 50 to 60 percent of hearing loss in babies is caused by genetic mutations, according to the Centers for Disease Control and Prevention. There are more than 150 genes that have been identified that can be tied to hearing loss, and countless more to be discovered.

The Promise of Gene Therapy

Historically, delivering medicines to the inner ear has been a challenge, and the tiny, tightly-enclosed cochlea – which transmits sound to the brain – was difficult to study. But Akouos saw promise in using gene therapy to address hearing loss. “We wanted to focus on forms of hearing loss where the biology and mechanisms were understood,” Simons explains. “This potentially gives us a higher probability of treating genetic hearing loss and addressing the root cause.”

Akouos chose to work on gene therapy first for OTOF because “everything else in the ear is intact – the connection between nerve cells is still there,” Simons explains. It affected just one thing in the ear: otoferlin, a protein involved in hearing. People with the condition have severe-to-profound hearing loss from birth. The gene therapy treatment is designed to return a healthy copy of OTOF, potentially taking a person from profoundly deaf to having functional hearing.

Listening to Those With Hearing Loss

Akouos is committed to keeping the concerns of those with hearing loss at the center of what they do. “We want to hear from the community,” says Simons. “The more we can be doing to have a bigger impact, the more effective we can be, even as the company grows.”

To that end, Akouos is sponsoring a genetic testing program called Resonate, which provides free genetic testing to people in the U.S. who have a diagnosis or medical history of auditory neuropathy.

In addition, you can subscribe to Akouos’ newsletter for company updates, and sign up for press releases to get the latest news. You can also follow Akouos on LinkedIn and Twitter.

Hearing Loss Help for Seniors

Whether you’re new to living with hearing loss or are an old pro, it can be tough to find reliable information about it. It’s always surprised me that for a health condition that affects so many people, there isn’t more about hearing loss written on the web.

Consolidated, practical information on hearing loss can especially be challenging for seniors — who are the population most likely to experience it. “Many seniors find themselves struggling with newly developed hearing loss, but it is an issue that can be helped with the right support and information,” says Sarah Martell, a web advocate at More Connected, an outreach organization that focuses on resources for those with under-served needs such as hearing loss. “In addition to the technology that is available, there are matters of lifestyle, financial support, and health considerations to be addressed,” she says.

Two comprehensive resources Ms. Marshall recommends are:

  • Help Advisor: A website for seniors, which includes a guide to treating and living with hearing loss
  • Medicare Advantage: Tips and resources for Medicare beneficiaries suffering from hearing loss

As with any health condition, having the right resources for hearing loss can make a world of difference!

Gene Therapy to Cure Hearing Loss: Sooner Than We Think?

For years, we’ve heard that gene therapy could one day offer a cure for hearing loss. And while that day is still not here, it may also not be as far off as some people think.

I recently heard updates from some of the researchers at the Stanford Initiative to Cure Hearing Loss (SICHL), detailing where they are in their current work and what they anticipate for the future. One update came from Teresa Nicolson, PhD, head of the Nicolson Research Lab at SICHL.

Dr. Nicolson discussed the fact that there is already a gene therapy on the market to treat a form of blindness: Luxturna, which is used to treat patients with inherited retinal disease due to mutations in both copies of the RPE65 gene. It was approved by the FDA in 2017. “I think we’re entering into a rapidly expanding translational phase for gene therapy,” she said to me in an email.

Luxturna is just one of six gene therapies that have been recently approved. The others are for muscle degeneration and immune disorders.

“There currently is an antisense oligo therapy in clinical trials for Usher syndrome (USH2A), which causes deaf/blindness,” Nicolson said. “The goal of the clinical trial is to restore vision, but this reagent could also be used to improve hearing loss in these Usher patients. So I think we are very near to these type of treatments!”

The Stanford researchers agree that curing hearing loss is not a matter of if, but when. As we’ve seen in the past year with the lightening-speed development of the COVID-19 vaccine, with enough money and resources, it’s possible to come up with novel treatments in an astonishingly short time.

While hearing loss doesn’t carry the same urgency as a potentially fatal condition like COVID, those of us who are personally affected know that it still has a profound impact on our lives — and that better treatments are needed.

With enough awareness, and enough money, the researchers assert that treating inner-ear hearing loss will one day be as effective as the treatments we currently have for middle ear problems (conductive hearing loss, which can be fixed).

Check out more about the work at SICHL or donate to help speed up science.

Frequency Therapeutics Ramps Up as FX-322 Trials Continue

Big things are happening at Frequency Therapeutics, the company with drug FX-322 in clinical trials to potentially restore sensorineural hearing loss.

Today, the company welcomed Kevin Franck, PhD, as Senior Vice President of Strategic Marketing and New Product Planning. Dr. Franck will be leading pre-commercial strategy and launch planning for
Frequency’s clinical pipeline, including FX-322.

Franck joins Frequency from Massachusetts Eye and Ear in Boston, a Harvard University teaching hospital that focuses on eye and ear care and research, where he was Director of Audiology. Prior to that, he was Head of Marketing for Bose Hear, a division of Bose Corporation, where he led new product management and channel marketing of an emerging category of business focused on hearing loss.

Franck’s addition to Frequency comes at an important time for the company, as they will be sharing phase 2A data of clinical trials for FX-322. “I’m excited to join Frequency at this important time and contribute to advancing the field toward hearing regeneration,” said Franck in a press release. “Currently available hearing devices have been an incomplete solution and many patients continue to struggle to understand speech and with sound clarity. Repairing the underlying damage that is the primary cause of acquired hearing loss has always been the ultimate objective, and Frequency may be on the cusp of addressing this ambitious goal.”

Sounds (pun intended) promising!

Decibel Therapeutics: Pivoting to Gene Therapy Treatment for Hearing Loss

Decibel Therapeutics, a Boston-based biotechnology company, announced last week that they have raised $82 million to pursue gene therapies for hearing loss. This is exciting for a few reasons:

  1. Genetics is one of the leading causes of hearing loss. According to the CDC, 50-60 percent of children born with hearing loss have it due to genetics. And genetic causes of hearing loss tend to be more severe, meaning they impact a person even more than milder forms of hearing loss.
  2. Other treatments in the works, such as Frequency’s FX-322, target other causes of hearing loss, but not genetics. So Decibel’s work has the potential to help an entirely different population of people.

Interestingly, Decibel was previously working on treatments that would help prevent hearing loss from happening in the first place. But according to Endpoint News, due to recent advances in genomic and regenerative technology, the company decided to shift to gene therapy for people who already live with hearing loss.

Currently, Decibel’s gene therapy program aims to test children with genetic deafness due to the otoferlin gene (OTOF). OTOF is one of the most frequent causes of sensorineural hearing loss. According to a May 2019 study published in PLos One, more than 160 mutations in OTOF have been identified so far. It tends to cause severe to profound hearing loss in children from birth. The idea is that the company’s technology will help to focus on the deficient hair cells in the ear and restore them.

Decibel’s long-term goal is to create cures for other genetic causes of hearing loss once the OTOF program is successful. That is currently in preclinical stages, and the company expects to start clinical testing in 2022, according to their press release.