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.
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.
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.
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.”
As I wrote recently, Frequency Therapeutics’ drug candidate FX-322 is shaping up to potentially be the first biopharmaceutical treatment for hearing loss on the market some time in the next decade.
Now here’s an update: The company is currently in phase 2a of clinical trials, and they announced last week that they will report a 90-day analysis of the phase 2a study of FX-322 by late Q1 2021, according to their Associate Director of Digital and Corporate Communication, Suzanne Day.
While the promise of new data is already exciting news for those with hearing loss, there’s more to share: Frequency is expanding the potential reach of FX-322 to include two important groups. New studies have begun in patients with age-related hearing loss (ages 66 – 85) and those with severe sensorineural hearing loss. These studies will provide data on the potential of FX-322 for a far broader group of patients.
Severe Hearing Loss Group
According to a 2016 study published in the American Journal of Public Health, an estimated 6.6 million Americans (2.5 percent) of Americans 12 years and older have severe to profound hearing loss. As the description implies, this degree of hearing loss has a severe impact on a person’s quality of life. The Hearing Health Foundation states that without hearing aids or cochlear implants, speech isn’t understandable for those with a severe hearing loss. If anyone is in need of a hearing breakthrough, it’s this group!
“The severe population study will include patients with more dramatic loss in hearing function, and likely no functional hearing in certain parts of cochlea,” says Carl LeBel, PhD, Frequency’s Chief Development Officer. This group will likely include patients whose hearing loss results from a range of causes (noise-induced, sudden hearing loss, and ototoxic, for example). “Since all of these causes are associated with a loss of sensory hair cells, we are interested in evaluating how these subjects compare to less severe subjects in their response to FX-322,” Dr. LeBel says.
Age-Related Hearing Loss Group
The National Institute on Deafness and Other Communication Disorders states that approximately one in three people in the United States between the ages of 65 and 74 has hearing loss, and nearly half of those older than 75 have difficulty hearing. There were over 54 million people aged 65 and over in 2019, according to the U.S. Census Bureau. Needless to say, the age-related hearing loss group is quite large. So the potential for FX-322 to help them in their golden years is profound (pun intended!).
Although Frequency’s test group includes people who are between 66 and 85 years old, “This type of hearing loss is acquired and gradually worsens over time, and can begin as early as a person’s 30s or 40s,” LeBel says. “It is often thought of as resulting from a chronic low-grade exposure to noise over a lifetime, and not just as a result of aging.”
Signing Up for a Trial
If you or someone you know fits into one of these categories and is interested in participating in a clinical trial, check out this link for the age-related study. There are multiple testing sites across the United States. The severe hearing loss study has not yet begun, but you can keep an eye on clinicaltrials.gov for when this opens up.
For as long as people have experienced hearing loss, they’ve been anxious for better treatments. And although that has remained elusive thus far, for certain types of hearing loss, a significant treatment may be coming before 2030: FX-322, the lead drug candidate from Massachusetts-based biotechnology company Frequency Therapeutics.
I recently spoke with Carl LeBel, PhD, Frequency’s Chief Development Officer, about the company, FX-322 and the potential of regenerative medicine to treat hearing loss (thanks to Suzanne Day, Associate Director of Digital and Corporate Communications, for her assistance). “We think within this decade, hopefully there’s the first hearing restoration therapeutic that’s available,” Mr. LeBel said.
FX-322 and the Formation of Frequency Therapeutics
To understand this potential treatment, it helps to understand the discoveries that lead to the formation of the company. In 2014, the company was founded based on scientific breakthroughs by Jeff Karp, PhD, Professor of Medicine at Brigham and Women’s Hospital, and Bob Langer, ScD, Institute Professor at Massachusetts Institute of Technology (MIT).
The researchers found that some body tissues regenerate much better than others. They studied the lining of the small intestine, which turns over roughly every four days, because it’s designed to absorb and distribute nutrients to other parts of the body. Drs. Karp and Langer saw the molecular pathways that signal the lining’s cells to turn over quickly and form new tissues.
Around the same time, another scientific group found very similar cells in the cochlea – but with one big difference: in the cochlea, these cells weren’t active. They saw that the cochlea’s cells didn’t regenerate and form new sensory hair cells. “So that was the formation of Frequency,” LeBel explains. “And Frequency was asking, why is that the case? Why is it that the cochlea isn’t regenerating cells and the small intestine is?”
This led to the discovery of two small molecules that make up FX-322, which targets these cells, called progenitor cells. Essentially, this process is meant to drive hair cell regeneration: The drug targets pathways to those cochlear cells, and when activated, they divide and form a new cell of themselves, called daughter cells. “And then most importantly, they form a new sensory hair cell,” LeBel says.
Six years after it was founded, the company now has a staff of close to 70 people. FX-322 has cleared phase 1/2 of clinical trials and is now in phase 2a. “That’s sort of the middle phase of clinical development where you’re really trying to characterize the efficacy of your drug,” LeBel explains.
Dr. Carl LeBel, Chief Development Officer, Frequency Therapeutics
FX-322 Findings So Far
As the company has progressed through clinical trials, they’ve made some interesting discoveries. The participants in the trials have been people with mild to moderately-severe hearing loss. And while FX-322 has a favorable safety profile for all participants, the hearing improvement was seen mostly in the moderate to moderately-severe individuals, as measured by improved word recognition. LeBel speculates that this is because people with more hearing loss have more to gain.
In a separate study, Frequency has found that delivering FX-322 directly into the ear by intratympanic injection effectively reaches the site of action in the cochlea – so it’s going right to the place where it’s needed. The drug candidate can be administered by an ear, nose throat doctor (ENT) in their office. “But importantly, you also don’t have to worry about any systemic side effects that oftentimes are challenging for other drugs, like if somebody’s taking a pill,” LeBel adds.
And in more promising news, individuals who were given FX-322 in 2018 were retested 1-2 years later, and many of them maintained their hearing improvements – which suggests that hearing function is maintained. “And that’s exactly what you want to see when you’re developing drugs to treat a chronic condition,” says LeBel.
Who Might FX-322 Help?
FX-322 is designed to treat what’s referred to as acquired sensorineural hearing loss, which includes forms such as:
Noise-induced hearing loss
Sudden sensorineural hearing loss
Age-related hearing loss
Ototoxic drug exposure
“All of those forms are associated primarily with a loss of sensory hair cells,” LeBel says. “So we think they can possibly be good candidates for FX-322.”
It should be noted that this likely excludes genetic forms of hearing loss.
Rather than being a full-on cure for all degrees of acquired hearing loss, LeBel says that Frequency sees FX-322 as “a disease-modifying drug,” meaning it may modify hearing loss. “The way we think possibly FX-322 could fit into the hearing-health world is, you could imagine there might be individuals that would be candidates for cochlear implants – you could treat them with FX-322, and it’s possible that you could take them from being a cochlear implant candidate to a hearing aid candidate,” LeBel says. Similarly, people with less severe hearing loss who are hearing aid candidates might not need hearing aids if the drug treatment is successful.
What Frequency Wants Individuals With Hearing Loss to Know
LeBel acknowledges that Frequency is treading completely new territory, and when FX-322 hopefully gets to the market in the coming years, it’s going to take a shift from all of those who deal with hearing loss – either personally or professionally – to integrate the product into the world. That means partnering with patient volunteers, patient advocates, audiologists and otolaryngologists. “All of those groups have to come together and work together for this to be successful. So we just want to tell everybody we want to be part of that partnership,” says LeBel. “We want to do whatever we can to build it and move it forward and support it. And we’re going to be successful if we do it together.”
