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).
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.”
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:
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.
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.
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.
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.”
It’s the dream of many (though not all) with hearing loss: a cure for deafness — a way to restore natural hearing, or provide it to some for the first time.
So far, it’s been elusive, and progress seems to move slowly. Partly this is because hearing loss is not easily corrected the way faulty vision can usually be with glasses or contact lenses. While hearing aids have gotten more sophisticated, they still can’t come close to replicating normal hearing, particularly in noisy environments.
However, I think the larger issue is the societal attitude towards hearing loss. It is mostly ignored, seen as an inevitable part of aging, or treated as a personal fault of the patient (“Just listen to me!”). Because it is not taken seriously, the research has not been well-funded or seen as urgent.
What is keeping progress from moving forward? This is something that I’ll seek to keep writing about. It’s on the mind of many those with hearing loss, who don’t want to hear that “someday” this will happen. “Someday” can be soon — if more people prioritize hearing loss as a fully curable condition.