June 1, 2018 (Vol. 38, No. 11)
Progenitor Cell Activation Can Regenerate Cochlear Hair Cells
Within a decade, chronic noise–induced hearing loss may be reversible and the need for hearing aids may be a mere memory. That potential is based on development work underway at Frequency Therapeutics.
This three-year-old biotech company is advancing research that began in the labs of Robert Langer, Sc.D., Institute Professor at Massachusetts Institute of Technology, and Jeffrey Karp, Ph.D., a professor of medicine at Brigham and Women’s Hospital, Harvard Medical School.
The Progenitor Cell Activation (PCA) approach developed by Drs. Langer and Karp is completely new.
“Rather than physically manipulating genes, we’re targeting the pathways that control cellular development,” says David L. Lucchino, cofounder, president, and CEO.
The approach uses small-molecule drugs to activate progenitor cells within the ear to regrow tissue—in this case hair cells, which transfer sound to the auditory nerve. So, by regrowing these cells and the neuronal connections, the approach may improve hearing.
This PCA technology is a breakthrough, but it’s not the only option. A competing approach using a gamma-secretase inhibitor is being investigated by University College London’s (UCL’s) Ear Institute. The approach studied at UCL uses forced differentiation—“a very different mechanism,” Dr. Langer says, to force stem cells to convert directly into other types of cells. UCL’s program entered clinical trials at about the same time as Frequency Therapeutics’ program.
“We, however, engage a different part of the signaling pathway. Rather than force cells to become something different, we’re causing precursor cells to behave in a native manner, mimicking the biology that humans experience during development,” Dr. Langer explains.
Early Results Are Promising
There’s a great correlation between hearing physiology among all animals and humans. “They have different scales, and the frequencies by which they hear are different,” Lucchino points out. “But the physiology is similar.”
In animal studies, PCA regenerates damaged hair cells in the inner ear. “Nothing like that had ever been done before,” Dr. Langer says. Early animal efficacy and ex vivo data with human cochlear tissue, he says, “is quite striking.” Those results gave the company the confidence to advance to clinical trials.
The program to improve hearing, dubbed FX-322, recently completed Phase I safety trials. It is scheduled to begin Phase II efficacy trials later this year.
FX-322 combines two proprietary, small-molecule drugs and delivers them in a slow-release gel. “We deliver the gel through the ear drum to the middle ear. From there, the drugs permeate into the cochlea,” Lucchino details.
“Our goal,” Dr. Langer declares, “is to help people hear again (or regain other lost functions). Ideally, we will be able to do this with one or two injections.”
“We’re seeing nice results with single injections in our animal work,” Lucchino agrees, but clinical work is in its early stages, he cautions. The optimal dosing regimen will be studied in Phase II trials.
The PCA technology platform can be applied to many areas. “There are examples throughout the body where the tissue has been worn down by nature or the environment,” Lucchino notes. Muscle regeneration, diabetes, alopecia, and wound care are a few examples. “We’re also looking at a solution to heal the myelin cover on nerves, which is attacked in multiple sclerosis.”
Although Frequency Therapeutics is well aware of multiple applications and is considering a second program, it’s tightly focused on hearing regeneration. Therefore, “There’s nothing regarding new programs to announce yet,” Lucchino states.
Convergence and Kendall Square
The pairing of Dr. Langer and Lucchino was organic. “David and I have been colleagues for years,” Dr. Langer underscores. “Jeff (Karp), grad student Xiaolei Yin, and I had made the PCA discovery and filed the patents. We had a vision for a simpler approach that we call ‘small-molecule regenerative medicine,’ and we quickly filed the foundational intellectual property.
“I then reached out to David to help us think through a strategy to commercialize this opportunity. David immediately went to work. Now, three years later, we have built a deep biological justification for our small-molecule regeneration approach and are now in the clinic with our hearing-regeneration asset.”
Lucchino was ready to listen. “Bob is the giver of life to so many ideas. He’s a great creative scientist who empowers the people he works with to do important things.”
Frequency Therapeutics was formed in 2015 based on the work of Drs. Langer and Karp. “We’re aligning key scientific insights to enable small molecule–based regeneration within the body to create a native healing response,” Lucchino says. “This insight has created substantial momentum that is helping to propel the company forward.”
Teaming with the Best
Typical of many biotech startups, Frequency Therapeutics is funded by a basket of diverse investors that includes high-net-worth individuals, professional investors, and family offices. The company, so far, has grants from the Juvenile Diabetes Research Foundation (JDRF) and the Department of Defense.
“Biotech is all about tenacity and overcoming adversity,” Lucchino acknowledges, and the company is years away from commercialization and profitability. Knowing that, “We worked to attract some of the best minds to join the team, and we are building out the vision one day at a time.”
For example, Frequency Therapeutics recently hired William W. Chin, M.D., as chief medical officer. Dr. Chin was most recently executive vice president of scientific and regulatory affairs at the Pharmaceutical Research and Manufacturers of America (PhRMA), and has held senior positions in research at Harvard Medical School and Eli Lilly.
Will McLean, Ph.D., co-founder and vice president, biology and regenerative medicine, is another example. Lucchino calls him one of the foremost inner ear stem-cell biologists in the world. Dr. McLean is a recent finalist in the first Sartorius & Science Prize for
Regenerative Medicine & Cell Therapy.
“The Sartorius & Science Prize is a global peer-reviewed analysis of some of the most important regenerative technologies in the world (including CAR-T work), and we were one of four finalists,” Lucchino says. “This was an important step for us, validating what we knew: that we’re on to something.”
Looking forward, Lucchino says he is expanding Frequency’s syndicate with some selected investors. At a scientific level, “We are advancing our hearing-regeneration program into Phase II trials as we perform our strategic portfolio expansion analysis.”
Ultimately, Frequency Therapeutics believes it is on track to reverse hearing loss. Given the progress to date, that seems an justifiable hope.