Advancing trials for hearing loss

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Frequency Therapeutics bases its science-based approach to treating disorders on harnessing the body’s biological repair mechanisms to repair or reverse the damage caused by degenerative diseases, including hearing loss. Overstimulation of cochlear hair cell receptors by noise or chemical exposure, or other insults, leads to their apoptosis.

Several non-mammalian species, such as birds and reptiles, are able to spontaneously regenerate these hair cells after damage caused by asymmetric division of progenitor stem cells, to form a hair cell and replace the original progenitor. “The system is there, it can be activated in other species, and we have it as well,” says Chris Loose, PhD, co-founder and CSO.

The discovery of cochlear progenitor cell activation comes from research conducted in the labs of Robert S. Langer, ScD, at MIT and Jeffrey Karp, PhD, at Harvard Medical School, which extensively characterized a type of cell similar progenitor in the intestinal crypts that constantly undergoes asymmetric cell divisions in response to environmental cues. “Once they knew the signal, they developed a way to target progenitor cells with small molecules and reactivate the system in dormant cochlear cells on demand,” Loose says.

The search for therapeutic agents capable of activating asymmetric cell divisions of cochlear hair cell progenitors led to the development of FX-322, a combination of a GSK-3 inhibitor that activates the Wnt signaling pathway and valproate of sodium, a histone deacetylase inhibitor. “The combination of the two showed profound synergy and led to a marked activation of cochlear progenitors,” Loose continues.

A major advantage of this small molecule approach is that it only transiently activates progenitor stem cells, causing them to undergo a single cell division. “Unlike gene editing or gene therapy, where the genome is modified, we only use the native programs of the cell and activate them temporarily during a cell cycle,” says Loose.

Drug discovery and development in the field of hearing loss has been severely hampered by the inability to deliver treatments to the mammalian cochlea, and this has been compounded by the difficulty of quantifying drug levels in the ear. internal.

“We overcame this challenge by collaborating with a leading cochlear implant clinic in Germany to test our drug delivery technology using their ability to collect fluid samples,” notes Carl LeBel, PhD, Chief Development Officer . FX-322, Frequency Therapeutics’ lead product, can be administered via a simple intratympanic injection, a procedure that is safe and has been used historically to deliver other treatments such as antibiotics and steroids. “We found that most of the drug is at the base of the cochlea, where high frequency sounds are detected, and this is also the site that is most often and earliest affected by hearing loss. “, emphasizes Loose.

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Historically, hearing has been assessed using audiograms, which map the audible threshold for the different frequencies a person can detect. “A much more relevant aspect is determining how well a person can understand a signal,” says Kevin Franck, PhD, senior vice president of strategic marketing and new product planning at Frequency. This is important because the ability to understand speech is the determining factor that affects a person’s personal and professional life. Therefore, one of the critical aspects of hearing endpoints in clinical trials conducted at Frequency Therapeutics is the focus not only on what a person can hear, but rather on what they can hear. to understand.

Statistically significant improvements in hearing function

Company scientists were the first to demonstrate that therapeutic concentrations of FX-322 in human cochlea are associated with statistically significant improvements in hearing function. These clinical trials administered the treatment to one ear, while the other ear of the same participant was used as a control and measured the percentage of participants who exceeded a 10% absolute improvement in speech perception, which is the threshold value where a change is considered. be clinically significant.

This threshold value represents five words in a 50-item word list that is commonly used for audiological testing. An analysis of all single-dose studies pooled, which included 71 participants treated with FX-322, found an improvement of more than 14% in speech perception threshold. These studies documented improvements that exceeded the threshold set for the study, and several participants experienced a 20% and even 40% increase in the number of words they could discern.

“It’s not only clinically but also statistically significant,” Franck says. At the same confidence level, the untreated ear and the placebo ear only showed an improvement of about 2% above the statistically significant threshold. In two randomized, multicenter, placebo-controlled clinical trials conducted by Frequency Therapeutics, a Phase I/II study and a Phase IB study that enrolled subjects with mild to moderately severe hearing loss, 33-34% of participants experienced achieves at least 10% absolute hearing. improved word recognition in the treated ear, a clinically and statistically significant result.

“We saw an improvement in speech perception only in the ear that was treated, and this gave us confidence that the effect was real, and we need larger trials that demonstrate the efficiency”, according to Carl LeBel. In some subjects with permanent sensorineural heat loss, improvement in speech perception was maintained for more than two years.

“At the highest level, what differentiates Frequency Therapeutics is that we have positive clinical data from several well-designed clinical trials, two of which are placebo-controlled and double-blind,” LeBel says.

More recently, Frequency Therapeutics launched a new phase II, prospective, multicenter, placebo-controlled, double-blind clinical trial. “FX-322-208 is also powered with speech perception as the primary endpoint, but it incorporates several important features,” notes Franck. To enroll in this clinical trial, potential participants must complete three visits during an introductory period that assesses the consistency of measurements from visit to visit. Subjects with noise-induced or sensorineural hearing loss, primarily in the moderate-to-mild-severe range, are randomized to the FX-322 arm or the placebo arm. The FX-322-208 has 62 participants per arm and began dosing participants in October 2021.

“Our learnings at the clinic allow us to reflect on our previous work and also help us develop another asset that we will be bringing to the clinic very soon,” continues LeBel. Alongside FX-322, Frequency Therapeutics scientists are advancing FX-345, which combines sodium valproate with a more potent GSK3 inhibitor, and are also applying the proof of concept behind this technology to develop therapies for multiple sclerosis in plaques by modulating a progenitor cell and a different cell target.

In multiple sclerosis, the autoimmune attack on myelin overwhelms the ability of the central nervous system to remyelinate axons, an activity that depends on the function of oligodendrocyte precursor cells. In a mouse model of multiple sclerosis, a therapeutic developed at Frequency, FREQ-162, given in a single dose, outperformed several other compounds, as shown by the formation of myelin basic protein.

“We believe this approach has enormous potential for many degenerative diseases,” Loose says.

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