Progress Reported in Reversing Cochlear Hair Cell Damage

Hearing loss currently has no cure and is managed mainly with the use of hearing aids or cochlear implants. Depending on the level and nature of hearing loss, the benefit of hearing aids may range from significantly life-changing to a useless, inconvenient bit of plastic in your ear. Cochlear implants are targeted at restoring a sense of hearing to those suffering from profound deafness but come with some risks and disadvantages that can be a significant deterrent.

Though hearing loss has traditionally been considered irreversible, if you strain hard enough you can hear a trickle of hope in the distance as medicine forges ever closer to developing a cure. While the world of biopharmaceuticals often operates under a cloud of protective secrecy, there are a few promising hearing loss treatment studies in recent news.

 
Studies Underway to Regenerate Damaged Cochlear Hair Cells
Sensorineural hearing loss is a result of damage to the cochlear hair cells and/or nerve fibers, both of which are crucial to hearing. Damage to these structures in the inner ear can be due to trauma, age, exposure to excessive noise, or it can be congenital (usually part of a genetic disorder). Unlike other vertebrates in the animal kingdom, mammals – of which humans are a species – are incapable of regenerating cochlear hair cells. Other animals, such as fish, frogs, and birds, appear a little more advanced than homo sapiens in this regard.

Back in 2012, scientists found a certain group of receptors in the auditory organs of birds that were responsible for regulating the proliferation and regrowth of sensory hair cells when appropriately triggered. Mammals also produce these same receptors, known as epidermal growth factor (EGF), but this signalling pathway to regeneration of cochlear hair cells just doesn’t seem to work for us.

In 2018, a study out of the University of Rochester (NY) was published in the European Journal of Neuroscience investigating the theory that stimulating the EGF pathway, whether by using medications, genetic modification, or a viral agent, would be able to trigger hair cell proliferation in mice. And lo and behold, not only did cells nearby cochlear-supporting cells targeted by the therapy begin to take on the form of sensory hair cells, but they also demonstrated the ability to integrate into the neuron network.

Though this potential therapy still needs a lot more work to be applicable to humans, it takes us one step closer to understanding the process of regenerating damaged inner ear hair cells and a cure for hearing loss.

 
Sensorion’s SENS-401 Drug May Reduce Sudden Sensorineural Hearing Loss
Sudden sensorineural hearing loss (SSHL) is exactly as it sounds – sudden. Within 72 hours, hearing is reduced by over 1000-fold (a 30-decibel loss), typically in one ear. Most cases (over 70%), occur for no known reason, though a small percentage can be attributed to infection, trauma, or cancerous lesions. Around 50% of SSHL cases are known to self-resolve over the following week or two – though not always to the same level of hearing sensitivity. Because of the ability to spontaneously recover, there is a high number of unreported and undiagnosed cases but in the US, it is estimated to occur at annual rate of about 5-20 cases for every 100,000 people. Early medical intervention improves the prognosis of recovering the hearing loss; among other therapies, this can involve treatments such as corticosteroid injections or tablets, antiviral medications, diuretics, or surgery.

There is now a new player in the game, currently undergoing phase 2 clinical trials in Europe, Canada, Israel, and Turkey. Biopharmaceutical company Sensorion expects to announce top-line data mid-2020 regarding the results of its investigation into the use of a new oral drug, currently referred to as SENS-401, to protect against progressive damage to the hair cells and nerves of the inner ear in the treatment of severe and profound SSHL. The drug has also been approved for the prevention of cancer drug cisplatin-induced hearing damage in children. Understandably, the exact details of this medication are still under wraps during the trial phases but we know that SENS-401 also goes by the name of arazasetron besylate.

 
The REGAIN Study Uses Injections to Reverse Age-Related Hair Cell Loss
If arazasetron besylate was difficult enough to remember, try LY3056480. The REGAIN clinical trials are currently being conducted at the University College London Hospitals.  The goal is to investigate the use of gamma-secretase inhibitor (GSI) injections to reverse the age-related loss of inner ear hair cells. Inhibition of this chemical pathway has been known to allow cochlear supporting cells to differentiate into sensory hair cells, thereby reversing a degree of hearing loss, but until now these studies have not been performed on human subjects.

The REGAIN trials are currently in phase 2, releasing positive safety results at the conclusion of phase 1 earlier this year. During phase 2, a larger group of adult participants with mild to moderate sensorineural hearing loss are receiving treatment with injections of the GSI drug LY3056480 into the ear drum (trans-tympanic injection), with the aim of collecting more data about the safety and effectiveness of this drug at curing hearing loss. Results of phase 2 have not been announced yet but are anticipated soon, hopefully as well as a more user-friendly medication name.

 
Frequency Therapeutics and FX-322
Another competitor in the race to find the cure to reverse sensorineural hearing loss is biotech company Frequency Therapeutics. Not a great deal is known about this injectable drug, FX-322, but at least there are fewer numbers to remember in its name. Frequency Therapeutics has based their research on the concept of progenitor cell activation in the human ear, the idea that manipulating certain signaling pathways can stimulate dormant stem cells to proliferate into other cell types and replace damaged or lost tissue, such as the all-important inner ear hair cells.

Phase 1/2 of the FX-322 trials were completed earlier this year with successful demonstration that the drug is safe and well tolerated. Also delivered via a trans-tympanic injection, FX-322 was already observed to improve hearing function in multiple participants during the early phases of this study. Phase 2a is expected to commence after a formal submission and review of the results of the first phase sometime this September.

Various other areas of research relating to the ear and hearing loss are also underway, including the delivery of drugs to the inner ear via magnetics and nanoparticles. Of course, medical research and development is usually more like writing a long and complicated symphony rather than a quick tuneless whistle so we may be waiting a little while longer before we see these cutting-edge treatments become commercially available.

 

References
Types and causes of hearing loss. https://www.cochlear.com/au/en/home/diagnosis-and-treatment/diagnosing-hearing-loss/types-and-causes-of-hearing-loss
Study points to possible new therapy for hearing loss. https://www.sciencedaily.com/releases/2018/10/181015132953.htm
ERBB2 signaling drives supporting cell proliferation in vitro and apparent supernumerary hair cells formation in vivo in the neonatal mouse cochlea. https://onlinelibrary.wiley.com/doi/abs/10.1111/ejn.14183
Reversing hearing loss by regrowing hairs. https://www.medicalnewstoday.com/articles/323925.php
Is sudden sensorineural hearing loss reversible? https://www.webmd.com/healthy-aging/qa/is-sudden-sensorineural-hearing-loss-reversible
SENS-401. http://www.sensorion-pharma.com/en/pipeline/sens-401
Sensorion receives FDA IND approval for arazasetron (SENS-401) for sudden hearing loss. https://www.trialsitenews.com/sensorion-receives-fda-ind-approval-for-arazasetron-sens-401-for-sudden-hearing-loss/
Treatments for hearing loss: what’s new? https://www.actiononhearingloss.org.uk/live-well/our-community/our-blog/treatments-for-hearing-loss-news/
Sensorion receives FDA IND approval for arazasetron (SENS-401). https://www.biospace.com/article/releases/sensorion-receives-fda-ind-approval-for-arazasetron-sens-401-/
Sudden hearing loss. https://emedicine.medscape.com/article/856313-overview
Regeneration of inner ear hair cells with gamma-secretase inhibitors. https://www.regainyourhearing.eu/
REGAIN update on the progress so far and a further opportunity for people with hearing loss to take part in the trial. https://www.actiononhearingloss.org.uk/live-well/our-community/our-blog/regain-update-an-opportunity-for-people-with-hearing-loss-to-take-part-in-a-clinical-trial/
Audion therapeutics and REGAIN consortium announce positive phase 1 results in patients with sensorineural hearing loss. https://www.b3cnewswire.com/201902051883/audion-therapeutics-and-regain-consortium-announce-positive-phase-i-results-in-patients-with-sensorineural-hearing-loss.html
Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573859/
Astellas Pharma and Frequency Therapeutics collaborate on hearing loss therapy. https://www.medicaldevice-network.com/comment/fx-322-hearing-loss-therapy/
PCA regeneration. https://www.frequencytx.com/our-approach/pca-regeneration.php
Frequency Therapeutics announces positive phase 1/2 data for drug candidate for hearing restoration. https://www.frequencytx.com/news-events/news-events-press-release-04-09-2019.php
Frequency Therapeutics to present major FX-322 update on September 18, 2019 at AAO-HNSF annual meeting in New Orleans. https://www.tinnitustreatmentreport.com/frequency-therapeutics-to-present-major-fx-322-update-on-september-18-2019-at-aao-hnsf-annual-meeting-in-new-orleans/