Over 5% of the world’s population (430 million people) require rehabilitation to address their “disabling” hearing loss, according to the World Health Organization (WHO). The organization predicts that nearly 2.5 billion people worldwide (1 in 4 people) will be living with some degree of hearing loss by 2050, and that at least 700 million will require access to ear and hearing care and other rehabilitation services unless action is taken.
A range of factors may cause or contribute to hearing loss, including noise, diseases, medication, heredity, and aging. While one shared feature across all forms of hearing loss is the lack of approved therapeutic drugs, results from recent animal studies and human clinical trials are encouraging.
“We are working towards an IND submission for our lead product candidate in the first half of 2022,” says Manny Simons, PhD, founder, president, and CEO of Akouos. AK-OTOF, the company’s lead program, uses an adeno-associated viral (AAV) vector-based gene therapy to treat sensorineural hearing loss caused by mutations in the otoferlin gene. Otoferlin, a transmembrane protein, is involved in the calcium-mediated exocytosis of synaptic vesicles in inner hair cells in response to sound, a process that is indispensable for the transmission of electric signals to the brain.
A second Akouos program, AK-anti-VEGF, uses the same AAV vector to deliver a therapeutic protein to treat vestibular schwannoma, a benign tumor with complex etiology that affects about 200,000 people in the United States and Europe and causes significant patient morbidity.
Human clinical studies have reported that VEGF inhibitors can reduce the volume of vestibular schwannoma and hearing. However, one of their major limitations is potential toxicity after systemic administration.
“The inner ear is amenable to local delivery and constitutes an ideal site where next-generation genetic medicine modalities can be successful,” says Simons. The human cochlea contains approximately 5,000 inner hair cells, which are the receptors that directly send signals to the central nervous system. “This small target cell population compared to that of other organs allows genetic medicines to be administered at relatively low doses to potentially treat the entire organ and achieve a desired therapeutic effect,” he continues.
Preclinical studies
In preclinical studies, Akouos scientists demonstrated the feasibility of using doses several-fold lower than what is required in other organs, and recently presented data demonstrating tolerability of AK-anti-VEGF administration intracochlearly. The strategy generated robust protein expression levels.
Akouos’ most advanced product candidates leverage the same AAV vector that is delivered to the inner ear and can be adapted to specific products needed for various therapeutic interventions. “This highlights the broad applicability of our platform to address a broad range of inner ear conditions, including much more common disorders with a complex etiology,” says Simons.
A third strategy that is being developed at Akouos involves combining gene transfer with gene knockdown. “This becomes relevant for hearing conditions that have an autosomal dominant inheritance pattern and often result from toxic gain-of-function mutations or dominant negative mutations,” explains Simons. In these instances, delivering a wildtype copy of a gene is not sufficient, as the pathogenic variant additionally needs to be knocked down. Akouos has a discovery program focused on autosomal dominant hearing loss.
The study of otoferlin-gene mediated hearing loss benefits from a reliable mouse model that recapitulates the natural history and the pathophysiology of the condition in humans. “But not every condition in the inner ear disease landscape has a robust animal model,” according to Simons. For example, for the more complex forms of hearing loss, such as age-related or noise-induced hearing loss, the animal models are less representative, and this makes dose selection for humans more challenging.
The novelty of the interface between drug development and the fields of otology and audiology represents yet another limitation. “Because there has been so little drug development in the hearing space, hearing experts are relatively new to drug development, and scientists with drug development experience are often learning the hearing space for the first time,” says Simons. Establishing cross-disciplinary endeavors between the two fields is emerging as a critical need. “Over time we will see more individuals who have that combined experience and that will be valuable to the field,” he points out.
Small-molecule therapeutics
Audion Therapeutics licensed a new and what the company thinks is an optimized gamma secretase inhibitor for noise-induced hearing loss from Eli Lilly, and it is the molecule the firm took into development, according to Rolf Jan Rutten, CEO of Audion Therapeutics. The drug development program at Audion was founded on seminal research on regenerative hearing conducted by Albert Edge, PhD, and colleagues at the Massachusetts Eye and Ear Infirmary (MEEI), who showed in studies on mice that treatment with a gamma-secretase inhibitor could restore hair cells and led to functional improvement after noise-induced hearing loss.
Audion’s lead product, AUD1001, is a small molecule gamma secretase inhibitor that was discovered and developed in collaboration with Eli Lilly and partners in the REGAIN consortium. A Phase I clinical trial in patients with mild-to-moderate sensorineural hearing loss revealed that intratympanic administration of AUD1001 is safe and was well tolerated.
“We just wrapped up our Phase IIa study and we believe the efficacy results observed in multiple patients across sites merit continued evaluation of the product in further clinical studies,” says Rutten.
Audion anticipates initiating new clinical trials in the second quarter of 2022 at several sites in the United States and Europe. One of these is a Phase IIb double-blind, placebo-controlled trial in adults with sensorineural hearing loss of several etiologies, including aging, noise, and idiopathic.
“This is a new field, and we still need to learn a lot about developmental pathways and what the most suitable and relevant endpoints are,” explains Rutten. Traditionally, hearing loss has been diagnosed and measured with pure tone audiograms. “But we don’t hear in a soundproof booth, and we need to find ways to accurately measure how a patient performs under the conditions that they need to perform,” he adds.
The field is increasingly recognizing that parameters of speech recognition are more relevant endpoints than pure tone endpoints. “There are many different ways to measure speech in noise understanding, and as a field, we are trying to find a consensus on the best endpoints and what the assessments for those endpoints should be,” continues Rutten.
Zebrafish screening assay
“Our discovery program utilized a zebrafish screening assay, which, through rounds of initial hit identification and subsequent SAR development, proved to be a powerful
demonstration of the strengths of phenotypic screening,” says Graham Johnson, PhD, COO and co-founder of Oricula Therapeutics.
This multidisciplinary research effort funded, in part by the NIH Blueprint Neurotherapeutics Network, paved the way for the identification and early development of ORC-13661, a small molecule that was patented by the University of Washington, and is exclusively licensed to Oricula Therapeutics.
ORC-13661 has excellent absorption and tissue distribution after oral administration, according to the company, and, in preclinical studies, protected hair cells in the inner ear from the hearing loss induced by the aminoglycoside family of antibiotics. Importantly, it does so without impairing the efficacy of the antibiotics or affecting hearing by itself. ORC-13661 has successfully completed SAD and MAD Phase I clinical testing in healthy human volunteers, and scientists at Oricula are currently planning Phase II proof-of-efficacy clinical trials.
Just like the hair cells in the mammalian cochlea, the zebrafish lateral line hair cells transduce mechanical deformation into an electrical signal and are sensitive to aminoglycoside-induced toxicity.
“The hair cells that are hidden in humans are exposed in zebrafish, so we basically turned the hearing problem inside out,” says Johnson. Studies on rodents revealed that ORC-13661 did not itself affect hearing but effectively protected against aminoglycoside-induced hair cell death. “The hypothesis was that if can find a molecule that blocks aminoglycoside toxicity in the zebrafish, that molecule could also block aminoglycoside toxicity in mammals,” adds Vince Groppi, PhD, CEO of Oricula.
The biology of the hair cells is conserved across species. “That conservation has preserved species-specific pharmacology that could have been wildly different but turned out that it is not,” points out Edwin W. Rubel, PhD, CSO and founder of Oricula, and professor emeritus in the departments of otolaryngology-head and neck surgery and physiology and biophysics at the University of Washington. Even though it was an organismal assay, the zebrafish assay was in fact cell-based, because the delivery of the aminoglycoside to the lateral line occurred from the extracellular media and did not rely on compounds to be injected or ingested or metabolized. “This is an organismal version of a cell-based assay,” says Groppi.
It has been known for a long time that one of the main ways that aminoglycosides enter hair cells is through the mechanoelectrical transduction (MET) channels of their stereocilia, which allow several types of cations to pass. “Early on we found that in zebrafish, fluorescently labeled aminoglycosides enter the stereocilia and rapidly fill up the entire hair cell, and we were able to watch as the hair cells died in a dose-dependent manner,” Rubel tells GEN.
Aminoglycosides are positively charged at physiological pH, and because of their low oral bioavailability, they are administered parenterally. They only penetrate well into the inner ear and the kidneys, which are also the two sites of aminoglycoside toxicity. “Aminoglycosides don’t have just one structure but due to their conformational flexibility they have many different structures, and that allows them to enter hair cells through their MET channel, whereas a rigid molecule would not get through,” explains Groppi. The kidneys, the other site of aminoglycoside cytotoxicity, do not have MET channels. “This is why our drug does not help prevent the generally reversible aminoglycoside-induced kidney toxicity,” he adds.
Even though aminoglycosides are an effective family of antibiotics, they have been underused because of their toxicity. “The impact of even a small amount of hearing loss or tinnitus (ringing in the ears) over a lifetime can be enormous,” explains Rubel, who along with a colleague published a seminal paper on hearing research in 2008 titled, “Three-dimensional imaging of the intact mouse cochlea by fluorescent laser scanning confocal microscopy.”
“Having discovered a molecule that we believe enables aminoglycosides to be used more widely, safely, and effectively, will not only save people from severe infections but will also prevent the morbidity that goes with treatment,” notes Johnson.
Better controlled human clinical trials
Jonathan Kil, MD, CEO and CMO of Sound Pharmaceuticals, tells GEN that his company is conducting a clinical trial in cystic fibrosis patients with acute respiratory infections that require intravenous aminoglycoside antibiotics, most notably tobramycin.
Despite clinical advances in managing cystic fibrosis, patients are still highly dependent on inhaled or intravenous tobramycin, an antibiotic that often causes high-frequency hearing loss, tinnitus, balance problems, and nephrotoxicity. Previous work at Sound Pharmaceuticals found that in adult cystic fibrosis patients, even one intravenous course of tobramycin caused ototoxicity, and the hearing loss and worsening of speech discrimination was more extensive four weeks after administration than at two weeks.
“That is significantly higher than in any other documented study,” says Kil, who adds that an ongoing Phase II clinical study is evaluating the safety and tolerability of SPI-1005, a proprietary oral formulation of ebselen that mimics glutathione peroxidase 1, the dominant catalytic enzyme in the mammalian cochlea, with several features that make it superior over other antioxidant compounds.
Historically, much of the ototoxicity work is based on retrospective reviews or limited prospective analyses. “Many of the past studies didn’t necessarily use rigorous methodologies and consistent time points of assessment,” explains Kil. Weaknesses of previous studies include the absence of a baseline, difficulties in quantitating disease progression, and the lack of systematic follow-up.
The published Sound Pharmaceuticals study, which revealed that audiometric assessments were more sensitive than the Tinnitus Functional Index and the Vertigo Symptoms Scale, was one of the first to use a rigorous set of inclusion and exclusion criteria and document baseline and two follow-ups after intravenous tobramycin administration.
The scarcity of successful clinical trials translates to a scarcity of literature in the field, and even though preclinical information is available, the utility of some of the data is limited with respect to extrapolating to human populations.
“One of the questions we always get asked by potential drug development partners and investors is whether the preclinical models that validate our target drug are in fact valid,” notes Kil. This shortcoming can only be satisfactorily addressed once rigorous clinical data will be generated. “Most publicly traded companies in our field suffer from a lack of truly positive randomized controlled trials, and in support of that, no one, including us, has completed a positive Phase III clinical trial,” he continues.
Sound Pharmaceutical scientists have recently initiated a first Phase III trial of SPI-1005 for Meniere’s disease at 16 sites in the United States. Previously, in Phase Ib and Phase IIb clinical trials, SPI-1005 improved tinnitus and sensorineural hearing loss in patients with Meniere’s disease, and the upcoming Phase III clinical trial will have hearing improvement as a primary endpoint and tinnitus reduction as a secondary endpoint.
“These challenges explain why as of now there are no FDA-approved drugs for hearing loss or tinnitus,” says Kil.
Article originally appeared on Genetic Engineering & Biotechnology News.
