San Diego-based Otonomy Inc.'s launch of the phase I/II trial for OTO-413, a sustained-exposure formulation of brain-derived neurotrophic factor (BDNF), in patients with hearing loss brought renewed investor attention to the company, consigned to the back burner after a late-stage failure.
The experiment is a randomized, double-blind, placebo-controlled, single ascending-dose study designed to evaluate the safety and exploratory efficacy of OTO-413 in patients with speech-in-noise hearing difficulty. Findings in neurotology have identified damage or loss of synaptic connections between inner ear hair cells and spiral ganglion neurons, known as cochlear synaptopathy, the company noted. Such pathology may also play a role in age-related and noise-induced hearing loss. Results are due in the second half of 2020.
When Otonomy is mentioned, it's typically a different therapy that comes to mind: Otividex. In the summer of 2017, more than seven years after first testing the Meniere's disease (MD) candidate in patients with the inner ear disorder, Otividex a sustained-exposure intratympanic steroid injection, proved no better than a placebo in reducing both the number and severity of vertigo episodes in the first of two phase III trials. A European twin of the U.S.-based trial and a separate phase II evaluation of the candidate in prevention of hearing loss for pediatric cancer patients at risk for ototoxicity from cisplatin chemotherapy was suspended along with the bid called Averts-1. CEO David Weber said he was "shocked and greatly disappointed" by the results. Wall Street was, too, and Otonomy's shares (NASDAQ:OTIC) lost 82% of their value on the day the news was disclosed, ending at $3.58. The stock never recovered, and was trading around $2.30 last week. (See BioWorld, Aug. 31, 2017.)
But since the blowup, Otividex has scored a positive second phase III trial, and data from an ongoing third phase III effort are expected in the first half of next year. Was the failed study an anomaly? Wainwright analyst Oren Livnat thinks so, using the word "outlier" instead. "We often see an extreme valuation discount in cases where a company has one positive and one negative phase III, with investors much more skeptical than they are about companies with no pivotal data at all," he pointed out. "In this case, we think sentiment is further impacted by a missed prior phase IIb primary endpoint as well." Still, he said he sees the scenario setting up for a "dramatic clinical turnaround" next year, Livnat said in an Aug. 29 report. "Further, we think proof-of-concept pipeline data for large untreated tinnitus and hearing loss conditions in the first half and second half of 2020, respectively, presents potential upside, and Otonomy has sufficient cash through all these catalysts." He called Wall Street "deaf" to prospects for Otonomy.
Others are warming to the story. During a conference call with investors on earnings at the start of August, Cowen analyst Stacy Ku had questions about pre-commercialization activities. "Beyond Otividex, obviously, we've had some experience with working with [ear, nose and throat specialists] in terms of their familiarity with buy-and-bill," Weber said, calling the practice "something relatively new with them, as we have learned through our work with Otiprio," though others such as ophthalmologists are "very familiar with it."
Otiprio (ciprofloxacin otic suspension) was first approved in late 2015 for pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement. In March 2018, U.S. regulators cleared the drug for acute otitis externa (AOE) in patients 6 months and older due to Pseudomonas aeruginosa and Staphylococcus aureus. Otiprio is the first single-dose antibacterial approved by the FDA for treating AOE. (See BioWorld, Dec. 14, 2015.)
MD is characterized by vertigo, hearing loss, and intermittent or constant tinnitus, and is believed to be due to a swelling or inflammation of the inner ear. The auditory symptoms of hearing loss (at low frequencies below 2,000 Hz) and tinnitus often involve a single ear. MD patients are typically diagnosed between 40 and 65 years of age. As patients get older, the hearing loss and/or tinnitus become worse. For the definitive diagnosis of MD, new American Academy of Otolaryngology-Head & Neck Surgery guidance requires documentation of ≥30 dB of low frequency hearing loss in at least one ear using pure tone audiometry (PTA). The upper limit of normal hearing sensitivity is 20 dB, and every 10 dB loss of hearing is deemed clinically relevant.
Making news recently in the MD space was Seattle-based Sound Pharmaceuticals Inc., which said the FDA granted fast track designation for SPI-1005 in the treatment. Data from two completed multicenter, randomized, placebo-controlled studies (phase Ib and IIb) served as the basis for the designation, and showed that oral delivery of SPI-1005 for 21 or 28 days improved tinnitus and restored sensorineural hearing loss. The experiments randomized 39 and 126 subjects, respectively, to placebo or active doses of SPI-1005, treating them for 21 or 28 days, respectively. Clinically relevant improvements in sensorineural hearing loss were determined using PTA and the words-in-noise test. The compound is a formulation of ebselen, which contains the mineral selenium and behaves like glutathione peroxidase, an enzyme that helps to rid the body of damaging chemicals caused by loud sounds.
Auris Medical Holding Ltd., of Hamilton, Bermuda, has AM-125 in early stage work. It's a spray formulation of betahistine, a small-molecule drug that acts as a partial H1 histamine receptor agonist and a H3 receptor antagonist. The compound increases inner ear and cerebral blood flow, histamine turnover and histamine release in the brain, and also the release of acetylcholine, dopamine and norepinephrine, leading to general brain arousal.