Sound Pharmaceuticals Announces Positive Topline Results from SPI-1005 Phase 2b Trial

Sound Pharmaceuticals announced positive top-line results from a randomized, double-blind, placebo-controlled, multi-center Phase 2b study in Meniere's Disease (MD). The study consented 149 adult patients with active MD, including a hearing loss at baseline of >30 dB in one of three low frequencies, to receive either placebo, 200, or 400 mg SPI-1005 by mouth, twice daily for 28 days, with follow-up assessments at 4 and 8 weeks after the start of treatment. The pre-specified audiometric endpoints were to determine if SPI-1005 could improve hearing sensitivity or thresholds in dB by a clinically relevant difference vs placebo.

In the trial, clinically relevant improvements in hearing loss (≥10 dB gain from baseline at one low frequency) using pure-tone audiometry (PTA) were significantly higher in the 400 mg dose group vs placebo (61% vs 37%, p<0.023), a relative improvement of 65% over placebo at 8 weeks. Clinically relevant improvements in word recognition (≥10% increase in word recognition from baseline) using the words-in-noise test (WINT) also showed higher responses when compared to placebo (75% vs 56%, p<0.060), a relative improvement of 34% over placebo at 8 weeks. Secondary efficacy endpoints were also tested using stricter responder criteria involving PTA and WINT. Using stricter PTA criteria (≥10 dB gain from baseline at two adjacent low frequencies), the 400 mg dose group showed higher relative response rates (39% vs 20%, p<0.044), a 95% improvement over placebo. Using stricter WINT criteria (≥4 words improvement from baseline), the 400 mg dose group showed higher relative response rates (60% vs 34%, p<0.017), a 76% improvement over placebo. Results from the Intent-to-Treat (ITT) analysis showed that SPI-1005 was well-tolerated in the 124 patients that received at least one oral dose of study drug during the 28-day dosing period. No serious adverse events occurred, and the majority of adverse events were mild to moderate, and consistent with those observed in prior studies. A more detailed presentation of the ITT and Per-Protocol analyses will occur at a scientific meeting later this year.

"This clinical trial indicates that SPI-1005 may have the potential to significantly improve the loss of hearing and loss of word recognition in Meniere's, a complex and chronic inner ear disease," said Jonathan Kil, MD, Co-Founder and CEO.

Enrollment occurred at 14 sites across the US between Sept 2017 and March 2019 and involved 149 consented adults (22-75 yo). Eligible patients with active Meniere's Disease (MD) symptoms, including a ≥30 dB hearing loss at baseline in one of three tested low frequencies (250, 500 or 1000 Hz), were randomized (1:1:1) to either placebo or one of two oral doses of SPI-1005 (200 or 400 mg, twice daily). Each study arm (n=41-42 adults) received 28 days of treatment and had follow-up assessments at 4 and 8 weeks after the start of treatment. Clinically relevant improvements in sensorineural hearing loss were determined using PTA and WINT, two validated measures of hearing sensitivity and specificity that are administered by an audiologist; patient-reported quality-of-life outcomes of tinnitus were self-assessed using the Tinnitus Functional Index (TFI); and patient-reported outcomes of vertigo were self-assessed using the Vertigo Symptoms Scale (VSS). The improvement in PTA/WINT and TFI/VSS scores were compared between SPI-1005 dose groups and the placebo group.

The average age in the ITT population was 54.5 years (66 females and 58 males) and some study participants had been diagnosed with MD over 20 years before study enrollment. In the ITT analysis, statistically significant improvements were not observed in low frequency hearing loss and word recognition at 4 weeks when compared to placebo. Therefore, this Phase 2b study provides important data for the design of our future Phase 3 clinical trials. The results suggest both an effective dose of SPI-1005 (400 mg twice daily) and period of follow-up (8 weeks from the start of study drug) to be used as our primary endpoint in future pivotal studies where an active MD population is treated. The continued auditory improvement in the 400 mg dose group (from 47% at 4 weeks to 61% at 8 weeks) suggests the potential for a durable neurotologic effect of SPI-1005 treatment.

"We are very excited by the magnitude of the positive results of this trial in this diverse Meniere's disease population," said Dr. Paul Lambert, Lead Principal Investigator of the Phase 2b study. Dr. Lambert is a world renowned neurotologist, past President of the American Neurotologic Society, and the Chairman of the Dept. of Otolaryngology-Head & Neck Surgery at the Medical University of South Carolina in Charleston, SC.

MD is diagnosed by episodic vertigo, fluctuating hearing loss, and intermittent or constant tinnitus, and is thought to be due to a swelling or inflammation of the inner ear. The auditory symptoms of hearing loss (low frequencies below 2000 Hz) and tinnitus (roaring/ringing) often involve one ear. MD patients are typically diagnosed between 40-65 years of age. As patients age, the hearing loss and/or tinnitus become progressively 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 PTA. The upper limit of normal hearing sensitivity is 20 dB, and every 10 dB loss of hearing is considered clinically relevant. Loss of word recognition is a common complaint in MD, especially when tinnitus is also present. Currently, there are no FDA approved drug treatments for MD, or any other inner ear disease. MD is managed with low salt diets, thiazide diuretics, and oral or locally injected steroids. Unfortunately, this type of medical management or standard of care has not been proven to be effective.

SPI-1005 is an investigational new drug that contains ebselen, a small molecule that is a new chemical entity or NCE under FDA classification. Ebselen is a selenorganic compound that mimics and induces glutathione peroxidase (GPx) activity, and represents a novel class of anti-inflammatory. GPx activity is critical to several cell types and tissues in the inner ear, retina, brain, lung and kidney, and is often reduced during exposures to environmental insults. Loss of GPx activity has been shown to result in sensorineural hearing loss in multiple animal models. SPI-1005 is given orally and is being tested in several neurotologic indications including noise induced hearing loss and tinnitus, and two types of ototoxicity (hearing loss, tinnitus, dizziness or vertigo), due to aminoglycoside antibiotics (such as tobramycin), and due to platinum-based chemotherapy. In earlier clinical trials, SPI-1005 demonstrated strong proof-of-concept data supporting the potential treatment in preventing and treating noise induced hearing loss and Meniere's disease.

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