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NEW ORLEANS -- Intratympanic injection of a progenitor-cell activator led to significant improvement in hearing in a small number of patients with noise-induced or sudden sensorineural hearing loss (NIHL, SSNHL).

Overall, treatment with either of two doses of FX-322 did not improve pure-tone thresholds across the frequency range of 500 to 8,000 Hz as compared with placebo. However, patients treated with FX-322 had statistically significant improvement in word recognition versus the placebo group.

Additionally, four of 15 patients in the FX-322 cohort had consistent pure-tone improvement at 8,000 Hz, whereas no patient in the placebo group improved, reported Susan M. King, MD, of Ear Medical Group in San Antonio, at the American Academy of Otolaryngology-Head and Neck Surgery Foundation meeting.

"A hearing signal was identified, as we observed a 10-decibel improvement in thresholds at 8,000 Hertz in several FX-322-treated subjects," said King. "Several FX-322 subjects showed clinically meaningful word recognition and word-in-noise improvements versus no subject in the placebo group."

"Response was observed within 15 to 30 days, with continued improvement at 3 months. Subjects with noise-induced hearing loss and sudden sensorineural hearing loss showed improvement," she stated.

The sense of hearing originates from hair cells within the cochlea. In contrast to most species, mammalian hair cell loss is permanent because a subset of progenitor cells fails to divide and differentiate during hair cell development, King and colleagues noted in the background of their report.

FX-322 comprises two small molecules that target and activate preprogrammed but dormant progenitor cells. Once activated, the progenitor cells undergo asymmetric division to form an inactive progenitor cell and a functional target cell, which becomes an activated hair cell, restoring the natural state of the cochlea, said King.

In laboratory studies, FX-322 restored the regenerative potential of mouse and human progenitor cells in vitro, and stimulated development of hair cells when applied to ototoxin-damaged mouse tissue. A single intratympanic injection of FX-322 restored hair cells and auditory function within 1 month in mice with trauma-induced hearing.

Multiple studies confirmed that a single injection of FX-322 resulted in therapeutic levels of the drug within the cochlea. The highest concentration of the drug accumulated in the highest frequency range of the cochlea, said King.

The body of favorable laboratory evidence provided the basis for a clinical trial involving patients with NIHL or SSNHL. Eligible patients had mild or moderately severe hearing loss that had remained stable for at least 6 months. Investigators randomized 23 patients 2:1 to a single intratympanic injection of one of two doses of FX-322 or placebo. Patients returned for follow-up evaluations at 15, 30, 60, and 90 days. At each visit, patients were evaluated by otometry, audiometry, and laboratory measures.

No patient had worsening of hearing loss during the trial, said King. However, the results showed no pure tone improvement in the between-group comparison. Individual patient data showed that four patients in the FX-322 group had a 10-decibel improvement at 8,000 Hz at 90 days, whereas no patient in the placebo group improved.

"We feel that this is consistent with the finding that the highest concentration of the drug in the cochlea is in the high frequencies," said King.

The four patients who improved had poor word-recognition scores at enrollment. By day 90, the word-recognition score for each of the four had almost doubled, including one patient whose word recognition improved to near normal. King said she and her colleagues considered the improvements clinically meaningful because all of the patients had stable hearing loss at entry to the trial.

Analysis of word recognition at the group level, also showed statistically significant improvement in the FX-322 group versus the placebo group (P=0.010). The FX-322 cohort had a 20% improvement in word recognition by day 15, increasing to about 30% by day 90. Word recognition in the placebo group did not improve significantly from baseline at any follow-up assessment.

Words-in-noise evaluation assessed patients' word recognition within the context of variable noise-to-signal ratio, simulating a social event. The FX-322 group exhibited improvement by day 15 and continued to improve to the 90-day evaluation, although the difference from placebo did not achieve statistical significance (about 20% vs <5%, P=0.211).

The two doses of FX-322 evaluated in the trial did not differ with respect to outcomes.

Asked how the four "responders" differed from other patients, King said the only common factor among the four was more severe hearing loss at enrollment. She also noted that patients with NIHL and SSNHL had improvement.

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