Day-90 data from a Phase IIa study of four dosing regimens of Frequency Therapeutics’ hearing loss treatment FX-322 in subjects with mild to moderately severe sensorineural hearing loss (SNHL) “did not demonstrate improvements in hearing measures versus placebo”, according to a company statement.

The disappointing results caused the company’s stock to drop as much as 72% in premarket trading on Tuesday morning. The data comes after the treatment achieved positive results in a Phase I trial testing a single dose regimen.

FX-322, Frequency’s front-running product candidate, is designed to trigger dormant progenitor cells in the ear to encourage the growth of new hair cells in the cochlea that are responsible for sensing and translating sound.

The Phase IIa trial was meant discern whether repeat dosing could enhance the effects of FX-322.

In the four-arm Phase IIa study, 95 subjects aged 18-65 were assessed for hearing improvement using Word Recognition (WR), Words-In-Noise (WIN), pure tone audiometry and other exploratory measures. All participants were dosed with a total of four weekly intratympanic injections in the eardrum. Some patients received four placebo shots or four shots of FX-322, while others received one, two or three doses of the drug, with placebo making up the remaining doses.

While WR scores improved across the board for all groups, repeated weekly injections were found to dampen the hearing benefit observed compared to previous single-injection studies.

Frequency stated there was no discernible hearing benefit of FX-322 over placebo in the trial.

The Phase IIa interim results also revealed an unexpected ostensible level of hearing benefit in the placebo group unseen in previous trials, indicating flaws and potential bias in the trial design.

“Patients, our subjects, they desperately need hearing solutions,” said the firm’s senior vice president of strategic marketing and new product planning Kevin Franck, PhD, as reported by Fierce Biotech. “When we communicated there were entry criteria of a depressed word score, we may have induced an unconscious bias in subjects who wanted to get into the trial.”

Despite the surprising results of the study, Frequency remains positive about its lead candidate.

“Our FX-322 interim Phase 2a clinical results were unexpected, especially given our prior published Phase 1/2 data. We have already gained important learnings from this study that will inform our future development efforts,” said Frequency’s president and chief executive officer David L. Lucchino.

“The results clearly demonstrated that a treatment regimen using four weekly injections is unfavourable and we will continue to move ahead with single-dose administrations in future studies. We believe in the potential of FX-322 given the demonstrated hearing signal and favourable safety profile observed with a single dose and in the future, we may evaluate re-treatment at longer intervals.”

The company also revealed confidence-boosting early results from a Phase Ib study in 33 patients with mild to moderate sensorineural hearing loss who received a dose of FX-322 in one ear, with the untreated ear as the control. 90 days after treatment, 34% of the patients logged a 10% or greater improvement in word recognition scores in their treated ear compared to the untreated ear.

Frequency plans to work through bias issues in its trial design, and is waiting on final results from the Phase IIa study as well as readouts from two more Phase Ib studies, which will inform next steps.

Final results from the Phase IIa trial will be reported in late Q2 2021, the company said.