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SENS-401 Effectively Reduces Severe Acoustic Trauma-Induced Hearing Loss in Male Rats With Twice Daily Administration Delayed up to 96 hours

Petremann, Mathieu*; Romanet, Charlotte*; Broussy, Audrey*; Van Ba, Christophe Tran*; Poli, Sonia; Dyhrfjeld-Johnsen, Jonas*

doi: 10.1097/MAO.0000000000002088
BASIC SCIENCE
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SDC

Hypothesis: SENS-401 (R-azasetron besylate) is effective against severe acoustic trauma-induced hearing loss.

Background: SENS-401 has calcineurin inhibiting properties and attenuates cisplatin-induced hearing loss in a rat model. Cisplatin-induced and acoustic trauma-induced hearing loss share common apoptotic pathways.

Methods: The dose–response relationship of SENS-401 (6.6 mg/kg BID, 13.2 mg/kg BID, 26.4 mg/kg QD) and treatment time-window (13.2 mg/kg BID starting 24, 72, and 96 h posttrauma) versus placebo for 28 days were evaluated in a male rat model of severe acoustic trauma-induced hearing loss (120 dB SPL, 2 h) using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) measures followed by cochlear outer hair cell (OHC) counting with myosin-VIIa immunolabeling.

Results: All SENS-401 doses improved ABR threshold shift and recovery, reaching statistical significance (p < 0.05) for ABR threshold recoveries after 28-days treatment. DPOAE amplitude loss and recovery improved markedly for 13.2 mg/kg BID SENS-401, reaching significance after 14 days (p < 0.05). Significant improvements in ABR threshold shifts/recovery and DPOAE amplitude loss occurred with up to 96-hours delay in initiating SENS-401 (p < 0.05), and in DPOAE amplitude recovery with up to 72-hours delay (p < 0.05). Significantly more surviving OHCs were present after SENS-401 treatment compared with placebo after 24 to 96-hours delay posttrauma, with up to 5.3-fold more cells in the basal cochlea turn.

Conclusions: In vivo data support the otoprotective potential of twice daily oral SENS-401. Improvements in hearing loss recovery make SENS-401 a promising clinical candidate for acoustic trauma-induced hearing loss, including when treatment is not initiated immediately.

*Sensorion, Montpellier, France

Consultant, Onex, Switzerland

Address correspondence and reprint requests to Jonas Dyhrfjeld-Johnsen, Ph.D., Sensorion, 375 rue du Professeur Joseph Blayac, 34080 Montpellier, France; E-mail: jonas.dyhrfjeld-johnsen@sensorion-pharma.com

Funding: None.

M.P., C.R., A.B., C.T.V.B., J.D.J., and the spouse of J.D.J. are employees of Sensorion. S.P. performed paid consulting services for Sensorion.

The authors disclose no conflicts of interest.

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