EP-4739318-A1 - AZASETRON FOR THE PRESERVATION OF RESIDUAL HEARING FOLLOWING COCHLEAR IMPLANTATION

Abstract

The present invention relates to azasetron or an analog of azasetron, or a pharmaceutically acceptable salt and/or solvate thereof, for use in the preservation of residual hearing following cochlear implantation in a subject in need thereof, wherein the subject has a hearing threshold at baseline in at least one ear corresponding to an unaided audiometric threshold at baseline greater than 65 dB, the unaided audiometric threshold being expressed as the average of at least 3 values each determined at a different frequency within the range from 0.25 kHz to 0.75 kHz.

Inventors

• HONNET, Géraldine
• LEMOINE, Margaux
• DELGADO BETANCOURT, Viviana
• GAY, ROBERT DANIEL
• PLANT, KERRIE
• SMYTH, DANIEL
• DUECK, Wolfram Frederick
• GOLDMAN, Denise Rachael

Assignees

• Sensorion
• Cochlear Limited

Dates

Publication Date

20260513

Application Date

20240703

Claims (13)

1. 1. Azasetron or an analog of azasetron, or a pharmaceutically acceptable salt and/or solvate thereof, for use in the preservation of residual hearing following insertion of a cochlear implant in a subject in need thereof, wherein the subject has a hearing threshold at baseline in at least one ear corresponding to an unaided audiometric threshold at baseline greater than 65 dB, the unaided audiometric threshold being expressed as the average of at least 3 values each determined at a different frequency within the range from 0.25 kHz to 0.75 kHz.
2. 2. Azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, for use according to claim 1, wherein the unaided audiometric threshold is expressed as the average of the values determined at 0.25 kHz, 0.5 kHz and 0.75 kHz.
3. 3. Azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, for use according to claim 1 or 2, wherein the unaided audiometric threshold is unaided pure-tone average (PT A).
4. 4. Azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, for use according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is selected from a besylate salt, a malate salt, and a hydrochloride salt.
5. 5. Azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, for use according to any one of claims 1 to 4, wherein azasetron is (/?)-azasetron, (,S')-azasetron, a mixture thereof, or a pharmaceutically acceptable salt and/or solvate thereof.
6. 6. Azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, for use according to any one of claims 1 to 5, wherein azasetron is (/?)-azasetron or a pharmaceutically acceptable salt and/or solvate thereof.
7. 7. Azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, for use according to any one of claims 1 to 6, wherein the pharmaceutically acceptable salt of azasetron is (A)-azasetron besylate.
8. 8. Azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, for use according to any one of claims 1 to 4, wherein the analog of azasetron is a benzoxazine compound or a pharmaceutically acceptable salt and/or solvate thereof, preferably selected from 6-chl oro-3, 4-dihydro-2-m ethyl-3-oxo-N- (3-quinuclidinyl)-2H-l,4-benzoxazine-8-carboxamide, 6-chl oro-3, 4-dihydro-2, 4- dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-benzoxazine-8-carboxamide, 6-chl oro-2- ethyl-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-l,4-benzoxazine-8- carboxamide, 6-bromo-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H- l,4-benzoxazine-8-carboxamide, 6-chl oro-3, 4-dihydro-2, 2, 4-trimethyl-3 -oxo-N- (3-quinuclidiny-l)-2H-l,4-benzoxazine-8-carboxamide, and pharmaceutically acceptable salts and/or solvates thereof.
9. 9. Azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, for use according to any one of claims 1 to 8, wherein azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, is for administration at a daily dose ranging from about 20 mg to about 200 mg.
10. 10. Azasetron or the analog of azasetron, or the pharmaceutically salt and/or solvate thereof, for use according to any one of claims 1 to 8, wherein azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, is for administration at a daily free base equivalent dose of about 40 mg or of about 60 mg.
11. 11. Azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, for use according to any one of claims 1 to 10, wherein azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, is for oral administration.
12. 12. Azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, for use according to any one of claims 1 to 10, wherein azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, is for local administration.
13. 13. Azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, for use according to any one of claims 1 to 12, wherein azasetron or the analog of azasetron, or the pharmaceutically acceptable salt and/or solvate thereof, is for administration from at least 3 days prior to insertion of the cochlear implant.

Description

AZASETRON FOR THE PRESERVATION OF RESIDUAL HEARING FOLLOWING COCHLEAR IMPLANTATION FIELD OF INVENTION [0001] The present invention relates to the preservation of residual hearing following insertion of a cochlear implant in a subject in need thereof. BACKGROUND OF INVENTION [0002] 466 million people worldwide have disabling hearing loss, with 900 million people worldwide expected to have disabling hearing loss by 2050 (World Health Organization (WHO) 2020). There are currently no medications approved by any regulatory agency to improve or treat hearing loss, and use of hearing aids and hearing implants, in particular cochlear implants, are the main treatment options. [0003] Cochlear implants started to be developed in the 1960s. Since that time, rapid advances in digital technology have led to the development of highly sophisticated devices that can deliver patterned auditory information at rapid rates to surviving auditory neurons. Their basic principle is based on the transformation of sound waves into an electrical signal by a processor. Equipped with an electrode, cochlear implants thus directly stimulate the intact auditory nerve in the cochlea. [0004] Originally, cochlear implants were only indicated for total congenital bilateral deafness in newborns and for profound acquired deafness in adults who could not achieve sufficient gain with conventional hearing aids. However, due to the improved performance and low complication rate of this technology, the indications for cochlear implants now extend to profound single ear hearing loss and severe high frequency hearing loss with residual hearing at low frequencies. [0005] Cochlear implantation is thus currently considered the "gold standard" treatment for severe to profound sensorineural hearing loss. However, one of the complications following the insertion of a cochlear implant is the loss of the residual hearing at low frequencies. Apart from purely surgical technical considerations that can reduce this risk, there are non-surgical factors that can help to improve rates of residual hearing preservation after cochlear implant surgery. Such non-surgical factors include the choice of electrode design and the use of corticosteroids, such as dexamethasone, for antiinflammatory action. [0006] Azasetron (also known as arazasetron) is a small molecule which is currently being investigated as a therapeutic and prophylactic treatment for sensorineural hearing loss (W02016/184900). In particular, azasetron is thought to be able to protect and preserve inner ear tissue from damage responsible for hearing impairment. Azasetron may thus be able to preserve residual hearing following insertion of a cochlear implant. It would be helpful to identify the subjects, recipients of a cochlear implant, most likely to benefit from the administration of azasetron. [0007] The Inventors have now obtained data indicating that azasetron preserves residual hearing in subjects being the recipient of a cochlear implant. In particular, the data indicate that subjects having a hearing threshold at baseline in at least one ear corresponding to an unaided audiometric threshold at baseline greater than 65 dB are more likely to benefit from the administration of azasetron. [0008] The present invention thus relates to azasetron or an analog of azasetron, or a pharmaceutically acceptable salt and/or solvate thereof, for use in the preservation of residual hearing following insertion of a cochlear implant in a subject in need thereof, in particular in a subject most likely to benefit from the administration of azasetron or an analog of azasetron, or a pharmaceutically acceptable salt and/or solvate thereof, such as a subject having a hearing threshold at baseline in at least one ear corresponding to an unaided audiometric threshold at baseline greater than 65 dB, the unaided audiometric threshold being preferably expressed as the average of at least 3 values each determined at a different frequency within the range from 0.25 kHz to 0.75 kHz. SUMMARY [0009] The present invention relates to azasetron or an analog of azasetron, or a pharmaceutically acceptable salt and/or solvate thereof, for use in the preservation of residual hearing following insertion of a cochlear implant in a subject in need thereof, wherein the subject has a hearing threshold at baseline in at least one ear corresponding to an unaided audiometric threshold at baseline greater than 65 dB, the unaided audiometric threshold being expressed as the average of at least 3 values each determined at a different frequency within the range from 0.25 kHz to 0.75 kHz. [0010] In some embodiments, the unaided audiometric threshold is expressed as the average of the values determined at 0.25 kHz, 0.5 kHz and 0.75 kHz. In some embodiments, the unaided audiometric threshold is unaided pure-tone average (PTA). [0011] In some embodiments, the pharmaceutically acceptable salt of azasetron or an analog thereof is selected from a besylate