Azasetron for preserving residual hearing after cochlear implantation

Abstract

The present invention relates to azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use in preserving residual hearing after cochlear implantation in subjects requiring it, having a baseline hearing threshold corresponding to a baseline unaided hearing threshold of 65 dB or higher in at least one ear (the unaided hearing threshold is expressed as the average of at least three values ​​determined at different frequencies within the range of 0.25 kHz to 0.75 kHz).

Description

[Technical Field]

[0001] This invention relates to the preservation of residual hearing after cochlear implantation in individuals who require it. [Background technology]

[0002] Globally, 466 million people suffer from hearing loss that impairs their daily lives, and it is projected that by 2050, 900 million people worldwide will suffer from hearing loss that impairs their daily lives (World Health Organization (WHO) 2020). Currently, there are no regulatory-approved medications to improve or treat hearing loss, and the use of hearing aids and auditory implants, particularly cochlear implants, is the primary treatment option.

[0003] Cochlear implants began to be developed in the 1960s. Since then, rapid advances in digital technology have led to the development of sophisticated devices that can rapidly transmit patterned auditory information to remaining auditory nerve cells. The basic principle is based on a processor converting sound waves into electrical signals. The cochlear implant, equipped with electrodes, then directly stimulates the intact auditory nerves in the cochlea.

[0004] Initially, cochlear implants were only indicated for neonates with complete congenital bilateral hearing loss and adults with severe acquired hearing loss, where conventional hearing aids could not achieve sufficient gain. However, due to improvements in the technology's performance and low complication rates, the indications for cochlear implants have now expanded to include severe unilateral hearing loss and severe high-frequency hearing loss with residual hearing in the low-frequency range.

[0005] Therefore, cochlear implantation is currently considered the "gold standard" treatment for moderate to severe sensorineural hearing loss. However, one complication after cochlear implantation is the loss of residual hearing in the low-frequency range. In addition to purely surgical technical considerations that can mitigate this risk, there are non-surgical factors that can help improve the rate of residual hearing preservation after cochlear implant surgery. Such non-surgical factors include the selection of electrode design and the use of corticosteroids such as dexamethasone for anti-inflammatory effects.

[0006] Azasetron (also known as arazasetron) is a small molecule compound currently being studied as a treatment and preventative agent for sensorineural hearing loss (International Publication No. 2016 / 184900). In particular, azasetron is thought to be able to protect and preserve inner ear tissue from damage that causes hearing impairment. Therefore, azasetron may be able to preserve residual hearing after cochlear implantation. It would be useful to identify the group most likely to benefit from azasetron administration, namely cochlear implant users.

[0007] The inventors have obtained data showing that azasetron preserves residual hearing in subjects with cochlear implants. In particular, the data indicates that subjects with a baseline hearing threshold corresponding to a baseline unaided hearing threshold of 65 dB or higher in at least one ear are more likely to benefit from azasetron administration.

[0008] Accordingly, the present invention relates to azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use in preserving residual hearing after cochlear implantation in subjects who are likely to benefit most from the administration of azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof, particularly subjects who have a baseline hearing threshold corresponding to a baseline unaided hearing threshold of 65 dB or higher in at least one ear (the unaided hearing threshold is preferably expressed as the average of at least three values ​​determined at different frequencies within the range of 0.25 kHz to 0.75 kHz). [Overview of the Initiative]

[0009] The present invention relates to azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use in preserving residual hearing after cochlear implantation in subjects requiring it, having a baseline hearing threshold corresponding to a baseline unaided hearing threshold of 65 dB or higher in at least one ear (the unaided hearing threshold is expressed as the average of at least three values ​​determined at different frequencies within the range of 0.25 kHz to 0.75 kHz).

[0010] In some embodiments, the uncorrected hearing threshold is expressed as the average of values ​​determined at 0.25 kHz, 0.5 kHz, and 0.75 kHz. In some embodiments, the uncorrected hearing threshold is the uncorrected pure-tone mean (PTA).

[0011] In some embodiments, pharmaceutically acceptable salts or analogs of azasetron are selected from besylates, malates, and hydrochlorides.

[0012] In some embodiments, azasetron is (R)-azasetron, (S)-azasetron, a mixture thereof, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, azasetron is (R)-azasetron or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, a pharmaceutically acceptable salt of azasetron is (R)-azasetron besylate.

[0013] In some embodiments, the azasetron analog is preferably 6-chloro-3,4-dihydro-2-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide, 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-benzoxazine-8-carboxamide, 6-chloro-2-ethyl-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8- The benzoxazine compound selected from carboxamide, 6-bromo-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide, 6-chloro-3,4-dihydro-2,2,4-trimethyl-3-oxo-N-(3-quinuclidinyl-1)-2H-1,4-benzoxazine-8-carboxamide, and pharmaceutically acceptable salts and / or solvates thereof, or pharmaceutically acceptable salts and / or solvates thereof.

[0014] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended for administration in a daily dose ranging from about 20 mg to about 200 mg. In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended for administration in a daily free base equivalent dose of about 40 mg or about 60 mg.

[0015] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is for oral administration. In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is for topical administration.

[0016] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended to be administered at least three days prior to cochlear implantation.

[0017] definition In this invention, the following terms have the meanings set forth below.

[0018] The terms "a" and "an" refer to one or more (i.e., at least one) of the grammatical objects of the article. For example, "one element" means one or more elements.

[0019] When "approximately" precedes a number, it encompasses a range of ±10% or less of the value of that number. The value referred to by the term "approximately" should also be understood to be specifically and preferably disclosed.

[0020] "Baseline" refers to the time prior to the initiation of administration to the subject of azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate as described herein, when setting conditions for parameters observed in the subject. For example, the baseline hearing threshold or pure-tone mean (PTA) for a given subject is the hearing threshold or PTA of that subject prior to the first administration of azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate as described herein.

[0021] As used herein, "PTA" refers to the pure tone average and corresponds to the average of the hearing thresholds determined at a series of fixed frequencies. For example, the pure tone average may correspond to the average of the hearing thresholds determined by pure tone audiometry at 0.250 kHz, 0.5 kHz, and 0.75 kHz.

[0022] "Pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to an excipient or carrier that does not cause side effects, allergic reactions, or other harmful reactions when administered to a subject. It includes all kinds of solvents such as dispersion media, coatings, antibacterial agents, antifungal agents, isotonic agents, and absorption delaying agents. Pharmaceutically acceptable excipients or carriers refer to all kinds of non-toxic solid, semi-solid or liquid fillers, diluents, encapsulating agents or formulation aids. For administration to humans, the formulation must meet the sterility, pyrogenicity, general safety and purity standards required by regulatory authorities such as the FDA (US Food and Drug Administration) or the EMA (European Medicines Agency).

[0023] "Subject" refers to a mammal, preferably a human. The mammal may be selected from cats, dogs, cows, pigs, horses, monkeys, apes, and humans. In particular, the mammal may be selected from cats, dogs, and humans. The mammal may be a primate, especially a human. The subject may be a "patient" who is waiting to receive or is receiving medical care, or who has been or is currently or will be the subject of medical treatment, or who is being observed for hearing loss, i.e., a mammal, preferably a human. A "subject in need of treatment" may be a subject who is waiting to receive or is receiving medical care, or who has been or is currently or will be the subject of medical treatment, or who is being observed for hearing loss.

[0024] "Therapeutic effective dose" refers to any amount or dosage of azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof that is intended to (i) preserve residual hearing after cochlear implantation, or (ii) prevent, slow, or reduce residual hearing loss after cochlear implantation, without causing significant adverse effects or adverse side effects in a patient requiring treatment.

[0025] "Treatment" or "treatment" refers to a therapeutic procedure or prophylactic treatment, or both, aimed at preventing or slowing (delaying progression) residual hearing loss after cochlear implantation. Therefore, "treatment" may be considered successful if, after administration of a therapeutically effective dose or amount of azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof, the patient demonstrates preservation of residual hearing and / or reduction of residual hearing loss, delay or minimization of its progression. Parameters for assessing treatment success are readily measurable by routine procedures familiar to physicians. Examples of methods for assessing residual hearing are specifically mentioned below. [Modes for carrying out the invention]

[0026] The present invention relates to azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use in preserving residual hearing after cochlear implantation in subjects requiring such preservation as described herein.

[0027] The term "cochlear implant insertion" as used herein may also be referred to as "cochlear implantation." In other words, the present invention relates to azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use in preserving residual hearing after cochlear implantation in subjects requiring such use as described herein.

[0028] In this specification, a person who has received or is receiving a cochlear implant may be referred to as a "cochlear implanter." In other words, the present invention relates to azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use in preserving residual hearing in a cochlear implanter subject as described herein.

[0029] As used herein, “preservation of residual hearing” may also be referred to as treatment of residual hearing loss (particularly preventive treatment or prevention). In other words, the present invention relates to azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment of residual hearing loss (particularly preventive treatment or prevention) after cochlear implantation in subjects requiring such treatment as described herein.

[0030] As used herein, “subject to be treated” or “subject requiring treatment” refers to a cochlear implant user (i.e., a person who has or will have a cochlear implant) whose residual hearing should be preserved (i.e., whose residual hearing loss should be prevented or minimized).

[0031] As used herein, “residual hearing” refers to the residual hearing assessed in the impaired ear (i.e., the ear suffering from hearing loss). In other words, residual hearing refers to the hearing that can be assessed in the impaired ear, i.e., the ear suffering from hearing loss. Therefore, “residual hearing loss” refers specifically to the loss of residual hearing that may occur after cochlear implantation.

[0032] Methods for evaluating hearing are well known to those skilled in the art. Examples of such methods include audiometry, particularly pure-tone audiometry corresponding to pure-tone air conduction audiometry and / or pure-tone bone audiometry, speech audiometry, auditory behavioral response audiometry, visually enhanced audiometry, and conditioned play audiometry. Other methods for evaluating hearing include ABR (auditory brainstem response) measurement, DPOAE (distortion component otoacoustic emissions) measurement, TEOAE (transient evoked otoacoustic emissions) measurement, speech-in-noise test, word comprehension test, tympanic membrane audiometry, acoustic reflection test, and tuning fork test.

[0033] In particular, residual hearing may be evaluated using an audiometric test, preferably a pure-tone audiometry test. Pure-tone audiometry is considered the gold standard test for evaluating hearing. Pure-tone audiometry is a standardized subjective audiometric test that determines air and / or bone conduction hearing thresholds (expressed in dB) at a given frequency or a set of fixed frequencies, usually selected within the range of 0.125 kHz to 8 kHz. The hearing thresholds determined at a given frequency may be plotted individually on an audiogram for each ear. For example, the hearing threshold (expressed as the average of the hearing thresholds at a given frequency or a set of fixed frequencies) may be defined as the lowest audible level measured in two out of three presentations to the subject.

[0034] Hearing thresholds, particularly those determined by pure-tone audiometry, are sometimes called pure-tone mean (PTA) thresholds, which correspond to the average of hearing thresholds determined at a series of fixed frequencies. For example, a pure-tone mean may correspond to the average of two, three, four, or more hearing thresholds determined at different frequencies. The frequencies may be selected from 0.125, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 8 kHz. In particular, the frequencies may be consecutive. Examples of consecutive frequencies selected from 0.125, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 8 kHz include 0.125, 0.25, and 0.75 kHz or 0.25, 0.5, and 0.75 kHz or 0.5, 0.75, and 1 kHz.

[0035] Residual hearing is assessed with the bare ear, that is, without the use of any hearing devices intended to amplify sound (e.g., behind-the-ear (BTE) hearing aids, behind-the-ear (RIC) hearing aids, in-the-ear (ITE) hearing aids, in-the-canal (ITC) hearing aids, or fully in-the-canal (CIC) hearing aids). Residual hearing in cochlear implant users is assessed without the assistance of the cochlear implant (e.g., after the device is turned off or after its external components are removed).

[0036] The preservation of residual hearing may be evaluated by performing hearing tests over time in the affected ear, particularly before and after cochlear implantation. When evaluated after cochlear implantation, residual hearing may be evaluated before the initial activation of the cochlear implant, which is usually performed approximately 2 to 4 weeks after cochlear implantation surgery. For example, residual hearing may be evaluated approximately 1, 2, 3, or 4 weeks after cochlear implantation. Alternatively or additionally, when evaluated after cochlear implantation, residual hearing may be evaluated after the initial activation of the cochlear implant, which is usually performed approximately 2 to 4 weeks after cochlear implantation surgery, as described above. For example, residual hearing may be evaluated approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after cochlear implantation.

[0037] Therefore, the preservation of residual hearing may be evaluated by determining hearing thresholds or audiometric thresholds (e.g., pure-tone mean or PTA) over time, particularly before and after cochlear implant insertion, as described above. Since cochlear implants are typically proposed for individuals experiencing hearing loss at higher frequencies (e.g., frequencies above 1 kHz), lower frequencies (e.g., 0.125, 0.25, 0.5, 0.75, and 1 kHz) are particularly important for evaluating residual hearing. Therefore, at the time of cochlear implantation, some cochlear implant wearers typically retain some hearing at lower frequencies (e.g., frequencies below 1 kHz). Thus, the preservation of residual hearing may be evaluated in particular by determining hearing thresholds or audiometric thresholds (e.g., pure-tone mean or PTA) at lower frequencies such as 0.125, 0.25, 0.5, 0.75, and / or 1 kHz.

[0038] For example, if, after cochlear implantation, the subject's hearing threshold in the naked ear or the hearing measurement threshold in the naked ear does not increase by 10 dB or more, especially when compared to the baseline hearing threshold in the naked ear or the hearing measurement threshold in the naked ear, then residual hearing may be considered preserved.

[0039] As used herein, the expression “no increase of 10 dB or more” encompasses the absence of any increase, decrease, or fluctuation of less than 10 dB. Therefore, according to such a definition, residual hearing would be considered preserved if, after cochlear implantation, the subject’s uncorrected hearing threshold or uncorrected hearing measurement threshold does not change or decrease, or increases by less than 10 dB, particularly compared to the baseline uncorrected hearing threshold or uncorrected hearing measurement threshold.

[0040] Furthermore, hearing preservation is calculated using the following method: Skarzynski et al. "Towards a consensus on a hearing preservation classification system." Acta Otolaryngol Suppl. 2013;(564):3-13 states that HP% = [1 - (Post-implantation PTA - Pre-implantation PTA / (Maximum PTA - Pre-implantation PTA))] × 100 (where PTA represents the pure tone mean). The evaluation may also be conducted by the following method. Classification may be established based on the calculated hearing preservation rate (HP%) (here, a hearing preservation rate of more than 75% corresponds to complete or near-complete preservation (HP1), a hearing preservation rate of more than 25% but less than 75% corresponds to partial preservation (HP2), a hearing preservation rate in the range of 0-25% corresponds to minimal preservation (HP3), and hearing that cannot be measured corresponds to hearing loss or deafness (HP4)).

[0041] Alternatively, residual hearing may be considered preserved if, after cochlear implantation, the subject's uncorrected hearing threshold or uncorrected hearing measurement threshold is less than 85 dB, particularly at 0.125 kHz, 0.25 kHz, and / or 500 kHz.

[0042] As used herein, “cochlear implant” refers to an electronic auditory device that stimulates the auditory nerve by electrodes placed in the cochlea of ​​the inner ear. The cochlear implant processes sound and speech and sends it to the brain, thus enabling the production of a useful auditory sensation. A cochlear implant generally consists of two main components: External components including microphone / receiver, sound processor (or speech processor) and transmitter system, and • Internal components including a receiver stimulator that receives signals from external components and converts them into electrical impulses, and an electrode array (sometimes simply called "electrodes") which is a group of electrodes that collects impulses from the stimulator and sends them to various areas of the auditory nerve. It consists of.

[0043] There are various designs and types of cochlear implants. In particular, various types of electrodes can be attached to cochlear implants, and these can be straight, curved, or proximal to the cochlear axis, and come in a range of lengths from short to long.

[0044] In some embodiments, cochlear implants are specifically designed to preserve residual hearing. Factors such as the type, length, and position of electrodes may be taken into consideration in the selection of a cochlear implant, all of which play an important role in minimizing damage to the existing auditory structure and thus preserving residual hearing.

[0045] In some embodiments, the cochlear implant has a slim, straight electrode. An example of a cochlear implant having a slim, straight electrode is the Nucleus® CI-622 cochlear implant (Cochlear®).

[0046] In some embodiments, the subjects requiring treatment suffer from sensorineural hearing loss. Examples of causes of sensorineural hearing loss include genetic factors, ototoxic compounds, exposure to excessive noise (e.g., noise above approximately 70 dB, 80 dB, 90 dB, 100 dB, 110 dB, 120 dB, or 130 dB) or blast exposure, aging, inflammation, inner ear infections (e.g., viral and bacterial infections), autoimmune conditions (e.g., autoimmune inner ear diseases), vascular disorders, diseases (including, but not limited to, hypertension and diabetes), head trauma, and tumors.

[0047] In some embodiments, the sensorineural hearing loss is unilateral; that is, in some embodiments, only one ear of the person requiring treatment is affected by sensorineural hearing loss. In some embodiments, the sensorineural hearing loss is bilateral; that is, in some embodiments, both ears of the person requiring treatment are affected by sensorineural hearing loss.

[0048] In some embodiments, the subject requiring treatment has not yet received a cochlear implant. In some embodiments, the subject requiring treatment has already received a cochlear implant.

[0049] In some embodiments, subjects requiring treatment may be more severely affected, with a baseline uncorrected hearing threshold exceeding 65 dB.

[0050] "Naked-ear hearing threshold" means determining the hearing threshold without using any hearing device, such as any hearing aids intended to amplify sound. For cochlear implant wearers, the naked-ear hearing threshold is determined after the device is turned off or its external components are removed.

[0051] According to the present invention, the baseline hearing threshold is determined in at least one ear. In subjects with unilateral hearing loss, the baseline hearing threshold is determined in the impaired ear.

[0052] "Baseline hearing threshold" means the hearing threshold of a subject before any administration of azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof as described herein. In some embodiments, the baseline hearing threshold corresponds to the hearing threshold of a subject before any administration of azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof as described herein, and before cochlear implantation.

[0053] In some embodiments, the unaided hearing threshold is expressed as the average of at least two, preferably at least three, values ​​determined at different frequencies in the range of 0.125 kHz to 4 kHz, preferably 0.125 kHz to 2 kHz, and more preferably 0.125 kHz to 1 kHz. In some embodiments, the unaided hearing threshold is expressed as the average of at least two, preferably at least three, values ​​determined at different frequencies selected from 0.125 kHz, 0.25 kHz, 0.5 kHz, 0.75 kHz, 1 kHz, 2 kHz, 3 kHz, and 4 kHz. In particular, the unaided hearing threshold may be expressed as the average of values ​​determined at two or more, preferably three or more, consecutive frequencies selected from 0.125 kHz, 0.25 kHz, 0.5 kHz, 0.75 kHz, 1 kHz, 2 kHz, 3 kHz, and 4 kHz. Examples of two consecutive frequencies selected from 0.125kHz, 0.25kHz, 0.5kHz, 0.75kHz, 1kHz, 2kHz, 3kHz, and 4kHz include 0.125kHz and 0.25kHz, 0.25kHz and 0.5kHz, 0.5kHz and 0.75kHz, and 0.75kHz and 1kHz.

[0054] In some embodiments, the hearing threshold for the unaided ear is expressed as the average of at least two, preferably at least three, values ​​determined at different frequencies within the range of 0.25 kHz to 0.75 kHz.

[0055] In some embodiments, the uncorrected hearing threshold is expressed as the average of at least two, preferably at least three, values ​​determined at different frequencies selected from 0.25 kHz, 0.5 kHz, and 0.75 kHz, respectively. In some embodiments, the uncorrected hearing threshold is expressed as the average of values ​​determined at 0.25 kHz, 0.5 kHz, and 0.75 kHz.

[0056] In some embodiments, the hearing threshold for uncorrected hearing is the pure-tone mean (PTA) for uncorrected hearing.

[0057] In some embodiments, the subject requiring treatment has a baseline hearing threshold corresponding to a baseline pure-tone mean (PTA) greater than 65 dB (the PTA is expressed as the average of at least three values ​​determined at different frequencies within the range of 0.25 kHz to 0.75 kHz, preferably the average of values ​​determined at 0.25 kHz, 0.5 kHz, and 0.75 kHz).

[0058] In some embodiments, the unaided hearing threshold is expressed as a value determined at a single frequency within the range of 0.125kHz to 4kHz, preferably 0.125kHz to 2kHz, and more preferably 0.125kHz to 1kHz. In some embodiments, the unaided hearing threshold is expressed as a value determined at a single frequency selected from 0.125kHz, 0.25kHz, 0.5kHz, 0.75kHz, 1kHz, 2kHz, 3kHz, and 4kHz. In some embodiments, the unaided hearing threshold is expressed as a value determined at 0.125kHz, 0.25kHz, 0.5kHz, 0.75kHz, or 1kHz. In some embodiments, the unaided hearing threshold is expressed as a value determined at a single frequency within the range of 0.25kHz to 0.75kHz. In some embodiments, the unaided hearing threshold is expressed as a value determined at a single frequency selected from 0.25kHz, 0.5kHz, and 0.75kHz. In some embodiments, the uncorrected hearing threshold is expressed as a value determined at 0.25 kHz, 0.5 kHz, or 0.75 kHz. In some embodiments, the uncorrected hearing threshold is expressed as a value determined at 0.5 kHz.

[0059] In some embodiments, the uncorrected hearing thresholds described herein are determined by pure-tone audiometry, particularly air conduction pure-tone audiometry (or pure-tone air conduction audiometry).

[0060] In some embodiments, the subjects requiring treatment are children, i.e., subjects under 21, 20, 19, or 18 years of age. In some embodiments, the subjects requiring treatment are children at least 12, 18, 24, or 36 months of age. In some embodiments, the subjects requiring treatment are adults, i.e., subjects 18, 19, 20, or 21 years of age or older. In some embodiments, the subjects requiring treatment are at least 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 years of age. In some embodiments, the subjects requiring treatment are 18 years of age or older, 20 years of age or older, 25 years of age or older, 30 years of age or older, 40 years of age or older, 50 years of age or older, 60 years of age or older, or 70 years of age or older.

[0061] In some embodiments, the subject requiring treatment is female. In some embodiments, the subject requiring treatment is male.

[0062] The azasetron (also known as the azasetron) is given by equation (I): [ka] (In the formula, * represents a compound of an (R)-enantiomer (or (+)-enantiomer), an (S)-enantiomer (or (-)-enantiomer), or a racemic or non-racemic mixture of (R)- and (S)-enantiomers (corresponding to a mixture of (+)- and (-)-enantiomers)).

[0063] Therefore, azasetron corresponds to N-(1-azabicyclo[2.2.2]octan-3-yl)-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide.

[0064] As mentioned above, azasetron has a single chiral center that can give rise to two stereoisomers. In some embodiments, azasetron is racemic azasetron or its pharmaceutically acceptable salts and / or solvates.

[0065] In some embodiments, azasetron is the (R)-enantiomer of azasetron or a pharmaceutically acceptable salt and / or solvate thereof. The (R)-enantiomer of azasetron is called (R)-azasetron or (+)-azasetron, and is given by formula (R)-I: [ka] It corresponds to.

[0066] Examples of processes that can be used to synthesize (R)-azasetron or its pharmaceutically acceptable salts and / or solvates are well known in the art (see, for example, Chinese Patent Applications Nos. 101786963 and 104557906). In some embodiments, the synthesis of (R)-azasetron or its pharmaceutically acceptable salts and / or solvates involves ab initio synthesis and / or chiral resolution. In some embodiments, when ab initio synthesis of (R)-azasetron or its pharmaceutically acceptable salts and / or solvates is performed, at least one racemic starting compound and / or intermediate compound is substituted with a chiral compound.

[0067] In some embodiments, azasetron is the (S)-enantiomer of azasetron or a pharmaceutically acceptable salt and / or solvate thereof. The (S)-enantiomer of azasetron is called (S)-azasetron or (-)-azasetron, and is given by the formula (S)-I: [ka] It corresponds to.

[0068] In some embodiments, azasetron includes compounds of formula I, preferably formula (R)-I, and all their polymorphs, crystalline and crystal habits, as well as isotopically labeled compounds of formula I, preferably formula (R)-I.

[0069] Azasetron or its analogues described herein may be in the form of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts of azasetron or its analogues include its acid addition salts. Preferred acid addition salts are formed from acids that form non-toxic salts. Examples of acid addition salts include besilates, hydrochlorides / chlorides, malates, benzoates, ethane-1,2-disulfonates, fumarates, tartrates, acetates, adipates, ascorbicates, aspartates, bicarbonates / carbonates, bisulfates / sulfates, borates, cansilates, citrates, cyclamates, edisylates, esylates, ethanesulfonates, formates, gluceptates, glucons, glucurons, glutamates, hexafluorophosphates, and hibenzates. Examples include hydrobromide / bromides, hydroiodide / iodides, isethionates, lactates, maleates, malons, mesylates, methylsulfates, naphthylates, 2-napsylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, sugarates, stearates, succinates, tannates, p-toluenesulfonates, tosylates, trifluoroacetates, and xinofoates.

[0070] pharmaceutically acceptable salts of azasetron may be prepared by reacting azasetron with a desired acid, or by converting one salt of azasetron to another salt by reaction with a suitable acid or by a suitable ion exchange column. All of these reactions are typically carried out in solution. The salt may be recovered by precipitation from the solution and filtration, or by evaporation of the solvent. The degree of ionization in the salt may vary from complete ionization to non-ionization (where cocrystal formation occurs).

[0071] In some embodiments, the azasetron or analogues described herein are in the form of pharmaceutically acceptable salts selected from besilates, hydrochlorides, malates, benzoates, ethane-1,2-disulfonates, fumarates, and tartrates, more preferably besilates, hydrochlorides, malates, and benzoates, and even more preferably besilates, hydrochlorides, and malates.

[0072] As used herein in relation to azasetron or its analogues, “pharmaceutically acceptable solvate” refers to a molecular complex comprising azasetron or its analogue and one or more pharmaceutically acceptable solvent molecules, such as ethanol or water, in stoichiometric or quasi-stoichiometric amounts. The term “hydrate” (as in “pharmaceutically acceptable hydrate”) may be used specifically when the solvent is water.

[0073] In some embodiments, azasetron is (R)-azasetron besylate, (R)-azasetron hydrochloride, (R)-azasetron malate, (R)-azasetron benzoate, (R)-azasetron ethane-1,2-disulfonate, (R)-azasetron fumarate and / or (R)-azasetron tartrate. In some embodiments, azasetron is (R)-azasetron besylate, (R)-azasetron hydrochloride, (R)-azasetron malate and / or (R)-azasetron benzoate, and more preferably azasetron is (R)-azasetron besylate, (R)-azasetron hydrochloride and / or (R)-azasetron malate.

[0074] In some embodiments, azasetron is (R)-azasetron besylate, also known as "SENS-401".

[0075] In some embodiments, the present invention relates to analogs of azasetron or pharmaceutically acceptable salts and / or solvates thereof for use in preserving residual hearing after cochlear implantation in subjects requiring the treatment described herein.

[0076] As used herein, "analog" refers to a modification or substitution of one or more chemical moieties on the parent compound, i.e., azacetron, and may include its functional derivatives, positional isomers, tautomers, zwitterions, enantiomers, diastereomers, racemates, homologs or stereochemical mixtures.

[0077] In some embodiments, the analog of azacetron is a benzoxazine compound or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the analog of azacetron is of formula (II):

Chemical formula

Chemical formula

Chemical formula

[0078] In some embodiments, analogs of azasetron include 6-chloro-3,4-dihydro-2-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide, 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-benzoxazine-8-carboxamide, and 6-chloro-2-ethyl-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzo The benzoxazine compounds include or are selected from the group comprising xazine-8-carboxamide, 6-bromo-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide, 6-chloro-3,4-dihydro-2,2,4-trimethyl-3-oxo-N-(3-quinuclidinyl-1)-2H-1,4-benzoxazine-8-carboxamide and their pharmaceutically acceptable salts or solvates.

[0079] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended for administration in a therapeutically effective dose.

[0080] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended to be administered in a daily dose ranging from about 20 mg to about 200 mg.

[0081] As used herein, the free base-equivalent dose refers to the dose of the active ingredient itself, i.e., azasetron or an azasetron analogue, and not to its pharmaceutically acceptable salt and / or solvate form. Therefore, compositional changes of azasetron or a pharmaceutically acceptable salt and / or solvate of an azasetron analogue do not affect the administered free base-equivalent dose.

[0082] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended to be administered in free base equivalent doses ranging from about 0.1 to about 2 mg / kg / day (mg per kg of body weight per day), preferably from about 0.2 to about 1 mg / kg / day. In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended to be administered in free base equivalent doses of about 0.5, 0.6, 0.7, 0.8, 0.9 or 1 mg / kg / day.

[0083] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended for administration in a daily free base equivalent dose ranging from about 10 to about 500 mg, preferably about 20 to about 200 mg, more preferably about 30 to about 100 mg, and even more preferably about 40 to about 60 mg. In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended for administration in a daily free base equivalent dose of about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, or 120 mg. In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended for administration in a daily free base equivalent dose of about 40 mg or about 60 mg.

[0084] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended for administration at least once daily, preferably twice daily. In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended for administration over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended for administration over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks. In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended for administration over a period of at least 1, 2, 3, 4, 5, or 6 months.

[0085] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof can be administered systemically.

[0086] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof can be administered orally. Therefore, in some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is suitable for oral administration. Examples of formulations suitable for oral administration include solids, liquids, and gels. Examples of solids suitable for oral administration include tablets, pills, capsules, soft gelatin capsules, hard gelatin capsules, caplets, compressed tablets, cachets, wafers, dispersible tablets and / or disintegrating tablets, powders, solids and effervescent tablets suitable for dissolving or suspending in liquid before oral administration. Examples of liquids suitable for oral administration include solutions, suspensions, drinking solutions, elixirs, single-dose liquids, liquid medicines, syrups, and concentrated solutions.

[0087] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof may be administered orally (immediate-acting or sustained-release), preferably as a tablet.

[0088] In some embodiments, tablets for oral administration contain or consist of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg of free base equivalents, preferably about 10 mg of free base equivalents of azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof, preferably (R)-azasetron besylate.

[0089] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof may be administered topically.

[0090] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof can be administered topically. Therefore, in some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is suitable for topical administration. Examples of formulations suitable for topical administration include sticks, waxes, creams, lotions, ointments, balms, gels, masks, and leave-on cleansers.

[0091] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof can be directly administered to the ear, such as the inner ear, middle ear, and / or outer ear, for example, by transtympanic or intratympanic administration. Therefore, in some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is suitable for direct administration to the ear, preferably the inner ear, for example, by transtympanic or intratympanic administration. Examples of formulations suitable for such administration include otowicks, round window catheters, various gels, foams, fibrins, emulsions, solutions, patches, or other drug carriers, which are placed in the ear and filled with azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof.

[0092] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof may be administered at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days prior to cochlear implantation (i.e., may be administered first).

[0093] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended to be administered together with at least one further pharmaceutically active agent.

[0094] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof may be administered concurrently, separately, or sequentially with the at least one further pharmaceutically active agent.

[0095] In some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof may be administered separately from at least one further pharmaceutically active agent.

[0096] In some embodiments, the further pharmaceutically active agent is a corticosteroid. Therefore, in some embodiments, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof is intended to be administered together with at least one corticosteroid. For example, the corticosteroid may be selected from oral corticosteroids and / or intratympanic corticosteroids. In some embodiments, the corticosteroid is an oral corticosteroid. Examples of oral corticosteroids include dexamethasone, methylprednisolone, prednisone, and prednisolone. In some embodiments, the corticosteroid is an intratympanic corticosteroid. Examples of intratympanic corticosteroids include dexamethasone, prednisone, hydrocortisone, betamethasone, and methylprednisolone.

[0097] Another object of the present invention is a method for preserving residual hearing after cochlear implantation in a subject requiring the treatment described herein, comprising administering to the subject azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof as described herein.

[0098] Another object of the present invention is a method for treating, in particular preventing, residual hearing loss after cochlear implantation in a subject requiring the treatment described herein, comprising administering to the subject azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof as described herein.

[0099] In some embodiments, the method further includes a step of determining whether the subject requiring treatment is likely to react with azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof.

[0100] In some embodiments, the step of determining whether a subject requiring treatment is likely to react to azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof includes evaluating the hearing threshold of the subject at baseline as described herein.

[0101] In some embodiments, evaluating the baseline hearing threshold includes evaluating the baseline pure-tone mean (PTA) as described herein. Examples of methods for evaluating the baseline PTA are mentioned herein.

[0102] In some embodiments, subjects readily reacting with azasetron or an analogue of azasetron or its pharmaceutically acceptable salts and / or solvates are subjects having a pure-tone mean (PTA) at a baseline of 65 dB or higher (the PTA is expressed as the average of at least three values ​​determined at different frequencies in the range of 0.25 kHz to 0.75 kHz, preferably the average of values ​​determined at 0.25 kHz, 0.5 kHz, and 0.75 kHz).

[0103] Another object of the present invention is a pharmaceutical composition for use in preserving residual hearing after cochlear implantation in subjects requiring the treatment described herein, comprising azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof and optionally at least one pharmaceutically acceptable excipient.

[0104] Another object of the present invention is the use of azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a drug or kit for preserving residual hearing after cochlear implantation in subjects requiring the treatment described herein.

[0105] In some embodiments, the pharmaceutical composition, drug, or kit is intended to be administered together with at least one further pharmaceutically active agent described herein. [Brief explanation of the drawing]

[0106] [Figure 1] This scheme describes a Phase IIa open-label, randomized controlled study involving adult participants with impaired hearing who had a preoperative hearing threshold in an ear with impaired hearing that was 80 dB or less (i.e., ≤80 dB) at 500 Hz, who met the locally approved indications for the Nucleus® CI-622 (Cochlear®) cochlear implant, and who consented to its implantation. [Examples]

[0107] The present invention is further illustrated by the following examples.

[0108] A Phase IIa multicenter, randomized, controlled, open-label study was initiated to investigate repeated twice-daily dosing of (R)-azasetron in adult participants administered at least 7 days prior to cochlear implantation. In addition to its primary objective of evaluating the presence of (R)-azasetron in the participants' perilymph, the Phase IIa study also aims to (i) evaluate the efficacy of (R)-azasetron in preserving residual hearing in subjects undergoing cochlear implantation surgery at the end of the treatment period and at the end of the study follow-up, and (ii) evaluate the safety and tolerability of (R)-azasetron throughout the entire study.

[0109] Hereafter, the term "SENS-401" refers to the investigational drug (R)-azasetron (administered to participants enrolled in this study as (R)-azasetron besylate).

[0110] material and method Participants included in this study Potential participants are adults aged 18 or older who have a preoperative threshold level in a impaired ear that shows an uncorrected hearing threshold of 80 dB or less (i.e., ≤80 dB) at 500 Hz, who meet the locally approved indications for the Nucleus® CI-622 (Cochlear®) cochlear implant, and who have already given their consent for implantation prior to study enrollment.

[0111] This study will enroll a total of 27 participants, who will be randomized on day 1 to either Arm A (participants who will receive SENS-401 for 7-13 days before cochlear implant surgery and for 5-6 weeks after surgery) or Arm B (participants who will not receive treatment with SENS-401).

[0112] Residual hearing (i.e., residual hearing at low frequencies in the impaired ear) is evaluated using pure-tone audiometry, particularly pure-tone air conduction audiometry, in an unprotected state (i.e., without any hearing aids). After cochlear implantation, residual hearing of the cochlear implant wearer is evaluated with the device powered off.

[0113] Pure-tone audiometry is a behavioral subjective test used to determine hearing thresholds (expressed in decibels, or dB). Air conduction hearing thresholds are typically measured using headphones for sound stimuli at a set frequency range of 0.125 kHz to 8 kHz. Bone conduction hearing thresholds are then typically measured using an oscillator-equipped headband for sound stimuli at a set frequency range of 0.25 to 4 kHz. Hearing thresholds, particularly those determined by pure-tone audiometry, are sometimes referred to as pure-tone mean audiometry (PTA) (which corresponds to the average of hearing thresholds determined at a set of fixed frequencies).

[0114] In this study, pure-tone air conduction hearing thresholds are determined at 0.125, 0.25, 0.5, 0.75, 1, 2, 3, and 4 kHz for the impaired ear to which a cochlear implant will be placed. Since cochlear implants are typically proposed for individuals experiencing hearing loss at higher frequencies, lower frequencies (e.g., 0.25, 0.5, and 0.75 kHz) are particularly important for assessing residual hearing. Therefore, at the time of cochlear implantation, cochlear implant wearers tend to retain some degree of hearing at lower frequencies. Because the most common type of residual hearing is residual hearing at lower frequencies, pure-tone air conduction hearing thresholds at lower frequencies (i.e., 0.25, 0.5, and 0.75 kHz) are particularly important for assessing residual hearing.

[0115] In this study, bone conduction hearing thresholds were determined at 0.25, 0.5, 0.75, 1, 2, 3, and 4 kHz for the impaired ear to which a cochlear implant was placed.

[0116] Pure-tone audiometry will be performed for all participants as described above: at screening, on day 1 after randomization (before the first dose of SENS-401 for participants enrolled in Arm A), at the visit on day 49, and at the end of the study visit (day 105).

[0117] The hearing threshold determined on day 1 (i.e., before any SENS-401 administration and before cochlear implant implantation between days 8 and 14) is defined as the baseline hearing threshold. Accordingly, the pure-tone mean (PTA) determined on day 1 (i.e., before any SENS-401 administration and before cochlear implant implantation between days 8 and 14) is defined as the baseline PTA. The baseline PTA is preferably expressed as the average of the hearing thresholds (in dB) determined at 0.25, 0.5, and 0.75 kHz (air conduction).

[0118] A higher pure-tone mean tautness (PTA) corresponds to a higher hearing threshold and therefore to lower hearing. An increase in PTA over time in a subject generally corresponds to hearing loss. Conversely, a lower PTA corresponds to a lower hearing threshold and therefore to better hearing. A decrease in PTA over time in a subject generally corresponds to hearing improvement.

[0119] For participants in this study, a time-dependent decrease in the uncorrected pure-tone mean (PTA) of less than 10 dB or a time-dependent increase in the uncorrected PTA is defined as preservation of residual hearing. Conversely, for participants in this study, a time-dependent increase in the uncorrected PTA of 10 dB or more may be defined as residual hearing loss, i.e., residual hearing impairment.

[0120] In addition, the exclusion criteria that would prevent participation in this study include, in particular, • Any treatment known to be ototoxic at present or in the past six months prior to study enrollment (e.g., aminoglycosides, cisplatin, quinine, etc.) (loop diuretics at usual therapeutic doses are permitted). • Radiographic evidence of bony closure of the round window membrane on preoperative high-resolution CT (computed tomography) images of the temporal bone. • Loss of cochlear flow signal on preoperative MRI (magnetic resonance imaging) suggesting cochlear fibrosis or ossification. These are some examples.

[0121] Drug administration After obtaining written informed consent and completing the screening procedure, eligible participants will be randomized on day 1 in a 2:1 ratio to either arm A (SENS-401 arm) or arm B (control arm) (18 participants in arm A and 9 participants in arm B).

[0122] Participants in Arm A (SENS-401 Arm) will be administered SENS-401 twice daily 7–13 days (days 8–14) prior to their scheduled cochlear implant surgery. Participants in Arm A (SENS-401 Arm) will continue to take SENS-401 twice daily, including the day of surgery and until they visit the hospital on day 49. Thus, SENS-401 will be administered for 7 weeks (49 days). SENS-401 is administered orally twice daily in a BID (twice daily) dose of 43.5 mg, corresponding to a total daily dose of 87 mg (60 mg free base equivalent).

[0123] Participants in Arm B (control arm) will not receive SENS-401. Participants in Arm B (control arm) will similarly undergo their planned cochlear implant surgery (days 8-14) and return for follow-up visits on day 49 and at the end of the study (day 105).

[0124] All participants will undergo cochlear implant surgery between day 8 and day 14 to receive a Nucleus® CI-622 cochlear implant (Cochlear®).

[0125] Participants in either arm (SENS-401 arm or control arm) may receive topical corticosteroids during cochlear implant surgery.

[0126] Target monitoring and purpose Participants enrolled in this study will be monitored at their initial visit between day -42 and day -1 (screening), followed by visits on day 1 (D1 - randomization), day 49 (±7 days), and day 105 (±21 days) (follow-up visits indicating the end of the study or end-of-surgery). Furthermore, participants will receive a Nucleus® CI-622 cochlear implant (Cochlear®) between days 8 and 14. For the convenience of the participants, the visits on day 49 and day 105 (EOS) should, if not necessarily, coincide with standard treatment visits for power-on and programming of the cochlear implant, respectively. Monitoring will include audiometry (pure-tone audiometry), immitance audiometry, and otoscopy. Electrocochleography will be performed during cochlear implantation surgery. For participants taking SENS-401 (Arm A), blood samples will be collected on the day of cochlear implant surgery, and perilymph samples will be collected during the cochlear implant surgery. Furthermore, participants will be closely monitored for adverse events throughout the study.

[0127] The primary objective of this study is to detect the presence of SENS-401 in the perilymph of participants undergoing cochlear implant surgery 7 days after oral administration of SENS-401. SENS-401 concentrations in perilymph and plasma samples of participants undergoing cochlear implant surgery will be measured and compared 7 days after oral administration of SENS-401.

[0128] Further objectives include (i) evaluating the effectiveness of repeated oral administration of SENS-401 to prevent residual hearing loss at low frequencies in participants undergoing cochlear implant surgery at visits on day 49 and day 105 (EOS), and (ii) evaluating the safety and tolerability of SENS-401 throughout the entire duration of this study. In particular, effectiveness can be assessed by determining the change from baseline in hearing thresholds at 0.25, 0.5, and 0.75 kHz in the cochlear implanted ear after repeated administration of SENS-401, which will be assessed by pure-tone audiometry at visits on day 49 and day 105 (EOS). Pure-tone audiometry will be performed in participants on days 49 and 105 with the cochlear implant powered off.

[0129] Monitoring also includes immittance audiometry, otoscopy, and electrocochleography (ECochG). Immittance audiometry assesses middle ear function through three steps: static immittance, tympanostomy, and measurement of acoustic reflection threshold sensitivity. Tympanostomy examines the condition of the middle ear and the mobility of the eardrum and conduction bone by creating changes in air pressure in the ear canal. Otoscopy allows for evaluation of the structure of the ear canal, eardrum, and middle ear. Otoscopy is part of the standard treatment to rule out possible external ear abnormalities such as otitis media or tympanostomy perforation. Electrocochleography (ECochG) records the electrical potentials generated in the inner ear and auditory nerve in response to acoustic stimuli.

[0130] result For all participants with cochlear implants, residual hearing was assessed before (day 1–baseline) and immediately after (day 49) the treatment period. Hearing thresholds were determined across the entire test frequency range of 0.125–4 kHz. Pure-tone mean (PTA) was calculated by averaging the hearing thresholds at three consecutive frequencies between 0.250–0.750 kHz. To assess the change in PTA from baseline to day 49, mean hearing thresholds at 0.25, 0.5, and 0.75 kHz were compared.

[0131] For the purposes of this study, a responder (i.e., a participant whose residual hearing was preserved) was defined as a pure-tone mean (PTA) increase of less than 10 dB from baseline. The response rate refers to the number of responders compared to the total number of participants in a given group.

[0132] The change in pure-tone mean (PTA) from baseline was determined both for the entire study population and for specific subgroups of subjects defined by their baseline pure-tone mean (PTA) values.

[0133] Table 1 below shows the mean pure-tone (PTA) measurements of participants in Arm A treated with SENS-401. PTA values ​​represent the mean hearing thresholds at frequencies of 0.25, 0.5, and 0.75 kHz. The mean baseline PTA for the entire study population was 66 dB. In a specific subgroup of participants with a baseline PTA above 65 dB, the mean baseline PTA was 75 dB. In another specific subgroup of participants with a baseline PTA of 65 dB or less, the mean baseline PTA was 52.5 dB. [Table 1]

[0134] Table 2 below shows the mean pure tone (PTA) measurements at day 49 for participants in arm A treated with SENS-401. PTA values ​​represent the mean hearing thresholds at frequencies of 0.25, 0.5, and 0.75 kHz. The mean PTA at day 49 for the entire study population was 78.2 dB. In a specific subgroup of participants with a baseline PTA above 65 dB, the mean PTA at day 49 was 78.9 dB. In another specific subgroup of participants with a baseline PTA of 65 dB or less, the mean PTA at day 49 was 77.1 dB. [Table 2]

[0135] Table 3 below shows the baseline pure-tone mean (PTA) measurements for participants in Arm B (control arm), who did not receive SENS-401. PTA values ​​represent the mean hearing thresholds at frequencies of 0.25, 0.5, and 0.75 kHz. For the entire study population, the mean baseline PTA was 69.6 dB. In a specific subgroup of participants with a baseline PTA above 65 dB, the mean baseline PTA was 74.2 dB. In another specific subgroup of participants with a baseline PTA of 65 dB or less, the mean baseline PTA was 65 dB. [Table 3]

[0136] Table 4 below shows the pure-tone mean (PTA) measurements at day 49 for participants in arm B (control arm) who did not receive SENS-401. PTA values ​​represent the mean hearing thresholds at frequencies of 0.25, 0.5, and 0.75 kHz. The mean PTA at day 49 for the entire study population was 95.4 dB. In a specific subgroup of participants with a baseline PTA above 65 dB, the mean PTA at day 49 was 95 dB. In another specific subgroup of participants with a baseline PTA of 65 dB or less, the mean PTA at day 49 was 95.8 dB. [Table 4]

[0137] Table 5 below shows the mean change in pure-tone mean (PTA) from baseline (calculated by subtracting the baseline PTA from the PTA at day 49, both expressed as the mean of hearing thresholds determined at 0.25, 0.5, and 0.75 kHz). Across the entire study population, the mean change in PTA from baseline was +25.83 dB in the control arm compared to +12.17 dB in the SENS-401 arm (a difference of 13.67 dB), which supports the effect of SENS-401 in preserving residual hearing after cochlear implantation. In a specific group of participants with a baseline PTA greater than 65 dB (expressed as the mean of hearing thresholds determined at 0.25, 0.5, and 0.75 kHz), the mean change in PTA from baseline was +20.83 dB in the control arm compared to +3.89 dB in the SENS-401 arm (a difference of 16.94 dB). [Table 5]

[0138] Table 6 below shows the response rates corresponding to the proportion of participants whose PTA increase from baseline was less than 10 dB. The overall response rate with SENS-401 treatment was 40% for the entire study population. In a specific group of participants with baseline PTA exceeding 65 dB (expressed as the mean of hearing thresholds determined at 0.25, 0.5, and 0.75 kHz), the response rate with SENS-401 treatment was 67%. [Table 6]

[0139] The clinical data provided herein provide evidence of increased benefit from SENS-401 in a specific group of cochlear implanters with baseline PTA exceeding 65 dB.

Claims

1. Azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use in preserving residual hearing after cochlear implantation in subjects requiring such use, having a baseline hearing threshold corresponding to a baseline unaided hearing threshold of 65 dB or higher in at least one ear (the unaided hearing threshold is expressed as the average of at least three values ​​determined at different frequencies within the range of 0.25 kHz to 0.75 kHz).

2. The audible hearing threshold in the unaided ear is expressed as the average of values ​​determined at 0.25 kHz, 0.5 kHz, and 0.75 kHz, for use of azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof according to claim 1.

3. The aforementioned hearing measurement threshold in the naked ear is the pure-tone mean (PTA) in the naked ear, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 1 or 2.

4. The pharmaceutically acceptable salt is selected from besylate, malate, and hydrochloride salts, and / or solvates of azasetron or an analogue of azasetron or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 3.

5. The azasetron is (R)-azasetron, (S)-azasetron, a mixture thereof, or a pharmaceutically acceptable salt and / or solvate thereof, for use according to any one of claims 1 to 4.

6. The azasetron is (R)-azasetron or a pharmaceutically acceptable salt and / or solvate thereof, azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 5.

7. Azasetron or an analogue of azasetron or a 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 (R)-azasetron besylate.

8. The analogs of azasetron are preferably 6-chloro-3,4-dihydro-2-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide, 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl)-2H-benzoxazine-8-carboxamide, 6-chloro-2-ethyl-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide, and 6-bromo-3,4-dihydro-2,4-dimethyl-3-oxo-N A benzoxazine compound or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 4, selected from -(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide, 6-chloro-3,4-dihydro-2,2,4-trimethyl-3-oxo-N-(3-quinuclidinyl-1)-2H-1,4-benzoxazine-8-carboxamide and pharmaceutically acceptable salts and / or solvates thereof, or a pharmaceutically acceptable salt and / or solvate thereof.

9. Azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 8, for administration in a daily dose ranging from approximately 20 mg to approximately 200 mg.

10. Azasetron or an analogue of azasetron or a pharmaceutically salt and / or solvate thereof for use according to any one of claims 1 to 8, for administration at a daily free base equivalent dose of approximately 40 mg or approximately 60 mg.

11. Azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 10, for oral administration.

12. Azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 10, for topical administration.

13. Azasetron or an analogue of azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 12, for administration starting at least three days prior to the insertion of the cochlear implant.

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