Azasetron for treating sudden sensorineural hearing loss

Abstract

The present invention relates to azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment of severe or very severe sudden sensorineural hearing loss (SSNHL) in a subject in need thereof. Specifically, the invention relates to azasetron or azasetron analogues or pharmaceutically acceptable salts and / or solvates of azasetron or azasetron analogues or pharmaceutically acceptable salts and / or solvates of azasetron or azasetron analogues, a composition for treating severe or extremely severe SSNHL in a subject suffering from severe or extremely severe SSNHL associated with: (i) a baseline hearing threshold corresponding to a baseline pure tone audiometry (PTA) equal to or greater than 70 dB, preferably equal to or greater than 80 dB, more preferably equal to or greater than 90 dB; (ii) a baseline hearing loss equal to or greater than 91 dB, corresponding to a very severe hearing loss classified according to the American Speech Language Hearing Association (ASHA); (iii) a frequency of baseline hearing loss impact equal to or lower than 2000 Hz; and / or (iv) the presence of vertigo at baseline.

Description

Technical Field

[0001] The present invention relates to the treatment of sudden sensorineural hearing loss (SSNHL), in particular to the treatment of severe or profound SSNHL. Background Art

[0002] Sudden sensorineural hearing loss (SSNHL), commonly referred to as sudden deafness, refers to the subjective sensation of hearing impairment that occurs suddenly. SSNHL is more specifically defined as a decrease in hearing of 30 dB or more at at least three consecutive audiometric frequencies occurring within a 72-hour period. In almost all subjects, SSNHL is unilateral and affects only one ear. In fact, less than 2% of SSNHL patients have bilateral involvement, and usually the bilateral involvement is sequential. It is estimated that up to 32% to 65% of SSNHL cases can recover spontaneously. However, clinical experience suggests that this recovery rate may be overestimated. In addition, although the recovery of hearing thresholds after SSNHL may be complete, it may also be partial and often may not occur at all.

[0003] SSNHL is a rare condition with an average overall annual incidence of 4 to 160 per 100,000 people. However, the true incidence of SSNHL may be higher because affected subjects who recover quickly may not receive medical care. Approximately 66,600 new cases are reported in the United States each year. The incidence increases with age, ranging from 11 per 100,000 in patients under 18 years of age to 77 per 100,000 in patients 65 years of age and older (Alexander et al. Incidence of sudden sensorineural hearing loss. Otol Neurotol. 2013 Dec; 34(9): 1586-9). The most commonly reported causes of SSNHL include infectious diseases and otologic diseases; trauma, including, for example, noise trauma, barotrauma, and head trauma; vascular / hematologic causes, including, for example, cerebrovascular accidents; and tumor causes, including, for example, schwannomas and meningiomas. However, in most subjects, SSNHL has no identifiable cause. In these subjects, SSNHL was classified as idiopathic.

[0004] SSNHL is a serious and debilitating condition. Hearing loss can adversely affect communication, speech perception in noisy environments, and social interactions, confirming that unilateral deafness is a significant disability. Disorientation and confusion due to the inability to localize sounds can put subjects at risk for accidents, and hearing loss is associated with a significant increase in falls in the elderly. Almost 75% of patients with even mild unilateral hearing loss report psychosocial impacts, with feelings of frustration, insecurity, and exclusion commonly reported.

[0005] There is currently no approved treatment to improve or promote complete or even partial recovery of hearing and / or SSNHL symptoms, regardless of the cause. Therefore, the treatment of SSNHL remains somewhat controversial, and varies greatly and often varies from place to place. The American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) published clinical practice guidelines for the management of SSNHL in 2012. The European Medical Association has not yet published such guidelines. In clinical practice, corticosteroids are usually administered systemically and / or intratympanically. A large number of other treatments have been used and / or evaluated, including, for example, antiviral drugs, antibiotics, diuretics, vasodilators, osmotic agents, plasma expanders, anticoagulants, mineral supplements, and high-pressure oxygen- or carbon dioxide-enriched gases, but none have achieved consistent success. A recent meta-analysis evaluating the efficacy and safety of medical interventions for the treatment of SSNHL did not find any effective treatments (Wei et al. Steroids for idiopathic sudden sensorineural hearing loss. Cochrane Database Syst Rev. 2013 Jul 2; 2013(7): CD003998; Lawrence et al. Controversies in the management of sudden sensorineural hearing loss: an evidence-based review. Clin Otolaryngol. 2015 Jun; 40(3): 176-82).

[0006] Therefore, there remains a need for an effective treatment for SSNHL, particularly for severe or very severe SSNHL. Therefore, it may be helpful to identify SSNHL subjects (particularly patients with severe or very severe SSNHL) who are most likely to benefit from treatment.

[0007] The inventors surprisingly demonstrated that (R)-azasetron significantly induced hearing improvement in subjects with severe or profound SSNHL associated with at least one of the following: (i) a baseline hearing threshold corresponding to a baseline pure tone audiometry (PTA) equal to or greater than 70 dB; (ii) a baseline hearing loss equal to or greater than 91 dB, corresponding to a profound hearing loss according to the American Speech-Language-Hearing Association (ASHA) classification; (iii) a baseline hearing loss affecting frequencies equal to or below 2000 Hz; and / or (iv) the presence of vertigo at baseline.

[0008] Thus, the present invention relates to azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof for use in treating severe or profound SSNHL in a subject in need thereof, in particular a subject who is most likely to benefit from the administration of azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof, such as a subject having the following characteristics: (i) a baseline hearing threshold corresponding to a baseline PTA of equal to or greater than 70 dB, preferably equal to or greater than 80 dB, more preferably equal to or greater than 90 dB; (ii) a baseline hearing loss of equal to or greater than 91 dB, corresponding to profound hearing loss according to the ASHA classification; (iii) a baseline hearing loss affecting frequencies equal to or below 2000 Hz; and / or (iv) the presence of vertigo at baseline. Summary of the invention

[0009] The present invention relates to azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof for use in treating sudden sensorineural hearing loss (SSNHL) in a subject in need thereof, wherein the subject suffers from severe or profound SSNHL associated with at least one of the following:

[0010] - a baseline hearing threshold corresponding to a baseline pure tone audiometry (PTA) of equal to or greater than 70 dB, preferably equal to or greater than 80 dB, more preferably equal to or greater than 90 dB;

[0011] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the American Speech-Language-Hearing Association (ASHA) classification;

[0012] - Baseline hearing loss affecting frequencies at or below 2000 Hz; and / or

[0013] -Presence of vertigo at baseline.

[0014] In some embodiments, the subject has severe or profound SSNHL associated with a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 80 dB. In some embodiments, the subject has severe or profound SSNHL associated with a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 90 dB. In some embodiments, the subject has severe or profound SSNHL associated with a baseline hearing loss affecting frequencies equal to or below 2000 Hz.

[0015] In some embodiments, the SSNHL is idiopathic SSNHL.In some embodiments, the SSNHL is unilateral.

[0016] In some embodiments, azasetron is (R)-azasetron, (S)-azasetron, a mixture thereof, or a pharmaceutically acceptable salt and / or solvate thereof; preferably, azasetron is (R)-azasetron or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of benzenesulfonate, malate and hydrochloride. In some embodiments, the pharmaceutically acceptable salt is (R)-azasetron benzenesulfonate. In some embodiments, the azasetron analog is a benzoxazine compound or a pharmaceutically acceptable salt and / or solvate thereof, preferably selected from the group consisting of 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, The invention relates to a group consisting of or consisting of oxazine-8-carboxamide, 6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-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 pharmaceutically acceptable salts or solvates thereof.

[0017] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered at a daily dose in the range of about 20 mg to about 200 mg. In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered at a daily dose in the range of about 40 mg or about 60 mg.

[0018] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof is administered within about 96 hours of the first onset of SSNHL.

[0019] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered with at least one additional pharmaceutically active agent. In some embodiments, at least one additional pharmaceutically active agent is a corticosteroid.

[0020] definition

[0021] In the present invention, the following terms have the following meanings:

[0022] “SSNHL” refers to sudden sensorineural hearing loss.

[0023] When "about" precedes a number, it encompasses plus or minus 10% or less of the numerical value. It is to be understood that the value referred to by the term "about" itself is also specifically and preferably disclosed.

[0024] "Baseline", when defining a parameter observed in a subject with SSNHL, particularly severe or very severe SSNHL, refers to the time before the start of administration of azasetron or an azasetron analog as described herein, or a pharmaceutically acceptable salt and / or solvate thereof, to the subject. For example, for a given subject, the baseline hearing loss is the hearing loss of the subject before the administration of azasetron or an azasetron analog as described herein, or a pharmaceutically acceptable salt and / or solvate thereof, to the subject.

[0025] A "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to an excipient or carrier that does not produce adverse, allergic or other untoward reactions when administered to a subject. It includes any and all solvents, such as dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents. A pharmaceutically acceptable excipient or carrier refers to any type of non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation adjuvant. For human administration, the formulation should meet the sterility, pyrogenicity, general safety and purity standards required by regulatory agencies such as the FDA (U.S. Food and Drug Administration) or EMA (European Medicines Agency).

[0026] "Subject" refers to a mammal, preferably a human. In some embodiments, the mammal is selected from cats, dogs, cows, pigs, horses, monkeys, apes and humans. In some embodiments, the mammal is selected from cats, dogs and humans. In some embodiments, the mammal is a primate. In some embodiments, the mammal is a human. In some embodiments, the subject can be a "patient", i.e., a mammal, preferably a human, who is waiting to receive or is receiving medical care, or was / is / will be the subject of a medical procedure, or is being monitored for SSNHL, particularly severe or very severe SSNHL. In some embodiments, a "subject in need of treatment" is a subject who is waiting to receive or is receiving medical care, or was / is / will be the subject of a medical procedure, or is being monitored for SSNHL, particularly severe or very severe SSNHL.

[0027] "Therapeutically effective amount" or "therapeutically effective dose" refers to an amount or dose of azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof, the purpose of which is to achieve at least one of the following effects without causing significant negative or adverse side effects to a subject in need of treatment: (1) slowing or stopping the progression, aggravation or worsening of one or more symptoms of SSNHL, especially severe or very severe SSNHL; (2) improving one or more symptoms of SSNHL, especially severe or very severe SSNHL; (3) reducing the severity of SSNHL, especially severe or very severe SSNHL; (4) curing SSNHL, especially severe or very severe SSNHL, and / or (5) improving the quality of life. Examples of symptoms of SSNHL include hearing loss and tinnitus. In some embodiments, the therapeutically effective amount or dose is an amount or dose of azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof, the purpose of which is to bring about hearing improvement without causing significant negative or adverse side effects to a subject in need of treatment. For example, the hearing improvement may correspond to a reduction in hearing loss; an improvement in hearing threshold, in particular an improvement in hearing threshold corresponding to an improvement in pure tone audiometry (PTA); and / or an improvement in word recognition scores. In some embodiments, the improvement in PTA is defined as an improvement of at least about 30, 35, 40, 45, 50, or 55 dB, preferably at least about 40 dB, in the most affected ear compared to a baseline PTA (i.e., a PTA before administration of azasetron or an azasetron analog, or a pharmaceutically acceptable salt and / or solvate thereof). In some embodiments, the improvement in word recognition scores is defined as an improvement of at least about 15% compared to a baseline word recognition score at 60 dB or 80 dB (i.e., a word recognition score before administration of azasetron or an azasetron analog, or a pharmaceutically acceptable salt and / or solvate thereof).

[0028] "Treating" or "treatment" refers to therapeutic treatment, prophylactic (or preventive) treatment, or both therapeutic and prophylactic (or preventive) treatment, wherein the purpose is to prevent, reduce or slow down (mitigate) one or more symptoms or manifestations of SSNHL, particularly severe or very severe SSNHL. In some embodiments, if the subject shows an improvement in hearing (e.g. as defined herein) after receiving a therapeutically effective amount or dose of azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof, the subject's SSNHL, particularly severe or very severe SSNHL is successfully "treated". Parameters for assessing successful treatment, particularly hearing improvement, can be easily measured by routine procedures familiar to doctors. Examples of methods for measuring hearing loss are mentioned below, which can also be used to assess hearing improvement. DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention relates to azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof for use in treating sudden sensorineural hearing loss (SSNHL) in a subject in need thereof. In some embodiments, the SSNHL is severe or very severe SSNHL. Therefore, in some embodiments, the subject in need of treatment is a subject suffering from severe or very severe SSNHL.

[0031] Sudden sensorineural hearing loss (SSNHL) is a subclass of sudden hearing loss. SSNHL is characterized by damage or impairment of the cochlea, auditory nerve, or other aspects of central auditory perception or processing. SSNHL can be defined by the following audiometric criteria: a decrease in hearing (i.e., hearing loss) of at least about 10, 20, or 30 decibels (dB) or more occurring within about 72 hours or less. In some embodiments, SSNHL is defined as a decrease in hearing (i.e., hearing loss) of at least about 10, 20, 30 decibels (dB) or more at at least three consecutive frequencies occurring within about 72 hours or less.

[0032] Hearing loss is typically determined by comparison with reference values, which are preferably results from previously obtained audiometry (i.e., obtained before the onset of SSNHL). When previously obtained audiometry (i.e., obtained before the onset of SSNHL) is not available, hearing loss can be determined by comparison with reference values ​​from a reference population. For unilateral SSNHL, hearing loss can be defined by comparison with unaffected hearing.

[0033] Methods for measuring hearing loss are well known to those skilled in the art. Examples of such methods include pure tone audiometry (PTA), which corresponds to pure tone audiometry air conduction test and / or pure tone audiometry bone conduction test, speech audiometry, behavioral observation audiometry, visual reinforcement audiometry, conditioning game audiometry, ABR (auditory brainstem response) measurement, DPOAE (distortion product otoacoustic emission) measurement, TEOAE (transient evoked otoacoustic emission) measurement, speech in noise test, word comprehension test, tympanometry, acoustic reflex test and tuning fork test.

[0034] In some embodiments, SSNHL is defined as a hearing loss of about 30 dB or more, corresponding to the difference between a PTA (preferably a pure tone audiometry air conduction test) expressed as the average of the hearing thresholds (in dB) at the 3 most affected consecutive test frequencies and a reference PTA (preferably a pure tone audiometry air conduction test) expressed as the average of the hearing thresholds at the same frequencies.

[0035] In some embodiments, SSNHL is defined as:

[0036] - a hearing loss of about 30 dB or more, corresponding to the difference between the PTA (preferably pure tone audiometry air conduction test) expressed as the average of the hearing thresholds (in dB) at the 3 most affected consecutive test frequencies and the reference PTA (preferably pure tone audiometry air conduction test) expressed as the average of the hearing thresholds at the same frequencies, and

[0037] - At least one hearing threshold of 50 dB or higher in the 3 most affected contiguous frequencies on PTA, preferably on pure tone audiometry air conduction testing.

[0038] In some embodiments, the reference PTA is a PTA of the unaffected contralateral ear, a previously obtained PTA (ie, a PTA obtained prior to the onset of SSNHL), or a reference PTA from a reference population.

[0039] Pure tone audiometry (PTA) is widely used to evaluate SSNHL. The main purpose of PTA is to determine the degree, type and configuration of hearing loss, as its measurements cover the entire auditory pathway from the outer ear to the cortex. PTA is a standardized subjective hearing test that determines the air conduction and / or bone conduction hearing thresholds (expressed in dB) at a fixed set of frequencies ranging from 0.25 kHz to 8 kHz. The hearing thresholds determined at each frequency are plotted on the audiogram separately for each ear. For example, the hearing threshold can be defined as the lowest audible level measured two out of three times provided to the subject. Therefore, PTA allows the determination of the hearing threshold.

[0040] In some embodiments, PTA is expressed as the average of the hearing thresholds (in dB) at the 3 most affected consecutive test frequencies. In some embodiments, PTA is expressed as the average of the hearing thresholds (in dB) at the 3 most affected consecutive test frequencies using a pure tone air conduction test.

[0041] For example, pure tone air conduction can be measured at 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz. For example, pure tone bone conduction hearing thresholds can be measured at 0.5, 1, 2, 3, 4 kHz. Testing can be performed using the descending method of limits (modified Hughson Westlake procedure as follows: initial descent toward threshold is done in 10-dB steps; starting from the first non-response, the level is increased by 5-dB for each non-response, and the level is decreased by 10-dB after each correctly detected response).

[0042] As mentioned above, a subject's hearing (including hearing loss and / or hearing improvement) can be assessed using speech audiometry. Speech audiometry is a diagnostic hearing test designed to test word or speech recognition ability. It has become an essential tool in the assessment of hearing loss. Used in conjunction with PTA, it can help determine the degree and type of hearing loss. Speech audiometry also provides information about discomfort or tolerance to speech stimulation and information about word recognition ability.

[0043] Speech audiometry includes, for example, speech recognition, which is assessed by determining a speech recognition threshold, and word recognition, which is assessed by determining a word recognition score.

[0044] The speech recognition threshold is the lowest hearing level (in dB) at which the subject can correctly identify 50% of the presented speech material. Spondaic words are the commonly recommended test material for determining the speech recognition threshold. Spondaic words are two-syllable words with equal stress on both syllables (e.g., "birthday"). Subjects are familiarized with the spondaic words prior to testing, as per ASHA (American Speech-Language-Hearing Association) guidelines. Subjects listen to the list of words and indicate if there are any unfamiliar words so that they can be removed from the list. The average speech reception threshold (SRT) for normal listeners is 20 dB sound pressure level or SPL (corresponding to 0 dB hearing loss). The standard time allotted for the subject to respond is approximately four seconds.

[0045] Speech discrimination or word recognition refers to the ability to correctly repeat a set of open monosyllabic words at suprathreshold intensities (e.g. 60dB or 80dB). The word recognition score (WRS) is the percentage of test words that the subject repeats correctly. The test is conducted in a quiet room without any interfering noise. The word list is derived from a standard list containing monosyllabic words of a specific language. The words are presented to each ear separately and randomly, with contralateral masking. They are phonetically balanced, meaning that the speech sounds used occur at the same frequency as in the entire language.

[0046] In some embodiments, SSNHL is unilateral. That is, in some embodiments, only one ear of a subject in need of treatment is affected by SSNHL. In some embodiments, SSNHL is bilateral. That is, in some embodiments, both ears of a subject in need of treatment are affected by SSNHL.

[0047] SSNHL may be caused by, for example, vestibular schwannoma (acoustic neuroma), stroke, malignancy, inner ear vascular ischemia, perilymph fistula, or autoimmune causes (including but not limited to IgE or IgG allergy). Other causes of SSNHL include, for example, excessive noise exposure (e.g., exposure to noise exceeding about 70, 80, 90, 100, 110, 120 or 130 dB or more), involvement of the inner ear by infectious factors (e.g., viral and bacterial infections), vascular lesions, ototoxic drugs, head trauma, and blast exposure. However, only 10% to 15% of subjects have the cause of SSNHL determined.

[0048] In some embodiments, SSNHL is idiopathic. That is, in some embodiments, despite adequate investigation, the cause of SSNHL has not been determined. In some embodiments, SSNHL is unilateral idiopathic SSNHL.

[0049] In some embodiments, SSNHL is noise-induced. Thus, in some embodiments, SSNHL is caused by acoustic trauma. In some embodiments, SSNHL is caused by acute acoustic trauma. In some embodiments, SSNHL is unilateral noise-induced SSNHL. In some embodiments, SSNHL is bilateral noise-induced SSNHL.

[0050] In some embodiments, severe or very severe idiopathic SSNHL is associated with at least one of the following:

[0051] - a baseline hearing threshold corresponding to a baseline pure tone audiometry (PTA) of equal to or greater than 70 dB, preferably equal to or greater than 80 dB, more preferably equal to or greater than 90 dB;

[0052] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the American Speech-Language-Hearing Association (ASHA) classification;

[0053] - Baseline hearing loss affects frequencies at or below 2000 Hz, particularly frequencies in the range 500 to 1000 Hz; and / or

[0054] -Presence of vertigo at baseline.

[0055] Thus, in other words, in some embodiments, a subject in need of treatment is a subject having severe or very severe SSNHL associated with at least one of:

[0056] - a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 70 dB, preferably equal to or greater than 80 dB, more preferably equal to or greater than 90 dB;

[0057] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to ASHA classification;

[0058] - Baseline hearing loss affects frequencies at or below 2000 Hz, particularly frequencies in the range 500 to 1000 Hz; and / or

[0059] -Presence of vertigo at baseline.

[0060] Thus, in some embodiments, the present invention relates to azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof for use in treating SSNHL in a subject in need thereof, wherein the subject has severe or very severe SSNHL associated with at least one of:

[0061] - a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 70 dB, preferably equal to or greater than 80 dB, more preferably equal to or greater than 90 dB;

[0062] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to ASHA classification;

[0063] - Baseline hearing loss affects frequencies at or below 2000 Hz, particularly frequencies in the range 500 to 1000 Hz; and / or

[0064] -Presence of vertigo at baseline.

[0065] In some embodiments, the present invention relates to azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof for use in treating SSNHL in a subject in need thereof, wherein the subject has severe or very severe SSNHL associated with at least one of:

[0066] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 80 dB;

[0067] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to ASHA classification;

[0068] - Baseline hearing loss affects frequencies at or below 2000 Hz, particularly frequencies in the range 500 to 1000 Hz; and / or

[0069] -Presence of vertigo at baseline.

[0070] In some embodiments, the present invention relates to azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof for use in treating SSNHL in a subject in need thereof, wherein the subject has severe or very severe SSNHL associated with at least one of:

[0071] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 90 dB;

[0072] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to ASHA classification;

[0073] - Baseline hearing loss affects frequencies at or below 2000 Hz, particularly frequencies in the range 500 to 1000 Hz; and / or

[0074] -Presence of vertigo at baseline.

[0075] In some embodiments, severe or profound SSNHL is associated with a baseline hearing threshold corresponding to a baseline PTA of equal to or greater than 70 dB, 80 dB, or 90 dB. Thus, in some embodiments, a subject in need of treatment is a subject with severe or profound SSNHL associated with a baseline hearing threshold corresponding to a baseline PTA of equal to or greater than 70 dB, 80 dB, or 90 dB.

[0076] As described above, PTA is a standardized subjective hearing test that determines air conduction and / or bone conduction hearing thresholds (expressed in dB) at a set of fixed frequencies ranging from 0.25 kHz to 8 kHz. In some embodiments, PTA is expressed as the average of the hearing thresholds (in dB) at the 3 most affected consecutive test frequencies. In some embodiments, PTA is expressed as the average of the hearing thresholds (in dB) at the 3 most affected consecutive test frequencies using a pure tone air conduction test.

[0077] In some embodiments, severe or profound SSNHL is associated with a baseline hearing loss equal to or greater than 91 dB (corresponding to profound hearing loss according to the ASHA classification). Thus, in some embodiments, a subject in need of treatment is a subject with severe or profound SSNHL associated with a baseline hearing loss equal to or greater than 91 dB (corresponding to profound hearing loss according to the ASHA classification).

[0078] ASHA has proposed a hearing loss classification method that depends on the degree of hearing loss, which is commonly used in the field (Clark. ASHA. 1981 Jul; 23 (7): 493-500). According to the ASHA classification, the degree of hearing loss is as follows:

[0079] -Hearing loss of -10 to 15dB: normal,

[0080] -Hearing loss of 16 to 25dB: mild hearing loss,

[0081] -Hearing loss of 26 to 40dB: mild hearing loss,

[0082] -Hearing loss of 41 to 55dB: moderate hearing loss,

[0083] -Hearing loss is 56 to 70dB: moderate to severe hearing loss,

[0084] -Hearing loss of 71 to 90dB: severe hearing loss,

[0085] -Hearing loss equal to or greater than 91dB: profound hearing loss.

[0086] In some embodiments, the baseline hearing loss is defined as the difference between the PTA of the baseline assessment of the ear most affected and the reference PTA. In some embodiments, preferably when SSNHL is unilateral, the reference PTA is the PTA of the baseline assessment of the contralateral ear (i.e., the ear that is not affected or least affected). In some embodiments, PTA is expressed as the average value of the hearing threshold (in dB) under the 3 most affected continuous test frequencies, preferably using pure tone air conduction test. Therefore, in some embodiments, the baseline hearing loss is defined as the difference between the baseline PTA and the reference PTA, the baseline PTA is expressed as the average value of the hearing threshold (in dB) under the 3 most affected continuous test frequencies, preferably using pure tone air conduction test, and the reference PTA is expressed as the average value of the hearing threshold (in dB) of the same frequency, preferably using pure tone air conduction test. In some embodiments, the reference PTA is the PTA previously assessed in the subject (i.e., the PTA previously obtained for the subject). In some embodiments, the reference PTA is the PTA from a reference population.

[0087] In some embodiments, severe or profound SSNHL is associated with a baseline hearing loss affecting frequencies at or below 2000 Hz. Thus, in some embodiments, a subject in need of treatment is a subject suffering from severe or profound SSNHL associated with a baseline hearing loss affecting frequencies at or below 2000 Hz.

[0088] In some embodiments, severe or profound SSNHL is associated with a baseline hearing loss affecting frequencies within the range of 500 to 1000 Hz. Thus, in some embodiments, a subject in need of treatment is a subject suffering from severe or profound SSNHL associated with a baseline hearing loss affecting frequencies within the range of 500 to 1000 Hz.

[0089] Humans can hear sounds with frequencies ranging from about 20 Hz to about 20 kHz. Hearing loss below 2000 Hz affects verbal communication and affects quality of life. Therefore, subjects with low-frequency hearing loss have difficulty hearing low-pitched, deeper voices, such as men's voices (which are generally deeper than women's or children's voices). They also have difficulty hearing conversations in a crowd and / or hearing voices in loud environments and places with background noise. Hearing loss below 2000 Hz also makes it difficult to hear bass when listening to music. Therefore, hearing loss affecting frequencies below 2000 Hz is considered a clinical marker of SSNHL severity.

[0090] As described above, methods of measuring hearing loss are well known to those skilled in the art. For example, hearing loss can be determined by pure tone audiometry (PTA), which, as described above, is a standardized subjective hearing test that determines hearing thresholds (expressed in dB) at a set of fixed frequencies in the range of 0.25 kHz to 8 kHz. Therefore, in some embodiments, the frequencies affected by the baseline hearing loss are determined when assessing the baseline PTA.

[0091] In some embodiments, severe or very severe SSNHL is associated with the presence of vertigo at baseline. Thus, in some embodiments, a subject in need of treatment is a subject with severe or very severe SSNHL associated with the presence of vertigo at baseline.

[0092] Methods for assessing the presence or absence of vertigo in a subject are well known to those skilled in the art. In some embodiments, the presence of vertigo at baseline is assessed on a numerical scale, such as a numerical scale of 0 to 10, where 0 corresponds to no vertigo and 10 corresponds to extreme vertigo.

[0093] In some embodiments, severe or profound SSNHL is associated with a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB; and is associated with a baseline hearing loss affecting frequencies equal to or below 2000 Hz. Thus, in some embodiments, a subject in need of treatment is a subject with severe or profound SSNHL, wherein the severe or profound SSNHL is associated with a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB; and is associated with a baseline hearing loss affecting frequencies equal to or below 2000 Hz.

[0094] In some embodiments, severe or profound sudden sensorineural hearing loss (SSNHL) is associated with a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB; and is associated with a baseline hearing loss affecting frequencies within the range of 500 to 1000 Hz. Thus, in some embodiments, a subject in need of treatment is a subject with severe or profound SSNHL, the severe or profound SSNHL being associated with a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB; and is associated with a baseline hearing loss affecting frequencies within the range of 500 to 1000 Hz.

[0095] In some embodiments, severe or profound SSNHL is associated with a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB; and associated with a baseline hearing loss equal to or greater than 91 dB (corresponding to profound hearing loss according to the ASHA classification). Thus, in some embodiments, a subject in need of treatment is a subject with severe or profound SSNHL, wherein the severe or profound SSNHL is associated with a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB; and associated with a baseline hearing loss equal to or greater than 91 dB (corresponding to profound hearing loss according to the ASHA classification).

[0096] In some embodiments, severe or profound SSNHL is associated with a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB; and is associated with the presence of vertigo at baseline. Thus, in some embodiments, a subject in need of treatment is a subject with severe or profound SSNHL, wherein the severe or profound SSNHL is associated with a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB; and is associated with the presence of vertigo at baseline.

[0097] In some embodiments, severe or profound SSNHL is associated with a baseline hearing loss affecting frequencies equal to or below 2000 Hz, particularly frequencies in the range of 500 to 1000 Hz; and associated with a baseline hearing loss equal to or greater than 91 dB (corresponding to profound hearing loss according to the ASHA classification). Thus, in some embodiments, a subject in need of treatment is a subject with severe or profound SSNHL, the severe or profound SSNHL being associated with a baseline hearing loss affecting frequencies equal to or below 2000 Hz, particularly frequencies in the range of 500 to 1000 Hz; and associated with a baseline hearing loss equal to or greater than 91 dB (corresponding to profound hearing loss according to the ASHA classification).

[0098] In some embodiments, severe or profound SSNHL is associated with a baseline hearing loss affecting frequencies equal to or below 2000 Hz, particularly frequencies in the range of 500 to 1000 Hz; and associated with the presence of vertigo at baseline. Thus, in some embodiments, a subject in need of treatment is a subject with severe or profound SSNHL, wherein the severe or profound SSNHL is associated with a baseline hearing loss affecting frequencies equal to or below 2000 Hz, particularly frequencies in the range of 500 to 1000 Hz; and associated with the presence of vertigo at baseline.

[0099] In some embodiments, severe or profound SSNHL is associated with a baseline hearing loss equal to or greater than 91 dB (corresponding to profound hearing loss according to the ASHA classification); and is associated with the presence of vertigo at baseline. Thus, in some embodiments, a subject in need of treatment is a subject with severe or profound SSNHL, which is associated with a baseline hearing loss equal to or greater than 91 dB (corresponding to profound hearing loss according to the ASHA classification); and is associated with the presence of vertigo at baseline.

[0100] In some embodiments, severe or very severe SSNHL is associated with:

[0101] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0102] - Baseline hearing loss affects frequencies at or below 2000 Hz; and

[0103] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the ASHA classification.

[0104] Thus, in some embodiments, a subject in need of treatment is a subject with severe or very severe SSNHL associated with:

[0105] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0106] - Baseline hearing loss affects frequencies at or below 2000 Hz; and

[0107] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the ASHA classification.

[0108] In some embodiments, severe or very severe SSNHL is associated with:

[0109] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0110] - Baseline hearing loss affects frequencies in the 500 to 1000 Hz range; and

[0111] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the ASHA classification.

[0112] Thus, in some embodiments, a subject in need of treatment is a subject with severe or very severe SSNHL associated with:

[0113] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0114] - Baseline hearing loss affects frequencies in the 500 to 1000 Hz range; and

[0115] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the ASHA classification.

[0116] In some embodiments, severe or very severe SSNHL is associated with:

[0117] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0118] - Baseline hearing loss affects frequencies at or below 2000 Hz; and

[0119] -Presence of vertigo at baseline.

[0120] Thus, in some embodiments, a subject in need of treatment is a subject with severe or very severe SSNHL associated with:

[0121] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0122] - Baseline hearing loss affects frequencies at or below 2000 Hz; and

[0123] -Presence of vertigo at baseline.

[0124] In some embodiments, severe or very severe SSNHL is associated with:

[0125] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0126] - Baseline hearing loss affects frequencies in the 500 to 1000 Hz range; and

[0127] -Presence of vertigo at baseline.

[0128] Thus, in some embodiments, a subject in need of treatment is a subject with severe or very severe SSNHL associated with:

[0129] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0130] - Baseline hearing loss affects frequencies in the 500 to 1000 Hz range; and

[0131] -Presence of vertigo at baseline.

[0132] In some embodiments, severe or very severe SSNHL is associated with:

[0133] - Baseline hearing loss affecting frequencies at or below 2000 Hz, particularly frequencies in the range of 500 to 1000 Hz;

[0134] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the ASHA classification; and

[0135] -Presence of vertigo at baseline.

[0136] Thus, in some embodiments, a subject in need of treatment is a subject with severe or very severe SSNHL associated with:

[0137] - Baseline hearing loss affecting frequencies at or below 2000 Hz, particularly frequencies in the range of 500 to 1000 Hz;

[0138] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the ASHA classification; and

[0139] -Presence of vertigo at baseline.

[0140] In some embodiments, severe or very severe SSNHL is associated with:

[0141] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0142] - Baseline hearing loss affecting frequencies at or below 2000 Hz;

[0143] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the ASHA classification; and

[0144] -Presence of vertigo at baseline.

[0145] Thus, in some embodiments, a subject in need of treatment is a subject with severe or very severe SSNHL associated with:

[0146] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0147] - Baseline hearing loss affecting frequencies at or below 2000 Hz;

[0148] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the ASHA classification; and

[0149] -Presence of vertigo at baseline.

[0150] In some embodiments, severe or very severe SSNHL is associated with:

[0151] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0152] - Baseline hearing loss affects frequencies in the 500 to 1000 Hz range;

[0153] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the ASHA classification; and

[0154] -Presence of vertigo at baseline.

[0155] Thus, in some embodiments, a subject in need of treatment is a subject with severe or very severe SSNHL associated with:

[0156] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0157] - Baseline hearing loss affects frequencies in the 500 to 1000 Hz range;

[0158] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the ASHA classification; and

[0159] -Presence of vertigo at baseline.

[0160] In some embodiments, the subject in need of treatment is a child, i.e., a subject under the age of 21, 20, 19, or 18 years. In some embodiments, the subject in need of treatment is an adult, i.e., a subject 18, 19, 20, 21 or older. In some embodiments, the subject in need of treatment is at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 years old. In some embodiments, the subject in need of treatment is 30 years or older, 40 years or older, 50 years or older, 60 years or older, or 70 years or older.

[0161] In some embodiments, the subject in need of treatment is female. In some embodiments, the subject in need of treatment is male.

[0162] In some embodiments, the present invention relates to azasetron or a pharmaceutically acceptable salt and / or solvate thereof for use in treating sudden sensorineural hearing loss (SSNHL) in a subject in need thereof as described above, particularly in a subject with severe or profound SSNHL as described above.

[0163] Azasetron is a compound of formula (I), wherein * represents the (R)-enantiomer (or (+)-enantiomer), the (S)-enantiomer (or (-)-enantiomer), the racemate or the non-racemic mixture of (R)- and (S)-enantiomers (corresponding to the mixture of (+)- and (-)-enantiomers):

[0164]

[0165] Thus, azasetron corresponds to 6-chloro-3,4-dihydro-N-(8-methyl-8-azabicyclo-[3.2.1]-oct-3-yl)-2,4-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxamide, which may also be referred to as N-(1-azabicyclo[2.2.2]oct-8-yl)-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide, as described in U.S. Pat. No. 4,892,872.

[0166] As described above, azasetron has one chiral center, which can produce two stereoisomers. In some embodiments, azasetron is racemic azasetron, or a pharmaceutically acceptable salt and / or solvate thereof.

[0167] 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 referred to as (R)-azasetron or (+)-azasetron, corresponding to formula (R)-I:

[0168]

[0169] Examples of methods that can be used to synthesize (R)-azasetron or a pharmaceutically acceptable salt and / or solvate thereof are well known in the art (see, for example, Chinese patents CN101786963 and CN104557906). In some embodiments, the synthesis of (R)-azasetron or a pharmaceutically acceptable salt and / or solvate thereof comprises de novo synthesis and / or chiral resolution. In some embodiments, when performing de novo synthesis of (R)-azasetron or a pharmaceutically acceptable salt and / or solvate thereof, at least one racemic starting compound and / or intermediate compound is replaced by a chiral compound.

[0170] 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 referred to as (S)-azasetron or (-)-azasetron, corresponding to formula (S)-I:

[0171]

[0172] In some embodiments, azasetron includes compounds of Formula I, preferably compounds of Formula (R)-I, and all polymorphs, crystals and crystal habits thereof, prodrugs and prodrugs thereof, and isotopically labeled compounds of Formula I, preferably compounds of Formula (R)-I.

[0173] Azasetron can be in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of azasetron include its acid addition salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples of acid addition salts include benzenesulfonate, hydrochloride / chloride, malate, benzoate, ethane-1,2-disulfonate, fumarate, tartrate, acetate, adipate, ascorbate, aspartate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, ethanesulfonate, ethanesulfonate, formate, glucoheptonate, gluconate, glucuronate, glutamate, hexafluorophosphate, hyphenate.

[0013] The invention also includes but is not limited to the following salts: hibenzate, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, sucrose, stearate, succinate, tannate, p-toluenesulfonate, toluenesulfonate, trifluoroacetate, and xinofoate.

[0174] Pharmaceutically acceptable salts of azasetron can be prepared by reacting azasetron with a desired acid, or by converting one azasetron salt into another salt by reacting with an appropriate acid or by means of a suitable ion exchange column. All of these reactions are usually carried out in solution. The salt can be precipitated from solution and collected by filtration, or can be recovered by evaporating the solvent. The degree of ionization in the salt can vary from fully ionized to non-ionized, thereby producing a co-crystal.

[0175] In some embodiments, azasetron is in the form of a pharmaceutically acceptable salt selected from benzenesulfonate, hydrochloride, malate, benzoate, ethane-1,2-disulfonate, fumarate and tartrate; more preferably benzenesulfonate, hydrochloride, malate and benzoate; even more preferably benzenesulfonate, hydrochloride and malate.

[0176] As used herein, "pharmaceutically acceptable solvate" in relation to azasetron refers to a molecular complex comprising azasetron and a stoichiometric or substoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol or water). When the solvent is water, the term "hydrate" (as in "pharmaceutically acceptable hydrate") may be particularly used.

[0177] In some embodiments, azasetron is (R)-azasetron benzenesulfonate, (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 benzenesulfonate, (R)-azasetron hydrochloride, (R)-azasetron malate and / or (R)-azasetron benzoate; more preferably, azasetron is (R)-azasetron benzenesulfonate, (R)-azasetron hydrochloride and / or (R)-azasetron malate.

[0178] In some embodiments, the azasetron is (R)-azasetron besylate, also known as "SENS-401."

[0179] In some embodiments, the present invention relates to an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof for use in treating sudden sensorineural hearing loss (SSNHL) in a subject in need thereof as described above, particularly in a subject with severe or profound SSNHL as described above.

[0180] As used herein, "analog" refers to a modification or substitution of one or more chemical moieties on the parent compound, i.e., azasetron, and may include functional derivatives, positional isomers, tautomers, zwitterions, enantiomers, diastereomers, racemates, isosteres, or stereochemical mixtures thereof.

[0181] In some embodiments, the analog of azasetron is a benzoxazine compound, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the analog of azasetron is a benzoxazine compound of formula (II):

[0182]

[0183] Where R 1 and R 2 are the same or different and each represents hydrogen or C 1-8 Alkyl; R 3 Represents hydrogen, C 1-8 Alkyl, phenylalkyl or substituted phenylalkyl; R 4 and R 5 are the same or different and each represents hydrogen, halogen, C 1-8 Alkyl, alkoxy, amino, amido, C 2-5 Alkylamino, hydroxyl or nitro; X ​​represents oxygen or NH; R 6 Representing a group of formula (III):

[0184]

[0185] Where m is 0 or 1,

[0186] or a group of formula (IV):

[0187]

[0188] Where R 7 Represents C 1-8 Alkyl, phenyl C 1-4 Alkyl, phenoxyalkyl, substituted phenyl C 1-4 Alkyl or substituted phenoxyalkyl, R 8 Represents hydrogen or C 1-8 Alkoxy, and m is as defined above,

[0189] or a group of formula (V):

[0190]

[0191] Where R 9 Represents C 1-8 Alkyl, phenyl C 1-4 Alkyl or substituted phenyl C 1-4 alkyl, n is 0 or 1, and m is as defined above,

[0192] or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the azasetron analog is a benzoxazine compound selected from the group consisting of or comprising 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, 6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-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 pharmaceutically acceptable salts or solvates thereof.

[0194] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered in a therapeutically effective dose.

[0195] As used herein, the free base equivalent dose refers to the dose of the active ingredient itself (i.e., azasetron or an azasetron analog) rather than its pharmaceutically acceptable salt and / or solvate form. Therefore, changes in the composition of azasetron or azasetron analog's pharmaceutically acceptable salt and / or solvate will not affect the free base equivalent dose to be administered.

[0196] In some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered at a free base equivalent dose ranging from about 0.1 to about 2 mg / kg / day (mg / kg body weight / day), preferably about 0.2 to about 1 mg / kg / day. In some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered at a free base equivalent dose of about 0.5, 0.6, 0.7, 0.8, 0.9 or 1 mg / kg / day.

[0197] In some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered at a total daily free base equivalent dose ranging from about 10 to about 500 mg, preferably from about 20 to about 200 mg, more preferably from about 30 to about 100 mg, and even more preferably from about 40 to about 60 mg. In some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered at a total 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 azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered at a total daily free base equivalent dose of about 40 mg or about 60 mg.

[0198] In some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered at least once a day, preferably twice a day. In some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered for 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, or 28 days. In some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered for at least 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered for at least 1, 2, 3, 4, 5, or 6 months.

[0199] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered by injection, orally, topically, transdermally, nasally, by inhalation, buccally, rectally, intratracheally, transmucosally, transtympanically, by transdermal application, intramuscularly, or by parenteral administration.

[0200] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered systemically.

[0201] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered orally. Therefore, in some embodiments, azasetron or an azasetron analog thereof, a pharmaceutically acceptable salt and / or solvate thereof is suitable for oral administration. Examples of formulations suitable for oral administration include: solid forms, liquid forms, and gels. Examples of solid forms suitable for oral administration include tablets, pills, capsules, soft gelatin capsules, hard gelatin capsules, caplets, compressed tablets, cachets, wafers, dispersible and / or disintegrating tablets, powders, solid forms suitable for dissolving or suspending in liquids prior to oral administration, and effervescent tablets. Examples of liquid forms suitable for oral administration include solutions, suspensions, drinkable solutions, elixirs, potions, drenches, syrups, and liquors.

[0202] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof, alone or in combination with at least one additional pharmaceutically active agent, will be administered as an oral route form (immediate release or sustained release), preferably as a tablet.

[0203] In some embodiments, tablets for oral administration comprise 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 free base equivalents (preferably about 10 mg free base equivalents) of azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof (preferably (R)-azasetron besylate).

[0204] In some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered by injection, preferably systemically. Thus, in some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof is suitable for injection, particularly systemic injection. Examples of formulations suitable for systemic injection include: liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to injection. Examples of systemic injection include intravenous, subcutaneous, intramuscular, intradermal, and intraperitoneal injections or infusions.

[0205] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered topically.

[0206] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof is for external use. Thus, in some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof is suitable for external use. Examples of formulations suitable for external use include sticks, waxes, creams, lotions, ointments, balms, gels, masks, and leave-on washes.

[0207] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof is administered directly to the ear, in particular the inner ear, middle ear and / or outer ear, for example, by transtympanic or intratympanic administration. Thus, in some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof is suitable for direct administration to the ear, in particular the inner ear, for example, by transtympanic or intratympanic administration. Examples of formulations suitable for such administration include otowicks, round window catheters, various types of gels, foams, fibrins, emulsions, solutions, patches or other drug carriers that are placed in the ear and loaded with azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof.

[0208] In some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered within about 24 hours to about 7 days after the first onset of SSNHL (i.e., the first administration). Therefore, in some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered within 1, 2, 3, 4, 5, 6 or 7 days after the first onset of SSNHL (i.e., the first administration). In some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered within about 24, 36, 48, 60, 72, 84 or 96 hours after the first onset of SSNHL (i.e., the first administration). In some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered within about 96 hours after the first onset of SSNHL (i.e., the first administration).

[0209] In some embodiments, azasetron or an azasetron analog, or a pharmaceutically acceptable salt and / or solvate thereof, will be administered with at least one additional pharmaceutically active agent.

[0210] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof may be administered simultaneously, separately or sequentially with the at least one additional pharmaceutically active agent.

[0211] In some embodiments, azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof and the at least one additional pharmaceutically active agent will be administered separately.

[0212] In some embodiments, the additional pharmaceutically active agent is a corticosteroid. Therefore, in some embodiments, azasetron or azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof will be administered together with at least one corticosteroid. For example, the corticosteroid can 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.

[0213] Another object of the present invention is to provide a method for treating sudden sensorineural hearing loss (SSNHL) in a subject in need thereof as described herein, in particular a method for treating severe or profound SSNHL in a subject in need thereof as described herein, the method comprising administering azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof to the subject.

[0214] In some embodiments, the method is used to treat SSNHL in a subject having severe or very severe SSNHL associated with at least one of:

[0215] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB;

[0216] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to ASHA classification;

[0217] - Baseline hearing loss affecting frequencies at or below 2000 Hz; and / or

[0218] -Presence of vertigo at baseline.

[0219] In some embodiments, the method is used to treat SSNHL in a subject having severe or very severe SSNHL associated with at least one of:

[0220] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 80 dB;

[0221] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to ASHA classification;

[0222] - Hearing loss affecting frequencies at or below 2000 Hz; and / or

[0223] -Presence of vertigo at baseline.

[0224] In some embodiments, the method is used to treat SSNHL in a subject having severe or very severe SSNHL associated with at least one of:

[0225] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 90 dB;

[0226] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to ASHA classification;

[0227] - Baseline hearing loss affecting frequencies at or below 2000 Hz; and / or

[0228] -Presence of vertigo at baseline.

[0229] In some embodiments, the method comprises administering a therapeutically effective amount of azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof.

[0230] In some embodiments, the method comprises administering at least one additional pharmaceutically active agent as described herein. In some embodiments, the method comprises administering at least one corticosteroid as described herein.

[0231] In some embodiments, the method further comprises the step of determining whether the subject in need of treatment is susceptible to responding to azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof.

[0232] In some embodiments, the step of determining whether a subject in need of treatment is susceptible to responding to azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof comprises assessing whether the subject has severe or very severe SSNHL as defined herein.

[0233] In some embodiments, the step of determining whether a subject in need of treatment is susceptible to responding to azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof comprises:

[0234] (i) assessing whether the subject has severe or very severe SSNHL as defined herein; and

[0235] (ii) determining whether the subject in need of treatment is susceptible to responding to azasetron or an analog or a pharmaceutically acceptable salt and / or solvate of azasetron, wherein having severe or very severe SSNHL as defined herein means that the subject is susceptible to responding to azasetron or an analog or a pharmaceutically acceptable salt and / or solvate of azasetron.

[0236] In some embodiments, assessing whether a subject has severe or profound SSNHL comprises assessing baseline PTA, baseline hearing loss (with respect to ASHA classification and / or with respect to affected frequencies), and / or assessing the presence or absence of vertigo at baseline.

[0237] Examples of methods for assessing baseline PTA, baseline hearing loss (regarding ASHA classification and / or regarding affected frequencies), and assessing the presence of vertigo at baseline are mentioned in this article.

[0238] In some embodiments, at least one of the following is present:

[0239] - Baseline hearing thresholds corresponding to a baseline PTA equal to or greater than 70 dB, 80 dB, or 90 dB;

[0240] - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to ASHA classification;

[0241] - Baseline hearing loss affecting frequencies at or below 2000 Hz; and / or

[0242] - Presence of vertigo at baseline,

[0243] It means that the subject has severe or very severe SSNHL and is therefore susceptible to responding to azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate.

[0244] Another object of the present invention is a method of treating sudden sensorineural hearing loss (SSNHL) in a subject in need thereof, comprising:

[0245] - determining whether a subject in need of treatment as described above is susceptible to responding to azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof; and

[0246] - administering azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof to a subject determined to be susceptible to responding to azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof.

[0247] Another object of the present invention is a pharmaceutical composition for treating or for use in treating sudden sensorineural hearing loss (SSNHL) in a subject in need thereof as described herein, in particular treating severe or profound SSNHL in a subject in need thereof as described herein, the pharmaceutical composition comprising azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof; and optionally at least one pharmaceutically acceptable excipient.

[0248] Another object of the present invention is a pharmaceutical composition for treating or for use in treating sudden sensorineural hearing loss (SSNHL) in a subject in need thereof as described herein, in particular for treating severe or profound SSNHL in a subject in need thereof as described herein, the pharmaceutical composition comprising azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof.

[0249] In some embodiments, the pharmaceutical composition is administered with at least one additional pharmaceutically active agent as described herein. In some embodiments, the pharmaceutical composition is administered with at least one corticosteroid as described herein.

[0250] Another object of the present invention is the use of azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament or kit for treating sudden sensorineural hearing loss (SSNHL) in a subject in need thereof as described herein, in particular for treating severe or profound SSNHL in a subject in need thereof as described herein.

[0251] In some embodiments, the medicament or kit is administered with at least one additional pharmaceutically active agent as described herein. In some embodiments, the medicament or kit is administered with at least one corticosteroid as described herein. Example

[0252] The present invention is further illustrated by the following examples.

[0253] Example:

[0254] A randomized, double-blind, placebo-controlled, parallel-group Phase 2b / 3 study was conducted to evaluate the efficacy and safety of (R)-azasetron in patients with sudden sensorineural hearing loss. Treatment was administered for 4 weeks (i.e., 28 days) and followed up for 8 weeks, with the study ending on day 84.

[0255] The designation "SENS-401" below corresponds to the investigational product (R)-azasetron (administered to subjects enrolled in the study as (R)-azasetron besylate).

[0256] Materials and methods

[0257] Participants included in the study

[0258] Subjects were included in the study if they presented with sudden sensorineural hearing loss (SSNHL) and met the following criteria:

[0259] -male or female,

[0260] - At least 18 years old,

[0261] - Subjects with unilateral idiopathic SSNHL or unilateral / bilateral acute acoustic trauma resulting in SSNHL defined by both of the following:

[0262] ○ A hearing threshold of 50 dB or greater in at least one of the 3 most affected contiguous frequencies on a pure tone audiometry air conduction test performed 24 hours or less before the first ingestion of study medication, and

[0263] ○ Mean hearing loss averaged over the 3 most affected contiguous frequencies on a pure tone audiometry air conduction test performed 24 hours or less before the first study treatment of 30 dB or greater compared with reference values ​​in the unaffected contralateral ear or a pre-existing audiogram (dated less than 2 years ago),

[0264] - Subjects with onset of sudden hearing loss within 96 hours prior to first intake of study medication.

[0265] As mentioned above, hearing loss is determined by pure tone audiometry (PTA) or pure tone audiometry testing, particularly pure tone audiometry air conduction testing.

[0266] Pure tone audiometry (PTA) is widely used to evaluate SSNHL. The main purpose of PTA is to determine the degree, type, and configuration of hearing loss, as its measurement covers the entire auditory pathway from the outer ear to the cortex. PTA is a standardized subjective hearing test that measures air conduction and / or bone conduction hearing thresholds (expressed in decibels, or dB) at a fixed set of frequencies ranging from 0.25 kHz to 8 kHz. The hearing thresholds measured at each frequency are plotted on the audiogram for each ear separately.

[0267] In this study, pure-tone air-conduction and bone-conduction hearing thresholds were measured for each ear (the best ear first) at 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz for air conduction and at 0.5, 1, 2, 3, 4, 4 kHz for bone conduction using the extreme descent method (a modified Hughson Westlake procedure as follows: the initial descent toward the threshold was done in 10-dB steps. Starting from the first non-response, the level was increased by 5-dB at each non-response and decreased by 10-dB after each correctly detected response). The hearing threshold was defined as the lowest audible level measured in two of the three presentations to the subject.

[0268] Baseline pure tone audiometry was defined as the last test performed at the site within 24 hours before the first study drug administration. PTA is expressed as the average (air conduction) of the hearing thresholds (in dB) at the 3 most affected consecutive test frequencies. Thus, a higher PTA corresponds to a higher hearing threshold and, therefore, to worse hearing. Conversely, a lower PTA corresponds to a lower hearing threshold and, therefore, to better hearing.

[0269] Hearing loss was defined as the difference between the PTA expressed as the mean (in dB) of the hearing thresholds at the 3 most affected consecutive test frequencies and the corresponding PTA expressed as the mean hearing threshold of the contralateral ear at the same frequencies or the value from a pre-existing audiogram (dated less than 2 years ago) (mandatory for bilateral acute acoustic trauma). The consecutive frequencies used to determine the baseline PTA remained the same in all subsequent assessments. In case of bilateral acute acoustic trauma resulting in sudden sensorineural hearing loss, the ear most affected according to the inclusion criteria was considered for analysis. If both ears were equally affected, the right ear was considered.

[0270] Of note, the exclusion criteria for recruitment into the study specifically included:

[0271] - Bilateral idiopathic hearing loss,

[0272] - Fluctuating hearing loss,

[0273] – Subject’s known history of asymmetric hearing (hearing difference between the two ears >20dB),

[0274] - Severe hearing loss (>90 dB) associated with unilateral (ipsilateral) complete vestibular loss,

[0275] – History of Ménière's disease, autoimmune hearing loss, radiation-induced hearing loss, acoustic neuroma (neurilemmoma),

[0276] - SSNHL in the affected ear within the past 6 weeks,

[0277] - History of otosclerosis, suspected perilymphatic fistula or membrane rupture, suspected retrocochlear lesions, barotrauma,

[0278] - congenital or hereditary hearing loss,

[0279] - History of severe head or neck trauma,

[0280] - Complete loss of peripheral vestibular function on the affected side,

[0281] - Any ongoing or past 6 weeks medication-based therapy for inner ear hearing loss,

[0282] - Any ongoing or planned concomitant medication for the treatment of tinnitus until 6 weeks after administration,

[0283] - Any known ototoxic therapy currently or in the past 6 months before study inclusion,

[0284] - The air-bone conduction distance is greater than 20dB at 3 consecutive frequencies,

[0285] - acute on-chronic otitis media or otitis externa terminated less than 7 days before randomization,

[0286] - History of chronic inflammatory or suppurative ear disease or cholesteatoma,

[0287] - Any type of prior ear surgery (except ventilation tubes), or cochlear implants (except oral corticosteroids).

[0288] Based on the criteria listed above, 134 subjects were assessed for eligibility. 115 subjects were randomized in a 1:1:1 ratio into the following three groups (i.e., treatment groups):

[0289] - The group that received placebo for 28 days (i.e. 4 weeks) included 38 subjects,

[0290] - the group administered a "low" dose of (R)-azasetron (defined as a total daily dose of 58 mg of (R)-azasetron (corresponding to a daily dose of 40 mg free base equivalent)) for 28 days (i.e. 4 weeks) comprised 38 subjects; and

[0291] - The group administered a "high" dose of (R)-azasetron, defined as a total daily dose of 87 mg of (R)-azasetron (corresponding to a daily dose of 60 mg free base equivalent) for 28 days (ie 4 weeks), included 39 subjects.

[0292] Thus, the overall intention-to-treat (ITT) population included 115 subjects. However, after accounting for protocol deviations that occurred in some subjects, the overall per-protocol (PP) population included 96 subjects. Of note, the more homogeneous overall ITT population of subjects with idiopathic SSNHL who received corticoids (also called corticosteroids) between 24 and 96 hours from the onset of hearing loss included 94 subjects.

[0293] Drug administration

[0294] Subjects were administered placebo or (R)-azasetron (also known as SENS-401) for 28 days (i.e., 4 weeks). (R)-azasetron was administered orally twice daily at a dose of 29 mg / BID (twice a day (bis in die)) or a dose of 43.5 mg / BID (corresponding to a total daily dose of 40 mg and 60 mg free base equivalents, respectively).

[0295] Except (R)-azasetron or placebo, subject can also take oral corticosteroid (also referred to as adrenocortical hormone), such as dexamethasone, methylprednisolone or prednisone / prednisolone.Therefore, a total of 106 subjects have received oral corticosteroid (35 subjects in " placebo " treatment group, 36 subjects in " SENS-401 high dose " treatment group, and 35 subjects in " SENS-401 low dose " treatment group).In addition, in the case of no response, rescue therapy can be carried out by using intratympanic corticosteroid (such as dexamethasone or prednisone) from the 14th day.Therefore, a total of 14 subjects have received intratympanic corticosteroid (4 subjects in " placebo " treatment group, 4 subjects in " SENS-401 high dose " treatment group, 6 subjects in " SENS-401 low dose " treatment group).

[0296] Subject Monitoring and Goals

[0297] Subjects included in the study were monitored from the first visit on day -4 to day 0 (screening), and then at visits on day 1 (D1-randomization and inclusion day), day 7 (D7, ±2 days), day 14 (D14, ±2 days), day 28 (D28±3 days-end of treatment) and day 84 (D84±3 days-follow-up visit marking the end of the study). Monitoring included audiometric tests (PTA), speech audiometry, numeric rating scales, and questionnaires. In addition, subjects included in the study were closely monitored for adverse events throughout the study.

[0298] The primary objective of this study is to evaluate the efficacy of SENS-401 (i.e., (R)-azasetron) on hearing loss compared with placebo at the end of the 4-week treatment period. Efficacy was assessed by measuring the change in pure tone audiometry or PTA (corresponding to the average of the hearing thresholds (in dB) at the 3 most affected continuous hearing frequencies determined at study entry) in the affected ear from baseline to the end of the treatment visit (Day 28 visit, ±3 days or D28±3). The change in PTA from baseline to the end of the study visit (Day 84 visit, ±3 days or D84±3) in the affected ear was also measured.

[0299] As described above, a higher PTA corresponds to a higher hearing threshold, and therefore to worse hearing. Conversely, a lower PTA corresponds to a lower hearing threshold, and therefore to better hearing. Thus, a negative change in PTA, compared to a baseline PTA, corresponds to a decrease in the hearing threshold, and therefore to an improvement in hearing. In other words, a lower PTA, compared to a baseline PTA, corresponds to a decrease in the hearing threshold, and therefore to an improvement in hearing.

[0300] In addition, the efficacy of SENS-401 was also evaluated by performing speech audiometry, specifically by performing a speech discrimination test (also known as a word recognition test) to determine the word recognition score (WRS).

[0301] Speech discrimination or word recognition refers to the ability to correctly repeat a set of open monosyllabic words at suprathreshold intensities (e.g. 60dB or 80dB). The word recognition score (WRS) is therefore the percentage of test words that the subject repeats correctly. The test is conducted in a quiet room without any interfering noise. The word list is derived from a standard list containing monosyllabic words of a specific language. The words are presented to each ear separately and randomly, with contralateral masking. They are phonetically balanced, meaning that the speech sounds used occur at the same frequency as in the entire language.

[0302] A higher word recognition score (WRS) corresponds to a higher percentage of test words correctly repeated by a higher subject, and therefore corresponds to better hearing. Conversely, a lower WRS corresponds to a lower percentage of test words correctly repeated by a subject, and therefore corresponds to worse hearing. Thus, a positive change in WRS compared to a baseline WRS corresponds to an improvement in hearing.

[0303] Statistical analysis

[0304] Mean changes from baseline in PTA at days 28 and 84 were analyzed using a repeated measures approach based on restricted maximum likelihood (REML). Analyses included categorical fixed covariates of site category (nonadjuvant, adjuvant), disease duration, and baseline oral corticosteroid intake (stratification factors) and fixed categorical effects of treatment, visit, and treatment-by-visit interaction, as well as continuous fixed covariates of baseline score and baseline score-by-visit interaction. An unstructured covariance structure was used to model within-patient error. The denominator degrees of freedom were estimated using the Kenward-Roger approximation. Estimates and standard errors for the contrasts of interest were derived from the model. For each time point, marginal predicted means (least squares means) and corresponding 90% confidence intervals were derived for each treatment group. For each time point, a 5% one-sided p value was derived for the comparison with placebo. The same approach was applied to other efficacy endpoints (e.g., a verbal discrimination test designed to determine word recognition scores).

[0305] result

[0306] The change of PTA relative to baseline is assessed by measuring the PTA at the end of treatment (the 28th day or D28) and / or the end of research (the 84th day or D84-follow-up visit).Data are expressed as the mean change (dB) of PTA relative to baseline, which corresponds to the difference between the PTA and baseline PTA measured by D28 or D84 as shown (the PTA calculated as D28 or D84 deducts the baseline PTA).As mentioned above, higher PTA corresponds to higher hearing threshold, and therefore corresponds to poorer hearing.On the contrary, lower PTA corresponds to lower hearing threshold, and therefore corresponds to better hearing.Therefore, the change of the PTA of D28 or D84 compared with the baseline PTA is negative value (i.e., the change of PTA relative to the baseline is negative value) corresponding to the reduction of hearing threshold, and therefore corresponds to hearing improvement.In other words, the PTA of D28 or D84 lower than the baseline PTA corresponds to the reduction of hearing threshold, and therefore corresponds to hearing improvement.

[0307] The treatment efficacy (i.e., SENS-401 efficacy) was assessed by determining the difference between the treatment groups (ΔPTA SENS-401 vs placebo), which was calculated as the mean change in PTA relative to baseline (SENS-401) minus the mean change in PTA relative to baseline (placebo). Considering that the change in PTA relative to baseline after treatment with SENS-401 is negative (indicating a decrease in hearing threshold and, therefore, an improvement in hearing), a negative ΔPTA indicates that SENS-401 has a greater decrease in PTA relative to baseline than placebo. Therefore, a negative ΔPTA indicates that SENS-401 has a beneficial treatment effect, i.e., an improvement in hearing, compared to placebo.

[0308] Similarly, word recognition scores (WRS) are evaluated relative to the change of baseline by measuring the WRS at the end of treatment (the 28th day or D28) and / or the end of the study (the 84th day or D84-follow-up visit). Data are expressed as the mean change (%) of WRS relative to baseline, which corresponds to the difference between the WRS measured at D28 or D84 as shown and the baseline WRS (calculated as the WRS of D28 or D84 minus the baseline WRS). As shown above, higher WRS corresponds to the percentage of test words correctly repeated by higher subjects, and therefore corresponds to better hearing. On the contrary, lower WRS corresponds to the percentage of test words correctly repeated by lower subjects, and therefore corresponds to poorer hearing. Therefore, the change of WRS of D28 or D84 compared with baseline WRS is positive (that is, WRS is positive relative to the change of baseline) corresponding to hearing improvement.

[0309] The efficacy of treatment (i.e., SENS-401 efficacy) was assessed by determining the difference between the treatment groups (ΔWRS SENS-401 vs placebo), which was calculated as the mean change in WRS relative to baseline (SENS-401) minus the mean change in WRS relative to baseline (placebo). Considering that the change in WRS relative to baseline after treatment with SENS-401 is positive (indicating improved hearing), a positive ΔWRS indicates that the increase in WRS relative to baseline for SENS-401 is greater than that for placebo. Therefore, a positive ΔWRS indicates that SENS-401 has a beneficial therapeutic effect, i.e., improved hearing, compared to placebo.

[0310] Changes from baseline in PTA (and / or WRS) were determined in both the overall homogeneous study population of patients with idiopathic SSNHL receiving corticosteroids and in specific subpopulations of subjects (with idiopathic SSNHL receiving corticosteroids) defined by clinical markers, particularly those associated with the severity of SSNHL. When indicated, changes from baseline in PTA (and / or WRS) were determined in both the overall study population and in specific subpopulations of subjects (selected from the overall study population) defined by clinical markers, particularly those associated with the severity of SSNHL. Subpopulation analyses were performed to identify patients with SSNHL who were most likely to benefit from treatment with SENS-401.

[0311] The clinical data detailed below surprisingly indicate that subjects with severe or profound SSNHL are more likely to benefit from treatment with SENS-401 (i.e., (R)-azasetron). Therefore, clinical markers associated with the severity of SSNHL can help identify or select SSNHL subjects who are most likely to benefit from treatment with (R)-azasetron, such as SSNHL subjects whose baseline hearing threshold corresponds to a baseline PTA of equal to or greater than 70 dB; SSNHL subjects whose baseline hearing threshold corresponds to a baseline PTA of equal to or greater than 80 dB; SSNHL subjects whose baseline hearing threshold corresponds to a baseline PTA of equal to or greater than 90 dB; SSNHL subjects whose baseline hearing loss is equal to or greater than 91 dB (corresponding to profound hearing loss according to the ASHA classification); SSNHL subjects whose baseline hearing loss affects frequencies equal to or below 2000 Hz; and / or SSNHL subjects who also suffer from vertigo at baseline.

[0312] As shown in Tables 1-3 below, the efficacy of SENS-401 was evaluated at Day 28 (Table 1) and Day 84 (Tables 2 and 3) in a subpopulation of SSNHL subjects selected according to their baseline hearing thresholds (corresponding to a baseline PTA equal to or greater than a specified value).

[0313] The baseline PTA corresponds to the hearing threshold of the affected ear (or the most affected ear), expressed as the average (in dB) of the hearing thresholds at the 3 most affected consecutive test frequencies (air conduction hearing thresholds). As described above, a higher PTA corresponds to a higher hearing threshold and, therefore, to worse hearing.

[0314] As shown in Tables 1 and 2 below, the efficacy of SENS-401 was first evaluated in two different subpopulations selected from an overall homogeneous study population of subjects with idiopathic SSNHL receiving corticosteroids: a subpopulation of subjects with a baseline PTA equal to or greater than 80 dB (≥80 dB), and a subpopulation of subjects with a baseline PTA equal to or greater than 90 dB (≥90 dB).

[0315] Table 1: Comparison of placebo-controlled treatment-effect at Day 28 (ΔPTA at D28) in subpopulations defined using the baseline PTA clinical marker versus the overall study population

[0316]

[0317] Overall Study Population: ITT Overall Study Population of Subjects with Idiopathic SSNHL Receiving Corticotropin. PTA: Pure Tone Audiometry. SENS-401 High: SENS-401 was administered at a daily dose of 43.5 mg / BID (corresponding to a total daily dose of 60 mg free base equivalent). ΔPTA SENS-401 vs Placebo (dB): Difference between treatment groups, calculated as the mean change in PTA from baseline (SENS-401) minus the mean change in PTA from baseline (placebo). A negative ΔPTA indicates a greater decrease in PTA from baseline with SENS-401 compared to placebo.

[0318] As shown in Table 1, at Day 28, significant beneficial effects of SENS-401 administered at a daily dose of 43.5 mg / BID (corresponding to a total daily dose of 60 mg free base equivalents) were observed in both the subpopulation of subjects with baseline PTA ≥ 80 dB and the subpopulation of subjects with baseline PTA ≥ 90 dB.

[0319] In fact, in the subject subgroup with baseline PTA≥80dB, the difference between the treatment groups on the 28th day (ΔPTASENS-401 vs placebo) was -17.7765dB (p=0.0442). In contrast, in the overall study population, the difference between the treatment groups on the 28th day was only -3.9111dB (p=0.2754). It is worth noting that on the 28th day, the beneficial effect of SENS-401 administered at a daily dose of 29mg / BID (equivalent to a total daily dose of 40mg free base equivalents) was also observed in the subject subgroup with baseline PTA≥80dB, and the difference between the treatment groups (ΔPTA SENS-401 vs placebo) was -15.2188, which was greater than the difference observed in the overall study population (ΔPTA SENS-401 vs placebo = -4.1236).

[0320] In the subject subgroup of baseline PTA≥90dB, the difference between the treatment groups on the 28th day (ΔPTA SENS-401 vs placebo) was -23.2680dB (p=0.0278), which was greater than the difference observed in the overall study population (ΔPTA SENS-401 vs placebo=-3.9111). It is worth noting that at the 28th day, the beneficial effect of SENS-401 administered at a daily dose of 29mg / BID (corresponding to the total daily dose of 40mg free base equivalents) was also observed in the subject subgroup of baseline PTA≥90dB, and the difference between the treatment groups (ΔPTA SENS-401 vs placebo) was -13.9239, which was greater than the difference observed in the overall study population (ΔPTA SENS-401 vs placebo=-4.1236).

[0321] Table 2: Comparison of treatment-effect of placebo control at Day 84 (ΔPTA at D84) in subpopulations defined using the baseline PTA clinical marker and the overall study population (per-protocol overall population)

[0322]

[0323]

[0324] Overall Study Population: ITT Overall Study Population of Subjects with Idiopathic SSNHL Receiving Corticotropin. PTA: Pure Tone Audiometry. SENS-401 High: SENS-401 was administered at a daily dose of 43.5 mg / BID (corresponding to a total daily dose of 60 mg free base equivalent). ΔPTA SENS-401 vs Placebo (dB): Difference between treatment groups, calculated as the mean change in PTA from baseline (SENS-401) minus the mean change in PTA from baseline (placebo). A negative ΔPTA indicates a greater decrease in PTA from baseline with SENS-401 compared to placebo.

[0325] As shown in Table 2, at Day 84, significant beneficial effects of SENS-401 administered at a daily dose of 43.5 mg / BID (corresponding to a total daily dose of 60 mg free base equivalents) were observed in both the subpopulation of subjects with baseline PTA ≥ 80 dB and the subpopulation of subjects with baseline PTA ≥ 90 dB.

[0326] In fact, in the subject subgroup with baseline PTA≥80dB, the difference between the treatment groups on day 84 (ΔPTASENS-401 vs placebo) was -25.6472dB (p=0.0031). In contrast, in the overall study population, the difference between the treatment groups on day 84 was only -9.0984dB (p=0.0845). It is worth noting that, on day 84, a significant beneficial effect of SENS-401 administered at a daily dose of 29mg / BID (equivalent to a total daily dose of 40mg free base equivalents) was also observed in the subject subgroup with baseline PTA≥80dB, with the difference between the treatment groups (ΔPTA SENS-401 vs placebo) being -19.4991 (p=0.0161), which is greater than the difference observed in the overall study population (ΔPTA SENS-401 vs placebo=-8.7086).

[0327] In the subject subgroup of baseline PTA≥90dB, the difference between the treatment groups on the 84th day (ΔPTA SENS-401 vs placebo) was -28.6788dB (p=0.0068), which was greater than the difference observed in the overall study population (ΔPTA SENS-401 vs placebo=-9.0984). It is noteworthy that on the 84th day, the beneficial effect of SENS-401 administered at a daily dose of 29mg / BID (corresponding to the total daily dose of 40mg free base equivalents) was also observed in the subject subgroup of baseline PTA≥90dB, and the difference between the treatment groups (ΔPTA SENS-401 vs placebo) was -19.0242, which was greater than the difference observed in the overall study population (ΔPTA SENS-401 vs placebo=-8.7086).

[0328] The efficacy of SENS-401 was also evaluated at Day 84 in a subpopulation of SSNHL subjects with a baseline PTA equal to or greater than 70 dB (≥70 dB) selected from the overall study population.

[0329] Table 3: Comparison of Placebo-Controlled Treatment-Effect at Day 84 (ΔWRS at D84) in Subgroups Defined Using Baseline PTA Clinical Markers and the Overall Study Population

[0330]

[0331] Overall study population: ITT overall study population. WRS: word recognition score determined at 60 dB. SENS-401 low: SENS-401 was administered at a daily dose of 29 mg / BID (corresponding to a total daily dose of 40 mg free base equivalent). ΔWRSS SENS-401 vs placebo (dB): difference between treatment groups, calculated as the mean change in WRS from baseline (SENS-401) minus the mean change in WRS from baseline (placebo). A positive ΔWRS indicates a greater increase in WRS from baseline for SENS-401 compared to placebo.

[0332] As shown in Table 3, at Day 84, a significant beneficial effect of SENS-401 was observed in the subpopulation of subjects with baseline PTA ≥ 70 dB.

[0333] In fact, when SENS-401 was administered at a daily dose of 29 mg / BID (corresponding to a total daily dose of 40 mg free base equivalent), the difference between treatment groups (ΔWRS SENS-401 vs placebo) was 26.2165 (p=0.0428) at day 84. In contrast, in the overall study population, the difference between treatment groups at day 84 was only 19.4399 (p=0.0303).

[0334] Notably, at Day 28, the beneficial effects of SENS-401 administered at a daily dose of 29 mg / BID were also observed in the subpopulation of subjects with baseline PTA ≥ 70 dB, with a difference between treatment groups (ΔWRS SENS-401 vs placebo) of 12.9673, which was greater than the difference observed in the overall study population (ΔWRS SENS-401 vs placebo = 8.8241).

[0335] As shown in Table 4 below, the efficacy of SENS-401 was evaluated in a subpopulation of SSNHL subjects selected from the overall homogeneous study population of subjects with idiopathic SSNHL receiving corticosteroids based on their baseline hearing loss at Day 84. Thus, the subjects of the test subpopulation had a baseline hearing loss equal to or greater than 91 dB (corresponding to profound hearing loss according to the ASHA (American Speech-Language-Hearing Association) classification).

[0336] Hearing loss was defined as the difference between the PTA expressed as the mean (in dB) of the hearing thresholds at the 3 most affected consecutive test frequencies (air-tone average) and the corresponding PTA expressed as the mean hearing threshold of the contralateral ear at the same frequencies or the value from a pre-existing audiogram (dated less than 2 years ago) (mandatory for bilateral acute acoustic trauma).

[0337] ASHA has proposed a hearing loss classification method that depends on the degree of hearing loss, which is commonly used in the field (Clark. ASHA. 1981 Jul; 23 (7): 493-500). According to the ASHA classification, the degree of hearing loss is as follows:

[0338] -Hearing loss of -10 to 15dB: normal,

[0339] -Hearing loss of 16 to 25dB: mild hearing loss,

[0340] -Hearing loss of 26 to 40dB: mild hearing loss,

[0341] -Hearing loss of 41 to 55dB: moderate hearing loss,

[0342] -Hearing loss is 56 to 70dB: moderate to severe hearing loss,

[0343] -Hearing loss of 71 to 90dB: severe hearing loss,

[0344] -Hearing loss equal to or greater than 91dB: profound hearing loss.

[0345] Table 4: Comparison of treatment-effect of placebo control at Day 84 (ΔPTA at D84) in subpopulations defined using baseline initial hearing loss clinical markers (ASHA definition) versus the overall study population

[0346]

[0347]

[0348] ASHA: American Speech-Language-Hearing Association. Overall Study Population: ITT overall study population of subjects with idiopathic SSNHL receiving corticosteroids. PTA: pure tone audiometry. SENS-401 Low: SENS-401 was administered at a daily dose of 29 mg / BID (corresponding to a total daily dose of 40 mg free base equivalents). SENS401 High: SENS-401 was administered at a daily dose of 43.5 mg / BID (corresponding to a total daily dose of 60 mg free base equivalents). ΔPTA SENS-401 vs Placebo (dB): The difference between treatment groups, calculated as the change in PTA from baseline (SENS-401) minus the change in PTA from baseline (placebo). A negative ΔPTA indicates a greater decrease in PTA from baseline with SENS-401 compared to placebo.

[0349] As shown in Table 4, at Day 84, a significant beneficial effect of SENS-401 was observed in the subpopulation of subjects with a baseline hearing loss (ie, initial hearing loss) equal to or greater than 91 dB (corresponding to profound hearing loss according to the ASHA classification).

[0350] In fact, when SENS-401 was administered at a daily dose of 29 mg / BID (corresponding to a total daily dose of 40 mg free base equivalents), the difference between the treatment groups on day 84 (ΔPTA SENS-401 vs placebo) was -28.0377 dB (p = 0.0428). In contrast, in the overall study population, the difference between the treatment groups on day 84 was only -8.7086 dB (p = 0.5128). Similarly, when SENS-401 was administered at a daily dose of 43.5 mg / BID (corresponding to a total daily dose of 60 mg free base equivalents), the difference between the treatment groups on day 84 (ΔPTA SENS-401 vs placebo) was -26.2796 dB (p = 0.0367). In contrast, in the overall study population, the difference between the treatment groups on day 84 was only -9.0984 dB (p = 0.0845).

[0351] It is noteworthy that, at the 28th day, the beneficial effect of SENS-401 can be observed in the subject subgroup whose baseline hearing loss is equal to or greater than 91dB. When SENS-401 is applied with a daily dose of 29mg / BID, the difference (ΔPTA SENS-401vs placebo) between the treatment groups at the 28th day is -19.8922dB, which is greater than the difference (ΔPTA SENS-401vs placebo=-4.1236) observed in the overall study population. Similarly, when SENS-401 is applied with a daily dose of 43.5mg / BID, the difference (ΔPTA SENS-401vs placebo) between the treatment groups at the 28th day is -14.8893, which is greater than the difference (ΔPTA SENS-401vs placebo=3.9111) observed in the overall study population.

[0352] As shown in Table 5 below, the efficacy of SENS-401 was evaluated in a subpopulation of SSNHL subjects selected from the overall study population based on the baseline hearing frequencies affected by hearing loss at Day 84. Thus, the efficacy of SENS401 was evaluated in the "initial frequency range ≤ 2000 Hz" subpopulation, where the subjects' baseline hearing loss affected frequencies equal to or below 2000 Hz (in other words, the subjects of this subpopulation had baseline hearing loss affecting a frequency range equal to or below 2000 Hz).

[0353] Humans can hear sounds with frequencies ranging from about 20 Hz to about 20 kHz. Hearing loss below 2000 Hz affects verbal communication and affects quality of life. Therefore, patients with low-frequency hearing loss have difficulty hearing low-pitched, deeper voices, such as men's voices (which are generally deeper than women's or children's voices). They also have difficulty hearing conversations in a crowd and / or hearing voices in loud environments and places with background noise. Hearing loss below 2000 Hz also makes it difficult to hear bass when listening to music. Therefore, hearing loss affecting frequencies below 2000 Hz is considered a clinical marker for the severity of SSNHL.

[0354] As mentioned above, hearing thresholds are usually determined by pure tone audiometry (PTA), which is a standardized subjective hearing test that measures air conduction and / or bone conduction hearing thresholds (expressed in dB) at a set of fixed frequencies in the range of 0.25 kHz to 8 kHz. PTA is usually expressed as the average of the hearing thresholds (in dB) at the 3 most affected consecutive test frequencies (air conduction hearing threshold). Therefore, the baseline hearing threshold (corresponding to the baseline PTA) is defined as the hearing threshold of the affected ear (or the most affected ear), which is expressed as the average of the hearing thresholds (in dB) at the 3 most affected consecutive test frequencies (air conduction hearing threshold).

[0355] Table 5: Comparison of treatment-effect of placebo control at Day 84 (ΔPTA at D84) in subpopulations defined using initial baseline frequency range clinical markers versus the overall study population

[0356]

[0357] Overall Study Population: ITT Overall Study Population. PTA: Pure Tone Audiometry. SENS-401 Low: SENS-401 was administered at a daily dose of 29 mg / BID (corresponding to a total daily dose of 40 mg free base equivalent). ΔPTA SENS-401 vs Placebo (dB): Difference between treatment groups, calculated as the change in PTA from baseline (SENS-401) minus the change in PTA from baseline (placebo). A negative ΔPTA indicates a greater decrease in PTA from baseline with SENS-401 compared to placebo.

[0358] As shown in Table 5, at Day 84, a significant beneficial effect of SENS-401 administered at a daily dose of 29 mg / BID (corresponding to a total daily dose of 40 mg free base equivalents) was observed in the subpopulation of subjects whose baseline hearing loss affected frequencies ≤ 2000 Hz.

[0359] In fact, the difference between treatment groups (ΔPTA SENS-401 vs placebo) was -11.6405 dB (p=0.0483) at Day 84. In contrast, in the overall study population, the difference between treatment groups at Day 84 was only -7.0694 dB (p=0.1269).

[0360] The efficacy of SENS-401 was also evaluated in a subpopulation of SSNHL subjects selected based on their baseline hearing thresholds and baseline hearing frequencies affected by hearing loss, as shown in Table 6 below. Thus, the subjects selected from the subpopulation of subjects with idiopathic SSNHL receiving adrenocorticoids had a baseline PTA equal to or greater than 80 dB (≥80 dB) and a baseline hearing loss affecting frequencies equal to or below 2000 Hz (initial frequency range ≤2000 Hz).

[0361] Table 6: Comparison of treatment-effect of placebo control at Day 28 and Day 84 in subpopulations defined using baseline PTA and baseline initial frequency range clinical markers with the overall study population (ΔPTA at D28 and D84)

[0362]

[0363]

[0364] Overall Study Population: ITT overall study population of subjects with idiopathic SSNHL receiving corticosteroids. PTA: pure tone audiometry. SENS-401 Low: SENS-401 was administered at a daily dose of 29 mg / BID (corresponding to a total daily dose of 40 mg free base equivalent). ΔPTA SENS-401 vs Placebo (dB): Difference between treatment groups, calculated as the change in PTA from baseline (SENS-401) minus the change in PTA from baseline (placebo). A negative ΔPTA indicates a greater decrease in PTA from baseline with SENS-401 compared to placebo.

[0365] As shown in Table 6, significant beneficial effects of SENS-401 were observed at both Day 28 and Day 84 in the subpopulation of subjects with baseline PTA equal to or greater than 80 dB and baseline hearing loss affecting frequencies equal to or below 2000 Hz.

[0366] In fact, when SENS-401 was administered at a daily dose of 29 mg / BID (corresponding to a total daily dose of 40 mg free base equivalent) on the 28th day, the difference between the treatment groups (ΔPTA SENS-401 vs placebo) was -21.7623 dB (p=0.0380). In contrast, in the overall study population, the difference between the treatment groups on the 28th day was only -4.1236 dB (p=0.2630). Similarly, when SENS-401 was administered at a daily dose of 29 mg / BID on the 84th day, the difference between the treatment groups (ΔPTA SENS-401 vs placebo) was -26.6903 dB (p=0.0050). In contrast, in the overall study population, the difference between the treatment groups on the 84th day was only -8.7086 dB (p=0.5128).

[0367] It is noteworthy that the beneficial effects of SENS-401 administered at a daily dose of 43.5 mg / BID (corresponding to a total daily dose of 60 mg free base equivalent) were also observed. Thus, at day 84, the difference between the treatment groups (ΔPTA SENS-401 vs placebo) was -27.9588 (p = 0.0030), which was greater than the difference observed in the overall study population (ΔPTASENS-401 vs placebo = -9.0984 (p = 0.0845)).

[0368] As shown in Table 7 below, the efficacy of SENS-401 was evaluated at Day 84 in a subpopulation of SSNHL subjects selected from the overall homogeneous study population of subjects with idiopathic SSNHL receiving corticosteroids based on the presence or absence of vertigo at baseline.

[0369] The presence of vertigo was assessed on a numerical scale ranging from 0 to 10, with 0 corresponding to no vertigo and 10 corresponding to extreme vertigo.

[0370] Table 7: Comparison of treatment-effect of placebo control at Day 84 (ΔPTA at D84) in subpopulations defined using clinical markers of vertigo at baseline versus the overall study population

[0371]

[0372] Overall Study Population: ITT overall study population of subjects with idiopathic SSNHL receiving corticosteroids. PTA: pure tone audiometry. SENS-401 Low: SENS-401 was administered at a daily dose of 29 mg / BID (corresponding to a total daily dose of 40 mg free base equivalent). ΔPTA SENS-401 vs Placebo (dB): Difference between treatment groups, calculated as the change in PTA from baseline (SENS-401) minus the change in PTA from baseline (placebo). A negative ΔPTA indicates a greater decrease in PTA from baseline with SENS-401 compared to placebo.

[0373] As shown in Table 7, at Day 84, a significant beneficial effect of SENS-401 administered at a daily dose of 29 mg / BID (corresponding to a total daily dose of 40 mg free base equivalents) was observed in the subpopulation of subjects with vertigo at baseline.

[0374] In fact, the difference between treatment groups (ΔPTA SENS-401 vs placebo) was -21.8040 dB (p=0.0204) at Day 84. In contrast, in the overall study population, the difference between treatment groups at Day 84 was -8.7086 (p=0.5128).

[0375] Notably, at Day 28, the beneficial effects of SENS-401 administered at a daily dose of 29 mg / BID were also observed in the subpopulation of subjects with vertigo at baseline, with a difference between treatment groups (ΔPTA SENS-401 vs placebo) of -14.0995, which was greater than the difference observed in the overall study population (ΔPTA SENS-401 vs placebo = -4.1236).

[0376] In a subgroup of SSNHL subjects selected based on the presence or absence of vertigo at baseline, a significant beneficial effect of SENS-401 administered at a daily dose of 29 mg / BID (corresponding to a total daily dose of 40 mg free base equivalent) was also observed when evaluating the change in WRS relative to baseline at 60 dB and 80 dB on day 84. For example, when evaluated at 60 dB, the difference between the treatment groups on day 84 (ΔWRS SENS-401 vs placebo) was 53.1273 (p = 0.0074). In contrast, in the overall study population, the difference between the treatment groups on day 84 was only 19.4399 (p = 0.0303). When evaluated at 60 dB, the difference between the treatment groups on day 28 (ΔWRS SENS-401 vs placebo) was 35.5287 (p = 0.0467). In contrast, in the overall study population, the difference between treatment groups at day 28 was only 8.8241 (p=0.1948).

Claims

1. Azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof for use in treating sudden sensorineural hearing loss (SSNHL) in a subject in need thereof, wherein the subject suffers from severe or profound SSNHL associated with at least one of the following: - a baseline hearing threshold corresponding to a baseline pure tone audiometry (PTA) of equal to or greater than 70 dB, preferably equal to or greater than 80 dB, more preferably equal to or greater than 90 dB; - Baseline hearing loss equal to or greater than 91 dB, corresponding to profound hearing loss according to the American Speech-Language-Hearing Association (ASHA) classification; - Baseline hearing loss affecting frequencies at or below 2000 Hz; and / or -Presence of vertigo at baseline.

2. Azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 1, wherein the subject suffers from severe or profound SSNHL associated with a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 80 dB.

3. Azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 1 or 2, wherein the subject suffers from severe or profound SSNHL associated with a baseline hearing threshold corresponding to a baseline PTA equal to or greater than 90 dB.

4. Azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 3, wherein the subject suffers from severe or profound SSNHL associated with a baseline hearing loss affecting frequencies equal to or below 2000 Hz.

5. Azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 4, wherein SSNHL is idiopathic SSNHL.

6. Azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 5, wherein SSNHL is unilateral.

7. Azasetron or an azasetron analog or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 6, wherein azasetron is (R)-azasetron, (S)-azasetron, a mixture thereof, or a pharmaceutically acceptable salt and / or solvate thereof; preferably, azasetron is (R)-azasetron or a pharmaceutically acceptable salt and / or solvate thereof.

8. Azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 7, wherein the pharmaceutically acceptable salt is selected from benzenesulfonate, malate and hydrochloride.

9. Azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 8, wherein the pharmaceutically acceptable salt is (R)-azasetron besylate.

10. Azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 9, wherein the azasetron analogue is a benzoxazine compound or a pharmaceutically acceptable salt and / or solvate thereof, preferably selected from 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, 6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-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 pharmaceutically acceptable salts and / or solvates thereof.

11. Azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 10, wherein azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof is to be administered in a daily dose ranging from about 20 mg to about 200 mg.

12. Azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 11, wherein azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof is to be administered in a daily dose of about 40 mg or about 60 mg.

13. Azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 12, wherein azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof is to be administered within about 96 hours from the first onset of SSNHL.

14. Azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof for use according to any one of claims 1 to 13, wherein azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof is to be administered together with at least one additional pharmaceutically active agent.

15. Azasetron or an azasetron analogue or a pharmaceutically acceptable salt and / or solvate thereof for use according to claim 14, wherein the at least one additional pharmaceutically active agent is a corticosteroid.

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