WO2019068888A1

WO2019068888A1 - Use of botulinum toxin for the treatment of subjective tinnitus

Info

Publication number: WO2019068888A1
Application number: PCT/EP2018/077175
Authority: WO
Inventors: Danièle RANOUX
Original assignee: Ranoux Daniele
Priority date: 2017-10-06
Filing date: 2018-10-05
Publication date: 2019-04-11

Abstract

The present invention relates to the treatment of subjective tinnitus. More precisely, it concerns the administration of botulinum toxin into the scalp, neck and face muscles, especially in the temporalis muscle, of patients suffering from subjective tinnitus.

Description

USE OF BOTULINUM TOXIN FOR THE TREATMENT OF SUBJECTIVE TINNITUS

The present invention relates to the treatment of subjective tinnitus. More precisely, it concerns the administration of botulinum toxin into at least one muscle selected from the scalp muscles, the neck muscles and the face muscles, especially into the temporalis muscle, in patients suffering from subjective tinnitus.

BACKGROUND(1 ,2)

Tinnitus is the perceived sensation of sound in the absence of a corresponding external acoustic stimulus. Unlike auditory hallucinations, which are phantom phenomena that occur mainly in people with mental disorders and manifest as the perception of voices and musical hallucinations, in which instrumental music or sound is perceived, tinnitus sensations are usually of an unformed acoustic nature such as a buzzing, hissing, or ringing. Tinnitus can be unilateral or bilateral, but can also be described to emerge within the head. The perceived sensation can be intermittent or have a pulsatile character. The matched loudness of the phantom sound ranges from a subtle noise slightly above the hearing threshold to high-intensity sounds.

Tinnitus is classified as objective tinnitus if a sound is generated in the body and is also audible by the examiner (eg, myoclonic contractions of the tensor tympani muscle or altered blood flow in vessels near the ear). Tinnitus is classified as subjective tinnitus, if it does not have a specific inner-body sound source. Subjective tinnitus is much more common. Decreased sound tolerance (hyperacusis) is a common accompanying symptom, noted in 40% of patients with tinnitus, and up to 86% of patients who report hyperacusis also report tinnitus.

Epidemiology(1-3) In a large survey in Norway, 21 .3% of men and 16.2% of women reported perception of tinnitus, with 4-4% of men and 2-1 % of women reporting high tinnitus intensity. Results of epidemiological studies show similar prevalence not only in other European countries, the USA and Japan but also in low-income and middle-income countries in Africa and Asia, which indicates that the perception of phantom sounds is a global burden.

Risk factors. Hearing impairment, increasing age, and male sex have been identified as the most relevant risk factors for tinnitus. The main risk factor is hearing loss but this association is not simple or straightforward: some people with troublesome tinnitus have audiometrically normal hearing and, conversely, many people with hearing loss do not report tinnitus.

People who report high levels of both occupational and recreational noise exposure are also more likely to have tinnitus. Other factors such as obesity, smoking, alcohol consumption, previous head injuries, history of arthritis, and hypertension have been suggested as possible risk factors and some results have suggested a small genetic predisposition. Because of demographic developments and an increase in professional and leisure noise exposure, tinnitus prevalence is expected to continue to increase. Moreover, tinnitus is among the most frequent sequelae of modern warfare.

Comorbidities. Many patients with tinnitus report symptoms such as frustration, annoyance, irritability, anxiety, depression, hearing difficulties, hyperacousis, insomnia, and concentration difficulties; these symptoms are highly relevant to determine tinnitus severity. Thus, tinnitus is a highly prevalent and potentially distressing condition with a wide range of symptoms that can place a huge burden on patients and substantially impair quality of life. Its socioeconomic relevance is shown by the greatly increased risk of receiving a disability pension among patients with tinnitus.

Causes and pathophysiology(4-7)

Tinnitus can arise from pathological changes along the entire auditory pathway. In most cases, tinnitus develops as a consequence of initial cochlear lesions such as sudden hearing loss, noise trauma, presbyacusis, otosclerosis, Meniere's disease, or administration of ototoxic drugs (including salicylates, quinine, aminoglycoside antibiotics, and some of the antineoplastic agents, particularly the platinum-based drugs). These lesions can result in abnormal neuronal activity in central auditory pathways that can then be finally perceived as tinnitus. Abnormal changes to the auditory nerve (eg, microvascular compression or vestibular schwannoma) can also lead to perception of tinnitus.

Temporomandibular joint disorders and neck injuries have been associated with the development or persistence of tinnitus. The underlying mechanism is probably the effect of afferent somatosensory input from the trigeminal nerve and C2 fibers on central auditory pathway activity via interaction at the dorsal cochlear nucleus at brainstem level.

The onset of tinnitus can also be associated with emotional factors and stress. Neuronal mechanisms (5,7-9)

Although neuroscientific research in recent decades has contributed to a substantial increase in knowledge about the neuronal mechanisms underlying phantom perceptions, the pathophysiology of the different forms of tinnitus is not fully understood. Although tinnitus is often triggered by peripheral mechanisms (eg, cochlear impairment), it usually persists after auditory nerve section, underscoring the crucial involvement of central mechanisms in its pathophysiology. These changes in neuronal activity seem to arise from dysfunctional activation of neuronal plasticity induced by altered sensory input - namely, auditory deprivation in most cases. Additionally, abnormal somatosensory afferent input from the neck and face region can affect activity in central auditory pathways and might also contribute to the generation of tinnitus.

Importantly, tinnitus-related activity changes in the central nervous system are not restricted to auditory pathways. They can be conceived as alterations of a network involving both auditory and non-auditory structures (the salience network comprising the anterior insula, anterior cingulate, and thalamus).

Diagnosis(6) Several health questionnaires are available that assess the effects of tinnitus, of which the Tinnitus Handicap Inventory is the most commonly used, although the Tinnitus Functional Index might replace it. Questionnaires to assess associated symptoms such as hyperacusis and psychological distress can also be helpful. Pure-tone audiometry (or age-appropriate equivalents for children) should be done, and, because many patients complain of a blocked sensation in the ears, tympanometry can be useful.

Clinical management (1 ,2,7,10)

Treatments for management of tinnitus in addition to specific treatment of underlying or co-occuring abnormal changes include counselling, cognitive behavioural therapy, sound therapy, hearing aids, cochlear implants and brain stimulation. Pharmacotherapy is largely deceiving. Evidence levels for most treatment strategies are low, which is at least partly due to the heterogeneity of tinnitus, the difficulties in the assessment of tinnitus, substantial placebo effects, and low methodological quality of many treatment trials.

Until now, no drug has been approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for the treatment of tinnitus. Hence, there is a need for an effective treatment for subjective tinnitus.

The botulinum toxins (1 1 )

The neurotoxins produced by the anaerobic bacteria Clostridium botulinum, known as "botulinum toxins" (BT), are the most potent toxins known to date. In man, their ingestion results in botulism, a rare paralytic disease. The various strains of Clostridium botulinum produce seven distinct serotypes of botulinum toxin, of which five are pharmacologically active in man (A, B, E, F, and G) and two are inactive (C and D). Today, two serotypes are used in therapeutics, BT type A (BTX-A) and BT type B (BTX- B).

BT acts by cleaving SNARE proteins, avoiding the cell from releasing vesicles of neurotransmitter. Hence, it inhibits acetylcholine release at the neuromuscular junction, inducing atrophy and paralysis of the injected muscle. BT is widely used for the treatment of conditions involving an increase in muscle tone, such as dystonia and spasticity. It was also shown that BTX-A inhibits release of various neurotransmitters involved in pain transmission, such as Calcitonine Gene-Related Peptid (CGRP), Substance P and glutamate, as well as SNARE-dependent expressions of Transient Receptor Potential Vanilloid (TRPV1 ), a multimodal pain receptor. This property is routinely used in the treatment of chronic migraine and peripheral neuropathic pain. US 6,265,379 B1 patent describes the administration of BT type A (BOTOX^®) in the stapedius and/or tensor tympani muscles of the middle ear of one 38 year old suffering from subjective tinnitus. Such treatment allowed alleviating symptoms during 2 to 4 months after administration.

Surprisingly, the inventor has shown that a single administration of BT into the temporalis muscle of a patient suffering from subjective tinnitus allows the disappearance of symptoms. Given the above described properties of BT, the inventor has hypothesized that tinnitus can be due to increased muscle tone in one or more of various scalp, neck and face muscles, including the occipitalis and frontalis muscles, the temporalis muscle, the masseter muscles, the outer ear muscles, the lateral pterygoid, the sternocleidomastoid and neck muscles. In some embodiments it is due to increased muscle tone in the temporalis muscle. Accordingly, the inventor proposes to treat subjective tinnitus by administration of BT into at least one muscle selected from at least one scalp muscle, at least one neck muscle and at least one face muscle. In some embodiments subjective tinnitus is treated by administering BT into at least one muscle selected from the occipitalis muscle, the frontalis muscles, the temporalis muscle, the masseter muscles, the outer ear muscles, the lateral pterygoid, the sternocleidomastoid and neck muscles. In some embodiments subjective tinnitus is treated by administering BT into the temporalis muscle. In some embodiments subjective tinnitus is treated by administering BT into the temporalis muscle and at least one second muscle selected from the scalp muscles, the neck muscles and the face muscles. In some embodiments, subjective tinnitus is treated by administering BT into the temporalis muscle and at least one second muscle selected from the occipitalis muscle, the frontalis muscles, the temporalis muscle, the masseter muscles, the outer ear muscles, the lateral pterygoid, the sternocleidomastoid and neck muscles.

It has been established that blockade of the superior cervical sympathetic ganglion by inducing a radiofrequency lesion was capable of alleviating tinnitus(12). Thus, modulation of the vegetative system by botulinum toxins may be of interest through the injection of otic ganglion, sphenopalatine ganglion, trigeminal ganglion or superior cervical sympathetic ganglion. Accordingly, in some embodiments, subjective tinnitus is treated by administering BT into otic ganglion, sphenopalatine ganglion, trigeminal ganglion or superior cervical sympathetic ganglion

DETAILED DESCRIPTION OF THE INVENTION

The object of the invention concerns a method of treatment of subjective tinnitus consisting in administrating a botulinum toxin at least in one scalp and face muscles chosen among the occipitalis and frontalis muscles, the temporalis muscle, the masseter muscles, the outer ear muscles, the lateral pterygoid, the sternocleidomastoid, neck muscles as well as the otic ganglion, the sphenopalatine ganglion, the trigeminal ganglion or the superior cervical sympathetic ganglion. In a preferred embodiment, the butolinum toxin is administered in scalp muscles.

In a particular embodiment, the method of treatment of subjective tinnitus consists in administrating a botulinum toxin at least into the temporalis muscle.

In another particular embodiment, the method of treatment of subjective tinnitus consists in administrating a botulinum toxin at least into outer ear muscles, including superior, posterior and anterior ear muscles.

In another particular embodiment, the method of treatment of subjective tinnitus consists in administrating a botulinum toxin at least into outer ear muscles and temporalis muscle.

In another particular embodiment, the method of treatment as defined herein, is directed toward patients suffering from chronic migraine.

The invention can either be defined as the therapeutical use of botulinum toxin for the treatment of subjective tinnitus by administration into at least one muscle chosen among one scalp and face muscles chosen among the occipitalis and frontalis muscles, the temporalis muscle, the masseter muscles, the outer ear muscles, the lateral pterygoid, the sternocleidomastoid, neck muscles as well as the otic ganglion, the sphenopalatine ganglion, the trigeminal ganglion or the superior cervical sympathetic ganglion. In a preferred embodiment, botulinum toxin is administered at least in temporalis muscle.

In another embodiment, botulinum toxin is administered at least in outer ear muscles. In yet another embodiment, botulinum toxin is administered at least in both temporalis muscle and outer ear muscles.

As used herein, the term "botulinum toxin" encompasses any of the toxin serotypes produced by Clostridium botulinum, preferably serotypes A, B, E, F, and G, and more preferably serotypes A and B. This term includes neurotoxin complex as well as pure neurotoxin obtained or processed by bacterial culturing, toxin extraction, concentration, preservation, freeze drying (or vacuum drying) and/or reconstitution. This term also includes recombinant or modified neurotoxin, meaning neurotoxin that has had one or more amino acids or amino acid sequences deliberately deleted, modified or replaced by chemical/biochemical amino acid modification procedures or by use of known host cell/recombinant vector recombinant technologies, as well as derivatives or fragments of neurotoxins so made, and includes neurotoxins with one or more attached or recombinantly fused neuronal targeting moieties. Any modified neurotoxins should present a conserved BT activity. Currently, BT preparations are commercialized by four different pharmaceutical companies. Allergan commercializes a purified neurotoxin complex of Botulinum toxin type A, under the name of BOTOX^®, but preparation of Botulinum toxin type A is also commercialized under the name of Xeomin^® by Merz Pharma, and Dysport^® by Ipsen Pharma. These three preparations benefit from distinct market authorizations. Importantly, the three preparations are not equivalent. For example for BOTOX^®, the leaflet mentions that "the recommended dosage is not interchangeable by other preparation of botulinum toxins". This non-interchangeability reflects the fact the three preparations of Botulinum Toxin type A are prepared through different processes of production (which may further be covered by trade secret, as for BOTOX^®), leading to different products. A preparation of BT type B is also commercialized by Solstice Neurosciences under the name of Myobloc^®. As used herein, the terms « treatment » or « treating » encompass both the disappearance, the alleviation and the decrease of the symptoms.

In a particular embodiment, the BT is BT type A. More specifically, BT type A can be onabotulinumtoxinA (BOTOX^@), incobotulinumtoxinA (Xeomin^@) or abobotulinumtoxinA (Dysport^@). In a preferred embodiment, the BT type A is administered at least into the temporalis muscle. In another preferred embodiment, the BT type A is administered at least in the outer ear muscles. In yet another preferred embodiment, the BT type A is administered at least in the outer ear muscles and temporalis muscle.

In a particular embodiment, the BT type A corresponds to onabotulinumtoxinA (BOTOX^®) and between 10 U and 200 U, preferably between 10 U and 100 U, more preferabley betweenI O U and 50 U are administered. In a more preferred embodiment, the dosage corresponds to 30 U of onabotulinumtoxinA (BOTOX^®). In another embodiment, the BT type A may be incobotulinumtoxinA or abobotulinumtoxinA. Since BT is a biological product, the dosage is not interchangeable between the different preparations of BT. Some efforts have been made to establish a dose ratio between the available BT preparations, but the results constitute only a working hypothesis. The ratio onabotulinumtoxinA / incobotulinumtoxinA is evaluated to 1 , and the ratio onabotulinumtoxinA / abobotulinumtoxinA seems to be around 3. The appropriate dose for each BT can be determined according to medical practice.

In another embodiment, BT consists in neurotoxin complex, pure neurotoxin, recombinant neurotoxin, modified neurotoxin, derivatives or fragments of neurotoxin, provided that such BT presents a BT activity (meaning BT is pharmaceutically active, as do the serotypes A, B, E, F, and G).

The activity of a BT preparation can be tested using a toxicity test based on an in vivo mouse assay. BT concentration is quantified from median lethality in a group of mice and expressed as median lethal dose (LD50) Units per milliliter. Accordingly, the appropriate dosage can be determined for any type of preparation containing BT.In a further embodiment, the treatment of subjective tinnitus consists in the inactivation of the scalp, neck and face muscles as defined above, alone or in association, by intramuscular administration of BT. Inactivating these muscles, alone or in association, with intramuscular administration of BT can indeed dramatically alleviate subjective tinnitus whatever its origin. Thus, the invention also concerns a method of treatment of subjective tinnitus consisting in administrating a botulinum toxin in more than one scalp and face muscles chosen among the occipitalis and frontalis muscles, the temporalis muscle, the masseter muscles, the outer ear muscles, the lateral pterygoid, the sternocleidomastoid, neck muscles, the otic ganglion, the sphenopalatine ganglion, the trigeminal ganglion or the superior cervical sympathetic ganglion.

In a particular embodiment, the BT is administered into the temporalis muscle and into the occipitalis and frontalis muscles, the masseter muscles, the outer ear muscles, the lateral pterygoid, the sternocleidomastoid, neck muscles, the otic ganglion, the sphenopalatine ganglion, the trigeminal ganglion or the superior cervical sympathetic ganglion.

In another particular embodiment, the BT is administered into the temporalis muscle and into the outer ear muscles. The invention also concerns BT for use in the treatment of subjective tinnitus wherein the BT is administered at least in the temporalis muscle, the outer ear muscles or both.

DESCRIPTION OF THE FIGURES

Figure 1 : Representation of muscles of forehead, ear and neck.

Figure 2 : (A) Representation of the area of the temporal muscle, as a target for administration of BT. Arrow is directed toward the temporal muscle. (B) Picture of an administration in a patient of BT type A in the temporal muscle.

EXPERIMENTAL DATA EXEMPLE 1 : Administration of BT for chronic migraine in patients further suffering from subjective tinnitus 1.1 : Study 1

Materials and methods. We treated 63 patients for chronic migraine with BT type A (BOTOX^®). The injections sites were the corrugator and/or the temporalis muscles, and/or the trapezius muscles. The results of this study have been published in 2017, with a response rate of 65% for migraine (13).

1 ) In a retrospective analysis of our results, we identified 5 patients suffering from subjective tinnitus among the 41 responders. Each tinnitus patient received 30 units of onabotulinumtoxinA (onaA) into the temporalis muscle, leading to alleviation of both chronic migraine and tinnitus.

2 ) Hypothesing that the alleviation of tinnitus was due to the injections into the temporalis muscle, we offered the patients not to inject this muscle in order to assess the impact of this injection on the intensity of tinnitus.

Results _1 ) In 2/5 patients suffering from tinnitus and chronic migraine, the administration of BT led to a disappearance of tinnitus. In the 3 other patients, the symptoms have been decreased by at least 50%.

2 ) In the session when patients did not undergo temporalis muscles injections, patients' tinnitus was not alleviated. We consider that these results establish the efficacy of an intratemporal administration of BT for the treatment of subjective tinnitus.

Further, we found 5 patients with tinnitus among the 41 OnaA responders (22%), and none in the 22 non-responders. These symptoms occured late in the time course of migraine (mean time from migraine onset to tinnitus: 20.4 years). The tinnitus dramatically improved after OnaA injection (30 U) into the temporalis muscle, suggesting that tinnitus could be due to myofascial disorder of this muscle.

1.2 ) Study 2 We have had the opportunity of treating 3 other patients (3 women) with chronic migraine, complaining of tinnitus.

In these patients, injections into the temporalis muscles did not improve tinnitus. We observed that tinnitus could be modulated by strong pressure over the outer ear muscles (i.e. tinnitus diminished when these muscles were strongly palpated) and decided to inject these muscles. We injected 10 units of OnaA bilaterally in each of the outer ear muscles: posterior, superior and anterior ear muscles. This intervention led to dramatic improvement (>90%) of tinnitus, lasting more than 6 months.

EXEMPLE 2 : Study of the usefulness of Onabotulinumtoxin A (OnaA) injections in identifying the source of otalgia and tinnitus symptoms and in treating them. Methods. We report here (a) the prevalence of otalgia and tinnitus in a cohort of 63 patients treated with OnaA injections for chronic migraine and (b) the modifications of these symptoms following targeted injections of OnaA.

Results. We found 9 patients with deep otalgia and/or tinnitus among the 41 OnaA responders (22%), and none in the 22 non-responders. Four patients presented with otalgia only, 2 with tinnitus only, and 3 had both otalgia and tinnitus. These symptoms occured late in the time course of migraine (mean time from migraine onset to otalgia: 16.6 years, and to tinnitus: 20.4 years). Interestingly, the otalgia and tinnitus dramatically improved after OnaA injection into the splenius capitis and temporalis muscles respectively.

Conclusion. Our data show that otalgia and tinnitus in chronic migraine respond well to OnaA injections into the splenius capitis and temporalis muscles respectively, which suggest that they are a manifestation of a myofascial disorder of these muscles. We conclude that OnaA may be a reliable tool for identifying signs and symptoms arising from myofascial pain sites, due to its wide range of properties fitting the metabolic changes observed in myofascial disorders, and to its long-lasting effect. This complete study will be published. REFERENCES 1 . Levine RA, Oron Y. Tinnitus. Handb Clin Neurol. 2015;129:409-31 .

2. Baguley D, McFerran D, Hall D. Tinnitus. Lancet Lond Engl. 2013 Nov

9;382(9904):1600-7.

3. Sanchez TG, Rocha CB. Diagnosis and management of somatosensory tinnitus: review article. Clin Sao Paulo Braz. 201 1 ;66(6):1089-94. 4. M0ller AR. Sensorineural Tinnitus: Its Pathology and Probable Therapies. Int J Otolaryngol. 2016;2016:2830157.

5. Pannese A, Grandjean D, Friihholz S. Subcortical processing in auditory

communication. Hear Res. 2015 Oct;328:67-77.

6. Zeman F, Koller M, Schecklmann M, Langguth B, Landgrebe M, TRI database study group. Tinnitus assessment by means of standardized self-report questionnaires: psychometric properties of the Tinnitus Questionnaire (TQ), the Tinnitus Handicap Inventory (THI), and their short versions in an international and multi-lingual sample. Health Qual Life Outcomes. 2012 Oct 18;10:128.

7. Langguth B, Kreuzer PM, Kleinjung T, De Ridder D. Tinnitus: causes and clinical management. Lancet Neurol. 2013 Sep;12(9):920-30.

8. Langguth B, Landgrebe M, Schlee W, Schecklmann M, Vielsmeier V, Steffens T, et al. Different Patterns of Hearing Loss among Tinnitus Patients: A Latent Class Analysis of a Large Sample. Front Neurol. 2017;8:46.

9. De Ridder D, Vanneste S, Langguth B, Llinas R. Thalamocortical Dysrhythmia:

A Theoretical Update in Tinnitus. Front Neurol. 2015;6:124.

10. Wolever RQ, Price R, Hazelton AG, Dmitrieva NO, Bechard EM, Shaffer JK, et al. Complementary Therapies for Significant Dysfunction from Tinnitus: Treatment Review and Potential for Integrative Medicine. Evid-Based

Complement Altern Med ECAM. 2015;2015:931418. Pirazzini M, Rossetto O, Eleopra R, Montecucco C. Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology. Pharmacol Rev. 2017 Apr 1 ;69(2):200- 35. Koning HM, Dyrbye BA, van Hemert FJ. Percutaneous Radiofrequency Lesion of the Superior Cervical Sympathetic Ganglion in Patients with Tinnitus. Pain Pract Off J World Inst Pain. 2016 Nov;16(8):994-1000. Ranoux D, Martine G, Espagne-Dubreuilh G, Amilhaud-Bordier M, Caire F, Magy L. OnabotulinunntoxinA injections in chronic migraine, targeted to sites of pericranial myofascial pain: an observational, open label, real-life cohort study. J Headache Pain. 2017 Dec;18(1 ):75.

Claims

1 . A method of treating subjective tinnitus in a subject, comprising administering a botulinum toxin in at least one muscle of the subject, wherein the at least one muscle is selected from at least one scalp muscle, at least one neck muscle and at least one face muscle.

2. A method of treating subjective tinnitus in a subject, comprising administering a botulinum toxin in at least one muscle of the subject, wherein the at least one muscle is selected from the occipitalis muscle, the frontalis muscles, the temporalis muscle, the masseter muscles, the outer ear muscles, the lateral pterygoid, the sternocleidomastoid and neck muscles, the otic ganglion, the sphenopalatine ganglion, the trigeminal ganglion or the superior cervical sympathetic ganglion.

3. The method of claim 1 or 2, wherein the botulinum toxin is administered at least in the temporalis muscle.

4. The method of claim 1 or 2, wherein the botulinum toxin is administered at least in the outer ear muscles.

5. The method of any one of claims 1 to 4, wherein the botulinum toxin is administered at least in both the temporalis muscle and the outer ear muscles.

6. The method of any one of claims 1 to 5, wherein the patient is suffering from chronic migraine.

7. The method of any one of claims 1 to 6, wherein the botulinum toxin is botulinum toxin type A.

8. The method of any one of claims 1 to 7, wherein the botulinum toxin selected from neurotoxin complex, pure neurotoxin, recombinant neurotoxin, modified neurotoxin, and derivatives and/or fragments of neurotoxin.

9. The method of any one of claims 1 to 8, wherein said BT of type A is chosen from onabotulinumtoxinA, incobotulinumtoxinA or abobotulinumtoxinA.