WO2023047127A1 - Modified bont/a for use in the treatment of a disorder affecting an eyelid muscle of a subject - Google Patents

Modified bont/a for use in the treatment of a disorder affecting an eyelid muscle of a subject Download PDF

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Publication number
WO2023047127A1
WO2023047127A1 PCT/GB2022/052415 GB2022052415W WO2023047127A1 WO 2023047127 A1 WO2023047127 A1 WO 2023047127A1 GB 2022052415 W GB2022052415 W GB 2022052415W WO 2023047127 A1 WO2023047127 A1 WO 2023047127A1
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Prior art keywords
unit dose
muscle
asn
modified bont
bont
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English (en)
French (fr)
Inventor
Nicolae GRIGORE
Laurent PONS
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Ipsen Biopharm Ltd
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Ipsen Biopharm Ltd
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Priority claimed from GBGB2113602.3A external-priority patent/GB202113602D0/en
Priority claimed from GBGB2206360.6A external-priority patent/GB202206360D0/en
Priority to AU2022351260A priority Critical patent/AU2022351260A1/en
Application filed by Ipsen Biopharm Ltd filed Critical Ipsen Biopharm Ltd
Priority to KR1020247012920A priority patent/KR20240067100A/ko
Priority to CN202280064373.8A priority patent/CN117979988A/zh
Priority to US18/690,479 priority patent/US20250179461A1/en
Priority to CA3228712A priority patent/CA3228712A1/en
Priority to JP2024518109A priority patent/JP2024534541A/ja
Priority to EP22782758.1A priority patent/EP4404955A1/en
Publication of WO2023047127A1 publication Critical patent/WO2023047127A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A61K38/4893—Botulinum neurotoxin (3.4.24.69)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6402—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from non-mammals
    • C12N9/6405—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from non-mammals not being snakes
    • C12N9/6416—Metalloendopeptidases (3.4.24)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Clostridium (G)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/24—Metalloendopeptidases (3.4.24)
    • C12Y304/24069—Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin

Definitions

  • the present invention relates to treatment of a disorder affecting an eyelid muscle of a subject.
  • blepharospasm and facial spasm are particularly unpleasant.
  • Blepharospasm is characterized primarily by abnormal contractions of the orbicularis oculi muscles. More specifically, blepharospasm can manifest as an uncontrollable excessive blinking and spasming of one or both eyes that is further characterized by uncontrollable eyelid closure of durations longer than the typical blink reflex. Blepharospasm symptoms can be recurrent and may last for a few hours or days at a time and, in some cases, the symptoms (e.g. twitching) may be chronic and persistent, causing life-long challenges for subjects suffering from the condition. Other symptoms may include twitching that can radiate into the nose, face and neck, dryness of the eyes, and sensitivity to the sun and bright lights.
  • blepharospasm can be induced by certain drugs such as, for example, drugs to treat Parkinson's disease, estrogen-replacement therapy, or acute withdrawal from benzodiazepines.
  • Blepharospasm may also be associated with brain disorders (e.g. including neurodegenerative conditions, abnormal functioning of the brain's basal ganglia, and multiple sclerosis), brain damage, or head injuries (e.g. concussion).
  • Hemifacial spasm is a movement disorder that is characterized by involuntarily tonic - clonic contractions of the mimetic muscles on one side of the face. While bilateral cases are sometimes seen, they are extremely rare. Affected muscles are those innervated by the facial nerve (cranial nerve VII). Initially, symptoms of the disorder are typically located to the orbicularis oculi muscle (e.g. typical hemifacial spasm) and may spread to include other muscles of facial expression. Hemifacial spasm (HFS) takes two forms: typical HFS and atypical HFS. In the typical form, the twitching/ spasm typically begins in the lower eyelid in orbicularis oculi muscle.
  • HFS Hemifacial spasm
  • twitching/ spasm typically begins in orbicularis oris muscle around the lips, and buccinator muscle in the cheekbone area in the lower face, then progresses up to the orbicularis oculi muscle in the eyelid over time.
  • the most common form is the typical form, and atypical form is only seen in about 2-3% of patients with hemifacial spasm.
  • Drug therapy for disorders affecting an eyelid muscle of a subject has proven generally unpredictable and short-termed.
  • Anticholinergics, tranquillizing drugs and botulinum neurotoxins e.g. Dysport®, Botox® or Xeomin®
  • these treatment options are not optimal and are associated with serious side effects, including toxicity and unwanted paralysis of facial muscles.
  • invasive surgical procedure may be envisaged for patients who do not respond well to medication or botulinum neurotoxin injection.
  • new and effective therapies for the treatment of blepharospasm are constantly being tested or sought after.
  • BoNT/A botulinum neurotoxin A selectively inhibits the release of acetylcholine from the presynaptic nerve terminals and thus blocks cholinergic transmission at the neuromuscular junction inducing a reduction in the muscle contraction and muscle tone, causing the injected muscles to relax.
  • the duration of action of the currently available BoNT/A products is about 12 to 14 weeks, which is when the new nerve endings sprout allowing the nerve function to return to normal, and the original symptoms reappear. Consequently, for the effect to be maintained, injections need to be repeated periodically.
  • the frequency of BoNT/A injections is an important consideration for the treatment of disorders affecting an eyelid muscle of a subject (e.g.
  • Dysport® is approved for the treatment of blepharospasm and hemifacial spasm with a maximum total dose per treatment session of 120 Units per eye.
  • a clinician is required to administer Dysport® to an eyelid muscle of the subject up to the upper threshold of 120 Units total per eye per treatment session (i.e. 240 Units when treating both eyes).
  • the clinician is forced to make difficult choices during treatment of a patient.
  • a clinician must find a balance between the relatively low total amount of BoNT/A that can be administered (necessitated by the highly toxic nature of BoNT/A) and the effective amount at a plurality of different muscles and/or sites thereof. Hence, certain muscles may be neglected while others receive a suboptimal amount of BoNT/A, resulting in suboptimal therapy.
  • the present invention overcomes one or more of the above-mentioned problems.
  • a modified BoNT/A finds particular utility in treating a disorder affecting an eyelid muscle of a subject (e.g. blepharospasm and/or hemifacial spasm).
  • the modified BoNT/A may comprise a BoNT/A light-chain and translocation domain and a BoNT/B receptor binding domain (He domain), which results in a modified BoNT/A that exhibits increased retention at (reduced diffusion away from) a site of administration and/or increased duration of action (e.g. 6-9 months).
  • the modified BoNT/A may comprise one or more modifications of surface exposed amino acid residues resulting in an increased net positive charge.
  • the increased charge promotes electrostatic interactions between the polypeptide and anionic extracellular components, thereby promoting binding between the polypeptide and cell surface. In turn this also increases retention at (reduces diffusion away from) a site of administration and/or results in an increased duration of action (e.g. 6-9 months).
  • modified BoNT/A has a safety profile that is improved when compared to unmodified BoNT/A (e.g. Dysport®).
  • This improved safety profile may be expressed by the high Safety Ratio described herein for the modified BoNT/A.
  • a higher total amount of modified BoNT/A may be administered to a subject while achieving a similar safety profile to unmodified BoNT/A (e.g. Dysport®) while at such high doses.
  • more modified BoNT/A may be injected and/or may be injected at a greater number of muscles and/or sites thereof in the treatment of a disorder affecting an eyelid muscle of a subject (e.g.
  • the treatment may be improved in that it provides for longer-lasting treatment (resulting in less frequent administration) and/or is capable of being tailored for the subject and/or results in an improved quality of life of a subject when compared to treatment with unmodified BoNT/A (e.g. Dysport®).
  • BoNT/A e.g. Dysport®
  • the present invention provides a convenient, safe, and effective single unit dose as well as a total (maximum) dosage that can be safely administered in a single treatment.
  • the present invention also provides a corresponding guide to the number of times at which said unit dose can be administered to a muscle (e.g. including the number of injection sites per muscle) without resultant patient toxicity.
  • Treatment of a disorder affecting an eyelid muscle of a subject e.g. blepharospasm and/or hemifacial spasm
  • treatment according to the invention is much more satisfactory to the patient, as it is better tailored to the patient’s needs, when compared to conventional treatments.
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating a disorder affecting an eyelid muscle of a subject, the method comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 240 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a
  • the eye proximal to the injection site may be referred to as an eye affected by the disorder.
  • the term “the lateral upper orbicularis oculi muscle” may refer to “the lateral pretarsal orbicularis oculi muscle of the upper eyelid”.
  • the term “the medial upper orbicularis oculi muscle” may refer to “the medial pretarsal orbicularis oculi muscle of the upper eyelid”.
  • the term “the lateral lower orbicularis oculi muscle” may refer to “the lateral pretarsal orbicularis oculi muscle of the lower eyelid”.
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • the method comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 240 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain
  • treating a disorder affecting an eyelid muscle of a subject may mean that one or more symptoms of said disorder of the subject are reduced.
  • treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A may mean that one or more symptoms of said disorder of the subject are reduced for a longer time period following administration of a modified BoNT/A of the invention, when compared to administration of an unmodified BoNT/A. Said reduction may be determined by comparison to an equivalent control subject exhibiting equivalent symptoms that has been treated with an unmodified BoNT/A. At a time period where the severity of one or more symptoms of the control subject are substantially the same (e.g.
  • a subject treated with a modified BoNT/A according to the invention may exhibit an improvement in the equivalent one or more symptoms of at least 5%, 10%, 25%, or 50% when compared to the severity of the one or more symptoms before treatment with the modified BoNT/A.
  • the unmodified BoNT/A is preferably SEQ ID NO: 2 present in a di-chain form.
  • the invention provides a method of treating a disorder affecting an eyelid muscle of a subject, the method comprising: administering a single unit dose of a modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 240 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides a method of treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), the method comprising: administering a single unit dose of a modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 240 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of a medicament for treating a disorder affecting an eyelid muscle of a subject, comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 240 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and
  • the invention provides use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • BoNT/A botulinum neurotoxin A
  • SEQ ID NO: 2 comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 240 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding
  • One aspect provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating blepharospasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A, wherein the total dose administered during the treatment is
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating blepharospasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and
  • the invention provides a method of treating blepharospasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and where
  • the invention provides a method of treating blepharospasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating blepharospasm in a subject, comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating blepharospasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • SEQ ID NO: 2 comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain (HN), and a BoNT/B receptor binding domain (He domain).
  • HN BoNT/A light-
  • Another aspect provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating typical hemifacial spasm, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in
  • BoNT/A botulinum neurotoxin A
  • HN botulinum neurotoxin A
  • He domain BoNT/B receptor binding domain
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating typical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in accordance with the following dosage regimen:
  • BoNT/A botulinum neurotoxin A
  • HN botulinum neurotoxin A
  • He domain BoNT/B receptor binding domain
  • the invention provides a method of treating typical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in accordance with the following dosage regimen:
  • BoNT/A botulinum neurotoxin A
  • HN botulinum neurotoxin A
  • He domain BoNT/B receptor binding domain
  • the invention provides a method of treating typical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or
  • BoNT/A botulinum neurotoxin A
  • HN botulinum neurotoxin A
  • He domain BoNT/B receptor binding domain
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating typical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hem
  • BoNT/A botulinum neurotoxin A
  • HN botulinum neurotoxin A
  • He domain BoNT/B receptor binding domain
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating typical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • BoNT/A botulinum neurotoxin A
  • the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in accordance with the following dosage regimen:
  • BoNT/A botulinum neurotoxin A
  • HN botulinum neurotoxin A
  • He domain BoNT/B receptor binding domain
  • BoNT/A botulinum neurotoxin A
  • a method of treating atypical hemifacial spasm wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a botulinum neurotoxin A (BoNT/A) lightchain and translocation domain (HN), and a BoNT/B receptor binding domain (He domain).
  • BoNT/A botulinum neurotoxin A
  • HN botulinum neurotoxin A
  • He domain BoNT/B receptor binding domain
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating atypical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • BoNT/A botulinum neurotoxin A
  • the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a botulinum neurotoxin A (BoNT/A) lightchain and translocation domain (HN), and a BoNT/B receptor binding domain (He domain).
  • BoNT/A botulinum neurotoxin A
  • HN botulinum neurotoxin A
  • He domain BoNT/B receptor binding domain
  • the invention provides a method of treating atypical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a botulinum neurotoxin A (BoNT/A) lightchain and translocation domain (HN), and a BoNT/B receptor binding domain (He domain).
  • BoNT/A botulinum neurotoxin A
  • HN botulinum neurotoxin A
  • He domain BoNT/B receptor binding domain
  • the invention provides a method of treating atypical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a botulinum neurotoxin A (BoNT/A) lightchain and translocation domain (HN), and a BoNT/B receptor binding domain (He domain).
  • BoNT/A botulinum neurotoxin A
  • HN botulinum neurotoxin A
  • He domain BoNT/B receptor binding domain
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating atypical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a botulinum neurotoxin A (BoNT/A) lightchain and translocation domain (HN), and a BoNT/B receptor binding domain (He domain).
  • BoNT/A botulinum neurotoxin A
  • HN botulinum neurotoxin A
  • He domain BoNT/B receptor binding domain
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating atypical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • BoNT/A botulinum neurotoxin A
  • the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a botulinum neurotoxin A (BoNT/A) lightchain and translocation domain (HN), and a BoNT/B receptor binding domain (He domain).
  • BoNT/A botulinum neurotoxin A
  • HN botulinum neurotoxin A
  • He domain BoNT/B receptor binding domain
  • hemifacial spasm typically hemifacial spasm
  • hemifacial spasm typically used interchangeably with the term “hemifacial spasm” throughout this disclosure.
  • the unit dose may be at least 240.4 pg, 500 pg, 1 ,000 pg, 2,000 pg, 3,000 pg or 4,000 pg, preferably at least 1 ,000 pg, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the upper limit of a unit dose of the invention may be determined based on the total dose administered during the treatment and the number of muscles and/or sites thereof to which the modified BoNT/A is administered. For example, where the total dose administered during the treatment is up to 24,000 pg of modified BoNT/A and administration is to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject, the medial upper orbicularis oculi muscle proximal to the first eye, and the lateral lower orbicularis oculi muscle proximal to the first eye only, then the upper limit of the unit dose may be 8,000 pg.
  • the upper limit may be 4,000 pg (e.g. upper limit of 4,000 pg per eye).
  • the unit dose may be 240 pg to 10,000 pg of modified BoNT/A, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 240 pg to 9,500 pg of modified BoNT/A, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 240 pg to 9,000 pg of modified BoNT/A, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 240 pg to 8,000 pg of modified BoNT/A, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • An upper limit of the unit dose range may be 7,500, 7,000, 6,500, 6,000, 5,500, 5,000, 4,800, 4,500, 4,000, 3,500, 3,000, 2,500, 2,400, 2,000, 1,500, or 1,250 pg of modified BoNT/A.
  • a lower limit of the unit dose range may be 300, 400, 500, 600, 700, 800, 900, 1 ,000, 1 ,500, 2,000, 2,500, 3,000, 3,500, 4,000, 4,500, or 5,000 pg of modified BoNT/A, preferably the lower limit is 1 ,000 pg.
  • the unit dose may be 1 ,000 pg to 4,800 pg, 1 ,000 pg to 4,000 pg, 1 ,000 pg to 2,400 pg, or 1 ,000 pg to 2,000 pg.
  • the unit dose may be 240.4 pg, 500 pg, 1 ,000 pg, 2,000 pg, 3,000 pg, 4,000 pg, 5,000 pg, 6,000 pg, 7,000 pg or 8,000 pg, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 240.4 pg, 500 pg, 1 ,000 pg, 2,000 pg, 3,000 pg or 4,000 pg, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 1 ,000 pg, 2,000 pg, 3,000 pg or 4,000 pg, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • a total dose administered when carrying out the treatment regimen of the present invention may be up to 24,000 pg of modified BoNT/A, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the total amount of modified BoNT/A administered at a given treatment session may be up to 24,000 pg.
  • the total dose may be up to 20,000, 15,000, 10,000, 7,500, or 6,000 pg.
  • the total dose may be at least 720, 800, 900, 1,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000, 12,500, 15,000, or 20,000 pg.
  • the total dose may be at least 3,000 pg of modified BoNT/A.
  • the total dose may be 720 pg to 24,000 pg, preferably 3,000 pg to 24,000 pg.
  • the total dose may be 720, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 7,500, 10,000, 12,500, 15,000, or 20,000 pg, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the total dose may be 6,000 pg, 7,500 pg, 10,000 pg, 15,000 pg or 20,000 pg, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 1,000 pg and the total dose may be 6,000 pg, 7,500 pg, 10,000 pg, 15,000 pg or 20,000 pg, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 2,000 pg and the total dose may be 6,000 pg, 7,500 pg, 10,000 pg, 15,000 pg or 20,000 pg, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 3,000 pg and the total dose may be 6,000 pg, 7,500 pg, 10,000 pg, 15,000 pg or 20,000 pg, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 4,000 pg and the total dose may be 6,000 pg, 7,500 pg, 10,000 pg, 15,000 pg or 20,000 pg, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating a disorder affecting an eyelid muscle of a subject, the method comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT
  • U
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • the method comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • U Units
  • the invention provides a method of treating a disorder affecting an eyelid muscle of a subject, the method comprising: administering a single unit dose of a modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-
  • the invention provides a method of treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), the method comprising: administering a single unit dose of a modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating a disorder affecting an eyelid muscle of a subject, comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT
  • U
  • the invention provides use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • BoNT/A botulinum neurotoxin A
  • SEQ ID NO: 2 comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating blepharospasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A, and wherein the
  • the invention provides a method of treating blepharospasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment
  • LD50
  • the invention provides a method of treating blepharospasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating blepharospasm in a subject, comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating blepharospasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • SEQ ID NO: 2 comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (
  • Another aspect provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating typical hemifacial spasm, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in
  • U Units
  • 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating typical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in accordance with the following dosage regimen:
  • U Units
  • 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides a method of treating typical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in accordance with the following dosage regimen: (i) one unit dose of the modified Bo
  • U Units
  • 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides a method of treating typical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or
  • U Units
  • 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating typical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hem
  • U Units
  • 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating typical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • BoNT/A botulinum neurotoxin A
  • the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in accordance with the following dosage regimen:
  • U Units
  • 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • BoNT/A botulinum neurotoxin A
  • a method of treating atypical hemifacial spasm wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating atypical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • BoNT/A botulinum neurotoxin A
  • the unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides a method of treating atypical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides a method of treating atypical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating atypical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating atypical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • BoNT/A botulinum neurotoxin A
  • the unit dose of the modified BoNT/A is at least 10 Units (U) of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 998 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be at least 21 U, 42 U, 83 U, 125 U, or 166 U, preferably at least 42 U, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 10 U to 332.7 U of modified BoNT/A, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • An upper limit of the unit dose range may be 312, 291, 270, 250, 229, 208, 199.6, 187, 166.3, 146, 125, 104, 99.8, 89.17, 62, or 52 U of modified BoNT/A.
  • a lower limit of the unit dose range may be 12, 17, 21 , 25, 29, 33, 37, 42, 62, 83, 104, 125, 146, 166, 187, or 208 U of modified BoNT/A, preferably the lower limit is 42 U.
  • the unit dose may be 42 U to 199.6 U, 42 U to 166.3 U, 42 U to 99.8 U, or 42 U to 83.17 U.
  • the unit dose may be 10 Units, 20.8 Units, 41.6 Units, 83.2 Units, 124.8 Units, 166.4 Units, 207.8 Units, 249.6 Units, 291.2 Units or 332.8 Units, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 10 Units, 20.8 Units, 41.6 Units, 83.2 Units, 124.8 Units, or 166.4 Units, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 41.6 Units, 83.2 Units, 124.8 Units, or 166.4 Units, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • a total dose administered when carrying out the treatment regimen of the present invention may be up to 998 U of modified BoNT/A, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the total amount of modified BoNT/A administered at a given treatment session may be up to 998 II.
  • the total dose may be up to 832, 624, 416, 312, or 250 II.
  • the total dose may be at least 30, 33, 37, 42, 83, 125, 166, 208, 312, 416, 520, 624, or 832 U.
  • the total dose may be at least 125 II of modified BoNT/A.
  • the total dose may be 30 U to 998 U, preferably 125 U to 998 U.
  • the total dose may be 29.9 Units, 33.3 Units, 37.4 Units, 41.6 Units, 83.2 Units, 124.8 Units, 166.4 Units, 208 Units, 312 Units, 416 Units, 520 Units, 624 Units, or 831.9 Units, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the total dose may be 249.6 Units, 312 Units, 416 Units, 624 Units, or 831.9 Units, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 41.6 Units and the total dose may be 249.6 Units, 312 Units, 416 Units, 624 Units, or 831.9 Units, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 83.2 Units and the total dose may be 249.6 Units, 312 Units, 416 Units, 624 Units, or 831.9 Units, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 124.8 Units and the total dose may be 249.6 Units, 312 Units, 416 Units, 624 Units, or 831.9 Units, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the unit dose may be 166.4 Units and the total dose may be 249.6 Units, 312 Units, 416 Units, 624 Units, or 831.9 Units, wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (He domain).
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating a disorder affecting an eyelid muscle of a subject, the method comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: A
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • the method comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 84 pg (preferably 84 pg to 666.7 pg) of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN
  • the invention provides a method of treating a disorder affecting an eyelid muscle of a subject, the method comprising: administering a single unit dose of a modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU
  • the invention provides a method of treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), the method comprising: administering a single unit dose of a modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of a medicament for treating a disorder affecting an eyelid muscle of a subject, comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of a medicament for treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • BoNT/A botulinum neurotoxin A
  • SEQ ID NO: 2 comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991,
  • One aspect provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating blepharospasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating blepharospasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 90
  • the invention provides a method of treating blepharospasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or
  • the invention provides a method of treating blepharospasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating blepharospasm in a subject, comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating blepharospasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • SEQ ID NO: 2 comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955,
  • Another aspect provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating typical hemifacial spasm, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating typical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in accordance with the following dosage regimen:
  • the invention provides a method of treating typical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in accordance with the following dosage regimen:
  • the invention provides a method of treating typical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating typical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hem
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating typical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • BoNT/A botulinum neurotoxin A
  • the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in accordance with the following dosage regimen:
  • BoNT/A botulinum neurotoxin A
  • a method of treating atypical hemifacial spasm wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032,
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating atypical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • BoNT/A botulinum neurotoxin A
  • the unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032,
  • the invention provides a method of treating atypical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032,
  • the invention provides a method of treating atypical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081 , GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243,
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating atypical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032,
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating atypical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.
  • the unit dose of the modified BoNT/A is at least 84 pg of modified BoNT/A, wherein the total dose administered during the treatment is up to 2,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081 , GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243,
  • the unit dose may be at least 84.4 pg, 100 pg or 250 pg, wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from: (i) substitution of an acidic surface exposed amino acid residue with a basic amino acid residue; (ii) substitution of an acidic surface exposed amino
  • the unit dose may be 84 pg to 666.7 pg of modified BoNT/A, wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991 , GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from: (i) substitution of an acidic surface exposed amino acid residue with a basic amino acid residue; (ii) substitution of an acidic
  • An upper limit of the unit dose range may be 650, 600, 550, 500, 450, 400, 350, 333.3, 300, 250, 200, 166.7, 150, or 100 pg of modified BoNT/A.
  • a lower limit of the unit dose range may be 100, 125, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, or 650 pg of modified BoNT/A.
  • the unit dose may be 100 pg to 400 pg, 100 pg to 333.3 pg, 100 pg to 200 pg, or 100 pg to 166.7 pg-
  • the unit dose may be greater than 300 pg or greater than 500 pg of modified BoNT/A, wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991 , GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from: (i) substitution of an acidic surface exposed amino acid residue with a basic amino acid residue; (ii) substitution of an acid
  • a total dose administered when carrying out the treatment regimen of the present invention may be up to 2,000 pg of modified BoNT/A, wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991 , GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081 , GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from: (i) substitution of an acidic surface exposed amino acid residue with a basic amino acid residue; (i
  • the total amount of modified BoNT/A administered at a given treatment session may be up to 2,000 pg.
  • the total dose may be up to 1 ,750, 1,500, 1 ,000, 750, 500, or 300 pg, preferably up to 1 ,500 pg.
  • the total dose may be at least 252, 300, 350, 400, 500, 600, 700, 800, 900, 1 ,000, or 1 ,250 pg.
  • the total dose may be 252 pg to 2,000 pg, preferably 300 pg to 1,500 pg.
  • the total dose may be greater than 500 pg, or greater than 750 pg, or greater than 1 ,000 pg of modified BoNT/A, wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081 , GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from: (i) substitution of an acidic surface exposed amino acid residue with a basic
  • the total dose may be greater than 500 pg and up to 2,000 pg of modified BoNT/A, wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991 , GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from: (i) substitution of an acidic surface exposed amino acid residue with a basic amino acid residue; (ii) substitution of an
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating a disorder affecting an eyelid muscle of a subject, the method comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 10 II of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 237 U of the modified BoNT/A, and
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • the method comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 10 U of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 237 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, A
  • the invention provides a method of treating a disorder affecting an eyelid muscle of a subject, the method comprising: administering a single unit dose of a modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 10 U of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 237 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue
  • the invention provides a method of treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), the method comprising: administering a single unit dose of a modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 10 II of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 237 U
  • LD50
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of a medicament for treating a disorder affecting an eyelid muscle of a subject, comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 10 II of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of a medicament for treating a disorder affecting an eyelid muscle of a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • BoNT/A botulinum neurotoxin A
  • SEQ ID NO: 2 comprising: administering a single unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; administering a single unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and administering a single unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the single unit dose of the modified BoNT/A is at least 10 II of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 237 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 9
  • One aspect provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating blepharospasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 10 U of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating blepharospasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 10 U of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 237 U of the modified BoNT/A, and wherein the modified BoNT/
  • the invention provides a method of treating blepharospasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 10 II of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 2
  • LD50
  • the invention provides a method of treating blepharospasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 10 II of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that correspond
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating blepharospasm in a subject, comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 10 II of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating blepharospasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • SEQ ID NO: 2 comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 10 II of modified BoNT/A, wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the total dose administered during the treatment is up to 237 U of the modified BoNT/A, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 9
  • Another aspect provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating typical hemifacial spasm, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in
  • the invention provides a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating typical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in accordance with the following dosage regimen:
  • the invention provides a method of treating typical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in accordance with the following dosage regimen:
  • the invention provides a method of treating typical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g. SEQ ID NO: 2), wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating typical hemifacial spasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hem
  • the invention provides the use of a modified botulinum neurotoxin A (BoNT/A) in the manufacture of medicament for treating typical hemifacial spasm in a subject for a longer duration than that treated by an unmodified BoNT/A (e.g.
  • BoNT/A botulinum neurotoxin A
  • the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to an eye affected by hemifacial spasm; and d) administering one or more unit dose of the modified BoNT/A to one or more further muscles affected by said hemifacial spasm in accordance with the following dosage regimen:
  • BoNT/A botulinum neurotoxin A
  • a method of treating atypical hemifacial spasm wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to an orbicularis oris muscle affected by hemifacial spasm (e.g.

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PCT/GB2022/052415 2021-09-23 2022-09-23 Modified bont/a for use in the treatment of a disorder affecting an eyelid muscle of a subject Ceased WO2023047127A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP22782758.1A EP4404955A1 (en) 2021-09-23 2022-09-23 Modified bont/a for use in the treatment of a disorder affecting an eyelid muscle of a subject
JP2024518109A JP2024534541A (ja) 2021-09-23 2022-09-23 被験体の眼瞼筋を冒す障害の治療における使用のための改変ＢｏＮＴ／Ａ
AU2022351260A AU2022351260A1 (en) 2021-09-23 2022-09-23 Modified bont/a for use in the treatment of a disorder affecting an eyelid muscle of a subject
KR1020247012920A KR20240067100A (ko) 2021-09-23 2022-09-23 대상체의 안검 근육에 이환된 장애의 치료에 사용하기 위한 변형된 bont/a
CN202280064373.8A CN117979988A (zh) 2021-09-23 2022-09-23 用于治疗影响受试者眼睑肌肉的疾病的修饰的BoNT/A
US18/690,479 US20250179461A1 (en) 2021-09-23 2022-09-23 Modified Bont/A for Use in the Treatment of a Disorder Affecting an Eyelid Muscle of a Subject
CA3228712A CA3228712A1 (en) 2021-09-23 2022-09-23 Modified bont/a for use in the treatment of a disorder affecting an eyelid muscle of a subject

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB2113602.3A GB202113602D0 (en) 2021-09-23 2021-09-23 Treatment of a disorder affecting an eyelid muscle of a subject
GB2113602.3 2021-09-23
GBGB2206360.6A GB202206360D0 (en) 2022-04-29 2022-04-29 Treatment of a disorder affecting an eyelid muscle of a subject
GB2206360.6 2022-04-29

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WO2024069176A1 (en) 2022-09-28 2024-04-04 Ipsen Biopharm Limited Clostridial neurotoxins comprising an activating exogenous protease cleavage site
WO2024069175A1 (en) 2022-09-28 2024-04-04 Ipsen Biopharm Limited Clostridial neurotoxins comprising an activating endosomal protease cleavage site
WO2025093844A1 (en) * 2023-11-01 2025-05-08 Ipsen Biopharm Limited Use of chimeric botulinum toxin a for treating blepharospasm and hemifacial spasm
WO2025125793A1 (en) 2023-12-11 2025-06-19 Ipsen Biopharm Limited Formulation

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Cited By (5)

* Cited by examiner, † Cited by third party
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WO2023209327A1 (en) * 2022-04-29 2023-11-02 Ipsen Biopharm Limited Bont/a for use in treating a facial dystonia
WO2024069176A1 (en) 2022-09-28 2024-04-04 Ipsen Biopharm Limited Clostridial neurotoxins comprising an activating exogenous protease cleavage site
WO2024069175A1 (en) 2022-09-28 2024-04-04 Ipsen Biopharm Limited Clostridial neurotoxins comprising an activating endosomal protease cleavage site
WO2025093844A1 (en) * 2023-11-01 2025-05-08 Ipsen Biopharm Limited Use of chimeric botulinum toxin a for treating blepharospasm and hemifacial spasm
WO2025125793A1 (en) 2023-12-11 2025-06-19 Ipsen Biopharm Limited Formulation

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