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METHODS OF TREATING DEVELOPMENTAL DISORDERS USING GABOXADOL
Abstract
Methods of treating a developmental disorder such as Dravet syndrome by
administering a pharmaceutical composition of gaboxadol or a
pharmaceutically acceptable salt thereof are provided.
1. A method of treating Lennox-Gastaut syndrome comprising administering
to a patient in need thereof a pharmaceutical composition comprising
gaboxadol or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 wherein the patient is administered 0.1 mg to 50
mg gaboxadol or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 wherein gaboxadol or a pharmaceutically
acceptable salt thereof is administered to the patient in a daily dosage
ranging from 1 mg to 50 mg.
4. The method of claim 1 wherein the pharmaceutical composition comprises
2.5 mg to 30 mg gaboxadol.
5. The method of claim 1 wherein gaboxadol or a pharmaceutically
acceptable salt thereof is administered in a dose ranging from 0.1 mg/kg
to 1 mg/kg.
6. The method of claim 1 wherein the composition is administered once,
twice, three times daily, or every other day.
7. The method of claim 1 further comprising administering a compound
selected from the group consisting of pipradrol, acetazolamide,
carbamazepine, clobazam, clonazepam, eslicarbazepine acetate,
ethosuximide, gabapentin, lacosamide, lamotrigine, leviteracetam,
nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital,
phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium
valproate, stiripentol, tiagabine, topiramate, vigabatrin, and
zonisamide.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent application Ser.
No. 15/597,611, filed May 17, 2017, which is a continuation of U.S.
patent application Ser. No. 15/191,068, filed Jun. 23, 2016, now U.S.
Pat. No. 9,682,069, which claims the benefit of and priority to U.S.
Provisional Application Ser. No. 62/193,717, filed Jul. 17, 2015,
62/207,595, filed Aug. 20, 2015, 62/215,831, filed on Sep. 9, 2015, and
62/332,567, filed on May 6, 2016, the entire contents of each of which
are herein incorporated by reference in their entireties.
TECHNICAL FIELD
[0002] Methods of using a composition including gaboxadol or a
pharmaceutically acceptable salt thereof for the treatment of
developmental disorders in a subject in need thereof.
BACKGROUND
[0003] Gaboxadol (4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol)
(THIP)) is described in EP Patent No. 0000338 and in EP Patent No.
0840601, U.S. Pat. Nos. 4,278,676, 4,362,731, 4,353,910, and WO
2005/094820. Gaboxadol is a selective GABA.sub.A receptor agonist with a
preference for .delta.-subunit containing GABA.sub.A receptors. In the
early 1980s gaboxadol was the subject of a series of pilot studies that
tested its efficacy as an analgesic and anxiolytic, as well as a
treatment for tardive dyskinesia, Huntington's disease, Alzheimer's
disease, and spasticity. In the 1990s gaboxadol moved into late stage
development for the treatment of insomnia. The development was
discontinued after the compound failed to show significant effects in
sleep onset and sleep maintenance in a three-month efficacy study.
Additionally, patients with a history of drug abuse who received
gaboxadol experienced a steep increase in psychiatric adverse events.
[0004] Pipradrol is a mild central nervous system stimulant that acts on
both dopamine and norepinephrine reuptake. It was originally marketed as
Meratran.RTM. (Wm. S. Merrell Co of Cincinnati Ohio) and also in
combination with several vitamins as Alertonic.RTM. Elixir. Pipradrol was
considered an "energetic" when it first came to market in the mid to late
1950's and used for obesity, narcolepsy, and depression. Pipradrol has
also been used in the setting of obstetric and gynecological practice,
with multiple benefits, for example improving nausea and vomiting,
premenstrual symptoms, post-partum psychosis, and menopausal-associated
depression Kistner and Duncan, The New England Journal of Medicine 254,
507-510 (1956).
[0005] There is limited evidence that suggests pipradrol may have some
efficacy in behavioral disorders in children. Oettinger, Diseases of the
Nervous System 16, 299-302 (1955). The report concludes that the action
of pipradrol lies in increasing the attention span and decreasing
irritability with a resultant increase in function. However, pipradrol
has been associated with side effects such as anxiety and alertness at
bedtime. Fabing, Diseases of the Nervous System 10-15 (January 1955). In
addition, although some anticonvulsant activity has been suggested, high
doses of pipradrol may cause incoordinated activity and ataxia, followed
by tremors and clonic convulsions. Following the Kefauver-Harris
amendments to the FDA act in 1962, pipradrol was one of thousands of
drugs that were assessed by special committees to define whether there
was sufficient safety and efficacy to remain an approved drug. This
process was called the Drug Efficacy Study Initiative or DESI. The
committee which reviewed pipradrol included the psychiatrist Karl
Rickels, who had published a study on 111 individuals with depression, in
which pipradrol was not superior to placebo (Rickels et al., The Journal
of Clinical Pharmacology 14, 127-133; 1974). As a result, pipradrol was
removed from the FDA register of approved drugs.
[0006] There remains a need for improved methods of treating developmental
disorders including Scn1a-related disorders such as Dravet syndrome.
SUMMARY
[0007] In embodiments, methods are provided for treatment of developmental
disorders including epilepsy, Landau-Kleffner Syndrome, Lennox-Gastaut
syndrome (LGS) and Dravet syndrome by administering to a patient in need
thereof a pharmaceutical composition of gaboxadol or a pharmaceutically
acceptable salt thereof.
[0008] In embodiments, methods of treating Dravet syndrome described
herein include administering to a patient in need thereof a
pharmaceutical composition comprising 0.1 mg to 50 mg gaboxadol or a
pharmaceutically acceptable salt thereof. In embodiments, methods of
treating Dravet syndrome described herein include administering to a
patient diagnosed with Dravet syndrome a pharmaceutical composition
comprising 0.1 mg to 50 mg gaboxadol or a pharmaceutically acceptable
salt thereof.
[0009] In embodiments, methods are provided for treatment of developmental
disorders including benign rolandic epilepsy (BRE), intractable childhood
epilepsy (ICE), childhood absence epilepsy (CAE), juvenile myoclonic
epilepsy (JME), infantile spasms (or West syndrome), Dravet syndrome and
Lennox-Gastaut syndrome (LGS) by administering to a patient in need
thereof a pharmaceutical composition of gaboxadol or a pharmaceutically
acceptable salt thereof.
[0010] In embodiments, methods are provided for treatment of developmental
disorders characterized as a sodium channel protein type 1 subunit alpha
(Scn1a)-related disorder. For example, Scn1a-related disorders include
generalized epilepsy with fibrile seizures plus, intractable childhood
epilepsy with generalized tonic-clonic seizures, intractable infantile
partial seizures, myoclonic-astatic epilepsy, severe myoclonic epilepsy
in infancy, simple febrile seizures, Dravet syndrome, Lennox-Gastaut
syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and
seizures by administering to a patient in need thereof a pharmaceutical
composition of gaboxadol or a pharmaceutically acceptable salt thereof.
[0011] The methods described herein may be particularly effective in
subjects experiencing intractable seizures, status epilepticus, akinetic
seizures, myoclonic seizures, absence seizures, or severe myoclonic
epilepsy in infancy (SMEI).
[0012] In embodiments, gaboxadol or a pharmaceutically acceptable salt
thereof is administered to a patient diagnosed with a developmental
disorder such as Dravet syndrome in a daily dosage range of about 0.05 mg
to about 50 mg.
[0013] In embodiments, gaboxadol or a pharmaceutically acceptable salt
thereof is co-administered with one or more of the following drugs:
pipradrol, acetazolamide, carbamazepine, clobazam, clonazepam,
eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide,
lamotrigine, leviteracetam, nitrazepam, oxcarbazepine, perampanel,
piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine,
rufinamide, sodium valproate, stiripentol, tiagabine, topiramate,
vigabatrin, and zonisamide.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 shows the arithmetic mean plasma concentration-time profiles
of gaboxadol following single oral doses (2.5, 5, 10, 15, and 20 mg) as
described in Example 1.
[0015] FIG. 2 is a schematic depiction of three dosing schedules (A, B and
C) in connection with a prospective assessment of the efficacy of
gaboxadol in patients with Dravet syndrome according to Example 5.
[0016] FIG. 3 is a graphic depiction of the three dosing schedules
depicted in FIG. 2. Solid gray ovals indicate active ingredient
containing dosage forms. Partial gray ovals indicate placebos.
DETAILED DESCRIPTION
[0017] Described herein are methods of treating developmental disorders
such as sodium channel protein type 1 subunit alpha (Scn1a)-related
disorders including Dravet syndrome with gaboxadol or a pharmaceutically
acceptable salt thereof. Although up to about 80% of Dravet syndrome
cases may test positive for an SCN1A gene mutation, the absence of an
SCN1A mutation does not exclude Dravet syndrome diagnosis. Accordingly,
in embodiments, methods described herein are directed to treating Dravet
syndrome with gaboxadol or a pharmaceutically acceptable salt thereof
whether or not the Dravet syndrome diagnosis is associated with an SCN1A
mutation.
[0018] Many pharmaceutical products are administered as a fixed dose, at
regular intervals, to achieve therapeutic efficacy. Its duration of
action is reflected by its plasma half-life. Gaboxadol is a selective
GABA.sub.A receptor agonist with a relatively short half-life (t1/2=1.5
h). Since efficacy is often dependent on sufficient exposure within the
central nervous system administration of CNS drugs with a short half-life
may require frequent maintenance dosing. Advantageously disclosed herein
are methods of treating development disorders by administration of
gaboxadol or a pharmaceutically acceptable salt thereof. For example, in
embodiments, methods of treating a developmental disorder are provided
which include administering to a patient in need thereof a pharmaceutical
composition including about 0.05 mg to about 50 mg gaboxadol or a
pharmaceutically acceptable salt thereof wherein the composition provides
improvement for more than 6 hours after administration to the patient.
[0019] Also provided herein are methods and compositions for treating
developmental disorders by administering to a patient in need thereof a
pharmaceutical composition comprising pipradrol, a derivative thereof, or
a pharmaceutically acceptable salt thereof. In embodiments, the methods
and compositions described herein include pipradrol or a pharmaceutically
acceptable salt thereof.
[0020] Also provided herein are methods and compositions for treating
developmental disorders by co-administering to a patient in need thereof
gaboxadol or a pharmaceutically acceptable salt thereof, and pipradrol, a
derivative thereof, or a pharmaceutically acceptable salt thereof. In
embodiments, the methods and compositions described herein include a
dosage form including gaboxadol or a pharmaceutically acceptable salt
thereof, and pipradrol or a pharmaceutically acceptable salt thereof.
[0021] In embodiments, the methods described herein may be used to treat
developmental disorders including epilepsy, Landau-Kleffner Syndrome,
Lennox-Gastaut syndrome (LGS) and Dravet syndrome. In embodiments, the
methods include treatment of Dravet syndrome.
[0022] In embodiments, the methods described herein may be used to treat
developmental disorders including benign rolandic epilepsy (BRE),
intractable childhood epilepsy (ICE), childhood absence epilepsy (CAE),
juvenile myoclonic epilepsy (JME), infantile spasms (or West syndrome),
generalized epilepsy with febrile seizure plus (GEFS+) and Lennox-Gastaut
syndrome (LGS).
[0023] In embodiments, the methods described herein may be used to treat
developmental disorders characterized as a sodium channel protein type 1
subunit alpha (Scn1A)-related disorder. For example Scn1A-related
disorders include generalized epilepsy with fibrile seizures plus,
intractable childhood epilepsy with generalized tonic-clonic seizures,
intractable infantile partial seizures, myoclonic-astatic epilepsy,
severe myoclonic epilepsy in infancy, simple febrile seizures, Dravet
syndrome, Lennox-Gastaut syndrome (LGS), infantile spasms, and
vaccine-related encephalopathy and seizures.
[0024] The methods described herein may be effective in subjects
experiencing intractable seizures, status epilepticus, akinetic seizures,
myoclonic seizures, absence seizures, or severe myoclonic epilepsy in
infancy (SMEI). In embodiments, the disorders are characterized by
intractable seizures. Intractable seizures (also referred to as
"uncontrolled" or "refractory" seizures) are seizures that cannot be
controlled with conventional treatments. For example, the subject can
have intractable epilepsy or another disorder characterized by
intractable seizures, or a disorder characterized by status epilepticus.
Status epilepticus is a condition in which seizures follow one another
without recovery of consciousness between them. Accordingly, in
embodiments, the disclosed methods are used to treat subjects that are
resistant to one or more conventional therapies.
[0025] The methods described herein may be particularly useful for
treating children and infants, and for treating disorders that onset
during infancy or childhood. In embodiments, the subject of the disclosed
method is a newborn, a baby, a toddler, a preschooler, a school-age
child, a tween, or a teenager. In embodiments, the subject is 18 years
old or younger, 12 years old or younger, 10 years old or younger, 8 years
old or younger, 6 years old or younger, 4 years old or younger, 2 years
old or younger, 1 year old or younger. In embodiments, the subject is an
adult that is over eighteen years old.
[0026] In embodiments, the developmental disorders are characterized by
seizures associated with epilepsy. In embodiments, the seizures are
non-epileptic seizures (NES) or dissociative seizures that are
distinguished from epilepsy. Non-epileptic seizures include organic
non-epileptic seizures and psychogenic seizures.
[0027] Epilepsy is a neurological disorder that occurs when nerve cell
activity in the brain becomes disrupted, leading to seizures or periods
of unusual behavior, sensations and sometimes loss of consciousness. A
subject can be said to have epilepsy when having two seizures without an
obvious cause. Epilepsy can occur in both adults and children, and can be
associated with a specific syndrome. Accordingly, in embodiments, the
subject has a childhood epilepsy syndrome such as benign rolandic
epilepsy (BRE), childhood absence epilepsy (CAE), juvenile myoclonic
epilepsy (JME), infantile spasms (or West syndrome), Dravet syndrome or
Lennox-Gastaut syndrome (LGS).
[0028] In embodiments, the subject does not experience diagnosable
seizures, but exhibits subclinical electrical discharges, which refers to
a high rate of seizure-like activity when their brain waves are measured
with an electroencephalogram. Epileptic syndromes associated with these
seizure-like discharges include Landau-Kleffner Syndrome, Dravet syndrome
and Continuous Spike-wave Activity during Slow-wave Sleep.
[0029] In embodiments, the developmental disorders treated by the methods
and compositions described herein include Scn1A-related seizure
disorders. Scn1A-related seizure disorders include simple febrile
seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+)
at the mild end to Dravet syndrome and intractable childhood epilepsy
with generalized tonic-clonic seizures (ICE-GTC) at the severe end.
Specific Scn1A-related seizure disorders disorders include, but are not
limited to, generalized epilepsy with fibrile seizures plus, intractable
childhood epilepsy with generalized tonic-clonic seizures, intractable
infantile partial seizures, myoclonic-astatic epilepsy, severe myoclonic
epilepsy in infancy, simple febrile seizures, Dravet syndrome,
Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related
encephalopathy.
[0030] In embodiments, the subject has an intellectual developmental
disability (IDD) such as an Autism Spectrum Disorders (ASD). In
embodiments, the subject of the disclosed method has epilepsy and an IDD
or ASD disorder. Common IDD and ASD that are comorbid with seizures and
epilepsy include, but are not limited to, fragile X syndrome (FXS), Rett
syndrome (RTT), Angelman syndrome, Prader-Willi syndrome,
Velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, neuroligin
mutations and "interneuronopathies" resulting from aristaless-related
homeobox, X-linked (ARX) and Nueropilin 2 (NRP2) gene mutations.
[0031] Embodiments described herein provide that a patient in need thereof
is administered a pharmaceutical composition including gaboxadol or a
pharmaceutically acceptable salt thereof. Gaboxadol or pharmaceutically
acceptable salt thereof may be provided as an acid addition salt, a
zwitter ion hydrate, zwitter ion anhydrate, hydrochloride or hydrobromide
salt, or in the form of the zwitter ion monohydrate. Acid addition salts,
include but are not limited to, maleic, fumaric, benzoic, ascorbic,
succinic, oxalic, bis-methylenesalicylic, methanesulfonic,
ethane-disulfonic, acetic, propionic, tartaric, salicylic, citric,
gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,
stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene
sulfonic or theophylline acetic acid addition salts, as well as the
8-halotheophyllines, for example 8-bromo-theophylline. In other suitable
embodiments, inorganic acid addition salts, including but not limited to,
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric or nitric acid
addition salts may be used.
[0032] In embodiments, gaboxadol is provided as gaboxadol monohydrate. One
skilled in the art will readily understand that the amounts of active
ingredient in a pharmaceutical composition will depend on the form of
gaboxadol provided. For example, pharmaceutical compositions of including
5.0, 10.0, or 15.0 mg gaboxadol correspond to 5.6, 11.3, or 16.9 mg
gaboxadol monohydrate.
[0033] In embodiments, gaboxadol is crystalline, such as the crystalline
hydrochloric acid salt, the crystalline hydrobromic acid salt, or the
crystalline zwitter ion monohydrate. In embodiments, gaboxadol is
provided as a crystalline monohydrate.
[0034] Deuteration of pharmaceuticals to improve pharmacokinetics (PK),
pharmacodynamics (PD), and toxicity profiles, has been demonstrated
previously with some classes of drugs. Accordingly the use of deuterium
enriched gaboxadol is contemplated and within the scope of the methods
and compositions described herein. Deuterium can be incorporated in any
position in replace of hydrogen synthetically, according to the synthetic
procedures known in the art. For example, deuterium may be incorporated
to various positions having an exchangeable proton, such as the amine
N--H, via proton-deuterium equilibrium exchange. Thus, deuterium may be
incorporated selectively or non-selectively through methods known in the
art to provide deuterium enriched gaboxadol. See Journal of Labeled
Compounds and Radiopharmaceuticals 19(5) 689-702 (1982).
[0035] Deuterium enriched gaboxadol may be described by the percentage of
incorporation of deuterium at a given position in the molecule in the
place of hydrogen. For example, deuterium enrichment of 1% at a given
position means that 1% of molecules in a given sample contain deuterium
at that specified position. The deuterium enrichment can be determined
using conventional analytical methods, such as mass spectrometry and
nuclear magnetic resonance spectroscopy. In embodiments deuterium
enriched gaboxadol means that the specified position is enriched with
deuterium above the naturally occurring distribution (i.e., above about
0.0156%). In embodiments deuterium enrichment is no less than about 1%,
no less than about 5%, no less than about 10%, no less than about 20%, no
less than about 50%, no less than about 70%, no less than about 80%, no
less than about 90%, or no less than about 98% of deuterium at a
specified position.
[0036] In embodiments, methods of treating a developmental disorder such
as Dravet syndrome include administering to a patient in need thereof a
pharmaceutical composition including about 0.05 mg to about 50 mg
gaboxadol or a pharmaceutically acceptable salt thereof. In embodiments,
methods of treating a developmental disorder such as Dravet syndrome
include administering to a patient in need thereof a pharmaceutical
composition including about 0.1 mg to about 30 mg gaboxadol or a
pharmaceutically acceptable salt thereof.
[0037] In embodiments, the pharmaceutical compositions include 0.1 mg to
25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25 mg, 0.5 mg to 20
mg, 0.5 to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to
25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2
mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to
25 mg, 3 mg to 20 mg, 3 mg to 15 mg gaboxadol or a pharmaceutically
acceptable salt thereof.
[0038] In embodiments, the pharmaceutical compositions include 5 mg to 20
mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12
mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg
gaboxadol or a pharmaceutically acceptable salt thereof.
[0039] In embodiments, the pharmaceutical compositions include 0.1 mg,
0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 10 mg,
12.5 mg, 15 mg, 17.5 mg, 20 mg gaboxadol or a pharmaceutically acceptable
salt thereof or amounts that are multiples of such doses. In embodiments,
the pharmaceutical compositions include 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15
mg, or 20 mg gaboxadol or a pharmaceutically acceptable salt thereof.
[0040] Pharmaceutical compositions herein may be provided with immediate
release, delayed release, extended release, or modified release profiles.
In embodiments, pharmaceutical compositions with different drug release
profiles may be combined to create a two phase or three-phase release
profile. For example, pharmaceutical compositions may be provided with an
immediate release and an extended release profile. In embodiments,
pharmaceutical compositions may be provided with an extended release and
delayed release profile. Such composition may be provided as pulsatile
formulations, multilayer tablets, or capsules containing tablets, beads,
granules, etc. Compositions may be prepared using a pharmaceutically
acceptable "carrier" composed of materials that are considered safe and
effective. The "carrier" includes all components present in the
pharmaceutical formulation other than the active ingredient or
ingredients. The term "carrier" includes, but is not limited to,
diluents, binders, lubricants, disintegrants, fillers, and coating
compositions.
[0041] In embodiments, the pharmaceutical compositions described herein
are administered once, twice, or three times daily, or every other day.
In embodiments, a pharmaceutical composition described herein is provided
to the patient in the evening. In embodiments, a pharmaceutical
composition described herein is provided to the patient once in the
evening and once in the morning. In embodiments, the total amount of
gaboxadol or a pharmaceutically acceptable salt thereof administered to a
subject in a 24-hour period is 1 mg to 30 mg. In embodiments, the total
amount of gaboxadol or a pharmaceutically acceptable salt thereof
administered to a subject in a 24-hour period is 1 mg to 20 mg. In
embodiments, the total amount of gaboxadol or a pharmaceutically
acceptable salt thereof administered to a subject in a 24-hour period is
5 mg, 10 mg, or 15 mg. In embodiments, the total amount of gaboxadol or a
pharmaceutically acceptable salt thereof administered to a subject in a
24-hour period is 20 mg. In embodiments, the subject may be started at a
low dose and the dosage is escalated. In this manner, it can be
determined if the drug is well tolerated in the subject. Dosages can be
lower for children than for adults. In embodiments, a dose of gaboxadol
for children can be 0.1 mg/kg to 1 mg/kg.
[0042] In embodiments, provided herein are methods of treating a
developmental disorder such as Dravet syndrome including administering to
a patient in need thereof a pharmaceutical composition including
gaboxadol or a pharmaceutically acceptable salt thereof wherein the
composition provides improvement in at least one symptom of the
developmental disorder. In embodiments, methods of treating developmental
disorders by administering to a subject in need thereof an effective
amount of gaboxadol or a pharmaceutically acceptable salt, derivative or
analogue, or combination thereof, are provided. An effective amount or
therapeutically effective amount can be a dosage sufficient to treat,
inhibit, or alleviate one or more symptoms of a developmental disorder
such as reducing the frequency or severity of seizures, reducing behavior
abnormalities (or otherwise improving behavior); or to provide a desired
pharmacologic and/or physiologic effect, for example, reducing,
inhibiting, or reversing one or more of the underlying pathophysiological
mechanisms underlying the neurological dysfunction, increasing dopamine
levels or signaling, or a combination thereof. The precise dosage will
vary according to a variety of factors such as subject-dependent
variables (e.g., age, immune system health, clinical symptoms etc.).
[0043] In embodiments, the methods described herein are effective to
reduce, delay, or prevent one or more other clinical symptoms of a
developmental disorder, particularly epilepsy or Dravet syndrome. For
example, the effect of a composition including gaboxadol or a
pharmaceutically acceptable salt thereof on a particular symptom,
pharmacologic, or physiologic indicator can be compared to an untreated
subject, or the condition of the subject prior to treatment. In
embodiments, the symptom, pharmacologic, and/or physiologic indicator is
measured in a subject prior to treatment, and again one or more times
after treatment is initiated. In embodiments, the control is a reference
level, or average determined based on measuring the symptom,
pharmacologic, or physiologic indicator in one or more subjects that do
not have the disease or condition to be treated (e.g., healthy subjects).
In embodiments, the effect of the treatment is compared to a conventional
treatment that is known the art.
[0044] In embodiments, the methods provided may also surprisingly and
unexpectedly reduce or prevent seizures, or symptoms thereof in a subject
in need thereof. In embodiments, the methods provided may reduce or
prevent one or more different types of seizures. Generally, a seizure can
include convulsions, repetitive movements, unusual sensations, and
combinations thereof. Seizures can be categorized as focal seizures (also
referred to as partial seizures) and generalized seizures. Focal seizures
affect only one side of the brain, while generalized seizures affect both
sides of the brain. Specific types of focal seizures include simple focal
seizures, complex focal seizures, and secondarily generalized seizures.
Simple focal seizures can be restricted or focused on a particular lobe
(e.g., temporal lobe, frontal lobe, parietal lobe, or occipital lobe).
Complex focal seizures generally affect a larger part of one hemisphere
than simple focal seizures, but commonly originate in the temporal lobe
or the frontal lobe. When a focal seizure spreads from one side
(hemisphere) to both sides of the brain, the seizure is referred to as a
secondarily generalized seizure. Specific types of generalized seizures
include absences (also referred to as petit mal seizures), tonic
seizures, atonic seizures, myoclonic seizures, tonic clonic seizures
(also referred to as grand mal seizures), and clonic seizures.
[0045] In embodiments, methods described herein may reduce the frequency
of seizures, reduce the severity of seizures, change the type of seizures
(e.g., from a more severe type to a less severe type), or a combination
thereof in a subject after treatment compared to the absence of treatment
(e.g., before treatment), or compared to treatment with an alternative
conventional treatment.
[0046] In embodiments, provided herein are methods of treating a
developmental disorder including administering to a patient in need
thereof a pharmaceutical composition including gaboxadol or a
pharmaceutically acceptable salt thereof wherein the composition provides
improvement of at least one symptom for more than 4 hours after
administration of the pharmaceutical composition to the patient. In
embodiments, the improvement of at least one symptom for more than 6
hours after administration of the pharmaceutical composition to the
patient is provided in accordance with the present disclosure. In
embodiments, improvement of at least one symptom for more than, e.g., 8
hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours
after administration of the pharmaceutical composition to the patient is
provided in accordance with the present disclosure. In embodiments,
improvement in at least one symptom for at least e.g., 8 hours, 10 hours,
12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration
of the pharmaceutical composition to the patient is provided in
accordance with the present disclosure. In embodiments, improvement in at
least one symptom for 12 hours after administration of the pharmaceutical
composition to the patient is provided in accordance with the present
disclosure.
[0047] In embodiments, provided herein methods of treating a developmental
disorder including administering to a patient in need thereof a
pharmaceutical composition including gaboxadol or a pharmaceutically
acceptable salt thereof wherein the composition provides improvement in
next day functioning to the patient.
[0048] In embodiments, provided herein are methods of treating a
developmental disorder wherein the amount of gaboxadol or
pharmaceutically acceptable salt thereof within the patient about 4 hours
after administration of the pharmaceutical composition is less than about
75% of the administered dose. In embodiments, provided herein are methods
wherein the amount of gaboxadol or pharmaceutically acceptable salt
thereof within the patient about, e.g., 6 hours, 8 hours, 10 hours, 12
hours, 15 hours, or 20 hours after administration of the pharmaceutical
composition is less than about 75%.
[0049] In embodiments, provided herein are methods of treating a
developmental disorder wherein the amount of gaboxadol or
pharmaceutically acceptable salt thereof within the patient about 4 hours
after administration of the pharmaceutical composition is less than about
80% of the administered dose. In embodiments, provided herein are methods
wherein the amount of gaboxadol or pharmaceutically acceptable salt
thereof within the patient about, e.g., 6 hours, 8 hours, 10 hours, 12
hours, 15 hours, or 20 hours after administration of the pharmaceutical
composition is less than about 80% of the administered dose.
[0050] In embodiments, provided herein are methods of treating a
developmental disorder wherein the amount of gaboxadol or
pharmaceutically acceptable salt thereof within the patient about 4 hours
after administration of the pharmaceutical composition is between about
65% to about 85% of the administered dose. In embodiments, the amount of
gaboxadol or pharmaceutically acceptable salt thereof within the patient
after about, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20
hours after administration of the pharmaceutical composition is between
about 65% to about 85% of the administered dose.
[0051] In embodiments, provided herein are methods of treating a
developmental disorder including administering to a patient in need
thereof a pharmaceutical composition including gaboxadol or a
pharmaceutically acceptable salt thereof wherein the composition provides
an in vivo plasma profile having a C.sub.max less than about 500 ng/ml.
In embodiments, the composition provides improvement for more than 6
hours after administration to the patient.
[0052] In embodiments, the composition provides an in vivo plasma profile
having a C.sub.max less than about, e.g., 450 ng/ml, 400 ng/ml 350 ng/ml,
or 300 ng/ml and wherein the composition provides improvement of next day
functioning of the patient. In embodiments, the composition provides an
in vivo plasma profile having a C.sub.max less than about, e.g., 250
ng/ml, 200 ng/ml 150 ng/ml, or 100 ng/ml and wherein the composition
provides improvement of next day functioning of the patient.
[0053] In embodiments, provided herein are methods of treating a
developmental disorder including administering to a patient in need
thereof a pharmaceutical composition including gaboxadol or a
pharmaceutically acceptable salt thereof wherein the composition provides
an in vivo plasma profile having a AUC.sub.0-.infin. of less than about
900 nghr/ml. In embodiments, the composition provides improvement in next
day functioning of the patient. In embodiments, the compositions provide
an in vivo plasma profile having a AUC.sub.0-.infin. of less than about,
e.g., 850 nghr/ml, 800 nghr/ml, 750 nghr/ml, or 700 nghr/ml and wherein
the composition provides improvement of next day functioning of the
patient. In embodiments, the composition provides improvement in one or
more symptom for more than 6 hours after administration.
[0054] In embodiments, provided herein are methods of treating a
developmental disorder including administering to a patient in need
thereof a pharmaceutical composition including gaboxadol or a
pharmaceutically acceptable salt thereof wherein the composition provides
an in vivo plasma profile having a AUC.sub.0-.infin. of less than about,
e.g., 650 nghr/ml, 600 nghr/ml, 550 nghr/ml, 500 nghr/ml, or 450 nghr/ml.
In embodiments, wherein the composition provides an in vivo plasma
profile having a AUC.sub.0-.infin. of less than about, e.g., 400 nghr/ml,
350 nghr/ml, 300 nghr/ml, 250 nghr/ml, or 200 nghr/ml. In embodiments,
the composition provides an in vivo plasma profile having a
AUC.sub.0-.infin. of less than about, e.g., 150 nghr/ml, 100 nghr/ml, 75
nghr/ml, or 50 nghr/ml. In embodiments, the composition provides
improvement of next day functioning of the patient after administration
for more than, e.g., 4 hours, 6 hours, 8 hours, 10 hours, or 12 hours,
after administration of the composition to the patient.
[0055] In embodiments, provided herein are methods of treating a
developmental disorder including administering to a patient in need
thereof a first pharmaceutical composition including gaboxadol or a
pharmaceutically acceptable salt thereof and a second pharmaceutical
composition including gaboxadol or a pharmaceutically acceptable salt
thereof wherein the second pharmaceutical composition provides an in vivo
plasma profile having a mean AUC.sub.0-.infin. of at least about 20% less
than the first pharmaceutical composition.
[0056] In embodiments the first and/or the second pharmaceutical
compositions are administered once, twice, or three times daily, or every
other day. In embodiments, the first or the second pharmaceutical
composition is provided to the patient in the evening. In embodiments,
the second pharmaceutical composition includes an amount of gaboxadol
that is at least one third of the amount of gaboxadol provided in the
first pharmaceutical composition. In embodiments, the second
pharmaceutical composition includes an amount of gaboxadol that is at
least half of the amount of gaboxadol provided in the first
pharmaceutical composition.
[0057] In embodiments, the first or the second pharmaceutical composition
is provided to the patient once in the evening and once in the morning.
In embodiments, the total amount of gaboxadol or pharmaceutically
acceptable salt thereof administered to a subject in a 24-hour period is
1 mg to 30 mg. In embodiments, the total amount of gaboxadol or a
pharmaceutically acceptable salt thereof administered to a subject in a
24-hour period is 1 mg to 20 mg. In embodiments, the total amount of
gaboxadol or a pharmaceutically acceptable salt thereof administered to a
subject in a 24-hour period is 10 mg, 15 mg, or 20 mg. In embodiments,
the total amount of gaboxadol or a pharmaceutically acceptable salt
thereof administered to a subject in a 24-hour period is 20 mg.
[0058] In embodiments, the first and/or the second pharmaceutical
compositions may be provided with immediate release, delayed release,
extended release, or modified release profiles. The first and second
pharmaceutical compositions may be provided at the same time or separated
by an interval of time, e.g., 6 hours, 12 hours etc. In embodiments, the
first and the second pharmaceutical compositions may be provided with
different drug release profiles to create a two-phase release profile.
For example, the first pharmaceutical composition may be provided with an
immediate release profile and the second pharmaceutical composition may
provide an extended release profile. In embodiments, one or both of the
first and second pharmaceutical compositions may be provided with an
extended release or delayed release profile. Such compositions may be
provided as pulsatile formulations, multilayer tablets or capsules
containing tablets, beads, granules, etc. In some embodiments, the first
pharmaceutical composition is an immediate release composition. In
embodiments, the second pharmaceutical composition is an immediate
release composition. In embodiments, the first and second pharmaceutical
compositions are provided as separate immediate release compositions,
e.g., tablets or capsules. In embodiments the first and second
pharmaceutical compositions are provided 12 hours apart.
[0059] In embodiments, provided herein are methods of treating a
developmental disorder including administering to a patient in need
thereof a first pharmaceutical composition including gaboxadol or a
pharmaceutically acceptable salt thereof and a second pharmaceutical
composition including gaboxadol or a pharmaceutically acceptable salt
thereof wherein the second pharmaceutical composition provides an in vivo
plasma profile having a mean AUC.sub.0-.infin. of at least about, e.g.,
25%, 30%, 35%, 40%, 45% or 50% less than the first pharmaceutical
composition. In embodiments, the composition provides improvement of next
day functioning of the patient. For example, the composition may provide
improvement in one or more symptoms for more than about, e.g., 6 hours, 8
hours, 10 hours, or 12 hours after administration of the first and/or
second pharmaceutical composition.
[0060] In embodiments, provided herein are methods of treating a
developmental disorder including administering to a patient in need
thereof a first pharmaceutical composition including gaboxadol or a
pharmaceutically acceptable salt thereof and a second pharmaceutical
composition including gaboxadol or a pharmaceutically acceptable salt
thereof wherein the second pharmaceutical composition provides an in vivo
plasma profile having a mean AUC.sub.0-.infin. of less than about 900
nghr/ml. In embodiments, the second pharmaceutical composition provides
an in vivo plasma profile having a AUC.sub.0-.infin. of less than about,
e.g., 800 nghr/ml, 750 nghr/ml, 700 nghr/ml, 650 nghr/ml, or 600 nghr/ml.
In embodiments, the second pharmaceutical composition provides an in vivo
plasma profile having a AUC.sub.0-.infin. of less than about, e.g., 550
nghr/ml, 500 nghr/ml, 450 nghr/ml, 400 nghr/ml, or 350 nghr/ml. In
embodiments, the second pharmaceutical composition provides an in vivo
plasma profile having a AUC.sub.0-.infin. of less than about, e.g., 300
nghr/ml, 250 nghr/ml, 200 nghr/ml, 150 nghr/ml, or 100 nghr/ml. In
embodiments, the first and second pharmaceutical composition are
administered wherein the compositions provide improvement of next day
functioning of the patient. In embodiments, the first pharmaceutical
composition provides improvement in one or more symptom for more than,
e.g., 6 hours, 8 hours or 12 hours after administration of the first
pharmaceutical composition.
[0061] In embodiments, provided herein are methods of treating a
developmental disorder including administering to a patient in need
thereof a first pharmaceutical composition including gaboxadol or a
pharmaceutically acceptable salt thereof and a second pharmaceutical
composition including gaboxadol or a pharmaceutically acceptable salt
thereof wherein the first composition provides an in vivo plasma profile
with a C.sub.max that is more than about 50% greater than the C.sub.max
provided by the administration of the second pharmaceutical composition.
As used herein the C.sub.max provided by the administration of the second
pharmaceutical composition may or may not include the plasma profile
contribution of the first pharmaceutical composition. In embodiments, the
administration of the second pharmaceutical composition does not include
the plasma profile contribution of the first pharmaceutical composition.
In embodiments, the first composition provides an in vivo plasma profile
having a C.sub.max that is more than about e.g., 60%, 70%, 80%, or 90%
greater than the C.sub.max provided by the administration of the second
pharmaceutical composition.
[0062] In embodiments, the T.sub.max of the first pharmaceutical
composition is less than 3 hours. In embodiments, the T.sub.max of the
first pharmaceutical composition is less than 2.5 hours. In embodiments,
the T.sub.max of the first pharmaceutical composition is less than 2
hours. In embodiments, the T.sub.max of the first pharmaceutical
composition is less than 1.5 hours. In embodiments, the T.sub.max of the
first pharmaceutical composition is less than 1 hour.
[0063] In embodiments, the first pharmaceutical composition provides a
dissolution of at least about 80% within the first 20 minutes of
administration to a patient in need thereof. In embodiments, the first
pharmaceutical composition provides a dissolution of at least about,
e.g., 85%, 90% or 95% within the first 20 minutes of administration to a
patient in need thereof. In embodiments, the first pharmaceutical
composition provides a dissolution of at least 80% within the first 10
minutes of administration to a patient in need thereof.
[0064] In embodiments the first and/or the second pharmaceutical
compositions are sub therapeutic dosages. A sub therapeutic dosage is an
amount of gaboxadol pharmaceutically acceptable salt thereof that is less
than the amount required for a therapeutic effect. In embodiments, a sub
therapeutic dosage is an amount of gaboxadol pharmaceutically acceptable
salt thereof that alone may not provide improvement in at least one
symptom of the developmental disorder but is sufficient to maintain such
improvement. In embodiments, the methods provide administering a first
pharmaceutical composition that provides improvement in at least one
symptom of a development disorder and a second composition that maintains
the improvement. In embodiments, after administration of the first
pharmaceutical composition the second pharmaceutical composition may
provide a synergistic effect to improve at least one symptom of a
developmental disorder. In embodiments the second pharmaceutical
composition may provide a synergistic effect to improve at least one
symptom of a developmental disorder.
[0065] In embodiments, provided herein are methods of treating a
developmental disorder including administering to a patient in need
thereof a pharmaceutical composition including a first pharmaceutical
dosage including gaboxadol or a pharmaceutically acceptable salt thereof
wherein the composition provides improvement for more than 6 hours after
administration and a second pharmaceutical composition including a sub
therapeutic dosage of gaboxadol or a pharmaceutically acceptable salt
thereof.
[0066] Administration of the first and second pharmaceutical compositions
may be separated by an interval of time to achieve long-term improvement
in at least one symptom. In embodiments, the first and second
pharmaceutical composition may be administered 6 hours apart. In
embodiments the first and second pharmaceutical composition may be
administered 12 hours apart. In embodiments, the first and second
pharmaceutical compositions may administered within, e.g., 6 hours, 12
hours, 18 hours, 24 hours etc. In embodiments, the first and second
pharmaceutical compositions may administered separated by at least, e.g.,
6 hours, 12 hours, 18 hours, 24 hours etc. In embodiments, improvement in
at least one symptom of a developmental disorder for more than 8 hours
after administration to the patient is provided. In embodiments,
improvement for more than about, e.g., 10 hours, 12 hours, 15 hours, 18
hours, 20 hours, or 24 hours after administration to the patient is
provided.
[0067] In embodiments, the first pharmaceutical composition and/or the
second pharmaceutical composition include about 0.1 mg to about 40 mg
gaboxadol or a pharmaceutically acceptable salt thereof. The amount of
gaboxadol or a pharmaceutically acceptable salt thereof in the first
pharmaceutical composition and the second pharmaceutical composition may
be the same or different. In embodiments, the administration of the first
and second pharmaceutical composition may provide a synergistic effect to
improve at least one symptom of a developmental disorder.
[0068] In embodiments, the first and/or the second pharmaceutical
composition include 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg,
0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 1 mg to 25 mg, 1 mg to 20
mg, 1 mg to 15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2
mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20
mg, 2.5 mg to 15 mg, 3 mg to 25 mg, 3 mg to 20 mg, or 3 mg to 15 mg
gaboxadol or a pharmaceutically acceptable salt thereof.
[0069] In embodiments, the first and/or the second pharmaceutical
composition include 5 mg to 15 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8
mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg
to 18 mg, or 18 mg to 20 mg gaboxadol or a pharmaceutically acceptable
salt thereof.
[0070] In embodiments, the first and/or the second pharmaceutical
composition include 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5
mg, 7 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg gaboxadol or a
pharmaceutically acceptable salt thereof or amounts that are multiples of
such doses. In embodiments, the first pharmaceutical compositions include
2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg gaboxadol or a
pharmaceutically acceptable salt thereof. In embodiments, the second
pharmaceutical compositions include 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg,
or 20 mg gaboxadol or a pharmaceutically acceptable salt thereof.
[0071] In embodiments, methods of treating developmental disorders include
administration of gaboxadol or a pharmaceutically acceptable salt thereof
in combination with one or more other active compounds. The combination
therapies can include administration of the active agents together in the
same admixture, or in separate admixtures. In embodiments, the
pharmaceutical composition includes two, three, or more active agents. In
embodiments, the combinations result in a more than additive effect on
the treatment of the disease or disorder. Thus, treatment is provided of
a developmental disorder with a combination of agents that combined, may
provide a synergistic effect that enhances efficacy.
[0072] In embodiments, gaboxadol or a pharmaceutically acceptable salt
thereof, is administered in combination with conventional therapy for
seizures, epilepsy, or one of the other disorders disclosed herein. For
example, common conventional therapies for seizures and epilepsy include
antiepileptic drugs and non-antiepileptic drug treatments such as low
carbohydrate diet (e.g., ketogenic diets, such as classical diet, medium
chain triglyceride (MCT) diet, modified Atkins diet (MAD), and low
glycemic index treatment (LGIT)), intravenous immunoglobulin, steroids,
elimination diet, valgus nerve stimulation, corticetomy, and multiple
subpial transections.
[0073] Common antiepileptic and anticonvulsive active compounds that may
be used in combination with gaboxadol or a pharmaceutically acceptable
salt thereof include, but are not limited to, acetazolamide,
carbamazepine, clobazam, clonazepam, eslicarbazepine acetate,
ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam,
nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital,
phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium
valproate, stiripentol, tiagabine, topiramate, vigabatrin, and
zonisamide.
[0074] In embodiments, methods and compositions are provided for treating
developmental disorders by administering to a patient in need thereof a
pharmaceutical composition comprising pipradrol or a pharmaceutically
acceptable salt thereof. In embodiments, compounds structurally related
to pipradrol or a derivative or analog thereof are administered. Such
compounds, can include, for example, desoxypipradrol, diphenylprolinol,
2-(diphenylmethyl)pyrrolidine, or pharmaceutically acceptable salts
thereof.
##STR00001##
[0075] Pipradrol, derivatives, analogues and structurally related
compounds thereof useful in the disclosed methods includes any form of
the compounds, such as the base (zwitter ion), pharmaceutically
acceptable salts, e.g., pharmaceutically acceptable acid addition salts,
hydrates or solvates of the base or salt, as well as anhydrates, and also
amorphous, or crystalline forms.
[0076] In embodiments, deuterated pipradrol or deuterated forms of
pipradrol derivatives may be used. Deuteration of pharmaceuticals to
improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity
profiles, has been demonstrated previously with some classes of drugs.
Accordingly the use of deuterium-enriched pipradrol is contemplated and
within the scope of the methods and compositions described herein.
Deuterium can be incorporated in any position in replace of hydrogen
synthetically, according to the synthetic procedures known in the art.
For example, deuterium may be incorporated to various positions having an
exchangeable proton, such as the amine N--H, via proton-deuterium
equilibrium exchange. Thus, deuterium may be incorporated selectively or
non-selectively through methods known in the art to provide deuterium
enriched pipradrol.
[0077] Deuterium enriched pipradrol may be described by the percentage of
incorporation of deuterium at a given position in the molecule in the
place of hydrogen. For example, deuterium enrichment of 1% at a given
position means that 1% of molecules in a given sample contain deuterium
at that specified position. The deuterium enrichment can be determined
using conventional analytical methods, such as mass spectrometry and
nuclear magnetic resonance spectroscopy. In embodiments, deuterium
enriched pipradrol means that the specified position is enriched with
deuterium above the naturally occurring distribution (i.e., above about
0.0156%). In embodiments, deuterium enrichment is, e.g., no less than
about 1%, no less than about 5%, no less than about 10%, no less than
about 20%, no less than about 50%, no less than about 70%, no less than
about 80%, no less than about 90%, or no less than about 98% of deuterium
at a specified position. In embodiments, deuterium enrichment may be
defined as, e.g., more than about 60%, more than about 65%, more than
about 75%, more than about 80%, more than about 85%, more than about 95%
deuterium at a specified position.
[0078] In embodiments, the pipradrol or a pharmaceutically acceptable salt
thereof may include the racemic mixture, as well as compositions
including each enantiomer individually. The compositions and methods
contemplated herein may provide reduced dosing frequency, reduced adverse
events and/or increased efficacy compared to a racemic mixture of
pipradrol. In embodiments, compositions and methods that include each
enantiomer individually may provide reduced dosing frequency, reduced
adverse events and/or increased efficacy compared to the minor
enantiomer. Thus, for example, contemplated herein are compositions and
methods of treatment that provide the S enantiomer of pipradrol or a
pharmaceutically acceptable salt thereof that is substantially free of
the R enantiomer. In embodiments, methods and compositions herein include
the R enantiomer of pipradrol or a pharmaceutically acceptable salt
thereof substantially free of the S enantiomer. By "substantially free"
it is meant that the composition includes less than 50% of the minor
enantiomer. In embodiments, the compositions and methods herein may
include less than about, e.g., 25%, 15%, 10%, 8%, 5%, 3%, 2%, or less
than 1% of the minor enantiomer.
[0079] In embodiments, the methods and compositions include (S)-pipradrol,
or a pharmaceutically acceptable salt thereof. In embodiments, the
compositions include more than, e.g., about 75%, about 85%, about 90%,
about 95% or about 98% (S)-pipradrol. In embodiments, the compositions
include between, e.g., about 50% to about 75%, about 75% to about 100%,
about 85% to about 100%, about 90% to about 100%, or about 95% to about
100% (S)-pipradrol.
[0080] In embodiments, the methods and compositions herein include
(R)-pipradrol, or a pharmaceutically acceptable salt thereof. In
embodiments, the compositions include more than, e.g., about 75%, about
85%, about 90%, about 95% or about 98% (R)-pipradrol. In embodiments, the
compositions include between, e.g., about 50% to about 75%, about 75% to
about 100%, about 85% to about 100%, about 90% to about 100%, or about
95% to about 100% (R)-pipradrol.
[0081] In embodiments, pipradrol or a pharmaceutically acceptable salt
thereof is administered at dosages ranging from about 0.001 mg/kg and
about 10 mg/kg of body weight of a patient in need thereof, e.g., from
about 0.01 mg/kg to 2.0 mg/kg at least once a day. For example, dosages
may include amounts of pipradrol or a pharmaceutically acceptable salt
thereof in the range of about, e.g., 1 mg to 30 mg, 1 mg to 20 mg, 1 mg
to 15 mg, 0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg, or 0.2
mg to 10 mg, with doses of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6
mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75
mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5
mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 10 mg, 11 mg, 12 mg, 15 mg, 20 mg,
25 mg, and 30 mg being specific examples of doses. Typically, dosages of
pipradrol or pharmaceutically acceptable salts thereof are administered
once or twice daily to a patient in need thereof. The methods and
compositions described herein may provide reduced dosing frequency and
reduced adverse events and/or increased efficacy. In embodiments, the
dosage is about, e.g., 0.1-20 mg/day, or 0.2-15 mg/day, or 0.5-10 mg/day,
or 0.75-5 mg/day, for example 0.2 mg/day, 0.5 mg/day, 0.75 mg/day, 1
mg/day, 1.5 mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7
mg/day, 8 mg/day, 9 mg/day, or 10 mg/day. In embodiments, pipradrol, or a
derivative or analogue thereof is administered at doses of 0.2 mg to 1 mg
in infants or 1-20 mg in adults, once daily.
[0082] Methods of treating developmental disorders by administering to a
subject in need thereof an effective amount of pipradrol or a
pharmaceutically acceptable salt, derivative or analogue, or combination
thereof, are provided. An effective amount or therapeutically effective
amount can be a dosage sufficient to treat, inhibit, or alleviate one or
more symptoms of a developmental disorder such as reducing the frequency
or severity of seizures, reducing behavior abnormalities (or otherwise
improving behavior); or to provide a desired pharmacologic and/or
physiologic effect, for example, reducing, inhibiting, or reversing one
or more of the underlying pathophysiological mechanisms underlying the
neurological dysfunction, increasing dopamine levels or signaling, or a
combination thereof. The precise dosage will vary according to a variety
of factors such as subject-dependent variables (e.g., age, immune system
health, clinical symptoms etc.).
[0083] In embodiments, the methods described herein are effective to
reduce, delay, or prevent one or more other clinical symptoms of a
developmental disorder, particularly epilepsy or Dravet syndrome. For
example, the effect of a composition including pipradrol or a
pharmaceutically acceptable salt, derivative or analogue thereof on a
particular symptom, pharmacologic, or physiologic indicator can be
compared to an untreated subject, or the condition of the subject prior
to treatment. In embodiments, the symptom, pharmacologic, and/or
physiologic indicator is measured in a subject prior to treatment, and
again one or more times after treatment is initiated. In embodiments, the
control is a reference level, or average determined based on measuring
the symptom, pharmacologic, or physiologic indicator in one or more
subjects that do not have the disease or condition to be treated (e.g.,
healthy subjects). In embodiments, the effect of the treatment is
compared to a conventional treatment that is known the art.
[0084] Pipradrol or a pharmaceutically acceptable salt, derivative or
analogue thereof as described herein may be considered stimulants because
they "stimulate" motor behavior. These effects may come at a cost, since,
in certain instances, stimulants can increase agitation and anxiety,
reduce sleep, and inhibit appetite. Moreover, many can be addictive and
have abuse potential. At higher doses stimulants may induce convulsions.
On the simplest level, a stimulant may be considered to be the opposite
of a depressant, and depressants, such as barbiturates and
benzodiazepines which may have robust anti-epileptic activity. Therefore,
it is commonly believed that certain stimulants can be pro-convulsant and
may typically be considered as contraindicated in the treatment of
developmental disorders. Indeed, there is some clinical evidence that
certain stimulants may lower the convulsive threshold in patients with
prior history of seizures, in patients with prior electroencephalogram
(EEG) abnormalities in the absence of seizures, and, rarely, in patients
without a history of seizures and no prior EEG evidence of seizures.
Accordingly, the methods and compositions described herein may
surprisingly provide reduction in the frequency of seizures, the severity
of seizures, or a combination thereof in a patient diagnosed with a
developmental disorder.
[0085] In embodiments, compositions and methods of treatment are provided
with low dosages of pipradrol such that the patient is provided one or
more beneficial effects related to a developmental disorder, such as,
reduced seizure activity, reduced fatigue, increased mood, increased
concentration, increased behavioral control and/or increased cognitive
ability. Pipradrol is known to have a relatively long half-life that may
lead to prolonged effects and drug accumulation in a patient. Provided
herein are dosing regimens that allow effective treatment of a
developmental disorder with potentially limited or substantially few
negative side effects, e.g., convulsions and/or sleep disruption.
Accordingly, the methods described herein may provide treatment of a
development disorder that may be considered surprising and unexpected.
For example, methods are provided herein of treating developmental
disorders in a patient in need thereof which may not cause sleep
disruption. In embodiments, methods described herein may provide
effective treatment of a development disorder without interrupting Slow
Wave Sleep. In embodiments methods of treating a developmental disorder
without causing insomnia or trouble falling asleep are provided.
[0086] The methods provided may also surprisingly and unexpectedly reduce
or prevent seizures, or symptoms thereof in a subject in need thereof.
The methods provided may reduce or prevent one or more different types of
seizures. Generally, a seizure can include convulsions, repetitive
movements, unusual sensations, and combinations thereof. Seizures can be
categorized as focal seizures (also referred to as partial seizures) and
generalized seizures. Focal seizures affect only one side of the brain,
while generalized seizures affect both sides of the brain. Specific types
of focal seizures include simple focal seizures, complex focal seizures,
and secondarily generalized seizures. Simple focal seizures can be
restricted or focused on a particular lobe (e.g., temporal lobe, frontal
lobe, parietal lobe, or occipital lobe). Complex focal seizures generally
affect a larger part of one hemisphere than simple focal seizures, but
commonly originate in the temporal lobe or the frontal lobe. When a focal
seizure spreads from one side (hemisphere) to both sides of the brain,
the seizure is referred to as a secondarily generalized seizure. Specific
types of generalized seizures include absences (also referred to as petit
mal seizures), tonic seizures, atonic seizures, myoclonic seizures, tonic
clonic seizures (also referred to as grand mal seizures), and clonic
seizures.
[0087] In embodiments, methods described herein may reduce the frequency
of seizures, reduce the severity of seizures, change the type of seizures
(e.g., from a more severe type to a less severe type), or a combination
thereof in a subject after treatment compared to the absence of treatment
(e.g., before treatment), or compared to treatment with an alternative
conventional treatment.
[0088] The disclosed compounds, such as gaboxadol or pharmaceutically
acceptable salts thereof, or pipradrol, pharmaceutically acceptable
salts, derivatives and/or analogues thereof, can be used individually as
a monotherapy as the only active agent. In embodiments, methods are
provided of treating development disorders using pipradrol or a
pharmaceutically acceptable salt thereof in a pharmaceutically acceptable
carrier. In embodiments, methods of treating developmental disorders
include administration of pipradrol, pharmaceutically acceptable salts,
derivatives and/or analogues thereof in combination with one or more
other active compounds. The combination therapies can include
administration of the active agents together in the same admixture, or in
separate admixtures. In embodiments, the pharmaceutical composition
includes two, three, or more active agents. In embodiments, the
combinations result in a more than additive effect on the treatment of
the disease or disorder. Thus, treatment is provided of a developmental
disorder with a combination of agents that combined, may provide a
synergistic effect that enhances efficacy.
[0089] In embodiments, gaboxadol or pharmaceutically acceptable salts
thereof, or pipradrol, pharmaceutically acceptable salts, derivatives
and/or analogues thereof, or both, is administered in combination with
conventional therapy for seizures, epilepsy, or one of the other
disorders disclosed herein. For example, common conventional therapies
for seizures and epilepsy include antiepileptic drugs and
non-antiepileptic drug treatments such as low carbohydrate diet (e.g.,
ketogenic diets, such as classical diet, medium chain triglyceride (MCT)
diet, modified Atkins diet (MAD), and low glycemic index treatment
(LGIT)), intravenous immunoglobulin, steroids, elimination diet, valgus
nerve stimulation, corticetomy, and multiple subpial transections.
[0090] Common antiepileptic and anticonvulsive active compounds that may
be used in combination with pipradrol include, but are not limited to,
acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine
acetate, ethosuximide, gabapentin, lacosamide, lamotrigine,
levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam,
phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide,
sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and
zonisamide.
[0091] In embodiments, a co-therapy of pipradrol, a pharmaceutically
acceptable salt thereof, or a derivative thereof and gaboxadol or a
pharmaceutically acceptable salt thereof is effective to reduce seizure
frequency or severity in the subject greater than either compound is
administered alone. In embodiments, the co-therapy produces a more than
additive result compared to compounds administered individually.
[0092] In embodiments, the subject may be started at a low dose and the
dosage is escalated. In this manner, it can be determined if the drug is
well tolerated in the subject. Dosages can be lower for children than for
adults.
[0093] In embodiments, such as combination therapies, a dose of gaboxadol
for children can be 0.1 mg/kg to 1 mg/kg, and the dose for pipradrol may
be 0.01 mg/kg to 0.1 mg/kg. The weight/weight ratio of gaboxadol and
pipradrol is can be 10-to-1. However, the dosing ratio based on
milligrams of active pharmaceutical ingredient (API) can range from
0.1-to-1 to 100-to-1 of gaboxadol-to-pipradrol respectively.
[0094] Effective treatment of a developmental disorder (e.g., SMEI or
Dravet syndrome) herein may be established by showing reduction in the
frequency of seizures (e.g., more than 50%) after a period of time
compared with baseline. For example, after a baseline period of 1 month,
the patients may be randomly allocated gaboxadol or pipradrol or placebo
as add-on therapy to standard therapies, such as valproate and clobazam,
during a double-blind period of 2 months. Primary outcome measurements
may include the percentage of responders on gaboxadol or pipradrol and on
placebo, defined as having experienced at least a 50% reduction of clonic
(or tonic-clonic) seizure frequency during the second month of the
double-blind period compared with baseline. Patients who present with
status epilepticus during the double-blind period may be regarded as
non-responders. Secondary outcomes may include the absolute count of
clonic (or tonic-clonic) seizures during the second month of the
double-blind period (normalized to 30 days, by dividing the raw count by
the exact number of days of observation and multiplying by 30) and the
percentage of change from baseline.
[0095] The effectiveness of gaboxadol and/or pipradrol for the treatment
of a disclosed developmental disorder, e.g., associated with Dravet
syndrome or Lennox-Gastaut syndrome, may be established in other
controlled studies. For example, a randomized, double-blind,
placebo-controlled study consisting of a 4-week baseline period followed
by a 3-week titration period and 12-week maintenance period may be used
in patients age 2-54 years with a current or prior diagnosis of Dravet
syndrome or LGS. Multiple target maintenance doses of gaboxadol and/or
pipradrol may be tested according to patient body weight and specific
dosing regime. A primary efficacy measure may include the percent
reduction in the weekly frequency of drop seizures (atonic, tonic, or
myoclonic), also known as drop attacks, from the 4-week baseline period
to 12-week maintenance period. Thus, efficacy may be measured as
percentage reduction in weekly seizure (e.g., atonic, tonic, or
myoclonic) frequency from baseline of, e.g., 0 to <20, 20 to <40,
40 to <60, 60 to <80, 80 to <100.
[0096] Unless defined otherwise, all technical and scientific terms used
herein have the same meanings as commonly understood by one of skill in
the art to which the disclosure herein belongs.
[0097] The term "about" or "approximately" as used herein means within an
acceptable error range for the particular value as determined by one of
ordinary skill in the art, which will depend in part on how the value is
measured or determined, i.e., the limitations of the measurement system.
For example, "about" can mean within 3 or more than 3 standard
deviations, per the practice in the art. Alternatively, "about" can mean
a range of up to 20%, preferably up to 10%, more preferably up to 5%, and
more preferably still up to 1% of a given value. Alternatively,
particularly with respect to biological systems or processes, the term
can mean within an order of magnitude, preferably within 5-fold, and more
preferably within 2-fold, of a value.
[0098] As used herein, the term "treating" or "treatment" refers to
alleviating, attenuating or delaying the appearance of clinical symptoms
of a disease or condition in a subject that may be afflicted with or
predisposed to the disease or condition, but does not yet experience or
display clinical or subclinical symptoms of the disease or condition. In
embodiments, treating" or "treatment" may refer to preventing the
appearance of clinical symptoms of a disease or condition in a subject
that may be afflicted with or predisposed to the disease or condition,
but does not yet experience or display clinical or subclinical symptoms
of the disease or condition. "Treating" or "treatment" may also refer to
inhibiting the disease or condition, e.g., arresting or reducing its
development or at least one clinical or subclinical symptom thereof
"Treating" or "treatment" further refers to relieving the disease or
condition, e.g., causing regression of the disease or condition or at
least one of its clinical or subclinical symptoms. The benefit to a
subject to be treated may be statistically significant, mathematically
significant, or at least perceptible to the subject and/or the physician.
Nonetheless, prophylactic (preventive) and therapeutic treatment are two
separate embodiments of the disclosure herein.
[0099] "Effective amount" or "therapeutically effective amount" means a
dosage sufficient to alleviate one or more symptom of a disorder,
disease, or condition being treated, or to otherwise provide a desired
pharmacological and/or physiologic effect.
[0100] "Pharmaceutically acceptable" refers to molecular entities and
compositions that are "generally regarded as safe"--e.g., that are
physiologically tolerable and do not typically produce an allergic or
similar untoward reaction, such as gastric upset and the like, when
administered to a human. In embodiments, this term refers to molecular
entities and compositions approved by a regulatory agency of the federal
or a state government, as the GRAS list under section 204(s) and 409 of
the Federal Food, Drug and Cosmetic Act, that is subject to premarket
review and approval by the FDA or similar lists, the U.S. Pharmacopeia or
another generally recognized pharmacopeia for use in animals, and more
particularly in humans.
[0101] As used herein, the term "prevention" or "preventing" means to
administer a composition to a subject or a system at risk for or having a
predisposition for one or more symptoms caused by a disease or disorder
to facilitate cessation of a particular symptom of the disease or
disorder, a reduction or prevention of one or more symptoms of the
disease or disorder, a reduction in the severity of the disease or
disorder, the complete ablation of the disease or disorder, stabilization
or delay of the development or progression of the disease or disorder.
[0102] "Prodrug", as used herein, refers to a pharmacological substance
(drug) that is administered to a subject in an inactive (or significantly
less active) form. Once administered, the prodrug is metabolized in the
body (in vivo) into a compound having the desired pharmacological
activity.
[0103] "Analog" and "Derivative" are used herein interchangeably and refer
to a compound that possesses the same core as the parent compound, but
may differ from the parent compound in bond order, the absence or
presence of one or more atoms and/or groups of atoms, and combinations
thereof. The derivative can differ from the parent compound, for example,
in one or more substituents present on the core, which may include one or
more atoms, functional groups, or substructures. In general, a derivative
can be imagined to be formed, at least theoretically, from the parent
compound via chemical and/or physical processes.
[0104] "Stereoisomer", as used herein, refers to isomeric molecules that
have the same molecular formula and sequence of bonded atoms
(constitution), but which differ in the three dimensional orientations of
their atoms in space. Examples of stereoisomers include enantiomers and
diastereomers. As used herein, an enantiomer refers to one of the two
mirror-image forms of an optically active or chiral molecule.
Diastereomers (or diastereoisomers) are stereoisomers that are not
enantiomers (non-superimposable mirror images of each other). Chiral
molecules contain a chiral center, also referred to as a stereocenter or
stereogenic center, which is any point, though not necessarily an atom,
in a molecule bearing groups such that an interchanging of any two groups
leads to a stereoisomer. In organic compounds, the chiral center is
typically a carbon, phosphorus or sulfur atom, though it is also possible
for other atoms to be stereocenters in organic and inorganic compounds. A
molecule can have multiple stereocenters, giving it many stereoisomers.
In compounds whose stereoisomerism is due to tetrahedral stereogenic
centers (e.g., tetrahedral carbon), the total number of hypothetically
possible stereoisomers will not exceed 2n, where n is the number of
tetrahedral stereocenters. Molecules with symmetry frequently have fewer
than the maximum possible number of stereoisomers. A 50:50 mixture of
enantiomers is referred to as a racemic mixture. Alternatively, a mixture
of enantiomers can be enantiomerically enriched so that one enantiomer is
present in an amount greater than 50%. Enantiomers and/or diasteromers
can be resolved or separated using techniques known in the art.
"Chirality" also includes axial and planar chirality.
[0105] The term "pharmaceutically acceptable salt", as used herein, refers
to derivatives of the compounds defined herein, wherein the parent
compound is modified by making acid or base salts thereof. Example of
pharmaceutically acceptable salts include but are not limited to mineral
or organic acid salts of basic residues such as amines; and alkali or
organic salts of acidic residues such as carboxylic acids. The
pharmaceutically acceptable salts include the conventional non-toxic
salts or the quaternary ammonium salts of the parent compound formed, for
example, from non-toxic inorganic or organic acids. Such conventional
non-toxic salts include those derived from inorganic acids such as
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
acids; and the salts prepared from organic acids such as acetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,
ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,
salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic,
naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and
isethionic salts.
[0106] The pharmaceutically acceptable salts of the compounds can be
synthesized from the parent compound, which contains a basic or acidic
moiety, by conventional chemical methods.
EXAMPLES
[0107] The Examples provided herein are included solely for augmenting the
disclosure herein and should not be considered to be limiting in any
respect.
Example 1
[0108] The following Example provides the plasma concentration profiles
and dose proportionality of gaboxadol monohydrate following single oral
doses ranging from 2.5 to 20 mg. The absolute bioavailability of
gaboxadol monohydrate capsules ranging from 2.5 to 20 mg is also
assessed.
[0109] This study was composed of separate groups of 10 healthy adult
subjects (at least 4 of each gender) who participated in a 6-period,
double-blind, randomized, crossover study designed to access the dose
proportionality and absolute bioavailabilty of 5 single oral doses of
gaboxadol across the dose range of 2.5 to 20 mg. The order in which the
subjects received the 5 single oral doses of gaboxadol (2.5; 5; 10; 15;
and 20 mg) was randomized within Treatment Periods 1 through 5. Each
subject was expected to complete all 6 treatment periods and there was a
washout of at least 4 days between each treatment period.
[0110] Each oral dosing within Treatment Periods consisted of 2 capsules
of test drug taken simultaneously at each scheduled dosing. The treatment
designations for the orally administered study drugs were as follows:
Treatment A--one 2.5 mg gaboxadol capsule and 1 matching placebo capsule;
Treatment B--one 5 mg gaboxadol capsule and 1 matching placebo capsule;
Treatment C--one 10 mg gaboxadol capsule and 1 matching placebo capsule;
Treatment D--one 15 mg gaboxadol capsule and 1 matching placebo capsule;
and Treatment E--20 mg gaboxadol (two 10 mg gaboxadol capsules). Subjects
received their study drug after an overnight fast with 240 mL of water in
the morning about 8:00 AM. Water was permitted ad libitum except within 1
hour prior to and after study drug administration. No food was allowed
for 4 hours post dose.
[0111] For each subject in each treatment, plasma and urine samples were
collected over 16 hours post-dosing for the determination of
pharmacokinetic parameters (e.g., AUC, C.sub.max, T.sub.max, apparent
t.sub.1/2, cumulative urinary excretion, renal clearance, clearance, and
steady-state volume of distribution, as appropriate). AUC and C.sub.max
for gaboxadol were potency adjusted to facilitate comparison of
pharmacokinetic data across studies. Table 1 provides the individual
potency-adjusted pharmacokinetic parameters of gaboxadol following single
oral doses (2.5, 5, 10, 15, and 20 mg).
Table 1. Pharmacokinetic Parameters for Gaboxadol Following Oral and IV
Administration
TABLE-US-00001
[0112] TABLE 1
Pharmacokinetic parameters for gaboxadol
following oral and IV administration
Geometric Mean (N = 10)
2.5 5 10 mg 10 mg 15 20 Slope
Parameter mg mg Oral I.V. mg mg (90% CI) .sup..dagger..dagger.
AUC.sub.0-.infin. 90 171 346 380 539 669 0.98
(ng hr/mL) (0.95, 1.01)
C.sub.max (ng/mL).sup..dagger. 61 110 232 212 382 393 0.95
(0.88, 1.02)
T.sub.max (hr).sup..dagger-dbl. 0.5 0.6 0.5 -- 0.5 0.6
Apparent t.sub.1/2 1.5 1.5 1.6 1.5 1.5 1.6
(hr).sup..sctn.
CL/F 461 488 476 438 469 499
(mL/min)
F.sub.e (%) 43 45 53 53 50 53
CL.sub.R (mL/min) 196 222 250 208 234 265
F (%) (90% CI).sup.# 92% (0.86, 0.97)
.sup..dagger.C.sub.coi (ng/mL) for 10 mg. IV.
.sup..dagger-dbl.Median.
.sup..sctn.Harmonic Mean.
CL (mL/min) for 10 mg IV.
.sup.#Bioavailability relative to 10 mg I.V. reference based on pooled
dose-adjusted (to 10 mg) oral AUC.sub.0-.infin. values.
.sup..dagger..dagger. Dose proportionality assessment of oral treatments
only.
[0113] FIG. 1 shows the arithmetic mean plasma concentration-time profiles
of gaboxadol following single oral doses (2.5, 5, 10, 15, and 20 mg). The
bioavailability of gaboxadol is approximately 92%. Plasma
AUC.sub.0-.infin. and C.sub.max of gaboxadol show dose proportional
increases and appear to be linear over the entire dose range examined,
from of 2.5 to 20 mg. The time to peak plasma concentrations (T.sub.max
30-60 min) and the half-life (t1/2 of 1.5 h) for gaboxadol appear to be
independent of dose across the gaboxadol dose range of 2.5 to 20 mg. The
excretion of gaboxadol is mainly via urine, where 96.5% of the dose is
recovered; 75% is recovered within 4 hours after administration.
Example 2
Assessment of Residual Effects Resulting from Gaboxadol Administration
[0114] This study was a double blind, double-dummy, randomized, active-
and placebo-controlled, single dose, 3-period crossover study, followed
by an open-label, single-dose, single period study in healthy elderly
male and female subjects. Subjects were randomized to each of 3
treatments (Treatments A, B, and C) to be administered in a crossover
manner over the first 3 treatment periods. For Treatment A, subjects
received a single dose of gaboxadol 10 mg; for Treatment B, subjects
received a single dose of flurazepam 30 mg; and for Treatment C, subjects
received a single dose of placebo. Doses were administered orally at
bedtime on Day 1. Subjects were domiciled from early in the evening of
dosing until .about.36 hours post-dose (morning of Day 3) during each
treatment period. The subjects who participated in treatment periods 1-3
participated in a fourth treatment period. In this period, a single dose
of gaboxadol 10 mg (Treatment D) was administered orally in an open-label
manner on the morning of Day 1 for PK of gaboxadol. There was at least a
14-day washout between the doses of consecutive treatment periods. Study
participants included healthy, elderly male and female subjects between
65 and 80 years of age, with a Mini Mental Status 24, weighing at least
55 kg.
All subjects received 10 mg gaboxadol monohydrate capsules and 30 mg
flurazepam (provided as 2.times.15 mg capsules), matching placebo was
provided for both gaboxadol and flurazepam.
[0115] The primary endpoints evaluated included pharmacodynamics
(measurement of psychomotor performance, memory, attention and daytime
sleepiness the following pm dosing), gaboxadol pharmacokinetics, and
safety. Gaboxadol (single dose 10 mg) did not show residual effect 9
hours post-dose on the primary endpoints Choice Reaction Time and
Critical Flicker Fusion, whereas the active reference Flurazepam (30 mg
single dose) showed significant effect on the same tests. In addition,
gaboxadol did not show any signs of residual effects on other
measurements applied in the study (Multiple Sleep Latency Test (MSLT);
Digit symbol substitution test (DSST), Tracking, Memory tests, Body Sway,
and Leeds Sleep Evaluation Questionnaire).
Example 3
Study of Driving Performance after Gaboxadol Administration
[0116] This study was a double blind, randomized, placebo and active
controlled 5 way cross over study to investigate the effect of evening
and middle of the night dosing of gaboxadol on driving performance. The
study participants included healthy, male and female subjects between 21
and 45 years of age, with a valid drivers license for at least 3 years.
[0117] The effects of gaboxadol on driving performance were investigated
using real driving on the road setting. Subjects received 15 mg gaboxadol
either in the evening prior to going to bed or at 4 am in the middle of
the night following a wake-up call. Following a cognitive and psychomotor
test battery, the driving test started at 9 am and lasted for one hour.
Gaboxadol 15 mg had a clinically relevant impairing effect on driving
following middle-of-the-night administration.
[0118] Following the evening dose, a statistically significant effect of
gaboxadol 15 mg was observed on driving. However, this effect was less
than the effect observed at a 0.05% blood alcohol concentration, the
concentration limit at which driving is prohibited in most European
countries. There was generally a numerically greater effect following
zopiclone (7.5 mg) and zolpidem (10 mg) administered in the evening and
in the middle of the night, respectively. Both the evening and the
middle-of-the-night dose of gaboxadol were well tolerated with the most
frequent adverse events being dizziness, nausea and somnolence for the
middle-of-the-night treatment and headache and somnolence for the evening
treatment.
[0119] Subjects on the active reference zopiclone had a numerically
greater effect in the same test. There was no effect on memory test, body
sway, DSST or critical tracking, whereas zopiclone had effect on several
of these tests.
Example 4
Study of Daytime Performance after Sleep Restriction
[0120] This study was a 4-night, parallel-group, randomized, double-blind
(with in-house blinding), placebo-controlled, fixed-dose study to assess
the effects of gaboxadol on daytime performance in healthy adults
subjected to a 5-hour sleep restriction. The study included a 2-night
single-blind placebo run-in period, a 4-night double-blind treatment
period during which sleep was restricted to 5 hours and a 2-night
single-blind placebo run-out period. The study included healthy male and
female volunteers 18 to <55 years of age.
[0121] 2-night run-in period: All patients received placebo
[0122] 4-night double-blind treatment period: Patients were randomized to
gaboxadol 15 mg or matching placebo
[0123] 2-night run-out period: All patients received placebo
[0124] The primary endpoints included observations based on the Multiple
Sleep Latency Test (MSLT) and Slow Wave Sleep (SWS) assessment. The
primary objective was to evaluate the efficacy of gaboxadol (15 mg)
compared to placebo in reducing daytime sleep propensity as measured by
MSLT. The gaboxadol subjects had significantly less daytime sleepiness
during the Sleep Restriction period than did placebo subjects (p=0.047, 1
sided). The MSLT was on average 2.01 minutes longer for subjects treated
with gaboxadol (15 mg) than for those with placebo on the last two Sleep
Restriction days.
[0125] In addition, a secondary objective was to evaluate the efficacy of
gaboxadol compared to placebo in increasing the amount of slow wave sleep
(SWS) during the last 2 nights of sleep restriction. Subjects receiving
gaboxadol experienced significantly more SWS during the Sleep Restriction
period than did placebo subjects (p<0.001, 1 sided). Moreover,
subjects treated with gaboxadol on average had 20.53 minutes of SWS
longer than those treated with placebo on the last two Sleep Restriction
nights.
[0126] Finally, this study examined the efficacy of gaboxadol compared to
placebo during the last 2 nights/days of sleep restriction in: (1)
improving memory and attention as assessed by a neurobehavioral battery;
(2) reducing subjective sleepiness as measured by the Karolinska
Sleepiness Score (KSS); (3) altering sleep parameters (e.g., total sleep
time, latency to onset of Slow Wave Sleep (SWS), slow wave activity
(SWA); and (4) reducing biological stress typified by increased heart
rate variability, and decreased cortisol levels and decreased
catecholamine levels, as well as decreased body temperature.
[0127] There was a trend towards less subjective daytime sleepiness for
the gaboxadol subjects during the Sleep Restriction period as compared
with placebo subjects. The Karolinska Sleepiness Score (KSS) was on
average 0.68 less for subjects treated with gaboxadol than for those
treated with placebo on the last two Sleep Restriction days (p=0.058, 1
sided) as evaluated by a Longitudinal data analysis (LDA) model with
adjustment for baseline KSS, gender, and age. A supportive analysis using
covariance (ANCOVA) also supports this finding. The effect sizes computed
for the neurocognitive battery showed that there was no strong evidence
that gaboxadol improves daytime performance. There were no differences
between gaboxadol and placebo with respect to biophysiological measures
of stress (heart rate variability, cortisol levels, catecholamine levels,
body temperature).
[0128] Compared with placebo, gaboxadol has a protective effect on
reducing daytime sleepiness as measured by the MSLT on the last 2 days of
4-nights of sleep restriction. Compared with placebo, gaboxadol increases
the amount of slow wave sleep (SWS) during the last 2 nights of 4-nights
of sleep restriction.
Example 5
Prospective Assessment of the Efficacy of Gaboxadol in Patients with
Dravet Syndrome
[0129] This study is designed to determine whether gaboxadol leads to an
improvement in one or more symptoms of Dravet syndrome. Individuals with
Dravet syndrome may suffer from severe disruptions in sleep, impairments
in speech, behavioral and developmental delays, movement and balance
issues, delayed language and speech issues, growth and nutrition issues,
chronic infections, sisruptions of the autonomic nervous system and
frequent seizures with characteristic abnormal electroencephalogram (EEG)
patterns. All main domains of symptoms of Dravet syndrome (e.g., seizure
activity, sleep, gross and fine motor function, behavior and
communication) will be investigated, using appropriate questionnaires,
diaries or actimetric data. Main focus may include seizure activity,
motor ability and sleep. Well-established scales may be used,
complemented by more innovative outcome measures for sleep and motor
function. A potential confounding factor for behavior in Dravet syndrome
is the co-existence of autism. At Screening, subjects may be assessed for
this co-morbidity, using the Autism Diagnostic Observation Schedule
(ADOS), and potentially excluded.
[0130] The primary objective of this study may be to evaluate the safety
and tolerability from Baseline to Week 6 and Week 12 of gaboxadol in
adult subjects with Dravet syndrome across different dose levels and in
two dosing schedules. The following dosing schedules may be tested
against placebo: (1) Once daily (o.d.): An evening dose, titrated to the
target dose of 15 mg unless not tolerated; and (2) Twice daily (b.i.d.):
Evening and morning doses titrated to the target doses of 15 mg evening
dose and 10 mg morning dose unless not tolerated.
[0131] The Safety endpoints that relate to this study may include: (1)
Frequency and severity of adverse events (AEs) and serious adverse
events; (2) Vital signs (weight, blood pressure, temperature); (3)
Laboratory parameters (electrolytes, lipids, glucose, liver and pancreas
function tests, hematology, creatinine); (4) Suicidality assessed by
ABC-Irritability Subscale; (5) EEG (change in background frequency,
intensity of epileptiform discharges); and/or (6) Caregivers may maintain
an electronic seizure diary (on same device as sleep log).
[0132] The secondary objective of this study may include the
identification of a set of parameters that may best characterize the
efficacy of gaboxadol in adult Dravet syndrome subjects for subsequent
efficacy trials. These tests may be administered at four full day site
visits (Screening, Baseline, Interim and End of Treatment) by an
appropriately trained professional to provide the test to an adult Dravet
syndrome patient. Assessments may be based on direct observation and
input from caregivers. The efficacy assessments that may be explored
include Gross Motor Ability/Function and Fine Motor Ability/Function.
Evaluation of Gross Motor Ability/Function may include analysis of
spatiotemporal and functional gait measurements (Zeno Walkway and PKMAS
software analysis, provided by ProtoKintetics) and Modified Performance
Oriented Mobility Assessment-Gait (MPOMA-G) scale assessed while subject
is walking on Zeno Walkway.
[0133] Evaluation of Fine Motor Ability/Function may include analysis of
Pediatric Evaluation of Disability Inventory (PEDI-CAT); ADL (to document
fine motor function) and mobility domains in the content-balanced (more
extensive) version.
[0134] Evaluation of sleep may include analysis by actigraphy to measure:
(1) Sleep Onset Latency (SOL); (2) Total Sleep Time (TST); (3) Wake After
Sleep Onset (WASO)=total # of wake epochs after sleep onset; (4)
Nocturnal Awakenings (NA); and/or (5) Sleep Efficiency=total sleep time
(TST) of time in bed (TIB). Additional evaluation of sleep may include
analysis of parent/caregiver logs of sleep patterns that may include: (1)
bed time; (2) time of sleep onset; (3) number and duration of awakenings;
(4) number of disruptive behavior; (5) time of last awakening; and (6)
daytime sleepiness.
[0135] Evaluation of seizure activity may include EEG monitoring (change
in background frequency, intensity of epileptiform discharges).
[0136] This study may include three treatment groups. For example, a total
of approximately 75 subjects may be enrolled and at the completion of the
study, there may be approximately 25 subjects in each of the three
treatment groups: 1) single evening dose 2) morning and evening dose and
3) placebo.
[0137] All subjects may receive a morning dose (either active or placebo)
and an evening dose (either active or placebo) during the entire duration
of treatment. For example, as shown schematically in FIG. 2, two dosing
schedules of gaboxadol may be tested: a single evening dose (o.d.;
Schedule A) and a morning plus evening dose (b.i.d; Schedule B) designed
to provide a more sustained exposure. Schedule C is morning and evening
placebo. All subjects may be up-titrated to the target dose unless this
target dose is not tolerated (titration conventions described below). All
subjects may receive treatment for a maximum of 12 weeks at their optimal
tolerated dose.
[0138] Doses may be progressively increased in 5 mg increments (active or
placebo) to a target dose of 3 capsules evening dose in schedule A and B,
and 2 capsules morning dose in schedule B. Each dose escalation may be
performed after adequate tolerability will be assessed by caregiver and
investigator. For example, as shown graphicallyin FIG. 3, treatment
initiation at Day 1 with 1 capsule (active or placebo) in the evening.
Then Target up-titration may begin at Day 3 (window+2 days): If no
adverse event (AE) related to the study drug is observed by caregiver
and/or the investigator, another capsule (active or placebo) is added in
the evening. Again at Day 7 (window+2 days), Day 10 (window+2 days and
Day 14 (window+2 days) if no AE related to the study drug is observed by
caregiver and/or the investigator, another capsule (active or placebo)
may be added in the morning.
[0139] Slowed up-titration or delayed up-titration will be acceptable if
tolerability does not allow immediate further dose-escalation at any of
the above detailed days (3, 7, 10, 14). Down-titration in the case
tolerability is not acceptable (e.g., somnolence, dizziness, change in
behavior) after a previous up-titration step or during the course of the
12 week treatment, dose can be reduced to the previous level or even
further. However, once a tolerable dose has been reached, it shall remain
constant for the duration of the treatment period. Once a target dose is
achieved the treatment may continue. For example, at Day 14: Earliest day
the target dose can be reached (2 capsules in the morning and 3 in the
evening) the subject may be kept stable until End of Treatment visit
(week 12) unless intolerability requires down-titration.
[0140] All subjects will be screened for participation in the study up to
28 days prior to the first dose administration. Inclusion criteria may
include one or more of the following: (1) Age .gtoreq.18 years,
.ltoreq.40 years; (2) Must possess a clinical diagnosis of Dravet
syndrome according to the consensus criteria with developmental delay,
movement or balance disorder, and speech disorder; (3) Must possess a
previous or current molecular confirmation of Dravet syndrome; (4)
Subjects must be receiving a stable dose of concomitant medications,
including anti-epileptic medication, supplements, and special diets, for
at least 4 weeks prior to Baseline, and be able to maintain these
throughout the duration of the study.
[0141] Exclusion Criteria may include one or more of the following: (1)
Non-ambulatory subjects (e.g. requiring a wheelchair) not able to perform
the tests for Assessment of Motor Ability/Function (as described above);
(2) Poorly controlled seizures defined as >3 absence-type seizure per
week and/or >1 major seizure episodes per month; (3) Concomitant
cardiovascular, respiratory diseases; Concomitant liver disease with
alanine aminotransferase or aspartate aminotransferase
>2.5.times.upper limit of normal (ULN); (4) Concomitant renal disease
with creatinine above ULN (5) Concomitant hematologic disease with
absolute neutrophil count >2.times.10.sup.9/L or platelets
<50.times.10.sup.9/L or hemoglobin <80 g/L; (6) Other genetic
disorders; (7) Concomitant use of minocycline, levodopa, sleep medication
and any other use of any investigational agent, device, and/or
investigational procedure 4 weeks prior to Baseline and during the study;
(8) At risk of suicide based on ABC--Irritability Subscale
[0142] Descriptive statistics may be used to summarize all primary and
secondary endpoints as well as baseline variables, by treatment group.
For continuous variables, n, number of missing values, mean, standard
deviation, median, minimum, and maximum will be provided. For categorical
variables, frequency and percentage will be presented for each category.
Confidence intervals (CI) will be provided where meaningful. All CIs will
be two-sided 95% confidence intervals.
Example 6
Prospective Assessment of the Efficacy of Gaboxadol in Patients with
Dravet Syndrome
[0143] This study is designed to determine whether lower doses of
gaboxadol lead to an improvement in younger patients or patients with
less severe clinically evaluated symptoms. For example, adolescent
patients (age 12-18 years) may have the similar clinical presentation and
baseline disease characteristics as the adult population but the
reduction in ambulation may be less severe. In these patients it is
anticipated that the target benefit of gaboxadol may also include the
reduction in seizures, ataxia and the improvement in ambulatory function.
[0144] In pediatric patients (6 months to 12 years) the diagnosis of
Dravet syndrome is usually made around 1 to 2 years of age based on
important delay in the development status and eventually persistent
seizures. As the child grows older, additional neurologic deficit will
contribute to the disease presentation. For these prospective
participants, the inclusion criteria for randomization and assessment
procedures is similar to that previously described.
[0145] After randomization the participants are placed into 6 separate
treatment groups (A-F) and a placebo group. Treatment group A receives
7.5 mg gaboxadol in the evening. Treatment group B receives 5 mg
gaboxadol in the evening. Treatment group C receives 5 mg gaboxadol in
the evening and 2.5 mg gaboxadol in the morning. Treatment group D
receives 2.5 mg gaboxadol in the evening. Treatment group E receives 2.5
mg gaboxadol in the evening and 1 mg gaboxadol in the morning. Treatment
group F receives 1 mg gaboxadol in the evening.
[0146] Those skilled in the art will recognize, or be able to ascertain
using no more than routine experimentation, many equivalents to the
specific embodiments described herein. Such equivalents are intended to
be encompassed by the claims.