U.S. patent application number 15/246346 was filed with the patent office on 2017-03-02 for methods of treating lennox-gastaut syndrome using fenfluramine.
This patent application is currently assigned to ZOGENIX INTERNATIONAL LIMITED. The applicant listed for this patent is ZOGENIX INTERNATIONAL LIMITED. Invention is credited to Stephen J. FARR, Bradley S. GALER.
Application Number | 20170056344 15/246346 |
Document ID | / |
Family ID | 58101064 |
Filed Date | 2017-03-02 |
United States Patent
Application |
20170056344 |
Kind Code |
A1 |
FARR; Stephen J. ; et
al. |
March 2, 2017 |
METHODS OF TREATING LENNOX-GASTAUT SYNDROME USING FENFLURAMINE
Abstract
A method of treating and/or preventing symptoms of
Lennox-Gastaut Syndrome (LGS) also known as Lennox Syndrome in a
patient such as a patient previously diagnosed with Lennox
Syndrome, by administering an effective dose of fenfluramine or its
pharmaceutically acceptable salt to that patient. Lennox Syndrome
patients are treated at a preferred dose of less than about 2.0 to
about 0.01 mg/kg/day.
Inventors: |
FARR; Stephen J.; (Orinda,
CA) ; GALER; Bradley S.; (West Chester, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ZOGENIX INTERNATIONAL LIMITED |
Berkshire |
|
GB |
|
|
Assignee: |
ZOGENIX INTERNATIONAL
LIMITED
Berkshire
GB
|
Family ID: |
58101064 |
Appl. No.: |
15/246346 |
Filed: |
August 24, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62209090 |
Aug 24, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/357 20130101;
A61K 9/0095 20130101; A61P 25/08 20180101; A61K 9/0053 20130101;
A61K 31/19 20130101; A61K 31/137 20130101; A61K 31/551 20130101;
A61K 9/7023 20130101; A61K 31/551 20130101; A61K 9/08 20130101;
A61K 31/19 20130101; A61K 45/06 20130101; A61K 31/137 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61K 9/08 20060101 A61K009/08; A61K 9/70 20060101
A61K009/70; A61K 31/357 20060101 A61K031/357; A61K 31/551 20060101
A61K031/551; A61K 31/19 20060101 A61K031/19; A61K 9/00 20060101
A61K009/00; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method of treating, and/or preventing symptoms of
Lennox-Gastaut syndrome (Lennox Syndrome) in a patient diagnosed
with Lennox-Gastaut syndrome, comprising: administering a
pharmacologically effective dose of fenfluramine or a
pharmaceutically acceptable salt thereof to the patient.
2. The method of claim 1, wherein the dose is in a range of from
10.0 mg/kg/day to 0.01 mg/kg/day.
3. The method of claim 2, wherein the dose is administered in a
dosage form selected from the group consisting of oral, injectable,
transdermal, inhaled, nasal, rectal, vaginal and parenteral
delivery.
4. The method of claim 3, wherein the dosage form is an oral
solution in an amount selected from the group consisting of 120 mg
or less, 60 mg or less, and 30 mg or less.
5. The method as claimed in claim 4 wherein the dosage form
consists essentially only of fenfluramine as the active
ingredient.
6. The method as claimed in claim 1, further comprising:
administering a co-therapeutic agent selected from the group
consisting of carbamazepine, ethosuximide, fosphenytoin,
lamotrigine, levetiracetam, phenobarbital, progabide, topiramate,
stiripentol, valproic acid, valproate, verapamil, and
benzodiazepines such as clobazam, clonazepam, diazepam, ethyl
loflazepate, lorazepam, midazolam and a pharmaceutically acceptable
salt or base thereof.
7. The method of claim 1, wherein the symptom is preventing and/or
ameliorating seizures in a patient diagnosed with Lennox-Gastaut
syndrome, and wherein the fenfluramine is formulated with a
pharmaceutically acceptable carrier and an effective dose is less
than 10.0 mg/kg/day to 0.01 mg/kg/day.
8. The method of claim 1 wherein the dose is selected from the
group consisting of 120 mg or less, 60 mg or less, and 30 mg or
less, and wherein the dose is administered in a dosage form
selected from the group consisting of forms for oral, injectable,
transdermal, inhaled, nasal, rectal, vaginal and parenteral
delivery.
9. The method as claimed in claim 2, wherein the fenfluramine is
the only active ingredient administered to the patient.
10. The method of claim 9, further comprising: administering a
co-therapeutic agent selected from the group consisting of
carbamazepine, ethosuximide, fosphenytoin, lamotrigine,
levetiracetam, phenobarbital, topiramate, stiripentol, valproic
acid, valproate, verapamil, and benzodiazepines such as clobazam,
clonazepam, diazepam, lorazepam, and midazolam and a
pharmaceutically acceptable salt or base thereof.
11. The method of claim 10 wherein the co-therapeutic agent is a
combination of stiripentol, clobazam, and valproate.
12. The method of claim 11, wherein the co-administration of the
stiripentol, clobazam and valproate increases fenfluramine blood
levels by 100% or more relative to fenfluramine blood levels
obtained in the absence of the co-administration of stiripentol,
clobazam and valproate, and further wherein blood levels of a
metabolized of fenfluramine are decreased relative to levels of a
flenfluramine metabolite obtained in the absence of the
co-administration of stiripentol, clobazam and valproate.
13. The method of claim 10, wherein the co-therapeutic agent is
stiripentol.
14. A kit, comprising: a container comprising a plurality of doses
of a formulation comprising a pharmaceutically acceptable carrier
and an active ingredient comprising fenfluramine; instructions for
treating the patient diagnosed with LGS by withdrawing the
formulation from the container, and administering the formulation
to the patient.
15. The kit as claimed in claim 14, wherein: the formulation is an
oral solution comprising 2.5 milligram of fenfluramine in each
milliliter of liquid solution; and the instructions indicate dosing
the patient based on patient weight and volume of oral solution
administered.
16. The kit as claimed in claim 14, wherein the formulation is a
solid oral formulation selected from the group consisting of: a
tablet, a disintegrating table, a capsule, a lozenge, and a
sachet.
17. The kit as claimed in claim 14, wherein said formulation is
provided in a transdermal patch.
18. A kit, comprising: a container comprising a plurality of doses
of a formulation comprising a pharmaceutically acceptable carrier
and an active ingredient comprising fenfluramine; a container
comprising a plurality of doses of a formulation comprising a
pharmaceutically acceptable carrier and an active ingredient
comprising stiripentol; instructions for treating a patient.
Description
FIELD OF THE INVENTION
[0001] This invention relates generally to the field of methods of
treatment and in particular, methods of treating human patients,
and more particularly towards treating human patients diagnosed
with Lennox-Gastaut Syndrome.
BACKGROUND OF THE INVENTION
[0002] This invention relates to the treatment of symptoms of
Lennox-Gastaut Syndrome ("LGS," sometimes referred to as "Lennox
Syndrome") using an amphetamine derivative, specifically
fenfluramine.
[0003] Fenfluramine, i.e. 3-trifluoromethyl-N-ethylamphetamine is
an amphetamine derivative having the structure:
##STR00001##
[0004] Fenfluramine was first marketed in the US in 1973 and had
been administered in combination with phentermine to prevent and
treat obesity. However, in 1997, it was withdrawn from the US and
global market as its use was associated with the onset of cardiac
valve fibrosis and pulmonary hypertension. Subsequently, the drug
was withdrawn from sale globally and is no longer indicated for use
in any therapeutic area. Without being bound by theory, the adverse
effects associated with the use of fenfluramine as an anorexic
agent are thought to be attributable to the interaction of
fenfluramine's major metabolite norfenfluramine with the 5-HT2B
receptor, which is associated with heart valve hypertrophy.
[0005] Fenfluramine is metabolized in vivo into norfenfluramine by
cytochrome P450 enzymes in the liver. Cytochrome P450 enzymes such
as CYP2D6 and CYP1A2 are primarily responsible for the production
of norfenfluramine from fenfluramine in humans. Such metabolism
includes cleavage of an N-ethyl group to produce norfenfluramine as
shown below.
##STR00002##
[0006] Despite past cardiovascular safety concerns that arose when
high doses of fenfluramine were used for treatment of adult
obesity, attempts have been made to identify further therapeutic
uses for that product, while weighing the known cardiovascular
risks of fenfluramine against potential therapeutic benefits. One
disorder for which new treatment options are sorely needed is
epilepsy, and in particular, epilepsy syndromes which are
refractory to known treatments. Epilepsy is a condition of the
brain marked by a susceptibility to recurrent seizures. There are
numerous causes of epilepsy including, but not limited to birth
trauma, perinatal infection, anoxia, infectious diseases, ingestion
of toxins, tumors of the brain, inherited disorders or degenerative
disease, head injury or trauma, metabolic disorders,
cerebrovascular accident and alcohol withdrawal.
[0007] Prior to the inventor's work, investigation of
fenfluramine's efficacy in epilepsy patients, while showing some
initial promise, was far from definitive, and shared a common
paradigm, i.e., that fenfluramine's primary effects were on
behaviors that caused or induced seizures, not treating or
preventing the seizure itself.
[0008] For example, Aicardi and Gastaut (New England Journal of
Medicine (1985), 313:1419 and Archives of Neurology (1988)
45:923-925) reported four cases of self-induced photosensitive
seizures, i.e., seizures caused by patients purposely staring into
bright lights or the sun, that responded to treatment with
fenfluramine.
[0009] Clemens, in Epilepsy Research (1988) 2:340-343 reported a
case study wherein a boy suffering pattern sensitivity-induced
seizures that were resistant to anticonvulsive treatment was
treated with fenfluramine to curb the patient's compulsive
seizure-inducing behavior. Fenfluramine reportedly successfully
terminated these self-induced seizures and the author concluded
that this was because fenfluramine blocked the seizure-sensitive
triggering mechanism, i.e., not by treating the seizure itself.
[0010] In Neuropaediatrics, (1996); 27(4):171-173, Boel and Casaer
reported on a study on the effects of fenfluramine on children with
refractory epilepsy, all of whom exhibited compulsive
seizure-inducing behavior. They observed that when fenfluramine was
administered at a dose of 0.5 to 1 mg/kg/day, this resulted in a
reduction in the number of seizures experienced by the patients,
and concluded that "this drug could have significant anti-epileptic
activity in a selected group of young patients with idiopathy or
symptomatic generalized epilepsy, namely, children with
self-induced seizures." The authors noted that "[i]t may well be
that fenfluramine has no direct antiepileptic activity but acts
through its effect on the compulsion to induce seizures." Hence the
authors seemed to suggest that fenfluramine affected behavior and
not the seizure itself.
[0011] In a letter to Epilepsia, published in that journal
(Epilepsia, 43(2):205-206, 2002), Boel and Casaer commented that
fenfluramine appeared to be of therapeutic benefit in patients with
intractable epilepsy and self-induced seizures. However, the
authors did not attribute fenfluramine's efficacy to generalized
anti-seizure activity.
[0012] A large number of subtypes of epilepsy have been
characterized, each with its own unique clinical symptoms, signs,
and phenotype, underlying pathophysiology and distinct responses to
different treatments. The most recent version, and the one that is
widely accepted in the art, is that adopted by the International
League Against Epilepsy's ("ILAE") Commission on Classification and
Terminology [See e.g., Berg et al., "Revised terminology and
concepts for organization of seizures," Epilepsia, 51(4):676-685
(2010)]:
[0013] I. ELECTROCHEMICAL SYNDROMES (Arranged by age of onset):
[0014] A. Neonatal period [0015] 1. Benign familial neonatal
epilepsy (BFNE) [0016] 2. Early myoclonic encephalopathy (EME)
[0017] 3. Ohtahara syndrome
[0018] B. Infancy [0019] 1. Epilepsy of infancy with migrating
focal seizures [0020] 2. West syndrome [0021] 3. Myoclonic epilepsy
in infancy (MEI) [0022] 4. Benign infantile epilepsy [0023] 5.
Benign familial infantile epilepsy [0024] 6. Dravet syndrome [0025]
7. Myoclonic encephalopathy in non-progressive disorders
[0026] C. Childhood [0027] 1. Febrile seizures plus (FS+) (can
start in infancy) [0028] 2. Panayiotopoulos syndrome [0029] 3.
Epilepsy with myoclonic atonic (previously astatic) seizures [0030]
4. Benign epilepsy with centrotemporal spikes (BECTS) [0031] 5.
Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) [0032]
6. Late onset childhood occipital epilepsy (Gastaut type) [0033] 7.
Epilepsy with myoclonic absences [0034] 8. Lennox-Gastaut syndrome
[0035] 9. Epileptic encephalopathy with continuous spike-and-wave
during sleep (CSWS), also known as Electrical Status Epilepticus
during Slow Sleep (ESES) [0036] 10. Landau-Kleffner syndrome (LKS)
[0037] 11. Childhood absence epilepsy (CAE)
[0038] D. Adolescence--Adult [0039] 1. Juvenile absence epilepsy
(JAE) [0040] 2. Juvenile myoclonic epilepsy (JME) [0041] 3.
Epilepsy with generalized tonic-clonic seizures alone [0042] 4.
Progressive myoclonus epilepsies (PME) [0043] 5. Autosomal dominant
epilepsy with auditory features (ADEAF) [0044] 6. Other familial
temporal lobe epilepsies
[0045] E. Less specific age relationship [0046] 1. Familial focal
epilepsy with variable foci (childhood to adult) [0047] 2. Reflex
epilepsies
[0048] II. DISTINCTIVE CONSTELLATIONS
[0049] A. Mesial temporal lobe epilepsy with hippocampal sclerosis
(MTLE with HS)
[0050] B. Rasmussen syndrome
[0051] C. Gelastic seizures with hypothalamic hamartoma
[0052] D. Hemiconvulsion-hemiplegia-epilepsy
[0053] E. Epilepsies that do not fit into any of these diagnostic
categories, distinguished on the basis of [0054] 1. Presumed cause
(presence or absence of a known structural or metabolic condition)
[0055] 2. Primary mode of seizure onset (generalized vs. focal)
[0056] III. EPILEPSIES ATTRIBUTED TO AND ORGANIZED BY
STRUCTURAL-METABOLIC CAUSES
[0057] A. Malformations of cortical development
(hemimegalencephaly, heterotopias, etc.)
[0058] B. Neurocutaneous syndromes (tuberous sclerosis complex,
Sturge-Weber, etc.)
[0059] C. Tumor
[0060] D. Infection
[0061] E. Trauma
[0062] IV. ANGIOMA
[0063] A. Perinatal insults
[0064] B. Stroke
[0065] C. Other causes
[0066] V. EPILEPSIES OF UNKNOWN CAUSE
[0067] VI. CONDITIONS WITH EPILEPTIC SEIZURES NOT TRADITIONALLY
DIAGNOSED AS FORMS OF EPILEPSY PER SE
[0068] A. Benign neonatal seizures (BNS)
[0069] B. Febrile seizures (FS)
[0070] Part V of the ILAE classification scheme underscores the
fact that the list is far from complete, and that there are still
subtypes of epilepsy that have not yet been fully characterized, or
that remain unrecognized as distinct syndromes.
[0071] Those skilled in the art will recognize that different
subtypes of epilepsy are triggered by different stimuli, are
controlled by different biological pathways, and have different
causes, whether genetic, environmental, and/or due to disease or
injury of the brain. In other words, the skilled artisan will
recognize that teachings relating to one epileptic subtype are most
commonly not necessarily applicable to any other subtype. Of
particular importance is the fact that there are a large number of
compounds that are used to treat different types of epilepsy, and
different epilepsy subtypes respond differently to different
anticonvulsant drugs. That is, while a particular drug may be
effective against one form of epilepsy, it may be wholly
ineffective against others, or even contra-indicated due to
exacerbation of symptoms, such as worsening the frequency and
severity of the seizures. As a result, efficacy of a particular
drug with respect to a particular type of epilepsy is wholly
unpredictable, and the discovery that a particular drug is
effective in treating in treating a type of epilepsy for which that
drug was not previously known to be effective is nearly always
surprising, even in cases where the drug is known to be effective
against another epilepsy type.
[0072] Lennox-Gastaut syndrome (LGS) was first described in 1960,
and named for neurologists William G. Lennox (Boston, USA) and
Henri Gastaut (Marseille, France). It is a difficult-to-treat form
of childhood-onset epilepsy that most often appears between the
second and sixth year of life, although it can occur at an earlier
or later age. LGS is characterized by frequent seizures and
different seizure types; it is typically accompanied by
developmental delay and psychological and behavioral problems. In
children, common causes of LGS include perinatal brain injury,
brain malformations such as tuberous sclerosis or cortical
dysplasia, central nervous system (CNS) infection, and degenerative
or metabolic disorders of the nervous system.
[0073] Daily multiple seizures of different types are typical in
LGS. Also typical is the broad range of seizures that can occur.
The most common seizure types are tonic-axial, atonic, and absence
seizures, but myoclonic, generalized tonic-clonic, and focal
seizures can also occur in any LGS patient. Atonic, atypical
absence, tonic, focal, and tonic-clonic seizures are also common.
Additionally, many LGS patients will have status epilepticus, often
of the nonconvulsive type, which is characterized by dizziness,
apathy, and unresponsiveness. Further, most patients have atonic
seizures, also called drop seizures, which cause their muscles to
go limp and result in the patient suddenly and unexpectedly to fall
to the ground, often causing significant injury, which is why
patients often wear a helmet to prevent head injury.
[0074] In addition to daily multiple seizures of various types,
children with LGS frequently have arrested/slowed psycho-motor
development and behavior disorders.
[0075] The syndrome is also characterized by a specific finding on
electroencephalogram (EEG), specifically an interictal (i.e.,
between-seizures) slow spike-wave complexes and fast activity
during sleep.
Diagnosis
[0076] LGS is a syndrome and hence its diagnosis is based on the
presence of specific clinical symptoms, signs, and laboratory
tests. LGS is typically identified by a triad of features including
multiple types of seizures, mental retardation or regression and
abnormal EEG with generalized slow spike and wave discharges.
Physicians use EEG to assist in diagnosing LGS. Diagnosis may be
difficult at the onset of the initial symptom(s) because the triad
of features associated with LGS, such as tonic seizures, may not be
fully established, and EEG during sleep is required to confirm the
condition. Thus, even though there may be overlap in clinical
presentation with other epilepsies, LGS is agreed to be a
well-defined distinct diagnosis by both the International League
Against Epilepsy (ILAE), considered the world's leading expert
medical society on epilepsy, and the FDA.
[0077] The diagnosis of LGS is more obvious when the patient
suffers frequent and manifold seizures, with the classic pattern on
the electro-encephalogram (EEG), i.e., a slowed rhythm with
Spike-wave-pattern, or with a multifocal and generalizing
sharp-slow-wave-discharges at 1.5-2.5 Hz. During sleep, tonic
patterns (fast activity) can often be seen.
[0078] General medical investigation usually reveals developmental
delay and cognitive deficiencies in children with LGS. These may
precede development of seizures, or require up to two years after
the seizures begin, in order to become apparent.
[0079] There may be multiple etiologies for LGS, including genetic,
structural, metabolic or unknown. Approximately one-quarter have no
prior history of epilepsy, neurological abnormality or
developmental delay prior to the onset of LGS symptoms. Underlying
pathologies causing LGS may include encephalitis and/or meningitis,
brain malformations (e.g., cortical dysplasias), birth injury,
hypoxia-ischemia injury, frontal lobe lesions, and trauma.
[0080] An important differential diagnosis is
`Pseudo-Lennox-Syndrome`, also called atypical benign partial
epilepsy of childhood, which differs from LGS, in that there are no
tonic seizures; sleeping EEG provides the best basis for
distinguishing between the two. In addition,
`Pseudo-Lennox-Syndrome` has an entirely different etiology and
prognosis than LGS.
Treatment
[0081] The optimum treatment for Lennox-Gastaut syndrome has yet to
be established. Many different treatments are currently used in the
treatment of this disorder and many more have been tried in the
past, most often with little success.
[0082] A variety of therapeutic approaches are currently used in
LGS, including conventional antiepileptic medications, diet and
surgery, however the evidence supporting these therapies is not
robust and treatment remains most often ineffective. The use of
several common first-line treatments is based on clinical
experience or conventional wisdom; examples include broad spectrum
anti-convulsant medications, such as valproic acid, and
benzodiazepines, most often clonazepam and clobazam. A few drugs
have been proven effective for some patients for certain seizure
types by double-blind placebo-controlled studies; examples include
clobazam, lamotrigine, topiramate, felbamate, and rufinamide,
although most patients continue to have significant seizures even
while taking these medications. Second-line medications currently
in use, such as zonisamide, are prescribed based on results of some
open-label uncontrolled studies. The ketogenic diet may be useful
in some patients with LGS refractory to medical treatment. Surgical
options for LGS include corpus callostomy (for drop attacks), vagus
nerve stimulation, and focal cortical resection (in the presence of
a single resectable lesion). However, it should be noted that
significant improvement from any of these therapies alone or in
combination is a rare occurrence.
[0083] Despite the severity of LGS's symptoms and the frequency
with which it occurs (it accounts for up to 10% of all childhood
epilepsies), there is currently no standard evidence-based
treatment for the disease. A comprehensive review of the literature
[see Hancock E C & Cross J H, Treatment of Lennox-Gastaut
syndrome (Review), published in The Cochrane Library 2013, Issue 2]
discovered only nine randomized controlled trials which evaluated
the pharmaceutical treatment of the syndrome. The authors concluded
that there is a paucity of research and " . . . that no monotherapy
(to date) has been shown to be highly effective in this syndrome."
Id at page 12. The authors further concluded that "[t]he optimum
treatment for LGS remains uncertain and no study to date has shown
any one drug to be highly efficacious". Id at page 12.
[0084] There is accordingly a dire and long-felt need to provide an
improved method for treating or preventing and/or ameliorating
seizures experienced by sufferers of Lennox-Gastaut Syndrome.
SUMMARY OF THE INVENTION
[0085] According to a first aspect of the present invention, there
is provided a method of treating and/or preventing one or more
symptoms of Lennox-Gastaut Syndrome in a patient comprising
administering an effective dose to a patient of fenfluramine alone
or in combination with one or more drugs as described here.
[0086] According to a further aspect of the present invention,
there is provided a method of treating, preventing and/or
ameliorating seizures in a patient diagnosed with Lennox-Gastaut
Syndrome comprising administering an effective dose to a patient of
fenfluramine alone or in combination with one or more drugs as
described here.
[0087] According to a further aspect of the present invention,
there is provided a method of treating a patient that exhibits a
mutation in one or more of a gene selected from the group
consisting of SCN1A, SCN1B, SCN2A, SCN3A, SCN9A, GABRG2, GABRD and
PCDH19 by administering to that patient an effective dose of
fenfluramine.
[0088] A still further aspect of this invention contemplates a
method for stimulating one or more 5-HT receptors in the brain of a
patient by administering an effective dose of fenfluramine or a
pharmaceutically acceptable salt thereof to that patient.
Illustrative one or more 5-HT receptors are selected from the group
consisting of one or more of 5-HT.sub.1, 5-HT.sub.1A, 5-HT.sub.1B,
5-HT.sub.1C, 5-HT.sub.1D, 5-HT.sub.1E, 5-HT.sub.1F, 5-HT.sub.2,
5-HT.sub.2A, 5-HT.sub.2B, 5-HT.sub.2S, 5-HT.sub.3, 5-HT.sub.4,
5-HT.sub.5, 5-HT.sub.5A, 5-HT.sub.5B 5-HT.sub.6, and 5-HT.sub.7. In
addition there may be non-5-HT binding in the brain including
Sigma, M1 muscarinic, B-adrenergic.
[0089] Yet another aspect of the invention contemplates
co-administration of an effective dose of one or more
co-therapeutic agents with the fenfluramine wherein the
co-therapeutic agents can be selected from the group consisting of
carbamazepine, ethosuximide, fosphenytoin, lamotrigine,
levetiracetam, phenobarbital, progabide, topiramate, stiripentol,
valproic acid, valproate, verapamil, and benzodiazepines such as
clobazam, clonazepam, diazepam, ethyl loflazepate, lorazepam,
midazolam. Use of a pharmaceutically acceptable salt or base of a
co-therapeutic agent is also contemplated.
[0090] An aspect of the invention is a method of treating or
preventing the symptoms of Lennox-Gastaut syndrome (LGS) in a
patient diagnosed with LGS comprising administering an effective
dose of fenfluramine or pharmaceutically acceptable salt to the
patient, wherein the dose is administered in an amount in the range
of from 10.0 mg/kg/day to about 0.01 mg/kg/day, or administered at
120 mg or less; or 60 mg or less or 30 mg or less and may be
administered in the absence of the administration of any other
pharmaceutically active compound.
[0091] In another aspect of the invention, the method is carried
out wherein the effective dose is administered in a form selected
from the group consisting of oral, injectable, transdermal, buccal,
inhaled, nasal, rectal, vaginal, or parental, and wherein the
formulation is oral, the formulation may be liquid which may be a
solution or a suspension may be present within a container closed
with a cap connected to a syringe graduated to determine the volume
extracted from the container wherein the volume extracted relates
to the amount of fenfluramine in a given liquid volume of
formulation e.g. one millimeter of formulation contains 2.5 mg of
fenfluramine. In another aspect of the invention, the method is
administered in a solid oral formulation in the form of a tablet,
capsule, lozenge, or sachet.
[0092] The method may be carried out as a co treatment with a
different pharmaceutically active compound. The method may be
carried out in a process wherein the patient is first then
subjected to a series of tests to confirm diagnoses of LGS.
[0093] Another aspect of the invention is a kit for treating
Lennox-Gastaut syndrome (LGS) in a patient diagnosed with LGS
wherein the kit comprises a formulation comprising a
pharmaceutically acceptable carrier and an active ingredient
comprising fenfluramine and instructions for treating a patient
diagnosed with LGS by admnistereing the formulation to the patient.
In yet another aspect, wherein the fenfluramine is in an oral
liquid or a solid oral dosage form or a transdermal patch; and the
kit further comprises instructions for treating a patient diagnosed
with LGS by administering the formulation to the patient.
[0094] In another aspect of the invention, the kit consists of an
oral liquid formulation in a container and a syringe with
instructions, wherein the concentration of the fenfluramine in the
liquid is calibrated based on calibrations on the syringe and
includes calibrations wherein a milliliter of solution equates to a
known amount of fenfluramine such as 0.1 mg, 0.2 mg etc., to 1.0
mg.
[0095] In another aspect of the invention, the kit includes
instructions relating to dosing the patient based on patient weight
and volume of solution based on the concentration of fenfluramine
in the solution.
[0096] Another aspect of the invention is a use of a fenfluramine
composition in treating and or preventing symptoms of
Lennox-Gastaut syndrome (LGS) and a patient diagnosed with LGS
which use may include placing the fenfluramine in a liquid solution
and withdrawing that liquid solution into a graduated syringe.
[0097] These and other objects, advantages, and features of the
invention will become apparent to those persons skilled in the art
upon reading the details of the methods of treating symptoms of
Lennox-Gastaut Syndrome as more fully described below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0098] The present disclosure is best understood from the following
detailed description when read in conjunction with the accompanying
drawings. Included in the drawings are the following figures.
[0099] FIG. 1 is a table summarizing the procedures followed during
each of the patient visits which are conducted over the course of
the clinical trial described in Example 1.
[0100] FIG. 2 is a flow chart illustrating the manner in which
fenfluramine dosages are increased for non-responding patients over
the course of the clinical trial.
DETAILED DESCRIPTION OF THE INVENTION
[0101] Before the present method, kits and formulations are
described, it is to be understood that this invention is not
limited to particular embodiments described, as such may, of
course, vary. It is also to be understood that the terminology used
herein is for the purpose of describing particular embodiments
only, and is not intended to be limiting, since the scope of the
present invention will be limited only by the appended claims.
[0102] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limits of that range is also specifically disclosed. Each
smaller range between any stated value or intervening value in a
stated range and any other stated or intervening value in that
stated range is encompassed within the invention. The upper and
lower limits of these smaller ranges may independently be included
or excluded in the range, and each range where either, neither or
both limits are included in the smaller ranges is also encompassed
within the invention, subject to any specifically excluded limit in
the stated range. Where the stated range includes one or both of
the limits, ranges excluding either or both of those included
limits are also included in the invention.
[0103] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, some potential and preferred methods and materials are
now described. All publications mentioned herein are incorporated
herein by reference to disclose and describe the methods and/or
materials in connection with which the publications are cited. It
is understood that the present disclosure supersedes any disclosure
of an incorporated publication to the extent there is a
contradiction.
[0104] It must be noted that as used herein and in the appended
claims, the singular forms "a", "an", and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a seizure" includes a plurality of such
seizures and reference to "the formulation" includes reference to
one or more formulations and equivalents thereof known to those
skilled in the art, and so forth.
[0105] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such publication
by virtue of prior invention. Further, the dates of publication
provided may be different from the actual publication dates which
may need to be independently confirmed.
[0106] After extensive research, it has unexpectedly been found
that fenfluramine can be used to treat, or at least minimize the
effects of Lennox-Gastaut Syndrome.
[0107] To avoid doubt, the term "prevention" of seizures means the
total or partial prevention (inhibition) of seizures. Ideally, the
methods of the present invention result in a total prevention of
seizures. However, the invention also encompasses methods in which
the instances of seizures are decreased in frequency by at least
40%, at least 50%, at least 55%, at least 60%, at least 65%, at
least 70%, at least 75%, at least 80%, at least 85%, or at least
90%. In addition, the invention also encompasses methods in which
the instances of seizures are decreased in duration or severity by
at least 40%, at least 50%, at least 55%, at least 60%, at least
65%, at least 70%, at least 75%, at least 80%, at least 85%, or at
least 90%.
[0108] Without being bound by theory, fenfluramine has been known
to trigger the release of serotonin (5-HT) in the brain due to
disruption of its vesicular storage and to inhibit serotonin
reuptake. However, until the present invention was made, it was not
known that fenfluramine's mechanism of action made it suitable for
the treatment of Lennox-Gastaut syndrome (LGS). In fact, there are
no scientific publications demonstrating or even hypothesizing that
5-HTabnormalities are a possible underlying pathophysiologic cause
for LGS or are causally related to the associated seizures in this
specific epilepsy condition. Furthermore, since there has been no
scientific hypothesis relating serotonin abnormalities in LGS,
there are no studies nor even individual case reports in the
medical literature which describe attempts to treat LGS using
medications that interacts with serotonin. The lack of data or even
speculation in the literature regarding the use of fenfluramine or
serotonergic agents in general to treat LGS are facts that strongly
support the unexpected nature of this invention: given that LGS is
a devastating refractory epilepsy condition and the number of
people affected, investigators would be strongly motivated to
investigate any treatment they perceived as having any potential
for efficacy.
[0109] Thus, according to a still further aspect of the present
invention, there is provided a method of stimulating one or more
5-HT receptors in the brain of a patient by administering an
effective dose of fenfluramine to said patient, said one or more
5-HT receptors being selected from one or more of 5-HT.sub.1,
5-HT.sub.1A, 5-HT.sub.1B, 5-HT.sub.1C, 5-HT.sub.1D, 5-HT.sub.1E,
5-HT.sub.1F, 5-HT.sub.2, 5-HT.sub.2A, 5-HT.sub.2B, 5-HT.sub.2C,
5-HT.sub.3, 5-HT.sub.4, 5-HT.sub.5, 5-HT.sub.5A, 5-HT.sub.5B
5-HT.sub.6, and 5-HT.sub.7 amongst others. In certain embodiments
of this aspect of the invention, the patient has been diagnosed
with Lennox-Gastaut Syndrome.
[0110] In embodiments of the invention, any effective dose of
fenfluramine can be employed. However, surprisingly low doses of
fenfluramine have been found by the inventors to be effective,
particularly for inhibiting or eliminating seizures in
Lennox-Gastaut Syndrome patients.
[0111] DOSE BY WEIGHT (MG/KG/DAY) Thus in some cases, in a
preferred embodiment of the invention, a daily dose of less than
about 10 mg/kg/day, such as less than about 10 mg/kg/day, less than
about 9 mg/kg/day, less than about 8 mg/kg/day, less than about 7
mg/kg/day, less than about 6 mg/kg/day, less than about 5
mg/kg/day, less than about 4 mg/kg/day, less than about 3.0
mg/kg/day, less than about 2.5 mg/kg/day, less than about 2.0
mg/kg/day, less than about 1.5 mg/kg/day, less than about 1.0
mg/kg/day, such as about 1.0 mg/kg/day, about 0.95 mg/kg/day, about
0.9 meg/kg/day, about 0.85 mg/kg/day, about 0.85 mg/kg/day, about
0.8 mg/kg/day, about 0.75 mg/kg/day, about 0.7 mg/kg/day, about
0.65 mg/kg/day, about 0.6 mg/kg/day, about 0.55 mg/kg/day, about
0.5 mg/kg/day, about 0.45 mg/kg/day, about 0.4 mg/kg/day, about
0.350 mg/kg/day, about 0.3 mg/kg/day, about 0.25 mg/kg/day, about
0.2 mg/kg/day, about 0.15 mg/kg/day to about 0.1 mg/kg/day, about
0.075 mg/kg/day, about 0.05 mg/kg/day, about 0.025 mg/kg/day, about
0.0225 mg/kg/day, about 0.02 mg/kg/day, about 0.0175 mg/kg/day,
about 0.015 mg/kg/day, about 0.0125 mg/kg/day, or about 0.01
mg/kg/day is employed.
[0112] Put differently, a preferred dose is less than about 10 to
about 0.01 mg/kg/day. In some cases the dose is less than about
10.0 mg/kg/day to about 0.01 mg/kg/day, such as less than about 5.0
mg/kg/day to about 0.01 mg/kg/day, less than about 4.5 mg/kg/day to
about 0.01 mg/kg/day, less than about 4.0 mg/kg/day to about 0.01
mg/kg/day, less than about 3.5 mg/kg/day to about 0.01 mg/kg/day,
less than about 3.0 mg/kg/day to about 0.01 mg/kg/day, less than
about 2.5 mg/kg/day to about 0.01 mg/kg/day, less than about 2.0
mg/kg/day to about 0.01 mg/kg/day, less than about 1.5 mg/kg/day to
about 0.01 mg/kg/day, or less than about 1.0 mg/kg/day to 0.01
mg/kg/day, such as less than about 0.9 mg/kg/day, less than about
0.8 mg/kg/day, less than about less than about 0.7 mg/kg/day, less
than about 0.6 mg/kg/day to about 0.01 mg/kg/day, less than about
0.5 mg/kg/day to about 0.01 mg/kg/day, less than about 0.4
mg/kg/day to about 0.01 mg/kg/day, less than about 0.3 mg/kg/day to
about 0.01 mg/kg/day, or less than about.0.2 mg/kg/day to about
0.01 mg/kg/day.
[0113] As indicated above the dosing is based on the weight of the
patient. However, for convenience the dosing amounts may be preset
such as in the amount of 1.0 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg,
30 mg, 40 mg, or 50 mg. In certain instances, the dosing amount may
be preset such as in the amount of about 0.25 mg to about 5 mg,
such as about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg,
about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about
2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg,
about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5
mg, about 4.75 mg, or about 5.0 mg.
[0114] In general the smallest dose which is effective should be
used for the particular patient.
[0115] The dosing amounts described herein may be administered one
or more times daily to provide for a daily dosing amount, such as
once daily, twice daily, three times daily, or four or more times
daily, etc.
[0116] In certain embodiments, the dosing amount is a daily dose of
30 mg or less, such as 30 mg, about 29 mg, about 28 mg, about 27
mg, about 26 mg, about 25 mg, about 24 mg, about 23 mg, about 22
mg, about 21 mg, about 20 mg, about 19 mg, about 18 mg, about 17
mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12
mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg,
about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, or
about 1 mg. In general the smallest dose which is effective should
be used for the particular patient. In some cases, the dose is
generally well below the dosing used in weight loss.
[0117] ROUTES OF ADMINISTRATION The dose of fenfluramine
administered according to the methods of the present invention can
be administered systemically or locally. Methods of administration
may include administration via enteral routes, such as oral,
buccal, sublingual, and rectal; topical administration, such as
transdermal and intradermal; and parenteral administration.
Suitable parenteral routes include injection via a hypodermic
needle or catheter, for example, intravenous, intramuscular,
subcutaneous, intradermal, intraperitoneal, intraarterial,
intraventricular, intrathecal, and intracameral injection and
non-injection routes, such as intravaginal rectal, or nasal
administration. In certain embodiments, it may be desirable to
administer one or more compounds of the invention locally to the
area in need of treatment. This may be achieved, for example, by
local infusion during, topical application, by injection, by means
of a catheter, by means of a suppository, or by means of an
implant, said implant being of a porous, non-porous, or gelatinous
material, including membranes, such as sialastic membranes, or
fibers.
[0118] DOSAGE FORMS/ROUTE OF ADMIN The dose of fenfluramine
administered in the methods of the present invention can be
formulated in any pharmaceutically acceptable dosage form
including, but not limited to (a) oral dosage forms such as tablets
including orally disintegrating tablets, capsules, and lozenges,
oral solutions or syrups, oral emulsions, oral gels, oral films,
buccal liquids, powder e.g. for suspension, and the like; (b)
injectable dosage forms; (c) transdermal dosage forms such as
transdermal patches, ointments, creams; (c) inhaled dosage forms;
and/or (e) nasally, (f) rectally, (g) vaginally administered dosage
forms.
[0119] DOSGE FORM/FREQUENCY OF ADMIN Such dosage forms can be
formulated for once a day administration, or for multiple daily
administrations (e.g. 2, 3 or 4 times a day administration).
Alternatively, for convenience, dosage forms can be formulated for
less frequent administration (e.g., monthly, bi-weekly, weekly,
every fourth day, every third day, or every second day), and
formulations which facilitate extended release are known in the
art.
[0120] DOSAGE FORMS/PREPARATION, COMPONENTS The dosage form of
fenfluramine employed in the methods of the present invention can
be prepared by combining fenfluramine or a pharmaceutically
acceptable salt thereof with one or more pharmaceutically
acceptable diluents, carriers, adjuvants, and the like in a manner
known to those skilled in the art of pharmaceutical
formulation.
[0121] ORAL DOSAGE FORMS/SUITABLE FORMULATION TYPES &
COMPONENTS THEREOF In some embodiments, formulations suitable for
oral administration can include (a) liquid solutions, such as an
effective amount of the compound dissolved in diluents, such as
water, or saline; (b) capsules, sachets or tablets, each containing
a predetermined amount of the active ingredient (fenfluramine), as
solids or granules; (c) suspensions in an appropriate liquid; and
(d) suitable emulsions. Tablet forms can include one or more of
lactose, mannitol, corn starch, potato starch, microcrystalline
cellulose, acacia, gelatin, colloidal silicon dioxide,
croscarmellose sodium, talc, magnesium stearate, stearic acid, and
other excipients, colorants, diluents, buffering agents, moistening
agents, preservatives, flavoring agents, and pharmacologically
compatible excipients. Lozenge forms can include the active
ingredient in a flavor, usually sucrose and acacia or tragacanth,
as well as pastilles including the active ingredient in an inert
base, such as gelatin and glycerin, or sucrose and acacia,
emulsions, gels, and the like containing, in addition to the active
ingredient, such excipients as are described herein.
[0122] ORAL DOSAGE FORMS/EXCIPIENTS, For an oral solid
pharmaceutical formulation, suitable excipients include
pharmaceutical grades of carriers such as mannitol, lactose,
glucose, sucrose, starch, cellulose, gelatin, magnesium stearate,
sodium saccharine, and/or magnesium carbonate. For use in oral
liquid formulations, the composition may be prepared as a solution,
suspension, emulsion, or syrup, being supplied either in solid or
liquid form suitable for hydration in an aqueous carrier, such as,
for example, aqueous saline, aqueous dextrose, glycerol, or
ethanol, preferably water or normal saline. If desired, the
composition may also contain minor amounts of non-toxic auxiliary
substances such as wetting agents, emulsifying agents, or
buffers.
[0123] By way of illustration, the fenfluramine composition can be
admixed with conventional pharmaceutically acceptable carriers and
excipients (i.e., vehicles) and used in the form of aqueous
solutions, tablets, capsules, elixirs, suspensions, syrups, wafers,
and the like. Such pharmaceutical compositions contain, in certain
embodiments, from about 0.1% to about 90% by weight of the active
compound, and more generally from about 1% to about 30% by weight
of the active compound. The pharmaceutical compositions may contain
common carriers and excipients, such as corn starch or gelatin,
lactose, dextrose, sucrose, microcrystalline cellulose, kaolin,
mannitol, dicalcium phosphate, sodium chloride, and alginic acid.
Disintegrators commonly used in the formulations of this invention
include croscarmellose, microcrystalline cellulose, corn starch,
sodium starch glycolate and alginic acid.
[0124] Formulations suitable for topical administration may be
presented as creams, gels, pastes, or foams, containing, in
addition to the active ingredient, such carriers as are
appropriate. In some embodiments the topical formulation contains
one or more components selected from a structuring agent, a
thickener or gelling agent, and an emollient or lubricant.
Frequently employed structuring agents include long chain alcohols,
such as stearyl alcohol, and glyceryl ethers or esters and
oligo(ethylene oxide) ethers or esters thereof. Thickeners and
gelling agents include, for example, polymers of acrylic or
methacrylic acid and esters thereof, polyacrylamides, and naturally
occurring thickeners such as agar, carrageenan, gelatin, and guar
gum. Examples of emollients include triglyceride esters, fatty acid
esters and amides, waxes such as beeswax, spermaceti, or carnauba
wax, phospholipids such as lecithin, and sterols and fatty acid
esters thereof. The topical formulations may further include other
components, e.g., astringents, fragrances, pigments, skin
penetration enhancing agents, sunscreens (e.g., sunblocking
agents), etc.
[0125] Particular formulations of the invention are in an oral
liquid form. The liquid can be a solution or suspension and may be
an oral solution or syrup, which is included in a bottle with a
syringe graduated in terms of milligram amounts which will be
obtained in a given volume of solution. The liquid solution makes
it possible to adjust the volume of solution for appropriate dosing
of small children, who can be administered fenfluramine in an
amount anywhere from 1.25 mg to 30 mg and any amount between in
0.25 milligram, increments and thus administered in amounts of 1.25
mg, 1.5 mg, 1.75 mg, 2.0 mg, etc.
[0126] A specific aspect of the invention is a treatment carried
out to relieve symptoms of Lennox-Gastaut by the administration of
only fenfluramine. However, the fenfluramine may be co-administered
with other known pharmaceutical drugs such as a co-therapeutic
agent selected from the group consisting of carbamazepine,
ethosuximide, fosphenytoin, lamotrigine, levetiracetam,
phenobarbital, progabide, topiramate, stiripentol, valproic acid,
valproate, verapamil, and benzodiazepines such as clobazam,
clonazepam, diazepam, ethyl loflazepate, lorazepam, midazolam and a
pharmaceutically acceptable salt or base thereof.
[0127] The co-therapeutic agents have recommended dosing amounts.
Those recommended dosing amounts are provided within the most
current version of the Physician's Desk Reference (PDR) or
http://emedicine.medscape.com/ both of which are incorporated
herein by reference specifically with respect to the co-therapeutic
agents listed above and more specifically with respect to the
dosing amounts recommended for those drugs.
[0128] In connection with the present invention, the co-therapeutic
agent can be used in the recommended dosing amount or can be used
in a range of from 100.sup.th to 100 times 1/10 to 10 times 1/5 to
5 times 1/2 to twice the recommended dosing amount or any
incremental 1/10 amount in between those ranges.
[0129] As a specific example of a combination of co-therapeutic
agents with fenfluramine, the co-therapeutic agent may be any one
of or all three of stiripentol, clobazam, and valproate. The
fenfluramine may be administered in the amount of 0.8 mg/kg of
patient body weight and co-administered with 3500 mg of
stiripentol, 20 mg of clobazam, and 25 mg per kg of valproate. Each
of those amounts may be increased to twice, three times, five
times, or ten times that amount or decreased by 10%, 50%, or
75%.
[0130] An aspect of the invention includes a kit for treating and
or preventing symptoms of LGS in a patient diagnosed with LGS, the
kit comprising:
[0131] a container holding a liquid formulation of
fenfluramine;
[0132] a dispensing device connected to the container and
configured to withdraw the liquid formulation from the
container;
[0133] instructions for administering the liquid formulation to a
patient in order to treat LGS.
[0134] In alternate embodiments, the dispensing device may be a
syringe or graduated pipette useful for delivering varying doses of
the fenfluramine liquid. In another embodiment, the dispensing
device is a metered dosing device capable of dispensing a fixed
volume of fenfluramine liquid. In one exemplary embodiment, the
dose delivered by the metered dosing device is adjustable.
[0135] The formulation may be a solution or suspension and is
prepared such that a given volume of the formulation contains a
known amount of active fenfluramine.
[0136] For example, in one embodiment of this aspect, the
dispensing device is a syringe is graduated in one millimeter
increments and the liquid fenfluramine formulation is characterized
such that one millimeter in volume of formulation includes
precisely one milligram of fenfluramine. In this manner, the
patient may be correctly dosed with a desired milligram dosage of
fenfluramine based on a volume of liquid formulation administered
to the patient orally.
[0137] In alternate embodiments, the dispenser is a syringe
connected to the container and configured to withdraw the liquid
formulation from the container, wherein the syringe is marked with
levels of graduation noting volume of formulation withdrawn, or a
metered dose dispenser for delivering a predetermined volume of the
formulation to said patient, or a metered dispensing device
calibrated to deliver a predetermined volume of the liquid,
permitting convenient, consistent, and accurate dosing.
[0138] In a method of the present invention, fenfluramine can be
employed as a monotherapy in the treatment of Lennox-Gastaut
Syndrome. Alternatively, fenfluramine can be co-administered in
combination with one or more pharmaceutically active agents, which
may be provided together with the fenfluramine in a single dosage
formulation, or separately, in one or more separate pharmaceutical
dosage formulations. Where separate dosage formulations are used,
the subject composition and ore or more additional agents can be
administered concurrently, or at separately staggered times, i.e.,
sequentially.
[0139] In one embodiment, the agents are co-therapeutic agents,
such as anticonvulsants. Preferred co-therapeutic agents can be
selected from the group consisting of carbamazepine, ethosuximide,
fosphenytoin, lamotrigine, levetiracetam, phenobarbital, progabide,
topiramate, stiripentol, valproic acid, valproate, verapamil, and
benzodiazepines such as clobazam, clonazepam, diazepam, ethyl
loflazepate, lorazepam, midazolam. Use of a pharmaceutically
acceptable salt of a co-therapeutic agent is also contemplated.
[0140] Fenfluramine can be administered in the form of the free
base, or in the form of a pharmaceutically acceptable salt, for
example selected from the group consisting of hydrochloride,
hydrobromide, hydroiodide, maleate, sulphate, tartrate, acetate,
citrate, tosylate, succinate, mesylate and besylate. Further
illustrative pharmaceutically acceptable salts can be found in
Berge et al., J. Pharm Sci. (1977) 68(1): 1-19.
[0141] Fenfluramine for use in the methods of the present invention
may be produced according to any pharmaceutically acceptable
process known to those skilled in the art. Examples of processes
for synthesizing fenfluramine are provided in the following
documents: GB 1413070, GB 1413078 and EP441160.
[0142] The dose of fenfluramine to be used in a method of the
present invention can be provided in the form of a kit, including
instructions for using the dose in one or more of the methods of
the present invention. In certain embodiments, the kit can
additionally comprise a dosage form comprising one or more
co-therapeutic agents.
[0143] A method of the present invention can be practiced on any
appropriately diagnosed patient. In alternate exemplary embodiments
of the present invention, the patient is aged about 18 or less,
about 16 or less, about 14 or less, about 12 or less, about 10 or
less, about 8 or less, about 6 or less or about 4 or less to about
0 months or more, about 1 month or more, about 2 months or more,
about 4 months or more, about 6 months or more or about 1 year or
more. Thus, in this embodiment, the diagnosed patient is about one
month old to about 18 years old when treated.
[0144] The invention is further illustrated in the following
Examples.
EXAMPLE 1
Add-On Therapy with Low Dose Fenfluramine (FFA) in
Lennox-Gastaut
[0145] The efficacy of fenfluramine as an add-on treatments in
Lennox-Gastaut patients is studied in a Phase 2 Clinical Trial. The
study protocol is described and preliminary results are presented
here.
Trial Objectives and Design
[0146] An open-label, non-placebo controlled add-on study was
designed to assess the efficacy and safety of low-dose add-on
fenfluramine across a range of fenfluramine doses (0.2, 0.4, 0.8
mg/kg/day, to a maximum of 30 mg/day). The trial was conducted over
a 20 week period, with responders eligible for follow-on treatment,
with follow-up appointments at three month intervals.
Inclusion and Exclusion Criteria
[0147] Patients were recruited from childhood epilepsy clinics in
Leuven and Antwerp, Belgium, and selected for inclusion in the
study according to criteria comprising a combination of age,
physical and psychological characteristics, and resistance to
treatment with conventional therapies. Details of selection
criteria are provided below.
TABLE-US-00001 MINIMUM Multiple seizure types; REQUIREMENTS: Tonic
seizures present in all cases Electro-clinical epilepsy syndrome
compatible with Lennox-Gastaut syndrome EEG showing slow spike
saves and abnormal background Abnormal cognitive development MRI
compatible with Lennox-Gastaut epilepsy (including no progressive
disease) Drug Resistant Seizures Patients received at least two
anti- epileptic drugs (AEDs), including VNS, during the 4 week
period prior to inclusion Eligible seizure types Tonic-clonic (GTC)
- REQUIRED Tonic (TS) Atonic (AS) Clearly recognizable focal (FS)
At least 4 documented seizures during 4 week period prior to
inclusion Minimum of 4 seizures in at least 2 separate weeks Age
Between 3 and 18 years
[0148] Once enrolled, subjects are removed from the study in cases
of serious adverse events, non-compliance, or lack of efficacy.
Treatment is also stopped in the event of increased severity and
frequency of seizures after discussion with the principle
investigator; cardiac abnormalities (specifically, valvular
problems), and/or adverse events (specifically, SAE, SAR or SUSAR)
after discussion with the principle investigator. Patients may also
withdraw voluntarily. Upon withdrawing, a safety examination (i.e.,
blood sampling and cardiac ultrasound) is performed and
fenfluramine use is tapered for one week at 50% of end dosage and
then withdrawn completely.
Trial Protocol
[0149] Study duration is 20 weeks, ending at week 20 after
inclusion of 20 patients, i.e., 20 weeks following the enrollment
of the 20.sup.th patient. Patients who respond to treatment are
enrolled in a follow-on study and assessed on an ongoing basis.
[0150] Patients are examined during six clinical visits (V1 through
V6) scheduled at four week intervals, ending with V6 at week 20.
Thereafter, responders continue in a follow-up study, with visits
scheduled every three months. At each visit, endpoints and safety
criteria are assessed, and dosages adjusted as necessary.
[0151] During the study period, patients are prohibited from
receiving certain medications and foods: (1) felbamate is
prohibited as a concomitant medication unless the following
criteria are met: the patient has been treated for at least 18
months prior to screening; has stable liver function and hematology
laboratory tests, and the dose is expected to remain constant
throughout the study; (2) drugs that interact with central
serotonin, including imipramine, monoamine oxidase inhibitors,
SSRIs, SNRIs, or vortioxetine; and (3) drugs or foods that
potentially interact with fenfluramine via the CYP-2D6, CYPD-3A4,
and/or CYP-2B6 pathways, except for pre-approved short-term use
where required by medical necessity. Pregnancy testing, use of
birth control, and breast feeding restrictions were also required
during the study period and for the duration of subsequent
fenfluramine treatment.
[0152] An abbreviated trial flowchart appears in Table 1, shown in
FIG. 1. At V1, inclusion and exclusion criteria are assessed,
clinical diagnosis confirmed, and the following information is
collected: baseline demographics, pre-baseline seizure counts,
current treatment regimens (both AEDs and VNS), and sleep quality.
In addition, safety blood samples are collected, blood levels of
anti-epileptic drugs ("AEDs") are determined, and cardiac function
is evaluated using ultrasound imaging and EKG traces. Urine
pregnancy tests in female subjects of childbearing potential are
also done, and the patient's quality of life is assessed by means
of clinical global impressions (both parents and physician) and
sleep quality. Patients meeting entry criteria are enrolled and
begin a prospective baseline period.
[0153] Add-on treatment is begun at V2. Participants being
receiving an initial fenfluramine dose of 0.2 mg/kg/day. Endpoints
and safety criteria are assessed (seizure counting, adverse
effects, pregnancy testing, and quality of life indicators (CGI,
sleep scale)). Additional safety blood samples, AED blood levels
and cardiac evaluation are done only if clinically indicated. A
seizure diary and medication are dispensed.
[0154] At each of V3-V5, endpoints and safety criteria are again
assessed. Dosages of non-responders are adjusted according to trial
protocol. A schema for dose escalation is shown in FIG. 2.
[0155] At V6, endpoints and safety criteria are again assessed.
Safety blood samples, AED blood levels and cardiac evaluation are
repeated. Responders may enter the follow-up study. Non-responders
begin FFA tapering, receiving 50% of the end dosage for 1 week and
then discontinuing treatment.
[0156] Follow-up study: Responders at 20 weeks continue in a
follow-up study, with visits scheduled at 3 month intervals.
Patients receive a starting dose equal to the dosage received at
week 20. At each visit, endpoints and safety criteria are assessed
(seizure counting, current treatment, adverse effects, quality of
life indicators (CGI, sleep scale)), pregnancy testing is
performed, safety blood samples are collected, blood level AEDs are
determined and cardiac function is evaluated using EKG and cardiac
ultrasound. Dosages may be increased as necessary, up to a maximum
of 30 mg/day. Follow up ends when fenfluramine becomes available as
a regular treatment or at the election of the patient and/or
treating physician if serious side effects occur and/or the drug is
no longer effective.
Materials and Methods
[0157] Ethics and regulatory approvals: Trial conduct complies with
the most recent version of the principles of the Declaration of
Helsinki, the principles of GCP, and in accordance with all
applicable regulatory requirements. The study protocol and related
documents is subject to ethical review by all requisite
authorities. Participants have given written informed consent prior
to their enrollment and participation in compliance with all
applicable laws, regulations and ethical guidelines as required,
and ICFs are retained at participating trial sites in accordance
with all applicable regulatory agencies and laws. All information
and data related to the Study and disclosed to the Participating
Site and/or Study Investigator are treated as confidential and will
not be disclosed to third parties or used for any purpose other
than the performance of the study. Data collection, processing and
disclosure of personal data is subject to compliance with
applicable personal data protections and personal data processing
requirements.
[0158] Fenfluramine: Oral fenfluramine solution (2.5 mg/ml or 5
mg/ml) is provided by Zogenix Pharma. Starting dosage is 0.2
mg/kg/day BID; second step at 0.4 mg/kg/day BID; maximum dosage at
0.8 mg/kg/day BID or 30 mg/day BID, whichever is less. The drug is
dispensed by Zogenix Pharma. Labeled bottles containing the oral
fenfluramine suspension is given to patients and controlled at each
visit. Bottle labels are kept in individual patient files.
Calculation of bottle number and control of labels are done at the
trial's conclusion. Patient compliance is assessed by control of
oral solution quantity at each visit and collection of seizure
diary with notification of drug intake.
[0159] Concomitant treatment: Lennox-Gastaut patients participating
in the study receive concomitant treatment with two or more
anti-epileptic drugs commonly used in the treatment of the
disorder. The drug regimen is unchanged during baseline (the period
from V1 to V2) and the full trial period (V2 to V6).
[0160] Laboratory tests: Blood analysis and urine pregnancy tests
are done in central lab at UZ Leuven. Safety blood samples are
tested for hemogram, electrolytes, liver function (SGOT, SGPT, LDH,
PT) and kidney function (urea, creatinine)). AED blood level
determination is limited to phenytoin, phenobarbital,
carbamazepine, and valproate.
[0161] Safety assessment: Treatment safety is assessed using a
combination of physical examination, blood testing, cardiac
evaluation, and adverse event reporting. With respect to adverse
event reporting, reporting is not required for expected AEs,
moderate weight loss and decrease of appetite with no significant
weight loss (<P3).
[0162] Data Handling and Statistical Analysis: Data is coded and is
protected from disclosure outside of research teams according to
the terms of the research protocol and the informed consent
document. Subjects' names or other identifiers must be stored
separately ("site file") from their research data and replaced with
a unique code to create a new identify for the subject. Coded data
are not anonymous. Data is collected in standardized CRF.
[0163] A priori data on possible efficacy is unavailable. Sample
size is set at 20. The study is not randomized. Descriptive
analysis of outcome parameters is done at weeks 8, 12, 16 and 20.
All included subjects are counted for analysis. Reasons for
withdrawal are documented.
Interim Results
[0164] At the time results were reported, a total of 13 patients
had been recruited and 12 enrolled. 9 patients were receiving
treatment; 3 others were within the baseline period (V1 to V2).
[0165] None of the 9 patients receiving fenfluramine reported
serious side effects. 3 patients receiving 0.2 mg/kg/day showed
significant decreases in total seizure frequency.
[0166] The early interim data suggests that low-dose fenfluramine
used as an add-on treatment is effective in reducing seizure
frequency in Lennox-Gastaut patients.
[0167] The preceding merely illustrates the principles of the
invention. It will be appreciated that those skilled in the art
will be able to devise various arrangements which, although not
explicitly described or shown herein, embody the principles of the
invention and are included within its spirit and scope.
Furthermore, all examples and conditional language recited herein
are principally intended to aid the reader in understanding the
principles of the invention and the concepts contributed by the
inventors to furthering the art, and are to be construed as being
without limitation to such specifically recited examples and
conditions. Moreover, all statements herein reciting principles,
aspects, and embodiments of the invention as well as specific
examples thereof, are intended to encompass both structural and
functional equivalents thereof. Additionally, it is intended that
such equivalents include both currently known equivalents and
equivalents developed in the future, i.e., any elements developed
that perform the same function, regardless of structure. The scope
of the present invention, therefore, is not intended to be limited
to the exemplary embodiments shown and described herein. Rather,
the scope and spirit of present invention is embodied by the
appended claims.
* * * * *
References