LAQUINIMOD AND PRIDOPIDINE FOR TREATING NEURODEGENERATIVE DISORDERS
This application claims priority of U.S. Provisional Application No. 61/879,004, filed September
17, 2013, and U.S. Provisional Application No. 61/706,695, filed September 27, 2012, the entire
contents of which are hereby incorporated by reference herein.
Throughout this application, various publications are referred to by first author and year of
publication. Full citations for these publications are presented in a References section
immediately before the claims. Disclosures of the documents and publications cited and those in
the References section are hereby incorporated by reference in their entireties into this application
in order to more fully describe the state of the art as of the date of the invention described herein.
Background
Huntington's disease (HD) is an inherited disease of the central nervous system (CNS) that is
characterized by chorea and progressive cognitive deterioration. Symptoms and signs of HD
develop insidiously, starting at about age 35-50 but can develop before adulthood. Dementia or
psychiatric disturbances (e.g., depression, apathy, irritability, anhedonia, antisocial behavior, fu ll
blown bipolar or schizophreniform disorder) can develop before or simultaneously with the
movement disorder. Symptoms of HD also include abnormal movements, such as myoclonic
jerks or irregular movements of extremities, a lilting gait, facial grimacing, ataxia and inability to
sustain motor act (motor impersistence) such as tongue protrusion. As the disease progresses,
walking and swallowing become more difficult and dementia becomes more severe. Most HD
patients will eventually require institutionalization, and death usually occurs 13-15 years after the
symptoms begin, usually due to an intercurrent infection (Tyagi et al., 2010; The Merck Manual).
HD is an autosomal dominant disorder resulting from a gene mutation causing abnormal
repetition of the DNA sequence CAG which codes for the amino acid glutamine. The resulting
huntingtin protein (Htt) is a mutant huntingtin (mHtt) with an expanded stretch of polyglutamine
residues, leading to the disease via unknown mechanisms (The Merck Manual).
There is currently no cure for HD. In addition, tetrabenzaine is the only medication currently
approved by the Food and Drug Amdnistration (FDA) to treat the symptoms of Huntington's
disease. However other supportive therapies are currently available to manage the symptoms.
Symptomatic treatment of Huntington's disease involves use of dopamine antagonists,
presynaptic dopamine depleters, antidepressants, tranquillizers, anxiolytic benzodiazepines,
anticonvulsants and antibiotics. Chorea and agitation may be partially suppressed by
antipsychotics (e.g., chloropromazine 25-300 mg po id, haloperidol 5-45 mg po bid); dose is
increased until intolerable or undesirable adverse effects (e.g., lethargy, parkinsonism) occur.
Alternatively, tetrabenazine may be used. The dose starts at 12.5 mg po once/day, and is
subsequently increased (to 12.5 mg bid in the second week, 12.5 tid in the third week, up to a total
of 100 mg/day divided into 3 doses) until intolerable adverse effects (e.g., sedation, akathisias,
parkinsonism, depression) occur or chorea resolves (Tyagi et al., 2010; The Merck Manual).
Several medications including baclofen, idebenone and vitamin E have been studied in clinical
trials with limited samples. Some experimental therapies for HD have aimed to reduce
glutamatergic neurotransmission via the N-methyl-D-aspartate receptor and to bolster
mitochondrial energy production. However, currently no other drug has been recommended for
HD (Tyagi et al., 2010; The Merck Manual).
Pridopidine (4-(3-(Methylsulfonyl)phenyD- 1-propylpiperidine)
Pridopidine (ACR16, Huntexil®, 4-[3-(methylsulfonyl)phenyl]-l-propyl-piperidine]) is a
dopamine receptor mixed antagonist/agonist (U.S. Patent Application Publication No.
201 1/0206782). Pridopidine shows benefits in treating neurodegenerative disorders including
Huntington' s Disease (Miller & Bezprozvanny 2010).
Pridopidine acts on central dopamine D2 receptors to potentially improve voluntary motor
function in Huntington's disease patients (Venuto, 2012). The method of action is still not
precisely known but pridopidine may stimulate or inhibit dopamine to normalize hypo- and
hyper-dopaminergic behavior (Miller & Bezprozvanny 2010).
Huntexil® is the brand name for pridopidine developed by Neurosearch, Denmark to treat
movement and psychiatric disorders (Miller & Bezprozvanny 2010). A recent MermaiHD Phase
III clinical trial in Europe showed benefits from a treatment of 45 mg daily, or 90 mg daily dose
(45 mg administered twice daily) for 6 months in Huntington's disease patients. Amounts of
pridopidine up to 90 mg per day were well tolerated in Huntington's disease patients. The
primary endpoint was the effect of Huntexil® on a specific subset of motor symptoms defined in
the mMS at 26 weeks and was not met. However, the tertiary endpoint, UHDRS-TMS measuring
changes in motor function, and individual items within the mMS (including gait and dysarthria)
found a statistically significant effect of treatment (de Yebenes, 201 1). Huntexil® slowed
Huntington's disease symptoms and may have slowed Huntington's disease progression (Miller &
Bezprozvanny 2010). The HART trial, initial Phase lib studies in the United States and Canada,
showed a significant effect on total motor function after twice-daily doses of 45 mg over 12
weeks (NeuroSearch-The HART Study). Clinical trials in the United States are ongoing to assess
the long-term safety and treatment effects (Clinical Trials: OPEN-HART, 201 1).
Laquinimod
Laquinimod is a novel synthetic compound with high oral bioavailability which has been suggested
as an oral formulation for the treatment of Multiple Sclerosis (MS) (Polman, 2005; Sandberg-
Wollheim, 2005). Laquinimod and its sodium salt form are described, for example, in U.S. Patent
No. 6,077,851.
The mechanism of action of laquinimod is not fully understood. Animal studies show it causes a
Thl (T helper 1 cell, produces pro-inflammatory cytokines) to Th2 (T helper 2 cell, produces anti
inflammatory cytokines) shift with an anti-inflammatory profile (Yang, 2004; Briick, 2011).
Another study demonstrated (mainly via the NFkB pathway) that laquinimod induced suppression
of genes related to antigen presentation and corresponding inflammatory pathways (Gurevich,
2010). Other suggested potential mechanisms of action include inhibition of leukocyte migration
into the CNS, increase of axonal integrity, modulation of cytokine production, and increase in
levels of brain-derived neurotrophic factor (BDNF) (Runstrom, 2006; Briick, 201 1).
Laquinimod showed a favorable safety and tolerability profile in two phase III trials (Results of
Phase III BRAVO Trial Reinforce Unique Profile of Laquinimod for Multiple Sclerosis
Treatment; Teva Pharma, Active Biotech Post Positive Laquinimod Phase 3 ALLEGRO Results).
Add-On/Combination Therapy
The effects of add-on or combination therapy using laquinimod and pridopidine on patients
afflicted with a neurodegenerative disorder, e.g., HD, have not been reported.
The administration of two drugs to treat a given condition, such as multiple sclerosis, raises a
number of potential problems. In vivo interactions between two drugs are complex. The effects of
any single drug are related to its absorption, distribution, and elimination. When two drugs are
introduced into the body, each drug can affect the absorption, distribution, and elimination of the
other and hence, alter the effects of the other. For instance, one drug may inhibit, activate or
induce the production of enzymes involved in a metabolic route of elimination of the other drug
(Guidance for Industry, 1999). In one example, combined administration of GA and interferon
(IFN) has been experimentally shown to abrogate the clinical effectiveness of either therapy.
(Brod 2000) In another experiment, it was reported that the addition of prednisone in combination
therapy with IFN- b antagonized its up-regulator effect. Thus, when two drugs are administered to
treat the same condition, it is unpredictable whether each will complement, have no effect on, or
interfere with, the therapeutic activity of the other in a human subject.
Not only may the interaction between two drugs affect the intended therapeutic activity of each
drug, but the interaction may increase the levels of toxic metabolites (Guidance for Industry,
1999). The interaction may also heighten or lessen the side effects of each drug. Hence, upon
administration of two drugs to treat a disease, it is unpredictable what change will occur in the
negative side profile of each drug. In one example, the combination of natalizumab and interferon
b-la was observed to increase the risk of unanticipated side effects. (Vollmer, 2008; Rudick 2006;
Kleinschmidt-DeMasters, 2005; Langer-Gould 2005)
Additionally, it is difficult to accurately predict when the effects of the interaction between the
two drugs will become manifest. For example, metabolic interactions between drugs may become
apparent upon the initial administration of the second drug, after the two have reached a steadystate
concentration or upon discontinuation of one of the drugs (Guidance for Industry, 1999).
Therefore, the state of the art at the time of filing is that the effects of an add-on or combination
therapy of two drugs, in particular laquinimod and pridopidine, cannot be predicted until the
results of a formal combination study are available.
Summary of the Invention
This invention provides a method of treating a human patient afflicted with a neurodegenerative
disorder comprising periodically administering to the patient an amount of laquinimod and an
amount of pridopidine, wherein the amounts when taken together are effective to treat the human
patient.
This invention also provides a package comprising (a) a first pharmaceutical composition
comprising an amount of laquinimod and a pharmaceutically acceptable carrier; (b) a second
pharmaceutical composition comprising an amount of pridopidine and a pharmaceutically
acceptable carrier; and (c) instructions for use of the first and second pharmaceutical
compositions together to treat a human patient afflicted with a neurodegenerative disease.
This invention also provides laquinimod for use as an add-on therapy or in combination with
pridopidine in treating a human patient afflicted with a neurodegenerative disorder.
This invention also provides a pharmaceutical composition comprising an amount of laquinimod
and an amount of pridopidine for use in treating a human patient afflicted with a
neurodegenerative disorder, wherein the laquinimod and the pridopidine are to be administered
simultaneously or contemporaneously.
This invention also provides use of an amount of laquinimod and an amount of pridopidine in the
preparation of a combination for treating a human patient afflicted with a neurodegenerative
disorder wherein the laquinimod or pharmaceutically acceptable salt thereof and the pridopidine are
administered simultaneously or contemporaneously.
This invention also provides a pharmaceutical composition comprising an amount of laquinimod
for use in treating a subject afflicted with a neurodegenerative disorder as an add-on therapy or in
combination with pridopidine by periodically administering the pharmaceutical composition and
the pridopidine to the subject.
This invention also provides a pharmaceutical composition comprising an amount of pridopidine
for use treating a subject afflicted with a neurodegenerative disorder as an add-on therapy or in
combination with laquinimod by periodically administering the pharmaceutical composition and
the laquinimod to the subject.
Detailed Description of the Invention
This invention provides a method of treating a human patient afflicted with a neurodegenerative
disorder comprising periodically administering to the patient an amount of laquinimod and an
amount of pridopidine, wherein the amounts when taken together are effective to treat the human
patient.
In an embodiment of the present invention, the amount of laquinimod and the amount of
pridopidine when taken together is more effective to treat the human patient than when each agent
is administered alone. In another embodiment, each of the amount of laquinimod when taken alone,
and the amount of pridopidine when taken alone is effective to treat the human patient. In another
embodiment, either the amount of laquinimod when taken alone, the amount of pridopidine when
taken alone, or each such amount when taken alone is not effective to treat the human patient.
In one embodiment, the neurodegenerative disorder is a trinucleotide repeat disorder. In another
embodiment, the neurodegenerative disorder is a polyglutamine disease. In another embodiment,
the neurodegenerative disorder is a proteinopathy. In another embodiment, the neurodegenerative
disorder is Parkinson's disease, Alzheimer's disease, Amyotorphic lateral sclerosis (ALS) or
Huntington's disease. In yet another embodiment, the neurodegenerative disorder is Huntington's
disease.
In one embodiment, the amount of laquinimod and the amount of pridopidine when taken together
is effective to reduce a symptom of the neurodegenerative disorder in the human patient. In another
embodiment, the symptom is depression, anxiety, motor function impairment, cognitive
impairment, a physical symptom, a mental symptom, an emotional symptom, a behavioral
symptom, impairment of the patient's functional capacity or reduced lifespan. In another
embodiment, the symptom is motor function impairment. In another embodiment, the motor
function impairment is abnormal movements, myoclonic jerks, irregular movements of extremities,
gait, facial grimacing, ataxia, inability to sustain motor act, hand movement or balance. In another
embodiment, the patient's motor function is assessed by UHDRS, TMS or the modified motor score
(mMS) derived from the Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS,
TMS). In yet another embodiment, the patient had an mMS score of 10 or greater at baseline.
In an embodiment of the present invention, the administration of laquinimod and pridopidine
improves a symptom of the neurodegenerative disorder by at least 20%. In another embodiment, the
administration of laquinimod and pridopidine improves a symptom of the neurodegenerative disorder
by at least 30%. In another embodiment, the administration of laquinimod and pridopidine improves
a symptom of the neurodegenerative disorder by at least 50%. In another embodiment,the
administration of laquinimod and pridopidine improves a symptom of the neurodegenerative disorder
by more than 100%. In another embodiment, the administration of laquinimod and pridopidine
improves a symptom of the neurodegenerative disorder by more than 300%. In another embodiment,
the administration of laquinimod and pridopidine improves a symptom of the neurodegenerative
disorder by more than 1000%.
In one embodiment, the human patient is receiving laquinimod therapy prior to initiating
pridopidine therapy. In another embodiment, the administration of laquinimod substantially
precedes the administration of pridopidine. In another embodiment, the human patient is receiving
pridopidine therapy prior to initiating laquinimod therapy. In another embodiment, the
administration of pridopidine substantially precedes the administration of laquinimod.
In one embodiment, the administration of laquinimod is 0 minutes to 48 hours after the
administration of pridopidine. In another embodiment, the administration of laquinimod is 3-5
hours after the administration of pridopidine. In another embodiment, the administration of
pridopidine is 0 minutes to 48 hours after the administration of laquinimod. In another
embodiment, the administration of pridopidine is 3-5 hours after the administration of laquinimod.
In one embodiment, laquinimod is laquinimod sodium. In another embodiment, the laquinimod is
administered via oral administration. In another embodiment, the laquinimod is administered daily.
In another embodiment, the laquinimod is administered more often than once daily. In another
embodiment, the laquinimod is administered less often than once daily.
In one embodiment, the amount laquinimod administered is less than 0.6 mg/day. In another
embodiment, the amount laquinimod administered is 0.1-40.0 mg/day. In another embodiment, the
amount laquinimod administered is 0.1-2.5 mg/day. In another embodiment, the amount
laquinimod administered is 0.25-2.0 mg/day. In another embodiment, the amount laquinimod
administered is 0.5-1.2 mg/day. In another embodiment, the amount laquinimod administered is
0.25 mg/day. In another embodiment, the amount laquinimod administered is 0.3 mg/day. In
another embodiment, the amount laquinimod administered is 0.5 mg/day. In another embodiment,
the amount laquinimod administered is 0.6 mg/day. In another embodiment, the amount laquinimod
administered is 1.0 mg/day. In another embodiment, the amount laquinimod administered is 1.2
mg/day. In another embodiment, the amount laquinimod administered is 1.5 mg/day. In another
embodiment, the amount laquinimod administered is 2.0 mg/day.
In one embodiment, pridopidine is administered orally. In another embodiment, pridopidine is
administered through an nasal, inhalation, subcutaneous, intravenous, intraperitoneal,
intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical or intradermal
route. In another embodiment, the pridopidine is administered daily. In another embodiment, the
pridopidine is administered more often than once daily. In another embodiment, the administration
of pridopidine is effected twice a day. In another embodiment, the pridopidine is administered less
often than once daily.
In one embodiment, the amount pridopidine administered is 0.1-1000 mg/day. In another
embodiment, the amount of pridopidine administered is greater than 135 mg/day. In another
embodiment, the amount of pridopidine administered is 180-225 mg/day. In another embodiment,
the amount pridopidine administered is 20-180 mg/day. In another embodiment, the amount
pridopidine administered is 50-180 mg/day. In another embodiment, the amount pridopidine
administered is 30-120 mg/day. In another embodiment, the amount pridopidine administered is
0.1-70 mg/day. In another embodiment, the amount pridopidine administered is 10-80 mg/day. In
another embodiment, the amount pridopidine administered is 45-90 mg/day. In another
embodiment, the amount pridopidine administered is 45 mg/day. In another embodiment, the
amount pridopidine administered is 90 mg/day. In another embodiment, the amount pridopidine
administered is about 45 mg/day. In another embodiment, the amount pridopidine administered is
about 90 mg/day. In another embodiment, the amount pridopidine administered is less than 90
mg/day. In another embodiment, the amount pridopidine administered is less than 45 mg/day.
In one embodiment, a loading dose of an amount different form the intended dose is administered
for a period of time at the start of the periodic administration. In another embodiment, the loading
dose is double the amount of the intended dose. In another embodiment, the loading dose is half
the amount of the intended dose.
In one embodiment, the method further comprises administration of an antidepressant, a psychotropic
drug, an antipsychotic, amisulpride, haloperidol, olanzapine, risperidone, sulpiride, or tiapride. In an
embodiment, the periodic administration of laquinimod and pridopidine continues for at least 3 days.
In another embodiment, the periodic administration of laquinimod and pridopidine continues for
more than 30 days. In another embodiment, the periodic administration of laquinimod and
pridopidine continues for more than 42 days. In another embodiment, the periodic administration of
laquinimod and pridopidine continues for 8 weeks or more. In another embodiment,the periodic
administration of laquinimod and pridopidine continues for at least 12 weeks. In another
embodiment, the periodic administration of laquinimod and pridopidine continues for at least 24
weeks. In another embodiment, the periodic administration of laquinimod and pridopidine continues
for more than 24 weeks. In yet another embodiment, the periodic administration of laquinimod and
pridopidine continues for 6 months or more.
This invention also provides a package comprising (a) a first pharmaceutical composition
comprising an amount of laquinimod and a pharmaceutically acceptable carrier; (b) a second
pharmaceutical composition comprising an amount of pridopidine and a pharmaceutically
acceptable carrier; and (c) instructions for use of the first and second pharmaceutical
compositions together to treat a human patient afflicted with a neurodegenerative disease. In an
embodiment, the neurodegenerative disorder is Huntington's disease.
In one embodiment, the first pharmaceutical composition, the second pharmaceutical
composition, or both the first and the second pharmaceutical composition are in the form of an
aerosol or inhalable powder. In another embodiment, the first pharmaceutical composition, the
second pharmaceutical composition, or both the first and the second pharmaceutical composition
are in liquid form. In another embodiment, the first pharmaceutical composition, the second
pharmaceutical composition, or both the first and the second pharmaceutical composition are in
solid form. In another embodiment, the first pharmaceutical composition, the second
pharmaceutical composition, or both the first and the second pharmaceutical composition are in
capsule form. In another embodiment, the first pharmaceutical composition, the second
pharmaceutical composition, or both the first and the second pharmaceutical composition are in
tablet form. In another embodiment, the tablets are coated with a coating which inhibits oxygen
from contacting the core. In another embodiment, the coating comprises a cellulosic polymer, a
detackifier, a gloss enhancer, or pigment.
In one embodiment, the first pharmaceutical composition further comprises mannitol. In another
embodiment, the first pharmaceutical composition further comprises an alkalinizing agent. In
another embodiment, the alkalinizing agent is meglumine.
In one embodiment, the first pharmaceutical composition further comprises an oxidation reducing
agent. In another embodiment, the first pharmaceutical composition is stable and free of an
alkalinizing agent or an oxidation reducing agent. In another embodiment, the first pharmaceutical
composition is free of an alkalinizing agent and free of an oxidation reducing agent. In another
embodiment, the first pharmaceutical composition is stable and free of disintegrant.
In one embodiment, the first pharmaceutical composition further comprises a lubricant. In another
embodiment, the lubricant is present in the composition as solid particles. In another embodiment,
the lubricant is sodium stearyl fumarate or magnesium stearate.
In one embodiment, the first pharmaceutical composition further comprises a filler. In another
embodiment, the filler is present in the composition as solid particles. In another embodiment, the
filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol,
lactose spray dried, lactose anhydrouse, or a combination thereof. In yet another embodiment, the
filler is mannitol or lactose monohydrate.
In an embodiment, the package further comprises a desiccant. In another embodiment, the
desiccant is silica gel.
In one embodiment, the first pharmaceutical composition is stable has a moisture content of no
more than 4%. In another embodiment, laquinimod is present in the composition as solid
particles. In another embodiment, the package is a sealed packaging having a moisture
permeability of not more than 15 mg/day per liter. In another embodiment, the sealed package is a
blister pack in which the maximum moisture permeability is no more than 0.005 mg/day. In
another embodiment, the sealed package is a bottle. In another embodiment, the bottle is closed
with a heat induction liner. In another embodiment, the sealed package comprises an HDPE
bottle. In another embodiment, the sealed package comprises an oxygen absorbing agent. In yet
another embodiment, the oxygen absorbing agent is iron.
In an embodiment of the present invention, the amount of laquinimod in the first composition is
less than 0.6 mg. In another embodiment, the amount of laquinimod in the composition is 0.1-40.0
mg. In another embodiment, the amount of laquinimod in the first composition is 0.1-2.5 mg. In
another embodiment, the amount of laquinimod in the first composition is 0.25-2.0 mg. In another
embodiment, the amount of laquinimod in the first composition is 0.5-1.2 mg. In another
embodiment, the amount of laquinimod in the first composition is 0.25 mg. In another embodiment,
the amount of laquinimod in the first composition is 0.3 mg. In another embodiment, the amount of
laquinimod in the first composition is 0.5 mg. In another embodiment, the amount of laquinimod in
the first composition is 0.6 mg. In another embodiment, the amount of laquinimod in the first
composition is 1.0 mg. In another embodiment, the amount of laquinimod in the first composition is
1.2 mg. In another embodiment, the amount of laquinimod in the first composition is 1.5 mg. In
another embodiment, the amount of laquinimod in the first composition is 2.0 mg.
In an embodiment of the present invention, the amount of pridopidine in the second composition
is 0.1-1000 mg. In another embodiment, the amount of pridopidine in the second composition is 10-
600 mg. In another embodiment, the amount of pridopidine in the second composition is 0.1-70 mg.
In another embodiment, the amount of pridopidine in the second composition is 10-80 mg. In
another embodiment, the amount of pridopidine in the second composition is 20-180 mg. In another
embodiment, the amount of pridopidine in the second composition is 30-120 mg. In another
embodiment, the amount of pridopidine in the second composition is 45-90 mg. In another
embodiment, the amount of pridopidine in the second composition is 45 mg. In another
embodiment, the amount of pridopidine in the second composition is 90 mg. In another
embodiment, the amount of pridopidine in the second composition is about 45 mg. In another
embodiment, the amount of pridopidine in the second composition is about 90 mg. In another
embodiment, the amount of pridopidine in the second composition is less than 90 mg. In another
embodiment, the amount of pridopidine in the second composition is less than 45 mg. In yet another
embodiment, the amount of pridopidine in the second composition is 1, 5, 15, 20, 30, 50, 100, or
300 mg.
This invention also provides laquinimod for use as an add-on therapy or in combination with
pridopidine in treating a human patient afflicted with a neurodegenerative disorder.
This invention also provides a pharmaceutical composition comprising an amount of laquinimod
and an amount of pridopidine for use in treating a human patient afflicted with a
neurodegenerative disorder, wherein the laquinimod and the pridopidine are to be administered
simultaneously or contemporaneously. In an embodiment, the neurodegenerative disorder is
Huntington's disease.
This invention also provides a pharmaceutical composition comprising an amount of laquinimod
and an amount of pridopidine. In one embodiment, the pharmaceutical composition is in the form
of an aerosol or inhalable powder. In an embodiment, the pharmaceutical composition is in liquid
form. In an embodiment, the pharmaceutical composition is in solid form. In an embodiment, the
pharmaceutical composition is in capsule form. In an embodiment, the pharmaceutical
composition is in tablet form.
In one embodiment, the tablets are coated with a coating which inhibits oxygen from contacting
the core. In another embodiment, the coating comprises a cellulosic polymer, a detackifier, a gloss
enhancer, or pigment.
In one embodiment, the pharmaceutical composition further comprises mannitol. In another
embodiment, the pharmaceutical composition further comprises an alkalinizing agent. In another
embodiment, the alkalinizing agent is meglumine. In an embodiment, the pharmaceutical
composition comprises an oxidation reducing agent.
In an embodiment the pharmaceutical composition is free of an alkalinizing agent or an oxidation
reducing agent. In another embodiment, the pharmaceutical composition is free of an alkalinizing
agent and free of an oxidation reducing agent.
In one embody, the pharmaceutical composition is stable and free of disintegrant. In another
embodiment, the pharmaceutical composition further comprises a lubricant. In another
embodiment, the lubricant is present in the composition as solid particles. In another embodiment,
the lubricant is sodium stearyl fumarate or magnesium stearate.
In an embodiment, the pharmaceutical composition further comprises a filler. In another
embodiment, the filler is present in the composition as solid particles. In another embodiment, the
filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol,
lactose spray dried, lactose anhydrouse, or a combination thereof. In another embodiment, the
filler is mannitol or lactose monohydrate.
In one embodiment, the amount of laquinimod in the composition is less than 0.6 mg. In another
embodiment, the amount of laquinimod in the composition is 0.1-40.0 mg. In another embodiment,
the amount of laquinimod in the composition is 0.1-2.5 mg. In another embodiment, the amount of
laquinimod in the composition is 0.25-2.0 mg. In another embodiment, the amount of laquinimod in
the composition is 0.5-1.2 mg. In another embodiment, the amount of laquinimod in the
composition is 0.25 mg. In another embodiment, the amount of laquinimod in the composition is
0.3 mg. In another embodiment, the amount of laquinimod in the composition is 0.5 mg. In another
embodiment, the amount of laquinimod in the composition is 0.6 mg. In another embodiment, the
amount of laquinimod in the composition is 1.0 mg. In another embodiment, the amount of
laquinimod in the composition is 1.2 mg. In another embodiment, the amount of laquinimod in the
composition is 1.5 mg. In another embodiment, the amount of laquinimod in the composition is 2.0
mg.
In an embodiment of the present invention, the amount of pridopidine is 0.1-1000 mg. In another
embodiment, the amount of pridopidine is 10-600 mg. In another embodiment, the amount of
pridopidine is 0.1-70 mg. In another embodiment, the amount of pridopidine is 10-80 mg. In
another embodiment, the amount of pridopidine is 20- 180 mg. In another embodiment, the amount
of pridopidine is 30-120 mg. In another embodiment, the amount of pridopidine is 45-90 mg. In
another embodiment, the amount of pridopidine is 45 mg. In another embodiment, the amount of
pridopidine is 90 mg. In another embodiment, the amount of pridopidine is about 45 mg. In another
embodiment, the amount of pridopidine is about 90 mg. In another embodiment, the amount of
pridopidine is less than 90 mg. In another embodiment, the amount of pridopidine is less than 45
mg. In yet another embodiment, the amount of pridopidine is 1, 5, 15, 20, 30, 50, 100, or 300 mg.
This invention also provides use of an amount of laquinimod and an amount of pridopidine in the
preparation of a combination for treating a human patient afflicted with a neurodegenerative
disorder wherein the laquinimod or pharmaceutically acceptable salt thereof and the pridopidine are
administered simultaneously or contemporaneously.
This invention also provides a pharmaceutical composition comprising an amount of laquinimod
for use in treating a subject afflicted with a neurodegenerative disorder as an add-on therapy or in
combination with pridopidine by periodically administering the pharmaceutical composition and
the pridopidine to the subject.
This invention also provides a pharmaceutical composition comprising an amount of pridopidine
for use treating a subject afflicted with a neurodegenerative disorder as an add-on therapy or in
combination with laquinimod by periodically administering the pharmaceutical composition and
the laquinimod to the subject.
In the methods, pharmaceutical compositions, packages, and uses as described herein, the
laquinimod can be partly or fully deuterium-enriched. In an embodiment, laquinimod has
deuterium enrichment of no less than about 10%. In another embodiment, laquinimod has
deuterium enrichment of no less than about 50%. In another embodiment, laquinimod has
deuterium enrichment of no less than about 90%. In another embodiment, laquinimod has
deuterium enrichment of no less than about 98%. Deuterium-enriched forms of laquinimod are
described in e.g., U.S. Patent No. 8,252,933 and U.S. Patent Application Publication No.
2010/0055072, which are hereby incorporated by reference in their entireties into this application.
In the methods, pharmaceutical compositions, packages, and uses described herein, the pridopidine
can be partly or fully deuterium-enriched. In an embodiment, pridopidine has deuterium enrichment
of no less than about 10%. In another embodiment, pridopidine has deuterium enrichment of no
less than about 50%. In another embodiment, pridopidine has deuterium enrichment of no less than
about 90%. In another embodiment, pridopidine has deuterium enrichment of no less than about
98%. Deuterium-enriched forms of pridopidine are described in e.g., PCT International Application
Publication Nos. WO 2012/028635 and WO 201 1/107583, which are hereby incorporated by
reference in their entireties into this application.
This invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a
subject afflicted with a neurodegenerative disorder or presenting a clinically isolated syndrome,
which comprises: a) one or more unit doses, each such unit dose comprising: i) an amount of
laquinimod and ii) an amount of pridopidine, wherein the respective amounts of said laquinimod
and said pridopidine in said unit dose are effective, upon concomitant administration to said
subject, to treat the subject, and b) a finished pharmaceutical container therefor, said container
containing said unit dose or unit doses, said container further containing or comprising labeling
directing the use of said package in the treatment of said subject.
For the foregoing embodiments, each embodiment disclosed herein is contemplated as being
applicable to each of the other disclosed embodiments. In addition, the elements recited in the
packaging and pharmaceutical composition embodiments can be used in the method and use
embodiments described herein.
Pridopidine
Pridopidine mixtures, compositions, the process for the manufacture thereof, the use thereof for
treatment of various conditions, and the corresponding dosages and regimens are described in,
e.g., PCT International Application Publication Nos. WO 2001/46145, WO 201 1/107583, WO
2006/040155, U.S. Patent Application Publication No. 201 1/0206782, U.S. Patent Application
Publication No. 2010/0197712, each of which is hereby incorporated by reference in its entireties
into this application.
Laquinimod
Laquinimod mixtures, compositions, and the process for the manufacture thereof are described in,
e.g., U.S. Patent No. 6,077,851, U.S. Patent No. 7,884,208, U.S. Patent No. 7,989,473, U.S.
Patent No. 8,178,127, U.S. Application Publication No. 2010-0055072, U.S. Application
Publication No. 2012-0010238, and U.S. Application Publication No. 2012-0010239, each of
which is hereby incorporated by reference in their entireties into this application.
Use of laquinimod for treatment of various conditions, and the corresponding dosages and
regimens, are described in U.S. Patent No. 6,077,851 (multiple sclerosis, insulin-dependent
diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel
disease, psoriasis, inflammatory respiratory disorder, atherosclerosis, stroke, and Alzhemier's
disease), U.S. Application Publication No. 201 1-0027219 (Crohn's disease), U.S. Application
Publication No. 2010-0322900 (Relapsing-remitting multiple sclerosis), U.S. Application
Publication No. 201 1-0034508 (brain-derived neurotrophic factor (BDNF)-related diseases), U.S.
Application Publication No. 201 1-0218179 (active lupus nephritis), U.S. Application Publication
No. 2011-02 18203 (rheumatoid arthritis), U.S. Application Publication No. 2011-02 17295 (active
lupus arthritis), and U.S. Application Publication No. 2012-0142730 (reducing fatigue,
improving quality of life, and providing neuroprotection in MS patients), each of which is hereby
incorporated by reference in their entireties into this application.
A pharmaceutically acceptable salt of laquinimod as used in this application includes lithium,
sodium, potassium, magnesium, calcium, manganese, copper, zinc, aluminum and iron. Salt
formulations of laquinimod and the process for preparing the same are described, e.g., in U.S.
Patent No. 7,589,208 and PCT International Application Publication No. WO 2005/074899, which
are hereby incorporated by reference into this application.
Laquinimod can be administered in admixture with suitable pharmaceutical diluents, extenders,
excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier)
suitably selected with respect to the intended form of administration and as consistent with
conventional pharmaceutical practices. The unit can be in a form suitable for oral administration.
Laquinimod can be administered alone but is generally mixed with a pharmaceutically acceptable
carrier, and co-administered in the form of a tablet or capsule, liposome, or as an agglomerated
powder. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or
tablets can be easily formulated and can be made easy to swallow or chew; other solid forms
include granules, and bulk powders.
Tablets may contain suitable binders, lubricants, disintegrating agents (disintegrants), coloring
agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral
administration in the dosage unit form of a tablet or capsule, the active drug component can be
combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose,
gelatin, agar, starch, sucrose, glucose, methyl cellulose, dicalcium phosphate, calcium sulfate,
mannitol, sorbitol, microcrystalline cellulose and the like. Suitable binders include starch, gelatin,
natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums such as
acacia, tragacanth, or sodium alginate, povidone, carboxymethylcellulose, polyethylene glycol,
waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium
stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate,
talc and the like. Disintegrators (disintegrants) include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the
like.
Specific examples of the techniques, pharmaceutically acceptable carriers and excipients that may
be used to formulate oral dosage forms of the present invention are described, e.g., in U.S. Patent
No. 7,589,208, PCT International Application Publication Nos. WO 2005/074899, WO
2007/047863, and 2007/146248. These references in their entireties are hereby incorporated by
reference into this application.
General techniques and compositions for making dosage forms useful in the present invention are
described-in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker &
Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel,
Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical
Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical
Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol
7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings
for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James
McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and
the Pharmaceutical Sciences, Vol 6 1 (Alain Rolland, Ed., 1993); Drug Delivery to the
Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical
Technology; J . G. Hardy, S. S. Davis, Clive G. Wilson, Eds).; Modern Pharmaceutics Drugs and
the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds). These
references in their entireties are hereby incorporated by reference into this application.
Disclosed is a method for treating a subject afflicted with a neurodegenerative disorder, e.g., HD,
using laquinimod as an add-on or in combination with pridopidine which provides a more
efficacious treatment than each agent alone. The use of laquinimod for certain neurodegenerative
disorder, e.g., Huntington's disease, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease
had been previously suggested in, e.g., U.S. Patent Application Publication No. 201 1-0034508.
However, the inventors have surprisingly found that the combination of laquinimod and
pridopidine is particularly effective for the treatment of neurodegenerative disorders such as HD
as compared to each agent alone.
Terms
As used herein, and unless stated otherwise, each of the following terms shall have the definition
set forth below.
As used herein, "laquinimod" means laquinimod acid or a pharmaceutically acceptable salt thereof.
As used herein, an "amount" or "dose" of laquinimod as measured in milligrams refers to the
milligrams of laquinimod acid present in a preparation, regardless of the form of the preparation. A
"dose of 0.6 mg laquinimod" means the amount of laquinimod acid in a preparation is 0.6 mg,
regardless of the form of the preparation. Thus, when in the form of a salt, e.g. a laquinimod
sodium salt, the weight of the salt form necessary to provide a dose of 0.6 mg laquinimod would be
greater than 0.6 mg (e.g., 0.64 mg) due to the presence of the additional salt ion.
As used herein, "about" in the context of a numerical value or range means ±10% of the
numerical value or range recited or claimed.
As used herein, a composition that is "free" of a chemical entity means that the composition
contains, if at all, an amount of the chemical entity which cannot be avoided although the
chemical entity is not part of the formulation and was not affirmatively added during any part of
the manufacturing process. For example, a composition which is "free" of an alkalizing agent
means that the alkalizing agent, if present at all, is a minority component of the composition by
weight. Preferably, when a composition is "free" of a component, the composition comprises less
than 0.1 wt%, 0.05 wt%, 0.02 wt%, or 0.01 wt% of the component.
As used herein, "alkalizing agent" is used interchangeably with the term "alkaline -reacting
component" or "alkaline agent" and refers to any pharmaceutically acceptable excipient which
neutralizes protons in, and raises the pH of, the pharmaceutical composition in which it is used.
As used herein, "oxidation reducing agent" refers to a group of chemicals which includes an
"antioxidant", a "reduction agent" and a "chelating agent".
As used herein, "antioxidant" refers to a compound selected from the group consisting of tocopherol,
methionine, glutathione, tocotrienol, dimethyl glycine, betaine, butylated hydroxyanisole, butylated
hydroxytoluene, turmerin, vitamin E, ascorbyl palmitate, tocopherol, deteroxime mesylate, methyl
paraben, ethyl paraben, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium
or potassium metabisulfite, sodium or potassium sulfite, alpha tocopherol or derivatives thereof, sodium
ascorbate, disodium edentate, BHA (butylated hydroxyanisole), a pharmaceutically acceptable salt or
ester of the mentioned compounds, and mixtures thereof.
The term "antioxidant" as used herein also refers to Flavonoids such as those selected from the
group of quercetin, morin, naringenin and hesperetin, taxifolin, afzelin, quercitrin, myricitrin,
genistein, apigenin and biochanin A, flavone, flavopiridol, isoflavonoids such as the soy
isoflavonoid, genistein, catechins such as the tea catechin epigallocatechin gallate, flavonol,
epicatechin, hesperetin, chrysin, diosmin, hesperidin, luteolin, and rutin.
As used herein, "reduction agent" refers to a compound selected from the group consisting of thiolcontaining
compound, thioglycerol, mercaptoethanol, thioglycol, thiodiglycol, cysteine, thioglucose,
dithiothreitol (DTT), dithio-bis-maleimidoethane (DTME), 2,6-di-tert-butyl-4-methylphenol (BHT),
sodium dithionite, sodium bisulphite, formamidine sodium metabisulphite, and ammonium
bisulphite."
As used herein, "chelating agent" refers to a compound selected from the group consisting of
penicillamine, trientine, N,N'-diethyldithiocarbamate (DDC), 2,3,2'-tetraamine (2,3,2'-tet),
neocuproine, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), 1,10-phenanthroline
(PHE), tetraethylenepentamine, triethylenetetraamine and tris(2-carboxyethyl) phosphine (TCEP),
ferrioxamine, CP94, EDTA, deferoxamine B (DFO) as the methanesulfonate salt (also known as
desferrioxanilne B mesylate (DFOM)), desferal from Novartis (previously Ciba-Giegy), and
apoferritin.
As used herein, a pharmaceutical composition is "stable" when the composition preserves the
physical stability/integrity and/or chemical stability/integrity of the active pharmaceutical ingredient
during storage. Furthermore, "stable pharmaceutical composition" is characterized by its level of
degradation products not exceeding 5% at 40°C/75%RH after 6 months or 3% at 55°C/75% RH
after two weeks, compared to their level in time zero.
As used herein, "combination" means an assemblage of reagents for use in therapy either by
simultaneous or contemporaneous administration. Simultaneous administration refers to
administration of an admixture (whether a true mixture, a suspension, an emulsion or other physical
combination) of laquinimod and pridopidine. In this case, the combination may be the admixture or
separate containers of laquinimod and pridopidine that are combined just prior to administration.
Contemporaneous administration refers to the separate administration of laquinimod and
pridopidine at the same time, or at times sufficiently close together that a synergistic activity
relative to the activity of either laquinimod or pridopidine alone is observed.
As used herein, "add-on" or "add-on therapy" means an assemblage of reagents for use in therapy,
wherein the subject receiving the therapy begins a first treatment regimen of one or more reagents
prior to beginning a second treatment regimen of one or more different reagents in addition to the
first treatment regimen, so that not all of the reagents used in the therapy are started at the same
time. For example, adding laquinimod therapy to a patient already receiving pridopidine therapy.
As used herein, "effective" when referring to an amount of laquinimod and/or pridopidine refers to
the quantity of laquinimod and/or pridopidine that is sufficient to yield a desired therapeutic
response without undue adverse side effects (such as toxicity, irritation, or allergic response)
commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
"Administering to the subject" or "administering to the (human) patient" means the giving of,
dispensing of, or application of medicines, drugs, or remedies to a subject/patient to relieve, cure,
or reduce the symptoms associated with a disease, disorder or condition, e.g., a pathological
condition.
"Treating" as used herein encompasses, e.g., inducing inhibition, regression, or stasis of a disease
or disorder, e.g., Huntington's disease, or lessening, suppressing, inhibiting, reducing the severity
of, eliminating or substantially eliminating, or ameliorating a symptom of the disease or disorder.
"Inhibition" of disease progression or disease complication in a subject means preventing or
reducing the disease progression and/or disease complication in the subject.
A "symptom" associated with a neurodegenerative disorder includes any clinical or laboratory
manifestation associated with the neurodegenerative disorder and is not limited to what the
subject can feel or observe. For example, a symptom of Huntington's disease includes, but is not
limited to, a patient's mMS, motor function as measured by, e.g., the UHDRS-TMS, cognitive
function, anxiety and depression. " Improvement of or "improving" a symptom as used herein
refers to a favorable change in the patient's symptom as compared to baseline or as compared to a
control subject not receiving the treatment.
As used herein, "substantially proceeds administration" means that the administration of one
agent precedes another agent; and the two agents are not administered simultaneously or
contemporaneously.
As used herein, "a subject afflicted with a neurodegenerative disorder" means a subject who has
been clinically diagnosed to have the neurodegenerative disorder.
As used herein, a subject at "baseline" is as subject prior to administration of laquinimod or
pridopidine.
"Polyglutamine disease" as used herein encompasses any inherited disorders characterized by an
expanded CAG triplet repeat which codes for a long glutamine repeat including but not limited to
Huntington's disease, spinobulbar muscular atrophy (SBMA), and dentatorubral pallidoluysian
atrophy. Chai et al. (1999) "Analysis of the Role of Heat Shock Protein (Hsp) Molecular
Chaperones in Polyglutamine Disease," Journal of Neuroscience 19(23): 10338-10347, which is
hereby incorporated by reference in its entirety into this application.
"Proteinopathy" as used herein encompasses any disease caused by a misfolding and/or
aggregation of proteins.
An HD patient's motor function can be assessed by the Unified Huntington's Disease Rating Scale
(UHDRS) Motor Score or "modified motor score (mMS)" derived from the UHDRS Total Motor
Score. UHDRS is a research tool which has been developed by the Huntington Study Group (HSG)
to provide a uniform assessment of the clinical features and course of HD. The modified motor
score is a modified version of the UHDRS made up of 19 items out of the 3 1 items on the
UHDRS motor score. The modified Motor Score is made up of negative motor features such as
bradykinesia, rigidity, hand function, eye movements, and gait. The 1 items not included in the
mMS but included in the UHDRS motor score include chorea and dystonia, which may differ in
their progression from the 19 items on the mMS. The UHDRS is described in, e.g., Huntington
Study Group (1996) "Unified Huntington's Disease Rating Scale: Reliability and Consistency"
Movement Disorders 11(2): 136- 142, which is hereby incorporated by reference in its entirety into
this application.
A "pharmaceutically acceptable carrier" refers to a carrier or excipient that is suitable for use with
humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic
response) commensurate with a reasonable benefit/risk ratio. It can be a pharmaceutically
acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the
subject.
It is understood that where a parameter range is provided, all integers within that range, and tenths
thereof, are also provided by the invention. For example, "0.1-2.5mg/day" includes 0.1 mg/day,
0.2 mg/day, 0.3 mg/day, etc. up to 2.5 mg/day.
This invention will be better understood by reference to the Experimental Details which follow,
but those skilled in the art will readily appreciate that the specific experiments detailed are only
illustrative of the invention as described more fully in the claims which follow thereafter.
Experimental Details
EXAMPLE 1: ANIMAL MODELS OF HUNTINGTON' S DISEASE
Most animal models of HD fall into two broad categories, genetic and non-genetic. Historically,
nongenetic models have dominated the field of HD research, and typically induce cell death either
by excitotoxic mechanisms of by disruption of mitochondrial machinery. Quinolinic acid and
kainic acid have been the two most commonly used excitotoxic agents in both rodent and primate
models of HD (Ramaswamy, 2007). Emerging molecular technology has enabled the
development of genetic murine and, more recently, rat models that attempt to capture the
hereditary nature of HD. There are two main categories of genetic mouse models, transgenic and
knock-in. Transgenic mice results from the random insertion of a portion of the human htt gene,
containing the polyglutamine repeat, in the mouse genome, the expression of which can be driven
by different promoters. Alternatively, "knocking in" a portion of the human htt gene in the mouse
htt gene locus on chromosome 7 results in the creation of knock-in mice. Transgenic models
include transgenic mice model R6/2, R6/1, N171-82Q, YAC, and transgenic rat. Knock-in models
include HdhQ92 mouse, HdhQl l l mouse, CAG140 mouse and CAG150 mouse (Ramaswamy,
2007).
Example 1.1: Toxin models ofHD
A quinolinic acid (QA) rat model is periodically administered an amount of laquinimod and an
amount pridopidine. The periodic administration of laquinimod and pridopidine is more effective
(provides at least an additive effect or more than an additive effect) in preventing or attenuating
weight loss, slowing, inhibiting, or reversing progression of motor, cognitive or behavioral
symptoms, improving performance on the rotarod test, gait test, clasping test, and open-field test,
slowing, inhibiting, or reversing progression of neurodegeneration in the brain, and prolonging
survival, in the rat than when pridopidine alone or laquinimod alone is administered at the same
repetitive dose.
A 3-Nitro-propionic acid (3-NP) rat model is periodically administered an amount of laquinimod
and an amount pridopidine. The periodic administration of laquinimod and pridopidine is more
effective (provides at least an additive effect or more than an additive effect) in preventing or
attenuating weight loss, slowing, inhibiting, or reversing progression of motor, cognitive or
behavioral symptoms, improving performance on the rotarod test, gait test, clasping test, and
open-field test, slowing, inhibiting, or reversing progression of neurodegeneration in the brain,
and prolonging survival, in the rat than when pridopidine alone or laquinimod alone is
administered at the same repetitive dose.
Example 1.2: Transgenic models of HD
A R6/2 mouse model is periodically administered an amount of laquinimod and an amount
pridopidine. The periodic administration of laquinimod and pridopidine is more effective
(provides at least an additive effect or more than an additive effect) in preventing or attenuating
weight loss, slowing, inhibiting, or reversing progression of motor, cognitive or behavioral
symptoms, improving performance on the rotarod test, gait test, clasping test, and open-field test,
slowing, inhibiting, or reversing progression of neurodegeneration in the brain, and prolonging
survival, in the mouse than when pridopidine alone or laquinimod alone is administered at the
same repetitive dose.
Example 1.3: Knock-in mouse models of HD
A CAG150 mouse model is periodically administered an amount of laquinimod and an amount
pridopidine. The periodic administration of laquinimod and pridopidine is more effective
(provides at least an additive effect or more than an additive effect) in preventing or attenuating
weight loss, slowing, inhibiting, or reversing progression of motor, cognitive or behavioral
symptoms, improving performance on the rotarod test, gait test, clasping test, and open-field test,
slowing, inhibiting, or reversing progression of neurodegeneration in the brain, and prolonging
survival, in the mouse than when pridopidine alone or laquinimod alone is administered at the
same repetitive dose.
EXAMPLE 2 : ADD-ON THERAPY FOR TREATING HUNTINGTON 'S DISEASE
Periodic oral administration of laquinimod (0.6 mg/day or 1.2 mg/day) as an add-on therapy for a
human patient afflicted with HD who is already receiving pridopidine (45 mg once daily or 45 mg
twice a day) provides a clinically meaningful advantage and is more effective (provides at least an
additive effect or more than an additive effect) in treating the patient than when pridopidine is
administered alone (at the same dose).
Periodic administration of pridopidine (45 mg once daily or 45 mg twice a day) as an add-on
therapy for a human patient afflicted with HD who is already receiving laquinimod (0.6 mg/day or
1.2 mg/day) provides a clinically meaningful advantage and is more effective (provides at least an
additive effect or more than an additive effect) in treating the patient than when laquinimod is
administered alone (at the same dose).
The add-on therapies also provides efficacy (provides at least an additive effect or more than an
additive effect) in treating the patient without undue adverse side effects or affecting the safety of
the treatment:
1. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in improving symptoms of depression, sedation and anxiety.
2. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in slowing, inhibiting or reversing the progression of motor function and cognitive
impairment.
3. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in reducing the severity of motor symptoms including abnormal movements, myoclonic
jerks, irregular movements of extremities, lilting gait, gait disturbances, facial grimacing, ataxia,
and inability to sustain motor act.
4. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in improving the patient's hand movements, gait and balance.
5. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in slowing or preventing deterioration of or improving the patient's motor function as
assessed by the modified motor score (mMS) derived from the Unified Huntington's Disease
Rating Scale Total Motor Score (UHDRS, TMS).
6. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in improving the patient's functional capacity.
7. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in reducing, preventing progression of, or reversing mental, emotional and behavioral
symptoms of HD.
8. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in prolonging the patient's lifespan.
9. The add-on therapy does not produce any significant side effects such as sedation and
depression.
EXAMPLE 3 : ADD-ON THERAPY FOR TREATING HUNTINGTON'S DISEASE
Periodic oral administration of laquinimod (0.6 mg/day or 1.2 mg/day) as an add-on therapy for a
human patient afflicted with HD who is already receiving pridopidine (67.5 mg once daily or 67.5
mg twice a day) provides a clinically meaningful advantage and is more effective (provides at
least an additive effect or more than an additive effect) in treating the patient than when
pridopidine is administered alone (at the same dose).
Periodic administration of pridopidine (67.5 mg once daily or 67.5 mg twice a day) as an add-on
therapy for a human patient afflicted with HD who is already receiving laquinimod (0.6 mg/day or
1.2 mg/day) provides a clinically meaningful advantage and is more effective (provides at least an
additive effect or more than an additive effect) in treating the patient than when laquinimod is
administered alone (at the same dose).
The add-on therapies also provides efficacy (provides at least an additive effect or more than an
additive effect) in treating the patient without undue adverse side effects or affecting the safety of
the treatment:
1. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in improving symptoms of depression, sedation and anxiety.
2. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in slowing, inhibiting or reversing the progression of motor function and cognitive
impairment.
3. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in reducing the severity of motor symptoms including abnormal movements, myoclonic
jerks, irregular movements of extremities, lilting gait, gait disturbances, facial grimacing, ataxia,
and inability to sustain motor act.
4. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in improving the patient's hand movements, gait and balance.
5. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in slowing or preventing deterioration of or improving the patient's motor function as
assessed by the modified motor score (mMS) derived from the Unified Huntington's Disease
Rating Scale Total Motor Score (UHDRS, TMS).
6. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in improving the patient's functional capacity.
7. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in reducing, preventing progression of, or reversing mental, emotional and behavioral
symptoms of HD.
8. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in prolonging the patient's lifespan.
9. The add-on therapy does not produce any significant side effects such as sedation and
depression.
EXAMPLE 4 : ADD-ON THERAPY FOR TREATING HUNTINGTON 'S DISEASE
Periodic oral administration of laquinimod (0.6 mg/day or 1.2 mg/day) as an add-on therapy for a
human patient afflicted with HD who is already receiving pridopidine (90 mg once daily or 90 mg
twice a day) provides a clinically meaningful advantage and is more effective (provides at least an
additive effect or more than an additive effect) in treating the patient than when pridopidine is
administered alone (at the same dose).
Periodic administration of pridopidine (90 mg once daily or 90 mg twice a day) as an add-on
therapy for a human patient afflicted with HD who is already receiving laquinimod (0.6 mg/day or
1.2 mg/day) provides a clinically meaningful advantage and is more effective (provides at least an
additive effect or more than an additive effect) in treating the patient than when laquinimod is
administered alone (at the same dose).
The add-on therapies also provides efficacy (provides at least an additive effect or more than an
additive effect) in treating the patient without undue adverse side effects or affecting the safety of
the treatment:
1. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in improving symptoms of depression, sedation and anxiety.
2. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in slowing, inhibiting or reversing the progression of motor function and cognitive
impairment.
3. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in reducing the severity of motor symptoms including abnormal movements, myoclonic
jerks, irregular movements of extremities, lilting gait, gait disturbances, facial grimacing, ataxia,
and inability to sustain motor act.
4. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in improving the patient's hand movements, gait and balance.
5. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in slowing or preventing deterioration of or improving the patient's motor function as
assessed by the modified motor score (mMS) derived from the Unified Huntington's Disease
Rating Scale Total Motor Score (UHDRS, TMS).
6. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in improving the patient's functional capacity.
7. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in reducing, preventing progression of, or reversing mental, emotional and behavioral
symptoms of HD.
8. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in prolonging the patient's lifespan.
9. The add-on therapy does not produce any significant side effects such as sedation and
depression.
EXAMPLE 5 : ADD-ON THERAPY FOR TREATING HUNTINGTON'S DISEASE
Periodic oral administration of laquinimod (0.6 mg/day or 1.2 mg/day) as an add-on therapy for a
human patient afflicted with HD who is already receiving pridopidine ( 112.5 mg once daily or
112.5 mg twice a day) provides a clinically meaningful advantage and is more effective (provides
at least an additive effect or more than an additive effect) in treating the patient than when
pridopidine is administered alone (at the same dose).
Periodic administration of pridopidine ( 1 12.5 mg once daily or 112.5 mg twice a day) as an add
on therapy for a human patient afflicted with HD who is already receiving laquinimod (0.6
mg/day or 1.2 mg/day) provides a clinically meaningful advantage and is more effective (provides
at least an additive effect or more than an additive effect) in treating the patient than when
laquinimod is administered alone (at the same dose).
The add-on therapies also provides efficacy (provides at least an additive effect or more than an
additive effect) in treating the patient without undue adverse side effects or affecting the safety of
the treatment:
1. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in improving symptoms of depression, sedation and anxiety.
2. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in slowing, inhibiting or reversing the progression of motor function and cognitive
impairment.
3. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in reducing the severity of motor symptoms including abnormal movements, myoclonic
jerks, irregular movements of extremities, lilting gait, gait disturbances, facial grimacing, ataxia,
and inability to sustain motor act.
4. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in improving the patient's hand movements, gait and balance.
5. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in slowing or preventing deterioration of or improving the patient's motor function as
assessed by the modified motor score (mMS) derived from the Unified Huntington's Disease
Rating Scale Total Motor Score (UHDRS, TMS).
6. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in improving the patient's functional capacity.
7. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in reducing, preventing progression of, or reversing mental, emotional and behavioral
symptoms of HD.
8. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in prolonging the patient's lifespan.
9. The add-on therapy does not produce any significant side effects such as sedation and
depression.
EXAMPLE 6 : COMBINATION THERAPY FOR TREATING HUNTINGTON'S DISEASE
HD is a fatal neurodegenerative disease characterized by uncoordinated and uncontrollable
movements, cognitive deterioration, and behavioral and/or psychological problems. The classic
onset of HD symptoms typically occurs in middle age, but the disease also manifests in children
and the elderly. Disease progression is characterized by a gradual decline in motor control,
cognition, and mental stability and generally results in death within 15-25 years of clinical
diagnosis.
HD is a genetic disease, transmitted via autosomal-dominant inheritance. The defective gene,
found on chromosome 4, causes the production of a mutant protein, huntingtin (Htt), which
aggregates in the central nervous system (CNS) and results in the pathogenesis of HD. The
prevalence of HD is approximately 10 per 100,000 in the US and Europe. The only currently
marketed product in the United States indicated for HD is tetrabenazine, which has no effect on
non-choreic symptoms and disease progression, and is associated with serious side effects such as
suicidality and depression. Significant unmet medical needs remain in the development of
alternative treatments for HD.
Huntexil® (pridopidine/ACR16) is a drug candidate being developed for the symptomatic
treatment of hand movement, balance and gait disturbances in HD. Previous trials in the United
States, Europe and Canada demonstrate significant symptomatic relief for patients with HD
including improved hand movements and improved gait and balance. These results were observed
without any side effects such as sedation and depression seen with other therapies such as
neuroleptics and tetrabenzine.
Disclosed herein is the use of laquinimod in addition to or in combination with pridopidine for the
treatment of HD.
Periodic oral administration of laquinimod (0.6 mg/day or 1.2 mg/day) in combination with
pridopidine (45 mg once daily or 45 mg twice a day) to a human patient afflicted with HD
provides increased efficacy (provides at least an additive effect or more than an additive effect) in
treating the patient than when pridopidine is administered alone or when laquinimod is
administered alone (at the same dose). The combination therapy also provides efficacy (provides at
least an additive effect or more than an additive effect) in treating the patient without undue
adverse side effects or affecting the safety of the treatment.
The combination therapy provides a clinically meaningful advantage and is more effective
(provides at least an additive effect or more than an additive effect) in treating the patient than
when laquinimod or pridopidine is administered alone (at the same dose) in the following manner:
1. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in improving symptoms of depression, sedation and anxiety.
2. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in slowing, inhibiting or reversing the progression of motor function and
cognitive impairment.
3. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in reducing the severity of motor symptoms including abnormal movements,
myoclonic jerks, irregular movements of extremities, lilting gait, gait disturbances, facial
grimacing, ataxia, and inability to sustain motor act.
4. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in improving the patient's hand movements, gait and balance.
5. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in slowing or preventing deterioration of or improving the patient's motor function as
assessed by the modified motor score (mMS) derived from the Unified Huntington's Disease
Rating Scale Total Motor Score (UHDRS, TMS).
6. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in improving the patient's functional capacity.
7. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in reducing, preventing progression of, or reversing mental, emotional and
behavioral symptoms of HD.
8. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in prolonging the patient's lifespan.
9. The combination therapy does not produce any significant side effects such as sedation and
depression.
EXAMPLE 7 : COMBINATION THERAPY FOR TREATING HUNTINGTON'S DISEASE
Disclosed herein is the use of laquinimod in addition to or in combination with pridopidine for the
treatment of HD.
Periodic oral administration of laquinimod (0.6 mg/day or 1.2 mg/day) in combination with
pridopidine (67.5 mg once daily or 67.5 mg twice a day) to a human patient afflicted with HD
provides increased efficacy (provides at least an additive effect or more than an additive effect) in
treating the patient than when pridopidine is administered alone or when laquinimod is
administered alone (at the same dose). The combination therapy also provides efficacy (provides at
least an additive effect or more than an additive effect) in treating the patient without undue
adverse side effects or affecting the safety of the treatment.
The combination therapy provides a clinically meaningful advantage and is more effective
(provides at least an additive effect or more than an additive effect) in treating the patient than
when laquinimod or pridopidine is administered alone (at the same dose) in the following manner:
1. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in improving symptoms of depression, sedation and anxiety.
2. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in slowing, inhibiting or reversing the progression of motor function and
cognitive impairment.
3. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in reducing the severity of motor symptoms including abnormal movements,
myoclonic jerks, irregular movements of extremities, lilting gait, gait disturbances, facial
grimacing, ataxia, and inability to sustain motor act.
4. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in improving the patient's hand movements, gait and balance.
5. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in slowing or preventing deterioration of or improving the patient's motor function as
assessed by the modified motor score (mMS) derived from the Unified Huntington's Disease
Rating Scale Total Motor Score (UHDRS, TMS).
6. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in improving the patient's functional capacity.
7. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in reducing, preventing progression of, or reversing mental, emotional and
behavioral symptoms of HD.
8. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in prolonging the patient's lifespan.
9. The combination therapy does not produce any significant side effects such as sedation and
depression.
EXAMPLE 8: COMBINATION THERAPY FOR TREATING HUNTINGTON'S DISEASE
Disclosed herein is the use of laquinimod in addition to or in combination with pridopidine for the
treatment of HD.
Periodic oral administration of laquinimod (0.6 mg/day or 1.2 mg/day) in combination with
pridopidine (90 mg once daily or 90 mg twice a day) to a human patient afflicted with HD
provides increased efficacy (provides at least an additive effect or more than an additive effect) in
treating the patient than when pridopidine is administered alone or when laquinimod is
administered alone (at the same dose). The combination therapy also provides efficacy (provides at
least an additive effect or more than an additive effect) in treating the patient without undue
adverse side effects or affecting the safety of the treatment.
The combination therapy provides a clinically meaningful advantage and is more effective
(provides at least an additive effect or more than an additive effect) in treating the patient than
when laquinimod or pridopidine is administered alone (at the same dose) in the following manner:
1. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in improving symptoms of depression, sedation and anxiety.
2. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in slowing, inhibiting or reversing the progression of motor function and
cognitive impairment.
3. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in reducing the severity of motor symptoms including abnormal movements,
myoclonic jerks, irregular movements of extremities, lilting gait, gait disturbances, facial
grimacing, ataxia, and inability to sustain motor act.
4. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in improving the patient's hand movements, gait and balance.
5. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in slowing or preventing deterioration of or improving the patient's motor function as
assessed by the modified motor score (mMS) derived from the Unified Huntington's Disease
Rating Scale Total Motor Score (UHDRS, TMS).
6. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in improving the patient's functional capacity.
7. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in reducing, preventing progression of, or reversing mental, emotional and
behavioral symptoms of HD.
8. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in prolonging the patient's lifespan.
9. The combination therapy does not produce any significant side effects such as sedation and
depression.
EXAMPLE 9 : COMBINATION THERAPY FOR TREATING HUNTINGTON'S DISEASE
Disclosed herein is the use of laquinimod in addition to or in combination with pridopidine for the
treatment of HD.
Periodic oral administration of laquinimod (0.6 mg/day or 1.2 mg/day) in combination with
pridopidine ( 112.5 mg once daily or 112.5 mg twice a day) to a human patient afflicted with HD
provides increased efficacy (provides at least an additive effect or more than an additive effect) in
treating the patient than when pridopidine is administered alone or when laquinimod is
administered alone (at the same dose). The combination therapy also provides efficacy (provides at
least an additive effect or more than an additive effect) in treating the patient without undue
adverse side effects or affecting the safety of the treatment.
The combination therapy provides a clinically meaningful advantage and is more effective
(provides at least an additive effect or more than an additive effect) in treating the patient than
when laquinimod or pridopidine is administered alone (at the same dose) in the following manner:
1. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in improving symptoms of depression, sedation and anxiety.
2. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in slowing, inhibiting or reversing the progression of motor function and
cognitive impairment.
3. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in reducing the severity of motor symptoms including abnormal movements,
myoclonic jerks, irregular movements of extremities, lilting gait, gait disturbances, facial
grimacing, ataxia, and inability to sustain motor act.
4. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in improving the patient's hand movements, gait and balance.
5. The add-on therapy is effective (provides at least an additive effect or more than an additive
effect) in slowing or preventing deterioration of or improving the patient's motor function as
assessed by the modified motor score (mMS) derived from the Unified Huntington's Disease
Rating Scale Total Motor Score (UHDRS, TMS).
6. The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in improving the patient's functional capacity.
The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in reducing, preventing progression of, or reversing mental, emotional and
behavioral symptoms of HD.
The combination therapy is effective (provides at least an additive effect or more than an
additive effect) in prolonging the patient's lifespan.
The combination therapy does not produce any significant side effects such as sedation and
depression.
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What is claimed is:
1. A method of treating a human patient afflicted with a neurodegenerative disorder
comprising periodically administering to the patient an amount of laquinimod and an
amount of pridopidine, wherein the amounts when taken together are effective to treat the
human patient.
2. The method of claim 1, wherein the amount of laquinimod and the amount of pridopidine
when taken together is more effective to treat the human patient than when each agent is
administered alone.
3. The method of claims 1 or 2, wherein each of the amount of laquinimod when taken alone,
and the amount of pridopidine when taken alone is effective to treat the human patient.
4. The method of claims 1 or 2, wherein either the amount of laquinimod when taken alone,
the amount of pridopidine when taken alone, or each such amount when taken alone is not
effective to treat the human patient.
5. The method of any one of claims 1-4, wherein the neurodegenerative disorder is a
polyglutamine disease.
6. The method of any one of claims 1-5, wherein the neurodegenerative disorder is a
proteinopathy.
7. The method of any one of claims 1-6, wherein the neurodegenerative disorder is
Parkinson's disease, Alzheimer's disease, Amyotorphic lateral sclerosis (ALS) or
Huntington's disease.
8. The method of claim 7, wherein the neurodegenerative disorder is Huntington's disease.
9. The method of any one of claims 1-8, wherein the amount of laquinimod and the amount of
pridopidine when taken together is effective to reduce a symptom of the neurodegenerative
disorder in the human patient.
10. The method of claim 9, wherein the symptom is depression, anxiety, motor function
impairment, cognitive impairment, a physical symptom, a mental symptom, an emotional
symptom, a behavioral symptom, impairment of the patient's functional capacity or reduced
lifespan.
11. The method of claim 10, wherein the symptom is motor function impairment.
12. The method of claim 11, wherein the motor function impairment is abnormal movements,
myoclonic jerks, irregular movements of extremities, gait, facial grimacing, ataxia, inability
to sustain motor act, hand movement or balance.
13. The method of claim 11, wherein the patient's motor function is assessed by the modified
motor score (mMS) derived from the Unified Huntington's Disease Rating Scale Total
Motor Score (UHDRS, TMS).
14. The method of claim 13, wherein the patient had an mMS score of 10 or greater at
baseline.
15. The method of any one of claims 1-14, wherein the administration of laquinimod and
pridopidine improves a symptom of the neurodegenerative disorder by at least 20%.
16. The method of claim 15, wherein the administration of laquinimod and pridopidine improves
a symptom of the neurodegenerative disorder by at least 30%.
17. The method of claim 16, wherein the administration of laquinimod and pridopidine improves
a symptom of the neurodegenerative disorder by at least 50%.
18. The method of claim 17, wherein the administration of laquinimod and pridopidine improves
a symptom of the neurodegenerative disorder by more than 100%.
19. The method of claim 18, wherein the administration of laquinimod and pridopidine improves
a symptom of the neurodegenerative disorder by more than 300%.
20. The method of claim 19, wherein the administration of laquinimod and pridopidine improves
a symptom of the neurodegenerative disorder by more than 1000%.
21. The method of any one of claims 1-20, wherein the human patient is receiving laquinimod
therapy prior to initiating pridopidine therapy.
22. The method of claim 21, wherein the administration of laquinimod substantially precedes
the administration of pridopidine.
23. The method of any one of claims 1-22, wherein the human patient is receiving pridopidine
therapy prior to initiating laquinimod therapy.
24. The method of claim 23, wherein the administration of pridopidine substantially precedes
the administration of laquinimod.
25. The method of any one of claims 1-24, wherein laquinimod is laquinimod sodium.
26. The method of any one of claims 1-25, wherein the laquinimod is administered via oral
administration.
27. The method of any one of claims 1-26, wherein the laquinimod is administered daily.
28. The method of any one of claims 1-26, wherein the laquinimod is administered more often
than once daily.
29. The method of any one of claims 1-26, wherein the laquinimod is administered less often
than once daily.
30. The method of any one of claims 1-29, wherein the amount laquinimod administered is
less than 0.6 mg/day.
31. The method of any one of claims 1-29, wherein the amount laquinimod administered is
0.1-40.0 mg/day.
32. The method of claim 31, wherein the amount laquinimod administered is 0.1-2.5 mg/day.
33. The method of claim 32, wherein the amount laquinimod administered is 0.25-2.0 mg/day.
34. The method of claim 33, wherein the amount laquinimod administered is 0.5- 1.2 mg/day.
35. The method of claim 31, wherein the amount laquinimod administered is 0.25 mg/day.
36. The method of claim 31, wherein the amount laquinimod administered is 0.3 mg/day.
37. The method of claim 31, wherein the amount laquinimod administered is 0.5 mg/day.
38. The method of claim 31, wherein the amount laquinimod administered is 0.6 mg/day.
39. The method of claim 31, wherein the amount laquinimod administered is 1.0 mg/day.
40. The method of claim 31, wherein the amount laquinimod administered is 1.2 mg/day.
41. The method of claim 31, wherein the amount laquinimod administered is 1.5 mg/day.
42. The method of claim 31, wherein the amount laquinimod administered is 2.0 mg/day.
43. The method of any one of claims 1-42, wherein pridopidine is administered orally.
44. The method of any one of claims 1-42, wherein pridopidine is administered through an
nasal, inhalation, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal,
buccal, vaginal, rectal, intraocular, intrathecal, topical or intradermal route.
45. The method of any one of claims 1-44, wherein the pridopidine is administered daily.
46. The method of any one of claims 1-44, wherein the pridopidine is administered more often
than once daily.
47. The method of claim 46, wherein the administration of pridopidine is effected twice a
day.
48. The method of any one of claims 1-44, wherein the pridopidine is administered less often
than once daily.
49. The method of any one of claims 1-48, wherein the amount pridopidine administered is 20-
180 mg/day.
50. The method of claim 49, wherein the amount pridopidine administered is 30-120 mg/day.
51. The method of claim 50, wherein the amount pridopidine administered is 45-90 mg/day.
52. The method of claim 51, wherein the amount pridopidine administered is 45 mg/day.
53. The method of claim 51, wherein the amount pridopidine administered is 90 mg/day.
54. The method of any one of claims 1-48, wherein the amount pridopidine administered is
less than 90 mg/day.
55. The method of claim 54, wherein the amount pridopidine administered is less than 45
mg/day.
56. The method of any one of claims 1-55, wherein a loading dose of an amount different form
the intended dose is administered for a period of time at the start of the periodic
administration.
57. The method of claim 56, wherein the loading dose is double the amount of the intended
dose.
58. The method of claim 56, wherein the loading dose is half the amount of the intended
dose.
59. The method of any one of claims 1-58, further comprising administration of an
antidepressant, a psychotropic drug, an antipsychotic, amisulpride, haloperidol, olanzapine,
risperidone, sulpiride, or tiapride.
60. The method of any one of claims 1-59, wherein the periodic administration of laquinimod
and pridopidine continues for at least 3 days.
61. The method of claim 60, wherein the periodic administration of laquinimod and pridopidine
continues for more than 30 days.
62. The method of claim 61, wherein the periodic administration of laquinimod and pridopidine
continues for more than 42 days.
63. The method of claim 62, wherein the periodic administration of laquinimod and pridopidine
continues for 8 weeks or more.
64. The method of claim 63, wherein the periodic administration of laquinimod and pridopidine
continues for at least 12 weeks.
65. The method of claim 64, wherein the periodic administration of laquinimod and pridopidine
continues for at least 24 weeks.
66. The method of claim 65, wherein the periodic administration of laquinimod and pridopidine
continues for more than 24 weeks.
67. The method of claim 66, wherein the periodic administration of laquinimod and pridopidine
continues for 6 months or more.
68. A package comprising
(a) a first pharmaceutical composition comprising an amount of laquinimod and a
pharmaceutically acceptable carrier;
(b) a second pharmaceutical composition comprising an amount of pridopidine and a
pharmaceutically acceptable carrier; and
(c) instructions for use of the first and second pharmaceutical compositions together
to treat a human patient afflicted with a neurodegenerative disease.
69. The package of claim 68, wherein the neurodegenerative disorder is Huntington's disease.
70. The package of claims 68 or 69, wherein the first pharmaceutical composition, the second
pharmaceutical composition, or both the first and the second pharmaceutical composition
are in the form of an aerosol or inhalable powder.
71. The package of claims 68 or 69, wherein the first pharmaceutical composition, the second
pharmaceutical composition, or both the first and the second pharmaceutical composition
are in liquid form.
72. The package of claims 68 or 69, wherein the first pharmaceutical composition, the second
pharmaceutical composition, or both the first and the second pharmaceutical composition
are in solid form.
73. The package of claim 72, wherein the first pharmaceutical composition, the second
pharmaceutical composition, or both the first and the second pharmaceutical composition
are in capsule form.
74. The package of claim 72, the first pharmaceutical composition, the second
pharmaceutical composition, or both the first and the second pharmaceutical composition
are in tablet form.
75. The package of claim 74, wherein the tablets are coated with a coating which inhibits
oxygen from contacting the core.
76. The package of claim 75, wherein the coating comprises a cellulosic polymer, a
detackifier, a gloss enhancer, or pigment.
77. The package of anyone of claims 68-76, wherein the first pharmaceutical composition
further comprises mannitol.
78. The package of anyone of claims 68-77, wherein the first pharmaceutical composition
further comprises an alkalinizing agent.
79. The package of claim 78, wherein the alkalinizing agent is meglumine.
80. The package of anyone of claims 68-79, wherein the first pharmaceutical composition
further comprises an oxidation reducing agent.
The package of anyone of claims 68-77, wherein the first pharmaceutical composition
stable and free of an alkalinizing agent or an oxidation reducing agent.
82. The package of claim 81, wherein the first pharmaceutical composition is free of an
alkalinizing agent and free of an oxidation reducing agent.
83. The package of anyone of claims 68-82, wherein the first pharmaceutical composition is
stable and free of disintegrant.
84. The package of anyone of claims 68-83, wherein the first pharmaceutical composition
further comprises a lubricant.
85. The package of claim 84, wherein the lubricant is present in the composition as solid
particles.
86. The package of claims 84 or 85, wherein the lubricant is sodium stearyl fumarate or
magnesium stearate.
87. The package of anyone of claims 84-86, wherein the first pharmaceutical composition
further comprises a filler.
88. The package of claim 87, wherein the filler is present in the composition as solid
particles.
89. The package of claims 87 or 88, wherein the filler is lactose, lactose monohydrate, starch,
isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose
anhydrouse, or a combination thereof.
90. The package of claim 89, wherein the filler is mannitol or lactose monohydrate.
91. The package of anyone of claims 68-90, further comprising a desiccant.
92. The package of claim 91, wherein the desiccant is silica gel.
93. The package of anyone of claims 68-92, wherein the first pharmaceutical composition is
stable has a moisture content of no more than 4%.
94. The package of anyone of claims 68-93, wherein laquinimod is present in the composition
as solid particles.
95. The package of anyone of claims 68-94, wherein the package is a sealed packaging
having a moisture permeability of not more than 15 mg/day per liter.
96. The package of claim 95, wherein the sealed package is a blister pack in which the
maximum moisture permeability is no more than 0.005 mg/day.
97. The package of claim 96, wherein the sealed package is a bottle.
98. The package of claim 97, wherein the bottle is closed with a heat induction liner.
99. The package of anyone of claims 95-98, wherein the sealed package comprises an HDPE
bottle.
100. The package of anyone of claims 95-99, wherein the sealed package comprises an oxygen
absorbing agent.
101. The package of claim 100, wherein the oxygen absorbing agent is iron.
102. The package of any one of claims 69-101, wherein the amount of laquinimod in the first
composition is less than 0.6 mg.
103. The package of any one of claims 69-102, wherein the amount of laquinimod in the
composition is 0.1-40.0 mg.
104. The package of claim 103, wherein the amount of laquinimod in the first composition is
0.1-2.5 mg.
105. The package of claim 104, wherein the amount of laquinimod in the first composition is
0.25-2.0 mg.
106. The package of claim 105, wherein the amount of laquinimod in the first composition is
0.5-1.2 mg.
107. The package of claim 103 wherein the amount of laquinimod in the first composition is
0.25 mg.
108. The package of claim 103, wherein the amount of laquinimod in the first composition is 0.3
mg.
109. The package of claim 103, wherein the amount of laquinimod in the first composition is 0.5
mg.
110. The package of claim 103, wherein the amount of laquinimod in the first composition is 0.6
mg.
1 1 1. The package of claim 103, wherein the amount of laquinimod in the first composition is 1.0
mg.
11 . The package of claim 103, wherein the amount of laquinimod in the first composition is 1.2
mg.
113. The package of claim 103, wherein the amount of laquinimod in the first composition is 1.5
mg.
114. The package of claim 103, wherein the amount of laquinimod in the first composition is 2.0
mg.
115. The package of any one of claims 68-1 14, wherein the amount pridopidine in the second
composition is 20-180 mg.
116. The package of claim 115, wherein the amount pridopidine in the second composition is
30-120 mg/day.
117. The package of claim 116, wherein the amount pridopidine in the second composition is
45-90 mg/day.
118. The package of claim 117, wherein the amount pridopidine in the second composition is 45
mg/day.
119. The package of claim 117, wherein the amount pridopidine in the second composition is 90
mg/day.
120. The package of any one of claims 68-1 14, wherein the amount pridopidine in the second
composition is less than 90 mg/day.
121. The package of any one of claims 68-1 14, wherein the amount pridopidine in the second
composition is less than 45 mg/day.
122. Laquinimod for use as an add-on therapy or in combination with pridopidine in treating a
human patient afflicted with a neurodegenerative disorder.
123. A pharmaceutical composition comprising an amount of laquinimod and an amount of
pridopidine for use in treating a human patient afflicted with a neurodegenerative
disorder, wherein the laquinimod and the pridopidine are to be administered
simultaneously or contemporaneously.
124. The pharmaceutical composition of claim 123, wherein the neurodegenerative disorder is
Huntington's disease.
1 5. A pharmaceutical composition comprising an amount of laquinimod and an amount of
pridopidine.
126. The pharmaceutical composition of any one of claims 123-125, wherein the
pharmaceutical composition is in the form of an aerosol or inhalable powder.
127. The pharmaceutical composition of any one of claims 123-125, in liquid form.
128. The pharmaceutical composition of any one of claims 123-125, in solid form.
129. The pharmaceutical composition of any one of claims 123-125, in capsule form.
130. The pharmaceutical composition of any one of claims 123-125, in tablet form.
131. The pharmaceutical composition of claim 130, wherein the tablets are coated with a
coating which inhibits oxygen from contacting the core.
132. The pharmaceutical composition of claim 131, wherein the coating comprises a cellulosic
polymer, a detackifier, a gloss enhancer, or pigment.
133. The pharmaceutical composition of anyone of claims 123-132, further comprising
mannitol.
134. The pharmaceutical composition of anyone of claims 123-133, further comprising an
alkalinizing agent.
135. The pharmaceutical composition of claim 134, wherein the alkalinizing agent is
meglumine.
136. The pharmaceutical composition of anyone of claims 123-135, further comprising an
oxidation reducing agent.
137. The pharmaceutical composition of anyone of claims 123-133, which is free of an
alkalinizing agent or an oxidation reducing agent.
138. The pharmaceutical composition of claim 137, which is free of an alkalinizing agent and
free of an oxidation reducing agent.
139. The pharmaceutical composition of anyone of claims 123-138, which is stable and free of
disintegrant.
140. The pharmaceutical composition of anyone of claims 123-139, further comprising a
lubricant.
141. The pharmaceutical composition of claim 140, wherein the lubricant is present in the
composition as solid particles.
142. The pharmaceutical composition of claims 140 or 141, wherein the lubricant is sodium
stearyl fumarate or magnesium stearate.
143. The pharmaceutical composition of anyone of claims 123-142, further comprising a filler.
144. The pharmaceutical composition of claim 143, wherein the filler is present in the
composition as solid particles.
145. The pharmaceutical composition of claims 143 or 144, wherein the filler is lactose,
lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose
spray dried, lactose anhydrouse, or a combination thereof.
146. The pharmaceutical composition of claim 145, wherein the filler is mannitol or lactose
monohydrate.
147. The pharmaceutical composition of any one of claims 123-146, wherein the amount of
laquinimod in the composition is less than 0.6 mg.
148. The pharmaceutical composition of any one of claims 123-146, wherein the amount of
laquinimod in the composition is 0.1-40.0 mg.
149. The pharmaceutical composition of claim 148, wherein the amount of laquinimod in the
composition is 0.1-2.5 mg.
150. The pharmaceutical composition of claim 149, wherein the amount of laquinimod in the
composition is 0.25-2.0 mg.
151. The pharmaceutical composition of claim 150, wherein the amount of laquinimod in the
composition is 0.5-1.2 mg.
152. The pharmaceutical composition of claim 148, wherein the amount of laquinimod in the
composition is 0.25 mg.
153. The pharmaceutical composition of claim 148, wherein the amount of laquinimod in the
composition is 0.3 mg.
154. The pharmaceutical composition of claim 148 wherein the amount of laquinimod in the
composition is 0.5 mg.
155. The pharmaceutical composition of claim 148, wherein the amount of laquinimod in the
composition is 0.6 mg.
156. The pharmaceutical composition of claim 148, wherein the amount of laquinimod in the
composition is 1.0 mg.
157. The pharmaceutical composition of claim 148, wherein the amount of laquinimod in the
composition is 1.2 mg.
158. The pharmaceutical composition of claim 148, wherein the amount of laquinimod in the
composition is 1.5 mg.
159. The pharmaceutical composition of claim 148, wherein the amount of laquinimod in the
composition is 2.0 mg.
160. The pharmaceutical composition of any one of claims 123-159, wherein the amount
pridopidine in the composition is 20-180 mg.
161. The pharmaceutical composition of claim 160, wherein the amount pridopidine in the
composition is 30-120 mg/day.
162. The pharmaceutical composition of claim 161, wherein the amount pridopidine in the
composition is 45-90 mg/day.
163. The pharmaceutical composition of claim 162, wherein the amount pridopidine in the
composition is 45 mg/day.
164. The pharmaceutical composition of claim 162, wherein the amount pridopidine in the
composition is 90 mg/day.
165. The pharmaceutical composition of any one of claims 123-159, wherein the amount
pridopidine in the composition is less than 90 mg/day.
166. The pharmaceutical composition of any one of claims 123-159, wherein the amount
pridopidine in the composition is less than 45 mg/day.
167. Use of an amount of laquinimod and an amount of pridopidine in the preparation of a
combination for treating a human patient afflicted with a neurodegenerative disorder
wherein the laquinimod or pharmaceutically acceptable salt thereof and the pridopidine are
administered simultaneously or contemporaneously.
168. A pharmaceutical composition comprising an amount of laquinimod for use in treating a
subject afflicted with a neurodegenerative disorder as an add-on therapy or in
combination with pridopidine by periodically administering the pharmaceutical
composition and the pridopidine to the subject.
169. A pharmaceutical composition comprising an amount of pridopidine for use treating a
subject afflicted with a neurodegenerative disorder as an add-on therapy or in
combination with laquinimod by periodically administering the pharmaceutical
composition and the laquinimod to the subject.
170. The method of any one of claims 1-48 or 56-67, wherein the amount pridopidine
administered is greater than 135 mg/day.
171. The method of any one of claims 1-48, 56-67, or 170 wherein the amount pridopidine
administered is 180-225 mg/day .
172. The method of any one of claims 1-23, 25-67, or 170-171 wherein the administration of
laquinimod is 0 minutes to 48 hours after the administration of pridopidine.
173. The method of any one of claims 1-23, 25-67, or 170-171 wherein the administration of
laquinimod is 3-5 hours after the administration of pridopidine.
174. The method of any one of claims 1-21, 23-67, or 170-171 wherein the administration of
pridopidine is 0 minutes to 48 hours after the administration of laquinimod.
175. The method of any one of claims 1-21, 23-67, or 170-171 wherein the administration of
pridopidine is 3-5 hours after the administration of laquinimod.
176. A therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted
with a neurodegenerative disorder or presenting a clinically isolated syndrome, which
comprises:
a) one or more unit doses, each such unit dose comprising:
i) an amount of laquinimod and
ii) an amount of pridopidine
wherein the respective amounts of said laquinimod and said pridopidine in said
unit dose are effective, upon concomitant administration to said subject, to treat
the subject, and
a finished pharmaceutical container therefor, said container containing said unit
dose or unit doses, said container further containing or comprising labeling
directing the use of said package in the treatment of said subject.