LAQU3NfMOD FOR REDUCING TEALAMfC DAMAGE fN MULTZPLE SCLEROSIS
This application claims priority of U.S. Provisional Application
No. 6 1 / 7 1 3 , 2 5 6 , filed October 1 2 , 2012, the entire cantent of
which is hereby incorporated by reference herein.
5 Throughout this application, variolas publications are referred t~
by first author and year of publication. Full citations for
these publications are presented in a References section
immediately before the claims. Bi sclosures of the docttlnents and
publications cited and those in the References section are hereby
10 incurporaCed by reference in their entireties into this
application in order to more fully describe the state sf the art
as of the date of the invention described herein.
Multiple Sclerosis ( M S I is a neurological disease affecting more
15 than 1 million people worldwide. It is the most common cause of
neurofogical disability in young and middle-aged adults and has a
major physical, psychological., social and f inancj-al impact on
subjects and their families, friends and bodies responsible f o r
health case (EMEA Guideline, 20061.
Z i j It 1s generally assa-xci that S is medisted by same kind cf
autoimmune process possibly triggered by infection and
superimposed upon a genetic predisposition. It is a chronic
inflammatory condition that damages the myelin of the Central
Nervous System ( C N S ) . The parhogenesis of M5 is characterized by
25 the infiltration of autoreactive T-cells from the circulation
directed against myelin antigens i n t o the CNS (Bjartmar, 2 0 0 2 ) .
In addition to the inflammatory phase in MS, axonal loss occurs
early in the course of the disease and can be extensive over time,
leading to the subsequent development af progressive, permanent,
30 neurologic impairment and, frequently, severe disability (Neuhaus,
20031. Symptoms associated with the disease include fatigue,
spasticity, ataxia, weakness, bladder and bowel disturbances,
sexual dysfunction, pain, tremor, paroxysmal manifestations,
SUsSTITUTE SHEET (RULE 26)
visual impairment, psychological problems and cognitive
dysfunction (EMEA Guideline, 2006) .
MS disease activity can be monitored by magnetic resonance
imaging (MRI) of the brain, accumulation of disability, as well
5 as rate and severity of relapses. The diagnosis of clinically
definite MS as determined by the Poser criteria (Poser, 1983)
requires at least two neurological events suggesting
demyelination in the CNS separated in time and in location. A
clinically isolated syndrome (CIS) is a single monosymptomatic
10 attack suggestive of MS, such as optic neuritis, brain stem
symptoms, and partial myelitis. Patients with CIS that experience
a second clinical attack are generally considered to have
clinically definite MS (CDMS). Over 80 percent of patients with a
CIS and MRI lesions go on to develop MS, while approximately 20
15 percent have a self-limited process (Brex, 2002; Frohman, 2003) .
Various MS disease stages and/or types are described in Multiple
Sclerosis Therapeutics (Duntiz, 1999). Among them, relapsingremitting
MS (RRMS) is the most common form at the time of
initial diagnosis. Many subjects with RRMS have an initial
20 relapsing-remitting course for 5-15 years, which then advances
into the secondary progressive MS (SPMS) disease course.
Relapses result from inflammation and demyelination, whereas
restoration of nerve conduction and remission is accompanied by
resolution of inflammation, redistribution of sodium channels on
25 demyelinated axons and remyelination (Neuhaus, 2003; Noseworthy,
2000).
In April 2001, an international panel in association with the
National MS Society of America recommended diagnostic criteria
for MS. These criteria became known as the McDonald Criteria.
30 The McDonald Criteria make use of MRI techniques and are intended
to replace the Poser Criteria and the older Schumacher Criteria
(McDonald, 2001). The McDonald Criteria was revised in March 2005
by an international panel (Polman, 2005) and updated again in
2010 (Polman, 2011).
Intervention with disease-modifying therapy at relapsing stages
of MS is suggested to reduce and/or prevent accumulating
neurodegeneration (Hohlfeld, 2000; De Stefano, 1999). There are
currently a number of disease-modifying medications approved for
5 use in relapsing MS (RMS), which includes RRMS and SPMS (The
Disease Modifying Drug Brochure, 2006). These include interferon
beta 1-a (Avonex@ and Rebif@), interferon beta 1-b (BetaseronB),
glatiramer acetate (Copaxone@), mitoxantrone (Novantrone@),
natalizumab (TysabriB) and fingolimod (GilenyaB). Most of them
10 are believed to act as immunomodulators. Mitoxantrone and
natalizumab are believed to act as immunesuppressants. However,
the mechanisms of action of each have been only partly elucidated
Immunosuppressants or cytotoxic agents are used in some subjects
after failure of conventional therapies. However, the
15 relationship between changes of the immune response induced by
these agents and the clinical efficacy in MS is far from settled
(EMEA Guideline, 2006) .
Other therapeutic approaches include symptomatic treatment which
refers to all therapies applied to improve the symptoms caused by
20 the disease (EMEA Guideline, 2006) and treatment of acute relapses
with corticosteroids. While steroids do not affect the course of
MS over time, they can reduce the duration and severity of
attacks in some subjects.
Thalamus and Thalamic Damaue
25 The human thalamus is a nuclear complex located in the
diencephalon and comprising of four parts, the hypothalamus, the
epythalamus, the ventral thalamus, and the dorsal thalamus. The
thalamus is a relay centre subserving both sensory and motor
mechanisms. Thalamic nuclei (50-60 nuclei) projects to one or a
30 few well-defined cortical areas. Multiple cortical areas receive
afferents from a single thalamic nucleus and send back
information to different thalamic nuclei. The corticofugal
projection provides positive feedback to the "correct" input,
while at the same time suppressing irrelevant information.
35 Topographical organization of the thalamic afferents and
efferents is contralateral, and the lateralization of the
thalamic function affects both sensory and motoric aspects.
Symptoms of lesions located in the thalamus are closely related
to the function of the areas involved. An infarction or
5 haemorrhage thalamic lesion and develop somatosensory
disturbances and/or central pain in the opposite hemibody,
analgesic or purely algesic thalamic syndrome characterized by
contralateral anaesthesia (or hypaesthesia), contralateral
weakenss, ataxia and, often, persistent spontaneous pain
10 (Trinidad Herrero, 2002). Other diseases and conditions which
have been associated with damage to the thalamus include movement
disorders, dystonia, athetosis, chorea, tremor, jerky, myoclonic
movements, involuntary movements, ataxia, pain, tremor,
spasticity Alzheimer's disease, Huntington's disease, MS and
15 Dejerine-Roussy syndrome (thalamic pain syndrome) (Kim, 2001;
Jong, 2008; Kassubek, 2005; Tuling, 1999; Lee, 1994; Sheline,
2003, Torres, 2010; Stachowiak, 2007).
Laquinimod
Laquinimod is a novel synthetic compound with high oral
20 bioavailability which has been suggested as an oral formulation
for the treatment of 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.
25 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; Bruck, 2011) . Another study demonstrated
(mainly via the NFkB pathway) that laquinimod induced suppression
30 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
35 neurotrophic factor (BDNF) (Runstrom, 2006; Bruck, 2011) .
Laquinimod showed a favorable safety and tolerability profile in
two phase I11 trials (Results of Phase I11 BRAVO Trial Reinforce
Unique Profile of Laquinimod for Multiple Sclerosis Treatment;
Teva Pharma, Active Biotech Post Positive Laquinimod Phase 3
5 ALLEGRO Results).
Summary of the Invention
This invention provides a method for inhibiting or reducing
thalamic damage in a subject afflicted with a form of MS or
presenting a CIS, comprising orally administering to the subject
10 an amount of laquinimod so as to thereby inhibit or reduce
thalamic damage in the subject, wherein the subject is a human
patient who has been determined to have thalamic damage at
baseline.
This invention also provides a method for inhibiting or reducing
15 thalamic damage in a subject afflicted with a disease or disorder
other than a form of MS or a CIS, comprising administering to the
subject an amount of laquinimod so as to thereby inhibit or reduce
thalamic damage in the subject.
This invention also provides a method for inhibiting or reducing
20 tremor or spasticity in a subject afflicted by tremor or
spasticity, comprising administering to the subject an amount of
laquinimod so as to thereby inhibit or reduce the tremor or the
spasticity in the subject,
This invention also provides laquinimod for use in inhibiting or
25 reducing thalamic damage in a human patient who has been
determined to have thalamic damage at baseline.
This invention also provides a pharmaceutical composition
comprising an amount of laquinimod for use in inhibiting or
reducing thalamic damage in a human patient who has been
30 determined to have thalamic damage at baseline.
This invention also provides laquinimod for use in inhibiting or
reducing thalamic damage in a subject afflicted with a disease or
disorder other than a form of MS or a CIS.
This invention also provides a pharmaceutical composition
comprising an amount of laquinimod for use in inhibiting or
reducing thalamic damage in a subject afflicted with a disease or
disorder other than a form of MS or a CIS.
5 This invention also provides laquinimod for use in inhibiting or
reducing thalamic damage in a subject not afflicted with a form of
MS or presenting a CIS.
This invention also provides a pharmaceutical composition
comprising an amount of laquinimod for use in inhibiting or
10 reducing thalamic damage in a subject not afflicted with a form of
MS or presenting a CIS.
This invention also provides laquinimod for use in inhibiting or
reducing tremor or spasticity in a subject.
This invention also provides a pharmaceutical composition
15 comprising an amount of laquinimod for use in inhibiting or
reducing tremor or spasticity in a subject.
B r i e f Description of the Drawinqs
Fiqure 1: Figure 1 is a graph of Patient Disposition from
Example 2. ("For technical reasons, baseline and/or
post-baseline scans from two patients in the
laquinimod arm and three patients in the placebo arm
were not evaluable. These patients were excluded from
this analysis. )
Detailed Description of the Invention
This invention provides a method for inhibiting or reducing
thalamic damage in a subject afflicted with a form of MS or
presenting a CIS, comprising orally administering to the subject
5 an amount of laquinimod so as to thereby inhibit or reduce
thalamic damage in the subject, wherein the subject is a human
patient who has been determined to have thalamic damage at
baseline.
In one embodiment of the present invention, the form of MS is
10 RRMS. In another embodiment, of the present invention, the form
of MS is a progressive form of MS.
In one embodiment, the patient is a naYve patient. In another
embodiment, the patient has previously received at least one MS
therapy.
15 In an embodiment, the subject has been determined to have at least
one thalamic lesion at baseline. In another embodiment, the
thalamic lesion is a T2 thalamic lesion
This invention also provides a method for inhibiting or reducing
thalamic damage in a subject afflicted with a disease or disorder
20 other than a form of MS or a CIS, comprising administering to the
subject an amount of laquinimod so as to thereby inhibit or reduce
thalamic damage in the subject.
In one embodiment of the present invention, the subject is a
human. In another embodiment, the subject is not afflicted with a
25 form of MS and is not presenting a CIS. In yet another embodiment,
the subject is a naYve subject.
In one embodiment, the subject is afflicted with a condition or
disorder which is associated with thalamic damage. In another
embodiment, the subject is afflicted with dystonia, athetosis,
30 chorea, tremor, jerky, myoclonic movements, involuntary
movements, ataxia, pain, tremor or spasticity .
In an embodiment, the subject is afflicted with a movement
disorder and the administration of laquinimod is effective to
treat the subject. In another embodiment, the movement disorder is
dystonia, paroxysmal dystonia, asterixis, chorea, ballism-chorea,
5 myorhythmic movements, dyskinesia, bepharospasm, ataxia, epilepsy,
seizures or convulsions.
In an embodiment, the subject is afflicted with a mood disorder
and the administration of laquinimod is effective to treat the
subject. In another embodiment, the mood disorder is depression,
10 anxiety or bipolar disorder.
In an embodiment, the subject is afflicted with Parkinson's
disease, Alzheimer's disease, schizophrenia or Huntington's
disease and the administration of laquinimod is effective to treat
the subject . In another embodiment, the subject is afflicted with
15 thalamic pain syndrome and the administration of laquinimod is
effective to treat the subject.
In one embodiment, the subject has been determined to have
thalamic damage at baseline. In another embodiment, the thalamic
damage is a thalamic lesion. In another embodiment, the thalamic
20 lesion is a T2 thalamic lesion In another embodiment, the thalamic
damage is measured using MRI.
In one embodiment, the subject is afflicted by tremor or
spasticity. In another embodiment, the subject is a human patient
diagnosed to be afflicted by tremor or spasticity. In another
25 embodiment, the subject is diagnosed to be afflicted by tremor or
spasticity which is treatable by laquinimod. In another
embodiment, the administration of laquinimod is effective to
reduce or inhibit tremor in the subject. In another embodiment,
the administration of laquinimod is effective to reduce or inhibit
30 spasticity in the subject. In yet another embodiment, the subject
has previously suffered a thalamic stroke.
In one embodiment, laquinimod is administered via oral
administration. In another embodiment, laquinimod is administered
periodically. In another embodiment, the periodic administration
is for a period of greater than 24 weeks. In another embodiment,
laquinimod is administered daily. In another embodiment,
laquinimod is administered more often than once daily. In another
embodiment, laquinimod is administered less often than once daily.
5 In one 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 0.3-0.9 mg/day. In another embodiment, the amount
laquinimod administered is 0.5-1.2 mg/day. In another embodiment,
10 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
15 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 yet another
embodiment, the amount laquinimod administered is 2.0 mg/day.
This invention also provides a method for inhibiting or reducing
20 tremor or spasticity in a subject afflicted by tremor or
spasticity, comprising administering to the subject an amount of
laquinimod so as to thereby inhibit or reduce the tremor or the
spasticity in the subject.
In one embodiment, the subject is a human patient afflicted with a
25 form of MS or presenting a CIS. In another embodiment, the subject
is a human patient not afflicted with a form of MS or presenting a
CIS. In another embodiment, the subject is a human patient
diagnosed to be afflicted by tremor or spasticity. In another
embodiment, the subject is afflicted by tremor or spasticity which
30 is treatable by laquinimod.
In one embodiment, the subject has been determined to have
thalamic damage at baseline. In another embodiment, the thalamic
damage is a thalamic lesion. In another embodiment, the thalamic
lesion is a T2 thalamic lesion In another embodiment, the thalamic
35 damage is measured using MRI.
This invention also provides laquinimod for use in inhibiting or
reducing thalamic damage in a human patient who has been
determined to have thalamic damage at baseline.
This invention also provides a pharmaceutical composition
5 comprising an amount of laquinimod for use in inhibiting or
reducing thalamic damage in a human patient who has been
determined to have thalamic damage at baseline.
This invention also provides laquinimod for use in inhibiting or
reducing thalamic damage in a subject afflicted with a disease or
10 disorder other than a form of MS or a CIS.
This invention also provides a pharmaceutical composition
comprising an amount of laquinimod for use in inhibiting or
reducing thalamic damage in a subject afflicted with a disease or
disorder other than a form of MS or a CIS.
15 This invention also provides laquinimod for use in inhibiting or
reducing thalamic damage in a subject not afflicted with a form of
MS or presenting a CIS.
This invention also provides a pharmaceutical composition
comprising an amount of laquinimod for use in inhibiting or
20 reducing thalamic damage in a subject not afflicted with a form of
MS or presenting a CIS.
This invention also provides laquinimod for use in inhibiting or
reducing tremor or spasticity in a subject.
This invention also provides a pharmaceutical composition
25 comprising an amount of laquinimod for use in inhibiting or
reducing tremor or spasticity in a 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
30 and pharmaceutical composition embodiments can be used in the
method and use embodiments described herein.
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,
5 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.
10 Use of laquinimod for treatment of various conditions, and the
corresponding dosages and regimens, are described in U.S. Patent
No. 6,077,851 (MS, insulin-dependent diabetes mellitus, systemic
lupus erythematosus, rheumatoid arthritis, inflammatory bowel
disease, psoriasis, inflammatory respiratory disorder,
15 atherosclerosis, stroke, and Alzhemierr s disease), U. S.
Application Publication No. 2011-0027219 (Crohnr s disease) , U. S.
Application Publication No. 2010-0322900 (Relapsing-remitting
multiple sclerosis), U.S. Application Publication No. 2011-
0034508 (brain-derived neurotrophic factor (BDNF)-related
20 diseases), U.S. Application Publication No. 2011-0218179 (active
lupus nephritis), U.S. Application Publication No. 2011-0218203
(rheumatoid arthritis), U.S. Application Publication No. 2011-
0217295 (active lupus arthritis), and U. S. Application
Publication No. 2012-0142730 (reducing fatigue, improving
25 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,
30 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, flowinducing
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, nontoxic,
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
5 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
10 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
15 and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed.,
1989) ; Pharmaceutical Particulate Carriers : Therapeutic
Applications: Drugs and the Pharmaceutical Sciences, Vol 61
(Alain Rolland, Ed., 1993) ; Drug Delivery to the Gastrointestinal
Tract (Ellis Horwood Books in the Biological Sciences. Series in
20 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.
25 Disclosed is the use of laquinimod for inhibiting or reducing
thalamic damage in a subject, particularly a subject who has
thalamic damage. The ability of laquinimod to inhibit or reduce
thalamic damages was not previously disclosed. In addition, a
method of inhibiting or reducing tremor and spasticity in a
30 subject using laquinimod is disclosed. Previously, it was not
known that laquinimod can inhibit or reduce tremor or spasticity
in a subject.
Terms
As used herein, and unless stated otherwise, each of the
35 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
5 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
10 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 ?lo% of the numerical value or range recited or
claimed.
15 As used herein, "effective" when referring to an amount of
laquinimod and/or pridopidine refers to the quantity of laquinimod
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
20 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
25 or condition, e.g., a pathological condition.
"Treating" as used herein encompasses, e.g., inducing inhibition,
regression, or stasis of a disease or disorder, or lessening,
suppressing, inhibiting, reducing the severity of, eliminating or
substantially eliminating, or ameliorating a symptom of the
30 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 disease or disorder includes any
clinical or laboratory manifestation associated with the disease
or disorder and is not limited to what the subject can feel or
observe.
5 As used herein, "a subject afflicted with" a disease, disorder or
condition means a subject who has been clinically diagnosed to
have the disease, disorder or condition.
As used herein, a subject at "baseline" is as subject prior to
administration of laquinimod.
10 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
15 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/dayU includes 0.1
20 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
25 the claims which follow thereafter.
Experimental Details
In phase I11 ALLEGRO and BRAVO clinical trials of oral laquinimod
it was demonstrated that laquinimod at O.Gmg/day slowed
disability and brain atrophy progression in RRMS patients,
30 suggesting that the drug may have neuroprotective in addition to
anti-inflammatory effects (U.S. Application Publication No. 2012-
0142730; Comi, 2012; Vollmer, 2011). As a small molecule,
laquinimod enters the CNS and interacts with resident
inflammatory cells, including microglia, astrocytes, and
oligodendrocytes. Laquinimod is thought to reduce astrocyte
activation induced by pro-inflammatory cytokines without causing
immunosuppression (Wegner, 2010; Bruck, 2012) .
5 Both the ALLEGRO and the BRAVO trial showed that laquinimod
decreased the rate of whole brain atrophy compared with placebo
(Comi, 2012; Vollmer 2011). However, it was not determined
whether protection from tissue damage is diffuse or limited to a
specific brain compartment.
10 A summary of the ALLEGRO trial is provided in Example 1 below:
EXAMPLE 1: Clinical Trial (Phase 111) - Assessment of Oral
Laquinimod in Preventing Progression of MS
A multinational (24 countries), multicenter (approximately 139
sites), randomized, double-blinded, parallel-group, placebo-
15 controlled clinical trial ("ALLEGRO" or MS-LAQ-301) was conducted
to evaluate the efficacy, safety and tolerability of daily oral
administration of laquinimod 0.6 mg in subjects with RRMS for a
24 months duration.
One thousand one hundred and six (1106) patients were equally
20 randomized to either laquinimod 0.6mg or placebo and treated in a
double-blind manner and baseline characteristics were balanced
between groups. The primary endpoint of the study was the number
of confirmed relapses during the double-blind treatment period,
which corresponds to the annualized relapse rate (ARR - number of
25 relapses divided by total exposure of all patients). Secondary
endpoints included disability as measured by Expanded Disability
Status Scale (EDSS) changes confirmed at 3 months, and cumulative
number of gadolinium enhancing (GdE) and new/enlarging T2 MRI
lesions.
WO 20141058979
Study Duration
Screening phase: 1 month.
Double blind treatment phase: 24 months of once-daily oral
administration of daily dose of 0.6 mg laquinimod or matching
5 placebo.
Upon blinded variance and power reassessment of the population
progression (planned prior to first subject completes the 20
months of treatment), the double blind study duration may be
extended to 30 months. This is planned in order to enhance the
10 statistical power to detect the effect of laquinimod on
disability accumulation. The recommendation to extend the study
duration is based on a pre-defined rule.
Study Design
Eligible subjects were equally randomized 1:l into one of the
15 following treatment arms:
1. Laquinimod capsules 0.6 mg: One 0.6 mg laquinimod capsule
was administered orally once daily. The 0.6 mg laquinimod
capsules contain 0.6 mg of Laquinimod Acid per capsule with
meglumine, and were manufactured according to the method
disclosed in PCT International Application Publication No.
W0/2007/146248, published December 21, 2007 (see, page 10,
line 5 to page 11, line 3).
2. Matching placebo for laquinimod arm: one capsule is
administered once daily.
25 Subjects were evaluated at study sites for 12 scheduled visits of
the double blind phase at months: -1 (screening) , 0 (baseline) , 1,
2, 3, 6, 9, 12, 15, 18, 21 and 24 (termination/early
discontinuation) . In case of the 6 months extended study,
subjects were evaluated at study sites at months 27 and 30
30 (termination/early discontinuation of extended study), in this
case month 24 was a regular scheduled visit.
EDSS was assessed every 3 months, MSFC every 6 months, and MRI
was performed annually in all patients. A subgroup of patients
(n=189) underwent additional MRI scans at months 3 and 6.
Subjects successfully completing the study were offered the
5 opportunity to enter into a 1-year open label extension.
Patients who discontinued the study underwent a final termination
visit and were not further evaluated, except for those who
discontinued due to adverse events.
The following assessments were performed at specified time points:
10 1. Vital signs were measured at each study visit.
2. A physical examination is performed at months -1 (screening),
0 (baseline) 1, 3, 6, 12, 18 and 24 (termination/early
discontinuation core study). In case of the 6 months
extended study, additional examination was performed at
15 month 30 (termination/early discontinuation of extended
study) .
3. The following safety clinical laboratory tests were
performed:
a. Complete blood count (CBC) with differential - at all
scheduled visits. A reticulocyte count was added to
the CBC at months 0 (baseline) and 24/30
(termination/early discontinuation).
b. Serum chemistry (including electrolytes, liver enzymes,
direct and total bilirubin and pancreatic amylase and
CPK), and urinalysis - at all scheduled visits.
c. A rapid urine P-hCG test was performed in women of
child-bearing potential at baseline (month 0) and at
each scheduled study visit thereafter (at site).
d. P-hCG in women of child-bearing potential was
performed at all scheduled visits.
e. Starting after visit Month 3 a rapid urine P-hCG test
was performed in women of child-bearing potential
every 28 (k2) days. The subject was contacted by
telephone within 72 hours after the test was scheduled
to be performed and asked specific questions regarding
the test. In case of suspected pregnancy (positive
urine P-hCG test result), the caller made sure that
the study drug has been discontinued and the subject
was instructed to arrive at the site as soon as
possible with all study drugs.
4. Markers of inflammation (serum conventional C-reactive
protein and fibrinogen) - at screening, baseline and all
scheduled visits thereafter.
5. During the first 3 months periodical phone calls were placed
15 by the site personnel every two weeks. A list of predefined
questions relating to signs/symptoms suggestive of vascular
thrombosis was presented to the subjects.
6. ECG was performed at months -1 (screening; additional
recording, up to 30 minutes apart is performed if QT, is
20 less than 450 msec), (baseline; three recordings, 15 minutes
apart), 1, 2, 3, 6, 12, 18 and 24 (termination/early
discontinuation). In case of the 6 months extended study,
ECG is performed at month 30 (termination/early
discontinuation of the extended study).
25 7. Chest X-ray is performed at months -1 (screening), (if not
performed within 7 months prior to the screening visit).
8. Adverse Events (AEs) are monitored throughout the study.
9. Concomitant medications are monitored throughout the study.
10. Neurological evaluations, including Expanded Disability
30 Status Scale (EDSS), 25 foot walk test/Ambulation Index (AI),
Functional systems (FS) are performed at months -1
(screening), 0 (baseline) and every 3 months during the
study and the extended study period.
11. MS functional Composite (MSFC) was assessed at months -1
(screening) (three practices for training purposes only), at
month 0 (baseline), 6, 12, 18 and 24 (termination/early
discontinuation). In case of the 6 months extended study,
5 the last MSFC was performed at months 30 (termination/early
discontinuation of the extended study).
12. Subject-reported fatigue was assessed by the Modified
Fatigue Impact Scale (MFIS) at months 0, 6, 12, 18, and 24
(termination/early discontinuation). In case of the 6 months
10 extended study, additional MFIS was performed at month 30
(termination/early discontinuation of the extended study).
13. The general health status was assessed by the EuroQoL (EQ5D)
questionnaire at month 0 (baseline) and month 24
(termination/early discontinuation of the study). In case of
15 the 6 months extended study, the last EuroQoL (EQ5D) was
performed at month 30 (termination/early discontinuation of
the extended study) instead of month 24.
14. The general health status was assessed by the Short-Form
general health survey (SF-36) subject-reported questionnaire
20 at month 0 (baseline) and every 6 months thereafter, until
termination/early discontinuation.
15. The subject undewent 5 assessments of binocular low-contrast
visual acuity using the loo%, 2.5% and 1.25% contrast level
charts [Sloan letter or Tumbling-El in each assessment, at
months 0 (baseline), 6, 12, 18 and 24 (termination/early
discontinuation). In case of extending the study for 6
months, additional binocular low-contrast visual acuity
assessment is performed at month 30 (termination/early
discontinuation of the extended study).
30 16. Serum samples were collected from all subjects in order to
investigate the potential mechanism of action of laquinimod
and additional biomarkers of inflammation and potential
biomarkers of MS disease at months: 0, 1, 12 and 24. In
case of extending the study for 6 months the last serum
22
sample is performed at month 30 (termination/early
discontinuation of the extended study) instead of month 24.
17. The subjects underwent 3 MRI scans at months 0 (baseline),
12 and 24 (termination/early discontinuation). In case of
5 the 6 months extended study, an additional MRI was performed
at month 30 (termination/early discontinuation of the
extended study) .
18. Population PK study (PPK) : Blood samples for PPK evaluation
were collected from all subjects at months 1, 12 and 24. In
10 case of extending the study for 6 months the last PPK
evaluation was performed at month 30 (termination/early
discontinuation of the extended study) instead of month 24.
19. Relapses were confirmed/monitored through the study. Since
the "in study" relapse definition must be supported by an
15 objective neurological evaluation, a neurological deficit
must sustain long enough to eliminate pseudo-relapses.
Therefore, in this clinical trial, a relapse was the
appearance of one or more new neurological abnormalities or
the reappearance of one or more previously observed
neurological abnormalities wherein the change in clinical
state lasts at least 48 hours and is immediately preceded by
an improving neurological state of at least thirty (30) days
from onset of previous relapse.
20. The allowed treatment for a relapse was intravenous
25 Methylprednisolone 1 gr/day for up to 5 consecutive days.
Re-consent criteria
Upon a confirmed diagnosis of MS relapse, (as defined in the
protocol) or an increase in EDSS in 22.0 points, sustained for 23
months, the following actions were taken:
30 1. The subject was reminded of the current available MS
medications and the opportunity to terminate the study as
written in the informed consent form.
2. The subject was requested to re-sign an informed consent
form if he/she chooses to continue to participate in the
study, in the same treatment assignment.
Safety stopping rules were set in place for the management of: 1)
5 elevated liver enzymes, 2) inflammatory events, 3) thrombotic
events and 4) pancreatitis.
Ancillary studies:
1. Frequent MRI (selected countries and sites only): The
cumulative number of TI-Gd enhancing lesions taken from
10 scans obtained at months 0, 3, 6, 12, and 24, and in case
the study is be extended, 30. Additional MRIs for the
ancillary study are performed at months 3 and 6.
2. Magnetization Transfer (MT) (selected countries and sites
only): the change from baseline to month 12 and 24/30 months
15 in magnetization transfer MRI. MT was assessed at months 0
(baseline), 12 and 24 (termination/early discontinuation).
In case of the 6 months extended study, the last MT was
performed at month 30 (termination/early discontinuation of
the extended study) instead of month 24.
20 3. Proton MR Spectroscopy ('H-MRS) (selected countries and
sites only): Change from baseline to 24/30 in 'H-MRS
metabolites. 'H-MRS was assessed at months 0 (baseline), and
24 (termination/early discontinuation). In case of the 6
months extended study, the last 'H-MRS was performed at
25 month 30 (termination/early discontinuation of the extended
study) instead of month 24.
4. Pharmacogenetic (PGx) assessment: Blood samples for PGx
parameters were collected from all subjects at screening.
5. Brain atrophy, as defined by the percentage of change from
30 one scan to the subsequent scan in brain volume, in addition
to the measurements done in the main study (Frequent MRI
Cohort) .
6. Whole blood and serum samples (selected countries and sites
only) were collected for evaluation of the immunological
response to treatment with laquinimod and further
investigation of the potential mechanism of action. Whole
blood samples were collected at months: 0, 1, 3, 6, 12 and
24. Serum samples were collected at month: 0, 1, 6, 12 and
24 (even if the study is extended to month 30) .
7. Relationship between PGx and response to laquinimod in terms
of clinical, MRI and safety parameters.
1 0 Incl usion/Excl usion C r i t e r i a
Inclusion Criteria
1. Subjects must have a confirmed and documented diagnosis as
defined by the Revised McDonald Criteria (Polman, 2005),
with relapsing-remitting disease course.
15 2. Subjects must be ambulatory with converted Kurtzke EDSS
score of 0-5.5.
3. Subjects must be in a stable neurological condition and free
of corticosteroid treatment [intravenous (iv), intramuscular
(im) and/or per os (po) 1 30 days prior to screening (month -
20 1) -
4. Subjects must have experienced one of the following:
a. At least one documented relapse in the 12 months prior
to screening.
b. At least two documented relapses in the 24 months
prior to screening.
c. One documented relapse between 12 and 24 months prior
to screening with at least one documented TI-Gd
enhancing lesion in an MRI performed within 12 months
prior to screening.
30 5. Subjects must be between 18 and 55 years of age, inclusive.
6. Subjects must have disease duration of at least 6 months
(from the first symptom) prior to screening.
7. Women of child-bearing potential must practice an acceptable
method of birth control. Acceptable method of birth control
5 in this study include: surgical sterilization, intrauterine
devices, oral contraceptive, contraceptive patch, longacting
injectable contraceptive, partner's vasectomy or
double barrier method (condom or diaphragm with spermicide) .
8. Subjects must be able to sign and date a written informed
10 consent prior to entering the study.
9. Subjects must be willing and able to comply with the
protocol requirements for the duration of the study.
Exclusion Criteria
1. Subjects with progressive forms of MS.
15 2. An onset of relapse, unstable neurological condition or any
treatment with corticosteroids [(iv), intramuscular (im)
and/or per os (po) 1 or ACTH between months -1 (screening)
and 0 (baseline).
3. Use of experimental or investigational drugs, and/or
20 participation in drug clinical studies within the 6 months
prior to screening.
4. Use of immunosuppressive including mitoxantrone (~ovantrone~)
or cytotoxic agents within 6 months prior to screening visit.
5. Previous use of any one of the following: natalizumab
25 ( ~ ~ s a b r i ~cl)a,dr ibine, laquinimod.
6. Previous treatment with glatiramer acetate (copaxoneg)
Interferon-P (either la or lb) or intravenous immunoglobulin
(IVIG) within 2 months prior to screening visit.
7. Systemic corticosteroid treatment of 230 consecutive days
30 duration within 2 months prior to screening visit.
8. Previous total body irradiation or total lymphoid
irradiation.
9. Previous stem cell treatment, autologous bone marrow
transplantation or allogenic bone marrow transplantation.
5 10. A known history of tuberculosis.
11. Acute infection two weeks prior to baseline visit.
12. Major trauma or surgery two weeks prior to baseline.
13. Use of inhibitors of CYP3A4 within 2 weeks prior to baseline
visit (1 month for fluoxetine) .
10 14. Use of amiodarone within 2 years prior to screening visit.
15. Pregnancy or breastfeeding.
16. A 23xULN serum elevation of either ALT or AST at screening.
17. Serum direct bilirubin which is 22xULN at screening.
18. A QTc interval which is 450 msec (according to machine
15 output) obtained from:
a. Two ECG recordings at screening visit, or
b. The mean value calculated from 3 baseline ECG
recordings.
19. Subjects with clinically significant or unstable medical or
20 surgical condition that would preclude safe and complete
study participation, as determined by medical history,
physical examination, ECG, laboratory tests or chest X-ray.
Such conditions may include:
a. A cardiovascular or pulmonary disorder that cannot be
well-controlled by standard treatment permitted by the
study protocol.
b. A gastrointestinal disorder that may affect the
absorption of study medication.
c. Renal or metabolic diseases.
d. Any form of chronic liver disease.
e. Known human immunodeficiency virus (HIV posibtive
status.
f. A family history of Long- QT syndrome.
g. A history of drug and/or alcohol abuse.
h. Major psychiatric disorder.
20. A known history of sensitivity to Gd.
21. Inability to successfully undergo MRI scanning.
10 22. Known drug hypersensitivity that would preclude
administration of laquinimod, such as hypersensitivity to:
mannitol, meglumine or sodium stearyl fumarate.
Outcome Measures
Neurological evaluations, including safety assessments, were
15 performed at screening, baseline and every three months up to
month 24. Patient neurological assessments and general medical
evaluations were conducted by two neurologists in order to
minimize the possibility of unblinding; a specially trained and
certified examining neurologist assessed neurological condition,
20 and the treating neurologist determined whether a subject had
experienced a relapse based on EDSS/Functional Systems scores.
The primary endpoint was the number of confirmed relapses during
the double-blind study period. A relapse was defined as the
appearance of one or more new neurological abnormalities or the
25 reappearance of one or more previously observed neurological
abnormalities lasting for at least 48 hours and after an improved
neurological state for at least 30 days. An event was counted as
a relapse if the subject's symptoms were accompanied by observed
objective neurological changes consistent with at least one of
30 the following: an increase of at least 0.5 in the EDSS score; an
increase of one grade in two or more of the seven functional
systems; or an increase of two grades in one functional system.
Standardized treatment of relapses was intravenous
methylprednisolone lg/day for up to five consecutive days based
5 on the treating neurologistrs decision.
Secondary endpoints were disability progression as measured by
the EDSS and the MSFC. Confirmed disability progression was
defined as an increase of 2 1.0 EDSS point from baseline if
baseline EDSS was between 0 and 5.0, or an increase of 2 0.5
10 point if baseline EDSS was 2 5.5. In order to confirm EDSS
progression, these increases had to be sustained for at least
three months. Additional predefined disability endpoints include
the proportion of patients without confirmed disability
progression at 24 months; confirmed disability progression
15 (defined as change in EDSS scores 2 1.0 points for baseline EDSS
0 to 5.0 or 2 5.5) sustained for six months; the accumulation of
physical disability as measured by mean EDSS and the mean change
in EDSS from baseline to last observed value (LOV).
For the MSFC, the measure was the total MSFC z score at 24 months
20 (including patients who terminated after 12 months). The 9-hole
peg test (9HPT) and the Paced Auditory Serial Addition Test
(PASAT) were performed three times at screening to reduce
confounding training effects during the trial.
MRI related secondary endpoints were the cumulative number of GdE
25 lesions at months 12 and 24; and the cumulative number of new T2
lesions (relative to previous scan) at months 12 and 24; MRI
exploratory endpoints included percent change of brain volume
using SIENA.1°
Additional MRI methodological details are as follows: In all
30 patients, MRI scans were performed at 0, 12, and 24 months.
Before a site could enrol study participants they were required
to image a volunteer patient with definite MS twice with
repositioning according to a strict study imaging protocol using
scanners with a minimum field strength of 1.5T. Fast/turbo spin
35 echo (repetition time [TR] = 2200-3500ms, echo time [TE] = 14-
50/90-120ms, echo train length = 2-7, slice thickness = 3mm, and
contiguous axial slices = 44) sequences were used to obtain
proton density and T2-weighted images. High resolution precontrast
3D TI-weighted sequences (TR = 8-15ms, TE = 3-5ms,
5 inversion time =1.1 s, number of slices 160, slice thickness 1.2
mm, flip angle [FA]= 10-15, orientation sagittal) were acquired
for quantification of brain atrophy. Finally, TI-weighted images
(1.5 T scanners: conventional spin echo sequence; TR = 600-650ms,
TE = 10-20ms, slice thickness = 3mm, and contiguous axial slices
10 = 44; 3.0 T scanners: 3D sequence; TR = 5-9ms, TE = 2-5ms, FA=15,
slice thickness = 3mm, and contiguous axial slices = 44) were
obtained 5 minutes after injection of O.lmmol/kg of gadolinium. A
series of axial, coronal, and sagittal images was obtained to
create an axial reference scan for subsequent careful
15 repositioning of each patient at the follow-up session. Axial
slices were positioned to run parallel to a line joining the most
inferioanterior and inferioposterior parts of the corpus
callosum.
Image quality was reviewed at the MRI-AC using predetermined
20 criteria. The identification of GdE and T2-hyperintense lesions
was done by consensus of two experienced observers. The number of
total and new GdE lesions and new/enlarging T2-hyperintense
lesions were counted. The identified lesions were then outlined
by trained technicians using a semiautomated segmentation
25 technique based on local thresholding (Jim 4.0; Xinapse System,
Leicester, UK) and lesion volumes were calculated automatically.
Percentage brain volume changes and cross-sectional normalized
brain volumes were measured on TI-weighted images, with
Structural Image Evaluation of Normalized Atrophy (SIENA)
30 software and a cross-sectional method (SIENAX) (available from
the FMRIB Software Library, Oxford University, Oxford, UK;
Results
The results of the ALLEGRO trial indicated that laquinimod
35 treatment effectively reduced annualized relapse rates, slowed
the progression of disability, reduced brain atrophy, and reduced
the development of new lesions. The detailed results from ALLEGRO
is disclosed in, e.g., U.S. Application Publication No. 2012-
0142730, which is hereby incorporated by reference in its
5 entirety into this application.
EXAMPLE 2: ALLEGRO Sub-studies
A number of ALLEGRO sub-studies were conducted to further
investigate the potential neuroprotective effects of laquinimod
shown in the ALLERO trial using multiple MRI techniques sensitive
10 to irreversible tissue damage in white matter (WM) and grey
matter (GM) .
Methods
WM, GM, and Thalamic Volume Analysis.
WM, GM, and thalamic volumes were derived from 3D TI-weighted
15 images at baseline and at months 12 and 24. Patients with
baseline and at least one valid scheduled post-baseline MRI were
included in the analysis. Patients with thalamic lesions at
baseline and a valid post-baseline MRI were included in the
thalamic lesion analysis.
20 Evolution of gadolinium-enhancing (GdE) and new T2 lesions into
~ermanent black holes IPBH) .
A subset of patients in ALLEGRO comprised a "frequent MRI" group
for PBH analysis; these patients had MRIs taken at months 3, 6,
12 and 24. Patients in the frequent MRI group with active
25 lesions at baseline or during the study were included in the PBH
analysis.
MT MRI to determine the MT ratio IMTR) of WM, GM, normal
appearing brain tissue (NABT) and T2 lesions.
Patients with valid baseline and month 12, and/or month 24 MT MRI
30 assessments were included in the analysis.
1 H-MRS to evaluate N-acetylaspartate to creatine (NAA/Cr) ratios
in WM.
Patients with baseline and month 24 or study exit 'H-MRS
assessments were included in the analysis.
5 Statistical Analysis.
Efficacy analysis included all patients with at least one valid
post-baseline MRI scan.
Longitudinal WM and GM volume changes were calculated as the
percentage difference from baseline to months 12 and 24. A
10 separate calculation was performed between months 12 and 24.
Since these measures did not follow normal distributional
assumptions, the rank values of these outcomes were analyzed as
follows: a) percentage change from baseline to month 12 and 24
using a mixed model repeated measures (MMRM) (SAS@ PROC MIXED)
15 adjusted to baseline value of the outcome, number of GdE lesions
at baseline, country/geographic region, visit, treatment and
visit by treatment interaction; b) for percentage changes between
months 12 and 24 using a separate ANCOVA model, since the MMRM
model uses the baseline denominator (for % change) and thus %
20 change from month 12 to 24 could not be derived. The ANCOVA (SAS@
PROC GLM) model used treatment group, baseline value of the
outcome, number of GdE lesions at baseline and country/geographic
region, as covariates. Additionally, analyses of percentage
changes in WM volume were also adjusted for GM volume at baseline
25 due to the imbalance that was found between treatment groups at
baseline. The Hodges-Lehmann (HL) large sample median estimator
associated with the ranked values analysis approach was used to
construct two-sided 95% confidence limits for the difference in
treatment effects.
30 Percent thalamic volume changes from baseline to months 12 and 24
followed normal distribution and thus were analysed using a
parametric MMRM (SAS@ PROC MIXED) model corrected for baseline
thalamic volume, number of baseline GdE lesions,
country/geographic region, visit, treatment and visit by
treatment interaction. The least square (LS) mean difference was
used to estimate treatment effect. As noted for the % change in
WM and GM volumes, percent thalamic volume change from month 12
to month 24 was analyzed using a separate analysis of covariance
5 (ANCOVA) (SAS@ PROC GLM) model, since these values could be
derived from the MMRM model. The ANCOVA model used treatment
group, baseline thalamic volume, number of baseline GdE lesions
and country/geographic region, as covariates. GM at baseline was
used as an additional covariate to account for between treatment
10 group imbalance in this measure at baseline.
A negative binomial regression analysis was used to estimate the
mean number of PBH at months 12 and 24 that evolved from GdE and
new T2 leasions detected at various time points in the study in
the "frequent MRI" subgroup.
15 Least squre (LS) mean changes from baseline MTR in NABT, WM, GM
and T2-lesions at months 12 and 24, and between months 12 an 24,
were evaluated using a MMRM analysis.
Changes in NAA/Cr from baseline to month 24 was analyzed using
ANCOVA .
20 Outcomes were assessed using all evaluable scans and all
endpoints were analyzed at a significance level of 5%.
Results
Baseline MRI measures (shown in tables 1 and 2 below) were
comparable between laquinimod and placebo arms for all analysis.
Table 1 : Baseline measures I Layuinimod I Placebo
White matter fraction, mean (SD)
Grey matter fraction, mean (SD)
0.32 (0.04) (n=478)
Thalamic fraction: mean (SD)
0.33 (0.04)
(n=46 1)
0.40 (0.04)
(n=4 7 8)
Thalamic T2 lesions volume, ml, mean
(SD)
p=0.3741*
0.41 (0.04)
(n=46 1)
0.0097 (0.0014)
(n=4 7 6)
Table 2:
GdE lesion number
mean (SD)
T1 hypointense lesions
volume, ml, mean (SD)
T2 lesions volume, ml,
mean (SD)
Normal-appearing brain
tissue MTR, mean (SD)
White matter MTR, mean
(SD)
Grey matter MTR, mean
(SD)
Average MTR of T2
Lesions, mean (SD)
NAAICr, mean (SD)
p=0.0441
0.0098 (0.0015)
(n=45 8)
"2 patients in the laquinimod arm and 3 patients in the placebo arm with missing baseline andlor
5 post-baseline thalamic volume data were excluded from analysis.
0.048 (0.1)
(n=4 7 6)
0.039 (0.08)
(n=45 8)
p=0.3383
PBH sub-study
Laquinim
od
N=55
2.6 (5.8)
Placebo
N=69
1.8 (3.0)
MT MRI sub-study
Laquinim
od
N=38
0.8 (1.6)
'H-MRS sub-study
Placebo
N=37
2.2 (4.3)
Laquinim
od
N=12
0.6 (0.9)
p=0.480
Placebo
N=15
0.6 (1.1)
1.98 (2.38) 1.55 (1.85)
p=0.059
3.45 (6.72)
p=0.914
2.61 (3.78) 1.51 (2.51)
p=0.466
0.71 (0.61)
8.95 (7.50) 7.71 (7.52)
p=0.641
9.81
(12. 7)
p=0.782
9.74 (9.20)
7.60
0.2
p=0.237
4.53 (3.04)
NA NA
p=0.3 17
36.64
(9.65)
p=0.890
35.72
(9.16)
NA
--
NA
NA NA
p=0.73 1
38.79
(9.64)
--
37.95
(9.24)
NA
--
NA
NA NA
p=0.6 18
34.64
(9.47)
--
33.58
(8.94)
NA
--
NA
NA NA
p=0.574
33.74
(9.39)
--
32.35
(8.39)
NA
--
NA
NA NA
p=0.472
--
NA
--
NA 2.79 (0.34) 3.00 (0.44)
p=0.213
WO 20141058979
MRI Outcomes.
WM, GM and thalamic atrophy results are shown i n table 3 below:
1 0 P a t i e n t s treated w i t h laquinimod showed lower p e r c e n t a g e l o s s e s
of WM and GM volume a t month 12 (p=0.004 f o r b o t h ) and
d i f f e r e n c e s a t month 24 w e r e s t a t i s t i c a l l y s i g n i f i c a n t f o r WM,
w h i l e approached s t a t i s t i c a l s i g n i f i c a n c e f o r GM (p=O.035 and
p = 0 . 0 7 8 ) . I n a d d i t i o n , p e r c e n t r e d u c t i o n from b a s e l i n e t h a l a m i c
1 5 volume w a s s i g n i f i c a n t l y lower i n l a q u i n i m o d - t r e a t e d p a t i e n t s a t
months 12 (p=0.005) and 24 (p=0.003) compared w i t h p l a c e b o .
Moreover, f o r p a t i e n t s w i t h t h a l a m i c l e s i o n s a t b a s e l i n e , t h e
t r e a t m e n t e f f e c t of laquinimod on t h a l a m i c f r a c t i o n w a s
s t a t i s t i c a l l y s i g n i f i c a n t a t 12 (p=O.018) and 24 months
20 ( p < 0 . 0 0 0 1 ) , w i t h a s i g n i f i c a n t c o r r e l a t i o n between change i n T2
Table 3:
% Change from baseline to month
12
Placebo (n = 457)
Laquinimod (n = 472)
p value
Treatlllellt effect
% Change from month 12 to
month 24
Placebo (n = 409)
Laquinimod (n = 4 19)
p value
Treatment effect
% Change from baseline to month
24
Placebo (n = 409)
Laquinimod (n = 4 1 8)
p value
Treatment effect
"Hodges-Lehmann median estimate
t h a l a m i c l e s i o n volume and change i n t h a l a m i c f r a c t i o n from
b a s e l i n e t o month 24 (r=-0.184, p<0.001) . However, f o r p a t i e n t s
fLS mean difference.
5 $Evaluable for thalamic volume at month 12: n=468 laquinimod, n = 454 placebo.
SEvaluable for thalamic volume at both month 12 and month 24: n=402 laquinimod, n=400
placebo. 11 Evaluable for thalamic volume at month 24: n=408 laquinimod, n=404 placebo.
White matter
fraction
median (range)
-0.4 (-22.2 to 40.8)
0.0 (-24.7 to 11.9)
p=0.004
0.394"
-0.2 (-21.1 to 10.6)
-0.2 (-15.3 to 15.0)
p=0.857
-0.013"
-0.5 (-25.7 to 39.8)
-0.3 (-27.3 to 19.2)
p=0.035
0.327"
for treatment difference.
Grey matter
fraction
median (range)
-0.8 (-25.3 to 21.1)
-0.3 (-19.4 to 22.4)
p=0.004
0.502"
-0.6 (-14.3 to 32.5)
-0.7 (-1 1.5 to 16.6)
p=0.664
-0.078"
-1.2 (-16.9 to 24.3)
-0.9 (-17.4 to 21.2)
p=0.078
0.372"
Thalamic
fraction
LS mean (SE)
-1.0 (0.12)~
-0.6 (0.12)
p=0.005
0.408'
-0.9 (0.13)~
-0.7 (0.13)
p=O. 13
0.233'
-1.8 (0.15)~~
-1.3 (0.15)
p=0.003
0.60'
without T2 t h a l a m i c l e s i o n s a t b a s e l i n e , t h e t r e a t m e n t e f f e c t of
laquinimod on t h a l a m i c f r a c t i o n change was not s i g n i f i c a n t l y
d i f f e r e n t from t h a t of placebo a t month 12 o r 24.
PBH results a r e shown i n t a b l e 4 below:

The mean number of PBH that developed from only GdE lesions
detected while on treatment was lower with laquinimod vs
placebo at month 12 (from GdE lesions detected at months 3 and
6, risk ratio=0.45, p=0.022) and at month 24 (from GdE lesions
5 at months 3, 6, and 12, risk ratio=O. 44, p=0.005) . A similar
trend was apparent for the mean numbers of PBH at months 12 and
24 that evolved from new T2 lesions in laquinimod vs placebo
comparisons (p=0.030 and p=0.009, respectively) .There was no
difference between placebo and laquinimod at 12 and 24 months
in the number of PBH evolved from GdE lesions present at
baseline. However, if all GdE lesions were included in the
analysis (those detected at baseline and while on treatment),
the mean number of PBH at month 24 was lower with laquinimod vs
placebo (risk ratio=0.45, p=0.001).
15 MT MRI results are shown in table 5 below:
Placebo (N=37)
LS mean (SE) change
(n=37)
-0.09 (0.12)
Laquinimod 0.6 mg (N=38)
LS mean (SE) change
NABT
Baseline to Month 12 (n=38)
0.31 (0.12)
Treatment difference
(95% CI)
Month 12 to Month 24
Treatment difference
Baseline to Month 24
Treatment difference
WM
Baseline to Month 12
Treatment difference
Month 12 to Month 24
Treatment difference
Baseline to Month 24
Treatment difference
-GM
Baseline to Month 12
Treatment difference
Month 12 to Month 24
0.40 (0.09, 0.71) p=0.013
(n=31)
-0.08 (0.14)
(n=32)
-0.18 (0.14)
0.1 0 (-0.31, 0.50) p=0.642
(n=31)
0.23 (0.15)
(n=32)
-0.27 (0.14)
0.50 (0.10, 0.89) p=0.015
(n=38)
0.32 (0.13)
0.40 (0.09, 0.72)
(n=31)
-0.05 (0.1 3)
(n=37)
-0.09 (0.12)
p=0.013
(n=32)
-0.18 (0.13)
0.13 (-0.24, 0.51) p=0.486
(n=31)
0.27 (0.16)
(n=32)
-0.27 (0.15)
0.53 (0.13, 0.94) p=O.OI 1
(n=38)
0.30 (0.13)
0.41 (0.08, 0.74)
(n=31)
-0.16 (0.15)
(n=37)
-0.1 I (0.12)
p=0.014
(n=32)
-0.22 (0.15)
NABT=normal appearing brain tissue; WM=white matter; GM=grey matter; LS=least square;
MTR=magnetization transfer ratio; CI=confidence intervals.
Treatment difference
Baseline to Month 24
Treatment difference
Average MTR of T2 lesions
Baseline to Month 12
Treatment difference
Month 12 to Month 24
Treatment difference
Baseline to Month 24
Treatment difference
LS mean changes in MTR values with placebo decreased from
baseline to months 12 and 24 and between months 12 and 24 for all
5 assessments, MTR values in the laquinimod group increased from
baseline to months 12 and 24 for all MTR outcomes and slightly
decreased from month 12 to month 24 for all assessments except
for T2 lesion, which slightly increased.
Significant differences between treatment arms in LS mean change
10 in MTR values favored laquinimod at months 12 and 24 for NABT
(p=0.013 and p=0.015, respectively), WM (p=0.013 and p=0.011),
and GM (p=0.014 and p=0.034) . Changes in LS mean MTR of T2
lesions did not differ significantly between laquinimod and
placebo patients at any time point. No significant treatment
15 differences were found for any MTR measures between month 12 and
month 24.
0.06 (-0.37, 0.49) p=0.787
'H MRS results :
(n=31)
0.14 (0.16)
At 24 months, WM NAA/Cr ratio tended to increase with laquinimod
and decrease with placebo though the difference was not
20 statistically significant (p - 0.179) in this small patient
population (N=27)
(n=32)
-0.33 (0.16)
0.47 (0.04, 0.90) p=0.034
(n=37)
0.39 (0.25)
0.38 (-0.26,
(n=30)
0.07 (0.24)
(n=37)
0.02 (0.24)
1.01) p=0.239
(n=32)
-0.08 (0.23)
0.15 (-0.51, 0.81) p=0.651
(n=30)
0.46 (0.29)
(n=32)
-0.07 (0.28)
0.53 (-0.23, 1.28) p=0.168
WO 20141058979
Conclusions
Laquinimod reduced brain volume loss in both WM and GM compared
with placebo, with more pronounced effects in the first year of
treatment.
5 Studies suggest thalamic atrophy may be more clinically relevant
than volume loss in the entire GM (Rocca 2010 and Audoin 2006).
Laquinimod significantly reduced thalamic atrophy at 12 and 24
months compared with placebo. Treatment effect was most apparent
in patients with thalamic lesions before beginning laquinimod
10 treatment.
Taken together, these findings, from a variety of MRI techniques,
suggest a neuroprotective effect of oral laquinimod in patients
with RRMS, and are consistent with clinical benefits of
laquinimod shown in the phase I11 ALLEGRO and BRAVO studies (Comi
15 2012 and Vollmer 2011).
EXAMPLE 3: Assessment of Oral Laquinimod in Treating Tremor and
Spasticity
It has been suggested that spasticity or tremor can be caused by
damages to the thalamus, and stimulation of the thalamus can be
20 beneficial for treating tremor and spasticity.
A composition comprising laquinimod as described herein is
administered to a subject afflicted by tremor. The
administration of the composition is effective to inhibit tremor
in the subject.
25 A composition comprising laquinimod as described herein is
administered to a subject afflicted by tremor. The
administration of the composition is effective to reduce tremor
in the subject.
A composition comprising laquinimod as described herein is
30 administered to a subject afflicted by spasticity. The
administration of the composition is effective to inhibit
spasticity in the subject.
A composition comprising laquinimod as described herein is
administered to a subject afflicted by tremor. The
administration of the composition is effective to reduce
spasticity in the subject.
WO 20141058979
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What is claimed is:
1. A method for inhibiting or reducing thalamic damage in a
subject afflicted with a form multiple sclerosis or
presenting a clinically isolated syndrome, comprising orally
administering to the subject an amount of laquinimod so as to
thereby inhibit or reduce thalamic damage in the subject,
wherein the subject is a human patient who has been
determined to have thalamic damage at baseline.
2. The method of claim 1, wherein the form of multiple
sclerosis is relapsing-remitting multiple sclerosis.
3. The method of claim 1, wherein the form of multiple
sclerosis is a progressive form of multiple sclerosis.
4. The method of any one of claims 1-3, wherein the patient is
a naYve patient.
5. The method of any one of claims 1-4, wherein the patient has
previously received at least one multiple sclerosis therapy.
6. The method of any one of claims 1-5, wherein the subject has
been determined to have at least one thalamic lesion at
baseline.
7. The method of claim 6, wherein the thalamic lesion is a T2
thalamic lesion
8. A method for inhibiting or reducing thalamic damage in a
subject afflicted with a disease or disorder other than a
form of multiple sclerosis or a clinically isolated
syndrome, comprising administering to the subject an amount
of laquinimod so as to thereby inhibit or reduce thalamic
damage in the subject.
9. The method of claim 8, wherein the subject is a human.
10. The method of claims 8 or 9, wherein the subject is not
afflicted with a form of multiple sclerosis and is not
presenting a clinically isolated syndrome.
11. The method of any one of claims 8-10, wherein the subject is
a naYve subject.
12. The method of any one of claims 8-11, wherein the subject is
afflicted with a movement disorder and the administration of
laquinimod is effective to treat the subject.
13. The method of claim 12, wherein the movement disorder is
dystonia, paroxysmal dystonia, asterixis, chorea, ataxia,
ballism-chorea, myorhythmic movements , dyskinesia,
bepharospasm, epilepsy, seizures or convulsions.
14. The method of any one of claims 8-13, wherein the subject is
afflicted with a mood disorder and the administration of
laquinimod is effective to treat the subject.
15. The method of claim 14, wherein the mood disorder is
depression, anxiety or bipolar disorder.
16. The method of any one of claims 8-15, wherein the subject is
afflicted with Parkinson's disease, Alzheimer's disease,
schizophrenia or Huntington's disease and the administration
of laquinimod is effective to treat the subject.
17. The method of any one of claims 8-16, wherein the subject is
afflicted with thalamic pain syndrome and the administration
of laquinimod is effective to treat the subject.
18. The method of any one of claims 8-17, wherein the subject has
been determined to have thalamic damage at baseline.
19. The method of any one of claims 1-18, wherein the thalamic
damage is a thalamic lesion.
20. The method of claim 19, wherein the thalamic lesion is a T2
thalamic lesion
21. The method of any one of claims 1-20, wherein the thalamic
damage is measured using Magnetic resonance imaging (MRI).
22. The method of any one of claims 1-21, wherein the subject is
afflicted by tremor or spasticity.
23. The method of any one of claims 1-22, where the subject is a
human patient diagnosed to be afflicted by tremor or
spasticity.
24. The method of claim 23, wherein the subject is diagnosed to
be afflicted by tremor or spasticity which is treatable by
laquinimod.
25. The method of any one of claims 1-24, wherein the
administration of laquinimod is effective to reduce or
inhibit tremor in the subject.
26. The method of any one of claims 1-25, wherein the
administration of laquinimod is effective to reduce or
inhibit spasticity in the subject.
27. The method of any one of claims 1-26, wherein the subject has
previously suffered a thalamic stroke.
28. The method of any one of claims 1-27, wherein laquinimod is
administered via oral administration.
29. The method of any one of claims 1-28, wherein laquinimod is
administered periodically.
30. The method of claim 29, wherein the periodic administration
is for a period of greater than 24 weeks.
31. The method of any one of claims 1-30, wherein laquinimod is
administered daily.
32. The method of any one of claims 1-30, wherein laquinimod is
administered more often than once daily.
33. The method of any one of claims 1-30, wherein laquinimod is
administered less often than once daily.
34. The method of any one of claims 1-33, wherein the amount
laquinimod administered is 0.1-2.5 mg/day.
35. The method of claim 34, wherein the amount laquinimod
administered is 0.25-2.0 mg/day.
36. The method of claim 35 wherein the amount laquinimod
administered is 0.3-0.9 mg/day.
37. The method of claim 35, wherein the amount laquinimod
administered is 0.5-1.2 mg/day.
38. The method of claim 34, wherein the amount laquinimod
administered is 0.25 mg/day.
39. The method of claim 34, wherein the amount laquinimod
administered is 0.3 mg/day.
40. The method of claim 34, wherein the amount laquinimod
administered is 0.5 mg/day.
41. The method of claim 34, wherein the amount laquinimod
administered is 0.6 mg/day.
42. The method of claim 34, wherein the amount laquinimod
administered is 1.0 mg/day.
43. The method of claim 34, wherein the amount laquinimod
administered is 1.2 mg/day.
44. The method of claim 34, wherein the amount laquinimod
administered is 1.5 mg/day.
45. The method of claim 34, wherein the amount laquinimod
administered is 2.0 mg/day.
46. A method for inhibiting or reducing tremor or spasticity in a
subject afflicted by tremor or spasticity, comprising
administering to the subject an amount of laquinimod so as to
thereby inhibit or reduce the tremor or the spasticity in the
subject .
47. The method of claim 46, where the subject is a human patient
afflicted with a form multiple sclerosis or presenting a
clinically isolated syndrome.
48. The method of claim 46, where the subject is a human patient
not afflicted with a form multiple sclerosis or presenting a
clinically isolated syndrome.
49. The method of any one of claims 46-48, wherein the subject is
a human patient diagnosed to be afflicted by tremor or
spasticity.
50. The method of claim 49, wherein the subject is afflicted by
tremor or spasticity which is treatable by laquinimod.
51. Laquinimod for use in inhibiting or reducing thalamic damage
in a human patient who has been determined to have thalamic
damage at baseline.
52. A pharmaceutical composition comprising an amount of
laquinimod for use in inhibiting or reducing thalamic damage
in a human patient who has been determined to have thalamic
damage at baseline.
53. Laquinimod for use in inhibiting or reducing thalamic damage
in a subject afflicted with a disease or disorder other than
a form of multiple sclerosis or a clinically isolated
syndrome.
54. A pharmaceutical composition comprising an amount of
laquinimod for use in inhibiting or reducing thalamic damage
in a subject afflicted with a disease or disorder other than
a form of multiple sclerosis or a clinically isolated
syndrome.
55. Laquinimod for use in inhibiting or reducing tremor or
spasticity in a subject.
56. A pharmaceutical composition comprising an amount of
laquinimod for use in inhibiting or reducing tremor or
spasticity in a subject.