U.S. patent application number 15/646583 was filed with the patent office on 2017-10-26 for dosage regimen of an s1p receptor modulator.
The applicant listed for this patent is Novartis AG. Invention is credited to Craig Boulton, Pascale BURTIN, Olivier DAVID, Ana de VERA, Thomas DUMORTIER, Irene HUNT, Robert SCHMOUDER.
Application Number | 20170304226 15/646583 |
Document ID | / |
Family ID | 43759693 |
Filed Date | 2017-10-26 |
United States Patent
Application |
20170304226 |
Kind Code |
A1 |
Boulton; Craig ; et
al. |
October 26, 2017 |
DOSAGE REGIMEN OF AN S1P RECEPTOR MODULATOR
Abstract
S1P receptor modulators are administered following a dosage
regimen providing a positive benefit-risk profile.
Inventors: |
Boulton; Craig; (Horsham,
GB) ; BURTIN; Pascale; (Huningue, FR) ; DAVID;
Olivier; (Mulhouse, FR) ; de VERA; Ana;
(Basel, CH) ; DUMORTIER; Thomas; (Basel, CH)
; HUNT; Irene; (Basel, CH) ; SCHMOUDER;
Robert; (Berkeley Heights, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novartis AG |
Basel |
|
CH |
|
|
Family ID: |
43759693 |
Appl. No.: |
15/646583 |
Filed: |
July 11, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15152894 |
May 12, 2016 |
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15646583 |
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14176504 |
Feb 10, 2014 |
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15152894 |
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13497349 |
Mar 21, 2012 |
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PCT/US2010/049441 |
Sep 20, 2010 |
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14176504 |
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61246706 |
Sep 29, 2009 |
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61258329 |
Nov 5, 2009 |
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61307992 |
Feb 25, 2010 |
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61352029 |
Jun 7, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 33/487 20130101;
A61P 35/00 20180101; A61P 31/04 20180101; A61P 29/00 20180101; G16H
50/20 20180101; G16H 50/70 20180101; A61P 9/12 20180101; A61P 25/00
20180101; A61B 5/024 20130101; G06F 19/326 20130101; G16H 70/40
20180101; A61P 25/28 20180101; A61P 11/06 20180101; A61P 37/00
20180101; A61P 37/02 20180101; A61P 37/06 20180101; G16H 40/63
20180101; A61B 5/021 20130101; A61K 31/135 20130101; A61K 31/137
20130101; G16H 20/10 20180101; A61K 31/138 20130101; A61B 5/0402
20130101; A61K 45/06 20130101; A61P 27/02 20180101; A61K 31/661
20130101; A61P 9/06 20180101; G16H 50/30 20180101; A61B 5/4833
20130101; A61P 1/16 20180101; A61B 5/444 20130101 |
International
Class: |
A61K 31/135 20060101
A61K031/135; G01N 33/487 20060101 G01N033/487; A61K 45/06 20060101
A61K045/06; A61K 31/661 20060101 A61K031/661; A61K 31/137 20060101
A61K031/137; A61B 5/021 20060101 A61B005/021; A61B 5/00 20060101
A61B005/00; A61B 5/00 20060101 A61B005/00; A61B 5/0402 20060101
A61B005/0402; A61B 5/024 20060101 A61B005/024; G06F 19/00 20110101
G06F019/00; A61K 31/138 20060101 A61K031/138 |
Claims
1. A method for treating an inflammatory or autoimmune disease or
disorder in a patient in need thereof, comprising administering to
said patient a therapeutically effective amount of a S1P receptor
modulator or agonist, in such as way that the adverse events
possibly associated with administering said S1P receptor modulator
or agonist are controlled, limited, reduced or abolished, wherein
said method comprises the steps of i) monitoring the patient during
a specific period of time after the first administration of said
S1P receptor modulator or agonist, wherein said patient monitoring
comprises one or more steps of a) monitoring infections or
infestations, e.g. viral infections, throughout administering said
S1P receptor modulator or agonist, b) performing an ophthalmologic
examination, ii) optionally interrupting the administration of said
S1P receptor modulator or agonist and/or modifying the treatment
regimen thereof.
2. A method of controlling, reducing, or abolishing the possible
adverse events associated with treating a patient suffering from an
inflammatory or autoimmune disease or disorder with a S1P receptor
modulator or agonist, comprising administering to said patient a
therapeutically effective amount of said S1P receptor modulator or
agonist, wherein said method comprises one or more steps of a)
monitoring infections or infestations, e.g. viral infections, and
b) performing an ophthalmologic examination, ii) optionally
interrupting the administration of said S1P receptor modulator or
agonist and/or modifying the treatment regimen thereof.
3. Method according to claim 1 wherein the patient monitoring
further comprises a step of c) monitoring the heart rate of the
patient at least during the first hours after the first
administration of said S1P receptor modulator or agonist, e.g. the
1 to 10 hours after the first administration of said S1P receptor
modulator or agonist.
4. Method according to claim 3 further comprises a step of d)
observing the patient for the 1 to 10 hours after the first
administration of said S1P receptor modulator or agonist to monitor
the heart rate of the patient, e.g. during the first 6 hours.
5. Method according to claim 1 wherein the ophthalmologic
examination is performed at least 3 to 4 months after starting
administration.
6. A method for treating an inflammatory or autoimmune disease or
disorder in a patient in need thereof, comprising administering to
said patient a therapeutically effective amount of S1P receptor
modulator or agonist in such as way that the adverse events
possibly associated with said S1P receptor modulator or agonist are
controlled, limited, reduced or abolished, wherein said method
comprises i) checking specific parameters of the patient before
initiating and/or during administration of said S1P receptor
modulator or agonist, wherein said parameters comprise one or more
of a) signs of infections or infestations, e.g. viral infections,
b) visual acuity c) liver enzymes d) blood pressure and ii) as
necessary, interrupting the administration of said S1P receptor
modulator or agonist and/or modifying the treatment regimen
thereof.
7. Method of claim 7 wherein signs of infections or infestations
are monitored throughout administering said S1P receptor modulator
or agonist.
8. Method of claim 7 wherein visual acuity is monitored at
initiating administration of said S1P receptor modulator or agonist
or within the months preceding the first administration of said S1P
receptor modulator or agonist, e.g. within the 6 months preceding
the first administration of said S1P receptor modulator or
agonist.
9. Method of claim 7 wherein visual acuity is monitored within the
next months following the first administration of said S1P receptor
modulator or agonist, e.g. within the 1 to 12 months following the
first administration of said S1P receptor modulator or agonist.
10. Method of claim 7 further comprising checking the heart rate of
the patient at initiating administration of said S1P receptor
modulator or agonist and optionally within the 1 to 10 hours
following the first administration of said S1P receptor modulator
or agonist.
11. Method according to claim 1 wherein step ii) is performed in
case the monitoring reveals infections or an eyes disease.
12. Method according to claim 1 wherein specific parameters of the
patient are checked before initiating said S1P receptor modulator
or agonist, said parameters being selected from blood analysis
(e.g. complete blood count), liver enzymes, ophthalmologic
examination, electrocardiogram (ECG), pulmonary functions tests,
dermatological examination, and liver function tests.
13. A method according to claim 1 wherein the S1P receptor
modulator or agonist is fingolimod (FTY720), a phosphate derivative
thereof or a pharmaceutically acceptable salt thereof.
14. A method according to claim 20 wherein the S1P receptor
modulator or agonist is administered at a daily dosage not
exceeding about 0.5 mg to the patient, e.g. of about 0.5 mg.
15. A method of controlling, reducing, limiting or abolishing the
possible adverse events associated with a treatment of a patient
suffering from an inflammatory or autoimmune disease or disorder,
wherein said treatment comprises administering a daily dosage of a
drug selected from fingolimod (FTY720), a phosphate derivative
thereof or a pharmaceutically acceptable salt thereof, not
exceeding about 0.5 mg to the patient, such a method comprising
monitoring the patient during a specific period of time after the
first administration of said drug, and if necessary either
interrupting the administration of said drug, either modifying the
treatment regimen thereof and/or administering a second drug which
mitigates said possible adverse events, wherein said monitoring
comprises one or more steps of a) monitoring infections or
infestations, e.g. viral infections, throughout drug
administration, and b) performing an ophthalmologic examination
after starting administration.
16. A method of claim 26, wherein step (b) comprises one or more
steps of i) monitoring infections or infestations, e.g. viral
infections, ii) performing an ophthalmologic examination, e.g. 3 to
4 months after starting drug administration.
17. Method according to claim 23 wherein the adverse events are
selected from bradycardia, atrioventricular conduction
abnormalities, macular edema, skin cancer, altered liver functions,
infections and hypertension.
18. Method of according to claim 1 wherein the patient is
vaccinated before initiating administration of said S1P receptor
modulator or agonist, e.g. vaccinated against viral infection.
Description
[0001] The present invention relates to a dosage regimen of an S1P
receptor modulator or agonist in the course of the treatment of
patients suffering from an inflammatory or autoimmune disease or
disorder, for example multiple sclerosis (MS).
[0002] Multiple sclerosis is the chief cause of neurological
disability in young adults and the most common demyelinating
disorder of the central nervous system. Available therapies such as
interferon-.beta. and glatiramer acetate have modest efficacy and
marginal effects on the progression of disability. These biological
agents are administered parenterally and are associated, e.g., with
injection site reactions and pyretic symptoms, such as flu-like
sypmtoms. Therefore, there is a strong medical need for a safe and
effective oral treatment of multiple sclerosis.
[0003] Of those people with multiple sclerosis who receive
treatment, a significant number continue to experience disease
activity clinically or experience side effects that include
flu-like symptoms, immediate post-injection reactions and injection
site reactions. As a result, a substantial population of patients
are untreated, including many with active disease. These MS
patients have either tried an existing therapy but discontinued due
to intolerance, adverse effects, or perceived lack of efficacy or
have not started any therapy because of their concern with adverse
effects, fear of self-injection, fear of needles, or belief that
currently available options are not effective enough to warrant
trial. Thus, there is a significant unmet need for effective new
therapies in MS, which limit or reduce the possible adverse events
or side effects.
[0004] S1P receptor modulators are compounds which signal as
agonists at one or more sphingosine1-phosphate receptors, e.g. S1P1
to S1P5. Agonist binding to a S1P receptor may e.g. result in
dissociation of intracellular heterotrimeric G-proteins into
G.alpha.-GTP and G.beta..gamma.-GTP, and/or increased
phosphorylation of the agonist-occupied receptor and activation of
downstream signaling pathways/kinases.
[0005] S1P receptor modulators are valuable compounds for the
manufacture of medication for the treatment of various conditions
in mammals, especially in human beings. For example, efficacy in
transplantation has been demonstrated in rats (skin, heart, liver,
small bowel), dogs (kidney), and monkeys (kidney) models. Due to
their immune-modulating potency, S1P receptor modulators are also
useful for the treatment of inflammatory and autoimmune diseases.
Treating such diseases usually requires prolonged taking of
medication, and maintaining the adequate drug regimen over
time.
[0006] Oral fingolimod is the first compound in the new class of
therapeutics called sphingosine 1-phosphate receptor modulators.
Fingolimod is believed to reduce the number of lymphocytes
circulating in the blood stream by reversibly trapping a proportion
of them in the lymph nodes. Consequently, the number of activated
lymphocytes reaching the brain is decreased, resulting in reduced
inflammatory destruction. This is a new mechanism of action for
MS.
[0007] FTY720 efficacy in the treatment of multiple sclerosis has
been shown in humans (e.g. as described in "FTY720 therapy exerts
differential effects on T cell subsets in multiple sclerosis".
Mehling M, et al., Neurology. 2008 Oct. 14; 71(16):1261-7; and
"Oral fingolimod (FTY720) for relapsing multiple sclerosis". Kappos
L, Antel J, Comi G, Montalban X, O'Connor P, Polman C H, Haas T,
Kom A A, Karlsson G, Radue E W; FTY720 D2201 Study Group. N Engl J
Med. 2006 Sep. 14; 355(11):1124-40.).
[0008] Administration of a S1P receptor modulator, such as
fingolimod may induce adverse events, such as a transient reduction
of the heart rate and cardiac conduction at treatment initiation.
In particular it has been described that administration of 1.25 mg
of FTY720 may induce a decrease in heart rate of approximately 8
beets/min ("FTY720: Placebo-Controlled Study of the Effect on
Cardiac Rate and Rhythm in Healthy Patients", Robert Schmouder,
Denise Serra, Yibin Wang, John M. Kovarik, John DiMarco, Thomas L.
Hunt and Marie-Claude Bastien. J. Clin. Pharmacol. 2006; 46;
895.).
[0009] Because of such a possible adverse event, administration of
the compound to the patients may have to be made under full and
constant medical control, in order to check that the cardiac rhythm
is maintained at an acceptable level and no high degree
atrioventricular block occurs. Patients may have to stay in
hospitals which complicate the treatment and increase the costs of
treatment. Occurrence of adverse events during a drug treatment may
induce patient hospitalization or prolongation of existing
hospitalization. Such possible events may also cause the patients
to interrupt their treatment, change the recommended dosing regimen
on their own or take the medication on an irregular basis, without
any medical support or recommendation for doing that. While it is
paramount for treating inflammatory or autoimmune diseases, such as
for example multiple sclerosis, that the adequate medication is
taken over a long period of time, sometimes during the whole life
of the patient, and the adequate drug regimen is kept over such a
long period of time.
[0010] Therefore there is a need to reduce or manage the possible
adverse events which may be generated by administration of such a
S1P receptor modulator, while administering a dosage which is
adequate to treat or prevent the disease for which the compound is
administered during the required period of treatment.
[0011] More specifically, there is a need to provide an efficient
treatment for treating an inflammatory or autoimmune disease or
disorder, such as multiple sclerosis, for a large population of
multiple sclerosis patients, including patients who could be more
exposed or more sensitive to said possible adverse events, patients
who were never treated or diagnosed for an inflammatory or
autoimmune disease or disorder
[0012] There is furthermore a need to ameliorate patient
compliance.
BRIEF DISCLOSURE OF THE INVENTION
[0013] Surprisingly it has been found that by administering a S1P
receptor modulator or agonist, such as fingolimod, according to the
specific dosage regimen or method of treatment of the invention, it
is possible to treat the patient efficiently while controlling,
reducing or abolishing the possible adverse events, e.g. side
effects, which may be associated with administration of such a
compound.
[0014] A further benefit is that the dosing regimen and methods of
treatment of the invention permit to administer a S1P receptor
modulator or agonist, such as fingolimod, to patients who otherwise
may have been reluctant or not could not have been instructed to
take that medication. In particular they permit to treat patients
suffering from an inflammatory or autoimmune disease or disorder,
such as multiple sclerosis, for which the ratio risk/benefit may
otherwise be less favourable. Such patients are for example
patients susceptible to or suffering from one or more disease or
disorders affecting the heart or heart rythme, respiratory
functions, eyes, hepatic functions. This also concerns patients
that have undergone an interruption or treatment holiday in the
maintenance dosage regime e.g. a holiday of greater than 10
days.
[0015] Furthermore the dosing regimen and methods of treatment of
the invention is applicable for patients who were already under
treatment for an inflammatory or autoimmune or disease, for example
under treatment for multiple sclerosis, as well as patients who
were never treated or were not diagnosed for an inflammatory or
autoimmune or disease before taking a S1P receptor modulator or
agonist.
[0016] The dosage regimen of the present invention is a regimen for
a S1P receptor modulator or agonist therapy, which enables
administration of a therapeutic dosage range of the S1P receptor to
be achieved with controlled or minimal side effects, which could
otherwise have been possibly associated with S1P receptor modulator
therapy.
[0017] Another benefit of the present invention is to provide an
therapeutic regimen for an inflammatory or autoimmune or disease,
such as multiple sclerosis, which can be personalized, e.g. adapted
to the specific profile of the patient to be treated and/or to the
state of the disease in this patient, in such as way that that the
disease is treated (or the disease severity is reduced), while the
adverse events which could otherwise have been associated with
administering said S1P receptor modulator or agonist are
controlled, reduced, or abolished. For example, therapeutic regimen
of the present invention may be personalized in view of the other
diseases or disorders the patient could be affected with, the other
medication he could be taken, e.g. depending of whether he is
suffering from a heart disease or disorder.
S1P Receptor Modulators or Agonists
[0018] According to the invention, specific S1P receptor modulators
of the invention are 2-amino-2-tetradecyl-1,3-propanediol. An
example of S1P receptor modulator is fingolimod (FTY720), i.e.
2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or
in a pharmaceutically acceptable salt form, e.g. the hydrochloride,
as shown:
##STR00001##
Another specific S1P receptor modulator of the invention is the
phosphorylated derivative of FTY720, also referred to as
fingolimod-phosphate, as shown:
##STR00002##
[0019] Preferably, the S1P receptor modulator or agonist of the
invention, e.g. fingolimod in free form, in a pharmaceutically
acceptable salt form or fingolimod-phosphate, is administered
orally.
Dosage Regimen
[0020] As previously stated, the present invention provides a new
dosage regimen and method for treating an inflammatory or
autoimmune disease or disorder in a patient in need thereof,
comprising administering to said patient a S1P receptor modulator
or agonist, such as fingolimod (FTY720), a phosphate derivative
thereof or a pharmaceutically acceptable salt thereof, in such a
way that the disease is treated or the disease severity is reduced,
while the adverse events possibly associated with administration of
said S1P receptor modulator or agonist are controlled, limited,
reduced or abolished. For example there is provided a method for
treating an inflammatory or autoimmune disease or disorder in a
patient in need thereof, comprising administering to said patient a
S1P receptor modulator or agonist, such fingolimod (FTY720), a
phosphate derivative thereof or a pharmaceutically acceptable salt
thereof, in such as way that the symptoms of the disease are
reduced or abolished while the adverse events possibly associated
with administration of said S1P receptor modulator or agonist are
controlled, limited, reduced or abolished.
[0021] According to the invention there is provided a method for
administering FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, to a patient in need
thereof preferably refers to a method for treating an inflammatory
or autoimmune disease or disorder, limiting the symptoms associated
thereof or the progression thereof, e.g. multiple sclerosis, in a
patient in need thereof. In particular it refers to a method for
treating RRMS, limiting the symptoms associated thereof or the
progression thereof in a patient in need thereof.
[0022] According to the present invention the terms "treatment" or
"treat" refer to both prophylactic or preventive treatment as well
as curative or disease-modifying treatment, including treatment of
patients at risk of contracting the disease or disorder, or
suspected to have contracted the disease or disorder, as well as
patients who are III or have been diagnosed as suffering from the
disease or disorder.
[0023] Autoimmune diseases or disorders according to the invention
are preferably chronic long term diseases, e.g. multiple sclerosis
(MS), for example relapsing remitting multiple sclerosis (RRMS) or
primary progressive multiple sclerosis (PPMS), e.g. RRMS. MS takes
several forms, with new symptoms occurring either in discrete
attacks (relapsing forms) or slowly accumulating over time
(progressive forms).
[0024] The dosing regimens and methods of treatment according to
the present invention are particularly adapted for multiple
sclerosis, e.g. RRMS.
[0025] As herein defined, treating multiple sclerosis refers to,
but is not limited to, reducing the frequency of clinical
exacerbations or delaying the accumulation of physical disability
induced by multiple sclerosis. It may also refer to limiting the
symptoms of the disease.
[0026] As herein defined, symptoms or disorders associated with
multiple sclerosis encompass neurological symptoms, physical and
cognitive disability and neuropsychiatric disorders.
[0027] As herein defined, adverse event refers to any adverse
change in health that occurs to a patient receiving a treatment or
within a specified period of time after the treatment has been
completed. Controlling the adverse events refers to limiting the
extension, outcome, consequences or impact of such events in such a
way that the patient's health is not a risk, or the treatment can
be continued without worsening the overall health of the patient.
The adverse events are not necessarily related to the medication
itself, they may also be related to the inflammatory or autoimmune
disease or disorder for which the patient is treated or another
disease or disorder that the patient is further affected with.
[0028] According to the invention reduction of the adverse events
refers to the reduction of the events, e.g. of side-effects, to a
level that is acceptable to the patient safety, e.g. which does not
require specific treatment and/or specific medical care,
hospitalization or medical monitoring. For example reduction of the
adverse events refers to the reduction of the events to a level
that is acceptable for the patient compliance.
[0029] According to the invention limitation of the adverse events
refers to limitation of the number or occurrence of adverse events,
e.g. of side-effects, in a patient, to a number or occurrence which
is acceptable to the patient, e.g. which does not require specific
treatment and/or specific medical care, hospitalization or medical
monitoring. For example limitation of the adverse events refers to
limitation of the number or occurrence of adverse events to a
number or occurrence that is acceptable for the patient safety
and/or compliance.
[0030] The monitoring of possible adverse events may be done as
described herein above. For example it may be done by ophthalmic
examination, dermatologic examination, pulmonary function tests,
chest X-ray and/or CT, Holter monitoring, and/or echocardiography.
In a specific embodiment of the invention, the monitoring and
reporting of adverse events comprises the monitoring and reporting
of bradycardia, syncope or pre-syncope, serious infectious, liver
toxicity, and macular edema.
[0031] As herein defined, a patient treated with fingolimod
(FTY720) refers to a patient receiving fingolimod (FTY720), a
phosphate derivative thereof (i.e. fingolimod-phosphate) or a
pharmaceutically acceptable salt thereof, for treating an
inflammatory or autoimmune disease or disorder according to the
invention, e.g. MS, e.g. RRMS.
[0032] As herein defined, a patient in need of prescribing
fingolimod refers to a patient suffering from an inflammatory or
autoimmune disease or disorder according to the invention, e.g. a
MS patient.
[0033] Patients treated with fingolimod (FTY720) and the patients
in need of prescribing fingolimod may be patients who have never
received treatment for an inflammatory or autoimmune disease or
disorder, such as patients who have never received a treatment for
treating or preventing MS, as well as patients who previously
received one or more treatment for an inflammatory or autoimmune
disease or disorder, for example who previously received one or
more treatment for MS.
[0034] The effectiveness of the S1P modulator of the invention in
treating multiple sclerosis may be evaluated by medical standards
and criteria known to the skilled person. For example, it can be
evaluated through annual relapse rate of multiple sclerosis.
[0035] For example, the dosage of the S1P receptor modulator or
agonist of the invention can be considered as efficient for
treating the disease or reducing the symptoms associated thereof,
e.g. for treating multiple sclerosis, when the relapse rate is
decreased by more than 45%, e.g. more than 50%, e.g. more than
60%.
[0036] In another embodiment effectiveness of the S1P receptor
modulator or agonist of the invention in treating multiple
sclerosis is evaluated through the disability progression, e.g.
according to the Kurtzke Expanded Disability Status Scale (EDSS).
The Kurtzke Expanded Disability Status Scale (EDSS) is a method of
quantifying disability in multiple sclerosis. The EDSS quantifies
disability in eight Functional Systems (FS) and allows neurologists
to assign a Functional System Score (FSS) in each of these. For
example, the dosage of the S1P receptor modulator or agonist of the
invention can be considered as efficient for treating the disease
or reducing the symptoms associated thereof, e.g. for treating
multiple sclerosis, when progression of the patient disability is
delayed by at least 25%, e.g. by at least 30%, e.g. by at least
32%.
[0037] The effectiveness of the dosing regimen of the invention may
also be evaluated by measuring brain lesions, e.g. by Magnetic
Resonance Imaging (RMI) scans.
Monitoring
[0038] The present invention provides a dosing regimen and a method
for treating an inflammatory or autoimmune disease or disorder in a
patient in need thereof, comprising administering to said patient a
therapeutically effective amount of a S1P receptor modulator or
agonist, wherein said method comprises the steps of [0039] i)
monitoring the patient during a specific period of time after the
first administration of said S1P receptor modulator or agonist, and
[0040] ii) optionally interrupting the administration of said S1P
receptor modulator or agonist and/or modifying the treatment
regimen thereof and/or administering a second drug which mitigates
said possible adverse events.
[0041] Such a dosing regimen is particularly adapted for
administering fingolimod, e.g. in patient suffering from multiple
sclerosis.
[0042] Furthermore there is provided a S1P receptor modulator or
agonist, e.g. FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, for use in the treatment
of an inflammatory or an autoimmune disease or disorder, e.g.
multiple sclerosis, wherein said treatment comprises the steps of
[0043] i) monitoring the patient during a specific period of time
after the first administration of said S1P receptor modulator or
agonist, and [0044] ii) optionally interrupting the administration
of said S1P receptor modulator or agonist and/or modifying the
treatment regimen thereof and/or administering a second drug which
mitigates said possible adverse events.
[0045] In a specific embodiment, the present invention provides
FTY720, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof, e.g. the hydrocloride salt of FTY720, for
use in the treatment of multiple sclerosis, wherein said treatment
comprises the steps of [0046] i) monitoring the patient during a
specific period of time after the first administration of FTY720, a
phosphate derivative thereof or a pharmaceutically acceptable salt
thereof, and [0047] ii) optionally interrupting the administration
of FTY720, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof, and/or modifying the treatment regimen
thereof, and/or administering a second drug which mitigates said
possible adverse events.
[0048] The present inventions further pertains to a S1P receptor
modulator or agonist, e.g. FTY720, a phosphate derivative thereof
or a pharmaceutically acceptable salt thereof, for use in a method
for treating an inflammatory or an autoimmune disease or disorder,
e.g. multiple sclerosis, wherein said method comprises the steps of
[0049] i) monitoring the patient during a specific period of time
after the first administration of said S1P receptor modulator or
agonist, and [0050] ii) optionally interrupting the administration
of said S1P receptor modulator or agonist and/or modifying the
treatment regimen thereof and/or administering a second drug which
mitigates said possible adverse events.
[0051] In a specific embodiment, the present invention pertains to
FTY720, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof for use in a method for the treatment of
multiple sclerosis, wherein said treatment comprises the steps of
[0052] i) monitoring the patient during a specific period of time
after the first administration of said S1P receptor modulator or
agonist, and [0053] ii) optionally interrupting the administration
of said S1P receptor modulator or agonist and/or modifying the
treatment regimen thereof and/or administering a second drug which
mitigates said possible adverse events.
[0054] According to the invention, the action taken on step ii)
depends on the results obtained under step i).
[0055] When the S1P receptor modulator or agonist is selected from
fingolimod (FTY720), a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, the step of modifying the
treatment regimen may consist of administering a daily dosage of
the drug that is lower than about 0.5 mg and then increasing the
dosage up to a daily dosage of about 0.5 mg. The daily dosage of
the drug may then be increased stepwise, e.g. by titration. It may
also consist of administering a daily dosage of the drug higher
than 0.5 mg, e.g. a daily dosage of about 1.0 mg or about 1.25
mg.
[0056] In a specific embodiment of the invention, e.g. when the S1P
receptor modulator or agonist is selected from fingolimod (FTY720),
a phosphate derivative thereof or a pharmaceutically acceptable
salt thereof, the step of modifying the treatment regimen may
consist of increasing the period of time between two consecutive
administrations of the medication.
[0057] According to the invention, there is provided a patient
monitoring, i.e. a specific monitoring of patients treated with a
S1P receptor modulator or agonist, such as fingolimod (FTY720), a
phosphate derivative thereof or a pharmaceutically acceptable salt
thereof, in order to control, limit or abolish the possible adverse
events, wherein said monitoring is performed before and/or during
administration of the medication.
[0058] The patient monitoring of the invention comprises [0059] a)
monitoring infections or infestations, e.g. viral infections,
throughout administering said S1P receptor modulator or agonist,
and/or [0060] b) performing an ophthalmologic examination.
[0061] The patient monitoring may further comprise one or more
steps of [0062] c) monitoring the heart rate of the patient at
least during the first hours after the first administration of said
S1P receptor modulator or agonist, [0063] d) observing the patient
during the first hours after the first administration of said S1P
receptor modulator or agonist, to monitor the heart rate of the
patient, [0064] e) performing liver function tests, [0065] f)
performing dermatological examinations, [0066] g) performing
pulmonary functions tests.
[0067] The patient monitoring may further comprise one or more
steps of [0068] h) determining complete blood counting (CBC),
[0069] i) lymphocytes counting and/or recording of blood key
parameters, [0070] j) monitoring and/or recording of vital signs,
e.g. heart rate, blood pressure, e.g. arterial blood pressure,
[0071] k) monitoring and/or recording of cardiac disorders, [0072]
l) monitoring and/or recording of other adverse events or
side-effects.
[0073] The invention also provides a dosing regimen and a method of
controlling, reducing, or abolishing the possible adverse events
associated with treating a patient suffering from an inflammatory
or autoimmune disease or disorder with a S1P receptor modulator or
agonist, comprising administering to said patient a therapeutically
effective amount of said S1P receptor modulator or agonist, wherein
said method comprises i) a patient monitoring as defined herein
above, and
ii) optionally interrupting the administration of said S1P receptor
modulator or agonist and/or modifying the treatment regimen
thereof.
[0074] In one embodiment of the invention, the patient monitoring
of the invention may comprise one or more of the following steps,
optionally all the steps of, [0075] complete blood counting (CBC),
[0076] lymphocytes counting, [0077] analysis of liver enzymes,
[0078] monitoring and/or recording of vital signs, e.g. heart rate,
blood pressure, e.g. arterial blood pressure, [0079] testing
history of viral infection or viral serology, e.g. regarding
chickenpox, [0080] monitoring and/or recording of infections or
infestations, e.g. viral infections, [0081] dermatological
examinations, [0082] ophthalmologic examinations, [0083]
examinations of pulmonary function, [0084] monitoring and/or
recording of cardiac disorders, [0085] monitoring and/or recording
of blood key parameters, [0086] monitoring and/or recording of
liver function tests, [0087] monitoring and/or recording of other
adverse events or side-effects.
[0088] Preferably, the patient monitoring of the invention
comprises one or more of the following steps, optionally all the
steps of: [0089] complete blood counting (CBC), [0090] analysis of
liver enzymes, [0091] ophthalmologic examinations, and [0092]
testing history of viral infection or viral serology, e.g.
regarding chickenpox, [0093] monitoring and/or recording of
infections or infestations, e.g. viral infection.
[0094] The patient monitoring of the invention may further comprise
[0095] establishing an electrocardiogram (ECG), e.g. at starting
administration with the medication, and/or [0096] vaccinate the
patient before starting administration, e.g. against varicella
zoster virus (VZV).
[0097] As herein defined, the patient monitoring of the invention
may comprise or more of the above described monitoring steps.
[0098] In one embodiment of the invention, the patient monitoring
comprises the steps of [0099] monitoring and/or recording of
infections or infestations, e.g. viral infections, [0100]
performing ophthalmologic examinations, and optionally further
comprises the steps of [0101] monitoring and/or recording of
cardiac disorders for specific category of patients, and/or [0102]
performing dermatological examinations.
[0103] In another embodiment of the invention, the patient
monitoring comprises the steps of [0104] monitoring and/or
recording of infections or infestations, e.g. viral infections,
[0105] ophthalmologic examinations, [0106] monitoring and/or
recording of cardiac disorders. e.g. for specific category of
patients, [0107] liver function tests; and optionally further
comprises the steps of [0108] dermatological examinations.
[0109] In yet a further embodiment of the invention, the patient
monitoring comprises the steps of [0110] monitoring the heart rate
of the patient, [0111] monitoring and/or recording of infections or
infestations, e.g. viral infections, [0112] performing
ophthalmologic examinations, and optionally further comprises the
steps of [0113] performing dermatological examinations.
[0114] In yet another embodiment of the invention, the patient
monitoring comprises the steps of [0115] monitoring and/or
recording of infections or infestations, e.g. viral infections,
[0116] performing an ophthalmologic examination within the first 1
to 10 after starting administration, [0117] observing patients for
at least 6 hours after the first dose administration, and
optionally further comprises the steps of [0118] dermatological
examinations. The patient monitoring may further comprise a step of
monitoring and/or recording of liver function tests in case
patients develop symptoms suggestive of hepatic dysfunction.
[0119] In a preferred embodiment of the invention, there is
provided a method of prescribing fingolimod (FTY720), a phosphate
derivative thereof or a pharmaceutically acceptable salt thereof,
to a patient in need thereof, in such a way as to limit the
possible adverse events before of during administration of
fingolimod, wherein said method comprises the patient monitoring as
herein above described.
[0120] For example the method of prescribing fingolimod may
comprise one or more of the following steps: [0121] performing
lymphocyte counting, [0122] monitoring and/or recording of vital
signs, e.g. blood pressure, e.g. arterial blood pressure, [0123]
monitoring and/or recording of infections or infestations, e.g.
viral infections, [0124] performing dermatological examinations,
[0125] performing ophthalmologic examinations, [0126] performing
examinations of pulmonary function, [0127] monitoring and/or
recording of cardiac disorders, [0128] monitoring and/or recording
of blood key parameters, e.g. level of serum ALT, [0129] performing
liver function tests, [0130] monitoring and/or recording of other
adverse events or side-effects, and wherein each of said steps is
performed for a specific period of time before and/or during the
period of administering the drug.
[0131] The specific and regular monitoring of the treated patients
may consist of one or more of the following steps [0132] performing
lymphocyte counting, [0133] monitoring and/or recording of vital
signs, e.g. blood pressure, e.g. arterial blood pressure, [0134]
monitoring and/or recording of infections or infestations, e.g.
viral infections, [0135] performing dermatological examinations,
[0136] performing ophthalmologic examinations, [0137] performing
examinations of pulmonary function, [0138] monitoring and/or
recording of cardiac disorders, [0139] monitoring and/or recording
of blood key parameters, e.g. level of serum ALT, [0140] performing
liver function tests, [0141] monitoring and/or recording of other
adverse events or side-effects, and wherein said steps are
performed for a specific period of time before and/or during the
period of administering the drug.
[0142] Each step may be performed as further explained below.
[0143] Preferably, the patient monitoring may consist of one or
more of the following steps: [0144] monitoring and/or recording of
infections or infestations, e.g. viral infections, during FTY720
therapy, [0145] ophthalmologic examinations as herein defined,
[0146] monitoring and/or recording of cardiac disorders for
specific category of patients, [0147] liver function tests in case
patients develop symptoms suggestive of hepatic dysfunction, and
optionally further comprises the steps of [0148] dermatological
examinations.
[0149] The different steps the patient monitoring of the invention
are performed at a specific period of time after administration of
the first dose.
[0150] These steps can be performed as described herein.
[0151] In a specific embodiment of the invention, the treated
patients are monitored under supervision of medical doctors for a
specific period of time after the first dose administration, for
the first 1 to 10 hours after the first administration of the S1P
receptor modulator or agonist, e.g. fingolimod, a phosphate
derivative thereof or a pharmaceutically acceptable salt thereof,
for at least 6 hours after the first dose administration.
[0152] According to the invention, one or more of these steps, e.g.
monitoring and/or recording of cardiac disorders, are performed at
least 4 hours after the first dose administration, e.g. at least
for 6 hours after the first dose administration, or at least 8
hours after the first dose administration, e.g. 3 to 8 hours after
the first dose administration, e.g. 4 to 6 hours after the first
dose administration, e.g. 4 to 6 hours after the first dose
administration. Preferably monitoring and/or recording of cardiac
disorders are performed about 6 hours after the first dose
administration The step of monitoring and/or recording of cardiac
disorders may consist of observing patients during that period of
time after the first dose administration, e.g. during at least 4
hours after the first dose administration, e.g. at least for 6
hours after the first dose administration, or at least 8 hours
after the first dose administration.
[0153] According to the invention, the cardiac disorders which are
monitored and/or recorded comprise but are not limited to
bradycardia and high-grade AV block.
[0154] According to the invention, the infections which are
recorded or monitored are for example viral infections, e.g.
varicella zoster virus (VZV), influenza viral infection, herpes
viral infection, lower respiratory tract infection, e.g. bronchitis
and pneumonia.
[0155] In an embodiment of the invention, the monitoring of
infections or infestations is performed within the first three
months after the first dose administration, e.g. within the first
two months after the first dose administration. In another
embodiment of the invention, the monitoring of infections or
infestations is performed throughout administration of the
medication.
[0156] Prior to starting administering the S1P receptor modulator
or agonist, the patient may be tested for history of infections,
e.g. viral infection, in particular chickenpox. In case the
searched serology is negative, the patient may be vaccinated, e.g.
against varicella zoster virus or influenza virus.
[0157] The monitoring or recording of infections or infestations,
e.g. viral infections, may be performed with medical techniques
available, for example through complete blood counting (CBC) and/or
lymphocytes counting.
[0158] According to the invention, the ophthalmologic examination
preferably comprises the checking and/or monitoring of disturbances
in visual acuity, e.g. appearance of macular edema.
[0159] In a specific embodiment of the invention, eye examinations
include at least one of eye history, visual acuity, dilated
ophthalmoscopy, Optical Coherence Tomography (OCT), evaluation of
the fundus. Such examinations are preferably performed by an
ophthalmologist.
[0160] According to the invention, ophthalmologic examination may
be performed after initiating the administration with S1P receptor
modulator or agonist, e.g. after commencing FTY720 therapy, e.g.
within the first 1 to 12 months, e.g. 2 to 10 months, e.g. 2 to 6
months, e.g. 2 to 5 months, e.g. 3 to 4 months. Additional
ophthalmologic examinations may be performed as needed based on
patient symptoms, e.g. at intervals determined by the
ophthalmologist.
[0161] According to the invention, the ophthalmologic examination
may comprising the steps of [0162] 1) identifying the eye diseases
history of the patient to be treated before commencing the
treatment with FTY720, [0163] 2) having ophthalmologic examinations
performed as herein above mentioned, e.g. 3 to 4 months after
commencing the treatment with FTY720, preferably by an
ophthalmologist, and optionally [0164] 3) having additional
ophthalmologic examinations performed based on patient symptoms,
e.g. at intervals determined by the ophthalmologist.
[0165] Ophthalmologic examination may also be performed before
starting the administration with S1P receptor modulator or agonist,
e.g. before starting FTY720 therapy. This embodiment is
particularly adapted for specific patients categories, for example
in case of patients who have an eyes disease or disorder, and/or
history of diabetes or uveitis.
[0166] According to the invention, the dermatological examination
may comprise the checking of appearance e.g. of neoplasms, skin
malignancies, melanoma, squamous cell carcinoma, basal cell
carcinoma. Dermatological screening may be performed prior to, or
shortly after initiation of therapy. In a specific embodiment of
the invention, dermatological screenings are performed annually in
patient receiving the S1P receptor modulator or agonist, e.g.
FTY720, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof.
[0167] Dermatological screening may be performed by a physician,
e.g. a dermatologist. In another embodiments, such screening is
performed more frequently, e.g. by the patient himself.
[0168] According to the invention, the examinations of pulmonary
function may be performed by spirometry, pulmonary function tests,
e.g. FEV1, FVC, FEF25-75%, DLCO, diffusion capacity for carbon
monoxide, or chest high resolution computed tomography (HRCT).
[0169] In a specific embodiment of the invention the pulmonary
function test (PFT) is performed a few hours to a few days after
the first administration, for example at the day of the first
administration, for example from 2 to 12 hours after the first drug
administration, for example from 2 to 8 hours after the first drug
administration, for example from 2 to 6 hours after the first
administration, for example at 6-hour after the first
administration. A second PFT may be performed a few days after the
first administration, for example from 2 to 10 days after the first
drug administration, for example from 3 to 8 days first drug
administration, for example abut a week after the first drug
administration.
[0170] In a specific embodiment of the invention the level of liver
enzyme, e.g. serum ALT, is evaluated at initiation of therapy and
optionally periodically thereafter. Continuous evaluation is
particularly adapted in case of patients who develop symptoms
suggestive of hepatic dysfunction.
[0171] According to the invention, the liver function tests may be
performed for specific category of patients, e.g. patients who
develop symptoms suggestive of hepatic dysfunction, e.g. nausea,
vomitting, abdominal pain, anorexia, or jaundice.
[0172] According to the invention, monitoring and/or recording of
liver function tests may comprise any one of the steps of [0173] 1)
identifying the level of liver enzyme, e.g. serum ALT, in the
patient to be treated before the first administration of the S1P
receptor modulator or agonist, e.g. FTY720, a phosphate derivative
thereof or a pharmaceutically acceptable salt thereof, and
administering the first dose only if alanine aminotransferase (ALT)
level is not more than 2 times the upper limit of the normal range
(ULN), [0174] 2) identifying the level of liver enzyme, e.g. serum
ALT, in the patient under therapy, and discontinue the therapy in
patients experiencing jaundice or elevation of liver enzyme is more
than 5 times the upper limit of the normal range (ULN).
[0175] The patient monitoring of the invention may comprise a step
of observing the patient for the first 1 to 10 hours after the
first administration of the S1P receptor modulator or agonist, e.g.
fingolimod, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof, e.g. the first 2 to 8 hours after the
first administration, e.g. the first 3 to 9 hours after the first
administration, e.g. the first 2 to 8 hours after the first
administration, e.g. the first 4 to 7 hours after the first
administration, e.g. the first 6 hours, e.g. the first 5 hours,
e.g. the first 4 hours after the first administration of said S1P
receptor modulator or agonist, e.g. fingolimod, a phosphate
derivative thereof or a pharmaceutically acceptable salt thereof.
For example, the patient monitoring of the invention may comprise a
step of observing the patient at least 2 hours after the first
administration of said S1P receptor modulator or agonist, e.g.
fingolimod, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof, e.g. at least 4 hours after the first
administration, e.g. at least 6 hours after the first
administration.
[0176] According to the present invention, there is provided a
method for treating an inflammatory or autoimmune disease or
disorder in a patient in need thereof, comprising administering to
said patient a therapeutically effective amount of S1P receptor
modulator or agonist, wherein specific parameters of the patient
are checked before initiating said treatment, and if necessary, the
treatment regimen is adapted and/or a second drug which mitigates
the adverse events which could possibly occur.
[0177] The invention further pertains to a S1P receptor modulator
or agonist, e.g. FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, for use in a method of
treating an inflammatory or an autoimmune disease or disorder, e.g.
multiple sclerosis, wherein said method comprises the steps of
checking specific parameters of the patient before initiating said
treatment, and If necessary adapting the treatment regimen thereof
and/or administering a second drug which mitigates the adverse
events which could possibly occur.
[0178] Said parameters are selected from signs of infections or
infestations (e.g. viral infections), visual acuity, presence of
eye disease, liver enzymes, blood pressure, blood analysis (e.g.
complete blood count), electrocardiogram (ECG), pulmonary function,
presence of skin disease or disorder, and liver function.
[0179] In a specific embodiment, these parameters are selected from
signs of infections or infestations (e.g. viral infections), visual
acuity, liver enzymes and blood pressure, and optionally heart
rate.
[0180] For example, a ECG is performed before initiating
administration with said S1P receptor modulator or agonist.
[0181] These parameters may also be checked throughout the
treatment with said S1P receptor modulator or agonist.
[0182] In a specific embodiment of the invention there is provided
[0183] 1--a method for administering a S1P receptor modulator or
agonist, e.g. fingolimod, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, in a patient in need
thereof, comprising the steps of [0184] a.) identifying the eye
diseases history of the patient to be treated before commencing the
treatment with said S1P receptor modulator or agonist, [0185] b.)
having ophthalmologic examinations performed as herein above
mentioned, e.g. 3 to 4 months after commencing the treatment with
said S1P receptor modulator or agonist, preferably by an
ophthalmologist, and optionally [0186] c.) having additional
ophthalmologic examinations performed based on patient symptoms,
e.g. at intervals determined by the ophthalmologist. [0187] 2--A
method for treating an inflammatory or autoimmune disease or
disorder (for example multiple sclerosis), and limiting the
symptoms associated thereof or reducing the severity of the
disease, in a patient in need thereof, comprising the steps a.),
b.) and c.) as defined above. [0188] 3--a S1P receptor modulator or
agonist, e.g. FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, for use in a method for
treating an inflammatory or an autoimmune disease or disorder, e.g.
multiple sclerosis, wherein said method comprises the steps a.),
b.) and c.) as defined above. [0189] 4--a S1P receptor modulator or
agonist, e.g. FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, for use in the treatment
of an inflammatory or an autoimmune disease or disorder, e.g.
multiple sclerosis, wherein said treatment comprises the steps a.),
b.) and c.) as defined above. [0190] 5--FTY720, a phosphate
derivative thereof or a pharmaceutically acceptable salt thereof,
e.g. the hydrochloride salt of FTY720, for use in a method for the
treatment of multiple sclerosis, wherein said treatment comprises
the steps of [0191] a.) identifying the eye diseases history of the
patient to be treated before commencing the treatment with FTY720,
phosphate derivative or pharmaceutically acceptable salt thereof,
[0192] a.) having ophthalmologic examinations performed as herein
above mentioned, e.g. 3 to 4 months after commencing the treatment
with FTY720, phosphate derivative or pharmaceutically acceptable
salt thereof, preferably by an ophthalmologist, and optionally
[0193] b.) having additional ophthalmologic examinations performed
based on patient symptoms, e.g. at intervals determined by the
ophthalmologist. [0194] 6--FTY720, a phosphate derivative thereof
or a pharmaceutically acceptable salt thereof, e.g. the
hydrochloride salt of FTY720, for use in the treatment of multiple
sclerosis, wherein said treatment comprises the steps a'.), b'.)
and c'.) as defined above.
[0195] In a specific embodiment of the invention there is provided
[0196] 7--A method for administering a S1P receptor modulator or
agonist, e.g. fingolimod, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, in a patient in need
thereof, comprising the steps of [0197] d) identifying the level of
liver enzyme, e.g. serum ALT, in the patient to be treated before
the first administration of said S1P receptor modulator or agonist,
and administering the first dose only if ALT level is not
>2.times.ULN, and [0198] e) identifying the level of liver
enzyme, e.g. serum ALT, in the patient under therapy, and
discontinue the therapy in patients experiencing jaundice or
elevation of liver enzyme >5.times.ULN. [0199] 8--A method for
treating an inflammatory or autoimmune disease or disorder (for
example multiple sclerosis), and limiting the symptoms associated
thereof or reducing the severity of the disease, in a patient in
need thereof, comprising the steps d.), and e.) as defined above.
[0200] 9--A S1P receptor modulator or agonist, e.g. FTY720, a
phosphate derivative thereof or a pharmaceutically acceptable salt
thereof, for use in a method for treating an inflammatory or an
autoimmune disease or disorder, e.g. multiple sclerosis, wherein
said method comprises the steps d.), and e.) as defined above.
[0201] 10--A S1P receptor modulator or agonist, e.g. FTY720, a
phosphate derivative thereof or a pharmaceutically acceptable salt
thereof, for use in the treatment of an inflammatory or an
autoimmune disease or disorder, e.g. multiple sclerosis, wherein
said treatment comprises the steps d.), and e.) as defined above.
[0202] 11--FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, e.g. the hydrochloride
salt of FTY720, for use in a method for the treatment of multiple
sclerosis, wherein said method comprises the steps of [0203] d')
identifying the level of liver enzyme, e.g. serum ALT, in the
patient to be treated before the first administration of FTY720, a
phosphate derivative thereof or a pharmaceutically acceptable salt
thereof, and administering the first dose only if ALT level is not
>2.times.ULN, and [0204] e') identifying the level of liver
enzyme, e.g. serum ALT, in the patient under therapy, and
discontinue the therapy in patients experiencing jaundice or
elevation of liver enzyme >5.times.ULN [0205] 12--FTY720, a
phosphate derivative thereof or a pharmaceutically acceptable salt
thereof, e.g. the hydrochloride salt of FTY720, for use in the
treatment of multiple sclerosis, wherein said treatment comprises
the steps d'.), and e'.) as defined above.
[0206] In yet another embodiment of the invention there is provided
[0207] 13--A method for administering a S1P receptor modulator or
agonist, e.g. FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, in a patient in need
thereof and receiving concomitant beta-blocker therapy, comprising
the steps of [0208] f) measuring heart rate and/or blood pressure
of the patient to be treated before commencing the treatment with
said S1P receptor modulator or agonist, [0209] g) either measuring
heart rate every 3 to 5 hour, e.g. every four hour, for at least 6
hour hereafter, and/or perform an ECG 3 to 6 hours, e.g. 4 to 6
hours, post-dose, and [0210] h) administering an adequate treatment
if bradyarrhythmia-related symptom is seen under step g), e.g.
atropine or isoprenaline.
[0211] In one embodiment, that method refers to a method for
administering FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, e.g. the hydrochloride
salt of FTY720, in a patient affected by multiple sclerosis. [0212]
14--A method for treating an inflammatory or autoimmune disease or
disorder (for example multiple sclerosis), and limiting the
symptoms associated thereof or reducing the severity of the
disease, in a patient in need thereof, comprising the steps f.),
g.) and h.) as defined above. [0213] 15--A S1P receptor modulator
or agonist, e.g. FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, for use in a method for
treating an inflammatory or an autoimmune disease or disorder, e.g.
multiple sclerosis, wherein said method comprises the steps f.),
g.) and h.) as defined above. [0214] 16--A S1P receptor modulator
or agonist, e.g. FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, for use in the treatment
of an inflammatory or an autoimmune disease or disorder, e.g.
multiple sclerosis, wherein said treatment comprises the steps f.),
g.) and h.) as defined above. [0215] 17--FTY720, a phosphate
derivative thereof or a pharmaceutically acceptable salt thereof,
e.g. the hydrochloride salt of FTY720, for use in a method for the
treatment of multiple sclerosis, wherein said method comprises the
steps of [0216] f') measuring heart rate and/or blood pressure of
the patient to be treated before commencing the treatment with
FTY720, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof, [0217] g') either measuring heart rate
every 3 to 5 hour, e.g. every four hour, for at least 6 hour
hereafter, and/or perform an ECG 3 to 6 hours, e.g. 4 to 6 hours,
post-dose, and [0218] h') administering an adequate treatment if
bradyarrhythmia-related symptom is seen under step g), e.g.
atropine or isoprenaline. [0219] 18--FTY720, a phosphate derivative
thereof or a pharmaceutically acceptable salt thereof, e.g. the
hydrochloride salt of FTY720, for use in the treatment of multiple
sclerosis, wherein said treatment comprises the steps of f.), g'.)
and h'.) as defined above.
[0220] In yet another embodiment of the invention there is provided
[0221] 19--A method for administering a S1P receptor modulator or
agonist, e.g. FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, in a patient in need
thereof, comprising the steps of [0222] i) observing the patient
after the first dose administration for an observing period as
defined hereinabove, e.g. for at least 6 hours [0223] j) measuring
heart rate of the patient after this period, [0224] k) either
releasing the patient if the if the is >40 bpm, or of 40-60 bpm
e.g. in case this value is not the lowest heart rate measured
during the 6-hour observation period; or maintaining the patient in
an appropriate setting.
[0225] Such a method is particularly adapted to patients with low
resting heart rate (e.g. lower than 50) or those taking beta
blockers, or having high grade atrio-ventricular (AV) block or
sick-sinus syndrome.
[0226] In a specific embodiment, that method refers to a method for
administering FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, e.g. the hydrochloride
salt of FTY720, in a patient affected by multiple sclerosis.
[0227] The present invention also provides [0228] 20--FTY720, a
phosphate derivative thereof or a pharmaceutically acceptable salt
thereof, e.g. the hydrochloride salt of FTY720, for use in the
treatment of multiple sclerosis, wherein said treatment comprises
the steps i.), j.) and k.) as defined above. [0229] 21--FTY720, a
phosphate derivative thereof or a pharmaceutically acceptable salt
thereof, e.g. the hydrochloride salt of FTY720, for use in a method
of treating multiple sclerosis, wherein said method comprises the
steps i.), j.) and k.) as defined above.
[0230] In specific cases, e.g. when patients experiencing
symptomatic events associated with braddyarrythmia not resolved by
the end of the 6 hour observation, day 2 dose may also be performed
with an observation period like the first administration, e.g. as
described above.
[0231] An observation period as defined hereinabove, e.g. 6 hour
observation, may also be performed in case of a patient restarting
the S1P receptor modulator or agonist, e.g. FTY720, a phosphate
derivative thereof or a pharmaceutically acceptable salt thereof,
after a drug interruption of more than 4 days, e.g. more than 6
days, e.g. more than 8 days, e.g. more than 10 days, e.g. more than
12 days, e.g. more than 14 days, e.g. more than 18 days, e.g. more
than 21 days.
[0232] In another embodiment of the invention, there is provided a
method for administering FTY720, a phosphate derivative thereof or
a pharmaceutically acceptable salt thereof, to a patient in need
thereof while controlling, limiting or abolishing the possible
adverse events associated or in relation to such an administering,
wherein the patients at possible risk of showing such events are
identified before administering the drug and specific and regular
monitoring of the treated patients is performed, e.g. by an
adequate physician.
[0233] The patients at possibly increased risk may be patients
selected from patients who have eyes diseases or disorders;
patients who show a high ALT level, patients who have hepatic
dysfunction, patients who have hypertension; and patients who have
heart failure or arrythmias. It may also concern patient affected
by asthma, for example moderate asthma and/or diabetic
patients.
[0234] In another embodiment, it can be pregnant women.
[0235] As herein defined, an eyes disease or disorder refers to a
disease or disorder impacting eyes, e.g. uveitis, diabetes.
[0236] Patients who show a high ALT level refers to patients who
show an ALT level of, or superior to, 2 times than ULN, e.g. before
initiating FTY720 treatment)
[0237] Patients who have heart disorders refers to one or more
disorders selected from high-grade AV block, sick sinus syndrome,
ischeamic heart disease, congestive heart failure, and arrhythmia.
For example, this concerns patients suffereing from or at risk of
bradyarrhythmia, patients with high grade atrio-ventricular blocks
or sick sinus syndrome, patients with a history of syncopal
episodes, or patients under beta blockers or anti-arrhythmic
treatment, such as patients under anti-arrhythmic drugs.
[0238] According to the invention, there is provided a specific
monitoring of patients treated with a S1P receptor modulator or
agonist, e.g. FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, wherein said patients are
suffering from an inflammatory or an autoimmune disease or
disorder, e.g. multiple sclerosis, comprising any ones of the
following steps of: [0239] i) observation period, e.g. at least 6
hour, e.g. 4 to 6 hours, during which or at the end of which heart
rate is checked, as defined herein, [0240] ii) annual skin
examination after first dose administration, as defined herein,
[0241] iii) regular review of liver enzyme, e.g. serum ALT, as
defined herein, [0242] iv) ophthalmologic examinations 2 to 12
months, e.g. 3 to 4 months, after first dose administration, as
defined herein, [0243] v) regular checking of patient visual
function, as defined herein.
[0244] There is further provided method of administering a S1P
receptor modulator or agonist, e.g. fingolimod in the form of
FTY720, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof, to patients suffering from an inflammatory
or an autoimmune disease or disorder, e.g. multiple sclerosis,
comprising
a) performing any ones of the following steps of: [0245] i)
observation period, e.g. at least 6 hour, e.g. 4 to 6 hours, during
which or at the end of which heart rate is checked, as defined
herein, [0246] ii) annual skin examination after first dose
administration, as defined herein, [0247] iii) regular review of
liver enzyme, e.g. serum ALT, as defined herein, [0248] iv)
ophthalmologic examinations 3 to 4 months after first dose
administration, as defined herein, [0249] v) regular checking of
patient visual function, as defined herein; and b) if required,
interrupting fingolimod administration based upon the results of
one of more of the above steps or changing the treatment regimen
and/or administering a second drug. Step b) may correspond to
appearance of adverse events. The second drug may be a drug which
mitigates said possible adverse events.
[0250] Interrupting fingolimod administration, changing the
treatment regimen and/or administering a second drug, may occur in
case of any of the following conditions: bradycardia or
atrioventricular conduction abnormalities, macular edema or other
visual disturbance, skin cancer, altered liver functions or liver
injury, infections or hypertension. Duration of the interruption is
defined by the physician.
[0251] Interrupting fingolimod administration, changing the
treatment regimen and/or administering a second drug, may also
occur in case the lymphocyte count of the patient becomes
abnormally low, or becomes lower than 200/mL.
[0252] For example, step a) may comprise one or more steps of
[0253] i) monitoring the heart rate of the patient, [0254] ii)
monitoring infections or infestations, e.g. viral Infections, and
[0255] iii) performing ophthalmologic examination within the first
1 to 10 after starting administration.
Therapeutic Dosages
[0256] In a preferred embodiment of the invention the methods for
administering FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof as defined herein above,
in particular the methods for treating an inflammatory or
autoimmune disease or disorder, limiting the symptoms associated
thereof or the progression thereof, e.g. multiple sclerosis, in a
patient in need thereof comprise administering a daily dosage of
FTY720, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof, e.g. FTY720 hydrochloride, of not more
than 0.5 mg, e.g. of about 0.5 mg.
[0257] According to the invention there is provided a compound
selected from fingolimod (FTY720), a phosphate derivative thereof
or a pharmaceutically acceptable salt thereof, e.g. fingolimod
hydrochloride, for use in treating or preventing an inflammatory or
autoimmune disease, whereby said compound is administered in such a
way to a patient that the adverse events possibly associated with
administration of said compound are controlled, limited, reduced or
abolished. For example, the daily dosage of fingolimod (FTY720), a
phosphate derivative thereof or a pharmaceutically acceptable salt
thereof, e.g. fingolimod hydrocholoride, does not exceed 0.5 mg,
e.g. is of about 0.5 mg.
[0258] In a specific embodiment of the invention there is provided
a method for treating multiple sclerosis, controlling or limiting
the symptoms associated thereof or reducing the severity of said
disease in a patient in need thereof, comprising administering a
daily dosage of fingolimod (FTY720), a phosphate derivative thereof
or a pharmaceutically acceptable salt thereof, e.g. fingolimod
hydrocholoride, wherein said daily dosage does not exceed 0.5 mg,
e.g. is of about 0.5 mg, and wherein the patient is further
affected by asthma (for example moderate asthma), by a disease or
disorder impacting eyes or has an history of eyes diseases or
disorders (for example is affected by uveitis or diabetes), show
high-grade AV block, sick sinus syndrome, hepatic dysfunction or
hypertension.
[0259] In a further embodiment of the invention there is provided a
method for treating multiple sclerosis, controlling or limiting the
symptoms associated thereof or reducing the severity of said
disease in a patient in need thereof, comprising administering a
daily dosage of fingolimod (FTY720), a phosphate derivative thereof
or a pharmaceutically acceptable salt thereof, e.g. fingolimod
hydrocholoride, wherein said daily dosage does not exceed 0.5 mg,
e.g. is of about 0.5 mg, and wherein the patient is pregnant.
[0260] In yet a further embodiment of the invention there is
provided a method for treating multiple sclerosis, limiting the
symptoms associated thereof or reducing the severity of said
disease in a patient in need thereof, comprising administering a
daily dosage of fingolimod (FTY720), a phosphate derivative thereof
or a pharmaceutically acceptable salt thereof, e.g. fingolimod
hydrocholoride, wherein said daily dosage does not exceed 0.5 mg,
e.g. is of about 0.5 mg, and wherein the patient is a MS patients
who has never received treatment for MS, e.g. de novo patient.
[0261] According to the invention, adopting the treatment regimen
may consist of decreasing the dosage, or increasing the time
between two consecutive administrations of the S1P receptor
modulator or agonist, e.g. fingolimod, a phosphate derivative
thereof or a pharmaceutically acceptable salt thereof. For example
it may consist of administering 0.25 mg of fingolimod, a phosphate
derivative thereof or a pharmaceutically acceptable salt thereof,
two times a day. It may also consist of increasing stepwise the
dosage of the drug during the first period of administration up to
a daily dosage of 0.5 mg or 1.25 mg, e.g. adopting a stepwise
administration, e.g. a titration.
[0262] The present invention pertains to a method for treating
multiple sclerosis comprising [0263] (a) administering a varied
dose of a drug selected from the group consisting of fingolimod
(FTY720), a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof in a patient in need thereof, [0264] (b)
monitoring adverse events occurring in said patient, [0265] (c)
monitoring reduction or abolition of symptoms associated with
multiple sclerosis, and [0266] (d) determining optimal dose for
said patient
[0267] The daily dose of the drug may be not exceeding 0.5 mg.
[0268] In another embodiment, the daily dose of the drug is above
0.5 mg, e.g. is about 1.00 mg, e.g. about 1.25 mg, e.g. about 1.5
mg.
[0269] There is also provided a S1P receptor modulator or agonist,
e.g. FTY720, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof, for use in a method for treating an
inflammatory or autoimmune disease, e.g. multiple sclerosis,
wherein said method comprises [0270] (a) administering a varied
dose of said S1P receptor modulator or agonist in a patient in need
thereof, [0271] (b) monitoring adverse events occurring in said
patient, [0272] (c) monitoring reduction or abolition of symptoms
associated with said inflammatory or autoimmune disease, and [0273]
(d) determining optimal dose for said patient.
[0274] This method is particularly adapted for FTY720, a phosphate
derivative thereof or a pharmaceutically acceptable salt thereof,
e.g. FTY720 hydrochloride, for treating multiple sclerosis.
[0275] When the S1P receptor modulator or agonist is selected from
FTY720, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof, e.g. is FTY720 hydrochloride, and the
disease is multiple sclerosis, the daily dose of the drug may not
be exceeding 0.5 mg.
[0276] In another embodiment, the S1P receptor modulator or agonist
is selected from FTY720, a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, e.g. FTY720
hydrochloride, and the daily dose is exceeding 0.5 mg, e.g. is
about 1.00 mg, e.g. about 1.25 mg, e.g. about 1.5 mg.
[0277] In yet a further embodiment of the invention, there is
provided a personalized method for treating an inflammatory or
autoimmune disease or disorder, e.g. multiple sclerosis, in a
patient in need thereof comprising administering to said patient a
therapeutically effective amount of a S1P receptor modulator or
agonist, wherein said method comprises [0278] (a) administering a
varied dose of said drug to the patient, [0279] (b) monitoring
adverse events occurring in said patient, [0280] (c) monitoring
reduction or abolition of symptoms associated with multiple
sclerosis, and [0281] (d) determining optimal dose for said
patient,
[0282] wherein said regimen is adapted for treating said disease or
disorder and controlling, reducing, or abolishing the possible
adverse events associated with administering said S1P receptor
modulator or agonist.
[0283] The steps (a) to (d) above may also be used in a method for
determining a personalized therapeutic treatment regimen of a drug
selected from the group consisting of fingolimod (FTY720), a
phosphate derivative thereof or a pharmaceutically acceptable salt
thereof, in a patient suffering from an inflammatory or autoimmune
disease, e.g. multiple sclerosis.
[0284] The present invention also pertains a compound selected from
FTY720, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof, e.g. FTY720 hydrochloride, for use in a
method for treating an inflammatory or autoimmune disease or
disorder in a patient in need thereof, wherein said method is
personalized, e.g. is adapted for treating said disease or disorder
to the specific profile of the patient in such a way that the
adverse events associated with administering said S1P receptor
modulator or agonist are controlled, reduced, or abolished. In such
a case, the patient to be treated my be selected from patients who
have never received treatment for that disease or disorder,
patients suffering or at risk of heart failure or arrythmias,
patients affected by asthma, patients who have eyes diseases or
disorders, hepatic dysfunction or hypertension.
[0285] The present invention provides for a compound selected from
FTY720, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof, e.g. FTY720 hydrochloride, for use in
treating patients suffering from an inflammatory or an autoimmune
disease or disorder, e.g. multiple sclerosis, wherein the compound
is administered through the administration pattern defined
above.
[0286] The present invention also provides for a compound selected
from FTY720, a phosphate derivative thereof or a pharmaceutically
acceptable salt thereof, e.g. FTY720 hydrochloride, for use in
treating patients suffering from an inflammatory or an or disorder
disease, e.g. multiple sclerosis, wherein the compound is
administered through the patient monitoring defined above.
Combination
[0287] In another embodiment of the invention, the S1P receptor
modulator, e.g. fingolimod (FTY720), a phosphate derivative thereof
or a pharmaceutically acceptable salt thereof, e.g. fingolimod
hydrochloride, is administered together with a second drug which
mitigates the possible adverse event associated with administration
of fingolimod.
[0288] Such a second drug may be administered only in the event
that an adverse event, e.g. a side-effect, occurs or increases in
intensity or frequency to a level which is not acceptable anymore,
e.g. as hereinabove described.
[0289] The second drug may be selected from the group consisting of
drugs which treat or prevent macular edema, anti-cancer agents
(e.g. chemotherapeutic agents), anti-infection agents,
anti-hypertensive drugs, anti-bradychardia agents, and mixture
thereof.
[0290] Examples of second drug include, but are not limited to,
calcium channel blocker (e.g. diltiazem), atenolol, valsartan,
[0291] When the S1P receptor modulator or agonist of the invention,
e.g. fingolimod (FTY720), a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, e.g. fingolimod
hydrochloride, is administered together with a second drug which
mitigates the possible adverse event associated with administration
of fingolimod, the daily dosage of said S1P receptor modulator or
agonist may be above 0.5 mg, e.g. may be about 1.00 mg, e.g. about
1.25 mg, e.g. about 1.5 mg.
[0292] For example there is provided a combination, e.g. a kit,
containing a S1P receptor modulator or agonist of the invention,
e.g. fingolimod (FTY720), a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, e.g. fingolimod
hydrocholoride, and a second drug which is selected from the group
consisting of anti-cancer agents, anti-infection agents,
anti-microbial agents, anti-viral therapy, and anti-hypertensive
drugs, whereby the dosage of said S1P receptor modulator or agonist
is above 0.5 mg, e.g. is about 1.25 mg.
[0293] The invention also provides a specific dosage regimen of
FTY720 for treating an inflammatory or autoimmune disease or
disorder, limiting the symptoms associated thereof or the
progression thereof, e.g. multiple sclerosis, in a patient in need
thereof, comprising administering to said patient a daily dosage of
fingolimod (FTY720), a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, which leads to a
reduction of peripheral lymphocyte count of about 70 to 75%, e.g.
of about 73%, 75% or 76%.
[0294] In another embodiment the invention provides a specific
dosage regimen of FTY720 for treating an inflammatory or autoimmune
disease or disorder, limiting the symptoms associated thereof or
the progression thereof, e.g. multiple sclerosis, in a patient in
need thereof, comprising administering to said patient a daily
dosage of fingolimod (FTY720), a phosphate derivative thereof or a
pharmaceutically acceptable salt thereof, which leads to a
reduction of peripheral lymphocyte count to a level low enough to
obtain the therapeutic effect on the disease while controlling,
limiting or abolishing the incidence of infections. Preferably this
daily dosage is not more than 0.5 mg of fingolimod (FTY720), a
phosphate derivative thereof or a pharmaceutically acceptable salt
thereof, e.g. of the hydrochloride salt thereof
[0295] Utility of the dosage regimen of the invention in treating
diseases and conditions as hereinabove specified may be
demonstrated in standard animal or clinical tests, e.g. in
accordance with the methods described hereinafter.
EXAMPLE 1
[0296] Study:
[0297] Two different daily dosages of fingolimod (0.5 mg and 1.25
mg) have been orally administered to patients with
Relapsing-remitting Multiple Sclerosis during 24-month 1292
patients with RRMS from 172 centers in 18 countries are randomized
to receive oral fingolimod, in a dose of 0.5 mg/day or 1.25 mg/day,
or interferon beta1-a 30 .mu.g intramuscularly once a week.
Patients randomized to fingolimod receive placebo injections once a
week, and those randomized to interferon beta1-a receive a placebo
pill once a day.
[0298] The patients are seen clinically every month for 3 months
and every 3 months thereafter. The Expanded Disability Status Scale
(EDSS) is performed every 3 months, the MS Functional Composite
(MSFC) every 6 months, and MRI annually. Monitoring by ophthalmic
examination, dermatologic examination, pulmonary function tests,
chest X-ray and/or CT, Holter monitoring, and echocardiography are
performed.
[0299] Participants who completed 1 year on treatment are offered
an optional extension phase. Those randomized to fingolimod
continue on their assigned dose, and those in the interferon
beta1-a group are randomized to the 2 fingolimod doses.
[0300] Results:
[0301] There are reduced relapses in both fingolimod groups
compared with interferon beta1-a. For the lower dose, there is a
52% reduction in relapses vs interferon beta1-a, and a 38%
reduction with the higher dose. Results in both fingolimod groups
are highly statistically significant vs interferon beta1-a, but not
statistically different from each other.
TABLE-US-00001 Interferon Fingolimod Fingolimod End Point beta1-a
0.5 mg/day P 1.25 mg/day P Annualized 0.33 0.16 <.0001 0.20
<.0001 relapse rate
[0302] The proportion of relapse-free patients is 83% with
fingolimod vs 69% in the interferon beta1-a group.
[0303] MRI lesion activity shows a reduction in both fingolimod
groups in the number of new or newly enlarging T2 lesions and the
number of gadolinium-enhancing T1 lesions at month 12.
[0304] Observed adverse events include bradycardia and
atrioventricular (AV) block, and infections, including 3 herpes
viral infections.
TABLE-US-00002 Interferon Fingolimod Fingolimod beta1-a, 0.5 mg/d,
1.25 mg/day, Type n (%) n (%) n (%) Basal-cell 1 (0.2) 3 (0.7) 2
(0.5) carcinoma Squamous-cell 1 (0.2) 0 0 carcinoma Malignant 0 3
(0.7) 0 melanoma Breast cancer 0 2 (0.5) 2 (0.5)
EXAMPLE 2
[0305] Study:
[0306] Patients with moderate asthma are divided into 3 dosing
cohorts of 12 patients each. In each cohort, the 12 patients are
randomized to FTY720 (0.5 mg, 1.25 mg, and 2.5 mg in cohorts 1, 2,
and 3 respectively) or placebo in a 3:1 ratio resulting in 9
patients treated with FTY720 at each dose level and 9 patients
treated with placebo.
[0307] The study consists of a screening period of between 12 and
26 days, baseline and a 10 day treatment period followed by a study
completion evaluation (performed 1-7 days after the last dose).
[0308] Two screening visits are performed, the initial Screening
visit and a second visit at Day -7 (+/-1 day). The initial
screening visit (Visit 1) is used to start pulmonary function test
(PFT) monitoring to assess eligibility for the study and to obtain
relevant background information and informed consent. The PFT is
performed at a clock time similar to the 6-hour post-dose timepoint
on Day 1. On Day -7a PFT is again performed at the specified time.
Short-acting .beta.2 agonist use prior to treatment with study
medication is also recorded in this 14 day period.
[0309] Patients return to the clinic one or 2 days prior to dosing
for baseline assessments. PFT profiling is assessed at 7 time
points during the visit and routine baseline evaluations are
performed. On Day 1, patients are randomized in a 3:1 ratio to
FTY720 or placebo and PFT profiling is assessed at 8 time points
(namely pre-dose, then at 1, 2, 3, 4, 5, 6 and 12 hours post-dose).
PFT assessments are also performed on Days 2, 3, 7 (all single time
points assessed at approximately the same clock time as the 6 hours
post-dose PFT on Day 1) and Day 10 (7 time points, namely pre-dose
and then at 1, 2, 3, 4, 5 and 6 hours post-dose). On each of the
days when PFT assessments are performed, a reversibility test
follows the last PFT assessment of the day. Short-acting .delta.2
agonist use is also recorded throughout the treatment period up to
and including Day 11 (24 hours post last dose).
[0310] Blood samples are collected on Day 1 at pre-dose and at 1,
2, 4, 6, 8, 12, 16, and 24h post-dose, on Days 2, 3 and 7 at 6
hours post-dose and on Day 10 at pre-dose and at 1, 2, 4, and 6h
post-dose.
[0311] Safety assessments include physical examinations, ECGs,
vital signs, spirometry assessments, standard clinical laboratory
evaluations (hematology, blood chemistry, urinalysis), adverse
event and serious adverse event monitoring.
[0312] Only one half of each treatment cohort, a maximum of 6
patients, is allowed to start treatment on any given day for safety
reasons. At least 1 day (24 hours) separates the initial dosing of
the first group of patients from the dosing of the second group
(and at least 1 further day separates the second group from any
subsequent groups required to complete each cohort).
[0313] The magnitude and time course of the effect of FTY720 on
FEV1 and other pulmonary function tests (FVC, FEF25-75%, and
FEV1/FVC) is measured.
Results:
[0314] The magnitude of the bronchoconstriction is primarily
assessed by the baseline-adjusted FEV.sub.1 AUC0-6h on Day 1. This
primary PD variable is defined as the ratio of the AUEC FEV.sub.1
over the 6-hour PFT profile on Day 1 divided by the same variable
at baseline (Day -1).
[0315] This primary PD variable is analyzed on the log-scale by
means of a linear model adjusted for the (log-transformed) baseline
FEV.sub.1 AUC0-6h and the treatment group as fixed effects. The
geometric mean baseline-adjusted FEV.sub.1 AUC0-6h is obtained from
the model for each treatment group; the geometric mean ratio
between each FTY720 group and placebo is also obtained along with
its 95% Cl, and is back-transformed to obtain the geometric mean
percent change from placebo and its 95% Cl.
[0316] Additional PD variables are calculated: baseline-adjusted
FEV.sub.1 AUC0-6h on Day 10 and baseline-adjusted FEV.sub.1
Emax1-6h on Days 1 and 10. The Emax variables are defined as the
ratio between Day 1 (or Day 10) and Day -1 regarding the minimum
from 6 assessments scheduled at 1 to 6 hours post dose. Those
variables are defined for FEV.sub.1 as well as for the other PFT
parameters (FVC, FEF.sub.25-75%, and FEV.sub.1/FVC) and are
analyzed using the same model as for the primary PD endpoint.
[0317] The time-course of the PFT parameters is explored on Day 1
over the 12-hour profile and on Day 10 over the 6-hour profile. The
percent change from time-matched baseline in FEV.sub.1, FVC,
FEF.sub.25-75%, and FE.sub.1/FVC is summarized by means of
descriptive statistics at each visit/time point. The
log-transformed ratio from time-match baseline is analyzed,
separately at each post-baseline visit/time point, by means of a
linear model adjusted for the time-matched log-transformed baseline
value and the treatment group as fixed effect. For each FTY720
group, the estimate for the mean treatment difference versus
placebo and its 95% CI are obtained from the model and are
back-transformed to obtain the geometric mean percent change from
placebo and its 95% Cl. No adjustment was made to the P values for
multiple testing.
[0318] The results show that at a daily dosage of 0.5 mg FTY720 is
safe and well tolerated in patients with moderate asthma.
* * * * *