U.S. patent application number 16/058404 was filed with the patent office on 2019-02-07 for treatment of autoimmune disease in a patient receiving additionally a beta-blocker.
The applicant listed for this patent is Novartis AG. Invention is credited to Vassilios Aslanis, Shibadas Biswal, Alan John Camm, Pierre Jordaan, Eric Legangneux, Parasar Pal, Atul Keshav Pawar, Florine Polus, Alexandros Sagkriotis, Kasra Shakeri-Nejad, Uday Kiran Veldandi.
Application Number | 20190038599 16/058404 |
Document ID | / |
Family ID | 55485022 |
Filed Date | 2019-02-07 |
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United States Patent
Application |
20190038599 |
Kind Code |
A1 |
Legangneux; Eric ; et
al. |
February 7, 2019 |
TREATMENT OF AUTOIMMUNE DISEASE IN A PATIENT RECEIVING ADDITIONALLY
A BETA-BLOCKER
Abstract
The present invention relates to methods of treating autoimmune
diseases with siponimod in patients receiving additionally a
beta-blocker.
Inventors: |
Legangneux; Eric;
(Levallois-Perret, FR) ; Sagkriotis; Alexandros;
(Basel, CH) ; Jordaan; Pierre; (Bettingen, CH)
; Polus; Florine; (Basel, CH) ; Camm; Alan
John; (London, GB) ; Biswal; Shibadas;
(Nucleos North Tower, Level 4, SG) ; Pal; Parasar;
(Hyderabad, Rangareddy, IN) ; Veldandi; Uday Kiran;
(Hyderabad, Rangareddy, IN) ; Pawar; Atul Keshav;
(Navi Mumbai, IN) ; Aslanis; Vassilios; (Basel,
CH) ; Shakeri-Nejad; Kasra; (Basel, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novartis AG |
Basel |
|
CH |
|
|
Family ID: |
55485022 |
Appl. No.: |
16/058404 |
Filed: |
August 8, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15552886 |
Aug 23, 2017 |
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PCT/IB2016/051004 |
Feb 24, 2016 |
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16058404 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61P 37/00 20180101; A61P 21/00 20180101; A61P 25/28 20180101; A61K
9/2018 20130101; A61K 31/397 20130101; A61P 29/00 20180101; A61K
31/138 20130101; A61K 31/397 20130101; A61K 2300/00 20130101; A61K
31/138 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/397 20060101
A61K031/397; A61K 31/138 20060101 A61K031/138; A61K 9/20 20060101
A61K009/20; A61K 45/06 20060101 A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 26, 2015 |
IN |
559/DEL/2015 |
Claims
1. A method of treating an autoimmune disease in a patient
comprising a) administering to said patient an initial titration
regimen of siponimod; b) administering to said patient 1-15 mg
siponimod daily as a maintenance regimen; and c) introducing in
said patient a beta-blocker treatment the earliest at the first day
when said patient is receiving the dosage of the maintenance
regimen; wherein said initial titration regimen comprises
administering siponimod at a dosage lower than the dosage of the
maintenance regimen and then increasing the dosage stepwise up to
the dosage of the maintenance regimen.
2. The method according to claim 1, wherein said autoimmune disease
is selected from inflammatory myopathy and multiple sclerosis.
3. The method according to claim 1, wherein said autoimmune disease
is selected from polymyositis, dermatomyositis, inclusion-body
myositis and secondary progressive multiple sclerosis.
4. The method according to claim 1, wherein said autoimmune disease
is secondary progressive multiple sclerosis.
5. The method according to claim 1, wherein the maintenance regimen
administered in step b) of said method comprises 2-10 mg
siponimod.
6. The method according to claim 5, wherein said maintenance
regimen comprises 2-5 mg siponimod.
7. The method according to claim 1, wherein the maintenance regimen
administered in step b) of said method is administered once
daily.
8. The method according to claim 1, wherein in the maintenance
regimen administered in step b) of said method an immediate release
dosage form is used.
9. The method according to claim 1, wherein said initial titration
regimen comprises administering siponimod such that the dosage
administered on a specific day of the initial titration regimen is
the sum of the dosages administered on the previous two days within
a range of .+-.40%.
10. The method according to claim 1, wherein said initial titration
regimen is conducted over 3-10 days.
11. The method according to claim 1, wherein the dosage of the
maintenance regimen is 2 mg siponimod and wherein said initial
titration regimen comprises administering 0.25 mg siponimod at day
1, 0.25 mg of siponimod at day 2, 0.5 mg siponimod at day 3, 0.75
mg siponimod at day 4, 1.25 mg siponimod at day 5 and 2 mg
siponimod at day 6.
12. The method according to claim 11, wherein said initial
titration regimen comprises one administration of 0.25 mg siponimod
at day 1, one administration of 0.25 mg siponimod at day 2, one
administration of 0.5 mg siponimod at day 3, one administration of
0.75 mg siponimod at day 4, one administration of 1.25 mg siponimod
at day 5 and one administration of 2 mg siponimod at day 6.
13. The method according to claim 12, wherein, in said initial
titration regimen, immediate release dosage forms comprising 0.25
mg, 0.5 mg, 1 mg and 2 mg siponimod are used.
14. The method according to claim 1, wherein said autoimmune
disease is secondary progressive multiple sclerosis; wherein the
maintenance regimen administered in step b) of said method is an
immediate release dosage form comprising 2 mg siponimod; wherein
the maintenance regimen administered in step b) of said method is
administered once daily; wherein the initial titration regimen
administered in step a) of said method comprises one administration
of 0.25 mg siponimod at day 1, one administration of 0.25 mg
siponimod at day 2, one administration of 0.5 mg siponimod at day
3, one administration of 0.75 mg siponimod at day 4, one
administration of 1.25 mg siponimod at day 5 and one administration
of 2 mg siponimod at day 6; and wherein in the initial titration
regimen administered in step a) of said method immediate release
dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and 2 mg siponimod
are used.
15. A method of treating an autoimmune disease in a patient
receiving a chronic beta-blocker treatment and having a resting
heart rate of >50 bpm under said chronic beta-blocker treatment
comprising introducing in said patient a siponimod treatment by a)
administering to said patient an initial titration regimen of
siponimod; and b) administering to said patient 1-15 mg siponimod
daily as a maintenance regimen; wherein said initial titration
regimen comprises administering siponimod at a dosage lower than
the dosage of the maintenance regimen and then increasing the
dosage stepwise up to the dosage of the maintenance regimen.
16. The method according to claim 15, wherein said autoimmune
disease is selected from inflammatory myopathy and multiple
sclerosis.
17. The method according to claim 15, wherein said autoimmune
disease is selected from polymyositis, dermatomyositis,
inclusion-body myositis and secondary progressive multiple
sclerosis.
16. The method according to claim 15, wherein said autoimmune
disease is secondary progressive multiple sclerosis.
19. The method according to claim 15, wherein the maintenance
regimen administered in step b) of said method comprises 2-10 mg
siponimod.
20. The method according to claim 19, wherein said maintenance
regimen comprises 2-5 mg siponimod.
21. The method according to claim 15, wherein the maintenance
regimen administered in step b) of said method is administered once
daily.
22. The method according to claim 15, wherein the maintenance
regimen administered in step b) of said method is administered as
an immediate release dosage form.
23. The method according to claim 15, wherein said initial
titration regimen comprises administering siponimod such that the
dosage administered on a specific day of the initial titration
regimen is the sum of the dosages administered on the previous two
days within a range of .+-.40%.
24. The method according to claim 15, wherein said initial
titration regimen is conducted over 3-10 days.
25. The method according to claim 15, wherein the dosage of the
maintenance regimen is 2 mg siponimod and wherein said initial
titration regimen comprises administering 0.25 mg siponimod at day
1, 0.25 mg of siponimod at day 2, 0.5 mg siponimod at day 3, 0.75
mg siponimod at day 4, 1.25 mg siponimod at day 5 and 2 mg
siponimod at day 6.
26. The Method according to claim 25, wherein said initial
titration regimen comprises one administration of 0.25 mg siponimod
at day 1, one administration of 0.25 mg siponimod at day 2, one
administration of 0.5 mg siponimod at day 3, one administration of
0.75 mg siponimod at day 4, one administration of 1.25 mg siponimod
at day 5 and one administration of 2 mg siponimod at day 6.
27. The method according to claim 26, wherein, in said initial
titration regimen, immediate release dosage forms comprising 0.25
mg, 0.5 mg, 1 mg and 2 mg siponimod are used.
28. The method according to claim 15, wherein said autoimmune
disease is secondary progressive multiple sclerosis; wherein the
maintenance regimen administered in step b) of said method is an
immediate release dosage form comprising 2 mg siponimod; wherein
the maintenance regimen administered in step b) of said method is
administered once daily; wherein the initial titration regimen
administered in step a) of said method comprises one administration
of 0.25 mg siponimod at day 1, one administration of 0.25 mg
siponimod at day 2, one administration of 0.5 mg siponimod at day
3, one administration of 0.75 mg siponimod at day 4, one
administration of 1.25 mg siponimod at day 5 and ; and one
administration of 2 mg siponimod at day 6; wherein in the initial
titration regimen administered in step a) of said method immediate
release dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and 2 mg
siponimod are used.
29. A method of treating an autoimmune disease in a patient
receiving a chronic beta-blocker treatment and having a resting
heart rate of .ltoreq.50 bpm under said chronic beta-blocker
treatment comprising a) interrupting said chronic beta-blocker
treatment in said patient until the baseline heart-rate is >50
bpm; b) initiating in said patient a siponimod treatment by b1)
administering to said patient an initial titration regimen of
siponimod; and b2) administering to said patient 1-15 mg siponimod
daily as a maintenance regimen; and c) re-initiating in said
patient a beta-blocker treatment the earliest at the first day when
said patient is receiving the dosage of the maintenance regimen;
wherein said initial titration regimen comprises administering
siponimod at a dosage lower than the dosage of the maintenance
regimen and then increasing the dosage stepwise up to the dosage of
the maintenance regimen.
30. The method according to claim 29, wherein said autoimmune
disease is selected from inflammatory myopathy and multiple
sclerosis.
31. The method according to claim 29, wherein said autoimmune
disease is selected from polymyositis, dermatomyositis,
inclusion-body myositis and secondary progressive multiple
sclerosis.
32. The method according to claim 29, wherein said autoimmune
disease is secondary progressive multiple sclerosis.
33. The method according to claim 29, wherein the maintenance
regimen administered in step b2) of said method comprises 2-10 mg
siponimod.
34. The method according to claim 33, wherein said maintenance
regimen comprises 2-5 mg siponimod.
35. The method according to claim 29, wherein the maintenance
regimen administered in step b2) of said method is administered
once daily.
36. The method according to claim 29, wherein the maintenance
regimen administered in step b2) of said method is administered as
an immediate release dosage form.
37. The method according to claim 29, wherein said initial
titration regimen comprises administering siponimod such that the
dosage administered on a specific day of the initial titration
regimen is the sum of the dosages administered on the previous two
days within a range of .+-.40%.
38. The method according to claim 29 wherein said initial titration
regimen is conducted over 3-10 days.
39. The method according to claim 29, wherein the dosage of the
maintenance regimen is 2 mg siponimod and wherein said initial
titration regimen comprises administering 0.25 mg siponimod at day
1, 0.25 mg of siponimod at day 2, 0.5 mg siponimod at day 3, 0.75
mg siponimod at day 4, 1.25 mg siponimod at day 5 and 2 mg
siponimod at day 6.
40. The method according to claim 39, wherein said initial
titration regimen comprises one administration of 0.25 mg siponimod
at day 1, one administration of 0.25 mg siponimod at day 2, one
administration of 0.5 mg siponimod at day 3, one administration of
0.75 mg siponimod at day 4, one administration of 1.25 mg siponimod
at day 5 and one administration of 2 mg siponimod at day 6.
41. The method according to claim 40, wherein, in said initial
titration regimen, immediate release dosage forms comprising 0.25
mg, 0.5 mg, 1 mg and 2 mg siponimod are used.
42. The method according to claim 29, wherein the beta-blocker
treatment re-initiated in step c) of said method is re-initiated
after 2-3 weeks of treatment with siponimod.
43. The method according to claim 29, wherein said autoimmune
disease is secondary progressive multiple sclerosis; wherein the
maintenance regimen administered in step b2) of said method is an
immediate release dosage form comprising 2 mg siponimod; wherein
the maintenance regimen administered in step b2) of said method is
administered once daily; wherein the initial titration regimen
administered in step b1) of said method comprises one
administration of 0.25 mg siponimod at day 1, one administration of
0.25 mg siponimod at day 2, one administration of 0.5 mg siponimod
at day 3, one administration of 0.75 mg siponimod at day 4, one
administration of 1.25 mg siponimod at day 5 and one administration
of 2 mg siponimod at day 6; wherein in the initial titration
regimen administered in step b1) of said method immediate release
dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and 2 mg siponimod
are used; and wherein the beta-blocker treatment re-initiated in
step c) of said method is re-initiated after 2 weeks of treatment
with siponimod.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to methods of treating
autoimmune diseases with siponimod (BAF312) in patients receiving
additionally a beta-blocker.
BACKGROUND
[0002] One of the most common inflammatory, demyelinating diseases
of the central nervous system (CNS) is multiple sclerosis (MS), in
which the insulating covers of nerve cells in the brain and spinal
cord are damaged. MS takes several forms, with new symptoms either
occurring in isolated attacks (relapsing forms) or building up over
time (progressive forms). Between attacks, symptoms may be
completely in remission. However, as the disease progresses over
time or relapses occur, permanent neurological problems result.
[0003] At the time of diagnosis, between 80% and 90% of MS patients
have relapsing-remitting MS (RRMS). This form of MS is
characterized by recurring relapses, i.e. acute episodes, of
neurological symptoms. In around 80% of the patients with RRMS,
this form then develops to secondary progressive MS (SPMS), around
19 years after disease onset. Progression proceeds with or without
occasional relapses with minor remissions between relapses and is
characterized symptomatically by continuous worsening of
disability, independent of relapses.
[0004] Sphingosine-1-phosphate (S1P) receptors belong to a family
of closely related, lipid-activated G-protein-coupled receptors.
S1P1, S1P2, S1P3, S1P4, and S1P5 (also respectively termed EDG-1,
EDG-5, EDG-3, EDG-6 and EDG-8) are identified as receptors specific
for S1P. Certain S1P receptors are associated with diseases
mediated by lymphocyte interactions, for example, in
transplantation rejections, autoimmune diseases, e.g. MS and
inflammatory myopathies, inflammatory diseases, infectious diseases
and cancer. Hence, S1P receptor modulators, such as fingolimod and
siponimod, are an interesting class of compounds for treating
autoimmune diseases such as MS.
[0005] Fingolimod is well established in clinical practice for the
treatment of relapsing forms of MS, e.g. RRMS.
[0006] Siponimod has achieved positive results in a clinical trial
for the treatment of RRMS patients [see: Selma] et al, Lancet
Neurol, 2013, 12, 756-767) and is currently being investigated in
an ongoing phase III study in patients with SPMS.
[0007] While S1P receptor modulators are interesting and mostly
effective compounds for treating diseases e.g. mediated by
lymphocyte interactions, they may produce negative chronotropic
side effects at therapeutic doses, i.e. they may reduce the heart
rate (bradycardia), as described in Cohen et al (N Engl J Med 2010,
362, 402-415) and in Kappos et al (N Engl J Med 2010, 362,
387-401). Pronounced bradycardia may result in e.g. fatigue,
weakness, dizziness and fainting, but may also be associated with
bradyarrhythmia (e.g. AV blocks, AVB, and Sinus pauses, SP). While
such bradycardia and its potential related side-effects might not
be highly problematic for healthy patients, it might be critical
for patients with a reduced clinical condition, e.g. patients with
SPMS--as e.g. cardiovascular co-morbidities are more frequent in
SPMS patients.
[0008] Beta-blockers, e.g. propranolol, are amongst the most
commonly used medications for hypertension, angina pectoris,
migraine, tremor, etc. and are known to also produce a negative
chronotropic effect (i.e. bradycardia and bradyarrhythmia).
[0009] Patients with MS may have co-morbidities requiring
beta-blocker therapy e.g. hypertension. A recent study calculated
the prevalence of hypertension in MS patients to be 20.8%, i.e.
similar to the prevalence of 22.5% in the general population
(Marrie et al, Multiple Sclerosis Journal, 2012, 18(9),1301-1319).
Prevalence of hypertension increased with age of MS patients and
was as high as 46.0% in MS patients being .gtoreq.60 years old (vs.
55.5% for general population being a 60 years old). As MS patients
develop SPMS only around 19 years after disease onset, prevalence
of hypertension in SPMS patients will be significantly higher than
the average value of 22.5% for general MS population.
[0010] In accordance with an expectation of additive effects
between SW modulators and beta-blockers on
bradycardia/bradyarrhythmia, the fingolimod label discourages
concomitant use. Furthermore, in the above mentioned clinical trial
for the treatment of RRMS patients with siponimod patients
requiring beta-blocker treatment have been excluded and concomitant
use has been avoided (see: Selma) et al, Lancet Neurol, 2013, 12,
756-767).
[0011] In clinical practice, there are two main scenarios where a
concomitant use may be beneficial are conceivable: (1) a patient
receiving a beta-blocker, e.g. a hypertensive patient, is diagnosed
with an autoimmune disease, e.g. SPMS, for which S1P modulator
treatment, e.g. siponimod treatment, would be an effective
treatment or (2) an autoimmune disease patient, e.g. a SPMS
patient, receiving a S1P modulator, e.g. siponimod, is diagnosed
with an indication for which a beta-blocker treatment would be an
effective treatment, e.g. hypertension. However, in accordance with
the teaching of the prior art, a physician would clearly be
discouraged to consider treating such a patient with both drugs
concomitantly although he may consider that both drugs would be the
optimal treatment for both diseases individually.
[0012] Taking into account the high prevalence for e.g.
hypertension in MS, especially in SPMS, avoiding concomitant use of
S1P modulators and beta-blockers would lead to a significant number
of patients not receiving an effective medication for the
management of their disease states.
[0013] Hence, there is a need for an effective method for the
treatment of autoimmune diseases, e.g. SPMS, in a patient in need
of a combined administration of a S1P modulator and a
beta-blocker.
SUMMARY OF THE INVENTION
[0014] Surprisingly it has been found that bradyarrhythmic effects
are markedly less pronounced, i.e. considerably less than additive,
when a beta-blocker is added to siponimod steady-state therapy,
compared with siponimod addition to beta-blocker steady state
therapy. These findings suggest that co-administration of a
beta-blocker on top of siponimod has a better safety profile than
co-administration of siponimod on top of a beta-blocker.
[0015] Based on their surprising finding that bradyarrhythmic
effects are more pronounced when siponimod is added to a
beta-blocker steady state therapy, the inventors have further found
that for patients receiving a stable dose of beta-blocker, the
resting heart-rate should be considered before introducing
siponimod treatment. Namely, if the resting heart-rate is >50
bpm under chronic beta-blocker treatment, siponimod can be
introduced. If on the other hand the resting heart rate is
.ltoreq.50 bpm, then beta-blocker treatment should be interrupted
until the baseline heart-rate is >50 bpm. Treatment with
siponimod can then be initiated and treatment with beta-blocker can
be re-initiated at a later point in time as described in detail
below.
[0016] In accordance with a first aspect of the invention, there is
provided a method of treating an autoimmune disease in a patient
comprising [0017] a) administering to said patient an initial
titration regimen of siponimod; [0018] b) administering to said
patient 1-15 mg siponimod daily as a maintenance regimen; and
[0019] c) introducing in said patient a beta-blocker treatment the
earliest at the first day when said patient is receiving the dosage
of the maintenance regimen; wherein said initial titration regimen
comprises administering siponimod at a dosage lower than the dosage
of the maintenance regimen and then increasing the dosage stepwise
up to the dosage of the maintenance regimen.
[0020] In accordance with a second aspect of the invention, there
is provided a method of treating an autoimmune disease in a patient
receiving a chronic beta-blocker treatment and having a resting
heart rate of >50 bpm under said chronic beta-blocker treatment
comprising introducing in said patient a siponimod treatment by
[0021] a) administering to said patient an initial titration
regimen of siponimod; and [0022] b) administering to said patient
1-15 mg siponimod daily as a maintenance regimen; wherein said
initial titration regimen comprises administering siponimod at a
dosage lower than the dosage of the maintenance regimen and then
increasing the dosage stepwise up to the dosage of the maintenance
regimen.
[0023] In accordance with a third aspect of the invention, there is
provided a method of treating an autoimmune disease in a patient
receiving a chronic beta-blocker treatment and having a resting
heart rate of .ltoreq.50 bpm under said chronic beta-blocker
treatment comprising [0024] a) interrupting said chronic
beta-blocker treatment in said patient until the baseline
heart-rate is >50 bpm; [0025] b) initiating in said patient a
siponimod treatment by [0026] b1) administering to said patient an
initial titration regimen of siponimod; and [0027] b2)
administering to said patient 1-15 mg siponimod daily as a
maintenance regimen; and [0028] c) re-initiating in said patient a
beta-blocker treatment the earliest at the first day when said
patient is receiving the dosage of the maintenance regimen; wherein
said initial titration regimen comprises administering siponimod at
a dosage lower than the dosage of the maintenance regimen and then
increasing the dosage stepwise up to the dosage of the maintenance
regimen.
BRIEF DESCRIPTION OF THE FIGURES
[0029] FIG. 1: Design of study on cardiovascular effects of
combined administration of siponimod and propranolol in healthy
volunteers (example 2). Key: Ad=admission to clinic for in-patient
stay; BP=blood pressure profile; Dis=discharge from clinic;
H=Holter assessment; P=pulmonary function test (spirometry);
R=randomization; T=telemetry (cardiac monitoring); EOS=end of
study.
[0030] FIG. 2: E.sub.max heart rate by time and treatment group as
assessed in example 2. Group A=propranolol at siponimod steady
state; group B=siponimod at propranolol steady state; group
C=placebo; group D=propranolol (see also FIG. 1). Time interval:
0-24 h. The median for each treatment is represented by circle
(Group A), plus (Group B), cross (Group C) and triangle (Group
D).
[0031] FIG. 3: Minimum heart rate by time and treatment group as
assessed in example 2. Group A=propranolol at siponimod steady
state; group B=siponimod at propranolol steady state; group
C=placebo; group D=propranolol (see also FIG. 1). Time interval:
0-24 h. The median for each treatment is represented by circle
(Group A), plus (Group B), cross (Group C) and triangle (Group D)
within the box. The upper (lower) edge of the box represents the
75th (25th) percentile. A whisker is drawn from the upper (lower)
edge of the box to the largest (smallest) value within
1.5.times.interquartile range above (below) the edge of the box,
and the values outside the whiskers are identified by the
respective symbols.
[0032] FIG. 4: Minimum heart rate by time and treatment group as
assessed in example 2. Group A=propranolol at siponimod steady
state; group B=siponimod at propranolol steady state; group
C=placebo; group D=propranolol (see also FIG. 1). Time interval:
0-24 h. The median for each treatment is represented by circle
(Group A), plus (Group B), cross (Group C) and triangle (Group
D).
DETAILED DESCRIPTION OF THE INVENTION
[0033] For the avoidance of doubt, it is hereby stated that the
information disclosed earlier in this specification under the
heading "Background" is relevant to the invention and is to be read
as part of the disclosure of the invention.
[0034] Throughout the description and claims of this specification,
the words "comprise" and "contain" and variations of them mean
"including but not limited to", and they are not intended to (and
do not) exclude other moieties, additives, components, integers or
steps.
[0035] Throughout the description and claims of this specification,
the singular encompasses the plural unless the context otherwise
requires. In particular, where the indefinite article is used, the
specification (which term encompasses both the description and the
claims) is to be understood as contemplating plurality as well as
singularity, unless the context requires otherwise.
[0036] Features, integers, characteristics, compounds, chemical
moieties or groups described in conjunction with a particular
aspect, embodiment or example of the invention are to be understood
to be applicable to any other aspect, embodiment or example
described herein unless incompatible therewith. All of the features
disclosed in this specification (including any accompanying claims,
abstract and drawings), and/or all of the steps of any method or
process so disclosed, may be combined in any combination, except
combinations where at least some of such features and/or steps are
mutually exclusive. The invention is not restricted to the details
of any foregoing embodiments. The invention extends to any novel
one, or any novel combination, of the features disclosed in this
specification (including any accompanying claims, abstract and
drawings), or to any novel one, or any novel combination, of the
steps of any method or process so disclosed.
[0037] Siponimod
[0038] "Siponimod" as used herein is understood to comprise the
compound of formula (I)
##STR00001##
as well as the pharmaceutically acceptable salts, polymorphs,
solvates and/or hydrates thereof. Siponimod as used herein has the
IUPAC-name
1-(4-[1-((E)-4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethy-
l-benzyl)- azetidine-3-carboxylic acid (BAF312).
[0039] In a preferred embodiment of the invention, siponimod is
present in the form of siponimod free base or siponimod salt.
Examples of pharmaceutically acceptable salts of siponimod include
salts with inorganic acids, such as hydrochloride, hydrobromide and
sulfate, salts with organic acids, such as acetate, fumarate,
hemifumarate, maleate, benzoate, citrate, malate, methanesulfonate
and benzenesulfonate salts, or, when appropriate, salts with metals
such as sodium, potassium, calcium and aluminium, salts with
amines, such as triethylamine and salts with dibasic amino acids,
such as lysine. In a preferred embodiment siponimod is in the
hemifumarate salt form.
[0040] In one embodiment of the invention, siponimod can be
provided in an amorphous form or crystalline form, preferably in a
crystalline form.
[0041] The term "crystalline" can be used in the context of this
invention to describe the state of a solid substance, whose
constituent atoms, molecules, or ions are arranged in an ordered
pattern extending in all three spatial dimensions.
[0042] The siponimod as used in the context of this invention may
consist of purely crystalline siponimod. Alternatively, it may also
contain small amounts of non-crystalline siponimod components. In
an embodiment of the invention the siponimod contained in the
administered dosage form(s) can be 85 to 99.999%, more preferably
90 to 99.99%, most preferably 95 to 99.9% by weight crystalline
siponimod.
[0043] Generally, siponimod as used in the context of this
invention can be used in particulate form. The siponimod can
preferably have an average particle size X90 of 10 to 100 .mu.m,
more preferably 15 to 80 .mu.m, most preferably 30 to 70 .mu.m.
[0044] The particle size X90, which is also denoted as X90 value of
the integral volume distribution, is defined in the context of this
invention as the particle diameter at which 90 per cent by volume
of the particles have a smaller diameter than the diameter which
corresponds to the X9D value. Likewise, 10 per cent by volume of
the particles have a larger diameter than the X90 value. The X10
and X50 values are defined accordingly.
[0045] Further, the siponimod can preferably have an average
particle size X50 of 1 to 25 .mu.m, more preferably 2 to 22 .mu.m,
even more preferably 4 to 20 .mu.m, especially 5 to 17 .mu.m.
[0046] Yet further, the siponimod can preferably have a particle
size X10 of 0.5 to 5 .mu.m, more preferably 1 to 4 .mu.m, even more
preferably 1.2 to 3 .mu.m, especially preferably 1.5 to 2.7
.mu.m.
[0047] In a preferred embodiment the ratio X90/X50 can be 1.0 to
100, preferably 1.2 to 10, more preferably 2.5 to 4.0. In a
preferred embodiment, the ratio X50/X10 can be 1.1 to 10,
preferably 1.2 to 5, more preferably 2.5 to 4.0.
[0048] The particle size distribution by volume can be measured
using laser diffractometry. In particular, it can be measured using
the Sympatec Helos device (from Sympatec GmbH, Germany) using the
Cuvette dispersion device. To make the measurement, a stock
dispersion was prepared by mixing the drug substance with a
dispersing aid (Octastat 5000 (Octel corp)) using a vortex until a
smooth and homogeneous paste was formed. The paste was then diluted
and mixed to a final volume of 3 to 6 ml using white spirit. The
optical concentration of the final solution was kept below 5%. The
percentage values were calculated from the mean cumulative volume
size curve by the software of the Sympatec instrument. Preferably,
the Fraunhofer method is used for calculation purposes.
[0049] Dosage Forms Comprising Siponimod
[0050] In one embodiment, the dosage form of the siponimod
maintenance regimen according to the present invention is an
immediate release dosage form. In a preferred embodiment of the
invention, the dosage form of both the siponimod maintenance
regimen and the siponimod titration regimen is an immediate release
dosage form.
[0051] In one embodiment, the maintenance regimen of siponimod
according to the invention comprises administering an immediate
release dosage form of siponimod containing 1-15 mg siponimod,
preferably 1-10 mg siponimod, more preferably 1-5 mg siponimod,
most preferably 1-2 mg siponimod, based on the amount of siponimod
in form of the free base. In a preferred embodiment, the siponimod
immediate release dosage form of the maintenance regimen contains 2
mg of siponimod. In another preferred embodiment, the siponimod
immediate release dosage form of the maintenance regimen contains 1
mg of siponimod.
[0052] Since siponimod can be present in the form of a salt (vide
supra), the amount of the respective salt former (e.g. the
respective acid) has to be added accordingly. Similar
considerations apply for the dosage forms of both the titration
regimen and the maintenance regimen. As an example, in a titration
regimen comprising administering 0.25 mg siponimod at day 1, 0.25
mg siponimod at day 2, 0.5 mg siponimod at day 3, 0.75 mg siponimod
at day 4,1.25 mg siponimod at day 5, and 2 mg siponimod at day 6,
each amount refers to the amount of siponimod in free form.
[0053] Preferably an immediate release dosage form is administered
in the maintenance regimen as well as in the titration regimen.
Generally, the term "immediate release dosage form" stands for a
dosage form with an in-vitro release profile of the dosage form
according to USP app. II (paddle, 500 mL for the 0.25 mg dosage
strength, 900 mL for the 0.5, 1 and 2 mg dosage strengths,
phosphate buffer+0.1% (m/v) Tween 80, 60 rpm .+-.2 rpm, 37.degree.
C..+-.0.5.degree. C.) wherein after 30 minutes preferably a content
release of at least 80% is achieved, preferably more than 90%, more
preferred of more than 95%. The release can be up to 100%.
[0054] Generally, the term "immediate release dosage form" stands
for a dosage form with a release profile of the dosage form
according to USP app. II (paddle, 900 ml, phosphate buffer+0.1%
(m/v) Tween 80, 60 rpm, 37.degree. C.) wherein after 30 minutes
preferably a content release of at least 80% is achieved,
preferably more than 90%, especially more than 95%, or a
bioequivalent dosage form to said dosage form.
[0055] Tween 80 has the name polyoxyethylene(20) sorbitan
monooleate of the formula
##STR00002##
and preferably has a density at 25.degree. C. of around 1.06-1.09
g/mL, a viscosity at 25.degree. C. of 300-500 mPas and a HLB-value
(hydrophilic-lipophilic balance value) of 15.0, determined by the
Griffin's method.
[0056] In the context of the invention it is understood that a
dosage form being a bioequivalent dosage form to a dosage form
which is described in Example 1 is an immediate release dosage
form.
[0057] Generally, the term "bioequivalent dosage form" stands for a
dosage form which fulfils the standard of the FDA or EMA with
respect to another dosage form, e.g. as described in "FDA Guidance
for Industry Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products--General Considerations" from 2003 or in
"EMEA Note for Guidance on the Investigation of Bioavailability and
Bioequivalence Bioequivalence" from 2000. According to these
recommendations, the parameters and the corresponding 90%
confidence intervals should lie within a range of acceptance of 80
to 125% of the reference preparation. In order to establish
bioequivalence, it is necessary for 9 out of 10 of the
pharmacokinetic measurement values of the test product to lie
within this range of acceptance. Parameters relevant for
bioequivalence according to those standards are Cmax and
AUClast.
[0058] In one embodiment of the invention, the dosage form of
siponimod is an oral solid dosage form. In one embodiment of the
invention, the dosage form of siponimod is preferably a tablet.
Alternatively, the dosage form of the invention could be a
capsule.
[0059] The immediate release dosage form as used in the present
invention can be formed by providing siponimod as described above
and by blending siponimod with at least one pharmaceutical
excipient. Typical pharmaceutical excipients comprise lubricants,
glidants, fillers, disintegrants, moisture protecting agents and
binders.
[0060] Fillers generally are substances suitable to add volume
and/or mass to a drug substance, thereby facilitating precise
metering and handling thereof in the preparation of dosage forms.
Fillers typically also fill out the size of a tablet or capsule,
making it practical to produce and convenient for the consumer to
use.
[0061] Suitable fillers are plant cellulose (pure plant filler),
hydroxypropyl cellulose, calcium phosphate, calcium hydrogen
phosphate, calcium dihydrogen phosphate, calcium carbonate,
magnesium carbonate, magnesium aluminosilicates, sugar alcohols,
such as mannitol, maltitol, isomalt, sorbitol, xylitol, threitol
and erythritol, a triglyceride, such as hydrogenated vegetable oil,
mucilage such as carrageenan, agar and pectin, a monosaccharide
such as arabinose, xylose, glucose, mannose, galactose, a
disaccharide, such as isomaltose, maltose, lactose, sucrose, an
oligosaccharide, such as raffinose, oligofructose, cyclodextrins,
maltodextrin, a polysaccharide, such as starch, such as corn
starch, glycogen and cellulose, such as microcrystalline cellulose,
and mixtures thereof. Preferably, microcrystalline cellulose and
lactose can be used as fillers.
[0062] Generally, the dosage form as used in the context of the
present invention can comprise 0 to 90 wt.-% fillers, preferably 20
to 90 wt.-%, more preferably 30 to 80 wt.-%, based on the total
weight of the dosage form.
[0063] Lubricants are generally substances suitable to reduce
sliding friction. In particular, the intention is to reduce the
sliding friction found during tablet pressing between the punch
moving up and down in the die and the die wall, on the one hand,
and between the edge of the tablet and the die wall, on the other
hand. Suitable lubricants are, for example, stearic acid, adipic
acid, sodium stearyl fumarate and/or glyceryl behenate.
[0064] Generally, the dosage form as used in the context of the
present invention can comprise 0 to 10 wt.-% lubricants, preferably
0.01 to 8 wt.-%, more preferably 0.1 to 5 wt.-%, based on the total
weight of the dosage form.
[0065] Binders are substances that ensure that granules or tablets
can be formed with the required mechanical strength. Binders can
be, for example, saccharose, gelatine, polyvinylpyrrolidone,
starch, cellulose derivatives such as hydroxylpropyl cellulose,
hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC).
Preferably, polyvinylpyrrolidone can be used as binder.
[0066] Generally, the dosage form as used in the context of the
present invention can comprise 0 to 30 wt.-% binders, preferably 1
to 15 wt.-%, more preferably 2 to 10 wt.-%, based on the total
weight of the dosage form.
[0067] Glidants can be used to improve the flowability. A preferred
glidant is colloidal silica.
[0068] Generally, the dosage form as used in the context of the
present invention can comprise 0 to 10 wt.-% glidants, preferably
0.1 to 5 wt.-%, more preferably 1 to 3 wt.-%, based on the total
weight of the dosage form.
[0069] Disintegrants are substances which can enhance the ability
of the intermediate to break into smaller fragments when in contact
with a liquid, preferably water. Preferred disintegrants are guar
galactomannan, sodium carboxymethyl starch (croscarmellose sodium),
cross-linked polyvinylpyrrolidone (crospovidone), sodium
carboxymethyl glycolate, sodium bicarbonate or mixtures thereof.
Preferably croscarmellose and crospovidone can be used.
[0070] Generally, the dosage form as used in the context of the
present invention can comprise 0 to 20 wt.-% disintegrants,
preferably 1 to 12 wt.-%, more preferably 2 to 8 wt.-%, based on
the total weight of the dosage form.
[0071] In a preferred embodiment of the invention, the immediate
release dosage form comprises a moisture protective agent. The
moisture protective agent is a substance suitable to protect the
siponimod particles from moisture during the dosage form formation
process and/or storage.
[0072] In one embodiment, the moisture protective agent is selected
from hydrogenated vegetable oil, castor oil, palmitol stearate,
glyceryl palmitostearate and glyceryl behenate. Preferably,
glyceryl behenate is used as moisture protective agent. The
moisture protective agent can also have lubricating properties. In
case a moisture protective agent is used it is preferred that the
dosage form does not contain any additional lubricants.
[0073] Generally, the dosage form as used in the context of the
present invention can comprise 0 to 20 wt.-% moisture protective
agent, preferably 0.1 to 12 wt.-%, more preferably 1 to 8 wt.-%,
based on the total weight of the dosage form.
[0074] In a preferred embodiment, a dosage form as used in the
context of the present invention comprises
[0075] 0.1 to 10 wt. %, preferably 0.2 to 5 wt. % siponimod,
[0076] 0 to 10 wt. %, preferably 0.2 to 6 wt. % moisture protective
agent,
[0077] 0 to 15 wt. %, preferably 1 to 8 wt. % disintegrant,
[0078] 0 to 15 wt. %, optionally 1 to 8 wt. % binder,
[0079] 0 to 99.9 wt. %, preferably 50 to 90 wt. % filler, and
[0080] 0 to 10 wt. %, preferably 0.2 to 5 wt. % glidant.
[0081] In a preferred embodiment, a dosage Form as used in the
context of the present invention, preferably for use in the
maintenance regimen comprises
[0082] 2 mg siponimod,
[0083] 0 to 15 mg, preferably 1 to 8 mg moisture protective
agent,
[0084] 0 to 25 mg, preferably 0.5 to 15 mg disintegrant,
[0085] 15 to 250 mg, preferably 30 to 85 mg filler,
[0086] 0 to 50 mg, optionally 5 to 20 mg binder, and
[0087] 0 to 20 mg glidant, preferably 1 to 10 mg glidant.
[0088] In a preferred embodiment, a dosage form as used in the
context of the present invention, preferably for use in the
maintenance regimen comprises
[0089] 1 mg siponimod,
[0090] 0 to 15 mg, preferably 1 to 8 mg moisture protective
agent,
[0091] 0 to 25 mg, preferably 0.5 to 15 mg disintegrant,
[0092] 15 to 250 mg, preferably 30 to 85 mg filler,
[0093] 0 to 50 mg, optionally 5 to 20 mg binder, and
[0094] 0 to 20 mg glidant, preferably 1 to 10 mg glidant.
[0095] In a preferred embodiment, a dosage form as used in the
context of the present invention, preferably for use in the
titration regimen comprises
[0096] 0.25 mg, 0.5 mg, 0.75 mg or 1 mg siponimod,
[0097] 0 to 15 mg, preferably 1 to 8 mg moisture protective
agent,
[0098] 0 to 25 mg, preferably 0.5 to 15 mg disintegrant,
[0099] 15 to 250 mg, preferably 30 to 85 mg filler,
[0100] 0 to 50 mg, optionally 5 to 20 mg binder, and
[0101] 0 to 20 mg glidant, preferably 1 to 10 mg glidant.
[0102] The above-mentioned mixtures of siponimod with the at least
one pharmaceutical excipient can be transformed into a dosage form,
e.g. a capsule or a tablet, preferably a tablet.
[0103] The dosage form can be formed by direct compression. Hence,
the above blending mixtures can be compressed into tablets.
[0104] Alternatively, the dosage form can be formed by dry
granulation. Dry granulation involves the steps of dry powder
blending, initial compaction (slugging or roller compaction),
milling, addition of extragranular excipients and lubrication
before compaction or capsule filling.
[0105] Further, if the dosage form is a tablet, the tablet can be
film-coated. For this purpose, standard methods of film coating
tablets may be employed. The above-mentioned amounts of siponimod
and excipients, however, relate to the uncoated tablet.
[0106] For film coating, macromolecular substances are preferably
used, such as modified celluloses, polymethacrylates,
polyvinylpyrrolidone, polyvinyl acetate phthalate and/or shellac.
In an embodiment the coating can have a thickness of 2 to 80 .mu.m,
more preferably 5 to 50 .mu.m.
[0107] Release Profiles of Dosage Forms Comprising Siponimod
[0108] The preferred dosage forms have been described above. In a
further preferred embodiment, a single 2 mg siponimod dosage form
is administered as a maintenance regimen, leading in-vivo to a Cmax
of 10 to 20 ng/ml, preferably 14.0 to 17.0 ng/ml, more preferably
14.5 to 16.5 ng/ml, still more preferably 15.0 to 16.0 ng/ml, and
to a AUClast of 300 to 700 h-ng/ml, preferably 500 to 560 h-ng/ml,
more preferably 510 to 550 h-ng/ml, still more preferably 520 to
540 h-ng/ml.
[0109] "Cmax" means the peak concentration of siponimod in the
plasma, e.g. determined as described below. "AUClast" describes
siponimod bioavailability and is measured by calculating the area
under curve (AUC) of the plasma drug concentration time profile
from time zero to the time of the last quantifiable concentration.
AUClast can be determined as described below.
[0110] In a further preferred embodiment, a single 2 mg siponimod
dosage form is administered as a maintenance regimen, the in-vivo
AUC-time profile from time zero to infinity (AUCinf) of said dosage
form being 350 to 750 h-ng/ml, preferably 520 to 600 h ng/ml, more
preferably 540 to 580 h-ng/ml, still more preferably 550 to 570
h-ng/ml.
[0111] In a further preferred embodiment, a single 2 mg siponimod
dosage form is administered as a maintenance regimen, leading
in-vivo to a Tmax of 3 to 8 h, preferably 3 to 7 h, more preferably
3 to 6 h, most preferably 3 to 5 h.
[0112] "Tmax" means the time from administration to reach Cmax.
[0113] The Cmax, AUClast, AUCinf and Tmax values typically can be
determined in vivo in healthy subjects, aged 20 to 40 years. The
subjects typically have maximal .+-.10% divergence from the ideal
weight, in order to minimize a strong fluctuation of the
distribution volume. Ideally, the administration of the medicament
occurs on an empty stomach. The type and amount of the
administration liquid is identical for every administration and for
every subject. Blood samples are taken at the initial phase with a
higher frequency than at a later stage, in order to increase the
accuracy of the measurement.
[0114] The AUC values are calculated after one administration,
preferably using the Trapezoidal Rule as is generally known in the
art.
[0115] In a further preferred embodiment, the titration regimen
comprises administering a 0.25 mg siponimod dosage form, said
administration leading in-vivo to a Cmax of 1.3 to 2.6 ng/ml,
preferably 1.5 to 2.4 ng/ml, more preferably 1.7 to 2.2 ng/ml,
still more preferably 1.9 to 2.0 ng/ml, and to a AUClast of 45 to
90 h-ng/ml, preferably 50 to 80 h-ng/ml, more preferably 55 to 75
h-ng/ml, still more preferably 60 to 70 h-ng/ml.
[0116] In another preferred embodiment, the titration regimen
comprises administering a 0.25 mg siponimod dosage form, the
in-vivo AUC-time profile from time zero to infinity (AUCinf) of
said dosage form being 47 to 95 h-ng/ml, preferably 55 to 85
h-ng/ml, more preferably 60 to 80 h-ng/ml, still more preferably 65
to 75 h-ng/ml.
[0117] In yet a further preferred embodiment of the invention, the
titration regimen comprises administering a 0.25 mg siponimod
dosage form, said administration leading in-vivo to a Tmax of 3 to
8 h, preferably 3 to 7 h, more preferably 3 to 6 h, most preferably
3 to 5 h.
[0118] In a further preferred embodiment, the titration regimen
comprises administering a 0.5 mg siponimod dosage form, said
administration leading in-vivo to a Cmax of 2.6 to 5.2 ng/ml,
preferably 3.0 to 4.8 ng/ml, more preferably 3.4 to 4.4 ng/ml,
still more preferably 3.7 to 4.0 ng/ml, and to a AUClast of 90 to
180 h-ng/ml, preferably 100 to 160 h-ng/ml, more preferably 110 to
150 h-ng/ml, still more preferably 120 to 140 h-ng/ml.
[0119] In a further preferred embodiment, the titration regimen
comprises administering a 0.5 mg siponimod dosage form, the in-vivo
AUC-time profile from time zero to infinity (AUCinf) of said dosage
form being 95 to 190 h-ng/ml, preferably 110 to 170 h-ng/ml, more
preferably 120 to 160 h-ng/ml, still more preferably 130 to 150
h-ng/ml.
[0120] In a further preferred embodiment of the invention, the
titration regimen comprises administering a 0.5 mg siponimod dosage
form, said administration leading in-vivo to a Tmax of 3 to 8 h,
preferably 3 to 7 h, more preferably 3 to 6 h, most preferably 3 to
5 h.
[0121] In a further preferred embodiment, the titration regimen
comprises administering a 1 mg siponimod dosage form, said
administration leading in-vivo to a Cmax of 5 to 10 ng/ml,
preferably 5.5 to 9.5 ng/ml, more preferably 6 to 9 ng/ml, still
more preferably 7 to 8 ng/ml, and to a AUClast of 180 to 360
h-ng/ml, preferably 200 to 320 h-ng/ml, more preferably 220 to 300
h-ng/ml, still more preferably 240 to 280 h-ng/ml.
[0122] In a further preferred embodiment, the titration regimen
comprises administering a 1 mg siponimod dosage form, the in-vivo
AUG-time profile from time zero to infinity (AUCinf) of said dosage
form being 190 to 370 h-ng/ml, preferably 220 to 340 h-ng/ml, more
preferably 140 to 320 h-ng/ml, still more preferably 260 to 300
h-ng/ml.
[0123] In a further preferred embodiment of the invention, the
titration regimen comprises administering a 1 mg siponimod dosage
form, said administration leading in-viva to a Tmax of 3 to 8 h,
preferably 3 to 7 h, more preferably 3 to 6 h, most preferably 3 to
5 h.
[0124] In a further preferred embodiment, the titration regimen
comprises administering a 2 mg siponimod dosage form, leading
in-vivo to a Cmax of 10 to 20 ng/ml, preferably 14.0 to 17.0 ng/ml,
more preferably 14.5 to 165 ng/ml, still more preferably 15.0 to
16.0 ng/ml, and to a AUClast of 300 to 700 h-ng/ml, preferably 500
to 560 h-ng/ml, more preferably 510 to 550 h-ng/ml, still more
preferably 520 to 540 h-ng/ml.
[0125] In a further preferred embodiment, the titration regimen
comprises administering a 2 mg siponimod dosage form, the in-vivo
AUC-time profile from time zero to infinity (AUCinf) of said dosage
form being 350 to 750 h-ng/ml, preferably 520 to 600 h-ng/ml, more
preferably 540 to 580 h-ng/ml, still more preferably 550 to 570
h-mg/ml.
[0126] In a further preferred embodiment of the invention, the
titration regimen comprises administering a 1 mg siponimod dosage
form, said administration leading in-vivo to a Tmax of 3 to 8 h,
preferably 3 to 7 h, more preferably 3 to 6 h, most preferably 3 to
5 h.
[0127] Siponimod Maintenance Regimen and Titration Regimen
[0128] Generally, the term "maintenance regimen" as used herein
refers to the administration of siponimod after the up-titration is
completed. Said maintenance regime comprises the administration of
the maintenance dose of 1-15 mg siponimod, preferably 1-10 mg
siponimod, more preferably 1-5 mg siponimod, most preferably 1-2 mg
siponimod. Preferably, the maintenance regime is carried out
continuously, for example over several days, weeks, months or
years.
[0129] In one embodiment, the initial titration regimen comprises
administering siponimod such that the dosage administered on a
specific day of the initial titration regimen is the sum of the
dosages administered on the previous two days within a range of
.+-.40%.
[0130] In general, the titration regimen is continued until the
maintenance dose is reached. In one embodiment, the titration
regimen is conducted over 3-10 days, whereafter the maintenance
dose is administered. In a preferred embodiment, the titration
regimen is conducted over 6 days, whereby the maintenance dose is
administered from day 6 onwards.
[0131] In one preferred embodiment, the maintenance regimen
comprises the administration of 1 mg siponimod. In another
preferred embodiment, the maintenance regime comprises the
administration of 2 mg siponimod.
[0132] In one embodiment, in the titration regimen dosage forms
comprising 0.25 mg, 0.5 mg, 1 mg or 2 mg siponimod are used.
[0133] In one embodiment, in the titration regimen immediate
release dosage forms comprising 0.25 mg, 0.5 mg, 1 mg or 2 mg
siponimod are used.
[0134] In one embodiment of the invention, siponimod is
administered once daily in the maintenance regimen as well as in
the titration regimen.
[0135] In one embodiment, the titration regimen comprises one
administration of a dosage form comprising 0.25 mg siponimod at day
1, one administration of a dosage form comprising 0.25 mg siponimod
at day 2, one administration of a dosage form comprising 0.5 mg
siponimod at day 3, one concomitant administration of a dosage form
comprising 0.5 mg siponimod together with a dosage form comprising
0.25 mg siponimod at day 4, one concomitant administration of a
dosage form comprising 1 mg siponimod together with a dosage form
comprising 0.25 mg siponimod at day 5, and one administration of a
dosage form comprising 2 mg siponimod at day 6.
[0136] Preferably, an immediate release dosage form is administered
in the maintenance regimen as well as n the titration regimen.
[0137] In a preferred embodiment of the invention, an immediate
release dosage form comprising 2 mg siponimod is administered once
daily to a patient as a maintenance regimen, after the patient has
experienced a titration regimen of 025 mg siponimod at day 1, 0.25
mg siponimod at day 2, 0.5 mg siponimod at day 3, 0.75 mg siponimod
at day 4, 1.25 mg siponimod at day 5, and 2 mg siponimod at day
6.
[0138] In a preferred embodiment of the invention, the siponimod
used in the titration regimen and in the maintenance regimen is
siponimod hemifumarate. Generally, all explanations given above of
preferred embodiments of siponimod (e.g. salts, particle size),
excipients and dissolution behaviour preferably apply to the dosage
form of the maintenance regimen as well as to the dosage form of
the titration regimen.
[0139] Beta-Blockers
[0140] Beta-blockers are a well-known family of beta adrenergic
receptor antagonists that function as competitive pharmacologic
inhibitors of catecholamine actions. It is known in the field that
beta-blockers have widespread utility in the treatment of
cardiovascular and non-cardiovascular diseases, in particular
hypertension, angina pectoris, tremor and migraine. In one
embodiment of the invention, the beta-blocker propranolol is used
in the treatment of hypertension. Typically, treatment with
propranolol comprises administering a daily dose of 30 to 320 mg
propranolol, e.g. 80 mg propranolol. Typical dosage forms comprise
10, 40 or 80 mg propranolol.
[0141] Beta-blockers include propranolol (Dociton.TM.,
Inderal.TM.), atenolol (Tenormin.TM.), carteolol (Cartrol.TM.,
Ocupress.TM.), carvedilol (Coreg.TM., Kredex.TM.), labetalol
(Normodyne.TM., Trandate.TM.), nadolol (Corgard.TM.), oxprenolol
(Trasacor.TM., Tevacor.TM.), penbutolol (Levatol.TM.,
Betapressin.TM.), pindolol (Visken.TM., Betapindol.TM.), sotalol
(Betapace.TM., Sotalex.TM.), timolol (Betimol.TM., Timoptic.TM.),
acebutolol (Sectral.TM., Prent.TM.), betaxolol (Betoptic.TM.,
Lokren.TM.), bisoprolol (Zebeta.TM.), celiprolol (Cardem.TM.,
Selectol.TM.), esmolol (Brevibloc.TM.), metoprolol (Lopressor.TM.,
Toprol-XL.TM.) and nebivolol (Nebilet.TM., Bystolic.TM.).
[0142] The structure/chemical name of an active ingredient
identified by a generic or trade name may be taken from the current
edition of a standard compendium, e.g. "The Merck Index", or from a
database, e.g. Patents International (e.g. IMS World Publications).
The corresponding contents thereof are herewith incorporated
hereinto by reference. Any person skilled in the art is fully
enabled to identify the active ingredients based on these
references.
[0143] Preferably, the beta-blocker is selected from the group
consisting of propranolol, atenolol, carteolol, carvedilol,
labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol,
timolol, acebutolol, betaxolol, bisoprolol, celiprolol, esmolol,
metoprolol and nebivolol.
[0144] In one embodiment, the beta-blocker as used in the context
of the invention is propranolol.
[0145] In one embodiment, the beta-blocker as used in the context
of the invention is atenolol.
[0146] In one embodiment, the beta-blocker as used in the context
of the invention is carteolol.
[0147] In one embodiment, the beta-blocker as used in the context
of the invention is carvedilol.
[0148] In one embodiment, the beta-blocker as used in the context
of the invention is labetalol.
[0149] In one embodiment, the beta-blocker as used in the context
of the invention is nadolol.
[0150] In one embodiment, the beta-blocker as used in the context
of the invention is oxprenolol.
[0151] In one embodiment, the beta-blocker as used in the context
of the invention is penbutolol.
[0152] In one embodiment, the beta-blocker as used in the context
of the invention is pindolol.
[0153] In one embodiment, the beta-blocker as used in the context
of the invention is sotalol.
[0154] In one embodiment, the beta-blocker as used in the context
of the invention is timolol.
[0155] In one embodiment, the beta-blocker as used in the context
of the invention is acebutolol.
[0156] In one embodiment, the beta-blacker as used in the context
of the invention is betaxolol.
[0157] In one embodiment, the beta-blocker as used in the context
of the invention is bisoprolol.
[0158] In one embodiment, the beta-blocker as used in the context
of the invention is celiprolol.
[0159] In one embodiment, the beta-blocker as used in the context
of the invention is esmolol.
[0160] In one embodiment, the beta-blocker as used in the context
of the invention is metoprolol.
[0161] In one embodiment, the beta-blocker as used in the context
of the invention is nebivolol.
[0162] It will be understood, that a reference to an active
ingredient throughout the description and the claims includes said
active ingredient in free form and in form of a pharmaceutically
acceptable salt. If an active ingredient has, e.g., at least one
basic center, it can form an acid addition salt. An active
ingredient having at least one acidic group can form a salt with a
base. An active ingredient, in free form or in pharmaceutically
acceptable salt form, may be in the form of a hydrate and/or may
include other solvents, for example solvents used for the
crystallization of a compound in solid form.
[0163] A "pharmaceutically acceptable salt" is intended to mean a
salt of a free base/free acid of an active ingredient that is not
toxic, biologically intolerable, or otherwise biologically
undesirable. Preferred pharmaceutically acceptable salts are those
that are pharmacologically effective and suitable for contact with
the tissues of patients without undue toxicity, irritation, or
allergic response. Such salts are known in the field (e.g. S M
Berge et al, "Pharmaceutical Salts", J Pharm Sd, 1977, 66:1-19; and
"Handbook of Pharmaceutical Salts, Properties, Selection, and Use",
R H Stahl, C G Wermuth, Eds, Wiley-VCH and VHCA: Zurich, 2002).
[0164] Clinically Relevant Scenario 1
[0165] In accordance with a first aspect of the invention, there is
provided a method of treating an autoimmune disease in a patient
comprising [0166] a) administering to said patient an initial
titration regimen of siponimod; [0167] b) administering to said
patient 1-15 mg siponimod daily as a maintenance regimen; and
[0168] c) introducing in said patient a beta-blocker treatment the
earliest at the first day when said patient is receiving the dosage
of the maintenance regimen; wherein said initial titration regimen
comprises administering siponimod at a dosage lower than the dosage
of the maintenance regimen and then increasing the dosage stepwise
up to the dosage of the maintenance regimen.
[0169] In a preferred embodiment of the first aspect of the
invention, there is provided a method of treating secondary
progressive multiple sclerosis in a patient comprising [0170] a)
administering to said patient an initial titration regimen of
siponimod; [0171] b) administering to said patient an immediate
release dosage form comprising 2 mg siponimod once daily as a
maintenance regimen; and [0172] c) introducing in said patient a
beta-blocker treatment the earliest at the first day when said
patient is receiving the dosage of the maintenance regimen; wherein
said initial titration regimen comprises one administration of 0.25
mg siponimod at day 1, one administration of 0.25 mg siponimod at
day 2, one administration of 0.5 mg siponimod at day 3, one
administration of D.75 mg siponimod at day 4, one administration of
1.25 mg siponimod at day 5, and one administration of 2 mg
siponimod at day 6; and wherein, in said initial titration regimen,
immediate release dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and
2 mg siponimod are used.
[0173] In a further preferred embodiment of the first aspect of the
invention, there is provided a method of treating secondary
progressive multiple sclerosis in a patient comprising [0174] a)
administering to said patient an initial titration regimen of
siponimod; [0175] b) administering to said patient an immediate
release dosage form comprising 2 mg siponimod once daily as a
maintenance regimen; and [0176] c) introducing in said patient a
beta-blacker treatment the earliest at the first day when a
pharmacokinetic steady state of siponimod is reached; wherein said
initial titration regimen comprises one administration of 0.25 mg
siponimod at day 1, one administration of 0.25 mg siponimod at day
2, one administration of 0.5 mg siponimod at day 3, one
administration of 0.75 mg siponimod at day 4, one administration of
1.25 mg siponimod at day 5, and one administration of 2 mg
siponimod at day 6; and wherein, in said initial titration regimen,
immediate release dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and
2 mg siponimod are used.
[0177] Clinically Relevant Scenario 2
[0178] In accordance with a second aspect of the invention, there
is provided a method of treating an autoimmune disease in a patient
receiving a chronic beta-blocker treatment and having a resting
heart rate of >50 bpm under said chronic beta-blocker treatment
comprising introducing in said patient a siponimod treatment by
[0179] a) administering to said patient an initial titration
regimen of siponimod; and [0180] b) administering to said patient
1-15 mg siponimod daily as a maintenance regimen; wherein said
initial titration regimen comprises administering siponimod at a
dosage lower than the dosage of the maintenance regimen and then
increasing the dosage stepwise up to the dosage of the maintenance
regimen.
[0181] In a preferred embodiment of the second aspect of the
invention, there is provided a method of treating secondary
progressive multiple sclerosis in a patient receiving a chronic
beta-blocker treatment and having a resting heart rate of >50
bpm under said chronic beta-blocker treatment comprising
introducing in said patient a siponimod treatment by [0182] a)
administering to said patient an initial titration regimen of
siponimod; and [0183] b) administering to said patient an immediate
release dosage form comprising 2 mg siponimod once daily as a
maintenance regimen; wherein said initial titration regimen
consists of one administration of 0.25 mg siponimod at day 1, one
administration of 0.25 mg siponimod at day 2, one administration of
0.5 mg siponimod at day 3, one administration of 0.75 mg siponimod
at day 4, one administration of 1.25 mg siponimod at day 5 and one
administration of 2 mg siponimod at day 6; and wherein, in said
initial titration regimen, immediate release dosage forms
comprising 0.25 mg, 0.5 mg, 1 mg and 2 mg siponimod are used.
[0184] In a third aspect of the invention, there is provided a
method of treating an autoimmune disease in a patient receiving a
chronic beta-blocker treatment and having a resting heart rate of
.ltoreq.50 bpm under said chronic beta-blocker treatment comprising
[0185] a) interrupting said chronic beta-blocker treatment in said
patient until the baseline heart-rate is >50 bpm; [0186] b)
initiating in said patient a siponimod treatment by [0187] B1)
administering to said patient an initial titration regimen of
siponimod; and [0188] b2) administering to said patient 1-15 mg
siponimod daily as a maintenance regimen; and [0189] c)
re-initiating in said patient a beta-blocker treatment the earliest
at the first day when said patient is receiving the dosage of the
maintenance regimen; wherein said initial titration regimen
comprises administering siponimod at a dosage lower than the dosage
of the maintenance regimen and then increasing the dosage stepwise
up to the dosage of the maintenance regimen.
[0190] In a preferred embodiment of the third aspect of the
invention, there is provided a method of treating secondary
progressive multiple sclerosis in a patient receiving a chronic
beta-blocker treatment and having a resting heart rate of
.ltoreq.50 bpm under said chronic beta-blocker treatment comprising
[0191] a) interrupting said chronic beta-blocker treatment in said
patient until the baseline heart-rate is >50 bpm; [0192] b)
initiating in said patient a siponimod treatment by [0193] b1)
administering to said patient an initial titration regimen of
siponimod; and [0194] b2) administering to said patient an
immediate release dosage form comprising 2 mg siponimod once daily
as a maintenance regimen; and [0195] c) re-initiating in said
patient a beta-blocker treatment after 2 weeks of treatment with
siponimod; wherein said initial titration regimen consists of one
administration of 0.25 mg siponimod at day 1, one administration of
0.25 mg siponimod at day 2, one administration of 0.5 mg siponimod
at day 3, one administration of 0.75 mg siponimod at day 4, one
administration of 0.25 mg siponimod at day 5 and one administration
of 2 mg siponimod at day 6; and wherein, in said titration regimen,
immediate release dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and
2 mg siponimod are used.
FURTHER DEFINITIONS AND EMBODIMENTS OF THE INVENTION
[0196] The terms "treatment"/"treating" as used herein includes:
(1) preventing or delaying the appearance of clinical symptoms of
the state, disorder or condition developing in an animal,
particularly a mammal and especially a human, that may be afflicted
with or predisposed to the state, disorder or condition but does
not yet experience or display clinical or subclinical symptoms of
the state, disorder or condition; (2) inhibiting the state,
disorder or condition (e.g. arresting, reducing or delaying the
development of the disease, or a relapse thereof in case of
maintenance treatment, of at least one clinical or subclinical
symptom thereof); and/or (3) relieving the condition (i.e. causing
regression of the state, disorder or condition or at least one of
its clinical or subclinical symptoms). The benefit to a patient to
be treated is either statistically significant or at least
perceptible to the patient or to the physician. However, it will be
appreciated that when a medicament is administered to a patient to
treat a disease, the outcome may not always be effective
treatment.
[0197] In one embodiment, the siponimod as used in the context of
the present invention is effective to reduce a symptom of relapsing
remitting multiple sclerosis (RRMS) or secondary progressive
multiple sclerosis (SPMS), preferably SPMS. In one embodiment, the
symptom is an MRI-monitored multiple sclerosis disease activity,
disability progression, brain atrophy, neuronal dysfunction,
neuronal injury, neuronal degeneration, deterioration of visual
function, impaired mobility, cognitive impairment, reduction of
brain volume, deterioration in general health status, functional
status and/or quality of life.
[0198] In another embodiment, the siponimod as used in the context
of the present invention is effective to reduce a symptom of
polymyositis or dermatomyositis, preferably polymyositis. In one
embodiment, the symptom is pain, with marked weakness and/or lass
of muscle mass in the muscles of the head, neck, torso and upper
arms and legs. In one embodiment, the symptom is dysphagia, low
grad fever, peripheral adenopathy, foot drop and interstitial lung
disease.
[0199] An example of an autoimmune condition according to the
present invention is multiple sclerosis (MS), for example
relapsing-remitting MS (RRMS), primary progressive MS (PPMS),
secondary progressive MS (SPMS) and relapsing SPMS. Preferably, the
siponimod as used in the context of the present invention is used
for treating RRMS and/or SPMS, most preferably SPMS.
[0200] A further example of an autoimmune condition according to
the present invention is inflammatory myopathy, for example
polymyositis and dermatomyositis. Preferably, the siponimod as used
in the context of the present invention is used for treating
polymyositis.
[0201] The expression "introducing a beta-blocker treatment" as
used herein means administering a first dose of beta-blocker
according to the respective summary of product characteristics
(SmPC). In the context of the present invention, beta-blocker
treatment is introduced the earliest at the first day of
administration of the dosage of the siponimod maintenance regimen,
preferably when a pharmacokinetic steady state of siponimod is
reached. A pharmacokinetic steady state of siponimod is reached in
general during the maintenance regimen, however the exact point in
time may vary between patients, e.g. depending on their
disease/disease state.
[0202] The expression "introducing a siponimod treatment" as used
herein means administering an initial titration regimen of
siponimod, followed by administering a respective maintenance
regimen.
[0203] The expression "re-initiating a beta-blocker treatment" as
used herein means administering a first dose of beta-blocker
according to the respective summary of product characteristics
(SmPC), following a beta-blocker treatment holiday, which in some
cases might be necessary due to upcoming introduction of siponimod
treatment. In a preferred embodiment of the invention, beta-blocker
treatment is re-initiated 8 days after the siponimod titration
regimen has been concluded. In a particularly preferred embodiment,
the siponimod titration regimen is distributed over 6 days and
beta-blocker treatment is re-initiated after 2 weeks of treatment
with siponimod, i.e. 2 weeks after the first administration of
siponimod.
[0204] It is common knowledge in the field that discontinuation of
beta-blocker therapy may be accompanied by withdrawal syndromes,
such as hyperadrenergic symptoms, exacerbations of angina, acute
myocardial infarction and sudden death. Generally, beta-blockers
should be tapered slowly rather than discontinued abruptly.
Accordingly, the expression "Interruption of beta-blocker
treatment" as used herein means interruption according to the SmPC
of the beta-blocker in question.
[0205] The term "resting heart rate" (RHR) as used herein means the
number of contractions of the heart that occur in a single minute
while the body is at complete rest. This number will vary depending
upon the age, gender, and general health of a person.
[0206] As used herein, "bradycardia" typically refers to a
RHR<50 bpm.
[0207] The term "baseline heart rate" as used herein means a
referential heart rate to which other heart rates, such as the
heart rate under chronic beta-blocker treatment, can be compared
to. Typically, the RHR in the absence of any heart rate-affecting
medication serves as the baseline heart rate.
[0208] The abbreviation "HR" as used herein means "heart rate". A
person having ordinary skill in the art will typically measure the
HR using an electrocardiograph.
[0209] The expression "E.sub.max" as used herein means the maximum
change from baseline in time matched, hourly average HR.
[0210] The expression "FEV.sub.1" as used herein is a pulmonary
parameter and means "forced expiratory volume in 1 second". A
person having ordinary skill in the art will be well acquainted
with the assessment of FEV.sub.1 and will follow the standard
pulmonary laboratory practice, which is consistent with the
American Thoracic Society/European Respiratory Society
Standardization of Spirometry.
[0211] The abbreviation "AVB" as used herein means
"atrioventricular block".
[0212] The abbreviation "SP" as used herein means "sinus pause",
also known as sinoatrial arrest.
[0213] A further aspect of the invention comprises the following
enumerated embodiments:
[0214] Enumerated Embodiment 1: A method of treating an autoimmune
disease in a patient comprising [0215] a) administering to said
patient an initial titration regimen of siponimod; [0216] b)
administering to said patient 1.15 mg siponimod daily as a
maintenance regimen; and [0217] c) introducing in said patient a
beta-blocker treatment the earliest at the first day when said
patient is receiving the dosage of the maintenance regimen; wherein
said initial titration regimen comprises administering siponimod at
a dosage lower than the dosage of the maintenance regimen and then
increasing the dosage stepwise up to the dosage of the maintenance
regimen.
[0218] Enumerated Embodiment 2: The method according to enumerated
embodiment 1, wherein said autoimmune disease is selected from
inflammatory myopathy and multiple sclerosis.
[0219] Enumerated Embodiment 3: The method according to enumerated
embodiment 1, wherein said autoimmune disease is selected from
polymyositis, dermatomyositis, inclusion-body myositis and
secondary progressive multiple sclerosis.
[0220] Enumerated Embodiment 4: The method according to enumerated
embodiment 1, wherein said autoimmune disease is secondary
progressive multiple sclerosis.
[0221] Enumerated Embodiment 5: The method according to any one of
the preceding enumerated embodiments, wherein the maintenance
regimen administered in step b) of said method comprises 2-10 mg
siponimod.
[0222] Enumerated Embodiment 6: The method according to enumerated
embodiment 5, wherein said maintenance regimen comprises 2-5 mg
siponimod.
[0223] Enumerated Embodiment 7: The method according to any one of
the preceding enumerated embodiments, wherein the maintenance
regimen administered in step b) of said method is administered once
daily.
[0224] Enumerated Embodiment 8: The method according to any one of
the preceding enumerated embodiments, wherein in the maintenance
regimen administered in step b) of said method an immediate release
dosage form is used.
[0225] Enumerated Embodiment 9: The method according to any one of
the preceding enumerated embodiments, wherein said initial
titration regimen comprises administering siponimod such that the
dosage administered on a specific day of the initial titration
regimen is the sum of the dosages administered on the previous two
days within a range of .+-.40%.
[0226] Enumerated Embodiment 10: The method according to any one of
the preceding enumerated embodiments, wherein said initial
titration regimen is conducted over 3-10 days.
[0227] Enumerated Embodiment 11: The method according to any one of
the preceding enumerated embodiments, wherein the dosage of the
maintenance regimen is 2 mg siponimod and wherein said initial
titration regimen comprises administering 0.25 mg siponimod at day
1, 0.25 mg of siponimod at day 2, 0.5 mg siponimod at day 3, 0.75
mg siponimod at day 4, 1.25 mg siponimod at day 5 and 2 mg
siponimod at day 6.
[0228] Enumerated Embodiment 12: The method according to enumerated
embodiment 11, wherein said initial titration regimen comprises one
administration of 0.25 mg siponimod at day 1, one administration of
0.25 mg siponimod at day 2, one administration of 0.5 mg siponimod
at day 3, one administration of 0.75 mg siponimod at day 4, one
administration of 1.25 mg siponimod at day 5 and one administration
of 2 mg siponimod at day 6.
[0229] Enumerated Embodiment 13: The method according to enumerated
embodiment 12, wherein, in said initial titration regimen,
immediate release dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and
2 mg siponimod are used.
[0230] Enumerated Embodiment 14: The method according to enumerated
embodiment 1, wherein [0231] said autoimmune disease is secondary
progressive multiple sclerosis; [0232] wherein the maintenance
regimen administered in step b) of said method is an immediate
release dosage form comprising 2 mg siponimod; [0233] wherein the
maintenance regimen administered in step b) of said method is
administered once daily; [0234] wherein the initial titration
regimen administered in step a) of said method comprises one
administration of 0.25 mg siponimod at day 1, one administration of
0.25 mg siponimod at day 2, one administration of 0.5 mg siponimod
at day 3, one administration of 0.75 mg siponimod at day 4,one
administration of 1.25 mg siponimod at day 5 and one administration
of 2 mg siponimod at day 6; and [0235] wherein in the initial
titration regimen administered in step a) of said method immediate
release dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and 2 mg
siponimod are used.
[0236] Enumerated Embodiment 15: A method of treating secondary
progressive multiple sclerosis in a patient comprising [0237] a)
administering to said patient an initial titration regimen of
siponimod; [0238] b) administering to said patient an immediate
release dosage form comprising 2 mg siponimod once daily as a
maintenance regimen; and [0239] c) introducing in said patient a
beta-blocker treatment the earliest at the first day when said
patient is receiving the dosage of the maintenance regimen; wherein
said initial titration regimen comprises one administration of 0.25
mg siponimod at day 1, one administration of 0.25 mg siponimod at
day 2, one administration of 0.5 mg siponimod at day 3, one
administration of 0.75 mg siponimod at day 4,one administration of
1.25 mg siponimod at day 5 and one administration of 2 mg siponimod
at day 6; and wherein, in said initial titration regimen, immediate
release dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and 2 mg
siponimod are used.
[0240] Enumerated Embodiment 16: Siponimod for use in the treatment
of an autoimmune disease in a patient comprising [0241] a)
administering to said patient an initial titration regimen of
siponimod; [0242] b) administering to said patient 1-15 mg
siponimod dally as a maintenance regimen; and [0243] c) introducing
in said patient a beta-blocker treatment the earliest at the first
day when said patient is receiving the dosage of the maintenance
regimen; wherein said initial titration regimen comprises
administering siponimod at a dosage lower than the dosage used as a
maintenance regimen and then increasing the dosage stepwise up to
the dosage of the maintenance regimen.
[0244] Enumerated Embodiment 17: Siponimod for use in the treatment
of secondary progressive multiple sclerosis in a patient comprising
[0245] a) administering to said patient art initial titration
regimen of siponimod; [0246] b) administering to said patient an
immediate release dosage form comprising 2 mg siponimod once daily
as a maintenance regimen; and [0247] c) introducing in said patient
a beta-blocker treatment the earliest at the first day when said
patient is receiving the dosage of the maintenance regimen; wherein
said initial titration regimen comprises one administration of 0.25
mg siponimod at day 1, one administration of 0.25 mg siponimod at
day 2, one administration of 0.5 mg siponimod at day 3, one
administration of 0.75 mg siponimod at day 4,one administration of
1.25 mg siponimod at day 5 and one administration of 2 mg siponimod
at day 6; and wherein, in said initial titration regimen, immediate
release dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and 2 mg
siponimod are used.
[0248] Enumerated Embodiment 18: Use of siponimod in the
manufacture of a medication for the treatment of an autoimmune
disease in a patient comprising [0249] a) administering to said
patient an initial titration regimen of siponimod; [0250] b)
administering to said patient 1-15 mg siponimod daily as a
maintenance regimen; and [0251] c) introducing in said patient a
beta-blocker treatment the earliest at the first day when said
patient is receiving the dosage of the maintenance regimen; wherein
said initial titration regimen comprises administering siponimod at
a dosage lower than the dosage used as a maintenance regimen and
then increasing the dosage stepwise up to the dosage of the
maintenance regimen.
[0252] Enumerated Embodiment 19: Use of siponimod in the
manufacture of a medication for the treatment of secondary
progressive multiple sclerosis in a patient comprising [0253] a)
administering to said patient an initial titration regimen of
siponimod; [0254] b) administering to said patient an immediate
release dosage form comprising 2 mg siponimod once daily as a
maintenance regimen; and [0255] c) introducing in said patient a
beta-blocker treatment the earliest at the first day when said
patient is receiving the dosage of the maintenance regimen; wherein
said initial titration regimen comprises one administration of 0.25
mg siponimod at day 1, one administration of 0.25 mg siponimod at
day 2, one administration of 0.5 mg siponimod at day 3, one
administration of 0.75 mg siponimod at day 4,one administration of
1.25 mg siponimod at day 5 and one administration of 2 mg siponimod
at day 6; and wherein, in said initial titration regimen, immediate
release dosage forms comprising 0.25 mg, 0.5 mg,1 mg and 2 mg
siponimod are used.
[0256] Enumerated Embodiment 20: A method of treating an autoimmune
disease in a patient receiving a chronic beta-blocker treatment and
having a resting heart rate of >50 bpm under said chronic
beta-blocker treatment comprising introducing in said patient a
siponimod treatment by [0257] a) administering to said patient an
initial titration regimen of siponimod; and [0258] b) administering
to said patient 1-15 mg siponimod daily as a maintenance regimen;
wherein said initial titration regimen comprises administering
siponimod at a dosage lower than the dosage used as a maintenance
regimen and then increasing the dosage stepwise up to the dosage of
the maintenance regimen.
[0259] Enumerated Embodiment 21: The method according to enumerated
embodiment 20, wherein said autoimmune disease is selected from
inflammatory myopathy and multiple sclerosis.
[0260] Enumerated Embodiment 22: The method according to enumerated
embodiment 20, wherein said autoimmune disease is selected from
polymyositis, dermatomyositis, inclusion-body myositis and
secondary progressive multiple sclerosis.
[0261] Enumerated Embodiment 23: The method according to enumerated
embodiment 20, wherein said autoimmune disease is secondary
progressive multiple sclerosis.
[0262] Enumerated Embodiment 24: The method according to any one of
enumerated embodiments 20 to 23, wherein the maintenance regimen
administered in step b) of said method comprises 2-10 mg
siponimod.
[0263] Enumerated Embodiment 25: The method according to enumerated
embodiment 24, wherein said maintenance regimen comprises 2-5 mg
siponimod.
[0264] Enumerated Embodiment 26: The method according to any one of
enumerated embodiments 20 to 25, wherein the maintenance regimen
administered in step b) of said method is administered once
daily.
[0265] Enumerated Embodiment 27: The method according to any one of
enumerated embodiments 20 to 26, wherein the maintenance regimen
administered in step b) of said method is administered as an
immediate release dosage form.
[0266] Enumerated Embodiment 28: The method according to any one of
enumerated embodiments 20 to 27, wherein said initial titration
regimen comprises administering siponimod such that the dosage
administered on a specific day of the initial titration regimen is
the sum of the dosages administered on the previous two days within
a range of .+-.40%.
[0267] Enumerated Embodiment 29: The method according to any one of
enumerated embodiments 20 to 28, wherein said initial titration
regimen is conducted over 3-10 days.
[0268] Enumerated Embodiment 30: The method according to any one of
enumerated embodiments 20 to 29, wherein the dosage of the
maintenance regimen is 2 mg siponimod and wherein said initial
titration regimen comprises administering 0.25 mg siponimod at day
1, 0.25 mg of siponimod at day 2, 0.5 mg siponimod at day 3, 0.75
mg siponimod at day 4, 1.25 mg siponimod at day 5, and 2 mg
siponimod at day 6.
[0269] Enumerated Embodiment 31: The method according to enumerated
embodiment 30, wherein said initial titration regimen comprises one
administration of 0.25 mg siponimod at day 1, one administration of
0.25 mg siponimod at day 2, one administration of 05 mg siponimod
at day 3, one administration of 0.75 mg siponimod at day 4,one
administration of 1.25 mg siponimod at day 5 and one administration
of 2 mg siponimod at day 6.
[0270] Enumerated Embodiment 32: The method according to enumerated
embodiment 31, wherein, in said initial titration regimen,
immediate release dosage forms comprising 0.25 mg, 0.5 mg,1 mg and
2 mg siponimod are used.
[0271] Enumerated Embodiment 33: The method according to enumerated
embodiment 20, wherein [0272] said autoimmune disease is secondary
progressive multiple sclerosis; [0273] wherein the maintenance
regimen administered in step b) of said method is an immediate
release dosage form comprising 2 mg siponimod; [0274] wherein the
maintenance regimen administered in step b) of said method is
administered once daily; [0275] wherein the initial titration
regimen administered in step a) of said method comprises one
administration of 0.25 mg siponimod at day 1, one administration of
0.25 mg siponimod at day 2, one administration of 0.5 mg siponimod
at day 3, one administration of 0.75 mg siponimod at day 4,one
administration of 1.25 mg siponimod at day 5 and one administration
of 2 mg siponimod at day 6; and [0276] wherein in the initial
titration regimen administered in step a) of said method immediate
release dosage forms comprising 0.25 mg, 0.5 mg,1 mg and 2 mg
siponimod are used.
[0277] Enumerated Embodiment 34: A method of treating secondary
progressive multiple sclerosis in a patient receiving a chronic
beta-blocker treatment and having a resting heart rate of >50
bpm under said chronic beta-blocker treatment comprising
introducing in said patient a siponimod treatment by [0278] a)
administering to said patient an initial titration regimen of
siponimod; and [0279] b) administering to said patient an immediate
release dosage form comprising 2 mg siponimod once daily as a
maintenance regimen; [0280] wherein said initial titration regimen
consists of one administration of 0.25 mg siponimod at day 1, one
administration of 0.25 mg siponimod at day 2, one administration of
0.5 mg siponimod at day 3, one administration of 0.75 mg siponimod
at day 4,one administration of 1.25 mg siponimod at day 5 and one
administration of 2 mg siponimod at day 6; and [0281] wherein, in
said initial titration regimen, immediate release dosage forms
comprising 0.25 mg, 0.5 mg, 1 mg and 2 mg siponimod are used.
[0282] Enumerated Embodiment 35: Siponimod for use in the treatment
of an autoimmune disease in a patient receiving a chronic
beta-blocker treatment and having a resting heart rate of >50 g
bpm under said chronic beta-blocker treatment comprising
introducing in said patient a siponimod treatment by [0283] a)
administering to said patient an initial titration regimen of
siponimod; and [0284] b) administering to said patient 1-15 mg
siponimod daily as a maintenance regimen; wherein said initial
titration regimen comprises administering siponimod at a dosage
lower than the dosage used as a maintenance regimen and then
increasing the dosage stepwise up to the dosage of the maintenance
regimen.
[0285] Enumerated Embodiment 36: Siponimod for use in the treatment
of secondary progressive multiple sclerosis in a patient receiving
a chronic beta-blocker treatment and having a resting heart rate of
>50 bpm under said chronic beta-blocker treatment comprising
introducing in said patient a siponimod treatment by [0286] a)
administering to said patient an initial titration regimen of
siponimod; and [0287] b) administering to said patient an immediate
release dosage form comprising 2 mg siponimod once daily as a
maintenance regimen; [0288] wherein said initial titration regimen
consists of one administration of 0.25 mg siponimod at day 1, one
administration of 0.25 mg siponimod at day 2, one administration of
0.5 mg siponimod at day 3, one administration of 0.75 mg siponimod
at day 4,one administration of 1.25 mg siponimod at day 5 and one
administration of 2 mg siponimod at day 6; and [0289] wherein, in
said initial titration regimen, immediate release dosage forms
comprising 0.25 mg, 0.5 mg, 1 mg and 2 mg siponimod are used.
[0290] Enumerated Embodiment 37: Use of siponimod far the
manufacture of a medication for the treatment of an autoimmune
disease in a patient receiving a chronic beta-blocker treatment and
having a resting heart rate of >50 bpm under said chronic
beta-blocker treatment comprising introducing in said patient a
siponimod treatment by [0291] a) administering to said patient an
initial titration regimen of siponimod; and [0292] b) administering
to said patient 1-15 mg siponimod daily as a maintenance regimen;
wherein said initial titration regimen comprises administering
siponimod at a dosage lower than the dosage used as a maintenance
regimen and then increasing the dosage stepwise up to the dosage of
the maintenance regimen.
[0293] Enumerated Embodiment 38: Use of siponimod for the
manufacture of a medication for the treatment of secondary
progressive multiple sclerosis in a patient receiving a chronic
beta-blocker treatment and having a resting heart rate of >50
bpm under said chronic beta-blocker treatment comprising
introducing in said patient a siponimod treatment by [0294] a)
administering to said patient an initial titration regimen of
siponimod; and [0295] b) administering to said patient an immediate
release dosage form comprising 2 mg siponimod once daily as a
maintenance regimen; [0296] wherein said initial titration regimen
consists of one administration of 0.25 mg siponimod at day 1, one
administration of 0.25 mg siponimod at day 2, one administration of
0.5 mg siponimod at day 3, one administration of 0.75 mg siponimod
at day 4,one administration of 125 mg siponimod at day 5 and one
administration of 2 mg siponimod at day 6; and [0297] wherein, in
said initial titration regimen, immediate release dosage forms
comprising 0.25 mg, 0.5 mg, 1 mg and 2 mg siponimod are used.
[0298] Enumerated Embodiment 39: A method of treating an autoimmune
disease in a patient receiving a chronic beta-blocker treatment and
having a resting heart rate of .ltoreq.50 bpm under said chronic
beta-blacker treatment comprising [0299] a) interrupting said
chronic beta-blocker treatment in said patient until the baseline
heart-rate to is >50 bpm; [0300] b) administering to said
patient an initial titration regimen of siponimod; and initiating
in said patient a siponimod treatment by [0301] b1) administering
to said patient an initial titration regimen of siponimod; and
[0302] b2) administering to said patient 1-15 mg siponimod daily as
a maintenance regimen; and [0303] c) re-initiating in said patient
a beta-blocker treatment the earliest at the first day when said
patient is receiving the dosage of the maintenance regimen; wherein
said initial titration regimen comprises administering siponimod at
a dosage lower than the dosage used as a maintenance regimen and
then increasing the dosage stepwise up to the dosage of the
maintenance regimen.
[0304] Enumerated Embodiment 40: The method according to enumerated
embodiment 39, wherein said autoimmune disease is selected from
inflammatory myopathy and multiple sclerosis.
[0305] Enumerated Embodiment 41: The method according to enumerated
embodiment 39, wherein said autoimmune disease is selected from
polymyositis, dermatomyositis, inclusion-body myositis and
secondary progressive multiple sclerosis.
[0306] Enumerated Embodiment 42: The method according to enumerated
embodiment 39, wherein said autoimmune disease is secondary
progressive multiple sclerosis.
[0307] Enumerated Embodiment 43: The method according to any one of
enumerated embodiments 39 to 42, wherein the maintenance regimen
administered in step b2) of said method comprises 2-10 mg
siponimod.
[0308] Enumerated Embodiment 44: The method according to enumerated
embodiment 43, wherein said maintenance regimen comprises 2-5 mg
siponimod.
[0309] Enumerated Embodiment 45: The method according to any one of
enumerated embodiments 39 to 44, wherein the maintenance regimen
administered in step b2) of said method is administered once
daily.
[0310] Enumerated Embodiment 46: The method according to any one of
enumerated embodiments 39 to 45, wherein the maintenance regimen
administered in step b2) of said method is administered as an
immediate release dosage form.
[0311] Enumerated Embodiment 47: The method according to any one of
enumerated embodiments 39 to 46, wherein said initial titration
regimen comprises administering siponimod such that the dosage
administered on a specific day of the initial titration regimen is
the sum of the dosages administered on the previous two days within
a range of .+-.40%.
[0312] Enumerated Embodiment 48: The method according to any one of
enumerated embodiments 39 to 47, wherein said initial titration
regimen is conducted over 3-10 days.
[0313] Enumerated Embodiment 49: The method according to any one of
enumerated embodiments 39 to 48, wherein the dosage of the
maintenance regimen is 2 mg siponimod and wherein said initial
titration regimen comprises administering 0.25 mg siponimod at day
1, 0.25 mg of siponimod at day 2, 0.5 mg siponimod at day 3, 0.75
mg siponimod at day 4, 1.25 mg siponimod at day 5 and 2 mg
siponimod at day 6.
[0314] Enumerated Embodiment 50: The method according to enumerated
embodiment 49, wherein said initial titration regimen comprises one
administration of 0.25 mg siponimod at day 1, one administration of
0.25 mg siponimod at day 2, one administration of 0.5 mg siponimod
at day 3, one administration of 0.75 mg siponimod at day 4,one
administration of 1.25 mg siponimod at day 5 and one administration
of 2 mg siponimod at day 6.
[0315] Enumerated Embodiment 51: The method according to enumerated
embodiment 50, wherein, in said initial titration regimen,
immediate release dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and
2 mg siponimod are used.
[0316] Enumerated Embodiment 52: The method according to any one of
enumerated embodiments 39 to 51, wherein the beta-blocker treatment
re-initiated in step c) of said method is re-initiated after 2-3
weeks of treatment with siponimod.
[0317] Enumerated Embodiment 53: The method according to enumerated
embodiment 39 wherein said autoimmune disease is secondary
progressive multiple sclerosis; [0318] wherein the maintenance
regimen administered in step b2) of said method is an immediate
release dosage form comprising 2 mg siponimod; [0319] wherein the
maintenance regimen administered in step b2) of said method is
administered once daily;
[0320] wherein the initial titration regimen administered in step
b1) of said method comprises one administration of 0.25 mg
siponimod at day 1, one administration of 0.25 mg siponimod at day
2, one administration of 0.5 mg siponimod at day 3, one
administration of 0.75 mg siponimod at day 4,one administration of
1.25 mg siponimod at day 5 and one administration of 2 mg siponimod
at day 6; [0321] in the initial titration regimen administered in
step b1) of said method immediate release dosage forms comprising
0.25 mg, 0.5 mg, 1 mg and 2 mg siponimod are used; and [0322]
wherein the beta-blocker treatment re-initiated in step c) of said
method is re-initiated after 2 weeks of treatment with
siponimod.
[0323] Enumerated Embodiment 54: A method of treating secondary
progressive multiple sclerosis in a patient receiving a chronic
beta-blocker treatment and having a resting heart rate of
.ltoreq.50 bpm under said chronic beta-blocker treatment comprising
[0324] a) interrupting said chronic beta-blocker treatment in said
patient until the baseline heart-rate is >50 bpm; [0325] b)
initiating in said patient a siponimod treatment by [0326] b1)
administering to said patient an initial titration regimen of
siponimod; and [0327] b2) administering to said patient an
immediate release dosage form comprising 2 mg siponimod once daily
as a maintenance regimen; and [0328] c) re-initiating in said
patient a beta-blocker treatment after 2 weeks of treatment with
siponimod; wherein said initial titration regimen consists of one
administration of 0.25 mg siponimod at day 1, one administration of
0.25 mg siponimod at day 2, one administration of 0.5 mg siponimod
at day 3, one administration of 0.75 mg siponimod at day 4one
administration of 1.25 mg siponimod at day 5, and one
administration of 2 mg siponimod at day 6; and wherein, in said
titration regimen, immediate release dosage forms comprising 0.25
mg, 0.5 mg,1 mg and 2 mg siponimod are used.
[0329] Enumerated Embodiment 55: Siponimod for use in the treatment
of an autoimmune disease in a patient receiving a chronic
beta-blocker treatment and having a resting heart rate of
.ltoreq.50 bpm under said chronic beta-blocker treatment comprising
[0330] a) interrupting said chronic beta-blocker treatment in said
patient until the baseline heart-rate is >50 bpm; [0331] b)
administering to said patient an initial titration regimen of
siponimod; and initiating in said patient a siponimod treatment by
[0332] b1) administering to said patient an initial titration
regimen of siponimod; and [0333] b2) administering to said patient
1-15 mg siponimod daily as a maintenance regimen; and [0334] c)
re-initiating in said patient a beta-blocker the earliest at the
first day when said patient is receiving the dosage of the
maintenance regimen; wherein said initial titration regimen
comprises administering siponimod at a dosage lower than the dosage
used as a maintenance regimen and then increasing the dosage
stepwise up to the dosage of the maintenance regimen.
[0335] Enumerated Embodiment 56: Siponimod for use in the treatment
of secondary progressive multiple sclerosis in a patient receiving
a chronic beta-blocker treatment and having a resting heart rate of
.ltoreq.50 bpm under said chronic beta-blocker treatment comprising
[0336] a) interrupting said chronic beta-blocker treatment in said
patient until the baseline heart-rate is >50 bpm; [0337] b)
initiating in said patient a siponimod treatment by [0338] b1)
administering to said patient an initial titration regimen of
siponimod; and [0339] b2) administering to said patient an
immediate release dosage form comprising 2 mg siponimod once daily
as a maintenance regimen; and [0340] c) re-initiating in said
patient a beta-blocker treatment after 2 weeks of treatment with
siponimod; wherein said initial titration regimen consists of one
administration of 0.25 mg siponimod at day 1, one administration of
0.25 mg siponimod at day 2, one administration of 0.5 mg siponimod
at day 3, one administration of 0.75 mg siponimod at day 4,one
administration of 1.25 mg siponimod at day 5 and one administration
of 2 mg siponimod at day 6; and wherein, in said titration regimen,
immediate release dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and
2 mg siponimod are used.
[0341] Enumerated Embodiment 57: Use of siponimod for the
manufacture of a medication for the treatment of an autoimmune
disease in a patient receiving a chronic beta-blacker treatment and
having a resting heart rate of .ltoreq.50 bpm under said chronic
beta-blocker treatment comprising [0342] a) interrupting said
chronic beta-blocker treatment in said patient until the baseline
heart-rate is >50 bpm; [0343] b) administering to said patient
an initial titration regimen of siponimod; and initiating in said
patient a siponimod treatment by [0344] b1) administering to said
patient an initial titration regimen of siponimod; and [0345] b2)
administering to said patient 1-15 mg siponimod daily as a
maintenance regimen; and [0346] c) re-initiating in said patient a
beta-blocker treatment the earliest at the first day when said
patient is receiving the dosage of the maintenance regimen; wherein
said initial titration regimen comprises administering siponimod at
a dosage lower than the dosage used as a maintenance regimen and
then increasing the dosage stepwise up to the dosage of the
maintenance regimen.
[0347] Enumerated Embodiment 58: Use of siponimod for the
manufacture of a medication for the treatment of secondary
progressive multiple sclerosis in a patient receiving a chronic
beta-blocker treatment and having a resting heart rate of
.ltoreq.50 bpm under said chronic beta-blocker treatment comprising
[0348] a) interrupting said chronic beta-blocker treatment in said
patient until the baseline heart-rate is >50 bpm; [0349] b)
initiating in said patient a siponimod treatment by [0350] b1)
administering to said patient an initial titration regimen of
siponimod; and [0351] b2) administering to said patient an
immediate release dosage form comprising 2 mg siponimod once daily
as a maintenance regimen; and [0352] c) re-initiating in said
patient a beta-blocker treatment after 2 weeks of treatment with
siponimod; wherein said initial titration regimen consists of one
administration of 0.25 mg siponimod at day 1, one administration of
0.25 mg siponimod at day 2, one administration of 0.5 mg siponimod
at day 3, one administration of 0.75 mg siponimod at day 4,one
administration of 1.25 mg siponimod at day 5 and one administration
of 2 mg siponimod at day 6; and wherein, in said titration regimen,
immediate release dosage forms comprising 0.25 mg, 0.5 mg, 1 mg and
2 mg siponimod are used.
[0353] Enumerated Embodiment 59: A method of treating an autoimmune
disease in a patient in need of a beta-blocker treatment comprising
[0354] a) administering to said patient an initial titration
regimen of siponimod; [0355] b) administering to said patient 1-15
mg siponimod daily as a maintenance regimen; and [0356] c)
introducing in said patient a beta-blocker treatment the earliest
at the first day when said patient is receiving the dosage of the
maintenance regimen; wherein said initial titration regimen
comprises administering siponimod at a dosage lower than the dosage
of the maintenance regimen and then increasing the dosage stepwise
up to the dosage of the maintenance regimen.
[0357] Enumerated Embodiment 60: A method of treating an autoimmune
disease in a patient in need of a beta-blocker treatment, receiving
a chronic beta-blocker treatment and having a resting heart rate of
>50 bpm under said chronic beta-blocker treatment comprising
introducing in said patient a siponimod treatment by [0358] a)
administering to said patient an initial titration regimen of
siponimod; and [0359] b) administering to said patient 1-15 mg
siponimod daily as a maintenance regimen; wherein said initial
titration regimen comprises administering siponimod at a dosage
lower than the dosage used as a maintenance regimen and then
increasing the dosage stepwise up to the dosage of the maintenance
regimen.
[0360] Enumerated Embodiment 61: A method of treating an autoimmune
disease in a patient in need of a beta-blocker treatment, receiving
a chronic beta-blacker treatment and having a resting heart rate of
.ltoreq.50 bpm under said chronic beta-blocker treatment comprising
[0361] a) interrupting said chronic beta-blocker treatment in said
patient until the baseline heart-rate is >50 bpm; [0362] b)
administering to said patient an initial titration regimen of
siponimod; and initiating in said patient a siponimod treatment by
[0363] b1) administering to said patient an initial titration
regimen of siponimod; and [0364] b2) administering to said patient
1-15 mg siponimod daily as a maintenance regimen; and [0365] c)
re-initiating in said patient a beta-blocker treatment the earliest
at the first day when said patient is receiving the dosage of the
maintenance regimen; wherein said initial titration regimen
comprises administering siponimod at a dosage lower than the dosage
used as a maintenance regimen and then increasing the dosage
stepwise up to the dosage of the maintenance regimen.
[0366] Enumerated Embodiment 62: A method of treating an autoimmune
disease in a patient having a co-morbidity susceptible to
beta-blocker treatment comprising [0367] a) administering to said
patient an initial titration regimen of siponimod; [0368] b)
administering to said patient 1-15 mg siponimod daily as a
maintenance regimen; and [0369] c) introducing in said patient a
beta-blocker treatment the earliest at the first day when said
patient is receiving the dosage of the maintenance regimen; wherein
said initial titration regimen comprises administering siponimod at
a dosage lower than the dosage of the maintenance regimen and then
increasing the dosage stepwise up to the dosage of the maintenance
regimen.
[0370] Enumerated Embodiment 63: A method of treating an autoimmune
disease in a patient having a co-morbidity susceptible to
beta-blocker treatment, receiving a chronic beta-blocker treatment
and having a resting heart rate of >50 bpm under said chronic
beta-blocker treatment comprising introducing in said patient a
siponimod treatment by [0371] a) administering to said patient an
initial titration regimen of siponimod; and [0372] b) administering
to said patient 1-15 mg siponimod daily as a maintenance regimen;
wherein said initial titration regimen comprises administering
siponimod at a dosage lower than the dosage used as a maintenance
regimen and then increasing the dosage stepwise up to the dosage of
the maintenance regimen.
[0373] Enumerated Embodiment 64: A method of treating an autoimmune
disease in a patient having a co-morbidity susceptible to
beta-blocker treatment, receiving a chronic beta-blocker treatment
and having a resting heart rate of .ltoreq.50 bpm under said
chronic beta-blocker treatment comprising [0374] a) interrupting
said chronic beta-blocker treatment in said patient until the
baseline heart-rate is >50 bpm; [0375] b) administering to said
patient an initial titration regimen of siponimod; and initiating
in said patient a siponimod treatment by [0376] b1) administering
to said patient an initial titration regimen of siponimod; and
[0377] b2) administering to said patient 1-15 mg siponimod daily as
a maintenance regimen; and [0378] c) re-initiating in said patient
a beta-blocker treatment the earliest at the first day when said
patient is receiving the dosage of the maintenance regimen; wherein
said initial titration regimen comprises administering siponimod at
a dosage lower than the dosage used as a maintenance regimen and
then increasing the dosage stepwise up to the dosage of the
maintenance regimen.
[0379] Enumerated Embodiment 65: A method of combined
administration of siponimod and a beta-blocker in a patient
comprising [0380] a) administering to said patient an initial
titration regimen of siponimod; [0381] b) administering to said
patient 1-15 mg siponimod daily as a maintenance regimen; and
[0382] c) introducing in said patient a beta-blocker treatment the
earliest at the first day when said patient is receiving the dosage
of the maintenance regimen; wherein said initial titration regimen
comprises administering siponimod at a dosage lower than the dosage
of the maintenance regimen and then increasing the dosage stepwise
up to the dosage of the maintenance regimen.
[0383] Enumerated Embodiment 66: A method of combined
administration of siponimod and a beta-blocker in a patient
receiving a chronic beta-blocker treatment and having a resting
heart rate of >50 bpm under said chronic beta-blocker treatment
comprising introducing in said patient a siponimod treatment by
[0384] a) administering to said patient an initial titration
regimen of siponimod; and [0385] b) administering to said patient
1-15 mg siponimod daily as a maintenance regimen; wherein said
initial titration regimen comprises administering siponimod at a
dosage lower than the dosage used as a maintenance regimen and then
increasing the dosage stepwise up to the dosage of the maintenance
regimen.
[0386] Enumerated Embodiment 67: A method of combined
administration of siponimod and a beta-blocker in a patient
receiving a chronic beta-blocker treatment and having a resting
heart rate of .ltoreq.50 bpm under said chronic beta-blocker
treatment comprising [0387] a) interrupting said chronic
beta-blacker treatment in said patient until the baseline
heart-rate is >50 bpm; [0388] b) administering to said patient
an initial titration regimen of siponimod; and initiating in said
patient a siponimod treatment by [0389] b1) administering to said
patient an initial titration regimen of siponimod; and [0390] b2)
administering to said patient 1-15 mg siponimod daily as a
maintenance regimen; and [0391] c) re-initiating in said patient a
beta-blocker treatment the earliest at the first day when said
patient is receiving the dosage of the maintenance regimen; wherein
said initial titration regimen comprises administering siponimod at
a dosage lower than the dosage used as a maintenance regimen and
then increasing the dosage stepwise up to the dosage of the
maintenance regimen.
[0392] Enumerated Embodiment 68: A method of co-administering
siponimod and a beta-blocker in a patient comprising [0393] a)
administering to said patient an initial titration regimen of
siponimod; [0394] b) administering to said patient 1-15 mg
siponimod daily as a maintenance regimen; and [0395] c) introducing
in said patient a beta-blocker treatment the earliest at the first
day when said patient is receiving the dosage of the maintenance
regimen; wherein said initial titration regimen comprises
administering siponimod at a dosage lower than the dosage of the
maintenance regimen and then increasing the dosage stepwise up to
the dosage of the maintenance regimen.
[0396] Enumerated Embodiment 69: A method of co-administering
siponimod and a beta-blocker in a patient receiving a chronic
beta-blocker treatment and having a resting heart rate of >50
bpm under said chronic beta-blocker treatment comprising
introducing in said patient a siponimod treatment by [0397] a)
administering to said patient an initial titration regimen of
siponimod; and [0398] b) administering to said patient 1-15 mg
siponimod daily as a maintenance regimen; wherein said initial
titration regimen comprises administering siponimod at a dosage
lower than the dosage used as a maintenance regimen and then
increasing the dosage stepwise up to the dosage of the maintenance
regimen.
[0399] Enumerated Embodiment 70: A method of co-administering
siponimod and a beta-blocker in a patient receiving a chronic
beta-blocker treatment and having a resting heart rate of
.ltoreq.50 bpm under said chronic beta-blocker treatment comprising
[0400] a) interrupting said chronic beta-blocker treatment in said
patient until the baseline heart-rate is >50 bpm; [0401] b)
administering to said patient an initial titration regimen of
siponimod; and initiating in said patient a siponimod treatment by
[0402] b1) administering to said patient an initial titration
regimen of siponimod; and [0403] b2) administering to said patient
1-15 mg siponimod daily as a maintenance regimen; and [0404] c)
re-initiating in said patient a beta-blocker treatment the earliest
at the first day when said patient is receiving the dosage of the
maintenance regimen; wherein said initial titration regimen
comprises administering siponimod at a dosage lower than the dosage
used as a maintenance regimen and then increasing the dosage
stepwise up to the dosage of the maintenance regimen.
[0405] Enumerated Embodiment 71: A method of treating an autoimmune
disease in a patient comprising [0406] a) administering to said
patient an initial titration regimen of siponimod; [0407] b)
administering to said patient 1-15 mg siponimod daily as a
maintenance regimen; and [0408] c) introducing in said patient a
beta-blocker treatment the earliest at the first day when a steady
state of siponimod is reached; wherein said initial titration
regimen comprises administering siponimod at a dosage lower than
the dosage of the maintenance regimen and then increasing the
dosage stepwise up to the dosage of the maintenance regimen.
EXAMPLES
Example 1: Preparation of Immediate Release Tablets
[0409] For the titration/maintenance regimen, 0.25 mg, 0.5 mg, 1 mg
and 2 mg siponimod immediate release film-coated tablets can be
prepared as described below.
Process Blending:
[0410] In order to obtain a final mixture ready to be processed to
a dosage form, e.g. a tablet, siponimod hemifumarate, e.g. having a
X90 value of 18 .mu.m, is blended with different excipients
according to the flow diagram of FIG. 1. Therefore, siponimod
hemifumarate is pre-blended in step 1 with a mixture of glyceryl
behenate as moisture protective agent and spray-dried lactose as
filler. The pre-blending is carried out in a diffusion mixer Bohle
PM400S (L. B. Bohle Maschinen+Verfahren GmbH, Ennigerloh, Germany)
for 10 min at 10 rpm. The mixture of step 1 is then sieved in step
2 using a screening mill having a mesh size of 800 .mu.m. The
sieved mixture is then blended in step 3 with further spray-dried
lactose as filler, Aerosil as glidant, polyvinylpolypyrrolidon XL
(crospovidone) as disintegrant and microcrystalline cellulose GR as
filler in a diffusion mixer Bohle PM400S for 5 min at 10 rpm. The
resulting mixture is again sieved in step 4 using an oscillating
screening mill Frewitt GLA ORV having a mesh size of 800 .mu.m and
mixed in step 5 in a diffusion mixer Bohle PM400S for 25 min at 10
rpm. In step 6 glyceryl behenate as lubricant, which has been
sieved using an oscillating screening mill Frewitt GLA ORV having a
mesh size of 800 .mu.m, is added to the mixture of step 5 and mixed
in step 7 in a diffusion mixer Bohle PM400S for 10 min at 10 rpm,
resulting in the final dosage form mixture.
[0411] The final dosage mixture resulted from the blending process
is then processed into a dosage form, preferably a tablet. The
tablets are formed using a rotary tablet press, a Korsch PH 250 or
Korsch XL400 with a compression force of 6 kN. The tablets are then
de-dusted with a Kramer deduster (Kramer AG, Switzerland) and
finally coated by a perforated pan coater Glatt Coater GC 750
(Glatt GmbH, Germany). Instead of siponimod hemifumarate having a
X90 value of 18 .mu.m, siponimod hemifumarate of higher X90 values,
e.g. 40-50 .mu.m, or lower X90 values, e.g. 6 .mu.m, can be
used.
[0412] Film Coated Tablets:
[0413] Following the process of Example 1, film-coated tablets with
the composition per tablet according to Tables 2 to 5 can be
prepared.
TABLE-US-00001 TABLE 2 Composition Composition per Component per
unit [%] unit [mg/unit] Siponimod hemifumarate* 0.33 0.278 (X90 =
18 .mu.m) Lactose-preblending step 1 7.32 6.220 Lactose-step 3
65.85 55.977 Total Lactose 73.17 62.197 Microcryst. cellulose 15.0
12.750 Polyvinylpolypyrrolidon XL 6.0 5.100 Aerosil 200 0.50 0.425
Glyceryl behenate-step 1 2.0 1.7 Glyceryl behenate-step 6 3.0 2.55
Total Glyceryl behenate 5.0 4.250 Total core tablet 100% 85.000 mg
Coating premix 5.134 4.6 Total film coating tablet 100% 89.600 mg
*The salt factor is 1.112
TABLE-US-00002 TABLE 3 Composition Composition per Component per
unit [%] unit [mg/unit] Siponimod hemifumarate* 0.65 0.556 (X90 =
18 .mu.m) Lactose-preblending step 1 7.29 6.192 Lactose-step 3
65.56 55.727 Total Lactose 72.85 61.919 Microcryst. cellulose 15.0
12.750 Polyvinylpolypyrrolidon XL 6.0 5.100 Aerosil 200 0.50 0.425
Glyceryl behenate-step 1 2.0 1.7 Glyceryl behenate-step 6 3.0 2.55
Total Glyceryl behenate 5.0 4.250 Total core tablet 100% 85.000 mg
Coating premix 5.134 4.6 Total film coating tablet 100% 89.600 mg
*The salt factor is 1.112
TABLE-US-00003 TABLE 4 Composition Composition per Component per
unit [%] unit [mg/unit] Siponimod hemifumarate* 1.31 1.112 (X90 =
18 .mu.m) Lactose-preblending step 1 7.22 6.136 Lactose-step 3
64.97 55.227 Total Lactose 72.19 61.363 Microcryst. cellulose 15.0
12.750 Polyvinylpolypyrrolidon XL 6.0 5.100 Aerosil 200 0.50 0.425
Glyceryl behenate-step 1 2.0 1.7 Glyceryl behenate-step 6 3.0 2.55
Total Glyceryl behenate 5.0 4.250 Total core tablet 100% 85.000 mg
Coating premix 5.134 4.6 Total film coating tablet 100% 89.600 mg
*The salt factor is 1.112
TABLE-US-00004 TABLE 5 Composition Composition per Component per
unit [%] unit [mg/unit] Siponimod hemifumarate* 2.62 2.224 (X90 =
18 .mu.m) Lactose-preblending step 1 7.09 6.025 Lactose-step 3
63.79 54.226 Total Lactose 70.88 60.251 Microcryst. cellulose 15.0
12.750 Polyvinylpolypyrrolidon XL 6.0 5.100 Aerosil 200 0.50 0.425
Glyceryl behenate-step 1 2.0 1.7 Glyceryl behenate-step 6 3.0 2.55
Total Glyceryl behenate 5.0 4.250 Total core tablet 100% 85.000 mg
Coating premix 5.134 4.6 Total film coating tablet 100% 89.600 mg
*The salt factor is 1.112
Example 2: Clinical Trial
[0414] Participants
[0415] Healthy volunteers (men and women) aged between 1.8 and 55
years with a body mass index of 18-30 kg/m.sup.2 were included in
the study. Subjects were required to have an FEV.sub.1 of
.gtoreq.90% of predicted normal, a systolic blood pressure (BP) of
90-140 mm Hg, a diastolic BP of 50-913 mm Hg and a pulse rate of
50-90 bpm. Women of childbearing potential, pregnant or lactating
women, homozygous carriers for CYP2C9*3 genotype, smokers, those
with current or medical history of cardiovascular disorders or
bronchospastic disease were excluded from this study. At screening,
a 24 h Halter recording was performed on all subjects to exclude
those with any significant arrhythmia.
[0416] Study Design
[0417] This was a double-blind, randomised, placebo-controlled
study consisting of the following periods: screening (28 days),
baseline evaluation (2 days), treatment (20 days) and study
completion evaluation (approximately 10 days after the last drug
administration; FIG. 1). Eligible subjects were domiciled for 22
days, starting approximately 36 h before dosing until 24 h
post-dose after Day 20. The baseline evaluations were performed on
Day -2 or Day -1. Subjects were randomised to one of the four
treatment groups (A, B, C and D) in a ratio of 1:1:1:1. Subjects in
Groups A and B received a combination of siponimod 2 mg once daily
(qd) and propranolol 80 mg [long acting (LA)] qd, administered in
two different sequences. In Group A, treatment was initiated with
the siponimod dose-titration regimen (Days 1-6) followed by
siponimod 2 mg (Days 7-20). Siponimod was uptitrated by one
administration of 1.25 mg siponimod on day 1, one administration of
0.25 mg siponimod on day 2, one administration of 0.5 mg siponimod
on day 3, one administration of 0.75 mg siponimod on day 4, one
administration of 1.25 mg siponimod on day 5 and one administration
of 2 mg siponimod on day 6, followed by a steady dose of 2 mg
siponimod qd thereafter. Concomitantly, the subjects also received
propranolol-placebo (Days 1-10) and propranolol 80 mg LA (Days
11-20). In Group B, the treatment was initiated with propranolol 80
mg LA and continued until Day 20. These subjects concomitantly
received siponimod-placebo (Days 1-10), followed by the siponimod
dose-titration regimen (Days 11-16) and siponimod 2 mg (Days
17-20). The subjects in Group C received siponimod-placebo and
propranolol-placebo, whereas those in Group D received
siponimod-placebo and propranolol 80 mg LA on all the treatment
days. During the treatment phase, the subjects were required to
fast (no food and liquid, except water) for at least 10 h before
the administration of the study medication. Owing to the non-exact
matching nature of propranolol-placebo, subjects were physically
blinded with a sleeping mask at the time of dose administration.
Post-dose, the subjects continued to fast for at least 1 h except
on the days of PK sampling (Days 10 and 20) when the subjects
fasted for 4 h.
[0418] Pharmacodynamic Assessments
[0419] The primary end point was the daily maximum effect on heart
rate (E.sub.max HR) at steady state. The E.sub.max was defined as
the maximum change from baseline in time matched, hourly average
HR. A secondary end point was changes from baseline in average
HR.
[0420] This study was designed to capture the treatment effects at
the start, at the highest dose and at the pharmacokinetic steady
state of siponimod dose titration. On the basis of previous reports
(e.g. Legangneux et al, Br J Clin Pharmacol, 2013, 75, 831-841, and
Murdoch et al, Br J Clin Pharmacol, 1991, 31, 323-332), it was
deduced that it would take approximately 10 days for siponimod and
7 days for propranolol to reach a pharmacokinetic steady state in
the study subjects. Accordingly, the cardiovascular effects were
evaluated at baseline (-1) and on Days 1, 6 and 10, which
correspond to the siponimod/propranolol monotherapy, and on Days
11, 16 and 20, which correspond to the combination treatment. Days
1 and 11 represented the initial dose of the siponimod titration
regimen whereas Days 6 and 16 represented the highest dose and Days
10 and 20 represented the pharmacokinetic steady state.
[0421] The HR and bradyarrhythmias were evaluated from the 12-Lead
Hotter electrocardiogram (ECG) recordings. For HR, the evaluation
interval began from the post-dose time or a corresponding time
during the baseline (Day -1). The hourly average HR in each
post-dose hour was calculated from the 60 intervals of per minute
HR data. In order to calculate the time-matched change from
baseline, each of the post-dose hourly average HR on a
post-baseline evaluation day was subtracted from the corresponding
hourly average HR at baseline.
[0422] The cardiac rhythm was evaluated from the 24 h post-dose
Halter evaluation as mentioned earlier. AVBs of different degrees,
SPs (>2 seconds) and any other arrhythmia were reported by the
time of occurrence, duration and frequency.
[0423] Statistical Methods
[0424] The sample size was determined based on an inter-subject
standard deviation (SD) of 5.6 bpm for E.sub.max HR from a previous
study, derived from a fixed effects model. With 16 subjects in the
propranolol alone arm (Group D) and in each of the combination
treatment arms (Groups A and B), the difference in E.sub.max [half
width of 90% confidence interval (CI)] was expected to be 2.82 bpm.
This allowed a 90% CI completely <5 bpm, when the observed mean
difference was approximately 2 bpm. Assuming a 15% drop-out, 76
subjects (19 per treatment arm) were randomised.
[0425] A mixed-effects ANCOVA model was used for analysing the
pharmacodynamic end points. For the end points of HR, the model was
applied on the E.sub.max data, with treatment, day and interaction
of treatment and day as fixed factors, the average 24 h baseline HR
as a covariate and subject as a random factor. An appropriate
contrast was used to estimate the difference of treatment arms A
and B combined versus the treatment arm D on Day 20. No imputation
was done for missing values, as the derivation of the primary end
point required both baseline and post-baseline data.
[0426] Subject Disposition and Demography
[0427] A total of 76 subjects were enrolled, and 73 subjects
completed the study. The mean age (SD) of this study population was
37.1 (10.27) years, with a majority of subjects being males [n (%):
61 (80.3)] and Caucasian [45 (59.2%)]. The mean (SD) BMI of this
population was 26.16 (2.57) kg/m.sup.2.
[0428] Effect on Heart Rate
[0429] Effects on heart rate are shown in FIG. 2.
[0430] Analysis of the primary end point revealed that siponimod
and propranolol alone led to a comparable E.sub.max HR. At Day 10,
the mean E.sub.max HR was 16.79 bpm [standard error (SE): 1.61] for
siponimod alone and 17.85 bpm (1.14) for propranolol alone (mean
difference: -1.06 bpm; 95% CI: -4.98, 2.87; P=0.595) in comparison
with 11.73 bpm (SE: 1.60) for placebo.
[0431] The actual additive effect of concomitant treatment of
siponimod and propranolol was assessed at pharmacokinetic steady
state of the combination (i.e. on Day 20).To measure the actual
additive effect, Group A and Group B subjects were pooled (i.e.
potential effects caused by the sequence of drug administration
were fully randomized). The actual additive effect at
pharmacokinetic steady state was an additional 6.21 bpm (95% CI:
2.32, 10.11; P=0.002) decrease in the mean E.sub.max HR versus
propranolol alone.
[0432] Surpsisingly, there was a significant effect caused by the
sequence of drug administration. Whereas adding siponimod on top of
propranolol led to a higher additional decrease in Emax HR versus
propranolol alone, i.e. 7.39 bpm (95% CI: 2.87, 11.90; P=0.0016;
Group B), adding propranolol on top of siponimod led to a much
lower additional decrease, i.e. 5.04 bpm (95% CI: 0.52, 936;
P=0.0292; Group A). This indicates that the sequence of drug
administration is important and adding propranolol on top of
siponimod has a better safety profile.
[0433] Said sequence effects were even more pronounced at the first
day when the highest dose of siponimod was applied in Group B (i.e.
2 mg on Day 16): there the mean E.sub.max HR maximum in all
Groups/days was observed. In Group B, the additional decrease was
10.24 bpm compared to 3.44 bpm in Group A.
[0434] Bradyarrhythmias
[0435] There were no episodes of second-degree AVBs or SPs of >3
seconds duration with siponimod alone or in combination with
propranolol. Two episodes of Mobitz I AVB were reported during the
propranolol only treatment. Sinus pauses (RR interval>2 seconds)
were experienced by one subject in Group A (Days -1, 6, 11, 16 and
20) and two subjects in Group B (Day 16). None of these events were
associated with clinical signs or symptoms.
* * * * *