U.S. patent application number 15/179800 was filed with the patent office on 2016-09-29 for treatment of multiple sclerosis with combination of laquinimod and fingolimod.
The applicant listed for this patent is Teva Pharmaceutical Industries, Ltd.. Invention is credited to Hussein Hallak, Joel Flaxman Kaye, Nora Tarcic.
Application Number | 20160279118 15/179800 |
Document ID | / |
Family ID | 48082429 |
Filed Date | 2016-09-29 |
United States Patent
Application |
20160279118 |
Kind Code |
A1 |
Hallak; Hussein ; et
al. |
September 29, 2016 |
TREATMENT OF MULTIPLE SCLEROSIS WITH COMBINATION OF LAQUINIMOD AND
FINGOLIMOD
Abstract
This invention provides a method of treating a subject afflicted
with multiple sclerosis or presenting a clinically isolated
syndrome comprising administering to the subject laquinimod as an
add-on therapy to or in combination with fingolimod. This invention
also provides a package and a pharmaceutical composition comprising
laquinimod and fingolimod for treating a subject afflicted with
multiple sclerosis or presenting a clinically isolated syndrome.
This invention also provides laquinimod for use as an add-on
therapy or in combination with fingolimod in treating a subject
afflicted with multiple sclerosis or presenting a clinically
isolated syndrome. This invention further provides use of
laquinimod and fingolimod in the preparation of a combination for
treating a subject afflicted with multiple sclerosis or presenting
a clinically isolated syndrome.
Inventors: |
Hallak; Hussein; (East
Jerusalem, IL) ; Tarcic; Nora; (Modiin, IL) ;
Kaye; Joel Flaxman; (Netanya, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Teva Pharmaceutical Industries, Ltd. |
Petach-Tikva |
|
IL |
|
|
Family ID: |
48082429 |
Appl. No.: |
15/179800 |
Filed: |
June 10, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14520145 |
Oct 21, 2014 |
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15179800 |
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13650060 |
Oct 11, 2012 |
8889627 |
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14520145 |
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61546102 |
Oct 12, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61P 37/06 20180101; A61K 31/47 20130101; A61P 17/06 20180101; A61P
19/02 20180101; A61P 43/00 20180101; A61P 37/02 20180101; A61K 9/14
20130101; A61J 1/035 20130101; A61P 25/02 20180101; A61K 9/0053
20130101; A61K 47/26 20130101; A61K 47/02 20130101; A61P 37/00
20180101; A61P 1/00 20180101; A61K 2300/00 20130101; A61P 25/00
20180101; A61K 9/28 20130101; A61K 31/137 20130101; A61K 9/48
20130101; A61K 31/137 20130101; A61P 25/28 20180101; A61P 21/00
20180101; A61P 3/10 20180101; A61K 31/4704 20130101; A61P 29/00
20180101; A61K 31/4704 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/47 20060101
A61K031/47; A61K 9/00 20060101 A61K009/00; A61K 45/06 20060101
A61K045/06; A61J 1/03 20060101 A61J001/03; A61K 9/28 20060101
A61K009/28; A61K 47/26 20060101 A61K047/26; A61K 9/14 20060101
A61K009/14; A61K 47/02 20060101 A61K047/02; A61K 31/137 20060101
A61K031/137; A61K 9/48 20060101 A61K009/48 |
Claims
1. A method of treating a subject afflicted with multiple sclerosis
or presenting a clinically isolated syndrome comprising
periodically administering to the subject an amount of laquinimod
and an amount of fingolimod, wherein the amounts when taken
together are effective to treat the subject.
2. The method of claim 1, wherein the amount of laquinimod or and
the amount of fingolimod when administered together is more
effective to treat the subject than when each agent at the same
amount is administered alone.
3. The method of claim 1 or 2, wherein the multiple sclerosis is
relapsing multiple sclerosis.
4. The method of claim 3, wherein the relapsing multiple sclerosis
is relapsing-remitting multiple sclerosis.
5. The method of any one of claims 1-4, wherein the amount of
laquinimod and the amount of fingolimod when taken together is
effective to reduce a symptom of multiple sclerosis in the
subject.
6. The method of claim 5, wherein the symptom is a MRI-monitored
multiple sclerosis disease activity, relapse rate, accumulation of
physical disability, frequency of relapses, decreased time to
confirmed disease progression, decreased time to confirmed relapse,
frequency of clinical exacerbation, brain atrophy, neuronal
dysfunction, neuronal injury, neuronal degeneration, neuronal
apoptosis, risk for confirmed progression, deterioration of visual
function, fatigue, impaired mobility, cognitive impairment,
reduction of brain volume, abnormalities observed in whole Brain
MTR histogram, deterioration in general health status, functional
status, quality of life, and/or symptom severity on work.
7. The method of claim 6, wherein the amount of laquinimod and the
amount of fingolimod when taken together is effective to decrease
or inhibit reduction of brain volume.
8. The method of claim 7, wherein brain volume is measured by
percent brain volume change (PBVC).
9. The method of claim 6, wherein the amount of laquinimod and the
amount of fingolimod when taken together is effective to increase
time to confirmed disease progression.
10. The method of claim 9, wherein time to confirmed disease
progression is increased by 20-60%.
11. The method of claim 9, wherein time to confirmed disease
progression is increased by at least 50%.
12. The method of claim 6, wherein the amount of laquinimod and the
amount of fingolimod when taken together is effective to decrease
abnormalities observed in whole Brain MTR histogram.
13. The method of claim 6, wherein the accumulation of physical
disability is measured by Kurtzke Expanded Disability Status Scale
(EDSS) score.
14. The method of claim 6, wherein the accumulation of physical
disability is assessed by the time to confirmed disease progression
as measured by Kurtzke Expanded Disability Status Scale (EDSS)
score.
15. The method of claim 13 or 14, wherein the subject had an EDSS
score of 0-5.5 at baseline.
16. The method of claim 13 or 14, wherein the subject had an EDSS
score of 1.5-4.5 at baseline.
17. The method of claim 13 or 14, wherein the subject had an EDSS
score of 5.5 or greater at baseline.
18. The method of any one of claims 13-17, wherein confirmed
disease progression is a 1 point increase of the EDSS score.
19. The method of any one of claims 13-17, wherein confirmed
disease progression is a 0.5 point increase of the EDSS score.
20. The method of claim 6, wherein impaired mobility is assessed by
the Timed-25 Foot Walk test.
21. The method of claim 6, wherein impaired mobility is assessed by
the 12-Item Multiple Sclerosis Walking Scale (MSWS-12) self-report
questionnaire.
22. The method of claim 6, wherein impaired mobility is assessed by
the Ambulation Index (AI).
23. The method of claim 6, wherein impaired mobility is assessed by
the Six-Minute Walk (6MW) Test.
24. The method of claim 6, wherein impaired mobility is assessed by
the Lower Extremity Manual Muscle Test (LEMMT) Test.
25. The method of claim 6, wherein the amount of laquinimod and the
amount of fingolimod when taken together is effective to reduce
cognitive impairment.
26. The method of claim 25, wherein cognitive impairment is
assessed by the Symbol Digit Modalities Test (SDMT) score.
27. The method of claim 6, wherein general health status is
assessed by the EuroQoL (EQ5D) questionnaire, Subject Global
Impression (SGI) or Clinician Global Impression of Change
(CGIC).
28. The method of claim 6, wherein functional status is measured by
the subject's Short-Form General Health survey (SF-36) Subject
Reported Questionnaire score.
29. The method of claim 6, wherein quality of life is assessed by
SF-36, EQ5D, Subject Global Impression (SGI) or Clinician Global
Impression of Change (CGIC).
30. The method of claim 28 or 29, wherein the subject's SF-36
mental component summary score (MSC) is improved.
31. The method of any one of claims 28-30, wherein the subject's
SF-36 physical component summary sore (PSC) is improved.
32. The method of claim 6, wherein fatigue is assessed by the EQ5D,
the subject's Modified Fatigue Impact Scale (MFIS) score or the
French valid versions of the Fatigue Impact Scale (EMIF-SEP)
score.
33. The method of claim 6, wherein symptom severity on work is
measured by the work productivity and activities impairment General
Health (WPAI-GH) questionnaire.
34. The method of any one of claims 1-33, wherein laquinimod is
laquinimod sodium.
35. The method of any one of claims 1-34, wherein fingolimod is
fingolimod hydrochloride.
36. The method of any one of claims 1-35, wherein the laquinimod
and/or the fingolimod is administered via oral administration.
37. The method of any one of claims 1-36, wherein the laquinimod
and/or the fingolimod is administered daily.
38. The method of any one of claims 1-36, wherein the laquinimod
and/or the fingolimod is administered more often than once
daily.
39. The method of any one of claims 1-36, wherein the laquinimod
and/or the fingolimod is administered less often than once
daily.
40. The method of any one of claims 1-39, wherein the amount
laquinimod administered is less than 0.6 mg/day.
41. The method of any one of claims 1-40, wherein the amount
laquinimod administered is 0.1-40.0 mg/day.
42. The method of claim 41, wherein the amount laquinimod
administered is 0.1-2.5 mg/day.
43. The method of claim 42, wherein the amount laquinimod
administered is 0.25-2.0 mg/day.
44. The method of claim 43, wherein the amount laquinimod
administered is 0.5-1.2 mg/day.
45. The method of claim 41, wherein the amount laquinimod
administered is 0.25 mg/day.
46. The method of claim 41, wherein the amount laquinimod
administered is 0.3 mg/day.
47. The method of claim 41, wherein the amount laquinimod
administered is 0.5 mg/day.
48. The method of claim 41, wherein the amount laquinimod
administered is 0.6 mg/day.
49. The method of claim 41, wherein the amount laquinimod
administered is 1.0 mg/day.
50. The method of claim 41, wherein the amount laquinimod
administered is 1.2 mg/day.
51. The method of claim 41, wherein the amount laquinimod
administered is 1.5 mg/day.
52. The method of claim 41, wherein the amount laquinimod
administered is 2.0 mg/day.
53. The method of any one of claims 1-52, wherein the amount
fingolimod administered is less than 0.5 mg/day.
54. The method of any one of claims 1-53, wherein the amount
fingolimod administered is 0.01-2.5 mg/day.
55. The method of claim 54, wherein the amount fingolimod
administered is 2.5 mg/day.
56. The method of claim 54, wherein the amount fingolimod
administered is 0.01-1 mg/day.
57. The method of claim 56, wherein the amount fingolimod
administered is 0.1 mg/day.
58. The method of claim 56, wherein the amount fingolimod
administered is 0.25 mg/day.
59. The method of claim 56, wherein the amount fingolimod
administered is 0.5 mg/day.
60. The method of any one of claims 1-59, wherein a loading dose of
an amount different form the intended dose is administered for a
period of time at the start of the periodic administration.
61. The method of claim 60, wherein the loading dose is double the
amount of the intended dose.
62. The method of any one of claims 1-61, wherein the subject is
receiving laquinimod therapy prior to initiating fingolimod
therapy.
63. The method claim 62, wherein the administration of laquinimod
substantially precedes the administration of fingolimod.
64. The method of any one of claims 1-61, wherein the subject is
receiving fingolimod therapy prior to initiating laquinimod
therapy.
65. The method of claim 64, wherein the administration of
fingolimod substantially precedes the administration of
laquinimod.
66. The method of claim 64, where in the subject is receiving
fingolimod therapy for at least 24 weeks prior to initiating
laquinimod therapy.
67. The method of claim 66, where in the subject is receiving
fingolimod therapy for at least 28 weeks prior to initiating
laquinimod therapy.
68. The method of claim 67, where in the subject is receiving
fingolimod therapy for at least 48 weeks prior to initiating
laquinimod therapy.
69. The method of claim 68, where in the subject is receiving
fingolimod therapy for at least 52 weeks prior to initiating
laquinimod therapy.
70. The method of any one of claims 1-69, further comprising
administration of nonsteroidal anti-inflammatory drugs (NSAIDs),
salicylates, slow-acting drugs, gold compounds, hydroxychloroquine,
sulfasalazine, combinations of slow-acting drugs, corticosteroids,
cytotoxic drugs, immunosuppressive drugs and/or antibodies.
71. The method of any one of claims 1-70, wherein the periodic
administration of laquinimod and fingolimod continues for at least
3 days.
72. The method claim 71, wherein the periodic administration of
laquinimod and fingolimod continues for more than 30 days.
73. The method of claim 72, wherein the periodic administration of
laquinimod and fingolimod continues for more than 42 days.
74. The method of claim 73, wherein the periodic administration of
laquinimod and fingolimod continues for 8 weeks or more.
75. The method of claim 74, wherein the periodic administration of
laquinimod and fingolimod continues for at least 12 weeks.
76. The method of claim 75, wherein the periodic administration of
laquinimod and fingolimod continues for at least 24 weeks.
77. The method of claim 76, wherein the periodic administration of
laquinimod and fingolimod continues for more than 24 weeks.
78. The method of claim 77, wherein the periodic administration of
laquinimod and fingolimod continues for 6 months or more.
79. The method of any one of claims 1-78, wherein the
administration of laquinimod and fingolimod inhibits a symptom of
relapsing multiple sclerosis by at least 20%.
80. The method claim 79, wherein the administration of laquinimod
and fingolimod inhibits a symptom of relapsing multiple sclerosis
by at least 30%.
81. The method of claim 80, wherein the administration of
laquinimod and fingolimod inhibits a symptom of relapsing multiple
sclerosis by at least 50%.
82. The method of claim 81, wherein the administration of
laquinimod and fingolimod inhibits a symptom of relapsing multiple
sclerosis by at least 70%.
83. The method of claim 82, wherein the administration of
laquinimod and fingolimod inhibits a symptom of relapsing multiple
sclerosis by more than 100%.
84. The method of claim 83, wherein the administration of
laquinimod and fingolimod inhibits a symptom of relapsing multiple
sclerosis by more than 300%.
85. The method of claim 84, wherein the administration of
laquinimod and fingolimod inhibits a symptom of relapsing multiple
sclerosis by more than 1000%.
86. The method of any one of claims 1-85, wherein each of the
amount of laquinimod or pharmaceutically acceptable salt thereof
when taken alone, and the amount of fingolimod when taken alone is
effective to treat the subject.
87. The method of any one of claims 1-85, wherein either the amount
of laquinimod or pharmaceutically acceptable salt thereof when
taken alone, the amount of fingolimod when taken alone, or each
such amount when taken alone is not effective to treat the
subject.
88. The method of any one of claims 1-87, wherein the subject is a
human patient.
89. A package comprising: a first pharmaceutical composition
comprising an amount of laquinimod and a pharmaceutically
acceptable carrier; b) a second pharmaceutical composition
comprising an amount of fingolimod and a pharmaceutically
acceptable carrier; and c) instructions for use of the first and
second pharmaceutical compositions together to treat a subject
afflicted with multiple sclerosis or presenting a clinically
isolated syndrome.
90. The package of claim 89, wherein the first pharmaceutical
composition, the second pharmaceutical composition, or both the
first and the second pharmaceutical composition are in an aerosol,
an inhalable powder, an injectable, a liquid, a solid, a capsule or
a tablet form.
91. The package of claim 89, wherein the first pharmaceutical
composition, the second pharmaceutical composition, or both the
first and the second pharmaceutical composition are in a liquid or
a solid form.
92. The package of claim 91, wherein the first pharmaceutical
composition, the second pharmaceutical composition, or both the
first and the second pharmaceutical composition are in capsule
form.
93. The package of claim 91, the first pharmaceutical composition,
the second pharmaceutical composition, or both the first and the
second pharmaceutical composition are in tablet form.
94. The package of claim 93, wherein the tablets are coated with a
coating which inhibits oxygen from contacting the core.
95. The package of claim 94, wherein the coating comprises a
cellulosic polymer, a detackifier, a gloss enhancer, or
pigment.
96. The package of anyone of claims 89-95, wherein the first
pharmaceutical composition further comprises mannitol.
97. The package of anyone of claims 89-96, wherein the first
pharmaceutical composition further comprises an alkalinizing
agent.
98. The package of claim 97, wherein the alkalinizing agent is
meglumine.
99. The package of anyone of claims 89-98, wherein the first
pharmaceutical composition further comprises an oxidation reducing
agent.
100. The package of anyone of claims 89-96, wherein the first
pharmaceutical composition is stable and free of an alkalinizing
agent or an oxidation reducing agent.
101. The package of claim 100, wherein the first pharmaceutical
composition is free of an alkalinizing agent and free of an
oxidation reducing agent.
102. The package of anyone of claims 89-101, wherein the first
pharmaceutical composition is stable and free of disintegrant.
103. The package of anyone of claims 89-102, wherein the first
pharmaceutical composition further comprises a lubricant.
104. The package of claim 103, wherein the lubricant is present in
the composition as solid particles.
105. The package of claim 103 or 104, wherein the lubricant is
sodium stearyl fumarate or magnesium stearate.
106. The package of anyone of claims 89-105, wherein the first
pharmaceutical composition further comprises a filler.
107. The package of claim 106, wherein the filler is present in the
composition as solid particles.
108. The package of claim 106 or 107, wherein the filler is
lactose, lactose monohydrate, starch, isomalt, mannitol, sodium
starch glycolate, sorbitol, lactose spray dried, lactose
anhydrouse, or a combination thereof.
109. The package of claim 108, wherein the filler is mannitol or
lactose monohydrate.
110. The package of anyone of claims 89-109, further comprising a
desiccant.
111. The package of claim 110, wherein the desiccant is silica
gel.
112. The package of anyone of claims 89-111, wherein the first
pharmaceutical composition is stable and has a moisture content of
no more than 4%.
113. The package of anyone of claims 89-112, wherein laquinimod is
present in the composition as solid particles.
114. The package of anyone of claims 89-113, wherein the package is
a sealed packaging having a moisture permeability of not more than
15 mg/day per liter.
115. The package of claim 114, wherein the scaled package is a
blister pack in which the maximum moisture permeability is no more
than 0.005 mg/day.
116. The package of claim 114, wherein the sealed package is a
bottle.
117. The package of claim 116, wherein the bottle is closed with a
heat induction liner.
118. The package of anyone of claims 114-117, wherein the sealed
package comprises an HDPE bottle.
119. The package of anyone of claims 114-118, wherein the sealed
package comprises an oxygen absorbing agent.
120. The package of claim 119, wherein the oxygen absorbing agent
is iron.
121. The package of any one of claims 89-120, wherein the amount of
laquinimod in the first composition is less than 0.6 mg.
122. The package of any one of claims 89-121, wherein the amount of
laquinimod in the first composition is 0.1-40.0 mg.
123. The package of claim 122, wherein the amount of laquinimod in
the first composition is 0.1-2.5 mg.
124. The package of claim 123, wherein the amount of laquinimod in
the first composition is 0.25-2.0 mg.
125. The package of claim 124, wherein the amount of laquinimod in
the first composition is 0.5-1.2 mg.
126. The package of claim 122, wherein the amount of laquinimod in
the first composition is 0.25 mg.
127. The package of claim 122, wherein the amount of laquinimod in
the first composition is 0.3 mg.
128. The package of claim 122, wherein the amount of laquinimod in
the first composition is 0.5 mg.
129. The package of claim 122, wherein the amount of laquinimod in
the first composition is 0.6 mg.
130. The package of claim 122, wherein the amount of laquinimod in
the first composition is 1.0 mg.
131. The package of claim 122, wherein the amount of laquinimod in
the first composition is 1.2 mg.
132. The package of claim 122, wherein the amount of laquinimod in
the first composition is 1.5 mg.
133. The package of claim 122, wherein the amount of laquinimod in
the first composition is 2.0 mg.
134. The package of any one of claim 89-133, wherein the amount of
fingolimod in the second composition is less than 0.5 mg.
135. The package of any one of claim 89-133, wherein the amount of
fingolimod in the second composition is 0.01-2.5 mg.
136. The package of claim 135, wherein the amount of fingolimod in
the second composition is 2.5 mg.
137. The package of claim 135, wherein the amount of fingolimod in
the second composition is 0.01-1 mg.
138. The package of claim 137, wherein the amount of fingolimod in
the second composition is 0.1 mg.
139. The package of claim 137, wherein the amount of fingolimod in
the second composition is 0.25 mg.
140. The package of claim 137, wherein the amount of fingolimod in
the second composition is 0.5 mg.
141. Laquinimod for use as an add-on therapy or in combination with
fingolimod in treating a subject afflicted with multiple sclerosis
or presenting a clinically isolated syndrome.
142. A pharmaceutical composition comprising an amount of
laquinimod and an amount of fingolimod for use in treating a
subject afflicted with multiple sclerosis or presenting a
clinically isolated syndrome, wherein the laquinimod and the
fingolimod are administered simultaneously, contemporaneously or
concomitantly.
143. A pharmaceutical composition comprising an amount of
laquinimod and an amount of fingolimod.
144. The pharmaceutical composition of claim 142 or 143, wherein
laquinimod is laquinimod sodium.
145. The pharmaceutical composition of any one of claims 142-144,
wherein fingolimod is fingolimod hydrochloride.
146. The pharmaceutical composition of any one of claims 142-145,
in an aerosol, an inhalable powder, an injectable, a liquid, a
solid, a capsule or a tablet form.
147. The pharmaceutical composition of any one of claims 142-145,
in a liquid or a solid form.
148. The pharmaceutical composition of claim 147, in capsule
form.
149. The pharmaceutical composition of claim 147, in tablet
form.
150. The pharmaceutical composition of claim 149, wherein the
tablets are coated with a coating which inhibits oxygen from
contacting the core.
151. The pharmaceutical composition of claim 150, wherein the
coating comprises a cellulosic polymer, a detackifier, a gloss
enhancer, or pigment.
152. The pharmaceutical composition of anyone of claims 142-151,
further comprising mannitol.
153. The pharmaceutical composition of anyone of claims 142-152,
further comprising an alkalinizing agent.
154. The pharmaceutical composition of claim 153, wherein the
alkalinizing agent is meglumine.
155. The pharmaceutical composition of anyone of claims 142-154,
further comprising an oxidation reducing agent.
156. The pharmaceutical composition of anyone of claims 142-152,
which is free of an alkalinizing agent or an oxidation reducing
agent.
157. The pharmaceutical composition of claim 156, which is free of
an alkalinizing agent and free of an oxidation reducing agent.
158. The pharmaceutical composition of anyone of claims 142-157,
which is stable and free of disintegrant.
159. The pharmaceutical composition of anyone of claims 142-159,
further comprising a lubricant.
160. The pharmaceutical composition of claim 159, wherein the
lubricant is present in the composition as solid particles.
161. The pharmaceutical composition of claim 159 or 160, wherein
the lubricant is sodium stearyl fumarate or magnesium stearate.
162. The pharmaceutical composition of anyone of claims 142-161,
further comprising a filler.
163. The pharmaceutical composition of claim 162, wherein the
filler is present in the composition as solid particles.
164. The pharmaceutical composition of claim 162 or 163, wherein
the filler is lactose, lactose monohydrate, starch, isomalt,
mannitol, sodium starch glycolate, sorbitol, lactose spray dried,
lactose anhydrouse, or a combination thereof.
165. The pharmaceutical composition of claim 164, wherein the
filler is mannitol or lactose monohydrate.
166. The pharmaceutical composition of any one of claims 142-165,
wherein the amount of laquinimod in the composition is less than
0.6 mg.
167. The pharmaceutical composition of any one of claims 142-166,
wherein the amount of laquinimod in the composition is 0.1-40.0
mg.
168. The pharmaceutical composition of claim 167, wherein the
amount of laquinimod in the composition is 0.1-2.5 mg.
169. The pharmaceutical composition of claim 168, wherein the
amount of laquinimod in the composition is 0.25-2.0 mg.
170. The pharmaceutical composition of claim 169, wherein the
amount of laquinimod in the composition is 0.5-1.2 mg.
171. The pharmaceutical composition of claim 167, wherein the
amount of laquinimod in the composition is 0.25 mg.
172. The pharmaceutical composition of claim 167, wherein the
amount of laquinimod in the composition is 0.3 mg.
173. The pharmaceutical composition of claim 167, wherein the
amount of laquinimod in the composition is 0.5 mg.
174. The pharmaceutical composition of claim 167, wherein the
amount of laquinimod in the composition is 0.6 mg.
175. The pharmaceutical composition of claim 167, wherein the
amount of laquinimod in the composition is 1.0 mg.
176. The pharmaceutical composition of claim 167, wherein the
amount of laquinimod in the composition is 1.2 mg.
177. The pharmaceutical composition of claim 167, wherein the
amount of laquinimod in the composition is 1.5 mg.
178. The pharmaceutical composition of claim 167, wherein the
amount of laquinimod in the composition is 2.0 mg.
179. The pharmaceutical composition of any one of claims 142-178,
wherein the amount of fingolimod in the composition is less than
0.5 mg.
180. The pharmaceutical composition of any one of claims 142-179,
wherein the amount of fingolimod in the composition is 0.01-2.5
mg.
181. The pharmaceutical composition of claim 180, wherein the
amount of fingolimod in the composition is 2.5 mg.
182. The pharmaceutical composition of claim 180, wherein the
amount of fingolimod in the composition is 0.01-1 mg.
183. The pharmaceutical composition of claim 182, wherein the
amount of fingolimod in the composition is 0.1 mg.
184. The pharmaceutical composition of claim 182, wherein the
amount of fingolimod in the composition is 0.25 mg.
185. The pharmaceutical composition of claim 182, wherein the
amount of fingolimod in the composition is 0.5 mg.
186. Use of an amount of laquinimod and an amount of fingolimod in
the preparation of a combination for treating a subject afflicted
with multiple sclerosis or presenting a clinically isolated
syndrome wherein the laquinimod and the fingolimod are administered
simultaneously, contemporaneously or concomitantly.
187. A pharmaceutical composition comprising an amount of
laquinimod for use in treating a subject afflicted with multiple
sclerosis or presenting a clinically isolated syndrome as an add-on
therapy or in combination with fingolimod by periodically
administering the pharmaceutical composition and the fingolimod to
the subject.
188. A pharmaceutical composition comprising an amount of
fingolimod for use treating a subject afflicted with multiple
sclerosis or presenting a clinically isolated syndrome as an add-on
therapy or in combination with laquinimod by periodically
administering the pharmaceutical composition and the laquinimod to
the subject.
189. A therapeutic package for dispensing to, or for use in
dispensing to, a subject afflicted with multiple sclerosis or
presenting a clinically isolated syndrome, which comprises: a) one
or more unit doses, each such unit dose comprising: i) an amount of
laquinimod and ii) an amount of fingolimod wherein the respective
amounts of said laquinimod and said fingolimod in said unit dose
are effective, upon concomitant administration to said subject, to
treat the subject, and b) a finished pharmaceutical container
therefor, said container containing said unit dose or unit doses,
said container further containing or comprising labeling directing
the use of said package in the treatment of said subject.
190. The therapeutic package of claim 189, wherein the respective
amounts of said laquinimod and said fingolimod in said unit dose
when taken together is more effective to treat the subject than
when compared to the administration of said laquinimod in the
absence of said fingolimod or the administration of said fingolimod
in the absence of said laquinimod.
191. A pharmaceutical composition in unit dosage form, useful in
treating a subject afflicted with multiple sclerosis or presenting
a clinically isolated syndrome, which comprises: a) an amount of
laquinimod; b) an amount of fingolimod, wherein the respective
amounts of said laquinimod and said fingolimod in said composition
are effective, upon concomitant administration to said subject of
one or more of said unit dosage forms of said composition, to treat
the subject.
192. The pharmaceutical composition of claim 191, wherein the
respective amounts of said laquinimod and said fingolimod in said
unit dose when taken together is more effective to treat the
subject than when compared to the administration of said laquinimod
in the absence of said fingolimod or the administration of said
fingolimod in the absence of said laquinimod.
Description
[0001] This application claims benefit of U.S. Provisional
Application No. 61/546,102, filed Oct. 12, 2011, the entire content
of which is hereby incorporated by reference herein.
[0002] Throughout this application, various publications are
referred to by first author and year of publication. Full citations
for these publications are presented in a References section
immediately before the claims. Disclosures of the documents and
publications referred to herein are hereby incorporated in their
entireties by reference into this application.
BACKGROUND
[0003] Multiple Sclerosis (MS) is a neurological disease affecting
more than 1 million people worldwide. It is the most common cause
of neurological disability in young and middle-aged adults and has
a major physical, psychological, social and financial impact on
subjects and their families, friends and bodies responsible for
health care (EMEA Guideline, 2006).
[0004] It is generally assumed that MS is mediated by some kind of
autoimmune process possibly triggered by infection and superimposed
upon a genetic predisposition. It is a chronic inflammatory
condition that damages the myelin of the Central Nervous System
(CNS). The pathogenesis of MS is characterized by the infiltration
of autoreactive T-cells from the circulation directed against
myelin antigens into the CNS (Bjartmar, 2002). In addition to the
inflammatory phase in MS, axonal loss occurs early in the course of
the disease and can be extensive over time, leading to the
subsequent development of progressive, permanent, neurologic
impairment and, frequently, severe disability (Neuhaus, 2003).
Symptoms associated with the disease include fatigue, spasticity,
ataxia, weakness, bladder and bowel disturbances, sexual
dysfunction, pain, tremor, paroxysmal manifestations, visual
impairment, psychological problems and cognitive dysfunction (EMEA
Guideline, 2006).
[0005] MS disease activity can be monitored by cranial scans,
including magnetic resonance imaging (MRI) of the brain,
accumulation of disability, as well as rate and severity of
relapses. The diagnosis of clinically definite MS as determined by
the Poser criteria (Poser, 1983) requires at least two neurological
events suggesting demyelination in the CNS separated in time and in
location. A clinically isolated syndrome (CIS) is a single
monosymptomatic attack suggestive of MS, such as optic neuritis,
brain stem symptoms, and partial myelitis. Patients with CIS that
experience a second clinical attack are generally considered to
have clinically definite multiple sclerosis (CDMS). Over 80 percent
of patients with a CIS and MRI lesion go on to develop MS, while
approximately 20 percent have a self-limited process (Brex, 2002;
Frohman, 2003). Various MS disease stages and/or types are
described in Multiple Sclerosis Therapeutics (Duntiz, 1999). Among
them, relapsing-remitting multiple sclerosis (RRMS) is the most
common form at the time of initial diagnosis. Many subjects with
RRMS have an initial relapsing-remitting course for 5-15 years,
which then advances into the secondary progressive MS (SPMS)
disease course. Relapses result from inflammation and
demyelination, whereas restoration of nerve conduction and
remission is accompanied by resolution of inflammation,
redistribution of sodium channels on demyelinated axons and
remyelination (Neuhaus, 2003; Noseworthy, 2000).
[0006] In April 2001, an international panel in association with
the National MS Society of America recommended diagnostic criteria
for multiple sclerosis. These criteria became known as the McDonald
Criteria: The McDonald Criteria make use of MRI techniques and are
intended to replace the Poser Criteria and the older Schumacher
Criteria (McDonald, 2001). The McDonald Criteria was revised in
March 2005 by an international panel (Polman, 2005) and updated
again in 2010 (Polman, 2011).
[0007] Intervention with disease-modifying therapy at relapsing
stages of MS is suggested to reduce and/or prevent accumulating
neurodegeneration (Hohlfeld, 2000; De Stefano, 1999). There are
currently a number of disease-modifying medications approved for
use in relapsing MS (RMS), which includes RRMS and SPMS (The
Disease Modifying Drug Brochure, 2006). These include interferon
beta 1-a (Avonex.RTM. and Rebif.RTM.), interferon beta 1-b
(Betaseron.RTM.), glatiramer acetate (Copaxone.RTM.), mitoxantrone
(Novantrone.RTM.), natalizumab (Tysabri.RTM.) and Fingolimod
(Gilenya.RTM.). Most of them are believed to act as
immunomodulators. Mitoxantrone and natalizumab are believed to act
as immunesuppressants. However, the mechanisms of action of each
have been only partly elucidated. Immunosuppressants or cytotoxic
agents are used in some subjects after failure of conventional
therapies. However, the relationship between changes of the immune
response induced by these agents and the clinical efficacy in MS is
far from settled (EMEA Guideline, 2006).
[0008] Other therapeutic approaches include symptomatic treatment
which refers to all therapies applied to improve the symptoms
caused by the disease (EMEA Guideline, 2006) and treatment of acute
relapses with corticosteroids. While steroids do not affect the
course of MS over time, they can reduce the duration and severity
of attacks in some subjects.
[0009] Fingolimod
[0010] Fingolimod (Fingolimod, Gilenya.TM.) is a new class of drugs
called sphingosine 1-phosphate (S1P) receptor modulators. These
medicines reduce inflammation and may also have a direct beneficial
effect on cells in the central nervous system (CNS). Upon
administration, fingolimod is phosphorylatcd by sphingosinc kinase
to form the the active metabolite fingolimod-phosphate-Fingolimod
is therefore a prodrug. Fingolimod-phosphate binds the sphingosine
1-phosphate receptors S1PR-1, S1PR3, S1PR4 and S1PR5 with high
affinity and thereby blocks the capacity of leukocytes to migrate
from lymph nodes into the peripheral blood. These receptors are
also known as EDG receptors, and are all members of the
rhodospin-like GPCR family, the largest single historical
successful family of drug targets (GPCR SARfari: S1PR-1 (aka.
EDG1)). The curative mechanism underlying fingolimod's therapeutic
effect is unknown but may involve a reduced migration of
lymphocytes into the CNS. The chemical structure of fingolimod was
derived from the myriocin (ISP-1) metabolite of the fungus Isaria
sinclairii. It is a structural analogue of sphingosine and gets
phosphorylated by sphingosine kinases in the cell (most importantly
sphingosine kinase 2) (Paugh S W 2003; Billich A, 2003; Sanchez, T,
2003). The molecular biology of phospho-fingolimod is thought to
lie in its activity at one of the five sphingosine-1-phosphate
receptors, S1PR1 (Hla T, 2001). It can sequester lymphocytes in
lymph nodes, preventing them from moving to the central nervous
system for auto-immune responses in multiple sclerosis and was
originally proposed as a anti-rejection medication indicated
post-transplantation. It has been reported to stimulate the repair
process of glial cells and precursor cells after injury (Alejandro
Horga, 2008). Fingolimod has also been reported to be a cannabinoid
receptor antagonist (Paugh S W, 2006), a cPLA2 inhibitor (Payne S
G, 2007) and a ceramide synthase inhibitor (Berdyshev E V,
2009).
##STR00001##
[0011] The approved medication Gilenya is an oral capsule
containing 0.56 mg of the hydrochloride salt of fingolimod which is
equivalent to 0.5 mg of fingolimod.
[0012] Laquinimod
[0013] Laquinimod is a novel synthetic compound with high oral
bioavailability which has been suggested as an oral formulation for
the treatment of Multiple Sclerosis (MS) (Polman, 2005;
Sandberg-Wollheim, 2005; Comi et al 2008). Laquinimod and its
sodium salt form are described, for example, in U.S. Pat. No.
6,077,851. The mechanism of action of laquinimod is not fully
understood.
[0014] Animal studies show it causes a Th1 (T helper 1 cell,
produces pro-inflammatory cytokines) to Th2 (T helper 2 cell,
produces anti-inflammatory cytokines) shift with an
anti-inflammatory profile (Yang, 2004; Brack, 2011). Another study
demonstrated (mainly via the NFkB pathway) that laquinimod induced
suppression of genes related to antigen presentation and
corresponding inflammatory pathways (Gurevich, 2010). Other
suggested potential mechanisms of action include inhibition of
leukocyte migration into the CNS, increase of axonal integrity,
modulation of cytokine production, and increase in levels of
brain-derived neurotrophic factor (BDNF) (Runstrom, 2006; Bruck,
2011).
[0015] Laquinimod showed a favorable safety and tolerability
profile in two phase III trials (Results of Phase III BRAVO Trial
Reinforce Unique Profile of Laquinimod for Multiple Sclerosis
Treatment; Teva Pharma, Active Biotech Post Positive Laquinimod
Phase 3 ALLEGRO Results).
[0016] Combination Therapy
[0017] The administration of two drugs to treat a given condition,
such as multiple sclerosis, raises a number of potential problems.
In vivo interactions between two drugs are complex. The effects of
any single drug are related to its absorption, distribution, and
elimination. When two drugs are introduced into the body, each drug
can affect the absorption, distribution, and elimination of the
other and hence, alter the effects of the other. For instance, one
drug may inhibit, activate or induce the production of enzymes
involved in a metabolic route of elimination of the other drug
(Guidance for Industry, 1999). In one example, combined
administration of fingolimod and interferon (IFN) has been
experimentally shown to abrogate the clinical effectiveness of
either therapy. (Brod 2000) In another experiment, it was reported
that the addition of prednisone in combination therapy with
IFN-.beta. antagonized its up-regulator effect. Thus, when two
drugs are administered to treat the same condition, it is
unpredictable whether each will complement, have no effect on, or
interfere with, the therapeutic activity of the other in a human
subject.
[0018] Not only may the interaction between two drugs affect the
intended therapeutic activity of each drug, but the interaction may
increase the levels of toxic metabolites (Guidance for Industry,
1999). The interaction may also heighten or lessen the side effects
of each drug. Hence, upon administration of two drugs to treat a
disease, it is unpredictable what change will occur in the negative
side profile of each drug. In one example, the combination of
natalizumab and interferon .beta.-1a was observed to increase the
risk of unanticipated side effects. (Vollmer, 2008; Rudick 2006;
Kleinschmidt-DeMasters, 2005; Langer-Gould 2005)
[0019] Additionally, it is difficult to accurately predict when the
effects of the interaction between the two drugs will become
manifest. For example, metabolic interactions between drugs may
become apparent upon the initial administration of the second drug,
after the two have reached a steady-state concentration or upon
discontinuation of one of the drugs (Guidance for Industry,
1999).
[0020] Therefore, the state of the art at the time of filing is
that the effects of combination therapy of two drugs, in particular
laquinimod and fingolimod, cannot be predicted until the results of
a combination study are available.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 is a graphical representation of the experimental
results from Example 1. The graph shows the clinical score for the
EAE rodents in each group (on the y-axis) against the days after
induction of the disease (on the x-axis).
SUMMARY OF THE INVENTION
[0022] This invention provides a method of treating a subject
afflicted with multiple sclerosis or presenting a clinically
isolated syndrome comprising periodically administering to the
subject an amount of laquinimod, and an amount of fingolimod,
wherein the amounts when taken together are effective to treat the
subject.
[0023] This invention also provides a method of treating a human
patient afflicted with multiple sclerosis or presenting a
clinically isolated syndrome comprising periodically administering
to the patient an amount of laquinimod and an amount of fingolimod,
wherein the amounts when taken together is more effective to treat
the human patient than when each agent is administered alone.
[0024] This invention also provides a method of treating a human
patient afflicted with an immune disease, comprising periodically
administering to the patient an amount of laquinimod and an amount
of fingolimod, wherein the amounts when taken together are
effective to treat the human patient, and wherein the immune
disease is an autoimmune disease, an arthritic condition, a
demyelinating disease, an inflammatory disease, multiple sclerosis,
relapsing-remitting multiple sclerosis, diabetes mellitus,
psoriasis, rheumatoid arthritis, inflammatory bowel disease,
Crohn's disease, or systemic lupus erythematosus.
[0025] This invention also provides a package comprising: a) a
first pharmaceutical composition comprising an amount of laquinimod
and a pharmaceutically acceptable carrier; b) a second
pharmaceutical composition comprising an amount of fingolimod and a
pharmaceutically acceptable carrier; and c) instructions for use of
the first and second pharmaceutical compositions together to treat
a subject afflicted with multiple sclerosis or presenting a
clinically isolated syndrome.
[0026] This invention also provides laquinimod for use as an add-on
therapy or in combination with fingolimod in treating a subject
afflicted with multiple sclerosis or presenting a clinically
isolated syndrome.
[0027] This invention also provides a pharmaceutical composition
comprising an amount of laquinimod and an amount of fingolimod for
use in treating a subject afflicted with multiple sclerosis or
presenting a clinically isolated syndrome, wherein the laquinimod
and the fingolimod are administered simultaneously,
contemporaneously or concomitantly.
[0028] This invention also provides a pharmaceutical composition
comprising an amount of laquinimod and an amount of fingolimod for
use in treating a human patient afflicted with an immune disease,
wherein the laquinimod and the fingolimod are administered
simultaneously, contemporaneously, or concomitantly and wherein the
immune disease is an autoimmune disease, an arthritic condition, a
demyelinating disease, an inflammatory disease, multiple sclerosis,
relapsing-remitting multiple sclerosis, diabetes mellitus,
psoriasis, rheumatoid arthritis, inflammatory bowel disease,
Crohn's disease, or systemic lupus erythematosus.
[0029] This invention also provides a pharmaceutical composition
comprising an amount of laquinimod and an amount of fingolimod.
[0030] This invention also provides use of an amount of laquinimod
and an amount of fingolimod in the preparation of a combination for
treating a subject afflicted with multiple sclerosis or presenting
a clinically isolated syndrome wherein the laquinimod and the
fingolimod are administered simultaneously, contemporaneously or
concomitantly.
[0031] This invention also provides pharmaceutical composition
comprising an amount of laquinimod for use in treating a subject
afflicted with multiple sclerosis or presenting a clinically
isolated syndrome as an add-on therapy or in combination with
fingolimod by periodically administering the pharmaceutical
composition and the fingolimod to the subject.
[0032] This invention also provides a pharmaceutical composition
comprising an amount of fingolimod for use in treating a subject
afflicted with multiple sclerosis or presenting a clinically
isolated syndrome as an add-on therapy or in combination with
laquinimod by periodically administering the pharmaceutical
composition and the laquinimod to the subject.
[0033] This invention also provides a therapeutic package for
dispensing to, or for use in dispensing to, a subject afflicted
with multiple sclerosis or presenting a clinically isolated
syndrome, which comprises: a) one or more unit doses, each such
unit dose comprising: i) an amount of laquinimod and ii) an amount
of fingolimod wherein the respective amounts of said laquinimod and
said fingolimod in said unit dose are effective, upon concomitant
administration to said subject, to treat the subject, and b) a
finished pharmaceutical container therefor, said container
containing said unit dose or unit doses, said container further
containing or comprising labeling directing the use of said package
in the treatment of said subject.
[0034] This invention further provides a pharmaceutical composition
in unit dosage form, useful in treating a subject afflicted with
multiple sclerosis or presenting a clinically isolated syndrome,
which comprises: a) an amount of laquinimod; b) an amount of
fingolimod, wherein the respective amounts of said laquinimod and
said fingolimod in said composition are effective, upon concomitant
administration to said subject of one or more of said unit dosage
forms of said composition, to treat the subject.
DETAILED DESCRIPTION OF THE INVENTION
[0035] This invention provides a method of treating a subject
afflicted with multiple sclerosis or presenting a clinically
isolated syndrome comprising periodically administering to the
subject an amount of laquinimod and an amount of fingolimod,
wherein the amounts when taken together are effective to treat the
subject.
[0036] This invention also provides a method of treating a human
patient afflicted with multiple sclerosis or presenting a
clinically isolated syndrome comprising periodically administering
to the patient an amount of laquinimod and an amount of fingolimod,
wherein the amounts when taken together is more effective to treat
the human patient than when each agent is administered alone.
[0037] This invention also provides a method of treating a human
patient afflicted with an immune disease, comprising periodically
administering to the patient an amount of laquinimod and an amount
of fingolimod, wherein the amounts when taken together are
effective to treat the human patient, and wherein the immune
disease is an autoimmune disease, an arthritic condition, a
demyelinating disease, an inflammatory disease, multiple sclerosis,
relapsing-remitting multiple sclerosis, diabetes mellitus,
psoriasis, rheumatoid arthritis, inflammatory bowel disease,
Crohn's disease, or systemic lupus erythematosus.
[0038] In an embodiment, the amount of laquinimod and the amount of
fingolimod when administered together is more effective to treat
the subject than when each agent at the same amount is administered
alone.
[0039] In one embodiment, the multiple sclerosis is relapsing
multiple sclerosis. In another embodiment, the relapsing multiple
sclerosis is relapsing-remitting multiple sclerosis.
[0040] In an embodiment, the amount of laquinimod and the amount of
fingolimod when taken together is effective to reduce a symptom of
multiple sclerosis in the subject. In one embodiment, the symptom
is a MRI-monitored multiple sclerosis disease activity, relapse
rate, accumulation of physical disability, frequency of relapses,
decreased tune to confirmed disease progression, decreased time to
confirmed relapse, frequency of clinical exacerbation, brain
atrophy, neuronal dysfunction, neuronal injury, neuronal
degeneration, neuronal apoptosis, risk for confirmed progression,
deterioration of visual function, fatigue, impaired mobility,
cognitive impairment, reduction of brain volume, abnormalities
observed in whole Brain MTR histogram, deterioration in general
health status, functional status, quality of life, and/or symptom
severity on work.
[0041] In one embodiment, the amount of laquinimod and the amount
of fingolimod when taken together is effective to decrease or
inhibit reduction of brain volume. In another embodiment, brain
volume is measured by percent brain volume change (PBVC).
[0042] In one embodiment, the amount of laquinimod and the amount
of fingolimod when taken together is effective to increase time to
confirmed disease progression. In another embodiment, time to
confirmed disease progression is increased by 20-60%. In another
embodiment, time to confirmed disease progression is increased by
at least 50%.
[0043] In one embodiment, the amount of laquinimod and the amount
of fingolimod when taken together is effective to decrease
abnormalities observed in whole Brain MTR histogram. In another
embodiment, the accumulation of physical disability is measured by
Kurtzke Expanded Disability Status Scale (EDSS) score. In another
embodiment, the accumulation of physical disability is assessed by
the time to confirmed disease progression as measured by Kurtzke
Expanded Disability Status Scale (EDSS) score.
[0044] In one embodiment, the subject had an EDSS score of 0-5.5 at
baseline. In another embodiment, the subject had an EDSS score of
1.5-4.5 at baseline. In another embodiment, the subject had an EDSS
score of 5.5 or greater at baseline. In another embodiment,
confirmed disease progression is a 1 point increase of the EDSS
score. In another embodiment, confirmed disease progression is a
0.5 point increase of the EDSS score.
[0045] In one embodiment, impaired mobility is assessed by the
Timed-25 Foot Walk test. In another embodiment, impaired mobility
is assessed by the 12-Item Multiple Sclerosis Walking Scale
(MSWS-12) self-report questionnaire. In another embodiment,
impaired mobility is assessed by the Ambulation Index (AI). In
another embodiment, impaired mobility is assessed by the Six-Minute
Walk (6MW) Test. In another embodiment, impaired mobility is
assessed by the Lower Extremity Manual Muscle Test (LEMMT)
Test.
[0046] In an embodiment, the amount of laquinimod and the amount of
fingolimod when taken together is effective to reduce cognitive
impairment. In another embodiment, cognitive impairment is assessed
by the Symbol Digit Modalities Test (SDMT) score.
[0047] In an embodiment, general health status is assessed by the
EuroQoL (EQ5D) questionnaire, Subject Global Impression (SGI) or
Clinician Global Impression of Change (CGIC). In another
embodiment, functional status is measured by the subject's
Short-Form General Health survey (SF-36) Subject Reported
Questionnaire score. In another embodiment, quality of life is
assessed by SF-36, EQ5D, Subject Global Impression (SGI) or
Clinician Global Impression of Change (CGIC). In another
embodiment, the subject's SF-36 mental component summary score
(MSC) is improved. In another embodiment, the subject's SF-36
physical component summary sore (PSC) is improved. In another
embodiment, fatigue is assessed by the EQ5D, the subject's Modified
Fatigue Impact Scale (MFIS) score or the French valid versions of
the Fatigue Impact Scale (EMIF-SEP) score. In another embodiment,
symptom severity on work is measured by the work productivity and
activities impairment General Health (WPAI-GH) questionnaire.
[0048] In one embodiment, laquinimod is laquinimod sodium. In
another embodiment, fingolimod is fingolimod hydrochloride.
[0049] In one embodiment, the laquinimod and/or the fingolimod is
administered via oral administration. In another embodiment, the
laquinimod and/or the fingolimod is administered daily. In another
embodiment, the laquinimod and/or the fingolimod is administered
more often than once daily. In another embodiment, the laquinimod
and/or the fingolimod is administered less often than once
daily.
[0050] In one embodiment, the amount laquinimod administered is
less than 0.6 mg/day. In another embodiment, the amount laquinimod
administered is 0.1-40.0 mg/day. In another embodiment, the amount
laquinimod administered is 0.1-2.5 mg/day. In another embodiment,
the amount laquinimod administered is 0.25-2.0 mg/day. In another
embodiment, the amount laquinimod administered is 0.5-1.2 mg/day.
In another embodiment, the amount laquinimod administered is 0.25
mg/day. In another embodiment, the amount laquinimod administered
is 0.3 mg/day. In another embodiment, the amount laquinimod
administered is 0.5 mg/day. In another embodiment, the amount
laquinimod administered is 0.6 mg/day. In another embodiment, the
amount laquinimod administered is 1.0 mg/day. In another
embodiment, the amount laquinimod administered is 1.2 mg/day. In
another embodiment, the amount laquinimod administered is 1.5
mg/day. In another embodiment, the amount laquinimod administered
is 2.0 mg/day.
[0051] In one embodiment, the amount of fingolimod administered is
less than 0.5 mg/day. In another embodiment, the amount of
fingolimod administered is 0.01-2.5 mg/day. In another embodiment,
the amount of fingolimod administered is 2.5 mg/day. In another
embodiment, the amount of fingolimod administered is 0.01-1 mg/day.
In another embodiment, the amount of fingolimod administered is 0.1
mg/day. In another embodiment, the amount of fingolimod
administered is 0.25 mg/day. In another embodiment, the amount of
fingolimod administered is 0.5 mg/day.
[0052] In one embodiment, the amount of laquinimod and the amount
of fingolimod when taken together is effective to alleviate a
symptom of multiple sclerosis in the subject. In another
embodiment, the symptom is a MRI-monitored multiple sclerosis
disease activity, relapse rate, accumulation of physical
disability, frequency of relapses, frequency of clinical
exacerbation, brain atrophy, risk for confirmed progression, or
time to confirmed disease progression.
[0053] In one embodiment, a loading dose of an amount different
form the intended dose is administered for a period of time at the
start of the periodic administration. In another embodiment, the
loading dose is double the amount of the intended dose.
[0054] In one embodiment, the subject is receiving laquinimod
therapy prior to initiating fingolimod therapy. In another
embodiment, the administration of laquinimod substantially precedes
the administration of fingolimod. In one embodiment, the subject is
receiving fingolimod therapy prior to initiating laquinimod
therapy. In another embodiment, the administration of fingolimod
substantially precedes the administration of laquinimod. In another
embodiment, the subject is receiving fingolimod therapy for at
least 24 weeks prior to initiating laquinimod therapy. In another
embodiment, the subject is receiving fingolimod therapy for at
least 28 weeks prior to initiating laquinimod therapy. In another
embodiment, the subject is receiving fingolimod therapy for at
least 48 weeks prior to initiating laquinimod therapy. In yet
another embodiment, the subject is receiving fingolimod therapy for
at least 52 weeks prior to initiating laquinimod therapy.
[0055] In one embodiment, the method further comprises
administration of nonsteroidal anti-inflammatory drugs (NSAIDs),
salicylates, slow-acting drugs, gold compounds, hydroxychloroquine,
sulfasalazine, combinations of slow-acting drugs, corticosteroids,
cytotoxic drugs, immunosuppressive drugs and/or antibodies.
[0056] In one embodiment, the periodic administration of laquinimod
o and fingolimod continues for at least 3 days. In another
embodiment, the periodic administration of laquinimod and
fingolimod continues for more than 30 days. In another embodiment,
the periodic administration of laquinimod and fingolimod continues
for more than 42 days. In another embodiment, the periodic
administration of laquinimod and fingolimod continues for 8 weeks
or more. In another embodiment, the periodic administration of
laquinimod and fingolimod continues for at least 12 weeks. In
another embodiment, the periodic administration of laquinimod and
fingolimod continues for at least 24 weeks. In another embodiment,
the periodic administration of laquinimod and fingolimod continues
for more than 24 weeks. In yet another embodiment, the periodic
administration of laquinimod and fingolimod continues for 6 months
or more.
[0057] In one embodiment, the administration of laquinimod and
fingolimod inhibits a symptom of relapsing multiple sclerosis by at
least 20%. In another embodiment, the administration of laquinimod
and fingolimod inhibits a symptom of relapsing multiple sclerosis
by at least 30%. In another embodiment, the administration of
laquinimod and fingolimod inhibits a symptom of relapsing multiple
sclerosis by at least 50%. In another embodiment, the
administration of laquinimod and fingolimod or inhibits a symptom
of relapsing multiple sclerosis by at least 70%. In another
embodiment, the administration of laquinimod and fingolimod
inhibits a symptom of relapsing multiple sclerosis by more than
100%. In another embodiment, the administration of laquinimod and
fingolimod inhibits a symptom of relapsing multiple sclerosis by
more than 300%. In another embodiment, the administration of
laquinimod and fingolimod inhibits a symptom of relapsing multiple
sclerosis by more than 1000%.
[0058] In one embodiment, each of the amount of laquinimod when
taken alone, and the amount of fingolimod or when taken alone is
effective to treat the subject. In another embodiment, either the
amount of laquinimod when taken alone, the amount of fingolimod or
when taken alone, or each such amount when taken alone is not
effective to treat the subject. In yet another embodiment, the
subject is a human patient.
[0059] This invention also provides a package comprising: a) a
first pharmaceutical composition comprising an amount of laquinimod
and a pharmaceutically acceptable carrier; b) a second
pharmaceutical composition comprising an amount of fingolimod and a
pharmaceutically acceptable carrier; and c) instructions for use of
the first and second pharmaceutical compositions together to treat
a subject afflicted with multiple sclerosis or presenting a
clinically isolated syndrome.
[0060] In one embodiment, the first pharmaceutical composition, the
second pharmaceutical composition, or both the first and the second
pharmaceutical composition are in an aerosol, an inhalable powder,
an injectable a liquid, a solid, a capsule or a tablet form. In one
embodiment, the first pharmaceutical composition, the second
pharmaceutical composition, or both the first and the second
pharmaceutical composition are in liquid form. In another
embodiment, the first pharmaceutical composition, the second
pharmaceutical composition, or both the first and the second
pharmaceutical composition are in solid form. In another
embodiment, the first pharmaceutical composition, the second
pharmaceutical composition, or both the first and the second
pharmaceutical composition are in capsule form. In another
embodiment, the first pharmaceutical composition, the second
pharmaceutical composition, or both the first and the second
pharmaceutical composition are in tablet form. In another
embodiment, the tablets are coated with a coating which inhibits
oxygen from contacting the core. In another embodiment, the coating
comprises a cellulosic polymer, a detackifier, a gloss enhancer, or
pigment.
[0061] In one embodiment, the first pharmaceutical composition
further comprises mannitol. In another embodiment, the first
pharmaceutical composition further comprises an alkalinizing agent.
In another embodiment, the alkalinizing agent is meglumine.
[0062] In one embodiment, the first pharmaceutical composition
further comprises an oxidation reducing agent. In another
embodiment, the first pharmaceutical composition is stable and free
of an alkalinizing agent or an oxidation reducing agent. In another
embodiment, the first pharmaceutical composition is free of an
alkalinizing agent and free of an oxidation reducing agent. In
another embodiment, the first pharmaceutical composition is stable
and free of disintegrant.
[0063] In one embodiment, the first pharmaceutical composition
further comprises a lubricant. In another embodiment, the lubricant
is present in the composition as solid particles. In another
embodiment, the lubricant is sodium stearyl fumarate or magnesium
stearate.
[0064] In one embodiment, the first pharmaceutical composition
further comprises a filler. In another embodiment, the filler is
present in the composition as solid particles. In another
embodiment, the filler is lactose, lactose monohydrate, starch,
isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray
dried, lactose anhydrouse, or a combination thereof. In yet another
embodiment, the filler is mannitol or lactose monohydrate.
[0065] In an embodiment, the package further comprises a desiccant.
In another embodiment, the desiccant is silica gel.
[0066] In one embodiment, the first pharmaceutical composition is
stable and has a moisture content of no more than 4%. In another
embodiment, laquinimod is present in the composition as solid
particles. In another embodiment, the package is a sealed packaging
having a moisture permeability of not more than 15 mg/day per
liter. In another embodiment, the sealed package is a blister pack
in which the maximum moisture permeability is no more than 0.005
mg/day. In another embodiment, the sealed package is a bottle. In
another embodiment, the bottle is closed with a heat induction
liner. In another embodiment, the sealed package comprises an HDPE
bottle. In another embodiment, the sealed package comprises an
oxygen absorbing agent. In yet another embodiment, the oxygen
absorbing agent is iron.
[0067] In an embodiment of the present invention, the amount of
laquinimod in the first composition is less than 0.6 mg. In another
embodiment, the amount of laquinimod in the first composition is
0.1-40.0 mg. In another embodiment, the amount of laquinimod in the
first composition is 0.1-2.5 mg. In another embodiment, the amount
of laquinimod in the first composition is 0.25-2.0 mg. In another
embodiment, the amount of laquinimod in the first composition is
0.5-1.2 mg. In another embodiment, the amount of laquinimod in the
first composition is 0.25 mg. In another embodiment, the amount of
laquinimod in the first composition is 0.3 mg. In another
embodiment, the amount of laquinimod in the first composition is
0.5 mg. In another embodiment, the amount of laquinimod in the
first composition is 0.6 mg. In another embodiment, the amount of
laquinimod in the first composition is 1.0 mg. In another
embodiment, the amount of laquinimod in the first composition is
1.2 mg. In another embodiment, the amount of laquinimod in the
first composition is 1.5 mg. In another embodiment, the amount of
laquinimod in the first composition is 2.0 mg.
[0068] In an embodiment of the present invention, the amount of
fingolimod in the second composition is less than 0.5 mg. In
another embodiment of the present invention, the amount of
fingolimod in the second composition is 0.01-2.5 mg. In another
embodiment, the amount of fingolimod in the second composition is
2.5 mg. In another embodiment, the amount of fingolimod in the
second composition is 0.01-1 mg. In another embodiment, the amount
of fingolimod in the second composition is 0.1 mg. In another
embodiment, the amount of fingolimod in the second composition is
0.25 mg. In another embodiment, the amount of fingolimod in the
second composition is 0.5 mg.
[0069] This invention also provides laquinimod for use as an add-on
therapy or in combination with fingolimod or in treating a subject
afflicted with multiple sclerosis or presenting a clinically
isolated syndrome.
[0070] This invention also provides a pharmaceutical composition
comprising an amount of laquinimod and an amount of fingolimod for
use in treating a subject afflicted with multiple sclerosis or
presenting a clinically isolated syndrome, wherein the laquinimod
and the fingolimod f are administered simultaneously,
contemporaneously or concomitantly.
[0071] This invention also provides a pharmaceutical composition
comprising an amount of laquinimod and an amount of fingolimod for
use in treating a human patient afflicted with an immune disease,
wherein the laquinimod and the fingolimod are administered
simultaneously, contemporaneously, or concomitantly and wherein the
immune disease is an autoimmune disease, an arthritic condition, a
demyelinating disease, an inflammatory disease, multiple sclerosis,
relapsing-remitting multiple sclerosis, diabetes mellitus,
psoriasis, rheumatoid arthritis, inflammatory bowel disease,
Crohn's disease, or systemic lupus erythematosus.
[0072] This invention also provides a pharmaceutical composition
comprising an amount of laquinimod and an amount of fingolimod.
[0073] In one embodiment, laquinimod is laquinimod sodium. In
another embodiment, fingolimod is fingolimod hydrochloride.
[0074] In one embodiment, the composition is in an aerosol, an
inhalable powder, an injectable, a liquid, a solid, a capsule or a
tablet form. In another embodiment, the composition is in liquid
form. In another embodiment, the composition is in solid form. In
another embodiment, the composition is in capsule form. In another
embodiment, the composition is in tablet form.
[0075] In one embodiment, the tablets are coated with a coating
which inhibits oxygen from contacting the core. In another
embodiment, the coating comprises a cellulosic polymer, a
detackifier, a gloss enhancer, or pigment.
[0076] In one embodiment, the pharmaceutical composition further
comprises mannitol. In another embodiment, the pharmaceutical
composition further comprises an alkalinizing agent. In another
embodiment, the alkalinizing agent is meglumine. In an embodiment,
the pharmaceutical composition comprises an oxidation reducing
agent.
[0077] In an embodiment the pharmaceutical composition is free of
an alkalinizing agent or an oxidation reducing agent. In another
embodiment, the pharmaceutical composition is free of an
alkalinizing agent and free of an oxidation reducing agent.
[0078] In one embodiment, the pharmaceutical composition is stable
and free of disintegrant. In another embodiment, the pharmaceutical
composition further comprises a lubricant. In another embodiment,
the lubricant is present in the composition as solid particles. In
another embodiment, the lubricant is sodium stearyl fumarate or
magnesium stearate.
[0079] In an embodiment, the pharmaceutical composition further
comprises a filler. In another embodiment, the filler is present in
the composition as solid particles. In another embodiment, the
filler is lactose, lactose monohydrate, starch, isomalt, mannitol,
sodium starch glycolate, sorbitol, lactose spray dried, lactose
anhydrouse, or a combination thereof. In another embodiment, the
filler is mannitol or lactose monohydrate.
[0080] In one embodiment, the amount of laquinimod in the
composition is less than 0.6 mg. In another embodiment, the amount
of laquinimod in the composition is 0.1-40.0 mg. In another
embodiment, the amount of laquinimod in the composition is 0.1-2.5
mg. In another embodiment, the amount of laquinimod in the
composition is 0.25-2.0 mg. In another embodiment, the amount of
laquinimod in the composition is 0.1-2.5 mg. In another embodiment,
the amount of laquinimod in the composition is 0.25 mg. In another
embodiment, the amount of laquinimod in the composition is 0.3 mg.
In another embodiment, the amount of laquinimod in the composition
is 0.5 mg. In another embodiment, the amount of laquinimod in the
composition is 0.6 mg. In another embodiment, the amount of
laquinimod in the composition is 1.0 mg. In another embodiment, the
amount of laquinimod in the composition is 1.2 mg. In another
embodiment, the amount of laquinimod in the composition is 1.5 mg.
In another embodiment, the amount of laquinimod in the composition
is 2.0 mg.
[0081] In one embodiment, the amount of fingolimod in the
composition is less than 0.5 mg. In another embodiment, the amount
of fingolimod in the composition is 0.01-2.5 mg. In another
embodiment, the amount of fingolimod in the composition is 2.5 mg.
In another embodiment, the amount of fingolimod in the composition
is 0.01-1 mg. In another embodiment, the amount of fingolimod in
the composition is 0.1 mg. In another embodiment, the amount of
fingolimod in the composition is 0.25 mg. In another embodiment,
the amount of fingolimod in the composition is 0.5 mg.
[0082] This invention also provides use of an amount of laquinimod
and an amount of fingolimod in the preparation of a combination for
treating a subject afflicted with multiple sclerosis or presenting
a clinically isolated syndrome wherein the laquinimod or
pharmaceutically acceptable salt thereof and the fingolimod or
pharmaceutically acceptable salt thereof are administered
simultaneously, contemporaneously or concomitantly.
[0083] In one embodiment, the multiple sclerosis is relapsing
multiple sclerosis. In another embodiment, the relapsing multiple
sclerosis is relapsing-remitting multiple sclerosis.
[0084] This invention also provides a pharmaceutical composition
comprising an amount of laquinimod for use in treating a subject
afflicted with multiple sclerosis or presenting a clinically
isolated syndrome as an add-on therapy or in combination with
fingolimod by periodically administering the pharmaceutical
composition and the fingolimod to the subject.
[0085] This invention also provides a pharmaceutical composition
comprising an amount of fingolimod for use treating a subject
afflicted with multiple sclerosis or presenting a clinically
isolated syndrome as an add-on therapy or in combination with
laquinimod by periodically administering the pharmaceutical
composition and the laquinimod to the subject.
[0086] This invention also provides a therapeutic package for
dispensing to, or for use in dispensing to, a subject afflicted
with multiple sclerosis or presenting a clinically isolated
syndrome, which comprises: a) one or more unit doses, each such
unit dose comprising: i) an amount of laquinimod and ii) an amount
of fingolimod wherein the respective amounts of said laquinimod and
said fingolimod in said unit dose are effective, upon concomitant
administration to said subject, to treat the subject, and b) a
finished pharmaceutical container therefor, said container
containing said unit dose or unit doses, said container further
containing or comprising labeling directing the use of said package
in the treatment of said subject. In an embodiment, the respective
amounts of said laquinimod and said fingolimod in said unit dose
when taken together is more effective to treat the subject than
when compared to the administration of said laquinimod in the
absence of said fingolimod or the administration of said fingolimod
in the absence of said laquinimod This invention further provides a
pharmaceutical composition in unit dosage form, useful in treating
a subject afflicted with multiple sclerosis or presenting a
clinically isolated syndrome, which comprises: a) an amount of
laquinimod; b) an amount of fingolimod, wherein the respective
amounts of said laquinimod and said fingolimod in said composition
are effective, upon concomitant administration to said subject of
one or more of said unit dosage forms of said composition, to treat
the subject. In an embodiment, the respective amounts of said
laquinimod and said fingolimod in said unit dose when taken
together is more effective to treat the subject than when compared
to the administration of said laquinimod in the absence of said
fingolimod or the administration of said fingolimod in the absence
of said laquinimod.
[0087] For the foregoing embodiments, each embodiment disclosed
herein is contemplated as being applicable to each of the other
disclosed embodiments.
[0088] Fingolimod
[0089] Fingolimod mixtures, compositions, the process for the
manufacture thereof, the use thereof for treatment of various
conditions, and the corresponding dosages and regimens are
described in, e.g., U.S. Patent Application Publication Nos.
2012-0184617, 2009-0176744, 2009-0082347, and 2011-0152380, U.S.
Pat. No. 5,719,176, and Pelletier and Hafler (2012) "Fingolimod for
Multiple Sclerosis" New England Journal of Medicine,
366(4):339-347, each of which is hereby incorporated by reference
in its entireties into this application.
[0090] Laquinimod
[0091] Laquinimod mixtures, compositions, and the process for the
manufacture thereof are described in, e.g., U.S. Pat. No.
6,077,851, U.S. Pat. No. 7,884,208, U.S. Pat. No. 7,989,473, U.S.
Pat. No. 8,178,127, U.S. Application Publication No. 2010-0055072,
U.S. Application Publication No. 2012-0010238, and U.S. Application
Publication No. 2012-0010239, each of which is hereby incorporated
by reference in its entireties into this application.
[0092] Use of laquinimod for treatment of various conditions, and
the corresponding dosages and regimens, are described in U.S. Pat.
No. 6,077,851 (multiple sclerosis, insulin-dependent diabetes
mellitus, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, psoriasis, inflammatory respiratory
disorder, atherosclerosis, stroke, and Alzheimer's disease), U.S.
Application Publication No. 2011-0027219 (Crohn's disease), U.S.
Application Publication No. 2010-0322900 (Relapsing-remitting
multiple sclerosis), U.S. Application Publication No. 2011-0034508
(brain-derived neurotrophic factor (BDNF)-related diseases), U.S.
Application Publication No. 2011-0218179 (active lupus nephritis),
U.S. Application Publication No. 2011-0218203 (rheumatoid
arthritis), U.S. Application Publication No. 2011-0217295 (active
lupus arthritis), and U.S. Application Publication No. 2012-0142730
(reducing fatigue, improving quality of life, and providing
neuroprotection in MS patients), each of which is hereby
incorporated by reference in its entireties into this
application.
[0093] A pharmaceutically acceptable salt of laquinimod as used in
this application includes lithium, sodium, potassium, magnesium,
calcium, manganese, copper, zinc, aluminum and iron. Salt
formulations of laquinimod and the process for preparing the same
are described, e.g., in U.S. Pat. No. 7,589,208 and PCT
International Application Publication No. WO 2005/074899, which are
hereby incorporated by reference into this application.
[0094] Laquinimod can be administered in admixture with suitable
pharmaceutical diluents, extenders, excipients, or carriers
(collectively referred to herein as a pharmaceutically acceptable
carrier) suitably selected with respect to the intended form of
administration and as consistent with conventional pharmaceutical
practices. The unit can be in a form suitable for oral
administration. Laquinimod can be administered alone but is
generally mixed with a pharmaceutically acceptable carrier, and
co-administered in the form of a tablet or capsule, liposome, or as
an agglomerated powder. Examples of suitable solid carriers include
lactose, sucrose, gelatin and agar. Capsule or tablets can be
easily formulated and can be made easy to swallow or chew; other
solid forms include granules, and bulk powders.
[0095] Tablets may contain suitable binders, lubricants,
disintegrating agents, coloring agents, flavoring agents,
flow-inducing agents, and melting agents. For instance, for oral
administration in the dosage unit form of a tablet or capsule, the
active drug component can be combined with an oral, non-toxic,
pharmaceutically acceptable, inert carrier such as lactose,
gelatin, agar, starch, sucrose, glucose, methyl cellulose,
dicalcium phosphate, calcium sulfate, mannitol, sorbitol,
microcrystalline cellulose and the like. Suitable binders include
starch, gelatin, natural sugars such as glucose or beta-lactose,
corn starch, natural and synthetic gums such as acacia, tragacanth,
or sodium alginate, povidone, carboxymethylcellulose, polyethylene
glycol, waxes, and the like. Lubricants used in these dosage forms
include sodium oleate, sodium stearate, sodium benzoate, sodium
acetate, sodium chloride, stearic acid, sodium stearyl fumarate,
talc and the like. Disintegrators include, without limitation,
starch, methyl cellulose, agar, bentonite, xanthan gum,
croscarmellose sodium, sodium starch glycolate and the like.
[0096] Specific examples of the techniques, pharmaceutically
acceptable carriers and excipients that may be used to formulate
oral dosage forms of the present invention are described, e.g., in
U.S. Pat. No. 7,589,208, PCT International Application Publication
Nos. WO 2005/074899, WO 2007/047863, and 2007/146248.
[0097] General techniques and compositions for making dosage forms
useful in the present invention are described in the following
references: Modern Pharmaceutics, Chapters 9 and 10 (Banker &
Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets
(Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical
Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical
Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985);
Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones,
Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David
Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous
Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the
Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);
Pharmaceutical Particulate Carriers: Therapeutic Applications:
Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed.,
1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood
Books in the Biological Sciences. Series in Pharmaceutical
Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds).;
Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40
(Gilbert S. Banker, Christopher T. Rhodes, Eds). These references
in their entireties are hereby incorporated by reference into this
application.
[0098] Disclosed is a method for treating a subject, e.g., human
patient, afflicted with relapsing multiple sclerosis or presenting
a CIS using laquinimod with fingolimod which provides a more
efficacious treatment than each agent alone. The use of laquinimod
for relapsing multiple sclerosis had been previously suggested in,
e.g., U.S. Pat. No. 6,077,851. However, the inventors have
surprisingly found that the combination of laquinimod and
fingolimod is particularly effective for the treatment of a subject
afflicted with MS or presenting a CIS as compared to each agent
alone.
TERMS
[0099] As used herein, and unless stated otherwise, each of the
following terms shall have the definition set forth below.
[0100] As used herein, "laquinimod" means laquinimod acid or a
pharmaceutically acceptable salt thereof.
[0101] As used herein, "fingolimod" means fingolimod acid or a
pharmaceutically acceptable salt thereof
[0102] As used herein, an "amount" or "dose" of laquinimod or
fingolimod as measured in milligrams refers to the milligrams of
laquinimod or fingolimod acid present in a preparation, regardless
of the form of the preparation. A "dose of 0.6 mg laquinimod" means
the amount of laquinimod acid in a preparation is 0.6 mg,
regardless of the form of the preparation. Thus, when in the form
of a salt, e.g. a laquinimod sodium salt, the weight of the salt
form necessary to provide a dose of 0.6 mg laquinimod would be
greater than 0.6 mg (e.g., 0.64 mg) due to the presence of the
additional salt ion. Similarly, when in the form of a salt, e.g.
fingolimod hydrochloride, the weight of the salt form necessary to
provide a dose of 0.5 mg fingolimod would be greater than 0.5 mg
(e.g., 0.56 mg) due to the presence of the additional salt ion.
[0103] As used herein, a "unit dose", "unit doses" and "unit dosage
form(s)" mean a single drug administration entity/entities.
[0104] As used herein, "about" in the context of a numerical value
or range means.+-.10% of the numerical value or range recited or
claimed.
[0105] As used herein, a composition that is "free" of a chemical
entity means that the composition contains, if at all, an amount of
the chemical entity which cannot be avoided although the chemical
entity is not part of the formulation and was not affirmatively
added during any part of the manufacturing process. For example, a
composition which is "free" of an alkalizing agent means that the
alkalizing agent, if present at all, is a minority component of the
composition by weight. Preferably, when a composition is "free" of
a component, the composition comprises less than 0.1 wt %, 0.05 wt
%, 0.02 wt %, or 0.01 wt % of the component.
[0106] As used herein, "alkalizing agent" is used interchangeably
with the term "alkaline-reacting component" or "alkaline agent" and
refers to any pharmaceutically acceptable excipient which
neutralizes protons in, and raises the pH of, the pharmaceutical
composition in which it is used.
[0107] As used herein, "oxidation reducing agent" refers to a group
of chemicals which includes an "antioxidant", a "reduction agent"
and a "chelating agent".
[0108] As used herein, "antioxidant" refers to a compound selected
from the group consisting of tocopherol, methionine, glutathione,
tocotrienol, dimethyl glycine, betaine, butylated hydroxyanisole,
butylated hydroxytoluene, turmerin, vitamin E, ascorbyl palmitate,
tocopherol, deteroxime mesylate, methyl paraben, ethyl paraben,
butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate,
sodium or potassium metabisulfite, sodium or potassium sulfite,
alpha tocopherol or derivatives thereof, sodium ascorbate, disodium
edentate, BHA (butylated hydroxyanisole), a pharmaceutically
acceptable salt or ester of the mentioned compounds, and mixtures
thereof.
[0109] The term "antioxidant" as used herein also refers to
Flavonoids such as those selected from the group of quercetin,
morin, naringenin and hesperetin, taxifolin, afzelin, quercitrin,
myricitrin, genistein, apigenin and biochanin A, flavone,
flavopiridol, isoflavonoids such as the soy isoflavonoid,
genistein, catechins such as the tea catechin epigallocatechin
gallate, flavonol, epicatechin, hesperetin, chrysin, diosmin,
hesperidin, luteolin, and rutin.
[0110] As used herein, "reduction agent" refers to a compound
selected from the group consisting of thiol-containing compound,
thioglycerol, mercaptoethanol, thioglycol, thiodiglycol, cysteine,
thioglucosc, dithiothreitol (DTT), dithio-bis-maleimidoethanc
(DTME), 2,6-di-tert-butyl-4-methylphenol (BHT), sodium dithionite,
sodium bisulphite, formamidine sodium metabisulphite, and ammonium
bisulphite."
[0111] As used herein, "chelating agent" refers to a compound
selected from the group consisting of penicillamine, trientine,
N,N'-diethyldithiocarbamate (DDC), 2,3,2'-tetraamine (2,3,2'-tet),
neocuproine, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
(TPEN), 1,10-phenanthroline (PHE), tetraethylenepentamine,
triethylenetetraamine and tris(2-carboxyethyl) phosphine (TCEP),
ferrioxamine, CP94, EDTA, deferoxainine B (DFO) as the
methanesulfonate salt (also known as desferrioxanilne B mesylate
(DFOM)), desferal from Novartis (previously Ciba-Giegy), and
apoferritin.
[0112] As used herein, a pharmaceutical composition is "stable"
when the composition preserves the physical stability/integrity
and/or chemical stability/integrity of the active pharmaceutical
ingredient during storage. Furthermore, "stable pharmaceutical
composition" is characterized by its level of degradation products
not exceeding 5% at 40.degree. C./75% RH after 6 months or 3% at
55.degree. C./75% RH after two weeks, compared to their level in
time zero.
[0113] As used herein, "combination" means an assemblage of
reagents for use in therapy either by simultaneous or
contemporaneous administration. Simultaneous administration refers
to administration of an admixture (whether a true mixture, a
suspension, an emulsion or other physical combination) of the
laquinimod and the fingolimod. In this case, the combination may be
the admixture or separate containers of the laquinimod and the
fingolimod that are combined just prior to administration.
Contemporaneous administration refers to the separate
administration of the laquinimod and the fingolimod at the same
time, or at times sufficiently close together that a synergistic
activity relative to the activity of either the laquinimod or the
fingolimod alone is observed.
[0114] As used herein, "concomitant administration" or
administering "concomitantly" means the administration of two
agents given in close enough temporal proximately to allow the
individual therapeutic effects of each agent to overlap.
[0115] As used herein, "add-on" or "add-on therapy" means an
assemblage of reagents for use in therapy, wherein the subject
receiving the therapy begins a first treatment regimen of one or
more reagents prior to beginning a second treatment regimen of one
or more different reagents in addition to the first treatment
regimen, so that not all of the reagents used in the therapy are
started at the same time. For example, adding laquinimod therapy to
a patient already receiving fingolimod therapy.
[0116] As used herein, "effective" when referring to an amount of
laquinimod and/or fingolimod refers to the quantity of laquinimod
and/or fingolimod that is sufficient to yield a desired therapeutic
response without undue adverse side effects (such as toxicity,
irritation, or allergic response) commensurate with a reasonable
benefit/risk ratio when used in the manner of this invention.
[0117] "Administering to the subject" or "administering to the
(human) patient" means the giving of, dispensing of, or application
of medicines, drugs, or remedies to a subject/patient to relieve,
cure, or reduce the symptoms associated with a condition, e.g., a
pathological condition.
[0118] "Treating" as used herein encompasses, e.g., inducing
inhibition, regression, or stasis of a disease or disorder, e.g.,
RMS, or alleviating, lessening, suppressing, inhibiting, reducing
the severity of, eliminating or substantially eliminating, or
ameliorating a symptom of the disease or disorder. "Treating" as
applied to patients presenting CIS can mean delaying the onset of
clinically definite multiple sclerosis (CDMS), delaying the
progression to CDMS, reducing the risk of conversion to CDMS, or
reducing the frequency of relapse in a patient who experienced a
first clinical episode consistent with multiple sclerosis and who
has a high risk of developing CDMS.
[0119] "Inhibition" of disease progression or disease complication
in a subject means preventing or reducing the disease progression
and/or disease complication in the subject.
[0120] A "symptom" associated with RMS includes any clinical or
laboratory manifestation associated with RMS and is not limited to
what the subject can feel or observe.
[0121] As used herein, "a subject afflicted with multiple
sclerosis" or "a subject afflicted with relapsing multiple
sclerosis" means a subject who has been clinically diagnosed to
have multiple sclerosis or relapsing multiple sclerosis (RMS),
which includes relapsing-remitting multiple sclerosis (RRMS) and
Secondary Progressive multiple sclerosis (SPMS).
[0122] As used herein, a subject at "baseline" is as subject prior
to administration of laquinimod
[0123] A "patient at risk of developing MS" (i.e. clinically
definite MS) as used herein is a patient presenting any of the
known risk factors for MS. The known risk factors for MS include
any one of a clinically isolated syndrome (CIS), a single attack
suggestive of MS without a lesion, the presence of a lesion (in any
of the CNS, PNS, or myelin sheath) without a clinical attack,
environmental factors (geographical location, climate, diet,
toxins, sunlight), genetics (variation of genes encoding HLA-DRB 1,
IL7R-alpha and IL2R-alpha), and immunological components (viral
infection such as by Epstein-Barr virus, high avidity CD4 T cells,
CD8 T cells, anti-NF-L, anti-CSF 114(Glc)).
[0124] "Clinically isolated syndrome (CIS)" as used herein refers
to 1) a single clinical attack (used interchangeably herein with
"first clinical event" and "first demyelinating event") suggestive
of MS, which, for example, presents as an episode of optic
neuritis, blurring of vision, diplopia, involuntary rapid eye
movement, blindness, loss of balance, tremors, ataxia, vertigo,
clumsiness of a limb, lack of co-ordination, weakness of one or
more extremity, altered muscle tone, muscle stiffness, spasms,
tingling, paraesthesia, burning sensations, muscle pains, facial
pain, trigeminal neuralgia, stabbing sharp pains, burning tingling
pain, slowing of speech, slurring of words, changes in rhythm of
speech, dysphagia, fatigue, bladder problems (including urgency,
frequency, incomplete emptying and incontinence), bowel problems
(including constipation and loss of bowel control), impotence,
diminished sexual arousal, loss of sensation, sensitivity to heat,
loss of short term memory, loss of concentration, or loss of
judgment or reasoning, and 2) at least one lesion suggestive of MS.
In a specific example, CIS diagnosis would be based on a single
clinical attack and at least 2 lesions suggestive of MS measuring 6
mm or more in diameter.
[0125] "Relapse Rate" is the number of confirmed relapses per unit
time. "Annualized relapse rate" is the mean value of the number of
confirmed relapses of each patient multiplied by 365 and divided by
the number of days that patient is on the study drug.
[0126] "Expanded Disability Status Scale" or "EDSS" is a rating
system that is frequently used for classifying and standardizing
the condition of people with multiple sclerosis. The score ranges
from 0.0 representing a normal neurological exam to 10.0
representing death due to MS. The score is based upon neurological
testing and examination of functional systems (FS), which are areas
of the central nervous system which control bodily functions. The
functional systems are: Pyramidal (ability to walk), Cerebellar
(coordination), Brain stem (speech and swallowing), Sensory (touch
and pain), Bowel and bladder functions, Visual, Mental, and Other
(includes any other neurological findings due to MS) (Kurtzke J F,
1983).
[0127] A "confirmed progression" of EDSS, or "confirmed disease
progression" as measured by EDSS score is defined as a 1 point
increase from baseline EDSS if baseline EDSS was between 0 and 5.0,
or a 0.5 point increase if baseline EDSS was 5.5. In order to be
considered a confirmed progression, the change (either 1 point or
0.5 points) must be sustained for at least 3 months. In addition,
confirmation of progression cannot be made during a relapse.
[0128] "Adverse event" or "AE" means any untoward medical
occurrence in a clinical trial subject administered a medicinal
product and which does not have a causal relationship with the
treatment. An adverse event can therefore be any unfavorable and
unintended sign including an abnormal laboratory finding, symptom,
or diseases temporally associated with the use of an
investigational medicinal product, whether or not considered
related to the investigational medicinal product.
[0129] "Gd-enhancing lesion" refers to lesions that result from a
breakdown of the blood-brain barrier, which appear in contrast
studies using gandolinium contrast agents. Gandolinium enhancement
provides information as to the age of a lesion, as Gd-enhancing
lesions typically occur within a six week period of lesion
formation.
[0130] "Magnetization Transfer Imaging" or "MTI" is based on the
magnetization interaction (through dipolar and/or chemical
exchange) between bulk water protons and macromolecular protons. By
applying an off resonance radio frequency pulse to the
macromolecular protons, the saturation of these protons is then
transferred to the bulk water protons. The result is a decrease in
signal (the net magnetization of visible protons is reduced),
depending on the magnitude of MT between tissue macromolecules and
bulk water. "MT" or "Magnetization Transfer" refers to the transfer
of longitudinal magnetization from the hydrogen nuclei of water
that have restricted motion to the hydrogen nuclei of water that
moves with many degrees of freedom. With MTI, the presence or
absence of macromolecules (e.g. in membranes or brain tissue) can
be seen (Mehta, 1996; Grossman, 1994).
[0131] "Magnetization Resonance Spectroscopy" or "MRS" is a
specialized technique associated with magnetic resonance imaging
(MRI). MRS is used to measure the levels of different metabolites
in body tissues. The MR signal produces a spectrum of resonances
that correspond to different molecular arrangements of the isotope
being "excited". This signature is used to diagnose certain
metabolic disorders, especially those affecting the brain, (Rosen,
2007) as well as to provide information on tumor metabolism
(Golder, 2007).
[0132] As used herein "mobility" refers to any ability relating to
walking, walking speed, gait, strength of leg muscles, leg function
and the ability to move with or without assistance. Mobility can be
evaluated by one or more of several tests including but not limited
to Ambulation Index, Time 25 foot walk, Six-Minute Walk (6MW),
Lower Extremity Manual Muscle Test (LEMMT) and EDSS. Mobility can
also be reported by the subject, for example by questionnaires,
including but not limited to 12-Item Multiple Sclerosis Walking
Scale (MSWS-12). Impaired Mobility refers to any impairment,
difficulty or disability relating to mobility.
[0133] "T1-weighted MRI image" refers to an MR-image that
emphasizes T1 contrast by which lesions may be visualized. Abnormal
areas in a T1-weighted MRI image are "hypointense" and appear as
dark spots. These spots are generally older lesions.
[0134] "T2-weighted MRI image" refers to an MR-image that
emphasizes T2 contrast by which lesions may be visualized. T2
lesions represent new inflammatory activity.
[0135] The "Six-Minute Walk (6MW) Test" is a commonly used test
developed to assess exercise capacity in patients with COPD
(Guyatt, 1985). It has been used also to measure mobility in
multiple sclerosis patients (Clinical Trials Website).
[0136] The "Timed-25 Foot Walk" or "T25-FW" is a quantitative
mobility and leg function performance test based on a timed
25-walk. The patient is directed to one end of a clearly marked
25-foot course and is instructed to walk 25 feet as quickly as
possible, but safely. The time is calculated from the initiation of
the instruction to start and ends when the patient has reached the
25-foot mark. The task is immediately administered again by having
the patient walk back the same distance. Patients may use assistive
devices when doing this task. The score for the T25-FW is the
average of the two completed trials. This score can be used
individually or used as part of the MSFC composite score (National
MS Society Website).
[0137] One of the central symptoms of multiple sclerosis is
fatigue. Fatigue can be measured by several tests including but not
limited to decrease of French valid versions of the Fatigue Impact
Scale (EMIF-SEP) score, and European Quality of Life (EuroQoL)
Questionnaire (EQ5D). Other tests, including but not limited to
Clinician Global Impression of Change (CGIC) and Subject Global
Impression (SGI), as well as EQ-5D, can be used to evaluate the
general health status and quality of life of MS patients.
[0138] "Ambulation Index" or "AI" is a rating scale developed by
Hauser et al. to assess mobility by evaluating the time and degree
of assistance required to walk 25 feet. Scores range from 0
(asymptomatic and fully active) to 10 (bedridden). The patient is
asked to walk a marked 25-foot course as quickly and safely as
possible. The examiner records the time and type of assistance
(e.g., cane, walker, crutches) needed. (Hauser, 1983)
[0139] "EQ-5D" is a standardized questionnaire instrument for use
as a measure of health outcome applicable to a range of health
conditions and treatments. It provides a simple descriptive profile
and a single index value for health status that can be used in the
clinical and economic evaluation of health care as well as
population health surveys. EQ-5D was developed by the "EuroQoL"
Group which comprises a network of international, multilingual,
multidisciplinary researchers, originally from seven centers in
England, Finland, the Netherlands, Norway and Sweden. The EQ-5D
questionnaire is in the public domain and can be obtained from
EuroQoL.
[0140] "SF-36" is a multi-purpose, short-form health survey with 36
questions which yields an 8-scale profile of functional health and
well-being scores as well as psychometrically-based physical and
mental health summary measures and a preference-based health
utility index. It is a generic measure, as opposed to one that
targets a specific age, disease, or treatment group. The survey is
developed by and can be obtained from QualityMetric, Inc. of
Providence, R.I.
[0141] A "pharmaceutically acceptable carrier" refers to a carrier
or excipient that is suitable for use with humans and/or animals
without undue adverse side effects (such as toxicity, irritation,
and allergic response) commensurate with a reasonable benefit/risk
ratio. It can be a pharmaceutically acceptable solvent, suspending
agent or vehicle, for delivering the instant compounds to the
subject.
[0142] It is understood that where a parameter range is provided,
all integers within that range, and tenths thereof, are also
provided by the invention. For example, "0.1-2.5 mg/day" includes
0.1 mg/day, 0.2 mg/day, 0.3 mg/day, etc. up to 2.5 mg/day.
[0143] This invention will be better understood by reference to the
Experimental Details which follow, but those skilled in the art
will readily appreciate that the specific experiments detailed are
only illustrative of the invention as described more fully in the
claims which follow thereafter.
Experimental Details
Example 1
Assessment of Efficacy of Laquinimod Alone or in-Combination with
Fingolimod in MOG-Induced EAE
[0144] In this experiment, MOG-induced EAE Mice were treated with a
sub-optimal dose of laquinimod (10 mg/kg) alone or with add on
fingolimod (0.3 mg/kg) to assess the efficacy of laquinimod alone
or in combination with fingolimod. MOG-induced Experimental
Autoimmune Encephalomyelitis (EAE) in the C57Bl strain of mice is
an established EAE model to test the efficacy of candidate
molecules for MS treatment.
[0145] The dosages were chosen based on known effective dose
amounts for laquinimod (0.6 mg/day) and for fingolimod (0.5 mg/day)
in humans (FDA News Release, 2010; U.S. Patent Application
Publication 2010-0322900). The National Institutes of Health (NTH)
provides a table of Equivalent Surface Area Dosage Conversion
Factors below (Table 1) which provides conversion factors that
account for surface area to weight ratios between species.
TABLE-US-00001 TABLE 1 Equivalent Surface Area Dosage Conversion
Factors To Mouse Rat Monkey Dog Man 20 g 150 g 3 kg 8 kg 60 kg FROM
Mouse 1 1/2 1/4 1/6 1/12 Rat 2 1 1/2 1/4 1/7 Monkey 4 2 1 3/5 1/3
Dog 6 4 1 2/3 1 1/2 Man 12 7 3 2 1
[0146] Accordingly, the data from this mice study is representative
of what can be expected in human patients with the treatment of
laquinimod and fingolimod at the corresponding human dosages.
[0147] Procedure
[0148] Disease was induced in all mice by the injection of the
encephalitogenic emulsion (MOG/CFA) and intraperitoneal injection
of pertussis toxin on the first day and 48 hours later. [0149]
Fingolimod at dose levels of 0.3 (sub optimal) and 1 mg/kg
(optimal) were administered by the oral dose, once daily (QD).
[0150] Laquinimod at dose levels of 10 (sub optimal) and 25 mg/kg
(optimal) were administered by the oral route, once daily (QD).
[0151] Both fingolimod and laquinimod were administered
prophylactic from disease induction--Day 1 until termination of the
study.
[0152] Induction of EAE:
[0153] EAE was induced by subcutaneous injection of
encephalitogenic emulsion at a volume of 0.2 ml/mouse in the right
flank. On the day of induction, pertussis toxin was injected i.p.
at a volume dose of 0.2 ml/mouse. The injection of the pertussis
toxin was repeated after 48 hours.
[0154] Test Procedure:
[0155] Day 0: Subcutaneous injection of MOG into right flank, i.p.
injection of Pertussis toxin, beginning of daily laquinimod
treatment.
[0156] Day 2: i.p. injection of Pertussis toxin.
[0157] Day 10: Initiation of scoring of mice for EAE clinical
signs.
[0158] Day 30: Termination of study.
[0159] Materials: [0160] 1. Fingolimod [0161] 2. Laquinimod [0162]
3. Mycobacterium tuberculosis (MT), Difco [0163] 4. Pertussis
toxin, Sigma [0164] 5. MOG 35-55, Mnf Novatide [0165] 6. Complete
Freund's Adjuvant (CFA), Sigma [0166] 7. Saline, Mnf-DEMO S.A
[0167] 8. Sterile double distilled water (DDW)
[0168] Experimental Animals:
[0169] Healthy, nulliparous, non-pregnant female mice of the
C57BL/6 strain were used in the study.
[0170] The animals weighed 18-22 grams, and were approximately 8
weeks old on receipt.
[0171] The body weights of the animals were recorded on the day of
delivery.
[0172] Overtly healthy animals were assigned to study groups
arbitrarily before treatment commenced.
[0173] The mice were individually identified by using ear tags. A
color-coded card on each cage gave information including cage
number, group number and identification.
[0174] EAE Induction:
[0175] EAE was induced by injecting the encephalitogenic mixture
(emulsion) consisting of MOG (150.0 .mu.g/mouse) and CFA containing
M. tuberculosis (2 mg MT/mL CFA).
[0176] A volume of 0.2 ml of emulsion was injected subcutaneously
into the flanks of the mice.
[0177] Pertussis toxin in 0.2 ml dosage volume was injected
intraperitoneally on the day of induction and 48 hours later (total
amount will be 0.1+0.1=0.2 .mu.g/mouse).
[0178] Study Design:
[0179] The mice were allocated randomly into 6 groups according to
Table 2 below.
TABLE-US-00002 Treatment Groups (treatment Administration Group
initiation) dose/day Route Regimen 1 Vehicle 10 ml/kg Oral, QD Both
2 laquinimod 10 mg/kg Oral, QD fingolimod and 2 laquinimod 25 mg/kg
Oral, QD laquinimod 4 fingolimod 0.3 mg/kg Oral, QD from Day 1 5
fingolimod 1 mg/kg Oral, QD to 30 daily 6 laquinimod + 10 mg/kg +
Oral (QD) + fingolimod 0.3 mg/kg Oral (QD)
[0180] Preparation and Administration of Encephalitogenic
Emulsion:
[0181] Oil portion: 20 mg MT was added to 20 ml CFA to yield 1+1=2
mg/ml MT).
[0182] Liquid portion: 15 mg MOG or equivalent was diluted in 10 ml
Normal Saline to yield 1.5 mg/ml MOG stock solution.
[0183] The emulsion was made from equal parts of oil and liquid
portions (1:1) in two syringes connected to each other with Leur
lock to yield 0.75 mg/ml and 1 mg/ml MT. The emulsion was
transferred to insulin syringe and 0.2 ml was injected to the right
flank of each mouse. Dose=0.15 mg MOG and 0.2 mg MT/mouse.
[0184] Preparation and Administration of Pertussis Toxin:
[0185] 50 .mu.L Pertussis toxin (200 .mu.g/ml) was added to 19.95
ml saline to yield 500 ng/ml. The pertussis toxin was administered
intraperitoneally on the day of encephalitogen injection and 48
hours later (100.0 ng/0.2 ml/mouse)--Total 200 ng/mouse.
[0186] Preparation and Administration of Test Articles
[0187] Fingolimod Formulations:
[0188] Fingolimod was weighed and sterile DDW was added to yield
0.03 and 0.1 mg/ml for dose levels of 0.3 and 1.0 mg/kg
respectively. The mice were administered with the two
concentrations of fingolimod (0.03 and 0.1 mg/ml) a volume dose
level of 200 .mu.l/mouse by the oral route for dose levels of 0.3
and 1.0 mg/kg respectively.
[0189] Laquinimod Formulations:
[0190] A concentration of 1.0 and 2.5 mg/ml laquinimod was prepared
in DDW. The test formulations were stored at 2-8.degree. C. until
use in amber colored bottles.
[0191] The mice were administered with the two concentrations of
laquinimod (1.0 and 2.5 mg/ml) a volume dose level of 200
.mu.l/mouse by the oral route for dose levels of 10 and 25 mg/kg
respectively.
[0192] Both the fingolimod and the laquinimod formulations were
administered from Day 1, once daily (QD).
[0193] Six hours interval was maintained daily between
administration of laquinimod and fingolimod.
[0194] EAE Clinical Signs:
[0195] The mice were observed daily from the 10th day post-EAE
induction (first injection of MOG) and the EAE clinical signs were
scored according to the grades described in the table presented
below.
TABLE-US-00003 TABLE 3 Evaluation of the EAE clinical signs Score
Signs Description 0 Normal behavior No neurological signs. 1 Limp
tail Part or the whole tail is limp and droopy. 2 righting reflex
Animal has difficulties rolling onto his feet when laid on its back
3 Hind leg weakness wobbly walk - when the mouse walks the hind
legs are unsteady 4 Hind leg paralysis The mouse drags its hind
legs but is able to move around using its fore legs 5 Full
paralysis The mouse can't move around, it looks thinner and
emaciated. 6 Moribund/Death
[0196] All mice with score 1 and above were considered sick. When
the first clinical sign appears all mice were given food soaked in
water, which was spread on different places on the bedding of the
cages.
[0197] Interpretation of Results
[0198] Calculation of the Incidence of Disease (Disease Ratio)
[0199] The number of sick animals in each group were summed [0200]
The incidence of disease was calculated as
[0200] INCIDENCE of DISEASE = ( No . of sick mice in treated group
No . of sick mice in control group ) ##EQU00001## [0201] The
percent inhibition according to incidence was calculated as
[0201] INHIBITION ( % ) of INCIDENCE = ( 1 - Number of sick mice in
treated group Number of sick mice in control group ) .times. 100
##EQU00002##
[0202] Calculation of the Mortality/Moribundity Rate (Mortality
Ratio) [0203] The number of dead or moribund animals in each group
were summed [0204] The mortality of disease was calculated as
[0204] MORTALITY of DISEASE = ( No . of dead or moribound mice in
treated group No . of dead or moribound mice in control group )
##EQU00003## [0205] The percent inhibition according to mortality
was calculated as
[0205] INHIBITION ( % ) of MORTALITY = ( 1 - Number of dead or
moribound mice in treated group Number of dead or moribound mice in
control group ) .times. 100 ##EQU00004##
[0206] Calculation of Duration of Disease [0207] The mean duration
of disease expressed in days was calculated as
[0207] Mean Duration = ( Duration of disease of each mouse No . of
mice in the group ) ##EQU00005##
[0208] Calculation of Mean Delay in Onset of Disease [0209] The
mean onset of disease expressed in days was calculated as
[0209] Mean Onset = ( Onset of disease of each mouse No . of mice
in the group ) ##EQU00006## [0210] The mean delay in onset of
disease expressed in days was calculated by subtracting the mean
onset of disease in control group from test group.
[0211] Calculation of the mean maximal score and percent inhibition
[0212] The mean maximal score (MMS) of each group was calculated
as
[0212] MMS = ( Maximal Score of each mouse No . of mice in the
group ) ##EQU00007## [0213] The percent inhibition according to MMS
was calculated as
[0213] INHIBITION ( % ) of MMS = ( 1 - MMS of treated group MMS of
control group ) .times. 100 ##EQU00008##
[0214] Calculation of the Group Mean Score and Percent Inhibition
[0215] The daily scores of each mouse in the test group were summed
and the individual mean daily score (IMS) was calculated as
[0215] IMS = ( Daily score of mouse Observation period ( days ) )
##EQU00009## [0216] The mean group score (GMS) was calculated
as
[0216] GMS = ( IMS of each mouse No . of mice in the group )
##EQU00010## [0217] The percent inhibition was calculated as
[0217] INHIBITION ( % ) of GMS = ( 1 - GMS of treated group GMS of
control group ) .times. 100 ##EQU00011##
[0218] Results
[0219] A summary of the incidence, mortality, Group Mean Score
(GMS), duration of the disease, onset of the disease and the
activity of each group compared to the vehicle treated control
group is shown in the Summarized Table 4. The Clinical profile of
the treatment groups are presented graphically in FIG. 1.
[0220] In groups treated with fingolimod at dose levels of 0.3
mg/kg (sub optimal dose), and 1 mg/kg (optimal dose), 56.3 and
81.3% activity, respectively, was observed according to GMS when
compared to the vehicle administered control group.
[0221] In groups treated with laquinimod at dose levels of 10 mg/kg
(sub optimal dose), and 25 mg/kg (optimal dose), 53.1 and 81.1%
activity, respectively, was observed according to GMS when compared
to the vehicle administered control group.
[0222] The total blocking of EAE in the group treated with
fingolimod at sub optimal dose level of 0.3 mg/kg in combination
with sub optimal dose of laquinimod (10 mg/kg) exhibited activity
superior to optimal dose of fingolimod (1 mg/kg) alone where 81.3%
activity was observed and optimal dose of laquinimod (25 mg/kg)
alone where 81.1% activity was observed according to GMS when
compared to the vehicle administered control group.
TABLE-US-00004 TABLE 4 Test Article: laquinimod and fingolimod
alone and in combination Mortality, incidence, GMS, Duration and
Onset. Mean Mortal- Inci- GMS Onset Duration Treatment ity dence
value (days) (days) Negative Control 1/15 15/15 3.2 .+-. 0.6 9.1
.+-. 0.9 21.9 .+-. 0.9 Vehicle 10 ml/kg p < 0.001 Laquinimod
0/15 13/15 1.5 .+-. 0.8 17.1 .+-. 6.3 14.1 .+-. 6.4 10 mg/kg p <
0.001 p < 0.001 p < 0.001 Laquinimod 0/15 7/15 0.6 .+-. 0.8
22.9 .+-. 9.0 8.1 .+-. 9.0 25 mg/kg p < 0.001 p < 0.001 p
< 0.001 Fingolimod 0/15 13/15 1.4 .+-. 0.8 16.0 .+-. 6.7 15.0
.+-. 6.7 0.3 mg/kg p < 0.001 p < 0.001 p < 0.001
Fingolimod 0/15 8/15 0.6 .+-. 0.8 21.7 .+-. 9.3 7.59 .+-. 9.1 1
mg/kg p < 0.001 p < 0.001 p < 0.001 Laquinimod + 0/15 0/15
0.0 .+-. 0.0 31.0 .+-. 0.0 0.0 .+-. 0.0 Fingolimod p < 0.001 p
< 0.001 p < 0.001 10 mg/kg + 0.3 mg/kg
CONCLUSIONS
[0223] In this study, each compound alone showed a dose dependent
inhibition of disease severity. However, while the lower dosages
tested (10 mg/kg laquinimod and 0.3 mg/kg fingolimod) were
moderately effective individually, the combination of fingolimod
and laquinimod when each was administered at its respective lower
dosage was so potent that it completely abrogated disease. This
unexpected result suggest that lower and suboptimal dosages of
laquinimod and fingolimod can be used in combination to achieve a
greater than additive therapeutic result, and provides evidence
that such a combination can be used for therapeutic treatment of
human MS and CIS patients.
Example 2
Assessment of Efficacy of Laquinimod as Add-on Therapy to
Fingolimod in Multiple Sclerosis (MS) Patients
[0224] Periodic oral administration of laquinimod (p.o. 0.6 mg/day
or 1.2 mg/day) as an add-on therapy for a human patient afflicted
with a form of MS who is already receiving fingolimod (p.o. 0.5
mg/day) provides a clinically meaningful advantage and is more
effective (provides at least an additive effect or more than an
additive effect) in treating the patient than when fingolimod is
administered alone (at the same dose).
[0225] Periodic oral administration fingolimod (p.o. 0.5 mg/day) as
an add-on therapy for a human patient afflicted with a form of MS
who is already receiving of laquinimod (p.o. 0.6 mg/day or 1.2
mg/day) provides a clinically meaningful advantage and is more
effective (provides at least an additive effect or more than an
additive effect) in treating the patient than when laquinimod is
administered alone (at the same dose).
[0226] The add-on therapies also provides efficacy (provides at
least an additive effect or more than an additive effect) in
treating the patient without undue adverse side effects or
affecting the safety of the treatment. As compared to when each
agent is administered alone: [0227] 1. The add-on therapy is more
effective (provides an additive effect or more than an additive
effect) in reducing the decrease in brain volume (determined by the
percent brain volume change (PBVC)), in multiple sclerosis
patients. [0228] 2. The add-on therapy is more effective (provides
an additive effect or more than an additive effect) in increasing
the time to confirmed disease progression (CDP), in multiple
sclerosis patients, where CDP is defined as a sustained increase in
EDSS of point from Baseline for at least 3 months. Progression
cannot be confirmed during a relapse. [0229] 3. The add-on therapy
is more effective (provides an additive effect or more than an
additive effect) in reducing abnormalities observed in whole Brain
MTR histogram, in multiple sclerosis patients. [0230] 4. The add-on
therapy is more effective (provides an additive effect or more than
an additive effect) in reducing the number of confirmed relapses
and therefore the relapse rate, in multiple sclerosis patients.
[0231] 5. The add-on therapy is also more effective (provides an
additive effect or more than an additive effect) in reducing the
accumulation of physical disability in multiple sclerosis patients,
as measured by the time to confirmed progression of EDS S. [0232]
6. The add-on therapy is more effective (provides an additive
effect or more than an additive effect) in reducing MRI-monitored
disease activity in multiple sclerosis patients, as measured by the
cumulative number of T1 Gd-enhancing lesions on T1-weighted images,
the cumulative number new T1 hypointense lesions, the cumulative
number of new T2 lesions, the cumulative number of new T1
hypointense lesions on T1-weight images (black holes), the number
of active (new T2 or GdE-T1) lesions, presence or absence of GdE
lesions, change in total volume of T1 Gd-enhancing lesions, change
in total volume of T2 lesions, and/or cortical thickness. [0233] 7.
The add-on therapy is more effective (provides an additive effect
or more than an additive effect) in reducing brain atrophy in
multiple sclerosis patients. [0234] 8. The add-on therapy is more
effective (provides an additive effect or more than an additive
effect) in reducing the frequency of relapses, the frequency of
clinical exacerbation, and the risk for confirmed progression in
multiple sclerosis patients. [0235] 9. The add-on therapy is more
effective (provides an additive effect or more than an additive
effect) in increasing the time to confirmed relapse in multiple
sclerosis patients. [0236] 10. The add-on therapy is more effective
(provides an additive effect or more than an additive effect) in
improving the general health status (as assessed by the EuroQoL
(EQ5D) questionnaire), symptom severity on work (as assessed by the
work productivity and activities impairment General Health
(WPAT-GH) questionnaire) and quality of life, in multiple
sclerosispatients. [0237] 11. The add-on therapy is more effective
(provides an additive effect or more than an additive effect) in
decreasing cerebral dysfunction/cognitive impairment (as assessed
by Symbol Digit Modalities Test (SDMT)), in multiple sclerosis
patients during the double blind study period.
[0238] Administration of laquinimod (p.o., 0.6 mg/day and 1.2
mg/day) as an add-on therapy to fingolimod (p.o., 0.5 mg/day)
provides a clinically meaningful advantage and is more effective
(provides an additive effect or more than an additive effect) in
delaying the conversion to clinically definite MS in patients
presenting a CIS suggestive of MS than when fingolimod is
administered alone (at the same dose).
[0239] Administration of laquinimod (p.o., 0.6 mg/day and 1.2
mg/day) as an add-on therapy to fingolimod (p.o., 0.5 mg/day)
provides a clinically meaningful advantage and is more effective
(provides an additive effect or more than an additive effect) in
reducing the rate of development of clinically definite MS, the
occurrence of new MRI-detected lesions in the brain, the
accumulation of lesion area in the brain and brain atrophy in
persons at high risk for developing MS, and is more effective in
reducing the occurrence of clinically definite MS and preventing
irreversible brain damage in these persons than when fingolimod is
administered alone (at the same dose).
[0240] Administration of fingolimod (p.o., 0.5 mg/day) as an add-on
therapy to laquinimod (p.o., 0.6 mg/day and 1.2 mg/day) provides a
clinically meaningful advantage and is more effective (provides an
additive effect or more than an additive effect) in delaying the
conversion to clinically definite MS in patients presenting a CIS
suggestive of MS than when laquinimod is administered alone (at the
same dose).
[0241] Administration of fingolimod (p.o., 0.5 mg/day) as an add-on
therapy to laquinimod (p.o., 0.6 mg/day and 1.2 mg/day) provides a
clinically meaningful advantage and is more effective (provides an
additive effect or more than an additive effect) in reducing the
rate of development of clinically definite MS, the occurrence of
new MRI-detected lesions in the brain, the accumulation of lesion
area in the brain and brain atrophy in persons at high risk for
developing MS, and is more effective in reducing the occurrence of
clinically definite MS and preventing irreversible brain damage in
these persons than when laquinimod is administered alone (at the
same dose).
Example 3
Assessment of Efficacy of Laquinimod in Combination with Fingolimod
in Multiple Sclerosis (MS) Patients
[0242] Periodic oral administration of laquinimod (0.6 mg/day or
1.2 mg/day) in combination with fingolimod (p.o., 0.5 mg/day) to a
human patient afflicted with relapsing form of multiple sclerosis
provides increased efficacy (provides at least an additive effect
or more than an additive effect) in treating the patient than when
laquinimod is administered alone or when fingolimod is administered
alone (at the same dose). The combination therapy also provides
efficacy (provides at least an additive effect or more than an
additive effect) in treating the patient without undue adverse side
effects or affecting the safety of the treatment.
[0243] The combination therapy provides a clinically meaningful
advantage and is more effective (provides at least an additive
effect or more than an additive effect) in treating the patient
than when laquinimod or fingolimod is administered alone (at the
same dose) in the following manner: [0244] 1. The combination
therapy is more effective (provides an additive effect or more than
an additive effect) in reducing the decrease in brain volume
(determined by the percent brain volume change (PBVC)), in multiple
sclerosis patients. [0245] 2. The combination therapy is more
effective (provides an additive effect or more than an additive
effect) in increasing the time to confirmed disease progression
(CDP), in multiple sclerosis patients, where CDP is defined as a
sustained increase in EDSS of point from Baseline for at least 3
months. Progression cannot be confirmed during a relapse. [0246] 3.
The combination therapy is more effective (provides an additive
effect or more than an additive effect) in reducing abnormalities
observed in whole Brain MTR histogram, in multiple sclerosis
patients during. [0247] 4. The combination therapy is more
effective (provides an additive effect or more than an additive
effect) in reducing the number of confirmed relapses and therefore
the relapse rate, in multiple sclerosis patients. [0248] 5. The
combination therapy is also more effective (provides an additive
effect or more than an additive effect) in reducing the
accumulation of physical disability in multiple sclerosis patients,
as measured by the time to confirmed progression of EDSS. [0249] 6.
The combination therapy is more effective (provides an additive
effect or more than an additive effect) in reducing MRI-monitored
disease activity in multiple sclerosis patients, as measured by the
cumulative number of T1 Gd-enhancing lesions on T1-weighted images,
the cumulative number new T1 hypointense lesions, the cumulative
number of new T2 lesions, the cumulative number of new T1
hypointense lesions on T1-weight images (black holes), the number
of active (new T2 or GdE-T1) lesions, presence or absence of GdE
lesions, change in total volume of T1 Gd-enhancing lesions, change
in total volume of T2 lesions, and/or cortical thickness. [0250] 7.
The combination therapy is more effective (provides an additive
effect or more than an additive effect) in reducing brain atrophy
in multiple sclerosis patients. [0251] 8. The combination therapy
is more effective (provides an additive effect or more than an
additive effect) in reducing the frequency of relapses, the
frequency of clinical exacerbation, and the risk for confirmed
progression in multiple sclerosis patients. [0252] 9. The
combination therapy is more effective (provides an additive effect
or more than an additive effect) in increasing the time to
confirmed relapse in multiple sclerosis patients. [0253] 10. The
combination therapy is more effective (provides an additive effect
or more than an additive effect) in improving the general health
status (as assessed by the EuroQoL (EQ5D) questionnaire), symptom
severity on work (as assessed by the work productivity and
activities impairment General Health (WPAI-GH) questionnaire) and
quality of life, in multiple sclerosis patients. [0254] 11. The
combination therapy is more effective (provides an additive effect
or more than an additive effect) in decreasing cerebral
dysfunction/cognitive impairment (as assessed by Symbol Digit
Modalities Test (SDMT)), in multiple sclerosis patients during the
double blind study period.
[0255] Administration of laquinimod (p.o., 0.6 mg/day and 1.2
mg/day) in combination with fingolimod (p.o., 0.5 mg/day) provides
a clinically meaningful advantage and is more effective (provides
an additive effect or more than an additive effect) in delaying the
conversion to clinically definite MS in patients presenting a CIS
suggestive of MS than when fingolimod is administered alone (at the
same dose).
[0256] Administration of laquinimod (p.o., 0.6 mg/day and 1.2
mg/day) in combination with fingolimod (p.o., 0.5 mg/day) provides
a clinically meaningful advantage and is more effective (provides
an additive effect or more than an additive effect) in reducing the
rate of development of clinically definite MS, the occurrence of
new MRI-detected lesions in the brain, the accumulation of lesion
area in the brain and brain atrophy in persons at high risk for
developing MS, and is more effective in reducing the occurrence of
clinically definite MS and preventing irreversible brain damage in
these persons than when fingolimod is administered alone (at the
same dose).
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