US20150306088A1 - Laquinimod for the treatment of relapsing-remitting multiple sclerosis (rrms) patients with a high disability status - Google Patents

Laquinimod for the treatment of relapsing-remitting multiple sclerosis (rrms) patients with a high disability status Download PDF

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US20150306088A1
US20150306088A1 US14/698,319 US201514698319A US2015306088A1 US 20150306088 A1 US20150306088 A1 US 20150306088A1 US 201514698319 A US201514698319 A US 201514698319A US 2015306088 A1 US2015306088 A1 US 2015306088A1
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laquinimod
patient
baseline
edss
score
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Volker Knappertz
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Teva Pharmaceutical Industries Ltd
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Teva Pharmaceutical Industries Ltd
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Priority to US14/946,586 priority patent/US9662322B2/en
Priority to US15/431,236 priority patent/US20170151224A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/103—Detecting, measuring or recording devices for testing the shape, pattern, colour, size or movement of the body or parts thereof, for diagnostic purposes
    • A61B5/11—Measuring movement of the entire body or parts thereof, e.g. head or hand tremor, mobility of a limb
    • A61B5/112—Gait analysis
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
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    • A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J7/00—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Definitions

  • MS Multiple Sclerosis
  • CNS Central Nervous System
  • RRMS relapsing-remitting MS
  • SPMS secondary progressive MS
  • Intervention with disease-modifying therapy at relapsing stages of MS is suggested to reduce and/or prevent accumulating neurodegeneration.
  • Disease-modifying medications currently approved for use in relapsing MS include interferon beta 1-a (Avonex® and Rebif®), interferon beta 1-b (Betaseron®), glatiramer acetate (Copaxone®), mitoxantrone (Novantrone®) and natalizumab (Tysabri®). Most of them are believed to act as immunomodulators.
  • Mitoxantrone and natalizumab are believed to act as immunesuppressants.
  • the mechanisms of action of each have been only partly elucidated.
  • Immunosuppressants or cytotoxic agents are sometimes used after failure of conventional therapies.
  • the relationship between changes of the immune response induced by these agents and the clinical efficacy in MS is far from settled.
  • 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.
  • Laquinimod sodium is a novel synthetic compound with high oral bioavailability, which has been suggested as an oral formulation for the treatment of MS.
  • Studies have shown laquinimod to reduce development of active MRI lesions in relapsing MS.
  • the clinical significance of MRI brain lesion reduction alone is still unsettled.
  • MRI lesions are used as the primary outcome measure in some studies, others have suggested that correlation between MRI abnormalities and clinical disease activity in RRMS patients is weak and that such measurement should be used as secondary outcomes rather than as surrogate markers of clinical responses.
  • the subject invention provides a method of treating a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), comprising periodically administering to only the patient diagnosed with RRMS and having a high baseline disability score an amount of laquinimod effective to treat the patient.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a method of treating a human patient afflicted with relapsing-remitting multiple sclerosis (RRMS), comprising a) diagnosing the patient as having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), and b) administering to the patient an amount of laquinimod effective to treat the patient only if the patient has been diagnosed as having a high baseline disability score.
  • RRMS relapsing-remitting multiple sclerosis
  • the subject invention also provides a method of treating a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0, comprising periodically administering to only the patient diagnosed with RRMS and having a EDSS score of greater than 3.0 an amount of laquinimod effective to treat the patient.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a method of treating a human patient afflicted with relapsing-remitting multiple sclerosis (RRMS), comprising a) diagnosing the patient as having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0, and b) administering to the patient an amount of laquinimod effective to treat the patient only if the patient has been diagnosed as having an EDSS score of greater than 3.0.
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a method of reducing ambulatory deterioration in a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), comprising periodically administering to only the patient diagnosed with RRMS and having a high baseline disability score an amount of laquinimod effective to reduce ambulatory deterioration.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a method of reducing ambulatory deterioration in a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0, comprising periodically administering to only the patient diagnosed with RRMS and having a baseline EDSS of greater than 3.0 an amount of laquinimod effective to reduce ambulatory deterioration.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides laquinimod for the manufacture of a medicament for use in treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS).
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a pharmaceutical composition comprising an effective amount of laquinimod for treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS).
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a package comprising: a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS).
  • a pharmaceutical composition comprising an amount of laquinimod
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to treat the patient, 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 patient.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides laquinimod for the manufacture of a medicament for use in treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a pharmaceutical composition comprising an effective amount of laquinimod for treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a package comprising: a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to treat the patient, 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 patient.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a method of treating a human patient diagnosed to be afflicted with RRMS and having impaired mobility, comprising periodically administering to only the patient diagnosed with RRMS and having impaired mobility an amount of laquinimod effective to treat the patient.
  • the subject invention further provides a method of treating a human patient afflicted with RRMS, comprising a) diagnosing the patient as having mobility impairment as assessed by the patient's Timed-25 foot walk test core, and b) administering to the patient an amount of laquinimod effective to treat the patient only if the patient has been diagnosed as having a mobility impairment.
  • the subject invention further provides a method of reducing mobility deterioration in a human patient diagnosed to be afflicted with RMS and having impaired mobility, comprising periodically administering to only the patient diagnosed with RRMS and having impaired mobility an amount of laquinimod effective to reduce mobility deterioration.
  • the subject invention further provides laquinimod for the manufacture of a medicament for use in treating only a human patient diagnosed to be afflicted with RRMS and having impaired mobility.
  • the subject invention further provides a pharmaceutical composition comprising an effective amount of laquinimod for use in treating only a human patient diagnosed to be afflicted with RRMS and having impaired mobility.
  • the subject invention further provides a package comprising a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat only a human patient diagnosed to be afflicted with RRMS and having impaired mobility.
  • the subject invention further provides a therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with RRMS and having impaired mobility, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to treat the patient, 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 patient.
  • the subject invention also provides a method of treating a human patient diagnosed to be afflicted with RRMS and having worsening MS, comprising periodically administering to only the patient diagnosed with RRMS and having worsening MS an amount of laquinimod effective to treat the patient.
  • the subject invention also provides laquinimod for the manufacture of a medicament for use in treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having worsening MS.
  • RRMS relapsing-remitting multiple sclerosis
  • the subject invention also provides a pharmaceutical composition comprising an effective amount of laquinimod for treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having worsening MS.
  • RRMS relapsing-remitting multiple sclerosis
  • the subject invention also provides a package comprising a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat only a human patient diagnosed to be afflicted with RRMS and having worsening MS.
  • the subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with RRMS and having worsening MS, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to treat the patient, 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 patient.
  • FIG. 1 Example 3: Time 25-Foot Walk (T25FW) Results (Mean Change from Baseline to 24 Months) in the EDSS Patient group versus the EDSS>3 Patient group.
  • FIG. 2 Example 3: Time 25-Foot Walk (T25FW) Results (Mean Change from Baseline to 24 Month) by Treatment in Patients with EDSS>3 who experienced CDP.
  • the subject invention provides a method of treating a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), comprising periodically administering to only the patient diagnosed with RRMS and having a high baseline disability score an amount of laquinimod effective to treat the patient.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a method of treating a human patient afflicted with relapsing-remitting multiple sclerosis (RRMS), comprising a) diagnosing the patient as having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), and b) administering to the patient an amount of laquinimod effective to treat the patient only if the patient has been diagnosed as having a high baseline disability score.
  • RRMS relapsing-remitting multiple sclerosis
  • the high baseline disability score is a baseline EDSS score of greater than 3. In another embodiment, the high baseline disability score is a baseline EDSS score of greater than 3.5. In another embodiment, the high baseline disability score is a baseline EDSS score of greater than 4.0. In another embodiment, the high baseline disability score is a baseline EDSS score of greater than 4.5. In another embodiment, the high baseline disability score is a baseline EDSS score of greater than 5.0. In another embodiment, the high baseline disability score is a baseline EDSS score of greater than 5.5.
  • the subject invention also provides a method of treating a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0, comprising periodically administering to only the patient diagnosed with RRMS and having a EDSS score of greater than 3.0 an amount of laquinimod effective to treat the patient.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a method of treating a human patient afflicted with relapsing-remitting multiple sclerosis (RRMS), comprising a) diagnosing the patient as having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0, and b) administering to the patient an amount of laquinimod effective to treat the patient only if the patient has been diagnosed as having an EDSS score of greater than 3.0.
  • EDSS Kurtzke Expanded Disability Status Scale
  • the amount of laquinimod is effective to reduce the patient's relapse rate. In another embodiment, the amount of laquinimod is effective to reduce the patient's accumulation of physical disability.
  • the accumulation of physical disability is assessed by the patient's Multiple Sclerosis Functional Composite (MSFC) score.
  • MSFC Multiple Sclerosis Functional Composite
  • the amount of laquinimod is effective to reduce deterioration of the patient's ambulation.
  • ambulation is assessed by the patient's Timed-25 foot walk test score.
  • after 24 months of periodic administration of laquinimod the patient's accumulation of physical disability is reduced as compared to a patient not receiving periodic administration of laquinimod.
  • the accumulation of physical disability is assessed by the time to confirmed disease progression (CDP) as measured by EDSS score.
  • CDP time to confirmed disease progression
  • the patient has a baseline EDSS score of 3.5-5.0 and CDP is a 1 point increase of the baseline EDSS score.
  • the patient has a baseline EDSS score of greater than 3.5, and CDP is a 1 point increase of the baseline EDSS score.
  • the patient has a baseline EDSS score of greater than 4.0, and CDP is a 1 point increase of the baseline EDSS score.
  • the patient has a baseline EDSS score of greater than 4.5, and CDP is a 1 point increase of the baseline EDSS score.
  • the patient has a baseline EDSS score of greater than 5.0, and CDP is a 1 point increase of the baseline EDSS score. In another embodiment, the patient has a baseline EDSS score of greater than 5.5, and CDP is a 1 point increase of the baseline EDSS score. In another embodiment, the patient has a baseline EDSS score of 5.5 or greater and CDP is a 0.5 point increase of the baseline EDSS score.
  • CDP is sustained for at least 3 months. In another embodiment, CDP is sustained for at least 6 months.
  • the subject invention also provides a method of reducing ambulatory deterioration in a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), comprising periodically administering to only the patient diagnosed with RRMS and having a high baseline disability score an amount of laquinimod effective to reduce ambulatory deterioration.
  • the high baseline disability score is a baseline EDSS score of greater than 3.
  • the subject invention also provides a method of reducing ambulatory deterioration in a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0, comprising periodically administering to only the patient diagnosed with RRMS and having a baseline EDSS of greater than 3.0 an amount of laquinimod effective to reduce ambulatory deterioration.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • ambulation is assessed by the patient's Timed-25 foot walk test score.
  • deterioration of the patient's ambulation is reduced as compared to a patient not receiving periodic administration of laquinimod.
  • the patient has been diagnosed with a baseline EDSS score of greater than 3.5. In another embodiment, the patient has been diagnosed with a baseline EDSS score of greater than 4.0. In another embodiment, the patient has been diagnosed with a baseline EDSS score of greater than 4.5. In another embodiment, the patient has been diagnosed with a baseline EDSS score of greater than 5.0. In another embodiment, the patient has been diagnosed with a baseline EDSS score of greater than 5.5. In yet another embodiment, the patient has been diagnosed with a baseline EDSS score of 3.5-5.5.
  • the patient is na ⁇ ve to an RRMS treatment. In another embodiment, the patient is na ⁇ ve to any RRMS treatment. In another embodiment, the patient is na ⁇ ve to laquinimod treatment. In another embodiment, the patient is na ⁇ ve to 0.3 mg/day laquinimod treatment. In another embodiment, the patient is na ⁇ ve to 0.6 mg/day laquinimod treatment. In another embodiment, the patient is na ⁇ ve to 1.2 mg/day laquinimod treatment.
  • laquinimod is laquinimod sodium. In another embodiment, laquinimod is administered orally. In another embodiment, laquinimod is administered daily.
  • laquinimod is administered at a daily dose of 0.1-2.5 mg laquinimod. In another embodiment of the present invention, 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 0.9 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.
  • the amount laquinimod administered is 1.8 mg/day. In another embodiment, the amount laquinimod administered is 2.0 mg/day. In another embodiment, the amount laquinimod administered is 2.5 mg/day. In yet another embodiment, the amount of laquinimod administered is about the amounts disclosed above.
  • the periodic administration is for a period of greater than 24 weeks.
  • laquinimod is administered as monotherapy for RRMS.
  • laquinimod is administered as adjunct therapy with an other RRMS treatment.
  • the other RRMS treatment is administration of interferon beta 1-a, interferon beta 1-b, glatiramer acetate, mitoxantrone or natalizumab.
  • the subject invention also provides laquinimod for the manufacture of a medicament for use in treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS).
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the high baseline disability score is a baseline EDSS score of greater than 3.
  • the subject invention also provides a pharmaceutical composition comprising an effective amount of laquinimod for treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS).
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the high baseline disability score is a baseline EDSS score of greater than 3.
  • the subject invention also provides a package comprising: a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS).
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the high baseline disability score is a baseline EDSS score of greater than 3.
  • the subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to treat the patient, 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 patient.
  • the high baseline disability score is a baseline EDSS score of greater than 3.
  • the subject invention also provides laquinimod for the manufacture of a medicament for use in treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a pharmaceutical composition comprising an effective amount of laquinimod for treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a package comprising: a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to treat the patient, 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 patient.
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides laquinimod for the manufacture of a medicament for use in reducing ambulatory deterioration only in a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS).
  • the high baseline disability score is a baseline EDSS score of greater than 3.
  • the subject invention also provides a pharmaceutical composition comprising an effective amount of laquinimod for reducing ambulatory deterioration only in a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS).
  • the high baseline disability score is a baseline EDSS score of greater than 3.
  • the subject invention also provides a package comprising: a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to reduce ambulatory deterioration only in a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS).
  • RRMS relapsing-remitting multiple sclerosis
  • EDSS Kurtzke Expanded Disability Status Scale
  • the high baseline disability score is a baseline EDSS score of greater than 3.
  • the subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to reduce ambulatory deterioration in the patient, 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 patient.
  • the high baseline disability score is a baseline EDSS score of greater than 3.
  • the subject invention also provides a method of treating a human patient diagnosed to be afflicted with RRMS and having impaired mobility, comprising periodically administering to only the patient diagnosed with RRMS and having impaired mobility an amount of laquinimod effective to treat the patient.
  • mobility is assessed by the patient's Timed-25 foot walk test score.
  • the mobility impairment is an ambulatory impairment. In another embodiment, the patient is not ambulatory.
  • mobility is assessed by the MSWS-12 self-report questionnaire. In another embodiment, mobility is assessed by the Ambulation Index. In another embodiment, mobility is assessed by the Six-Minute Walk (6MW) Test. In yet another embodiment, mobility is assessed by the LEMMT Test.
  • the subject invention also provides a method of treating a human patient afflicted with RRMS, comprising a) diagnosing the patient as having a mobility impairment as assessed by the patient's Timed-25 foot walk test score, and b) administering to the patient an amount of laquinimod effective to treat the patient only if the patient has been diagnosed as having a mobility impairment.
  • the mobility impairment is an ambulatory impairment. In another embodiment, the patient is not ambulatory
  • the amount of laquinimod is effective to reduce the patient's relapse rate. In another embodiment, the amount of laquinimod is effective to reduce the patient's accumulation of physical disability.
  • the accumulation of physical disability is assessed by the patient's MSFC score.
  • the amount of laquinimod is effective to reduce deterioration of the patient's ambulation.
  • the patient's accumulation of physical disability is reduced as compared to a patient not receiving periodic administration of laquinimod.
  • the accumulation of physical disability is assessed by the time to CDP as measured by EDSS score.
  • the patient has a baseline EDSS score of 3.5-5.0 and CDP is a 1 point increase of the baseline EDSS score.
  • the patient has a baseline EDSS score of greater than 3.5, greater than 4.0, greater than 4.5, greater than 5.0, or greater than 5.5, and CDP is a 1 point increase of the baseline EDSS score. In another embodiment, the patient has a baseline EDSS score of 5.5 or greater and CDP is a 0.5 point increase of the baseline EDSS score.
  • CDP is sustained for at least 3 months. In another embodiment, CDP is sustained for at least 6 months.
  • the subject invention also provides a method of reducing mobility deterioration in a human patient diagnosed to be afflicted with RRMS and having impaired mobility, comprising periodically administering to only the patient diagnosed with RRMS and having impaired mobility an amount of laquinimod effective to reduce mobility deterioration.
  • the mobility impairment is an ambulatory impairment. In another embodiment, the patient is not ambulatory.
  • mobility is assessed by the patient's Timed-25 foot walk test score.
  • deterioration of the patient's mobility is reduced as compared to a patient not receiving periodic administration of laquinimod.
  • the patient has been diagnosed with a baseline EDSS score of greater than 3.5, greater than 4.0, greater than 4.5, greater than 5.0, or greater than 5.5.
  • the patient has been diagnosed with a baseline EDSS score of 3.5-5.5.
  • the patient is na ⁇ ve to an RRMS treatment. In another embodiment, the patient is na ⁇ ve to laquinimod treatment. In another embodiment, the patient is na ⁇ ve to 0.3 mg/day laquinimod treatment. In another embodiment, the patient is na ⁇ ve to 0.6 mg/day laquinimod treatment. In another embodiment, the patient is na ⁇ ve to 1.2 mg/day laquinimod treatment.
  • laquinimod is laquinimod sodium. In another embodiment, laquinimod is administered orally. In another embodiment, laquinimod is administered daily. In another embodiment, laquinimod is administered at a daily dose of 0.1-2.5 mg laquinimod. In another embodiment, laquinimod is administered at a daily dose of 0.6 mg laquinimod. In another embodiment, the periodic administration is for a period of greater than 24 weeks.
  • laquinimod is administered as monotherapy for RRMS. In another embodiment, laquinimod is administered as adjunct therapy with an other RRMS treatment. In another embodiment, the other RRMS treatment is administration of interferon beta 1-a, interferon beta 1-b, glatiramer acetate, mitoxantrone or natalizumab.
  • the subject invention also provides laquinimod for the manufacture of a medicament for use in treating only a human patient diagnosed to be afflicted with RRMS and having impaired mobility.
  • the mobility impairment is an ambulatory impairment. In another embodiment, the patient is not ambulatory.
  • the subject invention also provides a pharmaceutical composition comprising an effective amount of laquinimod for use in treating only a human patient diagnosed to be afflicted with RRMS and having impaired mobility.
  • the mobility impairment is an ambulatory impairment. In another embodiment, the patient is not ambulatory.
  • mobility is assessed by the patient's Timed-25 foot walk test score.
  • the subject invention also provides a package comprising: a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat only a human patient diagnosed to be afflicted with RRMS and having impaired mobility.
  • the subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with RRMS and having impaired mobility, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to treat the patient, 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 patient.
  • the mobility impairment is an ambulatory impairment.
  • the patient is not ambulatory.
  • the patient's mobility is assessed by the patient's Timed-25 foot walk test score.
  • the subject invention also provides a method of treating a human patient diagnosed to be afflicted with RRMS and having worsening MS, comprising periodically administering to only the patient diagnosed with RRMS and having worsening MS an amount of laquinimod effective to treat the patient.
  • the patient has a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0.
  • EDSS Kurtzke Expanded Disability Status Scale
  • laquinimod is laquinimod sodium.
  • laquinimod is administered orally.
  • laquinimod is administered daily.
  • laquinimod is administered at a daily dose of 0.1-2.5 mg laquinimod.
  • laquinimod is administered at a daily dose of 0.6 mg laquinimod.
  • laquinimod is administered at a daily dose of 1.2 mg laquinimod.
  • laquinimod is administered as monotherapy for RRMS. In another embodiment, laquinimod is administered as adjunct therapy with another RRMS treatment. In another embodiment, the other RRMS treatment is administration of interferon beta 1-a, interferon beta 1-b, glatiramer acetate, mitoxantrone or natalizumab.
  • the subject invention also provides laquinimod for the manufacture of a medicament for use in treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having worsening MS.
  • RRMS relapsing-remitting multiple sclerosis
  • the subject invention also provides a pharmaceutical composition comprising an effective amount of laquinimod for treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having worsening MS.
  • RRMS relapsing-remitting multiple sclerosis
  • the patient has a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0.
  • EDSS Kurtzke Expanded Disability Status Scale
  • the subject invention also provides a package comprising: a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat only a human patient diagnosed to be afflicted with RRMS and having worsening MS.
  • the subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with RRMS and having worsening MS, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to treat the patient, 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 patient.
  • a dosage unit may comprise a single compound or mixtures of compounds thereof.
  • a dosage unit can be prepared for oral dosage forms, such as tablets, capsules, pills, powders, and granules.
  • 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 may 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.
  • suitable solid carriers include lactose, sucrose, gelatin and agar.
  • Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents flow-inducing agents, and melting agents.
  • Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • 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.
  • laquinimod means laquinimod acid or a pharmaceutically acceptable salt thereof.
  • a “pharmaceutically acceptable salt” of laquinimod as used in this application includes lithium, sodium, potassium, magnesium, calcium, manganese, copper, zinc, aluminum and iron. Salt formulations of laquinimod and the process for preparing the same are described, e.g., in U.S. Patent Application Publication No. 2005/0192315 and PCT International Application Publication No. WO 2005/074899, which are hereby incorporated by reference into this application.
  • an “amount” or “dose” of laquinimod as measured in milligrams refers to the milligrams of laquinimod acid present in a preparation, regardless of the form of the preparation.
  • a “dose of 0.6 mg laquinimod” means the amount of laquinimod acid in a preparation is 0.6 mg, regardless of the form of the preparation.
  • 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.
  • unit dose means a single drug administration entity/entities.
  • a subject at “baseline” is as subject prior to administration of laquinimod in a therapy as described herein.
  • a subject who is “na ⁇ ve” to a particular therapy is a subject who has not previously received said therapy.
  • a human patient “diagnosed to be afflicted with relapsing-remitting multiple sclerosis” means a human patient who has been clinically diagnosed to have relapsing-remitting multiple sclerosis.
  • “Relapsing-Remitting Multiple Sclerosis” or “RRMS” is characterized by clearly defined acute attacks with full recovery or with sequelae and residual deficit upon recovery (Lublin, 1996) Relapsing-remitting multiple sclerosis can be diagnosed, e.g., as defined by the Revised McDonald Criteria (Polman 2011).
  • a human patient “diagnosed to have” a high baseline disability score according to the Kurtzke Expanded Disability Status Scale means a human patient who has been clinically diagnosed to have “a high baseline disability score”, which, as used herein, means a baseline EDSS score of ⁇ 3, >3, ⁇ 3.5, >3.5, ⁇ 4, >4, ⁇ 4.5, >4.5, ⁇ 5, >5, ⁇ 5.5, or >5.5.
  • a human patient “diagnosed to have” a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0 means a human patient who has been clinically diagnosed to have a baseline EDSS score of >3.
  • administering to a/the human patient means the giving of, dispensing of, or application of medicines, drugs, or remedies to the human patient to relieve, cure, or reduce the symptoms associated with a disease, disorder or condition, e.g., a pathological condition.
  • administering only to a/the human patient . . . means the giving of, dispensing of, or application of medicines, drugs, or remedies to only the human patient population identified to the exclusion of all other potential patient populations.
  • the administration can be periodic administration.
  • periodic administration means repeated/recurrent administration separated by a period of time. The period of time between administrations is preferably consistent from time to time. Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times weekly and so on, etc.
  • treating encompasses, e.g., inducing inhibition, regression, or stasis of a disease or disorder, or lessening, suppressing, inhibiting, reducing the severity of, eliminating or substantially eliminating, or ameliorating a symptom of the disease or disorder.
  • inhibiting of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.
  • a “symptom” associated with a disease or disorder includes any clinical or laboratory manifestation associated with the disease or disorder and is not limited to what the subject can feel or observe.
  • an amount of laquinimod refers to the quantity of laquinimod that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
  • “Confirmed Relapse” is defined as the appearance of one or more new neurological abnormalities or the reappearance of one or more previously observed neurological abnormalities wherein the change in clinical state lasts at least 48 hours and is immediately preceded by an improving neurological state of at least thirty (30) days from onset of previous relapse. This criterion is different from the clinical definition of relapse which requires only 24 hours duration of symptoms. (EMEA Guideline, 2006) Since “in study” relapse definition must be supported by an objective neurological evaluation as discussed below, a neurological deficit must sustain long enough to eliminate pseudo-relapses.
  • An event is a relapse only when the subject's symptoms are accompanied by observed objective neurological changes, consistent with at least one of the following: an increase of at least 0.5 in the EDSS score as compared to the previous evaluation, an increase of one grade in the score of 2 or more of the 7 FS functions as compared to the previous evaluation, or an increase of 2 grades in the score of one FS as compared to the previous evaluation.
  • the subject must not be undergoing any acute metabolic changes such as fever or other medical abnormality.
  • a change in bowel/bladder function or in cognitive function must not be entirely responsible for the changes in EDSS or FS scores.
  • Relapse Rate is the number of confirmed relapses per unit time.
  • Annualized relapse rate or “ARR” 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.
  • “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)
  • 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.
  • the change either 1 point or 0.5 points
  • confirmation of progression cannot be made during a relapse.
  • an “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.
  • 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)
  • mobility refers to any ability relating to walking/ambulation, 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, Timed 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” as used herein refers to any impairment, difficulty or disability relating to mobility.
  • 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).
  • 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).
  • 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.
  • Gad-enhancing lesion refers to lesions that result from a breakdown of the blood-brain barrier, which appear in contrast studies using gadolinium contrast agents. Gadolinium enhancement provides information as to the age of a lesion, as Gd-enhancing lesions typically occur within a six week period of lesion formation.
  • Magneticization Transfer Imaging 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 Magneticization Transfer Imaging
  • MTI Magnetic Tunneling Transfer Imaging
  • Magnetic resonance Resonance Spectroscopy 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)
  • MFIS Modified Fatigue Impact Scale
  • MS Functional Composite or “MSFC” is a clinical outcome measure for MS.
  • the MSFC comprises quantitative functional measures of three key clinical dimensions of MS: leg function/ambulation, arm/hand function, and cognitive function. Scores on component measures are converted to standard scores (z-scores), which are averaged to form a single MSFC score. (Fischer, 1999)
  • 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 Buffalo, R.I.
  • 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.
  • 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.
  • 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.
  • 0.1-2.5 mg includes 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg etc. up to 2.5 mg.
  • EDSS Expanded Disability Status Scale
  • Double blind treatment phase 24 months of once-daily oral administration of daily dose of 0.6 mg laquinimod or matching placebo.
  • the double blind study duration may be extended to 30 months. This is planned in order to enhance the statistical power to detect the effect of laquinimod on disability accumulation.
  • the recommendation to extend the study duration is based on a pre-defined rule.
  • Subjects were evaluated at study sites for 12 scheduled visits of the double blind phase at months: ⁇ 1 (screening), 0 (baseline), 1, 2, 3, 6, 9, 12, 15, 18, 21 and 24 (termination/early discontinuation).
  • ⁇ 1 screening
  • 0 baseline
  • 1, 2, 3, 6, 9, 12, 15, 18, 21 and 24 terminal/early discontinuation
  • subjects were evaluated at study sites at months 27 and 30 (termination/early discontinuation of extended study), in this case month 24 was a regular scheduled visit.
  • EDSS was assessed every 3 months, MSFC every 6 months, and MRI was performed annually in all patients.
  • a subgroup of patients (n 189) underwent additional MRI scans at months 3 and 6.
  • Neurological evaluations including safety assessments, were performed at screening, baseline and every three months up to month 24.
  • Patient neurological assessments and general medical evaluations were conducted by two neurologists in order to minimize the possibility of unblinding; a specially trained and certified examining neurologist assessed neurological condition, and the treating neurologist determined whether a subject had experienced a relapse based on EDSS/Functional Systems scores.
  • the primary endpoint was the number of confirmed relapses during the double-blind study period.
  • a relapse was defined as the appearance of one or more new neurological abnormalities or the reappearance of one or more previously observed neurological abnormalities lasting for at least 48 hours and after an improved neurological state for at least 30 days.
  • An event was counted as a relapse if the subject's symptoms were accompanied by observed objective neurological changes consistent with at least one of the following: an increase of at least 0.5 in the EDSS score; an increase of one grade in two or more of the seven functional systems; or an increase of two grades in one functional system.
  • Standardized treatment of relapses was intravenous methylprednisolone 1 g/day for up to five consecutive days based on the treating neurologist's decision.
  • Secondary endpoints were disability progression as measured by the EDSS and the Multiple Sclerosis Functional Composite (MSFC). Confirmed disability progression was defined as an increase of ⁇ 1.0 EDSS point from baseline if baseline EDSS was between 0 and 5.0, or an increase of ⁇ 0.5 point if baseline EDSS was ⁇ 5.5. In order to confirm EDSS progression, these increases had to be sustained for at least three months. Additional predefined disability endpoints include the proportion of patients without confirmed disability progression at 24 months; confirmed disability progression (defined as change in EDSS scores ⁇ 1.0 points for baseline EDSS 0 to 5.0 or ⁇ 5.5) sustained for six months; the accumulation of physical disability as measured by mean EDSS and the mean change in EDSS from baseline to last observed value (LOV).
  • LUV last observed value
  • the measure was the total MSFC z score at 24 months (including patients who terminated after 12 months).
  • the 9-hole peg test (9HPT) and the Paced Auditory Serial Addition Test (PASAT) were performed three times at screening to reduce confounding training effects during the trial.
  • MRI related secondary endpoints were the cumulative number of GdE lesions at months 12 and 24; and the cumulative number of new T2 lesions (relative to previous scan) at months 12 and 24; MRI exploratory endpoints included percent change of brain volume using SIENA.
  • MRI scans were performed at 0, 12, and 24 months. Before a site could enroll study participants they were required to image a volunteer patient with definite MS twice with repositioning according to a strict study imaging protocol using scanners with a minimum field strength of 1.5T.
  • a series of axial, coronal, and sagittal images was obtained to create an axial reference scan for subsequent careful repositioning of each patient at the follow-up session.
  • Axial slices were positioned to run parallel to a line joining the most inferioanterior and inferioposterior parts of the corpus callosum.
  • Percentage brain volume changes and cross-sectional normalized brain volumes were measured on postcontrast T1-weighted images, with Structural Image Evaluation of Normalized Atrophy (SIENA) software and a cross-sectional method (SIENAX) (available from the FMRIB Software Library, Oxford University, Oxford, UK; http://www.fmrib.ox.ac.uk/analysis/research/siena/siena).
  • SIENA Structural Image Evaluation of Normalized Atrophy
  • SIENAX cross-sectional method
  • the analysis of the total number of confirmed relapses during the study period is based on baseline adjusted Quasi-Likelihood (over-dispersed) Poisson Regression.
  • the ARR of each group was calculated for the intent-to-treat (ITT) cohort as the total number of confirmed relapses for all patients in each group divided by the total patient years in that group.
  • the following covariates were included: baseline EDSS score, log of the (prior 2-year number of relapses +1) and country or geographical region.
  • the analysis of the accumulation of physical disability is based on Cox's Proportional Hazard model.
  • the analysis of MSFC is based on baseline-adjusted Analysis of Covariance.
  • the analysis of the secondary MRI endpoints is based on baseline-adjusted Negative Binomial Regression. To control against type-I error, the secondary endpoints were analyzed only after a significant effect was found for the primary endpoint.
  • the study's overall type-I error was further controlled in the analysis of the secondary endpoints by applying the following gate-keeping approach: both the cumulative number of new/enlarging T2 and the cumulative number of GdE lesions at months 12 and 24 were tested simultaneously and needed to be statistically significant at p ⁇ 0.05, or one needed to be significant at p ⁇ 0.025 if the other endpoint was not statistically significant at the 5% level. If the above condition was met, the study then proceeded to the analysis of the confirmed EDSS progression endpoint, if this endpoint was significant at 5% level, the analysis was done for the total MSFC z-scores.
  • Sample size calculations were based on assumptions that the number of confirmed relapses in one year reflects an over-dispersed Poisson distribution, and that the expected ARR was 0.65 in untreated subjects, 0.6 in the placebo group due to a placebo effect, and 0.45 in the laquinimod group based on 25% or more reduction in relapse rate compared to placebo.
  • a simulation study showed that 830 subjects (415 subjects per arm) would provide approximately 90% power to detect a significant change in the ARR. To correct for anticipated 20% withdrawal over 24 months, the sample was adjusted to 1000 subjects (500 subjects per arm).
  • the analysis of risk to confirmed disability progression using the ITT cohort was based on Cox's Proportional Hazard model adjusted to baseline EDSS, log of the prior 2 year number of relapses +1 and geographical region.
  • the MSFC at month 24 was analyzed using a baseline-adjusted ANCOVA (SAS@PROC GLM) with baseline MSFC as 1 degree of freedom covariate and baseline EDSS score, log of the 2-year prior relapse rate +1 and country or geographical region as additional covariates.
  • Analyses of the MSFC z score at 24 months and the secondary MRI endpoints included only patients who did not discontinue from the trial prior to month 12 visit.
  • the analysis of the brain atrophy endpoint involved a baseline-adjusted analysis of covariance (ANCOVA).
  • the covariates were the number of GdE lesions at baseline and the country or region.
  • the exploratory endpoints were all analyzed at a significance level of 5%.
  • g Cox Model regression analysis adjusted to baseline EDSS, log of the prior 2-year number of relapses + 1 and geographical region.
  • k Baseline-adjusted Negative Binomial Regression with an offset to adjust for early termination lack of exposure and baseline GdE lesions, and country or geographical region as covariates.
  • l Baseline-adjusted ANCOVA with the number of baseline GdE lesions, and country or geographical region as covariates.
  • Other relapse-related measures, such as time to first relapse and relapse free rates were also positively changed following laquinimod treatment as compared to placebo.
  • the annualized rate of relapses requiring IV steroids was 27% lower for laquinimod patients (0.263 vs 0.359, p ⁇ 0.0001).
  • the annualized rate of relapses requiring hospitalization was 0.071 vs.
  • laquinimod reduces the likelihood that a relapsing-remitting multiple sclerosis human patient would experience a confirmed relapse within a predetermined time period.
  • secondary endpoint on disability included the risk to disability progression (change in EDSS score ⁇ 1.0 points if baseline EDSS 0-5.0 or change ⁇ 0.5 point if baseline EDSS ⁇ 5.5) confirmed at 3 months.
  • Predefined additional disability endpoints included the risk of disability progression confirmed at 6 months, the risk of disability progression at last observed value (LOV), and the proportion of patients with confirmed disability progression sustained for 3 months.
  • Secondary endpoints of the ALLEGRO trial included disease activity as measured by MRI, including counts of Gadolinium enhancing T1 lesions and new-T2 hyperintense lesions.
  • the study evaluated laquinimod's effects on a variety of conventional (T1 hypointensity and brain volume) and advanced (magnetization transfer (MT) imaging and proton magnetic resonance spectroscopy ( 1 H-MRS)) MRI measures of tissue damage.
  • Conventional MRI scans for new T1 hypointense lesions, and brain volume using SIENA were performed at baseline, 12 and 24 months.
  • VOI volume of interest
  • the MRI data show that laquinimod had a clear effect in preventing irreversible tissue loss and is consistent with its impact on disability progression.
  • ALT alanine aminotransferase
  • 3 ⁇ ULN upper limit normal
  • ALT elevations ⁇ 5 ⁇ ULN occurred equally often in both groups (8 vs. 8) and led to equal rates of discontinuation. Elevations up to 5 ⁇ ULN usually occurred within the first 6 months and all were reversible either without study discontinuation or within 2 months of withdrawal.
  • Laquinimod is a promising a treatment for relapsing remitting MS, based on its effects on the accumulation of tissue damage, as indicated by consistent effects on clinical measures of disability and MRI measures of disease burden, its oral route of administration and its safety profile.
  • Laquinimod had a significant effect on inflammatory activity which characterizes the relapsing remitting course of MS. The effect was seen in the reduction of relapse rate, the primary end point of the study, as well as reduction of active MRI lesions. The reduction of relapse rate was highly consistent with effects seen on MRI measures of disease activity, which has not always been the case for other disease modifying treatments (DMTs) (The IFNB Multiple Sclerosis Study Group, 1993; Jacobs, 1996; PRISMS Study Group, 1998). Moreover, laquinimod had a significant effect on confirmed disability progression, which is considered a core outcome measure in MS.
  • DMTs disease modifying treatments
  • the ALLEGRO study further confirmed the very good safety profile of laquinimod demonstrated in phase II. There were no increased rates of serious adverse events in the trial.
  • One safety signal was liver enzyme elevations which occurred two times more frequently in the laquinimod treated arm. These elevations occurred mostly in the first treatment period and were usually modest; values exceeding 5 ⁇ ULN occurred equally often in the laquinimod and placebo arms. The liver enzyme elevations were always reversible even in patients with ⁇ 3 ⁇ ULN and were never associated with clinical, imaging or laboratory signs of liver insufficiency or failure.
  • One potential signal of a tolerability issue was abdominal pain which occurred more frequently and resulted in treatment discontinuation more frequently in the laquinimod arm. As with ALT elevations, abdominal pain was reported in the early phases of treatment exposure. It is worth noting that the safety concerns previously seen with roquinimex (Noseworthy, 2000) such as serositis, cardiovascular events and thrombosis did not emerge as signals in the ALLEGRO study.
  • BRAVO RRMS
  • BRAVO was conducted to assess the efficacy, safety and tolerability of laquinimod over placebo in a double-blinded and rater-blinded design and of a reference arm of Interferon ⁇ -1a (Avonex®).
  • the study was also conducted to perform a comparative benefit/risk assessment between oral laquinimod and injectable Interferon ⁇ -1a (Avonex®).
  • the primary objective of the study was to assess the efficacy of 0.6 mg daily dose of laquinimod in subjects with RRMS as measured by the number of confirmed relapses during the treatment period.
  • Secondary objectives of the study included assessing the effect of 0.6 mg daily dose of laquinimod on the accumulation of disability, as assessed by the MSFC score at the end of the treatment period; assessing the effect of 0.6 mg daily dose of laquinimod on the development of brain atrophy as defined by the percent brain volume change from baseline at the end of the treatment period; and assessing the effect of 0.6 mg daily dose of laquinimod on the accumulation of physical disability as measured by the time to confirmed progression of EDSS during the treatment period.
  • Avonex® (Interferon beta-1a) is a 166-amino acid glycoprotein produced by recombinant DNA technology using genetically engineered Chinese Hamster ovary cells into which the human interferon beta gene has been introduced.
  • the amino acid sequence of Avonex® is identical to that of natural human interferon beta.
  • Avonex® is a marketed drug indicated for the treatment of patients with relapsing forms of MS to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations.
  • Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with MS.
  • the recommended dosage of Avonex® is 30 mcg injected intramuscularly once a week.
  • Screening phase 1 month or up to 30 days.
  • Treatment phase 24 months of once-daily oral administration of laquinimod 0.6 mg, matching oral placebo or once-weekly intramuscular administration of Interferon ⁇ -1a (Avonex®) 30 mcg.
  • a month is defined as 30 ⁇ 4 days in this study.
  • a blinded relapse rate and sample size reassessment is performed prior to the end of the recruitment period. Based on the newly estimated relapse rate of the population, the sample size may be increased.
  • Eligible subjects are randomized in a 1:1:1 ratio (oral laquinimod:oral placebo:Avonex®) and assigned to one of the following three treatment arms:
  • 0.6 mg arm one capsule containing 0.6 mg laquinimod is administered orally once daily.
  • the 0.6 mg laquinimod capsule contains 0.6 mg of Laquinimod Acid per capsule with meglumine.
  • the 0.6 mg laquinimod capsule is manufactured according to the method disclosed in PCT International Application Publication No. WO/2007/146248, published Dec. 21, 2007 (see, page 10, line 5 to page 11, line 3).
  • Subjects on oral treatment are managed in a double-blind manner.
  • Subjects assigned to injectable treatment with Avonex® and their Treating Neurologist/Physician are unblinded to the treatment assignment, but assessed neurologically by an Examining Neurologist/Physician in a blinded manner (potential IM injection sites are covered).
  • Adverse events are recorded from when a subject has signed the Informed Consent Form and throughout the study, until 30 days following the termination visit.
  • a new condition or the worsening of a pre-existing condition is considered an AE.
  • Stable chronic conditions that are present prior to study entry and does not worsen during the study are not considered AEs.
  • PGt Pharmacogenetic
  • WPAI-GH work productivity and activities impairment-General Health
  • Additional disallowed concomitant medications/therapies interferons, glatiramer acetate (Copaxone®), Natalizumab (Tysabri®), inhibitors of CYP3A4, Mitoxantrone (Novantrone®), oral steroids, parenteral steroids (except as given as allowed for treatment of an acute relapse), chemotherapeutic agents, 4-amino pyridine or 3,4 diaminopyridine, IV Immunoglobulin (Ig) and any other experimental agents, and other Immunosuppressive or immunomodulating agents.
  • Cardiac drugs/antiarrhythmic agents such as amiodaronec, diltazem, nifedipine, verapamil, or mibefradil; Antimicrobial agents such as Erythromycin, Clarithromycin, Troleandomycin, Telithromycin, Fluconazole, Itraconazole, Ketoconazole, Miconazole, or Voriconazole; HIV drugs such as Delavirdine or Protease Inhibitors, such as indinavir, ritonavir and others; Antidepressants such as fluoxetine, fluvoxamine, or nefazodone; and other CYP3A4 inhibitors such as isoniazid, quinine, cimetidine, zileuton, or aprepitant.
  • Antimicrobial agents such as Erythromycin, Clarithromycin, Troleandomycin, Telithromycin, Fluconazole, Itraconazole, Ketoconazole, Miconazole, or Voriconazo
  • the analysis of the total numbers of confirmed relapses during the treatment period is based on baseline adjusted Quasi-Likelihood (over-dispersed) Poisson Regression.
  • the analysis of disability as assessed by MSFC at the end of the treatment period, and the analysis of brain atrophy as defined by the percent brain volume change from baseline to the end of the treatment period is based on the baseline adjusted Analysis of Covariance.
  • the analysis of the accumulation of physical disability measured by the time to a confirmed progression of EDSS is based on Cox' Proportional Hazard model.
  • Laquinimod arm one capsule containing laquinimod 0.6 mg is administered orally once daily, preferably at the same hour every day with a glass of water.
  • the 0.6 mg laquinimod capsule is manufactured according to the method disclosed in PCT International Application Publication No. WO/2007/146248, published Dec. 21, 2007 (see, page 10, line 5 to page 11, line 3).
  • Matching placebo for laquinimod arm one capsule is administered orally once daily, preferably at the same hour every day with a glass of water.
  • Avonex® arm one injection of Interferon ⁇ -1a (Avonex®) 30 mcg is administered intramuscularly once weekly, preferably on the same day.
  • the number of confirmed relapses during the treatment period is the number of confirmed relapses during the treatment period.
  • Type-I error is controlled by employing the Hierarchical Approach, (i.e. each endpoint is analyzed only in case the preceding endpoint has a p-value less or equal to 0.05 for laquinimod 0.6 mg over placebo comparison) according to the following order:
  • the Avonex® reference arm is compared to the placebo treatment group with respect to the same endpoints as for the comparison between the laquinimod group and the placebo group.
  • Neurostatus A complete neurological assessment is performed at months ⁇ 1 (screening), 0 (baseline) and every 3 months thereafter until termination/early discontinuation of the study.
  • the neurological assessment is a standardized neurological examination and assessment of Kurtzke's functional systems and expanded disability status.
  • the MS Functional Composite consists of 3 clinical examinations, the results of which are combined using z-scores.
  • the three clinical examinations include the PASAT, Timed 25 Foot walk and 9-Hole Peg Test.
  • the PASAT and 9-Hole Peg tests are performed at months ⁇ 1 (screening) (only for training purposes), 0 (baseline), 6, 12, 18 and 24 (termination/early discontinuation) visits.
  • the Timed 25 Foot walk test is performed each time the Neurostatus is performed.
  • the low-contrast visual acuity is assessed binocularly at months 0 (baseline), 6, 12, 18 and 24 (termination/early discontinuation) visits, along with the MSFC assessments.
  • MFIS Modified Fatigue Impact Scale
  • the general health status is assessed by the EuroQoL (EQ5D) questionnaire at months 0 (baseline) and 24 (termination/early discontinuation).
  • the general health status is also assessed by the Short-Form general health survey (SF-36) subject-reported questionnaire at month 0 (baseline) and every 6 months thereafter, until termination/early discontinuation.
  • SF-36 Short-Form general health survey
  • the SF-36 is a generic, self-administered health-related quality of life instrument. In this study the instrument is self-administrated during the visit.
  • Pharmacogenetic (PGt) assessment (ancillary study) is performed using an 8.5 ml blood sample taken at baseline visit.
  • WPAIGH Work Productivity and Activities Impairment
  • Serum samples are collected from all subjects at months 0 (baseline), 12 and 24 (termination/early discontinuation). They are collected for evaluation of immunological parameters and response to treatment with either laquinimod or Avonex®, as well as for further investigation of the potential mechanism of action of laquinimod.
  • Vital signs are measured at all scheduled and unscheduled visits. At baseline visit, blood pressure and pulse are measured 30 and 60 minutes after the first drug administration. Blood pressure and pulse are recorded in a sitting position after resting for 5 minutes.
  • Weight is measured at screening and month 24 (termination/early discontinuation) visits. Height is measured at month ⁇ 1 (screening) visit only.
  • ECGs are performed at months ⁇ 1 (screening) (additional recording, up to 30 minutes apart are performed if QTc is >450 msec according to the machine output), 0 (baseline), 1, 2, 3, 6, 12 18 and 24 (termination/early discontinuation).
  • three ECGs are performed at 15 minutes intervals to serve as integrated baseline ECG, by averaging baseline interval results for comparison to on-treatment values.
  • the subject rests for at least 10 minutes before measurement is taken. Twelve-lead ECG is performed following the subject being in a supine position for 5 minutes.
  • a physical examination is performed at months ⁇ 1 (screening), 0 (baseline) 1, 3, 6, 12, 18 and 24 (termination/early discontinuation).
  • a chest X-ray is performed at screening (month ⁇ 1) if not performed within 6 months prior to screening and provided a report thereof can be obtained.
  • Patients with an EDSS score of ⁇ 3 are fully ambulatory; however gait dysfunction is common in multiple sclerosis and is a key component of disability progression beyond this stage. Patients beyond this stage experience growing motor impairment. Patients with an EDSS of 3.5 are fully ambulatory but already manifest moderate disability in selected functional systems. Patients with an EDSS of 4 experience some restriction in ambulation, but are up and about most of the day despite clear neurological dysfunction. Subsequent EDSS progression is characterized by objective declines in ambulation and relatively severe disability in other functional domains.
  • RRMS patients who have demonstrated disease worsening (“worsening MS”) (Lublin, 2014) and reached an EDSS over 3 may experience confirmed disability progression (CDP) more detrimental to daily function than progression from lower EDSS steps.
  • CDP disability progression
  • the clinical need may be addressed by laquinimod treatment, which significantly reduced annualized relapse rate (ARR) and to a greater extent, CDP vs. placebo (PBO) in the phase III ALLEGRO and BRAVO studies.
  • Laquinimod reduced EDSS-based CDP overall and in EDSS subgroups.
  • the observed effect of LAQ on Confirmed Disability Progression (CDP) is disproportionately larger than would be predicted by the observed LAQ effect on relapse rate reduction.
  • Endpoints include ARR, time to CDP (defined as an increase from baseline in EDSS score of ⁇ 1 point if baseline EDSS is ⁇ 5, or of ⁇ 0.5 point if baseline EDSS is >5), sustained for 3 or 6 months; and MSFC components including the Timed 25-Foot Walk (T25FW) test.
  • MRI endpoints included brain atrophy measured percent brain volume change (PBVC), and cumulative numbers of gadolinium-enhancing (GdE) and new T2 lesions at months 12 and 24.
  • PBVC brain atrophy measured percent brain volume change
  • GdE gadolinium-enhancing
  • T25FW Timed 25-Foot Walk
  • T25FW data support the effect of laquinimod on CDP as an independent, relevant assessment in patients with EDSS greater than 3.
  • Laquinimod demonstrated significant benefits in relapse, disability, and MRI outcomes in patients with baseline EDSS>3.
  • Laquinimod is associated with substantial benefit on ambulatory function, producing clinically meaningful reductions in T25FW change amongst those with baseline EDSS>3.
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