WO2013016684A1 - Treatment of multiple sclerosis with combination of laquinimod and glatiramer acetate - Google Patents
Treatment of multiple sclerosis with combination of laquinimod and glatiramer acetate Download PDFInfo
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- WO2013016684A1 WO2013016684A1 PCT/US2012/048684 US2012048684W WO2013016684A1 WO 2013016684 A1 WO2013016684 A1 WO 2013016684A1 US 2012048684 W US2012048684 W US 2012048684W WO 2013016684 A1 WO2013016684 A1 WO 2013016684A1
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- laquinimod
- glatiramer acetate
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Definitions
- MS Multiple Sclerosis
- CNS Central Nervous System
- 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).
- 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.
- MRI magnetic resonance imaging
- 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 sc!erosis (CDMS).
- CDMS clinically definite multiple sc!erosis
- RRMS multiple sclerosis
- SPMS secondary progressive MS
- symptomatic treatment 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
- 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). Laquinimod and its sodium salt form are described, for example, in U.S. Patent No. 6,077,851.
- 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).
- Glatiramer acetate also known as Copolymer- 1
- MS multiple sclerosis
- COPAXONE® is the brand name for a formulation containing glatiramer acetate as the active ingredient. Glatiramer acetate is approved for reducing the frequency of relapses in relapsing- remitting multiple sclerosis (RRMS). Glatiramer acetate consists of the acetate salts of synthetic polypeptides containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L- tyrosine, and L-lysine with an average molar fraction in COPAXONE® of 0.141, 0.427, 0.095 and 0.338, respectively. In COPAXONE®, the average molecular weight of the glatiramer acetate is 4,700-1 1 ,000 daltons.
- glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structural formula is: (Glu, Ala, Lys, Tyr) x ACH 3 COOH (C5H 9 N0 4 AC 3 H 7 0 2 AC 6 H,4N 2 0 2 AC 9 H
- the recommended dosing schedule of COPAXONE® for relapsing-remitting multiple sclerosis is 20 mg per day injected subcutaneously (Physician's Desk Reference; see also U.S. Patent Nos. 3,849,550; 5,800,808; 5,858,964, 5,981 ,589; 6,048,898; 6,054,430; 6,214,791 ; 6,342,476; and 6,362, 161 , all of which are hereby incorporated by reference.
- GA is thought to bind to and to be displayed as an antigen within the groove of a major histocompatibility complex (MHC) molecule.
- MHC major histocompatibility complex
- APC antigen presenting cells
- the presentation of GA leads to the generation of GA-specific T cells.
- the GA-specific T cells are predominantly T helper 2 (Th2) biased.
- Th2 cells produce Th2 cytokines which inhibit the production of cytokines by Thl cells or macrophages, and tend to be anti-inflammatory.
- This invention provides a method of treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising orally administering to the patient a daily dose of 0.6mg laquinimod, and subcutaneously injecting the patient with a daily dose of 20mg glatiramer acetate, wherein the amounts when taken together is more effective to treat the human patient than when each agent is administered alone.
- 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 glatiramer acetate, wherein the amounts when taken together are effective to treat the human patient.
- 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 glatiramer acetate (GA), 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.
- 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,
- 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 glatiramer acetate and a pharmaceutically acceptable carrier; and c) instructions for use of the first and second pharmaceutical compositions together to treat a human patient afflicted with relapsing multiple sclerosis or presenting a clinically isolated syndrome.
- This invention also provides laquinimod for use as an add-on therapy or in combination with glatiramer acetate in treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome.
- This invention also provides a pharmaceutical composition comprising an amount of laquinimod and an amount of glatiramer acetate for use in treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein the laquinimod and the glatiramer acetate are administered simultaneously or contemporaneously.
- This invention also provides a pharmaceutical composition comprising an amount of laquinimod and an amount of glatiramer acetate for use in treating a human patient afflicted with an immune disease, wherein the laquinimod and the glatiramer acetate are administered simultaneously or contemporaneously, 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.
- 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,
- This invention also provides a pharmaceutical composition comprising an amount of laquinimod and an amount of glatiramer acetate.
- This invention also provides use of an amount of laquinimod and an amount of glatiramer acetate in the preparation of a combination for treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome wherein the laquinimod and the glatiramer acetate are administered simultaneously or contemporaneously.
- 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 glatiramer acetate by periodically administering the pharmaceutical composition and the glatiramer acetate to the subject.
- This invention further provides pharmaceutical composition comprising an amount of glatiramer acetate 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.
- Figure 1 is a graphical representation of the experimental results from Example
- 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).
- Figure 2 is a graphical representation of the experimental results from Example
- 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).
- Figure 3 is a graphical representation of the experimental results from Example
- 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).
- Figure 4 is a graphical representation summarizing experimental results from
- Figure 4A 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).
- Figure 4B shows the percent inhibition for the EAE rodents in each group.
- Figure 5 is a graphical representation of the experimental results from Example
- the graph shows the daily mean clinical score for the EAE rodents in each group (on the y-axis) against the days of observation (on the x-axis).
- This invention provides a method of treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising orally administering to the patient a daily dose of 0.6mg laquinimod or pharmaceutically acceptable salt thereof, and subcutaneously injecting the patient with a daily dose of 20mg glatiramer acetate, wherein the amounts when taken together is more effective to treat the human patient than when each agent is administered alone.
- the multiple sclerosis is relapsing multiple sclerosis. In another embodiment, the relapsing multiple sclerosis is relapsing-remitting multiple sclerosis.
- the amount of laquinimod and the glatiramer acetate when taken together is effective to reduce a symptom of multiple sclerosis in the human patient.
- 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.
- the accumulation of physical disability is assessed by the time to confirmed disease progression as measured by Kurtzke Expanded Disability Status Scale (EDSS) score.
- EDSS Kurtzke Expanded Disability Status Scale
- the patient had an EDSS score of 0-5 prior to administration of laquinimod.
- the patient had an EDSS score of 1-5.5 prior to administration of laquinimod.
- the patient had an EDSS score of 0-5.5 prior to administration of laquinimod.
- the patient had an EDSS score of 5.5 or greater prior to administration of laquinimod.
- confirmed disease progression is a 1 point increase of the EDSS score.
- confirmed disease progression is a 0.5 point increase of the EDSS score.
- time to confirmed disease progression is increased by 10-100%. In another embodiment, time to confirmed disease progression is increased by 20-80%. In another embodiment, time to confirmed disease progression is increased by 20-60%. In another embodiment, time to confirmed disease progression is increased by 30-50%. In yet another embodiment, time to confirmed disease progression is increased by at least 50%.
- laquinimod is laquinimod sodium.
- the patient is injected subcutaneously with 0.5ml of an aqueous pharmaceutical solution which contains in solution 20mg glatiramer acetate and 20mg mannitol.
- the patient is injected subcutaneously with 1.0 ml of an aqueous pharmaceutical solution which contains in solution 20mg glatiramer acetate and 40mg mannitol.
- the amount of glatiramer acetate administered is suboptimal.
- the glatiramer acetate is administered intramuscularly. In another embodiment, the glatiramer acetate is administered subcutaneously. In another embodiment, the glatiramer acetate is administered 1 -5 times a month. In another embodiment, the glatiramer acetate is administered 1 -3 times a month. In another embodiment, the glatiramer acetate is administered 1- 5 times a week. In another embodiment, the glatiramer acetate is administered 1 -3 times a week. In another embodiment, the glatiramer acetate is administered 1-5 times a day. In another embodiment, the glatiramer acetate is administered 1-3 times a day. In another embodiment, the glatiramer acetate is administered every other day. In yet another embodiment, the glatiramer acetate is administered daily
- the administration of laquinimod substantially precedes the administration of glatiramer acetate. In another embodiment, the administration of glatiramer acetate substantially precedes the administration of laquinimod.
- the human patient is receiving glatiramer acetate therapy prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving glatiramer acetate therapy for at least 24 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving glatiramer acetate therapy for about 24 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving glatiramer acetate therapy for at least 28 weeks prior to initiating laquinimod therapy.
- the human patient is receiving glatiramer acetate therapy for about 28 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving glatiramer acetate therapy for at least 48 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving glatiramer acetate therapy for about 48 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving glatiramer acetate therapy for at least 52 weeks prior to initiating laquinimod therapy. In yet another embodiment, the human patient is receiving glatiramer acetate therapy for about 52 weeks prior to initiating laquinimod therapy.
- the laquinimod is administered in the morning. In another embodiment, the laquinimod is administered at night. In one embodiment, the laquinimod is with food. In another embodiment, the laquinimod is administered without food. In one embodiment, the glatiramer acetate is administered in the morning. In another embodiment, the glatiramer acetate is administered at night. In one embodiment, the glatiramer acetate is administered with food. In another embodiment, the glatiramer acetate is administered without food.
- the laquinimod is administered simultaneously with the glatiramer acetate. In another embodiment, the laquinimod is administered contemporaneously with the glatiramer acetate. In another embodiment, the laquinimod is administered immediately before or immediately after the glatiramer acetate. In another embodiment, the laquinimod is administered within 1 hour before or after the glatiramer acetate. In another embodiment, the laquinimod is administered within 3 hour before or after the glatiramer acetate. In another embodiment, the laquinimod is administered within 6 hour before or after the glatiramer acetate. In another embodiment, the laquinimod is administered within 12 hour before or after the glatiramer acetate. In another embodiment, the laquinimod is administered within 24 hour before or after the glatiramer acetate.
- the method further comprises administration of nonsteroidal anti-inflammatory drugs (IS'SAlDs), salicylates, slow-acting drugs, gold compounds, hydroxychloroquine, sulfasalazine, combinations of slow-acting drugs, corticosteroids, cytotoxic drugs, immunosuppressive drugs and/or antibodies.
- IS'SAlDs nonsteroidal anti-inflammatory drugs
- salicylates slow-acting drugs
- gold compounds hydroxychloroquine
- sulfasalazine combinations of slow-acting drugs
- corticosteroids corticosteroids
- cytotoxic drugs cytotoxic drugs
- immunosuppressive drugs and/or antibodies.
- the periodic administration of laquinimod and glatiramer acetate continues for more than 30 days. In another embodiment, the periodic administration of laquinimod and glatiramer acetate continues for more than 42 days. In yet another embodiment, the periodic administration of laquinimod and glatiramer acetate continues for 6 months or more.
- the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by at least 20%. In another embodiment, the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by at least 30%. In another embodiment, the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by at least 40%. In another embodiment, the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by at least 50%.
- the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by more than 100%. In another embodiment, the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by more than 300%. In yet another embodiment, the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by more than 1000%.
- each of the amount of laquinimod when taken alone, and the amount of glatiramer acetate when taken alone is effective to treat the human patient. In another embodiment, either the amount of laquinimod when taken alone, the amount of glatiramer acetate when taken alone, or each such amount when taken alone is not effective to treat the human patient.
- 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 glatiramer acetate, wherein the amounts when taken together are effective to treat the human patient.
- the amount of laquinimod and the amount of glatiramer acetate when taken together is more effective to treat the human patient than when each agent is administered along.
- the multiple sclerosis is relapsing multiple sclerosis.
- the relapsing multiple sclerosis is relapsing-remitting multiple sclerosis.
- the amount of laquinimod and the amount of glatiramer acetate when taken together is effective to reduce a symptom of multiple sclerosis in the human patient.
- 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, 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.
- the amount of laquinimod and the amount of glatiramer acetate when taken together is effective to decrease or inhibit reduction of brain volume.
- brain volume is measured by percent brain volume change (PBVC).
- the amount of laquinimod and the amount of glatiramer acetate when taken together is effective to increase time to confirmed disease progression.
- time to confirmed disease progression is increased by 20-60%.
- time to confirmed disease progression is increased by at least 50%.
- the amount of laquinimod and the amount of glatiramer acetate when taken together is effective to decrease abnormalities observed in whole Brain MTR histogram.
- the accumulation of physical disability is measured by Kurtzke Expanded
- EDSS Disability Status Scale
- the accumulation of physical disability is assessed by the time to confirmed disease progression as measured by Kurtzke Expanded Disability Status Scale (EDSS) score.
- the patient had an EDSS score of 0-5.5 prior to administration of laquinimod.
- the patient had an EDSS score of 1 .5-4.5 prior to administration of laquinimod.
- the patient had an EDSS score of 5.5 or greater prior to administration of laquinimod.
- confirmed disease progression is a 1 point increase of the EDSS score.
- confirmed disease progression is a 0.5 point increase of the EDSS score.
- 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.
- MSWS- 12 12-Item Multiple Sclerosis Walking Scale
- AI Ambulation Index
- MI Ambulation Index
- impaired mobility is assessed by the Six-Minute Walk (6MW) Test.
- impaired mobility is assessed by the Lower Extremity Manual Muscle Test (LEMMT) Test.
- the amount of laquinimod and the amount of glatiramer acetate when taken together is effective to reduce cognitive impairment.
- cognitive impairment is assessed by the Symbol Digit Modalities Test (SDMT) score.
- general health status is assessed by the EuroQoL (EQ5D) questionnaire, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC).
- functional status is measured by the patient's Short-Form General Health survey (SF-36) Subject Reported Questionnaire score.
- quality of life is assessed by SF-36, EQ5D, Subject Global Impression (SGI) or Clinician Global Impression of Change (CG IC).
- the patient's SF-36 mental component summary score (MSC) is improved.
- the patient's SF-36 physical component summary sore (PSC) is improved.
- fatigue is assessed by the EQ5D, the patient's Modified Fatigue Impact Scale (MFIS) score or the French valid versions of the Fatigue Impact Scale (EMIF-SEP) score.
- MFIS Modified Fatigue Impact Scale
- EMIF-SEP French valid versions of the Fatigue Impact Scale
- symptom severity on work is measured by the work productivity and activities impairment General Health (WPAI-GH) questionnaire.
- laquinimod is laquinimod sodium. In another embodiment, laquinimod is administered via oral administration. In another embodiment, laquinimod is administered daily. In another embodiment, laquinimod is administered more often than once daily. In another embodiment, laquinimod is administered less often than once daily.
- 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.
- 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 yet another embodiment, the amount laquinimod administered is 2.0 mg/day.
- the amount glatiramer acetate administered is 0.1-1000 mg/day. In another embodiment, the amount glatiramer acetate administered is 50-150 mg/day. In another embodiment, the amount glatiramer acetate administered is 0.1-70 mg/day. In another embodiment, the amount glatiramer acetate administered is 10-80 mg/day. In another embodiment, the amount glatiramer acetate administered is 1 mg/day. In another embodiment, the amount glatiramer acetate administered is 5 mg/day. In another embodiment, the amount glatiramer acetate administered is 15 mg/day. In another embodiment, the amount glatiramer acetate administered is 20 mg/day.
- the amount glatiramer acetate administered is 30 mg/day. In another embodiment, the amount glatiramer acetate administered is 40 mg/day. In another embodiment, the amount glatiramer acetate administered is 50 mg/day. In another embodiment, the amount glatiramer acetate administered is 100 mg/day. In another embodiment, the amount glatiramer acetate administered is 10-600 mg/week. In another embodiment, the amount glatiramer acetate administered is 300 mg/week.
- administration of glatiramer acetate is effected daily. In another embodiment, administration of glatiramer acetate is effected twice a day at half the amount. In another embodiment, administration of glatiramer acetate is effected once every 5 to 9 days. In one embodiment, glatiramer acetate is administered orally. In another embodiment, glatiramer acetate is administered nasally. In another embodiment, glatiramer acetate is inhaled. In another embodiment, glatiramer acetate is administered by subcutaneous injection. In another embodiment, glatiramer acetate is administered over a period of seven days with at least one day between every subcutaneous injection. In another embodiment, glatiramer acetate is administered through an intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical or intradermal route.
- the patient is injected subcutaneously with 0.5ml of an aqueous pharmaceutical solution which contains in solution 20mg glatiramer acetate and 20mg mannitol.
- 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.
- the loading dose is double the amount of the intended dose.
- the administration of laquinimod substantially precedes the administration of glatiramer acetate. In another embodiment, the administration of glatiramer acetate substantially precedes the administration of laquinimod.
- the human patient is receiving glatiramer acetate therapy prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving glatiramer acetate therapy for at least 24 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving glatiramer acetate therapy for at least 28 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving glatiramer acetate therapy for at least 48 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving glatiramer acetate therapy for at least 52 weeks prior to initiating laquinimod therapy.
- 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.
- NSAIDs nonsteroidal anti-inflammatory drugs
- salicylates slow-acting drugs
- gold compounds hydroxychloroquine
- sulfasalazine combinations of slow-acting drugs
- corticosteroids corticosteroids
- immunosuppressive drugs and/or antibodies.
- the periodic administration of laquinimod and glatiramer acetate continues for at least 3 days. In another embodiment, the periodic administration of laquinimod and glatiramer acetate continues for more than 30 days. In another embodiment, the . periodic administration of laquinimod and glatiramer acetate continues for more than 42 days. In another embodiment, the periodic administration of laquinimod and glatiramer acetate continues for 8 weeks or more. In another embodiment, the periodic administration of laquinimod and glatiramer acetate continues for at least 12 weeks. In another embodiment, the periodic administration of laquinimod and glatiramer acetate continues for at least 24 weeks. In another embodiment, the periodic administration of laquinimod and glatiramer acetate continues for more than 24 weeks. In another embodiment, the periodic administration of laquinimod and glatiramer acetate continues for 6 months or more.
- the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by at least 20%. In another embodiment, the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by at least 30%. In another embodiment, the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by at least 50%. In another embodiment, the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by at least 70%.
- the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by more than 100%. In another embodiment, the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by more than 300%. In another embodiment, the administration of laquinimod and glatiramer acetate inhibits a symptom of relapsing multiple sclerosis by more than 1000%.
- each of the amount of laquinimod when taken alone, and the amount of glatiramer acetate when taken alone is effective to treat the human patient. In another embodiment, either the amount of laquinimod when taken alone, the amount of glatiramer acetate when taken alone, or each such amount when taken alone is not effective to treat the human patient.
- the patient has been identified as a responder to glatiramer treatment. In another embodiment, the patient has been identified as a non-responder to glatiramer treatment.
- 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 glatiramer acetate (GA), 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.
- 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,
- 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 glatiramer acetate and a pharmaceutically acceptable carrier; and c) instructions for use of the first and second pharmaceutical compositions together to treat a human patient afflicted with relapsing multiple sclerosis or presenting a clinically isolated syndrome.
- the first pharmaceutical composition is in the form of an aerosol or inhalable powder. In another embodiment, the first pharmaceutical composition is in liquid form. In another embodiment, the first pharmaceutical composition is in solid form. In another embodiment, the first pharmaceutical composition is in capsule form. In another embodiment, the first pharmaceutical composition is in tablet form. In another embodiment, the tablets are coated with a coating which inhibits oxygen from contacting the core. In yet another embodiment, the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, and pigment. 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.
- the first pharmaceutical composition further comprises an oxidation reducing agent.
- the first pharmaceutical composition is stable and free of an alkalinizing agent or an oxidation reducing agent.
- the first pharmaceutical composition is free of an ' alkalinizing agent and free of an oxidation reducing agent.
- the first pharmaceutical composition is stable and free of disintegrant.
- the first pharmaceutical composition further comprises a lubricant.
- the lubricant is present in the composition as solid particles.
- the lubricant is sodium stearyl fumarate or magnesium stearate.
- the first pharmaceutical composition further comprises a filler.
- the filler is present in the composition as solid particles.
- the filler is lactose, lactose mpnohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof.
- the filler is mannitol or lactose monohydrate.
- the package further comprises a desiccant.
- the desiccant is silica gel.
- the first pharmaceutical composition is stable has a moisture content of no more than 4%.
- laquinimod is present in the composition as solid particles.
- the package is a sealed packaging having a moisture permeability of not more than 15 mg/day per liter.
- the sealed package is a blister pack in which the maximum moisture permeability is no more than 0.005 mg/day.
- the sealed package is a bottle.
- the bottle is closed with a heat induction liner.
- the sealed package comprises an HDPE bottle.
- the sealed package comprises an oxygen absorbing agent.
- the oxygen absorbing agent is iron.
- the amount of laquinimod in the first 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 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.
- 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.
- the amount glatiramer acetate in the second composition is 0.1-1000 mg. In another embodiment, the amount glatiramer acetate in the second composition is 50-150 mg. In another embodiment, the amount glatiramer acetate in the second composition is 10-600 mg. In another embodiment, the amount glatiramer acetate in the second composition is 0.1-70 mg. In another embodiment, the amount glatiramer acetate in the second composition is 10-80 mg. In another embodiment, the amount glatiramer acetate in the second composition is 1 mg. In another embodiment, the amount glatiramer acetate in the second composition is 5 mg. In another embodiment, the amount glatiramer acetate in the second composition is 15 mg.
- the amount glatiramer acetate in the second composition is 20 mg. In another embodiment, the amount glatiramer acetate in the second composition is 30 mg. In another embodiment, the amount glatiramer acetate in the second composition is 40 mg. In another embodiment, the amount glatiramer acetate in the second composition is 50 mg. In another embodiment, the amount glatiramer acetate in the second composition is 100 mg. In another embodiment, the amount glatiramer acetate in the second composition is 300 mg.
- the second composition is a unit dose of 0.5 ml aqueous solution comprising 20 mg of glatiramer acetate. In another embodiment, the second composition is a unit dose of 0.5 ml aqueous solution comprising 20 mg of glatiramer acetate and 20mg mannitol. In another embodiment, the second composition is a unit dose of 1 ml aqueous pharmaceutical solution which contains in solution 20 mg glatiramer acetate and 40 mg mannitol. In another embodiment, the second composition is a unit dose of 1 ml aqueous pharmaceutical solution which contains in solution 40 mg glatiramer acetate. In another embodiment, the second composition in an enterically- coated form. This invention also provides laquinimod for use as an add-on therapy or in combination with glatiramer acetate in treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome.
- This invention also provides a pharmaceutical composition comprising an amount of laquinimod and an amount of glatiramer acetate for use in treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein the laquinimod and the glatiramer acetate are administered simultaneously or contemporaneously.
- This invention also provides a pharmaceutical composition comprising an amount of laquinimod and an amount of glatiramer acetate for use in treating a human patient afflicted with an immune disease, wherein the laquinimod and the glatiramer acetate are administered simultaneously or contemporaneously, 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.
- This invention also provides a pharmaceutical composition comprising an amount of laquinimod and an amount of glatiramer acetate.
- the pharmaceutical composition is in the form of an aerosol or inhalable powder.
- the pharmaceutical composition is in liquid form.
- the pharmaceutical composition is in solid form.
- the pharmaceutical composition is in capsule form.
- the pharmaceutical composition is in tablet form.
- the tablets are coated with a coating which inhibits oxygen from contacting the core.
- the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, and pigment.
- the pharmaceutical composition further comprises mannitol. In another embodiment, the pharmaceutical composition further comprises an alkalinizing agent. In an embodiment, the alkalinizing agent is meglumine. In another embodiment, the pharmaceutical composition further comprises an oxidation reducing agent.
- 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.
- the pharmaceutical composition is stable and free of disintegrant.
- the pharmaceutical composition further comprises a lubricant.
- the lubricant is present in the composition as solid particles.
- the lubricant is sodium stearyl fumarate or magnesium stearate.
- the pharmaceutical composition further comprises a filler.
- the filler is present in the composition as solid particles.
- the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof.
- the filler is mannitol or lactose monohydrate.
- 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 0.5-1.2 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.
- 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. In one embodiment, the amount glatiramer acetate in the composition is 0.1-1000 mg. In another embodiment, the amount glatiramer acetate in the composition is 50-150 mg. In another embodiment, the amount glatiramer acetate in the composition is 10-600 mg. In another embodiment, the amount glatiramer acetate in the composition is 0.1-70 mg.
- the amount glatiramer acetate in the composition is 10-80 mg. In another embodiment, the amount glatiramer acetate in the composition is 1 mg. In another embodiment, the amount glatiramer acetate in the composition is 5 mg. In another embodiment, the amount glatiramer acetate in the composition is 15 mg. In another embodiment, the amount glatiramer acetate in the composition is 20 mg. In another embodiment, n the amount glatiramer acetate in the composition is 30 mg. In another embodiment, the amount glatiramer acetate in the composition is 40 mg. In another embodiment, the amount glatiramer acetate in the composition is 50 mg. In another embodiment, the amount glatiramer acetate in the composition is 100 mg. In yet another embodiment, the amount glatiramer acetate in the composition is 300 mg.
- the composition is a unit dose of 0.5 ml aqueous solution comprising 20 mg of glatiramer acetate. In another embodiment, the composition is a unit dose of 0.5 ml aqueous solution comprising 20 mg of glatiramer acetate and 20mg mannitol. In another embodiment, the composition is a unit dose of 1 ml aqueous pharmaceutical solution which contains in solution 20 mg glatiramer acetate and 40 mg mannitol. In another embodiment, the composition is a unit dose of 1 ml aqueous pharmaceutical solution which contains in solution 40 mg glatiramer acetate.
- This invention further provides use of an amount of laquinimod and an amount of glatiramer acetate in the preparation of a combination for treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome wherein the laquinimod and the glatiramer acetate are administered simultaneously or contemporaneously.
- a method of treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising orally administering to the patient a daily dose of 0.6mg laquinimod, and subcutaneously injecting the patient with a daily dose of 20mg glatiramer acetate, wherein the amounts when taken together is more effective to treat the human patient than when each agent is administered alone.
- Disclosed also is a method of treating a human patient afflicted with multiple sclerosis or a patient presenting a clinically isolated syndrome suggestive of multiple sclerosis comprising periodically administering to the human patient an amount of laquinimod and an amount of glatiramer acetate, wherein the amounts when taken together is more effective to treat the human patient than when each agent is administered alone.
- the patient has experienced a single clinical attack suggestive of multiple sclerosis and has had at least one lesion suggestive of multiple sclerosis.
- the amount of laquinimod and the amount of glatiramer acetate when taken together is more effective to delaying the conversion to clinically definite multiple sclerosis in the patient than when each agent is administered alone.
- 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 glatiramer acetate by periodically administering the pharmaceutical composition and the glatiramer acetate to the subject.
- This invention further provides pharmaceutical composition comprising an amount of glatiramer acetate 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.
- Glatiramer acetate 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., PCT International Application Publication Nos. WO 1998/30227, WO 2000/05250, WO 2000/18794, WO 2004/103297, WO 2006/029393, WO 2006/02941 1 , WO 2006/083608, WO 2006/089164, WO 2006/1 16602. WO 2009/070298, WO 201 1/022063, WO 2012/051 106, WO 2003/048735, and WO 201 1/008274, U.S. Patent Application Publication Nos. 201 1-0230413 and 2008-027526, and U.S. Patent Nos. 8,008,258 and 7,556,767, each of which is hereby incorporated by reference in its entireties into this application. Laquinimod
- Laquinimod mixtures, compositions, and the process for the manufacture thereof are described in, e.g., U.S. Patent No. 6,077,851 , U.S. Patent no. 7,884,208, U.S. Patent No. 7,989,473, U.S. Patent No. 8, 178, 127, U.S. Application Publication No. 2010-0055072, U.S. Application Publication No. 2012-0010238, and U.S. Application Publication No. 2012-0010239, each of which is hereby incorporated by reference in its entireties into this application.
- 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.
- 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.
- a pharmaceutically acceptable carrier suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
- the unit will 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.
- suitable solid carriers include lactose, sucrose, gelatin and agar.
- Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, disintegrating agents (disintegrants), coloring agents, flavoring agents, 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 for relapsing multiple sclerosis had been previously suggested in, e.g., U.S. Patent No. 6,077,851.
- the inventors have surprisingly found that the combination of laquinimod and glatiramer acetate (GA) is particularly effective for the treatment of relapsing multiple sclerosis as compared to each agent alone.
- laquinimod means laquinimod acid or a pharmaceutically acceptable salt thereof.
- 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.
- 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.
- 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.
- the composition comprises less than 0.1 wt%, 0.05 wt%, 0.02 wt%, or 0.01 wt% of the component.
- 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.
- oxidation reducing agent refers to a group of chemicals which includes an “antioxidant”, a “reduction agent” and a “chelating agent”.
- 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 parabcn, 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.
- 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.
- Flavonoids such as those selected from the group of quercetin, morin, naringenin and hesperetin, taxifolin, afzelin, quercitrin, myricitrin, genistein, apigenin and biochanin A, flavone, flavopi
- reaction agent refers to a compound selected from the group consisting of thiol- containing compound, thioglycerol, mercaptoethanol, thioglycol, thiodiglycol, cysteine, thioglucose, dithiothreitol (DTT), dithio-bis-maleimidoethane (DTME), 2,6-di-tert-butyl-4-methylphenol (BHT), sodium dithionite, sodium bisulphite, formamidine sodium metabisulphite, and ammonium bisulphite.”
- chelating agent refers to a compound selected from the group consisting of penicillamine, trientine, ⁇ , ⁇ '-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.
- 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°C/75%RH after 6 months or 3% at 55°C/75% RH after two weeks, compared to their level in time zero.
- “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 GA.
- the combination may be the admixture or separate containers of the laquinimod and the GA that are combined just prior to administration.
- Contemporaneous administration refers to the separate administration of the laquinimod and the GA at the same time, or at times sufficiently close together that a synergistic activity relative to the activity of either the laquinimod or the GA alone is observed.
- additive-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 GA therapy.
- ⁇ when referring to an amount of laquinimod and/or glatiramer acetate (GA) refers to the quantity of laquinimod and/or glatiramer acetate (GA) 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.
- administering to the subject 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.
- Treating encompasses, e.g., inducing inhibition, regression, or stasis of a disease or disorder, e.g., RMS, or 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.
- CDMS clinically definite multiple sclerosis
- “Inhibition” of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.
- a "symptom" associated with RMS includes any clinical or laboratory manifestation associated with RMS and is not limited to what the subject can feel or observe.
- a subject afflicted with relapsing multiple sclerosis means a subject who has been clinically diagnosed to have relapsing multiple sclerosis (RMS) which includes relapsing-remitting multiple sclerosis (RRMS) and Secondary Progressive multiple sclerosis (SPMS).
- RMS relapsing multiple sclerosis
- RRMS relapsing-remitting multiple sclerosis
- SPMS Secondary Progressive multiple sclerosis
- a "responder" to GA treatment refers to a subject that is positively responsive, i.e. the patient's situation improves upon GA therapy.
- a "non-responder” to GA treatment is defined as a subject that does not adequately respond to GA-therapy.
- a “responder” and a “non-responder” to GA treatment can be measured in any of methods known in the art including that disclosed in PCT International Application No. WO 2006/1 16602, WO 2012/05 1 106, and U.S. Application Publication No. 201 1-0230413, which are hereby incorporated by reference herein.
- a subject at "baseline” is as subject prior to administration of laquinimod.
- a "patient at risk of developing MS” 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 1 14(Glc)).
- CIS Cerularly isolated syndrome
- 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 l imb, 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,
- 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.
- “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 JF, 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 sustained for at least 3 months. In addition, confirmation of progression cannot be made during a relapse.
- 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 invest igational medicinal product, whether or not considered related to the investigational medicinal product.
- 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.
- Magneticization 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 Magneticization Transfer Imaging 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)
- Magnetic resonance 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) 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.
- MSWS-12 12-Item Multiple Sclerosis Walking Scale
- Tl -weighted MRI image refers to an MR-image that emphasizes Tl contrast by which lesions may be visualized. Abnormal areas in a Tl-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.
- 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).
- 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 (E IF-SEP) score, and European Quality of Life (EuroQoL) Questionnaire (EQ5D).
- E IF-SEP Fatigue Impact Scale
- EQ5D European Quality of Life
- 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.
- 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)
- 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.
- 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 Quality Metric, Inc. of Buffalo, RI.
- 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.
- EAE Experimental autoimmune encephalomyelitis
- Example 2.1 MOG Study This study is designed to test the efficacy of laquinimod in abrogating MOG-induced EAE. Laquinimod was tested alone (5 and 25 mg/kg day) and in combination with GA blocking.
- EAE was induced by subcutaneous injection of encephalitogenic emulsion at a volume of 0.2 ml/mouse in the right flank.
- 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.
- Day 0 Subcutaneous injection of MOG into right flank, ip injection of Pertussis toxin. Beginning of daily laquinimod treatment.
- Day 2 ip injection of Pertussis toxin.
- mice On day 0 all mice were injected with the encephalitogenic emulsion (containing 150 ⁇ g myelin oligodendrocyte glycoprotein (MOG) and 500 ⁇ g M. tuberculosis enriched CFA. Emulsion for groups with GA-blocking included GA (250 ⁇ g/mouse). The emulsion was made from equal parts of oil and liquid portions ( 1 : 1 ) in two syringes connected to each other with Leur lock, transferred to insulin syringe and 0.2 ml injected to the right flank of each mouse. On the day of induction and 48 hours thereafter, mice were injected with Pertussis Toxin (i.p., 100 ng).
- Pertussis Toxin i.p., 100 ng
- EAE was induced by injecting the encephalitogenic mixture (emulsion) consisting of MSCH in PBS and commercial CFA containing 1 mg/mL Mycobacterium tuberculosis (in ratio 1 : 1). A total volume of 50 ⁇ of emulsion was injected in left foot pad of each mouse. Pertussis toxin was injected intravenously on the day of induction and 48 hours later at volume dose of 0.5 ml/mouse).
- Laquinimod treatment in mice The high dose (25mg/10ml/kg) solution (150 mg in 60 ml DDW) was prepared once weekly and stored at room temperature in an amber glass vial. For the dose of 5 mg/kg 12 ml of this solution was added to 48 ml DDW. The compound was administered by gavage once daily during the whole experiment (30 days) at a volume of 0.2 ml/mouse. Mice were observed daily from the 10 th day post-EAE induction and the EAE clinical signs were scored.
- CFA (containing 1 mg/ml MT) was enriched to the concentration of 5 mg/ml: 52 mg/ T was added to 13 ml CFA.
- Liquid Portion Groups 1 -3: 10.5 mg MOG was diluted in 7 ml PBS (1.5mg/ml, 150 mg/0.1 ml/mouse). Groups 4-6: 20 mg GA was diluted in 8 ml PBS (2.5mg/ml, 250 mg/0.1 ml/mouse). 12 mg MOG was added to this solution.
- the emulsion was made from equal parts of oil and liquid portions (1 : 1 ) in two syringes connected to each other with Leur lock, transferred to insulin syringe and 0.2 ml injected to the right flank of each mouse.
- EAE CLINICAL SIGNS The mice were observed daily from the 10 th 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 2: Evaluation of the EAE clinical signs
- MOG is a member of the immunoglobulin superfamily expressed exclusively in CNS myelin. It is one of the most encephalitogenic proteins and- is widely used to induce EAE in different rodent strains. In C57BL/6 mice, immunization with the MOG peptide pMOG35-55 in CFA induces chronic progressive EAE. In this study, the descending doses of laquinimod were tested in GA-blocked mice.
- Liquid portion 24 mg MOG was diluted in 8 ml PBS (3 mg/ml, stock solution). Groups 1 , 3 and 5: 3.5 ml of stock solution was diluted 1 : 1 with PBS. Groups 2, 4, 6, and 7: 22.5 mg GA was diluted in 4.5 ml PBS (5 mg/ml). 4.5 ml of MOG stock solution was added to this solution.
- the emulsion was made from equal parts of oil and liquid portions (1 : 1) in two syringes connected to each other with Leur lock, transferred to insulin syringe and 0.2 ml was injected to the right flank of each mouse.
- the high dose LAQ (5mg/10ml/kg) solution (40 mg in 80 ml DDW) was prepared once weekly and stored at room temperature. For the dose of 2.5 mg/kg LAQ, 25 ml of this solution were added to 25 ml DDW. For the dose 1 mg/kg 5 ml of stock solution (high dose) were added to 20 ml DDW. The compound was administered by gavage once daily during the whole experiment (30 days) at a volume of 0.2 ml/mouse.
- mice were observed daily from the 9 th day post-EAE induction (first injection of OG) and the EAE clinical signs were scored according to the grades described in the 2 above.
- Table 6 The effect of laquinimod alone and in combination with GA-blocking on disease severity.
- Oil portion CFA (containing 1 mg/ml MT) was enriched to the concentration of 2 mg/ml: 16 mg/MT was added to 16 ml CFA.
- Liquid portion 24 mg MOG was diluted in 8 ml PBS (3 mg/ml, stock solution). Groups 1 , 3, 5 and 7: 4 ml of stock solution was diluted 1 : 1 with PBS. Groups 2, 4, 6, and 8: 22.5 mg GA was diluted in 4.5 ml PBS (5 mg/ml). This solution was mixed 1 : 1 with the stock solution of MOG.
- the emulsion was made from equal parts of oil and liquid portions (1 : 1) in two syringes connected to each other with Leur lock, transferred to insulin syringe and 0.2 ml was injected to the right flank of each mouse.
- the high dose LAQ (25mg/10ml/kg) solution (150 mg in 60 ml DDW) was prepared once weekly and stored in the amber glass at room temperature.
- the lower LAQ doses were prepared daily.
- For the dose of 5 mg/kg 1.6 ml of stock solution were added to 6.4 ml DDW.
- the compound was administered by gavage once daily during the hole experiment (30 days) at a volume of 0.2 ml/mouse.
- mice were observed daily from the 10 th day post-EAE induction (first injection of MOG) and the EAE clinical signs were scored according to the grades described in the 2 above.
- laquinimod alone showed dose-depended efficacy from no effect at a dose of 1 mg/kg to 70% GMS reduction at 5 mg kg and 95% inhibition of GMS at 25 mg/kg.
- Table 8 The effect of laquinimod alone and in combination with GA-blocking on disease severity
- laquinimod given in combination showed additive effect at doses of 5mg/kg (89.5%) and 25mg/kg, where the higher dose resulted in complete inhibition of disease.
- laquinimod provides an additive effect over GA-blocking as summarized in Table 9 and shown on Figures 4A and 4B.
- the objective of this study was to test the additive effect of laquinimod and GA in the EAE model in C57B1 mice.
- the C57B1 strain of mouse was selected, as it is an established EAE model.
- Laquinimod was administered daily orally for 30 days at dose level of 5.0 mg/kg or 25.0 mg/kg. GA was administered subcutaneously for 10 days at a dose of 250 mg/kg or once, along with encephalitogen at dose level of 12.5 mg/kg. In order to study the additive effect of laquinimod and GA, laquinimod was administered to groups of mice where GA was administered subcutaneously at a dose of 250 mg/kg or along with encephalitogen at dose level of 12.5 mg/kg.
- the suppressive activity of groups with combination treatment was compared to group where laquinimod or GA were administered alone. GA at a dose of 12.5 mg/kg administered along with the encephalitogen (blocking) served as positive control group.
- mice of the C57B1 strain weighing about 15-22 g were approximately 7-8 weeks of age on arrival. The body weight of the animals was recorded on the day of delivery.
- EAE induction was induced by injecting the encep alitogenic mixture (emulsion) consisting of MOG (150.0 ⁇ g mouse). A volume of 0.2 ml of emulsion was injected subcutaneously into the flanks of the mice. Pertussis toxin was injected intraperitoneally on the day of induction and 48 hours later (total amount was 0.300 ⁇ in 0.2 ml dosage volume).
- mice were allocated to the following treatment groups as shown in Table 10: Table 10 :
- Oil portion CFA (containing 1 mg/ml MT) was enriched to the concentration of 2 mg/ml: 30.0 mg/MT was added to 30.0 ml CFA.
- the emulsion(for groups 2 and 3 and groups 1 and 4 to 8) were made from equal parts of oil and liquid portions ( 1 : 1 ) in two syringes connected to each other with Leur lock, transferred to insulin syringe and 0.2 ml was injected to the right flank of each mouse.
- the dose of the MOG in all the groups (1 to 8) was 150 ⁇ g/mouse.
- the dose of the GA in groups 2 and 3 was 250 3 ⁇ 4 / ⁇ 3 ⁇ .
- the test concentrations of laquinimod were prepared in purified water. For high dose (25.0 mg/kg) 2.5 mg/mL stock solution were prepared (groups # 3, 6 and 8). The stock solutions were diluted 1 :5 to yield 0.5 mg mL for dose level of 5.0 mg/kg for groups 5 and 7. Laquinimod was administered to the respective groups by gavage at a volume of 0.2 ml/mouse.
- Glatiramer acetate A 50.0 mg/ml stock solution of GA was prepared in Saline. 8.0 mL of 50.0 mg/mL GA was aliquoted in 10 tubes and stored at -20°C. Every day one tube was thawed and brought to RT. GA was administered subcutaneously daily for 10 days from the initiation of the study to the mice of groups 4, 7 and 8 at 0.1 mL.
- Clinical signs Scoring of EAE clinical signs was started from Day 10 post EAE induction and was continued daily until Day 30. The clinical signs were recorded according to a grading system described in the table 1 1 below
- mice having scores of 1 and above were considered sick. When the first clinical sign appeared all mice were given food soaked in water, which was spread on different places on the bedding of the cages. An animal which continued to have score 4 for three days was killed on humane grounds and given score 5 on the next day. For calculation purposes, the score of animals that were sacrificed or died was carried forward.
- mice in th e group No. of mice in th e group
- 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.
- mice in th e group J The percent inhibition was calculated as
- MMS Mean Maximal Score
- GMS Group Mean Score
- the MMS of the vehicle treated negative control group was 3.4 and of GA blocking positive control group was 0.5.
- Group treated with laquinimod (5 mg/kg) along with GA at dose level of 250 mg/kg (subcutaneous) exhibited additive effect (85.2% according to GMS) which was not significant because of high activity exhibited by laquinimod alone (71.4% according to GMS).
- GA administered subcutaneously exhibited 38.1% activity.
- the combination treatment GA blocking and laquinimod - 25 mg/kg was given, 100% activity was observed.
- the objective of this study was to test the suppressive effect of laquinimod alone and in combination with Glatiramer acetate in the EAE model in C57B1 mice.
- laquinimod and GA were administered alone or in combination and the suppressive activity of the groups with combination treatment were compared to group where laquinimod or GA were administered alone.
- GA was administered subcutaneous ly for 10 days at a dose of 250 mg/kg.
- Laquinimod was administered orally at dose levels of 2.5 and 5.0 mg/kg.
- the EAE is an animal model for multiple sclerosis.
- the C57B1 strain of mouse has been selected, as it is an established EAE model.
- EAE was induced in the mice by the injection of the encephalitogenic emulsion (MOG/CFA).
- Laquinimod was administered orally for 30 consecutive days.
- GA was administered subcutaneously for 10 consecutive days from the initiation of the study.
- mice of the C57B1 strain weighing about 15-22 g were approximately 7-8 weeks old on arrival. The body weights of the animals were recorded on the day of delivery. Overtly healthy animals were assigned to study groups arbitrarily before treatment commenced.
- mice were allocated to the following treatment groups (table 13):
- Oil portion CFA (containing 1 mg/ml MT) was enriched to the concentration of 2 mg/ml: 33.5 mg/MT were added to 33.5 ml CFA.
- Group 2 5 mg/mL stock solution of GA were prepared in Normal Saline. 2.5 mL of this solution was mixed with 2.5 mL of 3mg/ml MOG stock solution to yield 1.5 mg MOG /mL and 2.5 mg GA/mL.
- the emulsification was made from equal parts of oil and liquid portions (1 : 1 ) in two syringes connected to each other with Leur lock, transferred to insulin syringe and 0.2 ml was injected the right flank of each mouse.
- the dose of the MOG in all the groups (1 to 8) was 150 mg/mouse.
- the dose of the GA in group 2 was 250 mg/mouse.
- Pertussis toxin 60 mL Pertussis toxin (200 mg/ml) was added to 31.940 ml saline to yield about 375 ng/ml. The pertussis toxin was administered intraperitoneally on the day of encephalitogen injection and 48 hours later (75.0 ng/0.2ml mouse).
- the test concentrations of laquinimod were prepared in purified water. For high dose (25.0 mg/kg) 2.5 mg/mL stock solution was prepared (group 8). The 2.5 mg/mL stock solution was diluted 1 :5 and 1 : 10 to yield 0.5 and 0.25 mg/mL for dose levels of 5.0 mg/kg for groups 5 and 7 and 2.5 mg/kg respectively for groups # 4 and 6. Laquinimod was administered daily from the initiation of the study, to the respective groups by gavage at a volume of 0.2 ml/mouse.
- a 50.0 mg ml stock solution of GA was prepared in Saline. 5.0 mL of 50.0 mg/mL GA was aliquoted in 10 tubes and stored at -20° C. Every day one tube was thawed and brought to RT. GA was administered subcutaneously daily for 10 days from the initiation of the study to the mice of groups 3, 4 and 5 at a volume of 0.1 mL.
- Clinical signs Scoring of EAE clinical signs was started from Day 10 post EAE induction and was continued daily until Day 30. The clinical signs were recorded according to a grading system described in the Table 2 above.
- mice having scores of 1 and above were considered sick. When the first clinical sign appeared all mice were given food soaked in water, which was spread on different places on the bedding of the cages. An animal which continued to have score 5 for three days was killed on humane grounds and given score 6 on the next day. For calculation purposes, the score of animals that were sacrificed or died (6) was carried forward.
- MMS Mean Maximal Score
- GMS Group Mean Score
- the MMS of the vehicle treated negative control group was 3.4 + 1.1 and of GA blocking positive control group was 1.3 + 1.8.
- Group treated with laquinimod (5 mg/kg) along with GA at dose level of 250 mg/kg (subcutaneous) exhibited additive effect -
- EAE relapsing remitting
- Glatiramer acetate drug substance laquinimod drug substance; Lyophilized Mouse spinal cord homogenate (MSCH) from ICR mice; Incomplete Freund's Adjuvant (ICFA) "Difco”; Milli-Q purified water (pH20); Mycobacterium tuberculosis, H37Ra (MT); and Difco PBS, "Sigma”.
- ICFA Incomplete Freund's Adjuvant
- mice Healthy, specific pathogen free, female Biozzi mice were used in the study. The mice were 6- 1 1 weeks old at time of induction, and weighed 20g ⁇ 15%. Test procedure
- EAE Induction The EAE induction was performed according to procedure "RR-EAE.Biozzi" The Biozzi mice were weighed and injected subcutaneously and re-injected one week later with encephalitogenic agent (MSCH emulsion). 0.3 mL of the encephalitogenic agent containing 1.0 mg of MSCH and 200.0 ⁇ g of MT was injected subcutaneously, at two sites in the right flank of each mouse (0.15 mL at each site). The second injection was done in a similar manner in the left flank, one week later.
- MSCH emulsion encephalitogenic agent emulsion
- a 5.0 mg/mL stock solution of laquinimod and a 1.25 mg/mL stock solution of GA was prepared.
- the 5.0 mg/mL laquinimod stock solution was diluted 1 :2, 1 :4 and 1 : 10 to yield 2.5, 1.25 and 0.5 mg/mL for dose levels of 25.0 mg/kg, 12.5 mg/kg and 5.0 mg/kg laquinimod respectively.
- the 2.5 mg/mL GA stock solution was diluted 1 :2, to yield 1.25 mg/mL for dose level of 12.5 mg/kg GA.
- the 2.5 mg/mL GA stock solution was diluted 1 :2 with 5.0 mg mL laquinimod to yield 1.25 mg/m L GA and 2.5 mg/mL laquinimod for dose levels of 12.5 mg/kg GA and 25 mg/kg laquinimod.
- the 5.0 mg/mL laquinimod stock solution was diluted 1 :5 to yield 1 mg/mL.
- the 2.5 mg/mL GA stock solution was diluted 1 :2 with 1.0 mg/mL laquinimod to yield 1.25 mg/mL GA and 0.5 mg/mL laquinimod for dose levels of 12.5 mg/kg GA and 5.0 mg/kg laquinimod.
- Test article administration was diluted 1 :2 with 5.0 mg mL laquinimod to yield 1.25 mg/m L GA and 2.5 mg/mL laquinimod for dose levels of 12.5 mg/kg GA and 5.0 mg/kg laquinimod.
- mice in all the groups were administered daily by oral gavage a volume dose level of 250 mL/mouse of the respective test formulations from the day the mice are allocated to the treatment groups (first injection of encephalitogen) for 59 consecutive days until the termination of the study.
- Clinical observation and scoring a volume dose level of 250 mL/mouse of the respective test formulations from the day the mice are allocated to the treatment groups (first injection of encephalitogen) for 59 consecutive days until the termination of the study.
- mice were examined and scored according to the following table, until the termination of the study (60 days after initiation of treatment).
- Table 18 Evaluation of the EAE clinical signs.
- the activity of the test articles for the first and second phase of RR EAE was calculated by comparing the incidence of disease, mortality, onset and duration of disease, group mean score and mean maximal score to the control group. Calculations were carried separately and together for the first and the second relapse. The calculations are as shown in Example 2.4. Results
- a summary of the incidence, mean maximal score, group mean score/ individual mean scores and mean duration of disease during first attack, second attack and first and second attack together are shown in the summary tables 19-21.
- mice died, respectively in groups treated with GA ( 12.5 ⁇ mg/kg) and water (Control).
- Groups treated with laquinimod alone were more effective in the suppression of EAE during the first relapse than during the second relapse.
- the objective of this study was to compare the suppressive activity of laquinimod following daily administration by oral gavage alone and along with GA in the EAE model in CSJL/F l mice.
- MS is an immune-mediated disorder of the CNS leading to progressive decline of motor and sensory functions causing permanent disability.
- the CSJL/ FI strain of mouse was selected, as it is an established EAE model to test for the efficacy of candidate molecules for the treatment of MS.
- mice of the CSJL/FI strain weighting about 17-20 g on arrival were approximately 10 weeks of age. The body weights of the animals were recorded on the day of delivery. Overtly healthy animals were assigned to study groups arbitrarily before treatment commences. TEST Procedures
- mice were allocated to the following eight treatment groups on Table 22: Table 22
- the emulsion was made from equal parts of oil and liquid portions in two syringes connected to each other with Leur lock, transferred to insulin syringe.
- the concentration of MSCH in emulsion in all groups was 20 mg/mL.
- the dose of the MSCH in all the groups was 1.0 mg/0.05 ml/mouse.
- the concentration of MT in emulsion in all groups was 0.5 mg/mL.
- the dose of the MT in all the groups was 0.025 mg/0.05 ml/mouse.
- the concentration of GA in emulsion in all groups was 0.2 mg/mL.
- the dose of the GA in groups 2, 7 and 8 was 10 mg/0.05 ml/mouse equivalent to 0.5 mg/kg. This is the sub therapeutic dose which is 25 times lower than the therapeutic dose which is 12.5 mg/kg (250 mg/mouse).
- Pertussis toxin 200 mg/ml was added to 69.93 ml PBS to yield 200 ng/ml.
- the pertussis toxin was administered intravenous on the day of encephalitogen injection and 48 hours later ( 100.0 ng/0.5ml/mouse).
- Preparation and administration of working concentrations of Laquinimod Solutions at concentration of 0.001, 0.01 , 0.03 and 0.1 mg/mL laquinimod were prepared in water for dose levels of 0.01 , 0.1 , 0.3 and 1.0 mg/kg respectively.
- the test formulations were stored at 2 to 8 °C until use in amber colored bottles.
- mice were administered with the respective dose levels of laquinimod at volume dose level of 200 mL/mouse.
- the test formulations were vortexed before dispensing in syringe.
- the test article formulations were administered to the respective groups by oral gavage.
- the vehicle purified water
- the negative control group Group 1
- the different dose levels laquinimod were administered to the respective groups once a day.
- Clinical signs Scoring of EAE clinical signs was initiated from the 10th day post-EAE induction and was continued daily until Day 23. The clinical signs were recorded according to a grading system described in the table 23 below.
- mice having scores of 1 and above were considered sick. Animals with score 4 for more than three days were given score 5 and sacrificed for humane reasons. For calculation purposes, the score of animals that are sacrificed or died were carried forward. INTERPRETATION OF RESULTS
- the incidence of disease in the vehicle treated negative control group was 10/10. 90 to 100% incidence was observed in the groups treated with different dose levels of laquinimod alone. 7/10 mice were sick in the group treated with suboptimal dose of GA (0.5 mg/kg) administered along with encephalitogen.
- laquinimod at dose level of 1.0 mg/kg administered daily orally by gavagc exhibits additive effect with sub optimal dose of GA (0.5 mg kg) and is more effective in the suppression of chronic MOG induced EAE in C57B1 mice than administration of laquinimod ( 1.0 mg/kg) or alone sub optimal dose of GA (0.5 mg/kg).
- the objective of this study was to compare the suppressive activity of laquinimod following daily administration by oral gavage alone and along with GA in the EAE model in CSJL/F 1 mice.
- MS is an immune-mediated disorder of the CNS leading to progressive decline of motor and sensory functions causing permanent disability.
- the CSJL/ FI strain of mouse was selected, as it is an established EAE model to test for the efficacy of candidate molecules for the treatment of MS.
- mice of the CSJL FI strain weighed about 17-20 g on arrival, and were approximately 9 weeks of age. The body weights of the animals were recorded on the day of delivery.
- mice were allocated to the following eight treatment groups on Table 25:
- the emulsion was made from equal parts of oil and liquid portions in two syringes connected to each other with Leur lock, transferred to insulin syringe.
- 0.05 ml was injected into the left foot-pad of each mouse.
- the concentration of MSCH in emulsion in all groups was 60 mg/mL.
- the dose of the MSCH in all the groups was 3.0 mg 0.05 ml/mouse.
- the concentration of MT in emulsion in all groups was 0.25 mg mL.
- the dose of the MT in all the groups was 0.0125 mg/0.05 ml/mouse.
- the concentration of GA in emulsion in all groups was 0.2 mg/mL.
- the dose of the GA in groups 2, 7 and 8 was 10 ⁇ g/0.05 ml/mouse equivalent to 0.5 mg/kg. This is the sub therapeutic dose which is 25 times lower than the therapeutic dose which is 12.5 mg/kg (250 ⁇ g/mouse).
- Pertussis toxin 200 ⁇ g/ml was added to 44.964 ml PBS to yield 160 ng/ml.
- the pertussis toxin was administered intravenous on the day of encephalitogen injection and 48 hours later (80.0 ng/0.5ml/mouse).
- Solutions at concentration of 0.001 , 0.01 , 0.03 and 0.1 mg/mL laquinimod were prepared in water for dose levels of 0.01 , 0.1, 0.3 and 1.0 mg/kg respectively.
- the test formulations were stored at 2 to 8 °C until use in amber colored bottles.
- mice were administered with the respective dose levels of laquinimod at volume dose level of 200 ⁇ / ⁇ .
- the test formulations were vortexed before dispensing in syringe.
- test article formulations were administered to the respective groups by oral gavage.
- vehicle purified water
- the test article formulations were administered to the negative control group (Group 1) and to group 2 in a similar manner.
- Scoring of EAE clinical signs was initiated from the 10 th day post-EAE induction and was continued daily until Day 23.
- the clinical signs were recorded on observation cards according to a grading system described in the table 23 above. Animals with score 4 for more than three days were given score 5 and sacrificed for humane reasons. For calculation purposes, the score (5) of animals that are sacrificed or died were carried forward.
- mice Seven mice died in the Vehicle treated control group due to severe EAE clinical signs. Between 0 and 2 mice died in the other treatment groups.
- the incidence of disease in the vehicle treated negative control group was 1 1/1 1. 91% incidence was observed in the laquinimod (0.01 mg/kg) treated group.
- mice 4/1 1 mice were sick in the group treated with suboptimal dose of GA (0.5 mg/kg) administered along with encephalitogen.
- laquinimod 0.1 mg/kg
- suboptimal dose of GA 0.5 mg/kg
- the incidence was 0/1 1 (100% activity) indicating some additive effect.
- MMS Mean Maximal Score
- GMS Group Mean Score
- the MMS of the vehicle treated negative control group was 4.5 ⁇ 0.8.
- MMS of 1.1 ⁇ 15 was observed in group treated with sub optimal dose of GA (0.5 mg/kg) administered along with encephalitogen.
- laquinimod O. l mg/kg
- 100.0% activity p ⁇ 0.000001 was observed compared to the negative control group.
- Laquinimod at 1.0 mg/kg administered daily, orally by gavage exhibits additive effect with suboptimal dose of GA (0.5 mg/kg) and is more effective in the suppression of chronic MOG induced EAE in C57B1 mice (100% activity) than administration of laquinimod - 1.0 mg/kg (55.9%) or sub optimal dose of GA -0.5 mg/kg (79.4%) alone.
- mice dosing presented here cannot be used to determine human dosing by simply adjusting for body weight, because a gram of mouse tissue is not equivalent to a gram of human tissue. For this reason, the National Institutes of Health (NIH) provides a table of Equivalent Surface Area Dosage Conversion Factors below (Table 27) which provides conversion factors that account for surface area to weight ratios between species.
- NASH National Institutes of Health
- a multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study, followed by a double-blind active extension phase is conducted to assess the safety, tolerability and efficacy of two daily doses of oral laquinimod (0.6mg or 1.2mg) in adjunct to glatiramer acetate (GA) or interferon-beta (IFN-P)-la/lb preparations in subjects with relapsing multiple sclerosis (RMS).
- Study Duration The total study duration for each eligible subject will be up to 19 months: Screening phase: up to about 1 month.
- Double blind treatment phase about 9 months of once-daily oral administration of laquinimod 0.6 mg/day, 1.2/day or placebo in addition to current therapy (i.e., subcutaneous GA 20mg or any of the following IFN- ⁇ preparations: Avonex ® , Betaseron ® /Betaferon ® , Rebif ® or Extavia ® ).
- DBAE Double-Blind Active Extension
- Subjects originally assigned to placebo are equally randomized to either laquinimod 0.6mg or 1.2mg.
- the duration of this phase is 9 months.
- RMS Relapsing Multiple Sclerosis
- Eligible subjects are equally (1 : 1 : 1 ) randomized into one of the following treatment arms:
- the 0.6 mg laquinimod capsule can be manufactured according to the method disclosed in PCT International Application Publication No. WO/2007/146248, published December 21 , 2007 (see, page 10, line 5 to page 1 1 , line 3).
- Randomization is stratified in a way that in each arm the number of subjects treated by GA will be equal to the number of subjects treated by IFN- ⁇ preparations (Avonex ® , Betaseron ® /Betaferon ® , Rebif ® or Extavia ® ).
- subjects continue the same background injectable treatment which they used in the DBPC phase.
- Subjects who were originally assigned to either of the active oral arms [either laquinimod 0.6mg (arm 1) or 1.2mg (arm 2)] continue with their original oral treatment assignment.
- Subjects originally assigned to placebo (arm 3) are equally randomized to either laquinimod 0.6mg or 1.2mg.
- subjects are evaluated at study sites for 1 1 scheduled visits at Months: - 1 (screening), 0 (baseline) and every month thereafter until Month 9 (termination/ early termination).
- a physical examination is performed at Month -1 (Screening) and Months 0 (Baseline), 1 , 3, 6 and 9 (Termination/Early Termination visit of the DBPC phase).
- Month 9 a physical examination is performed at Month 9
- c Lipid profile (total cholesterol, HDL, LDL and triglycerides) is performed at month -1 (Screening) or Month 0 (Baseline) of the DBPC phase, under fasting conditions.
- Thyroid function tests (TSH, T3 and free T4) are performed at Months 0 (Baseline), 6 and 9 (Termination/ Early termination visit of the DBPC phase).
- thyroid function tests (TSH, T3 and free T4) are performed at Months 9 (Baseline EXT; termination visit of the DBPC phase), 15/4AE and 18/5AE (termination/ early termination visit of the DBAE phase).
- e Urinalysis is performed at the Screening visit.
- f Serum ⁇ -hCG human choriogonadotropin beta
- urine ⁇ -hCG test is performed at home twice between scheduled visits: a. At months 13AE and 14AE (30 ⁇ 4 days and 60 ⁇ 4 after Month 12AE visit, respectively). b. At months 16AE and 17AE (30 ⁇ 4 days and 60 ⁇ 4 after Month 15AE visit, respectively).
- the subject is contacted by the site staff via telephone within 72 hours after the test is scheduled to be performed and asked specific questions regarding the test.
- the caller instructs the subject to stop taking the study drug and to arrive to the site as soon as possible (but within 10 days) with all study drugs
- ECG electrocardiograms
- Chest X-ray is performed at months - 1 (screening), if not performed within 6 months prior to the screening visit.
- DBPC phase neurological evaluations, including Expanded Disability Status Scale (EDSS), Ambulation Index (AI) and Functional system score (FS) are performed at Months: -1 (screening), 0 (baseline), 3, 6, and 9 (Termination/Early Termination of the DBPC phase).
- EDSS Expanded Disability Status Scale
- AI Ambulation Index
- FS Functional system score
- Months 9 Baseline; termination visit of the DBPC phase
- 12/3AE, 15/4AE and 1.8/5AE Termination/Early Termination of the DBAE phase.
- SDMT Symbol Digit Modalities Test
- each subject undergoes 3 M I scans at Months: 0 (baseline), 3 and 9 (Termination/Early Termination visit of the DBPC phase).
- each subject undergoes 2 MRI scans at Months 9 (Baseline EXT; Termination visit scan of the DBPC phase) and 18/5AE (Termination/Early Termination visit of the DBAE phase).
- DBPC phase neurological evaluations, including Expanded Disability Status Scale (EDSS), Ambulation Index (AI) and Functional system score (FS) are performed at Months: - 1 (screening), 0 (baseline), 3, 6, and 9 (Termination/Early Termination of the DBPC phase).
- EDSS Expanded Disability Status Scale
- AI Ambulation Index
- FS Functional system score
- Months 9 Baseline; termination visit of the DBPC phase
- 12/3AE, 15/4AE and 18/5AE Termination/Early Termination of the DBAE phase.
- SDMT Symbol Digit Modalities Test
- each subject undergoes 2 MRI scans at Months 9 (Baseline EXT; Termination visit scan of the DBPC phase) and 18/5AE (Termination/Early Termination visit of the DBAE phase). 15 Relapses are confirmed/monitored throughout the study (both phases). Relapse Treatment
- the allowed treatment for a relapse is intravenous Methylprednisolone l gr/day for up to 5 consecutive days.
- DMC Data Monitoring Committee
- MRI reading center issues a notification letter to the Sponsor, investigator and the DMC.
- MRI parameters of activity are not considered stopping rules and the decision regarding individual subject's participation in the trial is at the discretion of the treating physician.
- PGx Pharmacogenetic
- Subjects must be relapse free, in a stable neurological condition and free of corticosteroid treatment [intravenous (IV), intramuscular (IM) and/or oral] 60 days prior to randomization.
- IV intravenous
- IM intramuscular
- oral 60 days prior to randomization.
- Subjects must be treated with GA (Copaxone ® ) or an IFN- ⁇ preparation (Avonex ® , Betaseron ® Betaferon ® , Rebif ® or Extavia ® ), at a stable dose for at least 6 months prior to randomization (switching between IFN- ⁇ preparations during the 6 months prior to randomization is allowed; switching between any IFN- ⁇ preparation and GA, or vice versa, is exclusionary), and there is no plan to change the subject's injectable treatment (either Copaxone® or IFN- ⁇ preparation) during the course of the study.
- GA Copaxone ®
- IFN- ⁇ preparation Avonex ® , Betaseron ® Betaferon ® , Rebif ® or Extavia ®
- Subjects must have an EDSS score of 1.5-4.5 (inclusive) at randomization.
- Subjects must be between 18 and 55 years of age, inclusive. 6. Women of child-bearing potential must practice an acceptable method of birth control.
- Acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, partner's vasectomy or double-barrier method (condom or diaphragm with spermicide). 7. Subjects must be able to sign and date a written informed consent prior to entering the study.
- Adrenocorticotropic hormone 60 days prior to randomization (last day of steroid treatment should be equal or greater than 60 days prior to randomization).
- natalizumab (Tysabri ® ), fingolimod (Gilenya ® ) or anti-B cell therapy within the 2 years prior to randomization.
- cytotoxic agents Mitoxantrone (Novantrone ® ), cladribine, laquinimod, total body irradiation, total lymphoid irradiation, stem cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation.
- IVIG intravenous immunoglobulin
- ALT alanine transaminase
- AST aspartate transaminase
- Serum direct bilirubin which is >2xULN at screening 13.
- Subjects with a potentially clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation, as determined by medical history, physical examinations, ECG, laboratory tests or chest X-ray.
- Such conditions may include: a. A cardiovascular or pulmonary disorder that cannot be well-controlled by standard treatment permitted by the study protocol. b. Renal diseases. c. Any form of acute or chronic liver disease.
- An unstable psychiatric disorder The abnormal atric disorder.
- BCC basal cell carcinoma
- GFR glomerular filtration rate
- the primary objectives of the study are to assess the safety, tolerability and efficacy of two daily doses of oral laquinimod (0.6mg or 1.2mg) in adjunct to GA or IFN- ⁇ preparation (Avonex ® , Betaseron ® /Betaferon ® , Rebif ® or Extavia ® ) in subjects with RMS.
- CDP Time to Confirmed Disease Progression
- 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 relapsing multiple sclerosis (RMS) patients.
- PBVC percent brain volume change
- RMS multiple sclerosis
- 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 relapsing multiple sclerosis (RMS) patients, where CDP is defined as a sustained increase in EDSS of >1 point from Baseline for at least 3 months. Progression cannot be confirmed during a relapse.
- 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 relapsing multiple sclerosis (RMS) patients during.
- 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 relapsing multiple sclerosis (RMS) patients.
- 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 relapsing multiple sclerosis (RMS) patients, as measured by the time to confirmed progression of EDSS. 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 relapsing multiple sclerosis (RMS) patients, as measured by the cumulative number of Tl Gd-enhancing lesions on Tl- weighted images, the cumulative number new Tl hypointense lesions, the cumulative number of new T2 lesions, the cumulative number of new Tl hypointense lesions on Tl- weight images (black holes), the number of active (new T2 or GdE-Tl) lesions, presence or absence of GdE lesions, change in total volume of Tl Gd-enhancing lesions, change in total volume of T2 lesions, and/or cortical thickness.
- the add-on therapy is more effective (provides an additive effect or more than an additive effect) in reducing brain atrophy in relapsing multiple sclerosis (RMS) patients.
- 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 relapsing multiple sclerosis (RMS) patients.
- 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 relapsing multiple sclerosis (RMS) patients.
- 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 (WPAI-GH) questionnaire) and quality of life, in relapsing multiple sclerosis (RMS) patients. .
- 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 relapsing multiple sclerosis (RMS) patients during the double blind study period.
- SDMT Symbol Digit Modalities Test
- RMS relapsing multiple sclerosis
- 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 relapsing multiple sclerosis (RMS) patients.
- PBVC percent brain volume change
- RMS multiple sclerosis
- 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 relapsing multiple sclerosis (RMS) patients, where CDP is defined as a sustained increase in EDSS of >1 point from Baseline for at least 3 months. Progression cannot be confirmed during a relapse.
- 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 relapsing multiple sclerosis (RMS) patients during.
- 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 relapsing multiple sclerosis (RMS) patients.
- 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 relapsing multiple sclerosis (RMS) patients, as measured by the time to confirmed progression of EDSS.
- RMS multiple sclerosis
- the combination therapy is more effective (provides an additive effect or more than an additive effect) in reducing MRJ-monitored disease activity in relapsing multiple sclerosis (RMS) patients, as measured by the cumulative number of Tl Gd-enhancing lesions on Tl- weighted images, the cumulative number new Tl hypo intense lesions, the cumulative number of new T2 lesions, the cumulative number of new Tl hypointense lesions on Tl- weight images (black holes), the number of active (new T2 or GdE-Tl) lesions, presence or absence of GdE lesions, change in total volume of Tl Gd-enhancing lesions, change in total volume of T2 lesions, and/or cortical thickness.
- RMS multiple sclerosis
- the combination therapy is more effective (provides an additive effect or more than an additive effect) in reducing brain atrophy in relapsing multiple sclerosis (RMS) patients.
- 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 relapsing multiple sclerosis (RMS) patients.
- RMS multiple sclerosis
- the combination therapy is more effective (provides an additive effect or more than an additive effect) in increasing the time to confirmed relapse in relapsing multiple sclerosis (RMS) patients.
- 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 relapsing multiple sclerosis (RMS) patients. 22.
- 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 relapsing multiple sclerosis (RMS) patients during the double blind study period.
- SDMT Symbol Digit Modalities Test
- Copolymer 1 reduces relapse rate and improves disability in relapsing- remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo- controlled trial.
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Priority Applications (16)
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KR1020147005638A KR20140054166A (en) | 2011-07-28 | 2012-07-27 | Treatment of multiple sclerosis with combination of laquinimod and glatiramer acetate |
EP12817089.1A EP2736335A4 (en) | 2011-07-28 | 2012-07-27 | Treatment of multiple sclerosis with combination of laquinimod and glatiramer acetate |
AU2012286699A AU2012286699A1 (en) | 2011-07-28 | 2012-07-27 | Treatment of multiple sclerosis with combination of laquinimod and glatiramer acetate |
MX2014001050A MX2014001050A (en) | 2011-07-28 | 2012-07-27 | Treatment of multiple sclerosis with combination of laquinimod and glatiramer acetate. |
CA2843433A CA2843433A1 (en) | 2011-07-28 | 2012-07-27 | Treatment of multiple sclerosis with combination of laquinimod and glatiramer acetate |
BR112014002095A BR112014002095A2 (en) | 2011-07-28 | 2012-07-27 | multiple sclerosis treatment with combination of laquinimod and glatiramer acetate |
EA201490377A EA201490377A1 (en) | 2011-07-28 | 2012-07-27 | TREATMENT OF MULTIPLE SCLEROSIS BY COMBINATION OF LAKVINIMODE AND GLATIRAMER ACETATE |
IN333MUN2014 IN2014MN00333A (en) | 2011-07-28 | 2012-07-27 | |
CN201280043755.9A CN103781354A (en) | 2011-07-28 | 2012-07-27 | Treatment of multiple sclerosis with combination of laquinimod and glatiramer acetate |
JP2014523092A JP2014521658A (en) | 2011-07-28 | 2012-07-27 | Treatment of multiple sclerosis combining laquinimod and glatiramer acetate |
TW101136273A TW201404395A (en) | 2012-07-27 | 2012-10-01 | Treatment of multiple sclerosis with combination of laquinimod and glatiramer acetate |
ARP120103662A AR088093A1 (en) | 2012-07-27 | 2012-10-01 | TREATMENT OF MULTIPLE SCLEROSIS WITH A COMBINATION OF LAQUINIMOD AND ACETATO DE GLATIRAMER |
UY0001034358A UY34358A (en) | 2011-07-28 | 2012-10-01 | ? TREATMENT OF MULTIPLE SCLEROSIS WITH A COMBINATION OF LAQUINIMOD AND ACETATO DE GLATIRAMER ?. |
ZA2014/01371A ZA201401371B (en) | 2011-07-28 | 2014-02-21 | Treatment of multiple sclerosis with combination of laquinimod and glatiramer acetate |
HK14111812.7A HK1198279A1 (en) | 2011-07-28 | 2014-11-21 | Treatment of multiple sclerosis with combination of laquinimod and glatiramer acetate |
IL251397A IL251397A0 (en) | 2011-07-28 | 2017-03-27 | Treatment of multiple sclerosis with combination of laquinimod and glatiramer acetate |
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- 2012-07-27 SG SG10201606191PA patent/SG10201606191PA/en unknown
- 2012-07-27 CA CA2843433A patent/CA2843433A1/en not_active Abandoned
- 2012-07-27 US US13/560,851 patent/US20130029916A1/en not_active Abandoned
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EP3773535A4 (en) * | 2018-04-13 | 2022-01-05 | Mordechai Chevion | Compositions and methods for treatment of demyelination |
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BR112014002095A2 (en) | 2017-02-21 |
KR20140054166A (en) | 2014-05-08 |
US20160038532A1 (en) | 2016-02-11 |
CN103781354A (en) | 2014-05-07 |
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IL251397A0 (en) | 2017-05-29 |
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AU2016204777A1 (en) | 2016-07-28 |
IN2014MN00333A (en) | 2015-09-25 |
HK1198279A1 (en) | 2015-03-27 |
JP2017081930A (en) | 2017-05-18 |
EA201490377A1 (en) | 2014-11-28 |
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PE20142319A1 (en) | 2015-01-24 |
HK1226940A1 (en) | 2017-10-13 |
CL2016002132A1 (en) | 2017-06-09 |
EP2736335A4 (en) | 2015-01-07 |
EP2736335A1 (en) | 2014-06-04 |
AU2012286699A1 (en) | 2014-03-13 |
US20130029916A1 (en) | 2013-01-31 |
CN105944081A (en) | 2016-09-21 |
SG10201606191PA (en) | 2016-09-29 |
JP2014521658A (en) | 2014-08-28 |
ZA201401371B (en) | 2015-08-26 |
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