A Phase 2 Clinical Study in Subjects With Primary Progressive Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of Two Oral Doses of Laquinimod Either of 0.6 mg/Day or 1.5mg/Day (Experimental Drug) as Compared to Placebo

Due to serious cardiovascular adverse events, Data Monitoring Committee (DMC) made a recommendation to stop all laquinimod treatment arms above 0.6 mg in the multiple sclerosis (MS) trials; therefore the 1.5 mg treatment arm in the ARPEGGIO study was discontinued as of 01 January 2016.

The DMC did not identify any definite cardiovascular risk in the 0.6 mg treatment arm, but felt that long term monitoring for emergence of any potential signal was necessary. Therefore, the 0.6 mg treatment arm was continued while the sponsor closely monitored cardiovascular events in all laquinimod studies. Prior to 01 January 2016, eligible patients were randomized in a 1:1:1 ratio into 1 of the following treatment arms (a total of 286 patients were randomized 1:1:1 prior to

01 January 2016):

• Laquinimod 0.6 mg daily
• Laquinimod 1.5 mg daily
• Daily placebo

As of 01 January 2016, following the decision to discontinue the laquinimod 1.5 mg dose arm, additional eligible patients (87 patients) who were enrolled were randomized in a 1:1 ratio into one of the following treatment arms:

• Laquinimod 0.6 mg daily
• Daily placebo

Inclusion criteria

• Patients must have a confirmed and documented PPMS diagnosis as defined by the 2010 Revised McDonald criteria
• Baseline magnetic resonance imaging (MRI) showing lesions consistent with PPMS in either or both brain and spinal cord
• Patients must have an Expanded Disability Status Scale (EDSS) score of 3 to 6.5, inclusive, at both screening and baseline visits
• Documented evidence of clinical disability progression in the 2 years prior to screening.
• Functional System Score (FSS) of > or equal 2 for the pyramidal system or gait impairment due to lower extremity dysfunction
• Patients must be between 25 to 55 years of age, inclusive
• Women of child-bearing potential must practice an acceptable method of birth control for 30 days before taking the study drug, and 2 acceptable methods of birth control during all study duration and until 30 days after the last dose of treatment is administered.
• Patients must sign and date a written informed consent prior to entering the study.
• Patients must be willing and able to comply with the protocol requirements for the duration of the study.

Exclusion criteria

• Patients with history of any multiple sclerosis (MS) exacerbations or relapses, including any episodes of optic neuritis.
• Progressive neurological disorder other than PPMS.
• Any MRI record showing presence of cervical cord compression.
• Baseline MRI showing other findings (including lesions that are atypical for PPMS) that may explain the clinical signs and symptoms.
• Relevant history of vitamin B12 deficiency.
• Positive human T-lymphotropic virus Type I and II (HTLV-I/II) serology.
• Use of experimental or investigational drugs in a clinical study within 24 weeks prior to baseline. Use of a currently marketed drug in a clinical study within 24 weeks prior to baseline would not be exclusionary, provided no other exclusion criteria are met.
• Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azathioprine within 48 weeks prior to baseline.
• Previous treatment with fingolimod (GILENYA®, Novartis), dimethyl fumarate (TECFIDERA®, Biogen Idec Inc), glatiramer acetate (COPAXONE®, Teva), interferon-β (either 1a or 1b), intravenous immunoglobulin, or plasmapheresis within 8 weeks prior to baseline.
• Use of teriflunomide (AUBAGIO®, Sanofi) within 2 years prior to baseline, except if active washout (with either cholestyramine or activated charcoal) was done 2 months or more prior to baseline.
• Prior use of monoclonal antibodies ever, except for:

• natalizumab (TYSABRI®, Biogen Idec Inc), if given more than 24 weeks prior to baseline AND the patient is John Cunningham (JC) virus antibody test negative (as per medical history)
• rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical history) is higher than 80 cells/μL
• Use of mitoxantrone (NOVANTRONE®, Immunex) within 5 years prior to screening. Use of mitoxantrone >5 years before screening is allowed in patients with normal ejection fraction and who did not exceed the total lifetime maximal dose.
• Previous use of laquinimod.
• Chronic (eg, more than 30 consecutive days or monthly dosing, with the intent of MS disease modification) systemic (intravenous, intramuscular or oral) corticosteroid treatment within 8 weeks prior to baseline.
• Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).
• Previous total body irradiation or total lymphoid irradiation.
• Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of any kind.
• Patients who underwent endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) within 12 weeks prior to baseline.
• Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to baseline.
• Use of inducers of CYP3A4 within 2 weeks prior to baseline.
• Pregnancy or breastfeeding.
• Serum levels ≥3× upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.
• Serum direct bilirubin which is ≥2×ULN at screening.
• Patients with a clinically significant or unstable medical or surgical condition that (in the opinion of the Investigator) would preclude safe and complete study participation, as determined by medical history, physical examinations, electrocardiogram (ECG), laboratory tests or chest X-ray.
• A known history of hypersensitivity to gadolinium (Gd).
• Glomerular filtration rate (GFR) < or equal 60 mL/min at screening visit.
• Inability to successfully undergo MRI scanning, including claustrophobia.
• Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.