J Neurol DOI 10.1007/s00415-014-7264-4

ORIGINAL COMMUNICATION

A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis T. L. Vollmer • P. S. Sorensen • K. Selmaj • F. Zipp • E. Havrdova • J. A. Cohen • N. Sasson • Y. Gilgun-Sherki • D. L. Arnold • On behalf of the BRAVO Study Group

Received: 12 November 2013 / Revised: 24 January 2014 / Accepted: 27 January 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7264-4) contains supplementary material, which is available to authorized users.

IFNb-1a IM 30 lg once-weekly (rater-blinded design), for 24 months. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included percent brain volume change (PBVC) and 3-month confirmed disability worsening. In all, 1,331 patients were randomized: laquinimod (n = 434), placebo (n = 450), and IFNb-1a (n = 447). ARR was not significantly reduced with laquinimod [-18 %, risk ratio (RR) = 0.82, 95 % CI 0.66–1.02; p = 0.075] vs. placebo. Laquinimod significantly reduced PBVC (28 %, p \ 0.001). Confirmed disability worsening was infrequent (10 % laquinimod, 13 % placebo). The change in confirmed disability worsening with laquinimod measured using EDSS was -31 % [hazard ratio (HR) 0.69, p = 0.063], and using Multiple Sclerosis Functional Composite (MSFC) z-score was -77 % (p = 0.150), vs. placebo. IFNb-1a reduced ARR 26 % (RR = 0.74, 95 % CI 0.60–0.92, p = 0.007), showed no effect on PBVC loss (?11 %, p = 0.14), and changes in disability worsening were -26 and -66 % as measured using the EDSS (HR 0.742, p = 0.13) and MSFC

T. L. Vollmer Department of Neurology, University of Colorado, Aurora, CO, USA

K. Selmaj Department of Neurology, Medical University of Ło´dz´, Lodz, Poland

T. L. Vollmer (&) Rocky Mountain MS Center, Rocky Mountain MS Clinic, Anschutz Medical Center, University of Colorado, Denver, RM L15-5511, A01, Mail stop B185, 12631 E 17th Avenue, Aurora, CO 80045, USA e-mail: [email protected]

F. Zipp Department of Neurology, Rhine Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

Abstract The phase III placebo-controlled BRAVO study assessed laquinimod effects in patients with relapsing-remitting MS (RRMS), and descriptively compared laquinimod with interferon beta (IFNb)-1a (AvonexÒ reference arm). RRMS patients age 18–55 years with Expanded Disability Status Scale (EDSS) scores of 0–5.5 and documented pre-study relapse (C 1 in previous year, 2 in previous 2 years, or 1 in previous 1–2 years and C 1 GdE lesion in the previous year) were randomized (1:1:1) to laquinimod 0.6 mg once-daily, matching oral placebo, or T. L. Vollmer and P. S. Sorensen were co-principal investigators for the BRAVO trial, contributed equally to the manuscript, and should be considered equal lead authors on this publication. N. Sasson of Teva Pharmaceutical Industries provided statistical support for the manuscript.

P. S. Sorensen Danish Multiple Sclerosis Center, University of Copenhagen, Copenhagen, Denmark P. S. Sorensen Department of Neurology, Rigshospitalet, Copenhagen, Denmark

E. Havrdova First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic J. A. Cohen The Mellen Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

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(p = 0.208), respectively. Adverse events occurred in 75, 82, and 70 % of laquinimod, IFNb-1a, and placebo patients, respectively. Once-daily oral laquinimod 0.6 mg resulted in statistically nonsignificant reductions in ARR and disability progression, but significant reductions in brain atrophy vs. placebo. Laquinimod was well-tolerated. Keywords Laquinimod
Multiple sclerosis
Disability
EDSS
Interferon beta-1a

tolerability profiles in ALLEGRO [7] and in phase 2 studies extending up to 42 months [8, 9, 23]. The objective of the Benefit-Risk Assessment of AVonex and LaquinimOd (BRAVO) trial was to further study the efficacy, safety, and tolerability of laquinimod compared with placebo, and to descriptively compare oral laquinimod with an established MS therapy, intramuscular (IM) interferon beta-1a (IFNb-1a, AvonexÒ, Biogen Idec [1]).

Introduction

Methods

Approaches to the treatment of multiple sclerosis (MS) are changing with the emergence of new therapies, including oral agents [5, 16]. The relative risks and benefits of these novel drugs are as yet unknown [16]. Evaluating effects of new treatments along with older immunomodulatory drugs with different modes of action in relapsing-remitting MS (RRMS) patients in a controlled clinical trial may be informative as to the relative risks and benefits of the newer therapies [11]. Laquinimod is a novel oral immunomodulator in clinical development for the treatment of RRMS [4, 7, 9, 23, 29]. Laquinimod, a quinoline-3-carboxamide derivative, is a small molecule that passively enters the central nervous system (CNS) where it modulates inflammatory activity of resident parenchymal cells [4]. Laquinimod has also shown CNS-protective properties in the cuprizone-induced demyelination model, in which myelin damage is not mediated by inflammation [3]. In the recently completed 24-month, double-blind, placebo-controlled, phase 3 ALLEGRO trial, laquinimod 0.6 mg once-daily reduced relapse rate, risk of confirmed worsening of disability (as measured by the Expanded Disability Status Scale (EDSS) [19] ), number of gadolinium-enhancing (GdE) lesions and new or newly enlarged T2-weighted brain lesions on magnetic resonance imaging (MRI), and percent brain volume change (PBVC), compared with placebo [7]. Laquinimod has demonstrated favorable safety and

Standard protocol approval, registration, and patient consent

N. Sasson Teva Statistical Data Management Team, Teva Pharmaceuticals, Netanya, Israel Y. Gilgun-Sherki Teva Innovative Research and Development, Teva Pharmaceuticals, Netanya, Israel D. L. Arnold McGill University, Montreal, QC, Canada D. L. Arnold NeuroRx Research, Montreal, QC, Canada

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The BRAVO protocol was approved by local Ethics Committees/Institutional Review Boards (EC/IRB), including Committees on Human Experimentation. Patients provided written informed consent before participating in study procedures. A Data Monitoring Committee periodically reviewed data to ensure patient welfare. The trial identifier number with www.clinicaltrials.gov is NCT00605215 and with EUDRACT is no. 2007-00545023. Patients Patients were recruited from 155 sites in 18 countries. Eligibility criteria included age 18–55 years, diagnosis of RRMS (revised McDonald criteria [24]), and EDSS scores of 0–5.5. Patients must have had at least one relapse in the previous 12 months, two relapses in the previous 24 months, or one relapse in the previous 12–24 months plus one GdE lesion in the previous 12 months. Major exclusion criteria included progressive forms of MS; corticosteroid use for relapses in the previous 30 days; use of experimental drugs, investigational drugs, or immunosuppressive therapy (including mitoxantrone) in the previous 6 months; use of glatiramer acetate in the previous 2 months; and prior use of natalizumab, laquinimod, cladribine, or any IFNb at any time. Study design This randomized, parallel-group, placebo-controlled, 24-month study began in April, 2008 and ended in June, 2011. The study was designed to: (1) assess the safety, efficacy, and tolerability of laquinimod compared with placebo in a double-blinded design; (2) assess the safety, efficacy, and tolerability of IFNb-1a IM compared with placebo in a rater-blinded design; and (3) descriptively compare oral laquinimod and IFNb-1a IM. The computer-

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generated randomization scheme prepared by the Teva Global Biostatistics Unit employed a 1:1:1 treatment assignment ratio stratified by study center, to laquinimod 0.6 mg capsule once-daily, matching oral placebo, or IFNb-1a IM 30 lg once-weekly injection. Patients were evaluated at 12 scheduled visits: months -1 (screening), 0 (baseline), 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24. Safety assessments (laboratory measures, vital signs) were performed at all visits, and electrocardiograms (ECGs) were performed at months -1, 0, 1, 2, 3, 6, 12, 18, and 24/early termination. Neurological evaluations by EDSS were performed at months -1, 0, and every 3 months thereafter, and multiple sclerosis functional composite (MSFC [10]) score was measured at month 0 and every 6 months thereafter to month 24. MRI scans were performed at baseline and months 12 and 24/early termination. Patients and treating neurologists were blinded to oral treatment assignment (laquinimod or placebo), but not to IFNb-1a IM assignment. The examining neurologist was blinded to all treatments. All patients, including those receiving oral treatment, wore clothing and/or a robe that ensured coverage of all potential IM injection sites during examination and were instructed not to discuss adverse events (AEs), routes of administration, or treatment assignments with the examining neurologist. Patients were instructed to report symptoms suggestive of a relapse to the study site within 48 h. The examining neurologist performed an EDSS assessment for relapse confirmation within 7 days of symptom onset. The treating neurologist treated patients’ relapses with steroids or other medications as needed. Study procedures and endpoints The primary endpoint was the annualized relapse rate (ARR) over the 24-month treatment period. A confirmed relapse was defined as the appearance of one or more new neurological abnormalities, or reappearance of one or more previously observed neurological abnormalities, in the absence of fever, persisting for C 48 h, preceded by [ 30 days of a stable or improving condition, and accompanied by at least one of the following: an increase of at least 0.5 point in EDSS score, an increase of one grade in the score of two of the seven functional systems (FS) on the EDSS, or an increase of two grades in one FS. Secondary endpoints included percent change in normalized brain volume from baseline to 24 months (see the online Supplementary Appendix for MRI acquisition parameters), and changes in disability measured by the risk of confirmed EDSS worsening. Disability progression was defined as a 1.0 point increase in EDSS score if baseline score was between 0 and 5.0, or a 0.5 point increase if baseline score was 5.5, sustained for 3 months. Disability

was also assessed by MSFC z-score at 24 months/early termination. As an exploratory endpoint, confirmed worsening of EDSS scores sustained for 6 months was assessed. Exploratory MRI endpoints included the cumulative numbers at 12 plus 24 months of GdE lesions and of new or enlarging ([50 % larger than previous scan) T2 lesions. MRI data were sent to the MRI-analysis center (NeuroRx Research, Montreal, Quebec, Canada) for evaluation and quantification. Safety and tolerability Patients who received at least one dose of study drug were evaluated for safety based on AEs, clinical laboratory parameters, vital signs, and ECGs. Tolerability was assessed by the proportions of patients who discontinued early for any reason and discontinuations due to AEs. Statistical analysis Sample size calculations were based on assumptions of an ARR of 0.6 in the placebo group and 0.45 in the laquinimod group (assuming a 25 % reduction with laquinimod). A simulation study showed 666 patients (333 patients per arm) would provide *90 % power to detect a significant difference in total number of confirmed relapses between the placebo and laquinimod groups. Anticipating 20 % withdrawal over 24 months, the sample was adjusted to 400 patients per arm (*1,200 participants in the threearmed study). The primary endpoint (ARR) was assessed for all randomized patients using all study assessments made before early termination or until study end, using the negative binomial regression model with treatment group as the contrast. In addition to treatment group, baseline EDSS score, log of the number of relapses in the previous 2 years (?1), and country/geographical region (CGR) were covariates in the model. If baseline disease characteristics were appreciably different between placebo and active treatment groups, a prespecified sensitivity analysis was performed to evaluate the robustness of treatment effects using a repeat of the negative binomial model with the imbalanced baseline characteristics as covariates. Time to EDSS progression confirmed at 3 months was analyzed based on a Cox Proportional Hazards model (SASÒ PROC PHREG). The model included baseline EDSS score, log of the number of relapses in the previous 2 years (?1) and CGR as covariates. The time to confirmed progression of EDSS was also presented by Kaplan–Meier (KM) curves stratified by treatment group. Disability as measured by MSFC z-score at month 24 was analyzed using an ANCOVA model (SASÒ PROC GLM) with baseline MSFC z-score, baseline EDSS score, log of the

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number of relapses in the previous 2 years (?1) and CGR as covariates. Per protocol, an IFNb-1a arm was included in this study to serve as a reference only, and comparative assessment of the efficacy, safety, and tolerability of laquinimod vs. IFNb-1a was descriptive. Additional post hoc exploratory statistical analyses were conducted to compare the effects of laquinimod and IFNb-1a on primary and secondary endpoints.

Results Of 1,544 patients screened, 1,331 were eligible to participate and were randomized with equal probability to receive once-daily laquinimod 0.6 mg (n = 434) or placebo (n = 450), or IFNb-1a 30 lg once-weekly (n = 447) (Fig. 1). At baseline, patients randomized to laquinimod or IFNb-1a had higher mean T2 lesion volume and were more likely to have GdE lesions than patients randomized to placebo (Table 1). There were no other significant imbalances at baseline. Overall, 1,090 patients (82 %) completed the 24-month treatment phase. The most common

Fig. 1 Patient disposition

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reasons for early termination were withdrawal of consent and AEs. Compared with placebo, there was a nonsignificant reduction in ARR in patients receiving laquinimod and a significant ARR reduction in the IFNb-1a group (Table 2). The difference in cumulative numbers of relapses at 24 months in the laquinimod group was not significantly different for laquinimod vs. placebo (Fig. 2). Because the primary endpoint did not achieve statistical significance, all additional efficacy endpoints were tested in an exploratory manner (at a nominal level of 5 %). PBVC from baseline to month 24 was significantly reduced (28 %) in the laquinimod group (treatment effect 0.28 %, p \ 0.001) compared with placebo. In contrast, IFNb-1a treatment did not affect PBVC at 24 months compared with placebo (treatment effect -0.11 %, p = 0.14) (Table 2; Fig. 3a). Disability worsening confirmed at 3 months occurred for 42 (10 %) laquinimod patients, 60 (13 %) placebo patients, and 47 (11 %) IFNb-1a patients. Figure 3b shows the KM curve for risk of disability progression over time. The Cox Proportional Hazards model indicated a 31.3 % reduced risk of disability worsening confirmed at 3 months

J Neurol Table 1 Baseline characteristics

Characteristic

Laquinimod (n = 434)

Placebo (n = 450)

IFNb-1a IM (n = 447)

Women, n (%)

282 (65.0 %)

321 (71.3 %)

307 (68.7 %)

36.7 (29.6, 44.0)

37.5 (30.3, 45.4)

38.5 (30.3, 45.9)

4.9 (2.2, 9.3)

4.7 (2.0, 9.7)

5.3 (2.4, 10.3)

Age (years) Median (P25, P75) Time from first MS symptom year Median (P25, P75) Time from MS diagnosis years Median (P25, P75) Patients with [ 1 relapse in 1 year before entry, n (%)

1.2 (0.3, 3.8)

1.2 (0.3, 4.0)

1.4 (0.3, 4.7)

425 (97.9)

435 (96.7)

430 (96.2)

1.0 (1.0, 2.0)

1.0 (1.0, 2.0)

1.0 (1.0, 2.0)

2.0 (1.0, 2.0)

2.0 (1.0, 2.0)

2.0 (1.0, 2.0)

Relapses in the previous year Median (P25, P75) Relapses in previous 2 years EDSS Expanded Disability Status Scale, MRI magnetic resonance imaging, GdE gadolinium-enhancing P25, 25th percentile; P75, 75th percentile a

At any time before study entry. DMAMS included mitoxantrone, immunoglobulin (Ig), IgG, glatiramer acetate, IFNb drugs, meglumine acridonacetate, and azathioprine

Median (P25, P75) EDSS score

2.5 (1.5, 3.5)

2.5 (1.5, 3.5)

2.5 (1.5, 3.5)

Prior disease-modifying treatment for MSa, n (%)

Median (P25, P75)

30 (6.9)

27 (6.0)

42 (9.4)

% of patients with GdE lesions

39.6

33.4

38.1

6.3 (2.3, 13.5)

4.7 (1.7, 10.3)

5.7 (1.9, 11.7)

1,582 (96)

1,586 (93)

1,586 (84)

Volume of T2 lesions (cm3) Median (P25, P75) Normalized brain volume (cm3) Mean (SD)

with laquinimod vs. placebo (p = 0.063) (Table 2). In the predefined exploratory analysis, risk of disability worsening confirmed at 6 months was significantly reduced 40.6 % (p = 0.042). IFNb-1a was associated with nonsignificant reductions in worsening of disability vs. placebo [25.8 % confirmed at 3 months (p = 0.13) and 28.3 % confirmed at 6 months (p = 0.14)]. There were no significant differences in MSFC z-scores at 24 months for laquinimod or IFNb-1a patients compared with placebo patients. For the exploratory MRI endpoints, cumulative number of GdE lesions and cumulative number of new/enlarging T2 lesions at 12 and 24 months, nonsignificant reductions were observed in laquinimod-treated patients and significant reductions were observed in IFNb-1a-treated patients compared with placebo-treated patients (Table 2). Post hoc analyses The phase 3 BRAVO and ALLEGRO trials had similar study design; however, laquinimod treatment was associated with a statistically significant reduction in ARR and disability progression in ALLEGRO [7]. Two post hoc analyses were conducted to explore differences in BRAVO and ALLEGRO outcomes. In the first analysis, results of the prespecified sensitivity analysis of baseline disease characteristics in the

BRAVO study showed significantly greater mean T2 lesions volume (p = 0.009) and a higher proportion of patients with GdE lesions (p = 0.055) in the laquinimod group vs. the placebo group (Table 1). There were also nonsignificant increases in the proportion of patients with GdE lesions (p = 0.14) and in T2 lesions volume (p = 0.24) in the IFNb1a group. Inclusion of these two MRI measures as covariates in the primary analysis model further reduced ARR with laquinimod vs. placebo to a still modest but statistically significant 21 % (p = 0.0264), and to 29 % (p = 0.0021) for IFNb-1a. PBVC at 12 and 24 months and MSFC z-scores at 24 months in both treatment groups were consistent with results of the unadjusted analyses. Risk of disability worsening confirmed at 3 months was reduced 33.5 % with laquinimod vs. placebo (p = 0.044) and 29 % with IFNb-1a vs. placebo (p = 0.088). Reduction in cumulative number of new/enlarging T2 lesions with laquinimod (-19 % vs. placebo) was modest but statistically significant [risk ratio (RR) = 0.81, p = 0.037]. Additional efficacy outcomes after inclusion of the two additional covariates into the primary analysis model are shown in the online Supplementary Table S-1. The second post hoc analysis indicated that the observed relapse rate in the placebo group (0.34 relapse/year) at 24 months was lower than anticipated during study design (0.6 relapse/year). A post hoc power calculation revealed

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J Neurol Table 2 Efficacy results Endpoint

Placebo (n = 450)

Laquinimod (n = 434)

IFNb-1a IM (n = 447)

Relapse Annualized relapse ratea Adjusted means (SE)

0.34 (0.03)

Risk ratio (95 % CI) p value vs. placebo

0.28 (0.03)

0.26 (0.02)

0.82 (0.66–1.02)

0.74 (0.60–0.92)

p = 0.075

p = 0.007

Relapse-free patients

276

285

308

Adjusted proportions (%) p value vs. placebo

61

66 p = 0.21

69 p = 0.023

13 % (60)

10 % (42)

11 % (47)

Hazard ratio (95% CI)

0.69 (0.46–1.02)

0.74 (0.51–1.09)

p value vs. placebo

p = 0.063

p = 0.13

Disability EDSS progression confirmed at 3 monthsb % patients (number of patients)

EDSS progression confirmed at 6 monthsb % patients (number of patients)

7 % (28)

8 % (35)

Hazard ratio (95 % CI)

10 % (46)

0.610 (0.38–0.98)

0.73 (0.47–1.14)

p value vs. placebo

p = 0.042

p = 0.17

MSFC total z-score at 24 months (including early terminations after 12 months) Adjusted mean (SE)

-0.030 (0.06)

-0.045 (0.06)

Treatment effect vs. placebo (95 % CI)

-0.14 (0.06)

0.10 (-0.04 to 0.25)

0.09 (-0.05 to 0.23)

p value vs. placebo

p = 0.15

p = 0.21

-0.75 % (0.06)

-1.14 % (0.06)

0.28 % (0.14–0.43 %)

-0.11 % (-0.25 to 0.04 %)

p \ 0.001

p = 0.14

Brain volume change Percent adjusted mean change in brain volume from baseline to month 24, mean (SE)

-1.03 % (0.06)

Treatment effect vs. placebo (95 % CI) p value vs. placebo Brain lesions Cumulative number of GdE lesions at months 12 and 24 Adjusted mean (SE)

1.84 (0.19)

0.90 (0.10)

Risk ratio (95 % CI)

2.34 (0.25)

0.79 (0.66–1.02)

0.39 (0.40–0.60)

p value vs. placebo

p = 0.069

p \ 0.001

Cumulative number of new/enlarged T2 lesions at months 12 and 24 Adjusted mean (SE)

10.88 (0.85)

6.37 (0.51)

Risk ratio (95 % CI)

13.03 (1.1)

0.84 (0.68–1.02)

0.49 (0.40–0.56)

p value vs. placebo

p = 0.078

p \ 0.001

EDSS Expanded Disability Status Scale, MSFC multiple sclerosis functional composite, GdE gadolinium-enhancing a

ARR was estimated from the primary endpoint, cumulative number of confirmed relapses on-study. Because the primary endpoint was not statistically significant, all other endpoints are considered exploratory

b

Adequacy of the use of the Cox Proportional Hazards model was assessed for the analyses of time to confirmed EDSS progression. Assessment was done by jointly testing the proportional hazards with inclusion of the time-dependent covariate of treatment group by log of time; p values for EDSS progression were 0.1903 and 0.1448 for the laquinimod 0.6 mg and IFNb-1a comparisons, thus demonstrating that the proportional hazard assumption was met

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J Neurol Fig. 2 Primary endpoint: cumulative numbers of confirmed relapses

only 48 % statistical power to detect a significant (p \ 0.05) treatment effect of laquinimod on ARR compared with placebo given the observed treatment effect and dispersion. Per protocol, prespecified comparisons of laquinimod, IFNb-1a, and placebo were descriptive only. Results of a post hoc statistical analysis showed no significant differences between laquinimod and IFNb-1a treatment effects on ARR, EDSS, or MSFC scores; however, laquinimod significantly reduced brain atrophy compared with IFNb-1a [adjusted mean difference 0.42 %, 95 % confidence interval (CI) 0.28–0.56 %, p \ 0.0001]. Safety and tolerability The safety-evaluable population comprised 433 laquinimod, 449 placebo, and 442 IFNb-1a patients. Twenty-one laquinimod patients (5 %), 19 placebo patients (4 %), and 26 IFNb-1a IM patients (6 %) discontinued early due to AEs. AEs leading to discontinuation in at least two patients and at higher incidence with laquinimod vs. placebo were abdominal pain (0.9 % vs. 0), upper abdominal pain (0.7 % vs. 0), and headache (0.5 % vs. 0). In the IFNb-1a group, AEs that led to early discontinuation included influenzalike illness (2 % vs. 0 with placebo), pyrexia (0.7 % vs. 0), toxic hepatitis (0.5 % vs. 0), and myalgia (0.5 % vs. 0).

Two deaths occurred: one in the laquinimod group due to sepsis following early termination (44-year-old male Chernobyl survivor with elevated serum cancer markers at baseline), and another in the IFNb-1a group due to cardiopulmonary failure (39-year-old male former alcoholic with history of hypertension, hypercholesterolemia, retinal vascular disorder, and myocardial infarction). Neither death was considered study drug-related. Similar proportions of patients in the laquinimod, IFNb1a, and placebo groups reported any AE (75, 82, and 70 %, respectively) and serious AEs (see online Supplementary Table S-2). Treatment-related AEs were more common with IFNb-1a (67 %) than with laquinimod (27 %) or placebo (22 %). The most frequently reported treatmentrelated AEs with laquinimod were headache (3 %), increased alanine transaminase (ALT) levels (2 %), and nausea (0.4 %). Liver function abnormalities were reported with slightly higher incidence with laquinimod than with placebo and IFNb-1a IM (9, 7, and 8 %, respectively). Descriptively, incidence of post-baseline shifts to [ 39 upper limit of normal (ULN) ALT was higher in the laquinimod group; however, shifts to [ 59 ULN were lower in the laquinimod group than in the placebo group (Supplementary Table S-2). Termination due to elevated ALT/ aspartate transaminase (AST) was lower with laquinimod (ALT, n = 7) than with placebo (ALT, n = 11) and IFNb-

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J Neurol Fig. 3 Secondary endpoints: a percent brain volume change (PBVC) at month 24; b risk of disability progression

a

b

30%

Placebo Laquinimod 0.6mg

Percentage of Patients with Confirmed Disability Progression

25%

IFNß-1a 30µg IM

20%

15%

10%

5% Laquinimod 0.6mg vs placebo: 31% reduction IFNβ-1a 30µg IM vs placebo: 26% reduction

0%

0

20

40

60

80

100

320 335 349

306 318 335

Weeks on Study Number of Patients Placebo 450 Laquinimod 0.6mg 434 IFNß-1a 30µg IM 447

413 398 418

1a (ALT, n = 12). There were no cases of liver failure or liver insufficiency as evidenced by concomitant elevations of total bilirubin (Hy’s law [26]). One laquinimod patient discontinued due to superficial thrombophlebitis.

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375 367 393

349 353 375

Discussion MS is characterized by inflammatory demyelination and neuronal damage in the CNS; both pathologies are

J Neurol

detectable in the earliest stages of disease and likely share common molecular mechanisms [25, 30, 33]. More often, MS clinical trials assess therapeutic effects on inflammatory activity rather than on neuronal damage, although the latter is more strongly correlated with disability progression [2, 12, 33]. Therapeutic effects on disability progression have been more difficult to demonstrate and replicate in clinical studies [6, 32]. BRAVO results suggest laquinimod and IFNb-1a have only partially overlapping activity across the spectrum of MS clinical outcomes. Treatment effects on focal inflammation-related endpoints (ARR, GdE and T2 lesions) were stronger with IFNb-1a, whereas the effect on disability progression was similar with laquinimod and IFNb-1a compared with placebo. Laquinimod had a significant effect on reducing brain atrophy, whereas IFNb-1a demonstrated no benefit at all. Laquinimod treatment in ALLEGRO met the primary endpoint (ARR was reduced 23 %, p = 0.002) [7], whereas laquinimod had no significant effect on relapse in this study. In BRAVO, baseline imbalances in MS disease measures were detected between active and placebo groups, with less favorable conditions in the active treatment groups, which could have influenced assessment of drug treatment effects [31]. Although post hoc analyses correcting for the baseline imbalances showed a statistically significant reduction of ARR with laquinimod (21 %, p = 0.026), ARR reduction remained modest. In previous studies, IFNb-1a IM was associated with more pronounced effects on disability and brain atrophy than was shown here [15, 27]. The lack of a statistically significant effect on disability by either active treatment in the current study may be related to a particularly low rate of disability progression compared with that seen in other controlled trials of MS treatments [15, 21]. Laquinimod and IFNb-1a treatment differences may be related to the proposed modes of action for each drug [3, 4]. IFNb drugs primarily modulate or suppress peripheral immune responses and reduce blood brain barrier (BBB) permeability to inflammatory cells (although they may not cross the BBB), thereby diminishing inflammatory activity in the CNS [18]. Accordingly, these agents demonstrate pronounced effects on MRI markers of inflammation and more modest effects on relapses. Laquinimod is a small molecule that enters the CNS, where it may modulate resident inflammatory cells, including microglia, astrocytes, and oligodendrocytes [3, 4, 20]. In addition to demonstrated antiinflammatory effects in experimental autoimmune encephalomyelitis animal models [28, 30], laquinimod prevented cuprizone-induced demyelination by attenuating astrocytic NF-jB activation [3], a CNS-intrinsic effect not mediated by peripheral immune cells. Modulating effects of laquinimod on demyelination-associated pathology in the form of CNSresident inflammatory response of astrocytes via NF-jB

interference may represent a novel protective means of restricting brain tissue damage in MS patients [3]. The safety of laquinimod in BRAVO is consistent with earlier studies [7, 9], and the rate of early discontinuation in this study is consistent with rates in several recent 24-month phase 3 trials of oral MS treatments [13, 14, 17, 22]. Common AEs in this and other placebo-controlled laquinimod studies include transient ALT increases and back and neck pain. In BRAVO, liver enzyme elevations in the laquinimod and IFNb-1a groups were reversible even at levels C 39 ULN, and were not associated with clinical, imaging, or laboratory signs of liver failure. As in ALLEGRO [7], abdominal pain was a potential laquinimod tolerability issue. No specific AE emerged as a safety concern for laquinimod. Both BRAVO and ALLEGRO phase 3 studies showed modest effects of laquinimod on measures of focal inflammatory disease activity, but more robust effects on reducing brain atrophy and, possibly, disability worsening. Therefore, laquinimod may be a good choice for decreasing progression of irreversible brain tissue damage and related disability in MS. Continued investigation of the therapeutic mechanisms of laquinimod activity should better elucidate its protective effects on myelin, oligodendrocytes, and neurons [3]. Both studies show laquinimod to be safe and well tolerated in RRMS patients. The proposed mechanism of action, safety, and tolerability of laquinimod may make it a good candidate for use in combination therapy approaches. By avoiding disadvantages of injectable treatments (e.g., injection-site reactions), safe and effective oral MS therapies may improve patient adherence to treatment, thereby maximizing the potential benefit from disease-modifying therapies over the long-term. Acknowledgments We thank the Independent Data Monitoring Committee, the staff of NeuroRx Research, the MRI Analysis Center, and the Principal Investigators for each country; Yulia Sidi, M.A. of the Teva Statistical Data Management Team (Netanya, Israel) managed the statistical analyses; Pippa Loupe, Ph.D. of Medical Affairs, Teva Pharmaceuticals (Kansas City, MO), and two independent medical writers, paid by the sponsor, James D. Bergstrom, Ph.D. of Mountain Stream Communications, LLC (Hillsborough, NJ), and Sheila Truten, B.S. of Medical Communication Company (Wynnewood, PA) collaborated with the authors on the first draft of the paper, copyedited the manuscript and prepared figures and tables. Supported by Teva Pharmaceutical Industries, Ltd., Petach Tikva, Israel. Conflicts of interest TL Vollmer has received consulting fees, and his institution has received a grant and consulting fee for his participation in the BRAVO study; he is a board member of Rocky Mountain MS Center; his institution has received consultancy fees from Biogen Idec, Teva, Elan, Hoffman-LaRoche, Accelerated Cure Project, Genzyme, Bristol-Myers Squibb, Acorda, Novartis, Questor, Medscape, Xenoport, and Sanofi; his institution received fees for expert testimony from Ham VS Bennett and Wagner VS Strand; his institution received grants/grants pending from Teva, Biogen Idec,

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J Neurol Genzyme, Ono, Eli Lilly, Novartis, BioMS, Orasi, Sanofi-Aventis, NIH, EMD Sorono, Acorda, Accelerated Cure Project, HoffmannLaRoche, Jensen Research, Daiichi Sankyo, Elan, Janssen Pharmaceutical, Avanir Pharmaceutical, MedImmune, Delta Quest, Biosite Inc., University of Alabama, and Genentech.PS Sorensen has received payment as co-principal investigator and for travel support for the BRAVO study from Teva; he has received consultancy fees from Merck Serono, Teva, Novartis, Sanofi-Aventis, and Biogen Idec; his institution has received research support grants/grants pending from Biogen Idec, Novartis, and Sanofi-Aventis; and he is on the speaker’s bureau of Merck Serono, Novartis, Bayer Schering, Teva, SanofiAventis, Biogen Idec, and Genzyme.K Selmaj has received compensation for consulting and speaking from Biogen Idec, Genzyme, Novartis, Merck Serono, Roche, and Teva.F Zipp’s institution received a grant from Teva for participation in BRAVO and has received grants/grants pending from Novartis and Merck Serono; she has received fees for consultancy with Merck-Serono, Ono, SanofiAventis, and Biogen; she is a board member of Octapharma; and serves on the speaker’s bureau of Novartis, Merck-Serono, Biogen, Genzyme, and Sanofi-Aventis.E Havrdova’s institution received funding for clinical trial participation, she has received compensation for consultancy from Biogen Idec, Genzyme, Merck Serono, and Novartis; serves on the speaker’s bureaus of Biogen Idec, Merck Serono, Novartis, and Teva; her institution has received a grant/grant pending from Biogen Idec.JA Cohen received, in the previous 2 years, compensation for consulting from Teva and Vaccinex; his institution received research support from Biogen Idec, Novartis, Receptos, Synthon, Teva, US Department of Defense, National Institutes of Health, and National MS Society.N Sasson is employed by Teva; owns stock in and receives travel/meeting expenses from Teva.Y Gilgun-Sherki is employed by Teva; owns stock in and receives travel/meeting expenses from Teva; and is a co-holder of patents with Teva.D Arnold has received fees for consulting, travel support, and research related to the BRAVO study; has received consultancy fees from Biogen Idec, EMD Serono, Genentech, Glaxo Smith Kline, Merck Serono, Mitsubishi, Novartis, and Roche; his institution has received grants/grants pending from Bayer Healthcare, CIHR, and MSSC and owns US patent No. 6,347,239.

References 1. AvonexÒ (interferon beta-1a) prescribing information (2013) Biogen Idec, Inc, Cambridge, MA, USA. Rev 03/2013 2. Agosta F, Rovaris M, Pagani E, Sormani MP, Comi G, Filippi M (2006) Magnetization transfer MRI metrics predict the accumulation of disability 8 years later in patients with multiple sclerosis. Brain 129:2620–2627 3. Bruck W, Pfortner R, Pham T, Zhang J, Hayardeny L, Piryatinsky V, Hanisch UK, Regen T, van Rossum D, Brakelmann L, Hagemeier K, Kuhlmann T, Stadelmann C, John GR, Kramann N, Wegner C (2012) Reduced astrocytic NF-kappaB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol 124:411–424 4. Bruck W, Wegner C (2011) Insight into the mechanism of laquinimod action. J Neurol Sci 306:173–179 5. Cohen BA, Rieckmann P (2007) Emerging oral therapies for multiple sclerosis. Int J Clin Pract 61:1922–1930 6. Cohen JA, Reingold SC, Polman CH, Wolinsky JS (2012) Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects. Lancet Neurol 11:467–476 7. Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca M, Filippi M, ALLEGRO Study Group (2012) Placebo-controlled trial of oral laquinimod in multiple sclerosis. N Engl J Med 366:1000–1009

123

8. Comi G, Obramsky O, Arbizu T, Boyko AN, Gold R, Havrdova E, Komoly S, Mesaros S, Selmaj K, Sharrack B, Filippi M (2009) Long-term open extension of oral laquinimod in patients with relapsing multiple sclerosis shows favourable safety and sustained low relapse rate and MRI activity. Mult Scler 15(suppl2): S127. Abstract P443 9. Comi G, Pulizzi A, Rovaris M, Abramsky O, Arbizu T, Boiko A, Gold R, Havrdova E, Komoly S, Selmaj K, Sharrack B, Filippi M (2008) Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 371:2085–2092 10. Cutter GR, Baier ML, Rudick RA, Cookfair DL, Fischer JS, Petkau J, Syndulko K, Weinshenker BG, Antel JP, Confavreux C, Ellison GW, Lublin F, Miller AE, Rao SM, Reingold S, Thompson A, Willoughby E (1999) Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 122(Pt 5):871–882 11. European Medicines Agency-Committee for Medicinal Products for Human Use (CHMP) (2006) Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis. London 12. Fisher E, Lee JC, Nakamura K, Rudick RA (2008) Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 64:255–265 13. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, Viglietta V, Dawson KT (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367:1087–1097 14. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367:1098–1107 15. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Granger CV, Simon JH, Alam JJ, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE III, Priore RL, Pullicino PM, Scherokman BJ, Whitham RH (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The multiple sclerosis collaborative research group (MSCRG). Ann Neurol 39:285–294 16. Johnson KP (2010) Risks vs benefits of glatiramer acetate: a changing perspective as new therapies emerge for multiple sclerosis. Ther Clin Risk Manag 6:153–172 17. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362:387–401 18. Kieseier BC (2011) The mechanism of action of interferon-beta in relapsing multiple sclerosis. CNS Drugs 25:491–502 19. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452 20. Mishra MK, Wang J, Silva C, Mack M, Yong VW (2012) Kinetics of proinflammatory monocytes in a model of multiple sclerosis and its perturbation by laquinimod. Am J Pathol 181:642–651 21. O’Connor P, Filippi M, Arnason B, Comi G, Cook S, Goodin D, Hartung HP, Jeffery D, Kappos L, Boateng F, Filippov V, Groth M, Knappertz V, Kraus C, Sandbrink R, Pohl C, Bogumil T, O’Connor P, Filippi M, Arnason B, Cook S, Goodin D, Harung HP, Kappos L, Jeffery D, Comi G (2009) 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol 8:889–897

J Neurol 22. O’Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, Benzerdjeb H, Truffinet P, Wang L, Miller A, Freedman MS (2011) Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 365:1293–1303 23. Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T (2005) Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology 64:987–991 24. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O’Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘‘McDonald Criteria’’. Ann Neurol 58:840–846 25. Popescu BF, Lucchinetti CF (2012) Pathology of demyelinating diseases. Annu Rev Pathol 7:185–217 26. Reuben A (2004) Hy’s law. Hepatology 39:574–578 27. Rudick RAM, Fisher EP, Lee J-CM, Simon JMP, Jacobs LM, the Multiple Sclerosis Collaborative Research Group (1999) Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology 53:1698–1704 28. Schulze-Topphoff U, Shetty A, Varrin-Doyer M, Molnarfi N, Sagan SA, Sobel RA, Nelson PA, Zamvil SS (2012) Laquinimod, a quinoline-3-carboxamide, induces type II myeloid cells that

29.

30.

31.

32.

33.

modulate central nervous system autoimmunity. PLoS One 7:e33797 Thone J, Gold R (2011) Laquinimod: a promising oral medication for the treatment of relapsing-remitting multiple sclerosis. Expert Opin Drug Metab Toxicol 7:365–370 Wegner C, Stadelmann C, Pfortner R, Raymond E, Feigelson S, Alon R, Timan B, Hayardeny L, Bruck W (2010) Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 227:133–143 Wei L, Zhang J (2001) Analysis of data with imbalance in the baseline outcome variable for randomized clinical trials. Drug Inf J 35:1201–1214 Whitaker JN, McFarland HF, Rudge P, Reingold SC (1995) Outcomes assessment in multiple sclerosis clinical trials: a critical analysis. Mult Scler 1:37–47 Zipp F, Aktas O (2006) The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci 29:518–527

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