Expert Insight Into: Placebo-Controlled Trial of an Oral Small Molecule for the Treatment of RRMS (Part 1 of Series)

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Clinical Insights

Oral agents – including fingolimod (FDA approved) and others in development, such laquinimod, BG-12, and teriflunomide – offer alternative efficacious treatments for RRMS.
The results of this 24-month, phase 3 study are in agreement with outcomes from two earlier proof-of-concept trials.
In addition to a significant reduction in annualized relapse rate, laquinimod also resulted in a reduction in brain volume loss which may be related to the reduction in confirmed disability progression observed in patients receiving this agent.

PLEASE NOTE: Each article is selected by faculty on the scientific merits of the new data. It is one part of a bundled series of articles that, as a group, provide a full and balanced perspective.

Laquinimod is a small molecule selected for its safety and efficacy from a pool of 60 quinolone-3-carboxamide derivatives of roquinimex. Roquinimex, a drug evaluated as a treatment for multiple sclerosis in phase 2 trials, was withdrawn because of safety concerns. In preclinical studies, laquinimod reduced inflammatory cell infiltrates in the central nervous system (CNS), decreased demyelination, and prevented axonal loss. In a 36-week phase 2 study, laquinimod significantly reduced the accumulation of gadolinium-enhancing CNS lesions. This journal article reports the safety and efficacy results from the Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis (ALLEGRO) trial, a multicenter, multinational, phase 3, randomized, placebo-controlled study.

The ALLEGRO study population randomized and included in outcomes analyses was 1106 adults with relapsing-remitting multiple sclerosis (RRMS). Study patients had an Expanded Disability Status Score (EDSS) of no more than 5.5 and a documented number of relapses prior to screening (≥2 within 24 months, ≥1 within 12 months, or ≥1 between 12 and 24 months plus at least 1 gadolinium-enhancing lesion in the previous year). Exclusion criteria included use of investigative or immunosuppressive agents within 6 months of screening, disease-modifying drugs or chronic (≥30 days) glucocorticoids within 2 months of screening, or prior treatment with natalizumab, cladribine or laquinimod.

Patients received laquinimod 0.6 mg (n = 550) or placebo (n = 556) once daily for 24 months. There were no significant differences in baseline characteristics between the two study groups. A similar proportion of patients in both groups completed the study (79.5%, laquinimod; 76.8%, placebo). The rate of study discontinuation was also similar in both groups: 13.7% in the first year (12.0%, laquinimod; 15.2%, placebo) and 8.2% in the second year (8.5%, laquinimod; 7.9%, placebo).

The primary endpoint was the annualized relapse rate; patients treated with laquinimod had a modest but significant reduction in adjusted mean annualized relapse rate (0.30+0.02) compared with placebo (0.39+0.03, P = .002). Significantly more patients treated with laquinimod remained free of relapse during the study than did those in the placebo group (Figure 1), and the time to first relapse was longer in laquinimod-treated patients. Laquinimod-treated individuals also experienced a lower annualized rate of relapse necessitating hospitalization or intravenous glucocorticoids. In the key secondary endpoint, disability progression measured by elevated EDSS scores sustained for at least 3 months was significantly reduced with laquinimod relative to placebo (Figure 2). The adjusted mean Multiple Sclerosis Functional Composite (MSFC) score at 24 months, another secondary endpoint, did not differ significantly between treatment groups.

Figure 1. Proportion of patients remaining relapse-free during a 24-month study of laquinimod 0.6 mg compared with placebo in patients with relapsing-remitting multiple sclerosis

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Figure 2. Proportion of patients with disability progression (increase in EDSS score ≥1.0 if baseline score ≤5.0, or ≥0.5 if baseline score 5.5, sustained for ≥3 months) during a 24-month study of laquinimod 0.6 mg compared with placebo in patients with relapsing-remitting multiple sclerosis

Click to Enlarge

Magnetic resonance imaging (MRI) scans at 12 and 24 months documented a significantly greater suppression of inflammatory disease activity with laquinimod than placebo. The mean cumulative numbers of gadolinium-enhancing lesions, as well as new or enlarged lesions on T₂-weighted images, were significantly reduced with laquinimod relative to placebo (P <.001, both comparisons). Furthermore, loss of brain volume at 24 months was significantly less with laquinimod than placebo (P <.001).

The proportion of patients who experienced adverse events was similar in patients receiving laquinimod or placebo (adverse events, 87% and 81%, respectively; serious adverse events, 11.1% and 9.5%, respectively). Abdominal pain, back pain, cough, and ALT elevations occurred more often with laquinimod than placebo, but rarely led to study discontinuation. Transient ALT elevations above the upper limit of normal (ULN) were observed more with laquinimod than placebo (>3 and ≤5 X ULN, 3.6% and 0.4%, respectively). Most ALT elevations occurred within the first 6 months and were reversible, without signs of liver failure.

The authors of this report concluded that oral laquinimod administered once daily is a disease-modifying treatment with demonstrated efficacy in RRMS. An open-label extension of this study is currently assessing the long-term safety of laquinimod in RRMS. While the demonstrated anti-inflammatory effects of laquinimod were modest, the effects on reducing disability and brain volume were more impressive.

Reference

Comi GC, Jeffery D, Kappos L, et al for the ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366(11):1000-1009.

Suggested Readings

O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-1303. Available at : http://www.nejm.org/doi/pdf/10.1056/NEJMoa1014656.

Kappos L, Radue EW, O’Connor P, et al for the FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401. Available at: http://www.nejm.org/doi/pdf/10.1056/NEJMoa0909494.

Kappos L, Gold R, Miller DH, et al for the BG-12 Phase IIb Study Investigators. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicenter, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372(9648):1463-1472.

Privacy Policy

Expert Insight Into:
Placebo-Controlled Trial of an Oral Small Molecule for the Treatment of RRMS (Part 1 of Series)

Based on the Article:

Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366(11):1000-1009.

Expert Faculty: Fred D. Lublin, MD
Medical Writer: Carol Gorman, MS

Available for CME/CE:

Physicians

Nurses

Pharmacists

Estimated time for completion of this activity:

Target Audience

Activity Goal

Learning Objective (s)

CME Information: Physicians

Statement of Accreditation

Credit Designation

CE Information: Nurses

CE Information: Pharmacists

CME/CE Instructions

Available for CME/CE:

Physicians

Nurses

Pharmacists

Estimated time for completion of this activity:

Target Audience

Activity Goal

Learning Objective (s)

CME Information: Physicians

Statement of Accreditation

Credit Designation

CE Information: Nurses

CE Information: Pharmacists

CME/CE Instructions

Privacy Policy

Expert Insight Into: Placebo-Controlled Trial of an Oral Small Molecule for the Treatment of RRMS (Part 1 of Series)

Based on the Article: Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366(11):1000-1009.

Expert Faculty: Fred D. Lublin, MD Medical Writer: Carol Gorman, MS

Available for CME/CE:

Physicians

Nurses

Pharmacists

Estimated time for completion of this activity:

Target Audience

Activity Goal

Learning Objective (s)

CME Information: Physicians

Statement of Accreditation

Credit Designation

CE Information: Nurses

CE Information: Pharmacists

CME/CE Instructions

Available for CME/CE:

Physicians

Nurses

Pharmacists

Estimated time for completion of this activity:

Target Audience

Activity Goal

Learning Objective (s)

CME Information: Physicians

Statement of Accreditation

Credit Designation

CE Information: Nurses

CE Information: Pharmacists

CME/CE Instructions

Expert Insight Into:
Placebo-Controlled Trial of an Oral Small Molecule for the Treatment of RRMS (Part 1 of Series)

Based on the Article:

Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366(11):1000-1009.

Expert Faculty: Fred D. Lublin, MD
Medical Writer: Carol Gorman, MS