Journal Club: April 13, 2012

Deirdre Dulak (Tisch MS) presented the following article in Journal Club.

Article Title: Placebo-Controlled Trial of Oral Laquinimod for Multiple Sclerosis

Reference: G. Comi, D. Jeffery, L. Kappos, X. Montalban, A. Boyko, M.A. Rocca, and M. Filippi. (2012) The New England Journal of Medicine. 366 (11): 1000-9.

Laquinimod, an oral quinoline-3-carboxamide small molecule, is currently being investigated as an oral therapy for multiple sclerosis (MS). Laquinimod is derived from roquinimex, which was previously investigated as a MS treatment but abandoned due to safety concerns, namely serositis, thrombosis, and cardiovascular issues. Preclinical studies of laquinimod have indicated anti-inflammatory and neuroprotective properties. In addition, a previous phase 2 clinical trial of laquinimod demonstrated positive MRI results. The results presented by Comi et al. (2012) were obtained from the Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis (ALLEGRO) study, a phase 3, placebo-controlled, double-blind, randomized trial to determine the safety, tolerability, and efficacy of oral laquinimod (0.6 mg daily) over a 24-month period in patients with relapsing remitting multiple sclerosis (RRMS). The primary study endpoint was the annualized relapse rate, and secondary endpoints were disability progression and MRI changes. The results indicated that patients receiving laquinimod had a significantly lower relapse rate than those receiving placebo, although the absolute differences were relatively modest. In addition, the risk of disability progression was significantly lower in the laquinimod group than in the placebo group, as assessed via increases in EDSS scores maintained for 3 and 6 months. The MRI results from the study were positive as well: the cumulative numbers of gadolinium-enhancing lesions and new or enlarged lesions on T₂-weighted images at 12 and 24 months were significantly reduced in the laquinimod group. Further, brain atrophy was significantly lower in the laquinimod group. Laquinimod was not associated with any deaths during the study period. The most prevalent serious adverse event in the laquinimod group (as opposed to the placebo group) was appendicitis. Relatively minor adverse events in the laquinimod group included abdominal pain, back pain, and cough. However, laquinimod was also associated with elevated alanine aminotransferase levels between three and five times the upper limit of the normal range. The authors concluded that laquinimod is a relatively safe treatment with modest effects on relapse rate, disability progression, and lesion load in patients with RRMS.