Laquinimod in Relapsing–Remitting Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that affects at least 400,000 people in the US alone. Estimates of the prevalence of MS were made in the early 1990s and may vastly underestimate the true prevalence of the disease.1,2 The cause of MS remains unknown, but it is clear that inflammatory demyelination and axonal damage lead to considerable disability in both early-and late-stage disease. The rate and extent of disability progression are highly variable.The mainstay of MS treatment over the past 17 years has primarily been treatment with interferons (IFNs) and glatiramer acetate. IFNβ-1b AbstractLaquinimod is a novel oral immunomodulatory agent in development for the treatment of relapsing-remitting multiple sclerosis (RRMS). It is a derivative of roquinimex that was structurally altered to maximize safety and efficacy. In animal models laquinimod was far more potent than its parent compound with no apparent propensity to induce inflammatory reactions. Laquinimod is a broad-spectrum immunomodulatory agent with a multitude of effects on the immune system but no effect on the ability of animals to mount a cellular or humoral immune response. In phase II trials selected for highly active RRMS patients, laquinimod reduced the frequency of gadolinium-enhancing lesions by 55%, significantly reduced the number of new T 2 lesions, and had a trend toward an effect on reducing brain volume loss. Laquinimod was well tolerated in phase II trials and had a favorable safety profile with a paucity of adverse events. It is metabolized by the cytochrome P-450 system (CYP-3A4) and may interact with some compounds used in symptomatic therapy. With a favorable efficacy and safety profile, laquinimod is a potential first-line agent in the future treatment of RRMS. KeywordsMultiple sclerosis, laquinimod, immunomodulatory, safety, efficacy Disclosure: Douglas R Jeffery, MD, PhD, has received honoraria for speaking and consulting from Teva, Bayer, Biogen-Idec, Novartis, Serono, Pfizer, Acorda, and GSK, and has received research support from Teva, Bayer, Biogen-Idec, Serono, Novartis, and Pfizer. The remaining authors have no conflicts of interest to declare.

New and Emerging Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis: What is New and What is to Come

“…Lastly, in the EAE murine model, laquinimod may increase CNS and serum levels of brain neurotrophic growth factor. Laquinimod is well-absorbed following oral administration and is highly bioavailable (up to 95%) 77. It has an extremely long half-life of 80 hours.…”

“…Laquinimod is well-absorbed following oral administration and is highly bioavailable (up to 95%). 77 It has an extremely long half-life of 80 hours. It does not readily cross the blood-brain barrier.…”

Profile of oral laquinimod and its potential in the treatment of multiple sclerosis

“…There is a relatively small volume of distribution of approximately 10 L in the circulation, and the drug is predominantly protein-bound in serum. 29 Laquinimod is metabolized in the liver as a low-affinity substrate of the cytochrome P450 (CYP) pathway, specifically the CYP3A4 isozyme. 30 The drug is broken down into at least six primary metabolites.…”