Multiple Sclerosis Society of Canada

Laquinimod


Overview:

  • Brand name: Nerventra (Teva Pharmaceuticals Industries Inc. and Active Biotech)
  • Route of Administration: Oral (tablet, once daily)
  • Emerging treatment for: RRMS
  • Status: In Phase III of clinical trials

Laquinimod is believed to modulate both anti-inflammatory and neuroprotective actions to limit demyelination and axonal injury.

How it Works

Laquinimod is believed to modulate both anti-inflammatory and neuroprotective actions to limit demyelination and axonal injury. Laquinimod is believed to restrict the passage of immune cells into the CNS and alter the cytokine profile, inhibiting pro-inflammatory cytokines and increasing anti-inflammatory cytokines. Evidence shows elevated brain-derived neurotrophic factor (BDNF) levels following laquinimod treatment. BDNF is an important factor in the brain as it supports the growth and survival of neurons and may help reduce axonal damage.

Research and Results

Recently, the European Medicine Agency (EAE) confirmed an earlier decision to not license laquinimod for RRMS treatment. In a May 2014 announcement, the EAE cited concerns regarding laquinimod including its unclear mechanism of action in the human body, a higher occurrence of cancers in animal studies with long-term exposure to laquinimod, and an unclear risk posed to pregnant women and fetuses. The EAE resolved the potential risks of treatment outweighed the benefits.

A phase II clinical study was conducted in RRMS patients over 24 weeks. Participants received 0.1mg or 0.3mg of laquinimod, or a placebo tablet daily. Participants administered 0.3mg of laquinimod had 44% fewer active brain lesions compared to the control group. There were no significant differences in clinical variables including relapse rate and disability progression. A follow-up phase II study examined the effect of placebo, 0.3mg or 0.6mg laquinimod daily treatment on lesions after 36 weeks. Participants treated with 0.6mg of laquinimod showed a 40% reduction in number of lesions compared to the placebo group. Treatment with 0.3mg of laquinimod did not reveal any significant effects compared to placebo. No significant change in relapse rate or disability progression was found.

Two phase III studies have been reported. ALLEGRO examined the effect of 0.6mg of laquinimod or placebo on RRMS patients over 24 months. Findings revealed participants taking laquinimod showed a 23% reduction in annualized relapse rate, a 36% reduction in disability progression, and a 33% reduction in brain volume loss compared to the placebo group. BRAVO examined the effect of treatment with 0.6mg of laquinimod compared to placebo and interferon beta-1a in RRMS patients. The primary outcome of interest in this study was annualized relapse rate. Results showed no significant reduction in relapse rate in laquinimod treated participants compared to placebo treated participants (with an unadjusted statistical comparison).

CONCERTO, a follow-up phase III study, is scheduled to complete in 2018. This trial will examine disability progression in participants treated with placebo, 0.6mg laquinimod, or 1.2mg laquinimod. (NCT01707992).

Adverse Effects Reported

Clinical trials have reported laquinimod is generally well tolerated. Back pain, increased liver enzyme levels, and headaches are the most common adverse effects reported. One patient who was administered 0.6mg of laquinimod/day developed a serious blood clot in a major vein leading away from the liver.

References

Polman C et al. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology. 2005; 64(6):987–91

Comi G et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing–remitting multiplesclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008; 371(9630):2085–92.

Comi G et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012; 366(11):1000–9

Vollmer T. A placebo-controlled and active comparator phase III trial (BRAVO) for relapsing remitting multiple sclerosis. Abstract 148. ECTRIMS/ACTRIMS; 2011.