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HD InsightsMeet the Compound: Laquinimod

By: Ryan E. Korn, BA

Laquinimod Source: pubchem.ncbi.nlm.nih.gov/compound/5467796
Source: pubchem.ncbi.nlm.nih.gov/compound/5467796

Manufacturer: TEVA Pharmaceutical Industries Ltd. and Active Biotech

Molecular Formula: C19H17ClN2O3

Molecular Weight: 357 g/mol

Mechanism of Action: Laquinimod exhibits both anti-inflammatory and neuroprotective effects. Potential mechanisms of action include its inhibition of cuprizone-induced demyelination; microglial activation; axonal transections; reactive gliosis; oligodendroglial apoptosis; as well as decreasing proinflammatory factors.1, 2

Laquinimod is an experimental immunomodulatory drug that has shown promising neuroprotective effects. The exact mechanism by which laquinimod exerts its neuroprotective effects is not fully understood, but it has been proposed that laquinimod reduces leukocyte migration into the central nervous system. The compound has been shown to modify the innate immune system to promote the differentiation of anti-inflammatory/regulatory T cells, activate microglia cells, increase the expression of brain-derived neurotrophic factor, and prevent inflammation-induced excitotoxicity.

In 2012, a study funded by TEVA Pharmaceutical Industries Ltd. and Active Biotech characterized the impact of laquinimod on CNS-intrinsic inflammation caused by cuprizone-induced demyelination in mice in vivo, and on primary CNS cells in vitro. Results suggest that laquinimod not only prevents cuprizone-induced demyelination but also prevents microglial activation, axonal transections, reactive gliosis, and oligodendroglial apoptoses in wildtype and Rag-1 – deficient mice. Most significantly, laquinimod is believed to inhibit astrocytic NF-κB transcription factor activation, thereby preserving myelin.2

TEVA and Active Biotech have investigated laquinimod as a potential oral treatment for a variety of autoimmune and neurodegenerative diseases. Laquinimod was first investigated for the treatment of relapsing-remitting multiple sclerosis (RRMS), an autoimmune disease that causes inflammation-induced demyelination and axonal degeneration of the CNS, resulting in chronic neurological complications and disability.2 Two of TEVA and Active Biotech’s most recent studies, BRAVO and ALLEGRO, showed that laquinimod decreases the rate of whole-brain atrophy compared to placebo.3 Results in both studies indicate that oral laquinimod is likely to exert a neuroprotective effect resulting in a reduced amount of irreversible brain tissue damage, which is consistent with possible slowing of disability accumulation in RRMS patients.4 These evident neuroprotective effects, reduced inflammatory response, and reduction in brain tissue damage shown in the BRAVO and ALLEGRO studies, could prove effective in other autoimmune and neurodegenerative diseases.

TEVA and Active Biotech recently initiated a Phase II randomized, double-blind, placebo-controlled parallel group study (LEGATO-HD) to evaluate the efficacy and safety of laquinimod as a treatment for HD.5 Laquinimod’s modulation of pathways common to key neurodegenerative disease through the immune cell lineages in the periphery and in the CNS, as well as its evident anti-inflammatory effects, may reduce neuronal death and the harmful inflammatory response seen in HD.4, 6 The HD trial is in the early phase of recruitment and enrollment. The study is expected to be completed in January 2017.5

1 Haggiag S, Ruggieri S, Gasperini C. Efficacy and safety of laquinimod in multiple sclerosis: current status. Ther Adv Neurol Disord. 2013 Nov; 6(6):343-52.

2 Brück W, Pförtner R, Pham T, et al. Reduced astrocytic NF-κB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol. 2012 Sep; 124(3):411-24.

3 Filippi M, Rocca MA, Pagani E, et al. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry 2014; 85:851-858.

4 Mishra MK, Wang J, Keough MB, et al. Laquinimod reduces neuroaxonal injury through inhibiting microglial activation. Ann Clin Transl Neurol. 2014 Jun; 1(6):409-22. doi: 10.1002/acn3.67. Epub 2014 May 26.

5 Clinicaltrials.gov. A service of the U.S. National Institutes of Health [Internet]. A clinical study in subjects with Huntington’s disease to assess the efficacy and safety of three oral doses of laquinimod (ClinicalTrial.gov identifier: NCT02215616). [cited Dec 30 2014]. Available from: clinicaltrials.gov/ct2/show/NCT02215616.

6 TEVA Pharmaceutical Industries Ltd [Internet]. Results of Phase III BRAVO trial reinforce unique profile of laquinimod for multiple sclerosis treatment. 2011 August 11 [cited 2014 Dec 30]. Available from: ir.tevapharm.com/phoenix.zhtml?c=73925&p=irolnewsArticle&id=1591070.

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Our mission is to promote, disseminate, and facilitate research on Huntington’s disease. To fulfill this mission, we are guided by an outstanding editorial board that includes representatives from three continents, academia, industry, and the HD community.