Investigators at Ruhr-University (Bochum, Germany) worked with the experimental autoimmune encephalomyelitis (EAE) model of MS, which was induced in mice with a conditional BDNF deficiency in immune cells (LLF mice) and in wild-type (WT) control mice. The animals were treated with laquinimod, and in some experiments, laquinimod-stimulated monocytes were transferred from one model type to another.
Results published in the December 8, 2011, online edition of the American Journal of Pathology revealed that treatment with laquinimod resulted in a significant reduction in EAE incidence and disease severity in the WT mice. The effect of laquinimod was significantly reduced in the LLF-mice. Injection of laquinimod-stimulated monocytes into WT mice at an early EAE disease stage resulted in a less severe disease course than in controls. Transfer of laquinimod-treated cells derived from LLF mice into WT mice with ongoing EAE did not influence disease course.
The results from the animal experiments complement those obtained by evaluating levels of BDNF in the serum of MS patients treated with laquinimod in phase II clinical trials. A significant and robust BDNF increase occurred in 76% of the laquinimod-treated patients, with up to an 11-fold increase in BDNF serum levels observed in individual patients.
“Our data are indicative of a direct and sustained effect of laquinimod on the upregulation of bioactive BDNF in patients with MS. Additionally, we demonstrate that laquinimod targets monocytes and skews the phagocyte population towards a regulatory phenotype, which in turn mediates immune modulation in vivo,” said senior author Dr. Jan Thöne, professor of neurology at Ruhr-University. “To date, selective targeting of monocytes has not been described for any other MS pipeline drug, highlighting an innovative mechanism of action of laquinimod.”
Commercial exploitation of laquinimod received a setback in mid-2011 when Teva (Petach Tikva, Israel) announced that its clinical trials involving laquinimod had failed, being unable to reduce significantly relapses in multiple sclerosis among patients beyond what a placebo was able to do. Failure for laquinimod to win US Food and Drug Administration approval is expected to cost Teva USD 627 million in sales in 2015.
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