Laquinimod Immunomodulatory Action Confers Both Neuroprotective and Anti-Inflammatory Properties
Posted by Allie Vance | 15 September 2009, 11:44 am
JERUSALEM & LUND, Sweden–(BUSINESS WIRE)–Sep 11, 2009 – Teva Pharmaceutical Industries Ltd. (NASDAQ: TEVA) and Active Biotech (NASDAQ OMX NORDIC: ACTI) today presented data further illuminating the novel, dual mechanism of action (MOA) of investigational oral, once-daily, laquinimod for the treatment of relapsing-remitting multiple sclerosis (RRMS), conferring neuroprotective and anti-inflammatory properties. Results from several preclinical studies suggest that laquinimod elicits a protective therapeutic effect by reducing demyelination and inducing axonal protection.
These studies expand upon a growing body of data suggesting the mechanism of oral laquinimod in RRMS patients is targeted immunomodulation, and may help contribute to the favorable benefit-to-risk profile associated with this compound.
“MS patients, and the physicians who treat them, await the availability of an oral agent with an efficacy and safety profile required to address the chronic, lifelong nature of the disease,” explains Prof. Wolfgang Brück, head of the Neuropathology Dept., the Georg-August-Universität, Göttingen, Germany. “The seemingly targeted immunomodulation that appears to be associated with the dual MOA of laquinimod and the favorable benefit-to-risk profile seen in patients studied for up to 3.5 years, make the drug a potential candidate to address this unmet need for an oral therapy.”
Laquinimod received Fast Track designation from the U.S. Food and Drug Administration (FDA) in February 2009. Two global Phase III clinical trials, BRAVO and ALLEGRO, have completed enrollment and are currently ongoing.
ABOUT THE STUDIES
The studies evaluating the properties of laquinimod being presented at ECTRIMS include:
* Laquinimod induces up-regulation of neurotrophins in serum of patients with relapsing-remitting multiple sclerosis (P 783, 15:30 – 17:00 Immunomodulation – 2, September 11, 2009)
R. Linker, J. Thöne, G. Comi, R. Gold (Bochum, DE; Rome, IT)
596 serum samples from RRMS patients participating in the LAQ/5062 trial were tested for the presence of neurotrophic factors, including neurotrophin (NT)-3, NT-4 and brain derived neurotrophic factor (BDNF). Data on the expression of neurotrophic factors were correlated with their functional activity in a neuronal survival assay. Treatment with 0.6 mg of laquinimod resulted in a significant and specific, up to 11-fold increase in BDNF serum levels as compared to baseline, as well as to placebo treatment after 3 months. Besides an immunomodulatory mechanism of action, laquinimod has the ability to increase levels of neurotrophic factors in vivo possibly contributing to neuroprotection in MS patients.
* Anti-inflammatory pathways activated by laquinimod in CD4+, CD8+, CD14+, CD19+ and NK peripheral blood cells subtypes of relapsing-remitting multiple sclerosis patients (P 264, 15:30-17:00 Immunomodulation – 2, September 10, 2009)
M. Gurevich, B. Timan, L. Hayardeny, A. Achiron (Ramat Gan, Netanya, IL)
High throughout gene expression analysis of in-vitro incubation of peripheral blood mononuclear cells from RRMS patients with laquinimod demonstrated that laquinimod induced in-vitro immunomodulatory effects that are characterized by activation of anti-inflammatory IL-4 pathway in CD4+ cells, promotion of apoptosis in CD8+ and B cells and suppression of metabolic activity of CD14+ and NK cells.
* Reduced inflammation, demyelination and axonal damage after therapeutic laquinimod treatment in experimental autoimmune encephalomyelitis (P 441, 15:30 – 17:30 Immunomodulation – 1, September 11, 2009)
C. Wegner, C. Stadelmann, W. Brück (Gottingen, DE)
In animal models of MS, laquinimod inhibits the development of acute and chronic experimental autoimmune encephalomyelitis (EAE). Laquinimod modulates the cytokine balance in favour of anti-inflammatory Th2/Th3 cytokines. Therapeutic treatment with laquinimod is effective in ameliorating the extent of macrophage and T cell infiltration, demyelination and axonal damage. Findings indicate that laquinimod might have an axon-protective effect in addition to its anti-inflammatory properties.
* The effect of laquinimod on the distribution of monocyte subsets (P 808, 15:30 – 17:00 Immunomodulation – 2, September 11, 2009)
T. Birnberg, S. Jung (Rehovot, IL)
Monocytes are circulating blood leukocytes that play important roles in inflammatory responses. In mice, monocytes originate in the bone-marrow from Macrophages and Dendritic cells precursor. Murine blood monocytes encompass two main Ly6Chi and Ly6Clow subsets. Recent evidence suggests that the ratio of the two monocyte subsets can have effects on the susceptibility of the organism to various disorders, including experimental autoimmune encephalomyelitis (EAE) lesions. These cells are accumulating in the blood and CNS immediately prior to EAE clinical episodes. The results indicate that the effect by which laquinimod exerts its clinical efficacy in autoimmune diseases may be due to its impact on the myeloid precursor cells.
ABOUT MULTIPLE SCLEROSIS
Multiple sclerosis (MS) is the leading cause of neurological disability in young adults. It is estimated that more than 400,000 people in the United States are affected by the disease and that two million people may be affected worldwide. MS is a progressive, demyelinating disease of the central nervous system affecting the brain, spinal cord and optic nerves. Demyelination is the destructive breakdown of the fatty tissue that protects nerve endings.
Laquinimod is a novel once-daily, orally administered immunomodulatory compound that is being developed as a disease-modifying treatment for RRMS. Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries, Ltd. in June 2004. A Phase IIb study in 306 patients was published in The Lancet and demonstrated that an oral 0.6 mg dose of laquinimod, administered daily, significantly reduced MRI disease activity by a median of 60 percent versus placebo in RRMS patients. In addition, the study showed a favorable trend toward reducing annual relapse rates and the number of relapse-free patients compared with placebo. Treatment was well tolerated, with only some transient and dose-dependent increases in liver enzymes reported. Over 1,000 MS patients have received laquinimod in various clinical trials.
In addition to the efficacy that laquinimod has shown in Phase II RRMS clinical trials, laquinimod has demonstrated potent therapeutic efficacy in preclinical models of other autoimmune diseases such as rheumatoid arthritis, insulin-dependent diabetes mellitus, Guillain Barré Syndrome, lupus and Inflammatory Bowel Disease. The broad profile of efficacy in animal models of inflammatory diseases suggests that laquinimod affects a pivotal pathway of inflammation and autoimmunity. Laquinimod is currently in Phase II development for Crohn’s disease and Teva expects to initiate the clinical development of the compound for Lupus Nephritis in the near future.