Multiple Sclerosis
showed that the addition of laquinimod resulted in a suppression of the genes known to be involved in NK signaling of effector T cells (Th1) that cause cytoxic activity upon antigen presentation.17
In MOG-immunized mice, laquinimod inhibited the ability of chemokine C-C motif ligand (CCL) 21 to stimulate very late antigen 4 (VLA-4) adhesiveness to vascular cell adhesion molecule 1 (VCAM-1). This is consistent with the idea that laquinimod may also decrease T-cell trafficking from the periphery into the CNS.18
Another factor that might contribute to the immunomodulatory effects of laquinimod is its ability to downregulate cytokine release from activated microglia.19
the release of TNFα, IL-10, and matrix metalloproteinase 9 (MMP-9). In addition, laquinimod reduced the elevation in microglial activity that was stimulated by lipolysacharide. In humans participating in a clinical trial of laquinimod in RRMS, laquinimod significantly increased plasma concentrations of brain-derived neurotrophic factor (BDNF).20
Three
months after treatment, levels of BDNF were increased by as much as 11-fold compared with the placebo-treated group. This suggests that laquinimod might also possess neuroprotective effects.
In short, laquinimod appears to have a wide array of immuno-modulatory effects. It downregulates pro-inflammatory cytokines while at the same time upregulating anti-inflammatory cytokines, promotes a Th1 to Th2/Th3 shift, downregulates MHC class II functions, inhibits microglial activation, and stimulates the production of BDNF. This is consistent with a broad-spectrum immunomodulatory effect and suggests that this agent could prove highly effective in MS.
Pharmacokinetics
Laquinimod is rapidly absorbed following oral administration and has a bioavailability of about 82–95%. The half-life is 80 hours and peak plasma concentration is within one hour.21
A high proportion of the
drug in circulation is protein-bound; in plasma only 1.4% is unbound. The volume of distribution is approximately 10 liters. At steady state there are only small fluctuations between minimum and maximum
concentration (Cmin and Cmax, respectively). There is no accumulation of the drug in tissues, and brain penetration is low with a blood to brain ratio of 0.01:0.08.
Laquinimod is extensively metabolized prior to elimination, with only 10% of the parent compound excreted unchanged. The primary metabolic pathway is glucuronidation of the parent compound and its hydroxylated metabolites. Metabolism of laquinimod occurs in the liver by the cytochrome P-450 enzyme system. The CYP3A4 isoenzyme is the predominant enzyme active in the metabolism of laquinimod.22 While there may be a small contribution from other P-450 iso-enzymes, CYP3A4 is predominant. As a result, laquinimod may interact with other agents metabolized by CYP3A4. This may be clinically important as many patients with MS are treated with symptomatic therapies metabolized by the CYP3A4 isoenzyme. Significant interactions may occur with fluoxetine, fluvoxamine, sertraline, floxin antibiotics, erythromycin, and antifungal agents such as fluconazole. Interactions may also occur with some calcium blockers and amiodarone. Drug-interaction studies with these agents will help determine whether
72
these potential interactions are clinically relevant and whether dose adjustments may be needed.
Phase II Trials in Relapsing–Remitting Multiple Sclerosis There have been two phase II trials of laquinimod in relapsing forms of MS. The first phase II trial of laquinimod compared doses of 0.1 and 0.3mg versus placebo in 209 patients.23
The primary outcome measure in this trial was the total number of gadolinium (Gd)-enhancing lesions In cultured microglia, laquinimod decreased
and the number of new non-Gd-enhancing T2 lesions over a 24-week treatment period. This trial used MRI every eight weeks with triple-dose contrast to improve lesion detection. In order to enrich the patient population by including those with more active inflammatory disease, the inclusion criteria stipulated that patients had to be 18–65 years of age and must have had at least one relapse in the year prior to study entry. In this study relapse was defined differently from previous definitions i.e. the presence of at least one Gd-enhancing lesion or a
new T2 lesion demonstrated on two consecutive MRI scans, one exacerbation in the last year or two exacerbations in the last two years (one could be subclinical) or Gd-enhancement on the screening MRI
scan. Patients were also required to have at least nine T2 lesions or three T2 lesions and one gadolinium-enhancing lesion. After the 24-week treatment period laquinimod was stopped and patients were monitored for an additional eight weeks.
Laquinimod at 0.3mg brought about a 44% reduction in the cumulative number of active lesions over the 24-week treatment period (p=0.0498). The 0.1mg dose did not appreciably decrease the number of new active lesions. The effects were more robust in patients with active disease. In those with Gd-enhancing lesions on their baseline MRI, there was a 52% reduction in active lesions (p=0.005) and a 64% decrease in lesion volume over the treatment period. After cessation of dosing, lesion frequency increased, suggesting a therapeutic effect at the 0.3mg dose. While these results were encouraging, it was felt that a higher dose might prove superior since the drug was well tolerated and there were few adverse events (AEs).23
The second phase II trial used doses of 0.3 and 0.6mg and employed a different strategy to enrich the patient population for disease activity.24 This trial enrolled 306 patients and stipulated that patients had to have had at least one relapse in the year prior to study entry and to have an active Gd-enhancing lesion on their baseline MRI in order to enter into the study. The use of these criteria resulted in a study population with far more active disease since Gd-enhancing lesions predict higher relapse rates, a higher frequency of new lesions, and a greater progression of cerebral atrophy;24
however, it also resulted in the
inclusion of patients with more aggressive disease, which may have led to an under-estimation of the efficacy of the agent under study.
MRI scans were carried out at baseline and then at four-week intervals beginning at week 12. The primary outcome measure was the cumulative number of Gd-enhancing lesions from week 24 to week 36. A number of secondary outcomes were also evaluated, including relapse rates, cumulative number of Gd-enhancing lesions at
each time-point, and cumulative number of new T2 lesions at weeks 24, 28, 32, and 36. The study was not powered to detect an effect on relapse rate.
US NEUROLOGY
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