Laquinimod, also known as ABR-215062 sodium salt ( ) is a new orally administered synthetic drug designed for the treatment of RRMS and relates to the antecessor substance roquinimex (Linomide®). Roquinimex has demonstrated beneficial effects in MS, however, due to its serious adverse profile including cardiopulmonary toxicity, further development was stopped.
Figure 1 Chemical structure of oral agents. (A) Laquinimod. Molecular formula: C19H16O3N2ClNa; relative molar weight salt: 378,78; relative molar weight corresponding acid: 356.803 g/mol. (B) Fingolimod. Molecular formula: C19H33NO2 • HCl; relative molar (more ...)
Laquinimod shows a clearly superior safety profile. Its exact mechanism of action has not been fully elucidated. Different studies conducted in the experimental autoimmune encephalomyelitis (EAE) model, which represents the major animal model of MS, clearly demonstrate the capacity of laquinimod to ameliorate clinical EAE disease course.2
Histopathological analyses elucidate reduced infiltration of both CD4+ T cells and macrophages into the central nervous system (CNS) and less axonal damage.4
Laquinimod acts via modulation of the brain-derived neurotrophic factor and targets the distribution of monocyte subsets towards an anti-inflammatory type II phenotype.5
Interestingly, its beneficial effect in EAE seems to be independent of endogenous IFN-β.4
Thus, laquinimod might be an alternative in RRMS patients not responding to IFN-β treatments.
In summary, the data available to date suggest both immunomodulatory and neuroprotective mechanisms of action of laquinimod ().
Oral agents in RRMS: Overview of mechanisms of action and efficiency.
Studies and clinical efficacy
To date, the efficacy of oral laquinimod in adult patients with RRMS has been studied in one phase II, one phase IIb (LAQ/5062), and one phase III (ALLEGRO) randomized, double-blind clinical trial of 6–24 months duration.9
In addition, one global phase III (BRAVO) study has been completed and the results will be published soon.
Phase II studies, including one double-blind active extension, investigated the beneficial effect of different doses of laquinimod (0.1 mg/day, 0.3 mg/day, and 0.6 mg/day) vs a placebo in RRMS.9
Studies were scheduled for 24 and 36 weeks. The active extension study was scheduled for 36 weeks. Magnetic resonance imaging (MRI) measures of disease activity were the basis for statistical power and sample size calculations in all studies. In summary, laquinimod (0.3 mg/day and 0.6 mg/day) demonstrated sustained beneficial effects on MRI surrogate parameters, but failed to detect statistically significant effects on the relapse rate in these phase II studies, where clinical effects were only exploratory/tertiary endpoints ().9
To further evaluate the clinical effects of laquinimod in RRMS and its safety profile two global, multicenter, randomized, parallel-group, double-blind phase III studies have been initiated. The ALLEGRO study (MS-LAQ-301) is a placebo-controlled study, encompassing over 1100 participants, designed to evaluate the efficacy, tolerability, and safety of laquinimod in a dosage of 0.6 mg/day in patients with RRMS. The BRAVO study (MS-LAQ-302) encompasses over 1300 participants and was designed to assess the efficacy, tolerability, and safety of laquinimod in a dosage of 0.6 mg/day in comparison to a placebo and IFN-β-1a (Avonex®) in patients with RRMS in a rater blinded-fashion. Both studies were scheduled for 24 months and the primary endpoint was defined as the number of confirmed relapses during the treatment phase.
Results of the ALLEGRO study were published recently.12
Treatment with laquinimod resulted in a 23% reduction of the mean annualized relapse rate (ARR) compared to the placebo (0.30 ± 0.02 vs 0.39 ± 0.03; P
= 0.002) (). Furthermore, there was a modest reduction in the risk of confirmed disability progression (11.1% vs 15.7%, P
= 0.01). Similar to phase II studies, laquinimod reduces the mean number of gadolinium (Gd)-enhancing lesions and new or enlarging MRI lesions on T2-weighted images (P
< 0.001 for both comparisons) ().12
First preliminary results of the BRAVO study have been announced.13
No statistical superiority was observed between the IFN-β-1a and laquinimod arm. Interestingly, participants who were randomized to receive laquinimod showed a significant reduction in the loss of brain volume and Expanded Disability Status Scale progression compared to intramuscular IFN-β-1a.13
At this point in time, results of the BRAVO study have to be interpreted with caution since data have not been published in a peer-reviewed publication.
Specific safety and tolerability
So far, different doses of laquinimod (0.1 mg/day vs 0.3 mg/day vs 0.6 mg/day) have been studied in placebo-controlled clinical trials in patients with RRMS.9
Based on the clinical data available to date, laquinimod is well tolerated in patients with RRMS. The drop-out rate in the Phase II study in the 0.6 mg/day treatment group was only 5%. The favorable safety profile was confirmed in the ALLEGRO trial. In the ALLEGRO study, serious adverse reactions occurred in 16.2% of placebo participants and 22.2% of laquinimod participants.13
The most common AE associated with the laquinimod 0.6 mg/day dosage was a dose dependent elevation of alanine aminotransferase. In the majority of cases elevated liver enzymes occurred within the first month of treatment and normalized without discontinuation of the drug. In only a few cases, an increase of liver enzymes caused termination of laquinimod. In those subjects, withdrawal of therapy was followed by rapid normalization of liver enzymes and no clinical sequelae was noted. In the ALLEGRO study, there were no cases of fatal liver failure, concomitant elevation of bilirubin, or coagulation values.13
Aside from the elevation of liver enzymes, laboratory examination revealed a shift of fibrinogen and C-reactive protein level more frequently in the laquinimod group in comparison to the placebo group.4
Other common AEs in the laquinimod group included abdominal pain, back pain, cough, respiratory tract infections, headache, asthenic conditions, insomnia, nausea and vomiting, dizziness, arthralgia, and diarrhea ().9
Based on current clinical data, there seems to be no evidence for cardiac AEs due to laquinimod.9
So far, three death cases were reported, however, all were assessed by the investigator as unrelated to the study medication. In the ALLEGRO study, there was no increased likelihood of herpes virus infections or cancer.13
Oral agents in RRMS: Overview of safety issues.
As the cytochrome isoenzyme CYP 3A4 was found to be the primary catalyst of laquinimod, a concomitant systemic use of CYP 3A4 inhibitors or inducers should be avoided. However, this point is still under investigation.
So far no reliable data exist concerning potential teratogenic effects in humans. Therefore in female patients of child bearing age, a consequent use of contraceptives is mandatory and regular pregnancy tests are recommended. In parallel, breastfeeding women should not be exposed to laquinimod ().
Place in therapy
Published studies demonstrate beneficial effects of laquinimod (0.6 mg/day) on clinical and neuroimaging surrogate markers in adult patients with RRMS. In parallel, laquinimod shows a favorable risk-benefit profile. In particular, there is no evidence for an increased risk of cardiac AEs. Interestingly, neuroimaging and EAE data suggest neuroprotective effects of laquinimod. However, further studies are required to evaluate the efficacy of laquinimod with respect to established disease modifying therapies.