Review: Clinical Trial Outcomes Clinical and experimental data on the use of laquinimod for the treatment of multiple sclerosis Clin. Invest. (2012) 2(8), 819–824 Laquinimod is a synthetic quinoline 3-carboxamide derivative with immuno- De-Hyung Lee* & Ralf A Linker modulatory properties. Treatment with laquinimod ameliorated disease Department of Neurology, University of activity in experimental autoimmune encephalomyelitis, a mouse model Erlangen, Schwabachanlage 6, 91054 Erlangen, for multiple sclerosis. In the past, an immunosuppressive mechanism of Germany action was initially assumed. With increasing knowledge on its effects, *Author for correspondence: Tel.: +49 9131 85 44534 the immunomodulatory and possibly also neuroprotective properties of Fax: +49 9131 85 33100 laquinimod came into the focus. Data from a Phase IIb trial in relapsing– E-mail: [email protected] remitting multiple sclerosis suggests this compound has clinical efficacy on MRI parameters of inflammation. In the recently published Phase III ALLEGRO trial, laquinimod 0.6 mg/day showed a reduction of relapse rates and even more pronounced effects on disability progression compared with placebo. Data from the additional Phase III BRAVO trial are awaited with great interest. In all published studies, laquinimod was well tolerated and no severe side effects were reported. In summary, laquinimod has the potential to add to our therapeutic armamentarium as a new oral immunomodulator in multiple sclerosis. Keywords: experimental autoimmune encephalomyelitis • immunomodulation • laquinimod • multiple sclerosis • oral • roquinimex Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and is the most common cause of neurological disability in young adults. It is widely assumed that MS is an autoimmune disease where inflammatory infiltration leads to de myelination and axonal damage in the CNS [1]. A better understanding of the immuno pathological processes of the disease led to new therapeutic approaches. Although new treatment options have entered the therapeutic stage in recent years, existing therapies are only partially effective and early treatment is still crucial to limit progression of disability. Approved immunomodulatory or immunosup- pressive drugs for relapsing–remitting MS need parenteral application and include IFN b-1a (which is administered either subcutaneously [sc.] or intramuscularly [im.]), IFN b-1a and glatiramer acetate for baseline therapy (sc.), as well as mitox- antrone and natalizumab for escalation therapy (intravenous application). For over a decade, these injectable disease-modifying drugs have dominated the treat- ment of MS. Here, patient compliance is a major concern for physicians treating MS. With licensing of fingolimod – an orally available immunodulator – for the treatment of MS, a new era of therapy has been initiated. At present, more than 100 therapeutic studies in MS are ongoing and a large proportion of these include formulations that are enterally incorporated. Indeed, up to 22% of the general population suffer from a needle phobia, which may prevent self-injections as treat- ment for MS. In relapsing–remitting MS patients, rates of treatment interruption range between 6 to 13% within the first 6 months[2–5] . A long-term follow-up study over 4 years reported that up to 46% of parenteral immunomodulatory therapies 10.4155/CLI.12.66 © 2012 Future Science Ltd ISSN 2041-6792 819 Review: Clinical Trial Outcomes Lee & Linker were at least temporarily discontinued [6]. While oral minimum serum level (Cmin) and Cmax once steady compounds are not generally characterized by better state is reached. Laquinimod is metabolized by adherence rates compared with sc. and im. therapy, CYP3A4 in liver microsomes. After metabolization, many patients with a fear or weariness of injections four hydroxylated and two alkylated products are would prefer the use of oral drugs and thus in recent metabolically inactive and exuded primarily through years drug companies have increased their effort to the urine. Less than 5% of laquinimod is eliminated design new orally available compounds. unchanged in urine and faces. Strong specific inhib- With increasing knowledge on the cellular and itors of CYP3A4 enzymes such as ketoconazole and molecular pathomechanisms of MS, the focus in nutritives, such as grapefruit juice, can interfere with the development of new therapeutic compounds has the elimination of laquinimod [16]. However, laquini- shifted from unselective immunosuppression towards mod is only a low-affinity substrate of CYP3A4, which more selective, target-specific treatments[7] . There is reduces the risk of competitive inhibition of other sub- still an unmet need for new high-efficacy drugs with strates. Consequently, other CYP enzyme inhibitors good safety and tolerability profiles. Meanwhile, a including steroids and erythromycin only showed new generation of MS therapies is emerging, many inhibitory effects in vitro. In vivo, erythromycin and of which are in or have just finished Phase III trials, steroids do not reach relevant plasma concentrations including laquinimod. to induce CYP3A4 for the drug–drug interaction [15]. With the current dosing protocol of laquinimod, the Pharmacologic & pharmacokinetic properties of serum plasma level, which is necessary to competi- the compound tively inhibit another common substrate, etinyl estra- Laquinimod (internal compound abbreviation ABR- diol (an important compound in contraceptives), is 215062, correct IUPAC name: 5-chloro-N-ethyl-1,2- 30-times above the expected Cmax. dihydro-4-hydroxy-1-methyl-2-oxo-N-phenyl-3- quinolinecarboxamide) has a molecular weight of Studies on laquinimod in experimental MS 357 Da. It is a synthetic compound that was synthe- models sized at Active Biotech Research AB and licensed to Experimental autoimmune encephalomyelitis (EAE) TEVA Pharmaceutical Industries Ltd in 2004 as an is a rodent model that reflects many aspects of MS[17] . immuno modulatory agent for studies in the treatment This autoimmune disease can be elicited in suscepti- of relapsing–remitting MS [8]. Efficacy had already been ble mouse or rat strains by active immunization with demonstrated in many animal models of autoimmune myelin antigen or the adoptive transfer of encepha- diseases, including Guillain–Barré–Strohl syndrome, litogenic T cells and shares many histopathological rheumatoid arthritis, systemic lupus erythematosus, and clinical features with MS [18]. Primary studies in autoimmune colitis and MS [9–13]. Thus, laquinimod EAE were carried out with roquinimex (Linomide®), seems to affect crucial common inflammatory path- the historical precursor compound of laquinimod. ways in autoimmunity. The efficacy of laquinimod is Roquinimex displayed its efficacy in a series of ani- believed to be at least partially based on a shift of the mal models for different autoimmune diseases, includ- T-helper (Th) cell balance from a ‘Th1’ reaction, with ing experimental autoimmune neuritis (EAN) [19–23]. secretion of pro inflammatory cytokines (e.g., IL-2, Roquinimex treatment also resulted in an amelio- IL-6, TNF-a or IFN-g), towards a ‘Th2’ response, with rated disease course in both acute and chronic EAE an increase in regulatory cytokines (e.g., IL-4 and models in SJL mice as well as in outbred rats [24,25]. IL-10) [14]. So far, the definite mechanism of laquini- Roquinimex induced the expression of Th2 cytokines, mod contributing to these immunomodulatory effects which may play a role in modulation of T-cell autoim- is only partially elucidated. munity [13]. Moreover, roquinimex had been evaluated First studies on the pharmacokinetic characteris- in several clinical trials with relapsing–remitting and tics of laquinimod were performed in preclinical trials secondary progressive MS patients and demonstrated in rats, mice, rabbits and dogs [15]. Laquinimod is char- disease modifying effects with a reduction of MRI acterized by a high oral bioavailability, small volume activity as a primary measure of disease activity in a of distribution and low total clearance rate, and thus clinical Phase II trial [26]. However, this trial had to reaches its highest plasma concentration within 1 h be stopped due to severe side effects, including pleu- after oral administration. Laquinimod is present in ritis and adverse cardiac events, such as pericarditis the CNS at 10–13% relative to blood levels. In humans, and myocardial infarction, which even lead to some the maximum serum level (Cmax) of laquinimod is fatalities [26,27]. below 5 µM after administration of 0.05–2.4 mg of As a consequence, laquinimod was developed as the drug. Little fluctuation is observed between the a derivative of roquinimex without these severe side 820 www.future-science.com future science group Data on the use of laquinimod for the treatment of multiple sclerosis Review: Clinical Trial Outcomes effects. While laquinimod is structurally related to 2.4 mg/day, an elevation of inflammatory markers its precursor compound, it is pharmacologically and was observed in some individuals. The first proof-of- structurally distinct. Laquinimod has been shown concept study in MS patients was performed in more to inhibit acute EAE in the Lewis rat via a reduction than 20 centers in the Netherlands, Russia, Sweden of inflammatory infiltration [28]. It is also effective in and the UK. This multicenter, double-blinded, pla- murine EAE in a preventive, as well as therapeutic, cebo-controlled, parallel-group Phase II trial investi-