Table 1.
Summary of oral therapies in late-stage development (phase III) for the treatment of multiple sclerosis
| Compound | Company | Structure | Side effects | Stage of development | Mechanism of action | Comments |
|---|---|---|---|---|---|---|
| Fumaric acid (BG-12) | Biogen Idec | HO2CCH = CHC02H (E)-butenedioic acid | Skin flushing, pruritis, gastrointestinal disturbance, myalgia, dizziness, headache | Phase III trial completed | Switching T-helper (Th)l cells into an interleukin-4-dominated Th2 phenotype; induction of the expression of phase II detoxifying enzymes; impairing cell traffic | Available as white solid tablets; long experience with psoriasis Three times a day, every day |
| Teriflunomide (HMR I726) | Sanofi-Aventis | C12H9F3N202(2Z)-2-cyano-3-hydroxy-N-(4-[trifluoromethyl]phenyl) but-2-enamide | Nasopharyngitis, alopecia, nausea, alanine aminotransferase increase, paresthesia, back and limb pain, diarrhea, and arthralgia | Phase III trial completed | Blocks de novo pyrimidine synthesis by inhibiting dihydroorotate dehydrogenase | Teriflunomide is the active metabolite of leflunomide, a well-known drug approved for the treatment of rheumatoid arthritis Once daily, every day |
| Cladribrine | Merck Serono | C10H12CIN5O3 5-(6-amino-2-chloro-purin-9-yl)-2-(hydroxymethyl) oxolan-3-ol | Dose-dependent myelosuppression, opportunistic infections | Phase III trial ongoing in MS. Approved in Russia and Australia* | Cladribine is a chlorinated purine analogue, resistant to the action of adenosine deaminase. In cells, cladribine is phosphorylate to the active triphosphate form, which impairs the deoxyribonucleic acid synthesis and the cellular metabolism | Cladribine twice received a negative European recommendation from the CHMP. Following feedback from regulatory authorities, the company decided no longer to pursue the global process for approvalOnce daily for 2–4 weeks per year |
| Fingolimod (FTY720) | Novartis | C19H33NO2 2-amino-2-(2-[4-octylphenyl]ethyl) propane-1,3-diol | Transient reduction in the heart rate within hours after the first dose, increased mean arterial blood pressure, and airway obstruction | Phase IlIa trial completed Approved in US and Russia | Agonist at the G protein-coupled sphingosine 1-phosphate receptor-1 (S1P1) on lymphocytes: downmodulating the receptor, the cells become unresponsive to S1P, required to egress from the limphonodes into blood | EMA adopted a positive opinion, recommending the granting of a marketing authorization for fingolimod, intended for the treatment of adult RRMS with high disease activityOnce daily, every day |
| Laquinimod (ABR-215062) | Teva pharmaceutical industries | C19H17CIN2O35-Chloro-N-ethyl-4-hydroxy-1 -methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide | Potential hepatotoxicity; possible proinflammatory effect. Reported pleuritis, Budd-Chiari syndrome, pituitary adenoma with hemorrhage and possible Crohn’s disease. Pharyngolaryngeal pain, dyspepsia | Phase III trial completed | Modulates of the balance of the T-helper cells 1 and 2 induction of transforming growth factor-β inhibit infiltration of CD4+ T cells and macrophages into the central nervous system | Potent therapeutic efficacy both in MS-like acute and chronic experimental autoimmune encephalomyelitis models Once daily, every day |
Note: *Merck Serono intends to withdraw the product from the market.
Abbreviations: RRMS, relapsing-remitting multiple sclerosis; CHMP, Committee for Medicinal Products for Human Use; EMA, European Medicines Agency.