Fingolimod: A potential first-in-class oral therapy for the treatment of relapsing-remitting multiple sclerosis

Fingolimod is an investigational drug being studied for the treatment of relapsing-remitting multiple sclerosis (RRMS) and may represent a first-in-class sphingosine 1-phosphate receptor modulator as well as the first oral therapy for the treatment of RRMS.

Key Points


Fingolimod is an investigational drug being studied for the treatment of relapsing-remitting multiple sclerosis (RRMS) and may represent a first-in-class sphingosine 1-phosphate receptor modulator as well as the first oral therapy for the treatment of RRMS. In phase 3 trials, fingolimod-treated patients had a significantly lower annualized relapse rate (ARR), a prolonged time to first relapse, were more likely to be relapse-free for the 24-month period, and had fewer new or enlarged lesions compared to placebo. When compared with interferon, patients treated with fingolimod had a lower ARR, prolonged time to disability progression, and fewer new or enlarged lesions at 12 months. The most common adverse events reported in phase 3 trials were fatigue, melanocytic nevus, influenza virus infection, lower respiratory tract or lung infection, fatigue, back pain, diarrhea, cough, and abnormal liver function tests. Fingolimod is unlikely to interact significantly with other drugs due to its metabolism via CYP4F2, although it may require dose adjustment in patients with hepatic impairment. (Formulary. 2010;45:245–251.)

Multiple sclerosis (MS) is an autoimmune, inflammatory and neurodegenerative disease that affects approximately 2.3 million people worldwide.1 Onset of MS is generally in the second to third decade of life and occurs earlier in females than in males by approximately 5 years. MS reduces life expectancy by 5 to 10 years and usually results in death at a median of 30 years from disease onset.2 Although the cause of MS is generally unknown, it is suggested that autoaggressive lymphocytes cross the blood-brain barrier and lead to inflammation and eventual neurodegenerative changes.2

Fingolimod (pronounced fin gole' i mod) is an investigational drug for the treatment of RRMS and belongs to a novel class of agents known as sphingosine 1-phosphate (S1P) receptor modulators. Recently, FDA's Peripheral and Central Nervous System Drugs Advisory Committee recommended approval of fingolimod.5 If FDA approved, fingolimod will represent the first oral therapy for the treatment of RRMS and a first-in-class agent in the S1P modulator class.


Fingolimod (2-amino-2-[2-(4-octyl-phenyl)ethyl]-1,3-propanediol hydrochloride) is a synthetic structural analog of S1P, a natural lysophospholipid.6,7 S1P interacts with 5 known subtypes of S1P receptors (S1P1-5) found throughout the body, which leads to the variety of physiologic processes in which natural S1Ps are involved.8 S1P1-3 are found throughout the immune, cardiovascular, and central nervous systems. Activation of these receptors on smooth muscle and endothelial cells regulates vascular homeostasis and permeability; activation of the S1P1 on atrial myocytes regulates heart rate. S1P4 is generally confined to the hematopoietic and lymphoid tissues, and S1P5 is expressed in the white matter of the central nervous system (CNS).8

Fingolimod is a prodrug that undergoes rapid phosphorylation in vivo by sphingosine kinase into fingolimod-phosphate, the biologically active compound. Fingolimod-phosphate is known to bind to 4 of the 5 S1P receptor subtypes (S1P1,2,4,5).9 However, the binding to S1P1 is of particular importance to fingolimod's proposed mechanism of action in MS. S1P1 is highly expressed on T and B lymphocytes and is responsible for regulating the egress of lymphocytes from lymphoid tissue. Binding of fingolimod-phosphate to S1P1 leads to down-regulation of the receptor and subsequent sequestration of lymphocytes in the lymph tissues, preventing their recirculation and reducing peripheral lymphocyte counts. Fingolimod is not thought to destroy lymphocytes, and therefore many immune functions including activation, proliferation, and effector functions of T and B lymphocytes are undisturbed during treatment.8 However, immune function that relies on naïve T cell and central memory cells, such as that necessary for some viral infections and the common cold, may be reduced or delayed.8 Given the theory that autoaggressive lymphocyte penetration into the CNS contributes to the inflammation and neural damage found in MS, fingolimod's benefit may be due to its ability to sequester lymphocytes in the lymphoid tissues.8 Additionally S1P1 receptors expressed in the CNS have been shown to modulate neurogenesis and neural function.8 Fingolimod has been shown to cross the blood-brain barrier in animal models and accumulate in the white matter of the CNS.10 Therefore, fingolimod may have the ability to facilitate restoration of nerve cell function and supplement endogenous CNS repair in patients with MS.


Single- and multiple-dose pharmacokinetic (PK) studies of fingolimod in healthy patients have been com- pleted.11–13 After multiple doses of fingolimod 1.25 mg/d or 5 mg/d for 7 days, the mean Cmax observed was 5.0±1.0 ng/mL and 18.2±4.1 ng/mL, respectively. The median Tmax was 12 hours (range, 6–16) for both doses.13

The elimination half-life of fingolimod is 8.8 days, and steady state is reached after daily dosing for 2 months.11,14 Fingolimod has a large volume of distribution (>1,000 L) and is highly protein bound (>99.8%).14,15 Fingolimod is extensively and irreversibly metabolized by CYP4F2 to inactive compounds primarily excreted via urine.11,14 Fingolimod's metabolism does not appear to involve CYP1, CYP2, and CYP3; therefore, significant PK drug interactions are unlikely.11 Clearance of oral fingolimod is 10.8 L/h and is not affected by age, gender, weight, or ethnicity.11

Fingolimod has been studied in patients with hepatic impairment.15,16 In patients with mild or moderate hepatic impairment, peak concentrations after a single dose of fingolimod 1 mg were not altered. Oral clearance of fingolimod was decreased by 10% in patients with mild hepatic impairment and 31% in patients with moderate hepatic impairment. The authors suggest that reduced clearance is likely due to reduced metabolite formation rather than impaired renal function given the observed patterns in blood metabolite concentrations, and because creatinine clearance (CrCl) was similar in all subjects.15 In patients with severe hepatic impairment, a single dose of fingolimod 5 mg led to a 2-fold increase in exposure to fingolimod, reduction of clearance by one-half, and increase in half-life by 50%. Therefore, the authors suggest alternate dosing in patients with severe hepatic impairment (Child-Pugh class C) of a standard first dose followed by half of the usual maintenance dose.16 In patients with severe renal impairment (CrCl<30 mL/min), exposure to fingolimod and inactive metabolites was increased compared with healthy subjects.17 In Asian patients, PK differences were not observed when compared with white patients in a single-dose study.14 When given multiple doses of fingolimod (5 mg/d for 7 days), the exposure to fingolimod and fingolimod-phosphate was similar in Asian and white patients; however, renal excretion of the 2 main metabolites of fingolimod were 2-fold lower in the Asian subjects. The significance of this finding is unclear, according to the authors.14

Lymphocyte responses to fingolimod have been characterized from a multiple-dose study.13 A decrease in the mean lymphocyte count of 58% from baseline in the 1.25-mg/d group and 76% from baseline in the 5-mg/d group began as early as the first sampling time (day after administration of the first dose). All treated patients reached an absolute lymphocyte count nadir at 3 to 7 days, which corresponded to an 80% and 88% decrease from baseline, in the low- and high-dose groups, respectively. A gradual dose-related increase in the lymphocyte count was observed in both groups during the month-long washout phase.

With the similarity of fingolimod's structure to naturally occurring S1P, which shares an absorption pathway with dietary fats, the effect of dietary fat on fingolimod's absorption has been studied.12 Fourteen healthy male subjects were administered a single 1-mg dose of fingolimod following either a 10-hour fast before and 4-hour fast after the dose, or 5 minutes after consuming a high-fat breakfast. The mean concentration time profiles were not significantly different between the fed and fasting states. The lymphocyte responses to fingolimod administration in the fed and fasting states were similar in terms of nadir lymphocyte count, time to nadir, and lymphocyte count recovery at day 8. The heart rate response was also observed, due to the known influence of S1P on heart rate regulation and was similar between fed and fasting states. The PK parameters observed in this study met criteria for bioequivalence between fed and fasting states, and the authors concluded that a high-fat meal has no effect on the absorption of fingolimod.12


The primary efficacy outcome was the total number of Gd+ lesions per patient on T1-weighted MRI at 6 months. Secondary end points included annualized relapse rate (ARR) as well as additional clinical and MRI outcomes. Both dosages of fingolimod were superior to placebo (P<.05) in the primary outcome as well as most other pre-specified MRI outcomes. The mean number of Gd+ lesions at 6 months was significantly lower in both fingolimod groups compared with placebo. Although the authors report the study was underpowered to show a significant difference in clinical outcomes, there was a relative reduction in ARR of 53% in the fingolimod 5-mg group and 55% in the fingolimod 1.25-mg group.

Two-hundred fifty patients continued a 6-month extension phase of the core study for a total of 12 months of follow-up.18 Patients who were previously randomly assigned to receive fingolimod 5 mg or 1.25 mg continued the same treatment. Patients originally randomly assigned to placebo were randomly assigned again to either fingolimod dose. While the number of Gd+ lesions remained low in patients who received continuous fingolimod treatment, there was a significant decrease in the number of Gd+ lesions at 12 months in patients who switched from placebo to either fingolimod groups. ARR for patients continuing fingolimod therapy for 12 months remained low, and the rate decreased in patients who switched from placebo to either fingolimod groups.

Two-year results of the extension study suggest continued benefit of fingolimod. However, due to concerns over the safety of fingolimod 5 mg without observed difference in efficacy compared with 1.25 mg, all patients randomly assigned to fingolimod 5 mg were switched to 1.25 mg during months 15 to 24.19

Results were reported separately for fingolimod 5 mg and 1.25 mg. Patients continuously treated with fingolimod 5 mg or 1.25 mg continued to show low levels of disease activity as there was no significant difference between the number of Gd+ lesions at months 6, 12, or 24. ARR was measured in a modified patient population of those who received at least 1 dose of fingolimod during the core or extension phase (n=271). Although not powered to determine clinical differences, the ARR remained low throughout months 7 to 24 for all treatment arms. The trends noticed in the 2-year follow-up were supported by 3- and 4-year results of the extension study (Table 2).18–21 At 4 years, data from 155 of the original 281 patients (55.2%) of the core study were available for descriptive analyses. The ARR in patients receiving fingolimod 5 mg or fingolimod 1.25 mg remained low.

Phase 3 trials. Two phase 3 studies have recently been completed evaluating fingolimod in patients with RRMS. In the FREEDOMS study, fingolimod was compared with placebo, and in the TRANSFORMS study, fingolimod was compared with interferon beta-1a. 22,23


FREEDOMS was a randomized, double-blind, placebo-controlled trial. Patients enrolled were aged 18 to 55 years and diagnosed with MS by the revised McDonald criteria, which was of a relapsing-remitting course, scored 0 to 5.5 on the EDSS, and had either 1 or more documented relapses in the previous year or 2 or more relapses in the previous 2 years. Patients were excluded if their disease had a relapse or if they used a corticosteroid within the previous 30 days, active infection, macular edema, immunosuppression, diabetes mellitus, or clinically significant coexisting systemic disease. Patients taking either interferon beta or glatiramer had to have stopped therapy at least 3 months prior to enrollment.

A total of 1,272 patients were randomly assigned to fingolimod 0.5 mg (n=425), fingolimod 1.25 mg (n=429), or placebo (n=418) daily for 24 months. The primary outcome was the ARR, defined as the number of confirmed relapses per year. The key secondary end point was the time to confirmed disability progression, defined as an increase of 1 point in the EDSS score (or a half point if baseline EDSS was equal to 5.5), confirmed after 3 months, with absence of relapse at the time of assessment and with all EDSS scores measured during that time meeting criteria for disability progression. Inflammatory activity, scar formation, tissue damage, or tissue loss were measured through MRI-related outcomes. All efficacy outcomes were analyzed using an intent-to-treat population (all randomly assigned patients).

A total of 1,033 patients (81.2%) completed the 24-month study. Discontinuation of study drug was most common in the fingolimod 1.25-mg group (30.5%) followed by placebo (27.5%) and fingolimod 0.5 mg (18.8%). The most common reason for discontinuation within the fingolimod groups was an abnormal laboratory value; while within the placebo group it was an unsatisfactory therapeutic effect.

The ARR was significantly lower in both fingolimod groups compared with placebo, with no differences observed between fingolimod groups (Table 3). Results remained significant when patients previously treated with disease-modifying agents were compared with patients who did not receive previous treatment. Patients randomly assigned to either fingolimod group also had a longer time to first relapse, reduced risk of relapse, and were more likely to experience a relapse-free 24-month period compared with placebo. The time to disability progression was significantly longer in both fingolimod groups compared with placebo. Patients randomly assigned to fingolimod 1.25 mg were 32% less likely to experience disease progression (HR, 0.68; 95% CI, 0.50–0.93; P=.02) and those randomly assigned to fingolimod 0.5 mg were 30% less likely to experience disease progression (HR, 0.70; 95% CI, 0.52–0.96; P=.02) during the 24-month period compared with placebo. Patients in either fingolimod group had fewer Gd+ lesions, fewer new or enlarged lesions, and a higher proportion of patients free of Gd+ lesions and new or enlarged lesions at 24 months compared with placebo.


Fingolimod has been compared with interferon beta-1a in the multicenter, randomized, double-blind, double-dummy, parallel group study TRANSFORMS. Inclusion and exclusion criteria were the same as reported for FREEDOMS, however, diabetes mellitus was not specified as an exclusion criterion, and previous recent therapy with interferon beta or glatiramer was allowed. Between May 2006 and September 2007, 1,292 patients were randomly assigned to receive either fingolimod 1.25 mg by mouth daily (n=426), fingolimod 0.5 mg by mouth daily (n=431), or interferon beta-1a 30 µg intramuscular injection weekly for 12 months. The primary outcome was ARR defined as confirmed relapses during the 12-month period; 2 key secondary outcomes included the number of new or enlarged T2-weighted lesions on MRI scan at 12 months and the time to confirmed disability progression. Efficacy outcomes were analyzed using a modified intent-to-treat population (all patients who received at least 1 dose of study drug).

A total of 1,153 patients (89%) completed the study. The most common reason for drug discontinuation in the fingolimod groups was occurrence of an adverse event, and in the interferon beta-1a group it was withdrawal of consent. The primary outcome of ARR was significantly lower in the fingolimod treatment groups compared to interferon beta-1a (Table 3). Additionally, the proportion of patients who had no relapse during the 12-month period was higher in both fingolimod groups compared to interferon beta-1a. A post-hoc analysis of the ARR comparing patients who had previously received disease-modifying therapy to patients who had no previous disease-modifying therapy was not significantly different from the original results.

The secondary outcome measuring the number of new or enlarged T2-weighted lesions also favored both fingolimod treatment groups over interferon beta-1a therapy (Table 3). However, the time to disability progression and the proportion of patients with confirmed progression did not differ significantly among the 3 treatment groups.


A total of 1,703 patients comprised the safety population in the FREEDOMS and TRANSFORMS trials.22,23 The most common adverse events occurring in 10% to 20% of fingolimod-treated patients were fatigue, melanocytic nevus, influenza virus infection, lower respiratory tract or lung infection, fatigue, back pain, diarrhea, cough, and abnormal liver function tests. Those occurring in greater than 20% of fingolimod-treated patients were nasopharyngitis and headache. Serious adverse events occurred in 7% to 11.9% of fingolimod-treated patients and included 3 deaths. The causes of death were listed as disseminated primary varicella zoster infection, herpes simplex encephalitis, and suicide. Serious adverse events occurring in >1% of fingolimod-treated patients included bradycardia or sinus bradycardia, MS relapse, and basal cell carcinoma.22,23

Infection may be of concern due to fingolimod's effect on lymphocyte recirculation, and particular attention to herpesvirus has been raised.22 Although incidence of herpesvirus was similar between fingolimod- and interferon-treated patients in TRANSFORMS (3.8% vs 2.8%), the 2 deaths during this study were due to herpesvirus infections.22 In TRANSFORMS, the incidence of upper respiratory tract infections was higher in patients treated with fingolimod, and in both phase 3 trials respiratory tract infections were amongst the most frequently reported adverse events.22,23

The cardiovascular adverse events observed in these trials are consistent with the known presence of S1P receptors in myocytes. Decrease in heart rate appears to be transient and dose related in response to the first dose of fingolimod. In FREEDOMS, maximal reduction in heart rate of 8 beats per minute in the 0.5-mg group and 10 beats per minute in the 1.25-mg group occurred 4 to 5 hours after the first dose and began restoring at 6 hours. Most cases of bradycardia were asymptomatic, and those with symptoms resolved within 24 hours. Authors suggest that the long-term implications are unclear.23

Other clinical adverse events observed during these trials are notable. Macular edema was reported in a small percentage of patients receiving fingolimod under investigation for renal transplant, which prompted investigators to incorporate ophthalmologic examinations during investigation for MS.19 Macular edema was diagnosed in 7 patients, all of whom were taking fingolimod, during the FREEDOMS trial.23 Six cases resolved within 6 months upon drug discontinuation. Skin cancer was reported in phase 2 testing and led to initiation of dermatologic monitoring during phase 3 trials.18,19 In the FREEDOMS AND TRANSFORMS trials, 15 fingolimod-treated patients were found to have skin cancer, all successfully excised.22,23 Laboratory abnormalities included a decrease in lymphocyte count, mild decrease in mean forced expiratory volume in 1 second, and a reversible increase of alanine transferase to greater than 3 times the upper limit of normal.22,23


Fingolimod is metabolized by CYP4F2, which is not commonly implicated in drug metabolism.25 Positive results of a drug interaction in vitro between fingolimod and ketoconazole during drug development suggested ketoconazole may inhibit CYP4F2.26 In a single-dose study of fingolimod 5 mg with steady-state ketoconazole in healthy subjects, the authors suggested that exposure of fingolimod was only weakly increased and therefore pre-emptive dose adjustments are not necessary. However, clinicians should be aware of the potential for this interaction.26

Given fingolimod's transient effect on decreasing heart rate, the combinations of fingolimod and atenolol and fingolimod and diltiazem have been evaluated.27 A single dose of fingolimod 5 mg added to atenolol 50 mg daily on day 5 resulted in additional lowering of heart rate by approximately 15%. Addition of a single-dose of fingolimod to diltiazem 240 mg daily on day 5 did not further lower the heart rate. Authors suggest that addition of fingolimod to a calcium-channel blocker is unlikely to further reduce heart rate more than what is observed with fingolimod alone, whereas addition to a beta-blocker may result in a moderately lower mean heart rate nadir.27


Although not yet FDA approved, fingolimod has the advantage over current FDA-approved therapies used to treat RRMS of being an oral formulation. Fingolimod has been studied in phase 2 and 3 trials with doses ranging from 0.5 to 5 mg by mouth once daily. However, safety concerns over the 5-mg dose were raised during the extension of a phase 2 trial.18 Subsequent phase 3 trials have used doses of 0.5 mg to 1.25 mg once daily as well as the ongoing TRANSFORM II trial, designed using fingolimod 0.5 mg once daily.22,21 At this time, Novartis has sought FDA approval for the 0.5-mg dose.28

Fingolimod can be administered without regard to the fat content or timing of meals.12 Reducing the maintenance dosage by half after the initial recommended dose has been suggested in patients with severe hepatic impairment (Child-Pugh class C).15,16


Fingolimod may represent the first-in-class of a novel class of drug for the treatment of RRMS. Together with the low potential for drug interactions and once-daily administration without regard to meals, fingolimod may be favorable to patients.

In a larger phase 3 trial, fingolimod was shown to be superior to placebo in reducing the risk of relapse, reducing the number of new or enlarged lesions, and prolonging the time to first relapse or disability progression. When studied in a head-to-head trial compared with interferon beta, a standard treatment for MS, fingolimod was superior in reducing relapse rates and prolonging the time to first relapse. Treated patients also had fewer new or enlarged lesions. Overall incidence of adverse events was similar when fingolimod was compared with interferon treatment although serious adverse events such as infection, bradycardia, and malignant neoplasms occurred more frequently in fingolimod-treated patients. On the other hand, interferon is associated with flu-like symptoms upon injection, the formation of neutralizing antibody production, which may have implications for long-term efficacy, and increases in liver-function tests. Overall, fingolimod appears to be a promising front-line agent for the treatment of RRMS.

Dr Sobieraj is senior research scientist at the University of Connecticut School of Pharmacy, Storrs.

Disclosure Information: The author reports no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, medical editor, University of Connecticut/Hartford Hospital, Evidence-Based Practice Center, Hartford, Conn., and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, associate professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.


1. Neurological disorders: a public health approach. World Health Organization. Available at: Accessed July 22, 2010.

2. ompston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502–1517.

3. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46:907–911.

4. Goodin DS, Frohman EM, Garmany GP Jr., et al. Disease modifying therapies in multiple sclerosis: Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58:169–178.

5. FDA Advisory committee endorses fingolimod for relapsing-remitting multiple sclerosis. Medscape Medical News. Available at: Accessed July 22, 2010.

6. Adachi K, Kohara T, Nakao N, et al. Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1,3-propanediols: discovery of a novel immunosuppressant, FTY720. Bioorg Med Chem Lett. 1995;5:853–856.

7. Brinkmann V, Cyster JG, Hla T. FTY720: Sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant. 2004;4:1019–1025.

8. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharm. 2010;33:91–101.

9. Billich A, Bornancin F, Dévay P, Mechtcheriakova D, Urtz N, Baumruker T. Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J Biol Chem. 2003;278:47408–47415.

10. Foster CA, Howard LM, Schweitzer A, et al. Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. J Pharmacol Exp Ther. 2007;323:469–476.

11. Kovarik JM, Schmouder RL, Slade AJ. Overview of FTY720 clinical pharmacokinetics and pharmacology. Ther Drug Monit. 2004;26:585–587.

12. Kovarik JM, Schmouder R, Barilla D, Wang Y, Kraus G. Single-dose FTY720 pharmacokinetics, food effect, and pharmacological response in healthy subjects. Br J Clin Pharmacol. 2004;57:586–591.

13. Kovarik JM, Schmouder R, Barilla D, Riviere GJ, Wang Y, Hunt T. Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. J Clin Pharmacol. 2004;44:532–537.

14. Kovarik JM, Slade A, Voss B, et al. Ethnic sensitivity study of fingolimod in white and Asian subjects. Int J Clin Pharmacol Ther. 2007;45:98–109.

15. Kovarik JM, Schmouder RL, Serra D, et al. FTY720 pharmacokinetics in mild to moderate hepatic impairment. J Clin Pharmacol. 2005;45:446–452.

16. Kovarik JM, Schmouder RL, Hartmann S, et al. Fingolimod (FTY720) in severe hepatic impairment: pharmacokinetics and relationship to markers of liver function. J Clin Pharmacol. 2006;46:149–156.

17. FDA. Draft Clinical Pharmacology/Biopharmaceutics Review of Fingolimod. Available at: Accessed July 22, 2010.

18. Kappos L, Antel J, Comi G, et al, for the FTY720 D2201 Study Group. Oral fingolimod (FTY720) for relapsing multiple sclerosis.
N Engl J Med. 2006;355:1124–1140.

19. O'Connor P, Comi G, Montalban X, et al, for the FTY720 D2201 Study Group. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology. 2009;72:73–79.

20. Comi G, O'Connor P, Montalban X, et al, for the FTY720 D2201 Study Group. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results. Mult Scler. 2010;16:197–207.

21. Kappos L, Radue EW, O'Connor PW, et al; on behalf of the FTY720 D2201 Study Group. Majority of patients with relapsing multiple sclerosis receiving oral fingolimod (FTY720, a sphingosine-1-phosphate receptor modulator) remain free from any inflammatory activity: results of a 4-yr, phase II extension. J Neurol. 2009;256:S9.

22. Cohen JA, Barkhof F, Comi G, et al; for the TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–415.

23. Kappos L, Radue EW, O'Connor P, et al; for the FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.

24. Miller DH, Grossman RI, Reingold SC, McFarland HF. The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain. 1998;121:3–24.

25. Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet. 2002;360:1155–1162.

26. Kovarik JM, Dole K, Riviere GJ, et al. Ketoconazole increases fingolimod blood levels in a drug interaction via CYP4F2. J Clin Pharmacol. 2009;49:212–218.

27. Kovarik JM, Lu M, Riviere GJ, et al. The effect on heart rate of combining single-dose fingolimod with steady-state atenolol or diltiazem in healthy subjects. Eur J Clin Pharmacol. 2008;64:457–463.

28. FDA Panel gives green light to oral MS drug. Medpage Today. Available at: Accessed July 22, 2010.