Patient experience and practice trends in multiple sclerosis – clinical utility of fingolimod

Figures & data

Table 1 S1PR in the immune system

Subtypes	Tissue expression	Function of S1PR
S1P1	CNS (neurons, astrocytes, oligodendrocytes, microglial cells)	CNS: migration of neuronal cells toward areas of damage; regulation of oligodendrocyte survival, function, and modulation of myelination following injury; regulation of microglial number and activation; and maintenance of blood–brain barrier
S1P3	Cardiovascular Immune	Cardiovascular: heart rate control
S1P4	Lymphoid tissue
S1P5	Natural killer cells CNS (oligodendrocytes)

Abbreviations: S1P, sphingosine-1-phosphate; S1PR, S1P receptor; CNS, central nervous system.

Figure 1 Proposed algorithm for patient management upon screening, FDO, and long-term follow-up for fingolimod therapy.

Abbreviations: MRI, magnetic resonance imaging; CBC, complete blood count; VZV, varicella zoster virus; LFT, liver function test; ECG, electrocardiogram; FDO, first-dose observation; PFT, pulmonary function test; diff, diffusion; HR, heart rate.

Table 2 Summary of pivotal trials

Study	Study design	Treatment arms	Primary end point	Main result
TRANSFORMS^Citation4	n=1,292, 12-month, double-blind, parallel-group, active comparator, multicenter	Fingolimod 0.5 mg orally, daily	ARR reduction over 12 months	ARR: 0.16–0.20 (vs 0.33; P<0.001 for each dose vs IFNβ-1a)
		Fingolimod 1.25 mg orally, daily IFNβ-1a 30 μg intramuscularly, weekly		Relapse free: 80%–83% of patients (vs 69%; P<0.0001 for each dose vs IFNβ-1a)
FREEDOMS^Citation3	n=1,272, 24-month, double-blind, parallel-group, placebo-controlled, multicenter	Fingolimod 0.5 mg orally, daily Placebo	ARR reduction over 24 months	ARR: 0.16–0.18 (vs 0.40; P<0.001 for each dose vs placebo) Relapse free: 70%–75% of patients (vs 46%; P<0.001 for each dose vs placebo)

Abbreviations: ARR, annualized relapse rate for confirmed relapses; IFNβ-1a, interferon beta-1a.

Table 3 Summary of other clinical trials

Study	Study design	Treatment armsx	Primary end point	Results
FREEDOMS II^Citation43	Phase II, 6-month, double-blind, parallel-group, placebo-controlled, multicenter	Fingolimod 0.5 mg orally, daily Fingolimod 1.25 mg orally, daily Placebo	Total number of Gd+ lesions on T1-w MRI at month 6	Free from Gd+ lesions: 82%
FIRST^Citation34	Phase IIIb, 4-month, open-label, single-arm, multicenter	Fingolimod 0.5 mg orally, daily ×16 weeks	Evaluate the short-term safety and tolerability profile of fingolimod 0.5 mg with focus on cardiac safety	Cardiac effects following FDO are transient, mostly asymptomatic, and observed in the first 6 hours post-dose Suggest no increased risk of symptomatic or serious cardiac events during treatment initiation in patients with preexisting cardiac conditions or in those receiving beta blockers or calcium-channel blockers
CFTY720^Citation45 DIT03^Citation40	Non-comparative, open-label, multicenter (Italy)	Fingolimod 0.5 mg orally on FDO	Evaluate the safety and tolerability data associated with initial dose of Fingolimod	Safety and tolerability in “real-world” setting was similar to what was seen in pivotal trials
EPOC^Citation46,Citation71	6-month, randomized, active comparator, open-label, multicenter	Fingolimod 0.5 mg orally, daily IFNβ-1a 44 μg subcutaneous, 3 times a week GA 20 mg, subcutaneous, daily	Evaluate the safety and tolerability and patient outcomes who are changing from previous disease-modifying therapy to fingolimod	Safety and tolerability similar to what was seen in pivotal trials

Abbreviations: Gd+, gadolinium-enhanced; T1-w, T1-weighted; MRI, magnetic resonance imaging; FDO, first-dose observation; IFNβ-1a, interferon beta-1a; GA, glatiramer acetate.

Figure 2 Proposed algorithm to start fingolimod for treatment-naïve patients and prior disease-modifying therapy use.

Abbreviations: MS, multiple sclerosis; IFN, interferon; GA, glatiramer acetate; DMF, dimethyl fumarate; PML, progressive multifocal leukoencephalopathy; JCV, John Cunningham virus; MRI, magnetic resonance imaging.

CohenJABarkhofFComiGTRANSFORMS Study GroupOral fingolimod or intramuscular interferon for relapsing multiple sclerosisN Engl J Med2010362402415 Pivotal Trial FREEDOMS20089954

 PubMed Web of Science ®Google Scholar

KapposLRadueEWO’ConnorPA placebo-controlled trial of oral fingolimod in relapsing multiple sclerosisN Engl J Med2010362387401 Pivotal Trial FREEDOMS20089952

 PubMed Web of Science ®Google Scholar

CalabresiPARadueEWGoodinDSafety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomized, placebo-controlled, phase 3 trialLancet Neurol201413654555624685276

 PubMed Web of Science ®Google Scholar

GoldRComiGPalaceJFIRST Study InvestigatorsAssessment of cardiac safety during fingolimod treatment initiation in a real-world relapsing multiple sclerosis population: a phase 3b, open-label studyJ Neurol2014261226727624221641

 PubMed Web of Science ®Google Scholar

RosenstielPVGottschalkRCappielloLZhangYSaidMKapposLLong-term safety of fingolimod: interim evaluation of data from the longterms trialMult Scler Relat Disord20143675225891590

 PubMedGoogle Scholar

LaroniABrogiDMorraVBEAP InvestigatorsSafety of the first dose of fingolimod for multiple sclerosis: results of an open-label clinical trialBMC Neurol2014146524690227

 PubMed Web of Science ®Google Scholar

HughesBCascioneMFreedmanMSFirst-dose effects of fingolimod after switching from injectable therapies in the randomized, open-label, multicenter, evaluate patient outcomes (EPOC) study in relapsing multiple sclerosisMult Scler Relat Disord201435620628

 Web of Science ®Google Scholar

FoxEEdwardsKBurchGOutcomes of switching directly to oral fingolimod from injectable therapies: results of the randomized, open-label, multicenter, evaluate patient outcomes (EPOC) study in relapsing multiple sclerosisMult Scler Relat Disord201435607619

 PubMed Web of Science ®Google Scholar