Adv Ther DOI 10.1007/s12325-014-0154-4

ORIGINAL RESEARCH

Efficacy and Safety of Fingolimod in Hispanic Patients with Multiple Sclerosis: Pooled Clinical Trial Analyses Angel R. Chinea Martinez • Jorge Correale • Patricia K. Coyle

•

Xiangyi Meng • Nadia Tenenbaum

To view enhanced content go to www.advancesintherapy.com Received: August 20, 2014 Ó Springer Healthcare 2014

ABSTRACT

of relapsing MS, has been shown to significantly

Introduction: The disease characteristics of

reduce annualized relapse rates (ARRs), lesionbased magnetic resonance imaging (MRI)

multiple

activity,

sclerosis

(MS)

appear

to

differ

confirmed

disability,

and

brain

between Hispanic and Caucasian patients, with Hispanic patients having a younger age

volume loss, compared with placebo or intramuscular interferon beta-1a (IFNb-1a IM)

at onset, and a higher prevalence of optic nerve and spinal cord involvement. Fingolimod, the

in randomized, double-blind, controlled clinical studies. Here, the efficacy and safety

first-in-class

1-phosphate

profile of fingolimod in Hispanic patients was

receptor modulator approved for the treatment

compared to that observed in the overall study populations.

oral

sphingosine

Trial registration: ClinicalTrials.gov # NCT00289978 (FREEDOMS), NCT00355134 (FREEDOMS II), NCT00340834 (TRANSFORMS).

Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0154-4) contains supplementary material, which is available to authorized users. A. R. Chinea Martinez (&) San Juan MS Center, Guaynabo, PR, USA e-mail: [email protected] J. Correale Department of Neurology, Institute for Neurological Research Rau´l Carrea, FLENI, Buenos Aires, Argentina P. K. Coyle Department of Neurology, Stony Brook University Medical Center, New York, NY, USA X. Meng
N. Tenenbaum Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Methods: This was a post hoc analysis of relapses and safety data for Hispanic patients with

relapsing–remitting

MS

(RRMS)

randomized to receive daily fingolimod 0.5 mg, weekly IFNb-1a IM (30 mg) or placebo, in the phase 3, controlled FREEDOMS, FREEDOMS II, and TRANSFORMS fingolimod studies. The ARR was estimated for each treatment group; only relapses that were confirmed by an independent examining neurologist were included in these analyses. Safety assessments included the incidence of adverse events and serious adverse events. Results: Eligible Hispanic patients aged 18–55 years (n = 181) had been treated as follows: fingolimod 0.5 mg (n = 89), IFNb-1a

Adv Ther

IM (n = 65), and placebo (n = 27). Hispanic

Ultimately, however, most patients advance to

patients treated with fingolimod for up to 2 years had lower ARRs (ARR: 0.22, 95%

a progressive disease state that is associated with

confidence interval [CI]: 0.14–0.35) than those receiving placebo (ARR: 0.46, 95% CI: 0.24–0.88) or IFNb-1a IM (ARR: 0.34, 95% CI: 0.18–0.63), with relative reductions of 52% and 35%, respectively. A transient decrease in heart rate that started to attenuate 6 h after fingolimod administration was observed, consistent with the well-characterized

pharmacologic

effect

following fingolimod treatment initiation. No cases of symptomatic bradycardia were reported in Hispanic patients. The incidence of firstdegree atrioventricular block was low and similar across all treatment groups (3.1–4.5%). The safety profile of fingolimod in Hispanic patients was consistent with that reported in the overall population of each study. Conclusion: Overall, this study demonstrates that fingolimod is efficacious and well tolerated in Hispanic patients with RRMS. Keywords: Fingolimod; FREEDOMS; FREEDOMS II; Hispanic; Multiple sclerosis; Neurology;

Relapsing-remitting

multiple

sclerosis; TRANSFORMS

more severe neurologic effects and irreversible disability [4]. During the past decade, more information on the prevalence and disease course of MS in Hispanic patients has become available, and observations in several countries point to an increase in the frequency of MS in these individuals [5]. The disease course of MS appears to differ between Hispanic and Caucasian populations, with Hispanic patients having a younger age at onset and higher prevalence of optic nerve and spinal cord involvement than Caucasian patients [6, 7]. Fingolimod (FTY720; GilenyaÒ, Novartis Pharma AG, Basel, Switzerland) is a first-inclass sphingosine 1-phosphate receptor modulator approved as a once-daily oral therapy at a dose of 0.5 mg for relapsing forms of MS [8]. The efficacy of fingolimod has been demonstrated in three large, randomized, controlled, clinical trials of patients with RRMS [9–11]. In the TRial Assessing injectable interferoN versuS FTY720 Oral in RRMS (TRANSFORMS), at the approved dose of 0.5 mg daily, fingolimod significantly reduced annualized relapse rate (ARR) by 52% relative to intramuscular interferon beta-1a (IFNb-1a IM)

INTRODUCTION

over 1 year (ARR: 0.16 versus 0.33, respectively; p\0.001) [10]. Treatment with the same dose of

Multiple sclerosis (MS) is the most common immune-mediated inflammatory disease of the

fingolimod over 2 years in the FTY720 Research Evaluating Effects of Daily Oral therapy

central nervous system [1]. It typically manifests in adults aged 20–40 years and affects at least

in

Multiple

Sclerosis

(FREEDOMS)

and

2.3 million people worldwide [2]. The clinical

FREEDOMS II studies reduced ARR by 54% (ARR: 0.18 versus 0.40, p\0.001) and 48%

presentation of MS is highly variable among patients and includes: optic neuritis, limb

(ARR: 0.21 versus 0.40, p\0.001), respectively, compared with placebo [9, 11].

weakness, fatigue, incoordination, numbness, and paresthesias [3]. The majority of patients

Analysis of a clinical trial in Hispanic

have the relapsing–remitting form (RRMS), in

patients with RRMS demonstrated that fingolimod was well tolerated during the first

which symptoms occur and then resolve.

month of treatment in this patient group [12].

Adv Ther

In the present study, we aimed to evaluate the

are based on previously conducted studies and

efficacy and safety of fingolimod in Hispanic

do not involve new patients.

patients with RRMS using a large, integrated dataset pooled from phase 3 clinical trials of

Eligible individuals were aged 18–55 years and had been diagnosed with RRMS in

fingolimod.

accordance with the revised McDonald criteria [13]. In addition, patients had to have

METHODS

experienced either at least one confirmed relapse in the previous year or at least two confirmed relapses in the previous 2 years, and

Study Designs and Participants The pooled dataset included all randomized patients from three phase 3, randomized,

needed to have had an Expanded Disability Status Scale (EDSS) [14] score of 0–5.5. During study recruitment, ethnicity was

clinical trials, with a specific focus on the Hispanic cohort receiving the approved

recorded by the study investigator, based on the patient’s self-reported ethnic ancestral

fingolimod 0.5 mg dose. Patients (n = 1,225)

origin. Patients were classified as Hispanic when they were recorded in the ‘Hispanic/

randomized to the fingolimod 1.25 mg treatment group of the studies were not

Latino’ ethnic category.

included in the current analysis. In the FREEDOMS [11] and FREEDOMS II [9] studies (ClinicalTrials.gov number, NCT00289978 and

Analyses

NCT00355134, respectively), patients received daily fingolimod 0.5 mg or placebo for 2 years.

Efficacy and safety data from all randomized

In the TRANSFORMS (ClinicalTrials.gov number,

[10] study NCT00340834),

Hispanic patients in the three studies were pooled to give the largest possible dataset.

patients received daily fingolimod 0.5 mg or weekly IFNb-1a IM (30 mg) for 1 year. All of

Relapses were recorded between baseline and end of study (EOS) for each patient. EOS was the

these studies were conducted in accordance

last available visit for randomized patients

with the International Conference on Harmonization of Technical Requirements for

between initiation and completion of the study. From these data, the ARR was estimated

Registration of Pharmaceuticals for Human Use, the Harmonized Tripartite Guidelines for Good

for each treatment group using a negative binomial regression model, adjusted for

Clinical

local

treatment, study, number of relapses in the

regulations, and the ethical principles of the Declaration of Helsinki. The Institutional

previous 2 years, and baseline EDSS score as exploratory variables, and duration of exposure

Review Board at each participating medical center provided ethical approval of the study

as an offset variable, using SAS software (version 8.2; SAS Institute, Inc., Cary, NC, USA). Only

protocol as well as the case report forms, patient

relapses that were confirmed by an independent

information, and informed consent forms. Written informed consent was obtained from

examining neurologist were included in the analysis. Safety assessments included the

each patient, or their legal representative, before enrollment. The analyses in this article

incidence of adverse events (AEs) and serious adverse events (SAEs).

Practice

with

applicable

Adv Ther

First-Dose Observations

IFNb-1a

IM

group

were,

on

average,

significantly younger (p[0.003 or p[0.04, The initial dose of study treatment was administered by an independent physician acting as the first-dose administrator to preserve blinding. Patients were observed in a clinical setting, and their vital signs were recorded at hourly intervals for at least 6 h. The mean change from baseline in hourly heart rate (HR) was determined. A 12-lead electrocardiogram (ECG) was obtained before drug administration, at 6 h post-dose and at any

respectively) and proportion were

a numerically higher male (although not

statistically significant). Patients in the placebo group had a numerically greater number of inflammatory lesions and a higher T2 lesion burden than those in the other groups (not statistically significant). The mean duration of exposure to study drug at EOS was 545 days in the placebo group, 345 days in the IFNb-1a IM group, and 414 days

time when symptoms or major changes in vital

in the fingolimod 0.5 mg group.

signs were noted. Participants were eligible for discharge 6 h after the first dose if all the

Relapse Rates

following criteria were met: HR of at least 51 bpm; HR greater than 80% of baseline value; HR not the lowest hourly value of the monitoring period; no symptoms of decreased HR; no treatment given for bradycardia; and an ECG reading not showing any significant abnormalities versus pre-dose, except sinus

Over the analysis period (baseline to EOS), the ARRs of Hispanic patients were numerically lower in the fingolimod 0.5 mg group (ARR: 0.22, 95% confidence interval [CI]: 0.14–0.35) than in placebo (ARR: 0.46, 95% CI: 0.24–0.88)

was

and IFNb-1a IM groups (ARR: 0.34, 95% CI: 0.18–0.63) (Fig. 1a). This was similar to findings

extended for patients who did not meet one or more of these criteria, and hospitalization was

in the overall study population, in which ARRs were significantly lower in the fingolimod

permitted at the discretion of the first-dose administrator. Symptomatic bradycardia

0.5 mg group (ARR: 0.20, 95% CI: 0.18–0.23)

bradycardia.

The

observation

period

(bradycardia symptoms during first dosing)

than in the placebo (ARR: 0.45, 95% CI: 0.40–0.50) and IFNb-1a IM groups (ARR: 0.38,

was noted and administrator.

95% CI: 0.30–0.46; comparisions) (Fig. 1b).

graded

by

the

first-dose

p\0.05

for

all

RESULTS

First-Dose Observations

Study Population

At pre-dose assessment in the fingolimod 0.5 mg group, the mean (standard deviation

The Hispanic cohort (n = 181) had been treated

[SD]) sitting HR was 72.0 (9.25) beats per minute (bpm). Following first-dose administration, HR

as follows: fingolimod 0.5 mg (n = 89), IFNb-1a IM (n = 65), and placebo (n = 27). There were

reached a nadir of 63.9 (8.37) bpm at 5 h (mean

slight differences in baseline demographics and disease characteristics between the groups

change from baseline: -8.1 bpm) and began to recover after 6 h. During the first 6 h after drug

(Table 1).

administration, 79.8% of patients in the fingolimod 0.5 mg group had a HR of at least

Compared

with

those

in

the

fingolimod or placebo groups, patients in the

Adv Ther

Table 1 Baseline demographics and disease characteristics of all randomized patients and the Hispanic cohort; pooled dataset from three phase 3, randomized, controlled fingolimod studies (FREEDOMS, FREEDOMS II, and TRANSFORMS) Characteristic

All randomized patientsa

Hispanic cohort

Placebo (n 5 773)

IFNb-1a IM (n 5 435)

Fingolimod 0.5 mg (n 5 1,214)

Placebo (n 5 27)

IFNb-1a IM (n 5 65)

Fingolimod 0.5 mg (n 5 89)

38.6 (8.6)

36 (8.3)

37.8 (8.9)

37.2 (7.3)

33.4 (8.1)b

37.6 (9.1)

Male

187 (24.2)

140 (32.2)

361 (29.7)

7 (25.9)

21 (32.3)

19 (21.3)

Female

586 (75.8)

295 (67.8)

853 (70.3)

20 (74.1)

44 (67.7)

70 (78.7)

26.0 (5.6)

25.2 (5.4)

25.8 (5.3)

25.6 (5.5)

24.5 (5.4)

25.3 (4.7)

Time since first symptom, years

9.3 (7.2)

7.4 (6.3)

8.5 (7.0)

8.8 (6.9)

7.3 (5.8)

9.3 (7.5)

Number of relapses in past 1 year

1.5 (0.8)

1.5 (0.8)

1.5 (1.0)

1.6 (0.9)

1.4 (0.7)

1.5 (0.9)

Number of relapses in past 2 years

2.2 (1.3)

2.3 (1.2)

2.2 (1.7)

2.3 (1.0)

2.1 (0.9)

2.1 (1.4)

EDSS score

2.5 (1.3)

2.2 (1.3)

2.3 (1.3)

2.3 (1.6)

2.2 (1.3)

2.2 (1.2)

345 (44.6)

190 (43.7)

531 (43.7)

6 (22.2)

30 (46.2)

34 (38.2)

Number of Gd-enhancing lesions

1.2 (3.1)

1.1 (2.8)

1.3 (4.1)

2.0 (4.1)

1.5 (3.2)

1.4 (4.7)

Gd-enhancing lesion volume, mm3

137 (374)

101 (264)

135 (465)

214 (379)

152 (339)

193 (718)

Total T2 lesion volume, mm3

5,882 (7,443)

4,924 (5,711)

5,598 (7,414)

9,754 (15,750)

5,396 (7,047)

4,183 (4,885)

Patient demographics Age, years Sex, n (%)

Body mass index, kg/m2 Disease characteristics

Treatment-naive patients, n (%) Key MRI features

All values are mean (standard deviation) unless otherwise stated EDSS Expanded Disability Status Scale, Gd gadolinium, IFNb-1a IM intramuscular interferon beta-1a, MRI magnetic resonance imaging a Patients (n = 1,225) randomized to the fingolimod 1.25 mg treatment group of the studies were not included in the current analysis b Significant difference from placebo (p[0.04) and fingolimod (p[0.003) treatment groups 55 bpm, 20.2% had a HR of 45–54 bpm, and no patient had a HR lower than 45 bpm. In the

from 73.8 (10.0) bpm pre-dose to 79.3 (12.1) bpm at 3 h and remained maximally elevated at

IFNb-1a IM group, the mean (SD) HR increased

6 h post-dose (80.5 [11.6] bpm [mean change

Adv Ther

A

b

0.50 0.45

52%

a

0.46

0.40 35%a

0.35 0.34

ARR

0.30 0.25 0.20

0.22

0.15 0.10 0.05 0.00

B

Placebo (n = 27)

IFN β-1a IM (n = 65)

Fingolimod 0.5 mg (n = 89)

0.50 54%b

0.45 0.45 0.40

46%b 0.38

0.35

with fingolimod 0.5 mg had a Mobitz type I AV block (Table 2). No 2:1 AV blocks were detected

ARR

0.30 0.25 0.20

0.20

0.15

in any group. Most patients (88.8%) in the fingolimod 0.5 mg group were discharged at 6 h post-dose (Table 3). One patient in the IFNb-1a IM group

0.10 0.05 0.00

Fig. 1 Annualized relapse rates in Hispanic patients (a) and in the overall population (b) from baseline to end of study; pooled dataset from three phase 3, randomized, controlled fingolimod studies (FREEDOMS, FREEDOMS II, and TRANSFORMS). aRelative reduction based on rate ratios of 0.484 for fingolimod 0.5 mg versus placebo and 0.652 for fingolimod 0.5 mg versus IFN-b-1a IM. bRelative reduction based on rate ratios of 0.458 for fingolimod 0.5 mg versus placebo and 0.544 for fingolimod 0.5 mg versus IFNb–1a IM. End of study was the last available visit for randomized patients between initiation and completion of the study. ARR was estimated for each treatment group using a negative binomial regression model, adjusted for treatment, study, number of relapses in the previous 2 years, and baseline Expanded Disability Status Scale (EDSS) score as exploratory variables, and duration of exposure as an offset variable. Only relapses that were confirmed by an independent examining neurologist were included in the analysis. ARR annualized relapse rate, IFNb-1a IM intramuscular interferon beta-1a

required monitoring on day 2. A single patient in Placebo (n = 733)

IFN β-1a IM (n = 431)

Fingolimod 0.5 mg (n = 1212)

from baseline: ?6.7 bpm]). Symptomatic bradycardia was not reported in any Hispanic

the fingolimod group was admitted to hospital after drug administration owing to sinus bradycardia and Mobitz type I AV block, and withdrew informed consent (Tables 2 and 3). Adverse Events

patient during the first-dose observation period. Transient, newly occurring ECG events after 6 h were reported in 3.8% of patients receiving

The overall incidence of AEs was similar across the fingolimod, placebo, and IFNb-1a IM groups

placebo, 9.4% of those receiving IFNb-1a IM, and 11.4% of those receiving fingolimod 0.5 mg

(Table 4). A small number of AEs led to treatment discontinuation, regardless of study

(Table 2).

first-degree

drug relationship, in each group: three patients

atrioventricular (AV) block after 6 h was low in all groups, occurring in 3.8% of patients

(11.1%) in the placebo group, one patient (1.5%) in the IFNb-1a IM group, and seven

receiving placebo, 3.1% of those taking IFNb-1a IM, and 4.5% of those receiving

patients (7.9%) in the fingolimod 0.5 mg group. In all treatment groups, nasopharyngitis,

fingolimod 0.5 mg. One patient (1.1%) treated

headache, and urinary tract infection were

The

incidence

of

Adv Ther

Table 2 Frequency of newly occurringa ECG events 6 h after administration of the first dose of fingolimod in the Hispanic cohort Placebo (n 5 27)

IFNb-1a IM (n 5 65)

Fingolimod 0.5 mg (n 5 89)

26 (96.3)

64 (98.5)

88 (98.9)

1 (3.8)

6 (9.4)

10 (11.4)

1 (3.8)

4 (6.3)

7 (8.0)

First-degree AV block

1 (3.8)

2 (3.1)

4 (4.5)

2:1 AV block

0

0

0

Mobitz type I AV block

0

0

1 (1.1)

Left anterior hemiblock

0

1 (1.6)

2 (2.3)

Right bundle branch block

0

1 (1.6)

1 (1.1)

Incomplete right bundle branch block

0

0

1 (1.1)

0

0

1 (1.1)

0

0

1 (1.1)

0

0

1 (1.1)

0

0

1 (1.1)

0

2 (3.1)

4 (4.5)

Flat

0

0

4 (4.5)

Inverted

0

2 (3.1)

0

Patients, n (%) Patients who had a post-dose ECG New ECG events

b

Conduction

Morphology Left ventricular hypertrophy Rhythm Sinus bradycardia T waves

AV atrioventricular, ECG electrocardiogram, IFNb-1a IM intramuscular interferon beta-1a Newly occurring ECG events were defined as those not observed during the pre-dose ECG, but present on the 6-h postdose ECG b Percentage based on the number of patients who had a post-dose ECG; some patients experienced [1 event a

Table 3 Patient first-dose administration experience in the Hispanic cohort Patients, n (%)

Placebo (n 5 27)

IFNb-1a IM (n 5 65)

Fingolimod 0.5 mg (n 5 89)

Discharged at 6 h

27 (100)

64 (98.5)

79 (88.8)

Required extended monitoring beyond 6 h on day 1

0

1 (1.5)

8 (9.0)

Admitted to hospital

0

0

1 (1.1)

Required monitoring on day 2

0

1 (1.5)

0

Study drug permanently discontinued

0

0

0

IFNb-1a IM intramuscular interferon beta-1a among the most common AEs. Influenza-like illness was the most common AE in patients

reported in all treatment groups; two patients reported nephrolithiasis in the fingolimod

who received IFNb-1a IM (Table 4). SAEs were

0.5 mg group.

Adv Ther

Table 4 Incidence of AEs in the Hispanic cohort reported during the studies Placebo (n 5 27)

IFNb-1a IM (n 5 65)

Fingolimod 0.5 mg (n 5 89)

26 (96.3)

62 (95.4)

78 (87.6)

3 (11.1)

1 (1.5)

7 (7.9)

1 (3.7)

1 (1.5)

7 (7.9)

1 (3.7)

37 (56.9)

4 (4.5)

10 (37.0)

7 (10.8)

17 (19.1)

Headache

7 (25.9)

9 (13.8)

17 (19.1)

Urinary tract infection

5 (18.5)

7 (10.8)

12 (13.5)

Dizziness

5 (18.5)

1 (1.5)

6 (6.7)

Upper respiratory tract infection

4 (14.8)

5 (7.7)

10 (11.2)

Migraine

4 (14.8)

2 (3.1)

4 (4.5)

Cough

4 (14.8)

1 (1.5)

2 (2.2)

Pyrexia

2 (7.4)

8 (12.3)

5 (5.6)

Nausea

3 (11.1)

3 (4.6)

8 (9.0)

Cystitis

3 (11.1)

0 (0.0)

1 (1.1)

Back pain

3 (11.1)

4 (6.2)

6 (6.7)

Neck pain

3 (11.1)

3 (4.6)

3 (3.4)

Dyspnea

3 (11.1)

0 (0.0)

1 (1.1)

Diarrhea

2 (7.4)

2 (3.1)

9 (10.1)

Depression

2 (7.4)

2 (3.1)

9 (10.1)

Patients, n (%) Any AE AEs leading to treatment discontinuation SAEsb

a

AEs reported by [10% of patients Influenza-like illness Nasopharyngitis

AE adverse event, ALT alanine aminotransferase, AST aspartate transaminase, IFNb-1a IM intramuscular interferon beta1a, MS multiple sclerosis, SAE serious AE a AEs leading to discontinuation (regardless of study drug relationship): placebo group—macular edema, AST increased, exposure to communicable disease; IFNb-1a IM group—hepatic enzyme increased; fingolimod 0.5 mg group—lymphopenia (two cases), ALT increased (two cases), AST increased, hepatic enzyme increased (two cases), transaminases increased. Some patients experienced [1 event b SAEs: placebo group—MS relapse; IFNb-1a IM group—uterine leiomyoma; fingolimod 0.5 mg group—second-degree atrioventricular block, sinus bradycardia, retinal detachment, uterine leiomyoma, convulsion, nephrolithiasis (two cases), hemorrhagic ovarian cyst. Some patients experienced [1 event

DISCUSSION

up to 2 years had lower ARRs than those receiving placebo or IFNb-1a IM in this pooled

In this study, pooled data from three randomized, controlled, phase 3 clinical trials

analysis, with relative numerical reductions of

were used to assess the safety and efficacy of

52% and 35%, respectively. The ARRs observed in Hispanic patients were similar to those

fingolimod in Hispanic patients with RRMS. Hispanic patients treated with fingolimod for

observed in the overall study population of heterogeneous ethnicity, in which there was a

Adv Ther

54% and a 46% reduction in ARR in the

in the fingolimod group than in the placebo or

fingolimod group compared with the placebo

IFNb-1a IM groups. These events included first-

and IFNb-1a IM groups, respectively. The 35% relative ARR reduction in Hispanic patients

degree AV block and flattened T waves (both of which occurred in 4.5% of patients receiving

treated with fingolimod compared with IFNb1a IM was lower than that reported in the

fingolimod), which were typically asymptomatic. In previous studies, the rates of

overall population. This may be due to the

AV block in the overall population of patients

differences in baseline demographics and disease characteristics of the Hispanic

receiving fingolimod have been in the range 0–5% [9–11, 16], which is consistent with that

population compared

observed in the Hispanic cohort.

who with

received IFNb-1a IM those who received

fingolimod. Alternatively, responsiveness to fingolimod versus IFNb-1a IM among Hispanic MS patients might reflect genetic differences among individuals or variability in clinical features [6, 7]. When interpreting these

CONCLUSION Overall,

this

study

demonstrates

that

fingolimod is efficacious and well tolerated in Hispanic patients with RRMS.

findings, it should be noted that this study was not powered prospectively for subgroup analyses, and Hispanic patient numbers in each

ACKNOWLEDGMENTS

treatment group were low; therefore, statistical analyses should be interpreted with caution.

This study and article processing charges were

Nevertheless, these findings indicate that Hispanic patients respond well to fingolimod

funded

by

Novartis

Pharmaceuticals

therapy, with findings broadly consistent with

Corporation. Oxford PharmaGenesisÒ provided editorial support during

those in the overall population, even though the course of the disease may be clinically

development of this manuscript. Funding for this editorial support was provided by Novartis

distinct in this patient group. Fingolimod first-dose effects in Hispanic

Pharmaceuticals

Corporation.

All

Ltd the

named

patients with RRMS were also consistent with

authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the

those reported in the overall patient populations of previous phase 3 studies [9–11].

integrity of the work as a whole, and have given final approval for the version to be published.

A transient decrease in HR was observed in some Hispanic patients and this has previously been well characterized as a pharmacologic effect following fingolimod treatment initiation [8, 15]. In both the overall population and in the Hispanic cohort, HR started to attenuate 6 h after initial fingolimod administration [9–11]. No cases of symptomatic bradycardia were reported in the Hispanic patients. The overall incidence of newly occurring ECG events in the Hispanic patient population was slightly higher

Conflict

of

interest. Angel

R

Chinea

Martinez is a consultant for and is a member of the speaker bureau for Allergan, Biogen Idec, Novartis, Sanofi-Genzyme, and Teva. He has also received grant/research support from Biogen Idec, Novartis, and Teva. Jorge Correale has served as an advisory board member for Merck Serono Argentina, Novartis Argentina, Biogen Idec, and Merck Serono. He has received reimbursement for developing educational

Adv Ther

presentations for Merck Serono Argentina, Biogen Idec Argentina, and TEVA Tuteur Argentina, as well as professional travel and

study. I. Clinical course and disability. Brain. 1989;112(Pt 1):133–46. 5.

Correale J. MS in Latin America. Int MS J. 2008;15:3–5.

6.

Amezcua L, Lund BT, Weiner LP, et al. Multiple sclerosis in Hispanics: a study of clinical disease expression. Mult Scler. 2011;17:1010–6.

7.

Corona T, Roman GC. Multiple sclerosis in Latin America. Neuroepidemiology. 2006;26:1–3.

8.

US Food and Drug Administration. GILENYAÒ (fingolimod) prescribing information. 2014. Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2014/022527s009lbl.pdf. Accessed on August 6, 2014.

9.

Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsingremitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545–56.

accommodation stipends. Patrick K Coyle has received grant/research support or honoraria for educational or consultative services related to MS from the following companies: Acorda, Actelion, Avanir, Bayer, Biogen Idec, EMD Serono,

Novartis,

Questcor,

Roche,

Sanofi

Aventis, and Teva Neurosciences. Xiangyi Meng is an employee of Novartis Pharmaceuticals Corporation. Tenenbaum is an employee of

Nadia Novartis

Pharmaceuticals Corporation. Compliance with ethics guidelines. All procedures followed were in accordance with the ethical standards of committee on human

the responsible experimentation

(institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 and 2008. Informed consent was obtained from all patients for being included in the study. Funding. Sponsorship for this study was funded by Novartis.

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