Multiple Sclerosis and Related Disorders (2014) 3, 355–363
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
Effect of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod vs. interferon β-1a intramuscular: Subgroup analyses of the Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS) B.O. Khatria,n, J. Pelletierb, L. Kapposc, H.-P. Hartungd, G. Comie, F. Barkhoff, P. von Rosenstielg, X. Mengh, A. Grinspanh,1, R. Hashmonayh, J.A. Coheni, on behalf of the TRANSFORMS Study Group a
The Regional MS Center, Center for Neurological Disorders, Wheaton Franciscan Health Care, 3237 S. 16th Street, Milwaukee, WI 53215, USA b CHU La Timone, CRMBM-CNRS 6612, Marseille, France c University Hospital, Petersgraben 4, Basel 4031, Switzerland d Heinrich Heine University, Moorenstr 5, Dusseldorf 40225, Germany e Università Vita-Salute San Raffaele, Milan 20123, Italy f VU Medical Center, P.O. Box 7057, Amsterdam 1007 MB, The Netherlands g Novartis Pharma AG, Kirschgarten Site, Basel 4002, Switzerland h Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA i Mellen Center, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA Received 9 July 2013; received in revised form 13 November 2013; accepted 20 November 2013
n
Corresponding author. Tel.: +1 414 385 1801; fax: +1 414 385 1899. E-mail addresses: [email protected] (B.O. Khatri), [email protected] (J. Pelletier), [email protected] (L. Kappos), [email protected] (H.-P. Hartung), [email protected] (G. Comi), [email protected] (F. Barkhof), [email protected] (P. von Rosenstiel), [email protected] (X. Meng), [email protected] (A. Grinspan), [email protected] (R. Hashmonay), [email protected] (J.A. Cohen). 1 Present address: Teva Pharmaceuticals, 41 Moores Road, Frazer, PA, USA. 2211-0348/$ - see front matter & 2014 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.msard.2013.11.006
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KEYWORDS Disease-modifying therapy; Fingolimod; Interferon; Multiple sclerosis; Sphingosine 1-phosphate receptor modulator; Relapse rate
1.
Abstract Background: Fingolimod demonstrated superior efficacy compared with interferon β-1a
intramuscular in relapsing multiple sclerosis. The impact of treatment history on fingolimod efficacy is unknown. Objectives: This post-hoc analysis of phase 3 TRANSFORMS data compared the efficacy and safety of fingolimod and interferon β-1a intramuscular among patient subgroups defined by prior treatment history. Methods: Annualized relapse rate and safety of once-daily oral fingolimod 0.5 mg, 1.25 mg, or once-weekly interferon β-1a 30 μg intramuscular for 12 months were analyzed in 1292 patients with relapsing multiple sclerosis according to prior disease-modifying therapy, reason for prior disease-modifying therapy discontinuation (adverse events or unsatisfactory therapeutic effect), and prior disease-modifying therapy duration. Results: Compared with interferon β-1a intramuscular, fingolimod 0.5 mg significantly reduced annualized relapse rate in patients who were treatment naive, received prior interferon-β treatment, discontinued prior disease-modifying therapy for unsatisfactory therapeutic effect, or had prior disease-modifying therapy duration of Z1 year (Pr0.05, all comparisons). Similar trends were observed in patients with prior glatiramer acetate treatment. Significant reductions were also seen with fingolimod 1.25 mg for treatment-naive and prior interferon-β-treated patients. Conclusions: This analysis demonstrates superiority of fingolimod over interferon β-1a intramuscular regardless of prior (interferon-β) treatment and prior treatment efficacy and duration. ClinicalTrials. gov identifier: NCT00340834. & 2014 Published by Elsevier B.V.
Introduction
Until recently, interferon (IFN) β and glatiramer acetate (GA) were the only approved first-line disease-modifying therapies (DMTs) for multiple sclerosis (MS). Prior studies have shown that most patients will experience disease activity on these compounds: 62–75% will relapse and 20–27% will worsen by 1 point on the Expanded Disability Status Scale (EDSS) within 2 years (The IFNB Multiple Sclerosis Study Group, 1993; Jacobs et al., 1996; Johnson et al., 1995; PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group, 1998). Not surprisingly, reported discontinuation rates after 1–3 years of IFNβ treatment range from 23% to 55%; for GA, discontinuation rates tend to be lower, but still range widely, from 9% to 57% (Haas and Firzlaff, 2005; Kleinman et al., 2010; Milanese et al., 2005; Reynolds et al., 2010; Ruggieri et al., 2003; Wong et al., 2011). One study of treatment adherence reported an unsatisfactory therapeutic response in 16–48% of IFNβ discontinuations and 25% of GA discontinuations (Milanese et al., 2005). Intolerable side effects are another important reason for DMT discontinuation, accounting for 10–50% of IFNβ discontinuations and 16% of GA discontinuations (Milanese et al., 2005; Ruggieri et al., 2003). Because IFNβ and GA responses vary among patients, with relatively high rates of failure and intolerable side effects, there remains a need for additional therapeutic options that are effective and well-tolerated. Fingolimod is an oral sphingosine 1-phosphate modulator approved in North America and Europe to treat relapsing MS at a dose of 0.5 mg once daily. Its approval was based on efficacy and safety demonstrated in 2 pivotal trials. In the 2-year phase 3 Fingolimod Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study, the annualized relapse rate (ARR) was significantly lower with once-daily treatment with fingolimod 0.5 mg ( 54%; Po0.001) or fingolimod 1.25 mg ( 60%; Po0.001) compared with placebo (Kappos et al.,
2010). In the 12-month, phase 3 Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS) study, the ARR was significantly lower with once-daily fingolimod 0.5 mg ( 52%; Po0.001) or fingolimod 1.25 mg ( 38%; Po0.001) compared with once-weekly intramuscular (IM) injection of IFNβ-1a 30-μg (Cohen et al., 2010). Previous subgroup analyses of TRANSFORMS study data showed that fingolimod 0.5 mg significantly reduced ARR in treatment-naive patients (P=0.002) and in patients with prior DMT treatment (Po0.001), as well as in subgroups by baseline disease characteristics (Cohen et al., 2013). To confirm the clinical benefit of fingolimod across treatment history subgroups, additional post-hoc analyses of the TRANSFORMS trial data were conducted to compare the efficacy and safety of fingolimod and IFNβ-1a IM in IFNβor GA-naive patients and in patients switching from prior IFNβ or GA therapy, as well as those who discontinued prior DMT for unsatisfactory treatment response or intolerable side effects. The impact of prior DMT treatment duration on efficacy and safety was also examined.
2. 2.1.
Material and methods Study design and patient population
TRANSFORMS was a 12-month, phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled trial, with optional extension (ClinicalTrials.gov number, NCT00340834) (Cohen et al., 2010). A total of 1292 patients with relapsing MS were randomly assigned to receive, with equal probability, once-daily fingolimod 0.5 mg (the dose approved by the United States Food and Drug Administration and other health authorities) or 1.25 mg or once-weekly interferon β-1a IM 30 μg for 12 months. The detailed study methodology was previously published in accordance with
Subgroup analyses of the TRANSFORMS study
357
2.3.
CONSORT guidelines (Cohen et al., 2010). The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by each site's institutional review board and all patients gave written informed consent.
2.2.
In the core TRANSFORMS study, statistical analyses were conducted in the intent-to-treat (ITT) population using a negative binomial regression model adjusted for treatment, country, the number of relapses within 2 years prior to enrollment, and baseline EDSS (Cohen et al., 2010). For the subgroup populations, ARRs with associated confidence intervals and ARR ratios with associated P values were estimated using a negative binomial regression model adjusted for treatment, subgroup variable, and treatment-by-subgroup variable interaction. AE data refer to treatment-emergent events, regardless of causality.
Study endpoints and subanalysis groups
The primary efficacy variable in the TRANSFORMS core study was ARR, defined as the number of confirmed relapses during a 12-month period. Confirmed relapse criteria included symptoms accompanied by one of the following: an increase of at least half a point in the EDSS score, 1 point increases in each of 2 EDSS functional system scores, or of 2 points in one EDSS functional system score (excluding scores for bowel-bladder or cerebral functioning systems). Secondary efficacy endpoints included time to disability progression confirmed at 3 months and MRI outcomes, including brain atrophy. Safety was assessed through adverse event (AE) reporting. Post-hoc analyses of the TRANSFORMS core study data were performed to evaluate ARR in subgroups of patients based on prior use of IFNβ therapy, prior use of GA therapy, discontinuation of prior DMT due to unsatisfactory therapeutic effect, discontinuation of prior DMT for AEs, and duration of prior DMT. Table 1
Statistical analysis
3.
Results
3.1.
Patients
A total of 1292 patients were randomly assigned to treatment. Demographic and baseline clinical characteristics for all patient subgroups are shown in Tables 1 and 2. The majority of patients (57.6%) had received treatment with a DMT prior to enrollment; 218 patients (17.0%) had a history of treatment with multiple DMTs.
Baseline patient demographics and clinical characteristics by treatment subgroup (randomized population).
Characteristic
Age, years Female, n (%) Duration of MS, years Relapses in previous 1 year, n Relapses in previous 2 years, n EDSS score Gd + lesions, n T2 lesion volume, mm3 Patients free of Gd + lesions, n (%)
IFNβ-naive patients
IFNβ-treated patients
Fingolimod 0.5 mg (n= 212)
Fingolimod 1.25 mg (n = 217)
IFNβ-1a IM (n = 228)
Fingolimod 0.5 mg (n= 219)
Fingolimod 1.25 mg (n = 209)
IFNβ-1a IM (n= 207)
35.8 130 3.36 1.6
35.0 144 3.25 1.6
35.0 155 3.27 1.5
37.6 152 6.23 1.5
36.6 149 5.97 1.4
37.1 140 6.73 1.4
(8.8) (61.3) (4.75) (0.8)
2.1 (1.1) 1.94 1.20 4338 134
(1.21) (3.53) (6078) (64.1)
(8.4) (66.4) (4.89) (0.9)
2.1 (1.1) 1.99 2.04 4980 119
(1.18) (6.13) (5771) (56.4)
(8.1) (68.0) (5.00) (7.9)
2.1 (1.1) 1.93 1.20 4212 135
(1.23) (3.23) (4691) (61.1)
(8.7) (69.4) (4.63) (1.5)
2.48 (2.9)
2.25 (1.3)
2.53 0.76 5971 154
2.45 0.91 5197 151
(1.37) (1.85) (7065) (70.6)
GA-naive patients
Age, years Female, n (%) Duration of MS, years Relapses in previous 1 year, n Relapses in previous 2 years, n EDSS score Gd + lesions, n
(8.3) (71.3) (4.52) (0.8)
(1.40) (2.58) (6170) (75.1)
(8.4) (67.6) (5.33) (0.8)
2.4 (1.4) 2.46 0.91 5695 133
(1.24) (2.25) (6567) (65.2)
GA-treated patients
Fingolimod 0.5 mg (n= 374)
Fingolimod 1.25 mg (n = 359)
IFNβ-1a IM (n = 368)
Fingolimod 0.5 mg (n = 67)
Fingolimod 1.25 mg (n= 57)
IFNβ-1a IM (n= 67)
36.5 24 4.49 1.5
35.7 237 4.03 1.5
35.7 245 4.37 1.4
38.0 41 7.00 1.5
35.9 56 7.48 1.6
37.6 50 7.99 1.8
(9.0) (64.4) (4.88) (1.2)
(8.4) (66.0) (4.53) (0.8)
(8.1) (66.6) (5.02) (0.7)
(7.3) (71.9) (4.50) (0.9)
(8.6) (83.6) (5.73) (1.1)
(9.3) (74.6) (6.59) (1.1)
2.3 (2.3)
2.2 (1.1)
2.2 (1.1)
2.4 (1.2)
2.3 (1.4)
2.8 (1.8)
2.16 (1.30) 0.99 (2.91)
2.14 (1.29) 1.37 (4.80)
2.12 (1.26) 1.12 (2.98)
2.77 (1.41) 0.75 (1.40)
2.60 (1.37) 0.88 (1.99)
2.55 (1.22) 2.14 (4.64)
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Table 1. (continued ) T2 lesion volume, mm3 Patients free of Gd + lesions, n (%)
4990 (6596)
4867 (5777)
4926 (5850)
6364 (6882)
6225 (6789)
4910 (4895)
252 (67.9)
236 (68.2)
224 (62.0)
36 (64.3)
34 (51.5)
44 (68.8)
Discontinued prior DMT owing to unsatisfactory therapeutic effect
Age, years Female, n (%) Duration of MS, years Relapses in previous 1 year, n Relapses in previous 2 years, n EDSS score Gd + lesions, n T2 lesion volume, mm3 Patients free of Gd + lesions, n (%)
Fingolimod 0.5 mg (n= 41)
Fingolimod 1.25 mg (n= 54)
IFNβ-1a IM (n = 45)
Fingolimod 0.5 mg (n = 390)
Fingolimod 1.25 mg (n= 372)
IFNβ-1a IM (n= 390)
37.2 25 6.99 1.6
34.0 44 7.11 1.8
36.5 29 8.41 1.7
36.7 257 4.59 1.5
36.0 249 4.21 1.5
35.9 266 4.52 1.4
(8.3) (61.0) (4.50) (1.0)
(8.7) (81.5) (4.50) (1.1)
(8.1) (64.4) (5.92) (1.0)
(8.9) (65.9) (4.89) (1.2)
(8.3) (66.9) (4.85) (0.8)
(8.3) (68.2) (5.24) (0.8)
3.0 (1.8)
2.6 (1.5)
3.0 (1.9)
2.2 (2.2)
2.1 (1.1)
2.2 (1.1)
2.60 (1.38) 0.71 (1.15) 7120 (7529)
2.81 (1.59) 1.77 (4.21) 8212 (9115)
2.76 (1.30) 0.89 (1.56) 6102 (6108)
2.20 (1.32) 1.01 (2.93) 4963 (6518)
2.13 (1.24) 1.45 (4.85) 4635 (5224)
2.12 (1.24) 1.08 (2.91) 4784 (5654)
27 (65.9)
34 (65.4)
28 (62.2)
261 (67.6)
236 (65.6)
240 (63.2)
Discontinued prior DMT owing to AE
Age, years Female, n (%) Duration of MS, years Relapses in previous 1 year, n Relapses in previous 2 years, n EDSS score Gd + lesions, n T2 lesion volume, mm3 Patients free of Gd + lesions, n (%)
Discontinued prior DMT for reason other than unsatisfactory therapeutic effect (includes DMT-naive patients)
Discontinued prior DMT for reason other than AE (includes DMT-naive patients)
Fingolimod 0.5 mg (n= 59)
Fingolimod 1.25 mg (n= 47)
IFNβ-1a IM (n = 51)
Fingolimod 0.5 mg (n = 372)
Fingolimod 1.25 mg (n= 379)
IFNβ-1a IM (n= 384)
37.5 45 7.09 1.5
36.4 35 8.28 1.5
37.2 43 7.41 1.6
36.6 237 4.46 1.5
35.7 258 4.11 1.5
35.8 252 4.60 1.4
(9.3) (76.3) (5.59) (0.9)
(8.4) (74.5) (6.14) (0.8)
(8.9) (84.3) (5.13) (0.9)
(8.7) (63.7) (4.68) (1.2)
(8.4) (68.1) (4.52) (0.9)
(8.2) (65.6) (5.40) (0.8)
2.4 (1.4)
2.3 (1.4)
2.5 (1.3)
2.3 (3.3)
2.2 (1.2)
2.2 (1.2)
2.65 (1.35) 1.19 (2.80) 5996 (6423)
2.86 (1.28) 1.00 (2.08) 4287 (3867)
2.64 (1.25) 0.96 (2.47) 4637 (4963)
2.17 (1.31) 0.94 (2.81) 5037 (6675)
2.13 (1.29) 1.55 (5.01) 5185 (6171)
2.13 (1.25) 1.07 (2.85) 4961 (5806)
38 (64.4)
30 (65.2)
30 (61.2)
250 (67.9)
240 (65.6)
238 (63.3)
AE=adverse event; DMT =disease-modifying therapy; EDSS=Expanded Disability Status Scale; GA=glatiramer acetate; Gd+ =gadolinium-enhancing; IFNβ =interferon beta; IM=intramuscular; MS=multiple sclerosis. All values are mean (SD) unless otherwise noted.
3.2. IFNβ-naive patients vs. those who received prior IFNβ Approximately 50% of patients had previously received IFNβ therapy (Table 1). Patients previously treated with IFNβ had a longer duration of MS than IFNβ-naive patients (6.31 years vs. 3.29 years, respectively), as well as higher EDSS scores (2.48 vs. 1.95), and greater mean baseline T2 lesion volume (5631 mm3 vs. 4506 mm3). Fingolimod 0.5 mg and 1.25 mg significantly reduced ARR compared with IFNβ-1a IM in patients with prior IFNβ treatment ( 58% and 39%, respectively, Po0.0001 and P=0.0069; Figs. 1 and 2). Fingolimod 0.5 mg and 1.25 mg were
also superior to IFNβ-1a IM in patients with no previous IFNβ treatment ( 43% and 41%, respectively (P=0.0092 and P=0.0131).
3.3. GA-naive patients vs. those that received prior GA A total of 179 patients had received prior GA, constituting a minority of all treatment subgroups (13–16%). Overall, patients with a history of GA treatment had longer mean duration of MS (7.52 years), higher EDSS score (2.63), and greater mean T2
Subgroup analyses of the TRANSFORMS study
359
Table 2 Baseline patient demographics and clinical characteristics by duration of prior disease-modifying therapy (randomized population). Characteristic
Age, years Female, n (%) Duration of MS, years Relapses in previous 1 year, n Relapses in previous 2 years, n EDSS score Gd + lesions, n T2 lesion volume, mm3 Patients free of Gd + lesions, n (%)
r1 year
No prior treatment Fingolimod 0.5 mg (n =184)
Fingolimod 1.25 mg (n= 170)
IFNβ-1a IM (n= 186)
Fingolimod 0.5 mg (n = 64)
Fingolimod 1.25 mg (n = 55)
IFNβ-1a IM (n= 64)
35.5 113 2.61 1.6
35.2 106 2.44 1.6
34.8 123 2.49 1.5
35.9 36 3.60 1.6
33.4 47 3.95 1.8
35.3 46 3.39 1.4
(8.9) (61.4) (3.77) (0.8)
(8.4) (62.4) (4.30) (0.8)
(7.9) (66.1) (4.02) (0.7)
(6.9) (73.4) (4.87) (1.0)
(8.7) (71.9) (3.77) (0.8)
2.1 (1.0)
2.1 (1.1)
2.1 (1.0)
2.2 (1.1)
2.3 (1.2)
2.3 (1.1)
1.85 (1.17) 1.10 (3.15) 4010 (5920)
1.95 (1.20) 1.92 (6.37) 4534 (5565)
1.84 (1.19) 1.31 (3.50) 4302 (4925)
2.36 (1.16) 1.36 (4.05) 6503 (6904)
2.24 (1.25) 1.69 (4.19) 6030 (6963)
2.22 (1.16) 0.68 (1.24) 4132 (4122)
120 (66.3)
98 (59.4)
107 (59.4)
33 (60.0)
39 (60.9)
40 (63.5)
41–3 years
Age, years Female, n (%) Duration of MS, years Relapses in previous 1 year, n Relapses in previous 2 years, n EDSS score Gd + lesions, n T2 lesion volume, mm3 Patients free of Gd + lesions, n (%)
(8.9) (65.5) (4.81) (0.7)
43 years
Fingolimod 0.5 mg (n =80)
Fingolimod 1.25 mg (n= 86)
IFNβ-1a IM (n= 75)
Fingolimod 0.5 mg (n = 111)
Fingolimod 1.25 mg (n = 101)
IFNβ-1a IM (n= 108)
36.9 56 4.50 1.4
35.7 66 4.27 1.4
35.6 50 5.13 1.4
39.1 76 9.46 1.5
38.3 70 8.62 1.3
38.5 75 9.70 1.4
(9.0) (70.0) (3.35) (1.0)
(9.4) (76.7) (3.25) (0.9)
(8.6) (66.7) (4.48) (0.8)
(8.1) (68.5) (4.47) (1.9)
(8.0) (69.3) (4.53) (0.8)
(7.9) (69.4) (5.75) (0.9)
2.5 (1.5)
2.4 (1.3)
2.6 (1.3)
2.4 (1.2)
2.3 (1.2)
2.3 (1.1)
2.23 (1.34) 0.81 (2.02) 4602 (5825)
2.05 (1.26) 1.22 (3.20) 5247 (6512)
2.24 (1.25) 0.80 (2.24) 4692 (5578)
2.82 (1.41) 0.70 (1.78) 6818 (7728)
2.78 (1.41) 0.88 (2.65) 5262 (5402)
2.68 (1.25) 0.99 (2.37) 6643 (7365)
55 (68.8)
56 (67.5)
54 (72.0)
80 (72.1)
77 (77.0)
67 (63.2)
DMT=disease-modifying therapy; EDSS=Expanded Disability Status Scale; Gd+ =gadolinium-enhancing; IFNβ =interferon beta; IM=intramuscular; MS=multiple sclerosis. All values are mean (SD) unless otherwise noted.
lesion volume (5814 mm3) compared with GA-naive patients (4.30 years, 2.12, and 4930 mm3, respectively). Compared with IFNβ-1a IM, fingolimod 0.5 mg and 1.25 mg significantly reduced ARR in GA-naive patients by 56% and 42%, respectively (Pr0.0005; Figs. 1 and 2). Fingolimod 0.5 mg and 1.25 mg numerically reduced ARR compared with IFNβ-1a IM by 28% and 31%, respectively, in patients with prior GA treatment (P=0.2804 and P=0.2118).
3.4. Prior DMT discontinuation owing to unsatisfactory therapeutic effect Unsatisfactory therapeutic effect of prior DMT was cited by 140 patients as a reason for participation in TRANSFORMS; more than 85% of these patients (37/41, 46/54, and 42/45 patients in
the fingolimod 0.5 mg, fingolimod 1.25 mg, and IFNβ-1a IM groups, respectively) were considered IFN treatment failures (i.e., previously treated with IFN and discontinued prior DMT owing to unsatisfactory treatment effect), so a separate analysis of IFN failures was not conducted. The subgroup of patients that did not discontinue prior DMT owing to unsatisfactory therapeutic effect included those who were DMT-naive. Baseline demographics and disease characteristics were generally comparable among patient subgroups based on unsatisfactory therapeutic response to DMT (Table 1). ARR was significantly reduced by fingolimod 0.5 mg compared with IFNβ-1a IM in patients who discontinued prior DMT for unsatisfactory therapeutic effect ( 57%; P=0.0369) and in those who discontinued prior DMT for other reasons ( 50%; Po0.0001; Fig. 1). Reductions in ARR with fingolimod 1.25 mg vs. IFNβ-1a IM were –38% in those who discontinued for unsatisfactory
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B.O. Khatri et al. ARR
Subgroup
N*
Fingolimod 0.5 mg
IFNβ-1a IM
Reduction vs IFNβ-1a , %
P
Overall
860
0.16
0.33
52
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
Effect of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod vs. interferon β-1a intramuscular: Subgroup analyses of the Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS) B.O. Khatria,n, J. Pelletierb, L. Kapposc, H.-P. Hartungd, G. Comie, F. Barkhoff, P. von Rosenstielg, X. Mengh, A. Grinspanh,1, R. Hashmonayh, J.A. Coheni, on behalf of the TRANSFORMS Study Group a
The Regional MS Center, Center for Neurological Disorders, Wheaton Franciscan Health Care, 3237 S. 16th Street, Milwaukee, WI 53215, USA b CHU La Timone, CRMBM-CNRS 6612, Marseille, France c University Hospital, Petersgraben 4, Basel 4031, Switzerland d Heinrich Heine University, Moorenstr 5, Dusseldorf 40225, Germany e Università Vita-Salute San Raffaele, Milan 20123, Italy f VU Medical Center, P.O. Box 7057, Amsterdam 1007 MB, The Netherlands g Novartis Pharma AG, Kirschgarten Site, Basel 4002, Switzerland h Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA i Mellen Center, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA Received 9 July 2013; received in revised form 13 November 2013; accepted 20 November 2013
n
Corresponding author. Tel.: +1 414 385 1801; fax: +1 414 385 1899. E-mail addresses: [email protected] (B.O. Khatri), [email protected] (J. Pelletier), [email protected] (L. Kappos), [email protected] (H.-P. Hartung), [email protected] (G. Comi), [email protected] (F. Barkhof), [email protected] (P. von Rosenstiel), [email protected] (X. Meng), [email protected] (A. Grinspan), [email protected] (R. Hashmonay), [email protected] (J.A. Cohen). 1 Present address: Teva Pharmaceuticals, 41 Moores Road, Frazer, PA, USA. 2211-0348/$ - see front matter & 2014 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.msard.2013.11.006
356
B.O. Khatri et al.
KEYWORDS Disease-modifying therapy; Fingolimod; Interferon; Multiple sclerosis; Sphingosine 1-phosphate receptor modulator; Relapse rate
1.
Abstract Background: Fingolimod demonstrated superior efficacy compared with interferon β-1a
intramuscular in relapsing multiple sclerosis. The impact of treatment history on fingolimod efficacy is unknown. Objectives: This post-hoc analysis of phase 3 TRANSFORMS data compared the efficacy and safety of fingolimod and interferon β-1a intramuscular among patient subgroups defined by prior treatment history. Methods: Annualized relapse rate and safety of once-daily oral fingolimod 0.5 mg, 1.25 mg, or once-weekly interferon β-1a 30 μg intramuscular for 12 months were analyzed in 1292 patients with relapsing multiple sclerosis according to prior disease-modifying therapy, reason for prior disease-modifying therapy discontinuation (adverse events or unsatisfactory therapeutic effect), and prior disease-modifying therapy duration. Results: Compared with interferon β-1a intramuscular, fingolimod 0.5 mg significantly reduced annualized relapse rate in patients who were treatment naive, received prior interferon-β treatment, discontinued prior disease-modifying therapy for unsatisfactory therapeutic effect, or had prior disease-modifying therapy duration of Z1 year (Pr0.05, all comparisons). Similar trends were observed in patients with prior glatiramer acetate treatment. Significant reductions were also seen with fingolimod 1.25 mg for treatment-naive and prior interferon-β-treated patients. Conclusions: This analysis demonstrates superiority of fingolimod over interferon β-1a intramuscular regardless of prior (interferon-β) treatment and prior treatment efficacy and duration. ClinicalTrials. gov identifier: NCT00340834. & 2014 Published by Elsevier B.V.
Introduction
Until recently, interferon (IFN) β and glatiramer acetate (GA) were the only approved first-line disease-modifying therapies (DMTs) for multiple sclerosis (MS). Prior studies have shown that most patients will experience disease activity on these compounds: 62–75% will relapse and 20–27% will worsen by 1 point on the Expanded Disability Status Scale (EDSS) within 2 years (The IFNB Multiple Sclerosis Study Group, 1993; Jacobs et al., 1996; Johnson et al., 1995; PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group, 1998). Not surprisingly, reported discontinuation rates after 1–3 years of IFNβ treatment range from 23% to 55%; for GA, discontinuation rates tend to be lower, but still range widely, from 9% to 57% (Haas and Firzlaff, 2005; Kleinman et al., 2010; Milanese et al., 2005; Reynolds et al., 2010; Ruggieri et al., 2003; Wong et al., 2011). One study of treatment adherence reported an unsatisfactory therapeutic response in 16–48% of IFNβ discontinuations and 25% of GA discontinuations (Milanese et al., 2005). Intolerable side effects are another important reason for DMT discontinuation, accounting for 10–50% of IFNβ discontinuations and 16% of GA discontinuations (Milanese et al., 2005; Ruggieri et al., 2003). Because IFNβ and GA responses vary among patients, with relatively high rates of failure and intolerable side effects, there remains a need for additional therapeutic options that are effective and well-tolerated. Fingolimod is an oral sphingosine 1-phosphate modulator approved in North America and Europe to treat relapsing MS at a dose of 0.5 mg once daily. Its approval was based on efficacy and safety demonstrated in 2 pivotal trials. In the 2-year phase 3 Fingolimod Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study, the annualized relapse rate (ARR) was significantly lower with once-daily treatment with fingolimod 0.5 mg ( 54%; Po0.001) or fingolimod 1.25 mg ( 60%; Po0.001) compared with placebo (Kappos et al.,
2010). In the 12-month, phase 3 Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS) study, the ARR was significantly lower with once-daily fingolimod 0.5 mg ( 52%; Po0.001) or fingolimod 1.25 mg ( 38%; Po0.001) compared with once-weekly intramuscular (IM) injection of IFNβ-1a 30-μg (Cohen et al., 2010). Previous subgroup analyses of TRANSFORMS study data showed that fingolimod 0.5 mg significantly reduced ARR in treatment-naive patients (P=0.002) and in patients with prior DMT treatment (Po0.001), as well as in subgroups by baseline disease characteristics (Cohen et al., 2013). To confirm the clinical benefit of fingolimod across treatment history subgroups, additional post-hoc analyses of the TRANSFORMS trial data were conducted to compare the efficacy and safety of fingolimod and IFNβ-1a IM in IFNβor GA-naive patients and in patients switching from prior IFNβ or GA therapy, as well as those who discontinued prior DMT for unsatisfactory treatment response or intolerable side effects. The impact of prior DMT treatment duration on efficacy and safety was also examined.
2. 2.1.
Material and methods Study design and patient population
TRANSFORMS was a 12-month, phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled trial, with optional extension (ClinicalTrials.gov number, NCT00340834) (Cohen et al., 2010). A total of 1292 patients with relapsing MS were randomly assigned to receive, with equal probability, once-daily fingolimod 0.5 mg (the dose approved by the United States Food and Drug Administration and other health authorities) or 1.25 mg or once-weekly interferon β-1a IM 30 μg for 12 months. The detailed study methodology was previously published in accordance with
Subgroup analyses of the TRANSFORMS study
357
2.3.
CONSORT guidelines (Cohen et al., 2010). The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by each site's institutional review board and all patients gave written informed consent.
2.2.
In the core TRANSFORMS study, statistical analyses were conducted in the intent-to-treat (ITT) population using a negative binomial regression model adjusted for treatment, country, the number of relapses within 2 years prior to enrollment, and baseline EDSS (Cohen et al., 2010). For the subgroup populations, ARRs with associated confidence intervals and ARR ratios with associated P values were estimated using a negative binomial regression model adjusted for treatment, subgroup variable, and treatment-by-subgroup variable interaction. AE data refer to treatment-emergent events, regardless of causality.
Study endpoints and subanalysis groups
The primary efficacy variable in the TRANSFORMS core study was ARR, defined as the number of confirmed relapses during a 12-month period. Confirmed relapse criteria included symptoms accompanied by one of the following: an increase of at least half a point in the EDSS score, 1 point increases in each of 2 EDSS functional system scores, or of 2 points in one EDSS functional system score (excluding scores for bowel-bladder or cerebral functioning systems). Secondary efficacy endpoints included time to disability progression confirmed at 3 months and MRI outcomes, including brain atrophy. Safety was assessed through adverse event (AE) reporting. Post-hoc analyses of the TRANSFORMS core study data were performed to evaluate ARR in subgroups of patients based on prior use of IFNβ therapy, prior use of GA therapy, discontinuation of prior DMT due to unsatisfactory therapeutic effect, discontinuation of prior DMT for AEs, and duration of prior DMT. Table 1
Statistical analysis
3.
Results
3.1.
Patients
A total of 1292 patients were randomly assigned to treatment. Demographic and baseline clinical characteristics for all patient subgroups are shown in Tables 1 and 2. The majority of patients (57.6%) had received treatment with a DMT prior to enrollment; 218 patients (17.0%) had a history of treatment with multiple DMTs.
Baseline patient demographics and clinical characteristics by treatment subgroup (randomized population).
Characteristic
Age, years Female, n (%) Duration of MS, years Relapses in previous 1 year, n Relapses in previous 2 years, n EDSS score Gd + lesions, n T2 lesion volume, mm3 Patients free of Gd + lesions, n (%)
IFNβ-naive patients
IFNβ-treated patients
Fingolimod 0.5 mg (n= 212)
Fingolimod 1.25 mg (n = 217)
IFNβ-1a IM (n = 228)
Fingolimod 0.5 mg (n= 219)
Fingolimod 1.25 mg (n = 209)
IFNβ-1a IM (n= 207)
35.8 130 3.36 1.6
35.0 144 3.25 1.6
35.0 155 3.27 1.5
37.6 152 6.23 1.5
36.6 149 5.97 1.4
37.1 140 6.73 1.4
(8.8) (61.3) (4.75) (0.8)
2.1 (1.1) 1.94 1.20 4338 134
(1.21) (3.53) (6078) (64.1)
(8.4) (66.4) (4.89) (0.9)
2.1 (1.1) 1.99 2.04 4980 119
(1.18) (6.13) (5771) (56.4)
(8.1) (68.0) (5.00) (7.9)
2.1 (1.1) 1.93 1.20 4212 135
(1.23) (3.23) (4691) (61.1)
(8.7) (69.4) (4.63) (1.5)
2.48 (2.9)
2.25 (1.3)
2.53 0.76 5971 154
2.45 0.91 5197 151
(1.37) (1.85) (7065) (70.6)
GA-naive patients
Age, years Female, n (%) Duration of MS, years Relapses in previous 1 year, n Relapses in previous 2 years, n EDSS score Gd + lesions, n
(8.3) (71.3) (4.52) (0.8)
(1.40) (2.58) (6170) (75.1)
(8.4) (67.6) (5.33) (0.8)
2.4 (1.4) 2.46 0.91 5695 133
(1.24) (2.25) (6567) (65.2)
GA-treated patients
Fingolimod 0.5 mg (n= 374)
Fingolimod 1.25 mg (n = 359)
IFNβ-1a IM (n = 368)
Fingolimod 0.5 mg (n = 67)
Fingolimod 1.25 mg (n= 57)
IFNβ-1a IM (n= 67)
36.5 24 4.49 1.5
35.7 237 4.03 1.5
35.7 245 4.37 1.4
38.0 41 7.00 1.5
35.9 56 7.48 1.6
37.6 50 7.99 1.8
(9.0) (64.4) (4.88) (1.2)
(8.4) (66.0) (4.53) (0.8)
(8.1) (66.6) (5.02) (0.7)
(7.3) (71.9) (4.50) (0.9)
(8.6) (83.6) (5.73) (1.1)
(9.3) (74.6) (6.59) (1.1)
2.3 (2.3)
2.2 (1.1)
2.2 (1.1)
2.4 (1.2)
2.3 (1.4)
2.8 (1.8)
2.16 (1.30) 0.99 (2.91)
2.14 (1.29) 1.37 (4.80)
2.12 (1.26) 1.12 (2.98)
2.77 (1.41) 0.75 (1.40)
2.60 (1.37) 0.88 (1.99)
2.55 (1.22) 2.14 (4.64)
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B.O. Khatri et al.
Table 1. (continued ) T2 lesion volume, mm3 Patients free of Gd + lesions, n (%)
4990 (6596)
4867 (5777)
4926 (5850)
6364 (6882)
6225 (6789)
4910 (4895)
252 (67.9)
236 (68.2)
224 (62.0)
36 (64.3)
34 (51.5)
44 (68.8)
Discontinued prior DMT owing to unsatisfactory therapeutic effect
Age, years Female, n (%) Duration of MS, years Relapses in previous 1 year, n Relapses in previous 2 years, n EDSS score Gd + lesions, n T2 lesion volume, mm3 Patients free of Gd + lesions, n (%)
Fingolimod 0.5 mg (n= 41)
Fingolimod 1.25 mg (n= 54)
IFNβ-1a IM (n = 45)
Fingolimod 0.5 mg (n = 390)
Fingolimod 1.25 mg (n= 372)
IFNβ-1a IM (n= 390)
37.2 25 6.99 1.6
34.0 44 7.11 1.8
36.5 29 8.41 1.7
36.7 257 4.59 1.5
36.0 249 4.21 1.5
35.9 266 4.52 1.4
(8.3) (61.0) (4.50) (1.0)
(8.7) (81.5) (4.50) (1.1)
(8.1) (64.4) (5.92) (1.0)
(8.9) (65.9) (4.89) (1.2)
(8.3) (66.9) (4.85) (0.8)
(8.3) (68.2) (5.24) (0.8)
3.0 (1.8)
2.6 (1.5)
3.0 (1.9)
2.2 (2.2)
2.1 (1.1)
2.2 (1.1)
2.60 (1.38) 0.71 (1.15) 7120 (7529)
2.81 (1.59) 1.77 (4.21) 8212 (9115)
2.76 (1.30) 0.89 (1.56) 6102 (6108)
2.20 (1.32) 1.01 (2.93) 4963 (6518)
2.13 (1.24) 1.45 (4.85) 4635 (5224)
2.12 (1.24) 1.08 (2.91) 4784 (5654)
27 (65.9)
34 (65.4)
28 (62.2)
261 (67.6)
236 (65.6)
240 (63.2)
Discontinued prior DMT owing to AE
Age, years Female, n (%) Duration of MS, years Relapses in previous 1 year, n Relapses in previous 2 years, n EDSS score Gd + lesions, n T2 lesion volume, mm3 Patients free of Gd + lesions, n (%)
Discontinued prior DMT for reason other than unsatisfactory therapeutic effect (includes DMT-naive patients)
Discontinued prior DMT for reason other than AE (includes DMT-naive patients)
Fingolimod 0.5 mg (n= 59)
Fingolimod 1.25 mg (n= 47)
IFNβ-1a IM (n = 51)
Fingolimod 0.5 mg (n = 372)
Fingolimod 1.25 mg (n= 379)
IFNβ-1a IM (n= 384)
37.5 45 7.09 1.5
36.4 35 8.28 1.5
37.2 43 7.41 1.6
36.6 237 4.46 1.5
35.7 258 4.11 1.5
35.8 252 4.60 1.4
(9.3) (76.3) (5.59) (0.9)
(8.4) (74.5) (6.14) (0.8)
(8.9) (84.3) (5.13) (0.9)
(8.7) (63.7) (4.68) (1.2)
(8.4) (68.1) (4.52) (0.9)
(8.2) (65.6) (5.40) (0.8)
2.4 (1.4)
2.3 (1.4)
2.5 (1.3)
2.3 (3.3)
2.2 (1.2)
2.2 (1.2)
2.65 (1.35) 1.19 (2.80) 5996 (6423)
2.86 (1.28) 1.00 (2.08) 4287 (3867)
2.64 (1.25) 0.96 (2.47) 4637 (4963)
2.17 (1.31) 0.94 (2.81) 5037 (6675)
2.13 (1.29) 1.55 (5.01) 5185 (6171)
2.13 (1.25) 1.07 (2.85) 4961 (5806)
38 (64.4)
30 (65.2)
30 (61.2)
250 (67.9)
240 (65.6)
238 (63.3)
AE=adverse event; DMT =disease-modifying therapy; EDSS=Expanded Disability Status Scale; GA=glatiramer acetate; Gd+ =gadolinium-enhancing; IFNβ =interferon beta; IM=intramuscular; MS=multiple sclerosis. All values are mean (SD) unless otherwise noted.
3.2. IFNβ-naive patients vs. those who received prior IFNβ Approximately 50% of patients had previously received IFNβ therapy (Table 1). Patients previously treated with IFNβ had a longer duration of MS than IFNβ-naive patients (6.31 years vs. 3.29 years, respectively), as well as higher EDSS scores (2.48 vs. 1.95), and greater mean baseline T2 lesion volume (5631 mm3 vs. 4506 mm3). Fingolimod 0.5 mg and 1.25 mg significantly reduced ARR compared with IFNβ-1a IM in patients with prior IFNβ treatment ( 58% and 39%, respectively, Po0.0001 and P=0.0069; Figs. 1 and 2). Fingolimod 0.5 mg and 1.25 mg were
also superior to IFNβ-1a IM in patients with no previous IFNβ treatment ( 43% and 41%, respectively (P=0.0092 and P=0.0131).
3.3. GA-naive patients vs. those that received prior GA A total of 179 patients had received prior GA, constituting a minority of all treatment subgroups (13–16%). Overall, patients with a history of GA treatment had longer mean duration of MS (7.52 years), higher EDSS score (2.63), and greater mean T2
Subgroup analyses of the TRANSFORMS study
359
Table 2 Baseline patient demographics and clinical characteristics by duration of prior disease-modifying therapy (randomized population). Characteristic
Age, years Female, n (%) Duration of MS, years Relapses in previous 1 year, n Relapses in previous 2 years, n EDSS score Gd + lesions, n T2 lesion volume, mm3 Patients free of Gd + lesions, n (%)
r1 year
No prior treatment Fingolimod 0.5 mg (n =184)
Fingolimod 1.25 mg (n= 170)
IFNβ-1a IM (n= 186)
Fingolimod 0.5 mg (n = 64)
Fingolimod 1.25 mg (n = 55)
IFNβ-1a IM (n= 64)
35.5 113 2.61 1.6
35.2 106 2.44 1.6
34.8 123 2.49 1.5
35.9 36 3.60 1.6
33.4 47 3.95 1.8
35.3 46 3.39 1.4
(8.9) (61.4) (3.77) (0.8)
(8.4) (62.4) (4.30) (0.8)
(7.9) (66.1) (4.02) (0.7)
(6.9) (73.4) (4.87) (1.0)
(8.7) (71.9) (3.77) (0.8)
2.1 (1.0)
2.1 (1.1)
2.1 (1.0)
2.2 (1.1)
2.3 (1.2)
2.3 (1.1)
1.85 (1.17) 1.10 (3.15) 4010 (5920)
1.95 (1.20) 1.92 (6.37) 4534 (5565)
1.84 (1.19) 1.31 (3.50) 4302 (4925)
2.36 (1.16) 1.36 (4.05) 6503 (6904)
2.24 (1.25) 1.69 (4.19) 6030 (6963)
2.22 (1.16) 0.68 (1.24) 4132 (4122)
120 (66.3)
98 (59.4)
107 (59.4)
33 (60.0)
39 (60.9)
40 (63.5)
41–3 years
Age, years Female, n (%) Duration of MS, years Relapses in previous 1 year, n Relapses in previous 2 years, n EDSS score Gd + lesions, n T2 lesion volume, mm3 Patients free of Gd + lesions, n (%)
(8.9) (65.5) (4.81) (0.7)
43 years
Fingolimod 0.5 mg (n =80)
Fingolimod 1.25 mg (n= 86)
IFNβ-1a IM (n= 75)
Fingolimod 0.5 mg (n = 111)
Fingolimod 1.25 mg (n = 101)
IFNβ-1a IM (n= 108)
36.9 56 4.50 1.4
35.7 66 4.27 1.4
35.6 50 5.13 1.4
39.1 76 9.46 1.5
38.3 70 8.62 1.3
38.5 75 9.70 1.4
(9.0) (70.0) (3.35) (1.0)
(9.4) (76.7) (3.25) (0.9)
(8.6) (66.7) (4.48) (0.8)
(8.1) (68.5) (4.47) (1.9)
(8.0) (69.3) (4.53) (0.8)
(7.9) (69.4) (5.75) (0.9)
2.5 (1.5)
2.4 (1.3)
2.6 (1.3)
2.4 (1.2)
2.3 (1.2)
2.3 (1.1)
2.23 (1.34) 0.81 (2.02) 4602 (5825)
2.05 (1.26) 1.22 (3.20) 5247 (6512)
2.24 (1.25) 0.80 (2.24) 4692 (5578)
2.82 (1.41) 0.70 (1.78) 6818 (7728)
2.78 (1.41) 0.88 (2.65) 5262 (5402)
2.68 (1.25) 0.99 (2.37) 6643 (7365)
55 (68.8)
56 (67.5)
54 (72.0)
80 (72.1)
77 (77.0)
67 (63.2)
DMT=disease-modifying therapy; EDSS=Expanded Disability Status Scale; Gd+ =gadolinium-enhancing; IFNβ =interferon beta; IM=intramuscular; MS=multiple sclerosis. All values are mean (SD) unless otherwise noted.
lesion volume (5814 mm3) compared with GA-naive patients (4.30 years, 2.12, and 4930 mm3, respectively). Compared with IFNβ-1a IM, fingolimod 0.5 mg and 1.25 mg significantly reduced ARR in GA-naive patients by 56% and 42%, respectively (Pr0.0005; Figs. 1 and 2). Fingolimod 0.5 mg and 1.25 mg numerically reduced ARR compared with IFNβ-1a IM by 28% and 31%, respectively, in patients with prior GA treatment (P=0.2804 and P=0.2118).
3.4. Prior DMT discontinuation owing to unsatisfactory therapeutic effect Unsatisfactory therapeutic effect of prior DMT was cited by 140 patients as a reason for participation in TRANSFORMS; more than 85% of these patients (37/41, 46/54, and 42/45 patients in
the fingolimod 0.5 mg, fingolimod 1.25 mg, and IFNβ-1a IM groups, respectively) were considered IFN treatment failures (i.e., previously treated with IFN and discontinued prior DMT owing to unsatisfactory treatment effect), so a separate analysis of IFN failures was not conducted. The subgroup of patients that did not discontinue prior DMT owing to unsatisfactory therapeutic effect included those who were DMT-naive. Baseline demographics and disease characteristics were generally comparable among patient subgroups based on unsatisfactory therapeutic response to DMT (Table 1). ARR was significantly reduced by fingolimod 0.5 mg compared with IFNβ-1a IM in patients who discontinued prior DMT for unsatisfactory therapeutic effect ( 57%; P=0.0369) and in those who discontinued prior DMT for other reasons ( 50%; Po0.0001; Fig. 1). Reductions in ARR with fingolimod 1.25 mg vs. IFNβ-1a IM were –38% in those who discontinued for unsatisfactory
360
B.O. Khatri et al. ARR
Subgroup
N*
Fingolimod 0.5 mg
IFNβ-1a IM
Reduction vs IFNβ-1a , %
P
Overall
860
0.16
0.33
52
