Multiplehttp://msj.sagepub.com/ Sclerosis Journal
Five-year results from a phase 2 study of oral fingolimod in relapsing multiple sclerosis G Izquierdo, P O'Connor, X Montalban, P von Rosenstiel, M Cremer, A de Vera, N Sfikas, G Francis, EW Radue and L Kappos Mult Scler published online 30 November 2013 DOI: 10.1177/1352458513513059 The online version of this article can be found at: http://msj.sagepub.com/content/early/2013/11/30/1352458513513059
Published by: http://www.sagepublications.com
On behalf of: European Committee for Treatment and Research in Multiple Sclerosis
Americas Committee for Treatment and Research in Multiple Sclerosis
Pan-Asian Committee for Treatment and Research in Multiple Sclerosis
Latin American Committee on Treatment and Research of Multiple Sclerosis
Additional services and information for Multiple Sclerosis Journal can be found at: Email Alerts: http://msj.sagepub.com/cgi/alerts Subscriptions: http://msj.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Downloaded from msj.sagepub.com at UNIV ESTDL DE MARINGA on May 21, 2014
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513059 2013
MSJ0010.1177/1352458513513059Multiple Sclerosis JournalIzquierdo et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Short Report
Five-year results from a phase 2 study of oral fingolimod in relapsing multiple sclerosis
Multiple Sclerosis Journal 0(0) 1–5 © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458513513059 msj.sagepub.com
G Izquierdo1, P O’Connor2, X Montalban3, P von Rosenstiel4, M Cremer4, A de Vera4, N Sfikas4, G Francis5, EW Radue6 and L Kappos7
Abstract We present here results at 60 months (M), from the extension component of a phase 2, randomized, placebo-controlled, double-blind, six-month study evaluating oral fingolimod (1.25 mg or 5 mg daily) in relapsing multiple sclerosis. Placebo patients from the core study were re-randomized to fingolimod 1.25 mg or 5 mg in the extension. All patients received 1.25 mg fingolimod after the M24 visit. A total of 140/281 (49.8%) patients completed M60. Fingolimod treatment was associated with a low annualized relapse rate (0.2 relapses/ year), low MRI activity, and a modest rate of disability progression in those treated for five years. No new safety issues were reported. Keywords Fingolimod, sphingosine 1-phosphate receptor modulator, disease-modifying therapy, relapsing–remitting multiple sclerosis, phase 2, long term Date received: 14 October 2013; accepted: 24 October 2013
Introduction Fingolimod (FTY720, GilenyaTM, Novartis Pharma AG), a sphingosine 1-phosphate receptor (S1PR) modulator,1 was the first oral disease-modifying therapy (DMT) to be approved for the treatment of relapsing multiple sclerosis (MS) and is administered at a dose of 0.5 mg once daily. Phase 3 trials have demonstrated the efficacy of fingolimod in comparison to intramuscular interferon β-1a (Avonex®)2 and placebo.3 We report here the results at five years from the longterm extension of a six-month phase 2, randomized, placebo-controlled trial,4 involving two doses of fingolimod (1.25 mg, 5 mg) higher than the approved dose (0.5 mg).
Methods The first patient in Study FTY720D2201 (NCT00785083) was dosed in May 2003 and the Month (M) 60 visit for the last patient was May 2009. Follow-up is ongoing until 2016 in an umbrella extension study. The study design, patient populations and eligibility criteria of the core4 and extension phases of this phase 2 study have been reported
previously.5,6 In the optional dose-blinded extension, patients assigned to placebo were re-randomized to oncedaily fingolimod 1.25 or 5.0 mg; patients originally on fingolimod continued their same dose.5,6 Between M15 and M24, patients receiving fingolimod 5.0 mg were switched, in a blinded fashion, to the 1.25 mg dose, based on a benefit risk assessment. After M60, dosing was further reduced to 0.5 mg based on results of phase 3 studies. Patients provided written informed consent for participation and the 1Department
of Neurology,Virgen Macarena Hospital, Spain. Michael’s Hospital, Canada. 3Hospital Universitari Vall d’Hebron, Spain. 4Novartis Pharma AG, Switzerland. 5Novartis Pharmaceuticals Corporation, USA. 6MS MRI Evaluation Center, Switzerland. 7Department of Neurology, University Hospital, University of Basel, Switzerland. 2St
Corresponding author: Ludwig Kappos, Department of Neurology, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. Email: [email protected]
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study conformed to the International Conference on Harmonization Guidelines for Good Clinical Practice7 and the Declaration of Helsinki.8 Visits were scheduled every three months up to M60. Clinical outcomes presented here include annualized relapse rates (ARR), time to-first-relapse, proportion of patients free of relapses, and six-month confirmed disability progression. Magnetic resonance imaging (MRI) scans were performed monthly until M6 and thereafter at M12, M18, M24, M36, M48 and M60. Results (patients free of MRI lesion activity and mean percentage change in brain volume [using the structural image evaluation using normalization of atrophy method, SIENA]) presented here include only patients with evaluable scans for the interval under consideration. Safety assessments were performed every three months. Statistical methods, power and sample size calculations have been published earlier.5,6 The study population was that of intention-to-treat and no imputation was made for missing data. Considering the length of the extension and the proportion of patients discontinuing (noncompleters), we also compared on-study behavior of completers and noncompleters in a post hoc analysis (see supplementary material).
Results Of the 281 patients recruited, 250 entered the extension and 140 patients (49.8%) completed the study at M60. Baseline demographic and disease characteristics were similar across treatment groups. Adverse events (AEs) (19.9%) and withdrawal of consent (14.6%) were the most common reasons of discontinuation. A low aggregate ARR (M0–M60) was sustained throughout the extension. The switch group experienced a two-thirds reduction in ARR within six months of the switch to fingolimod but showed a marginally higher ARR versus continuously treated patients in the extension (Table 1[a]). Over the entire study, risk of relapse was reduced and more continuously treated patients were relapse free (61%–68%) relative to switch patients, of whom 51% were relapse free. Six-month confirmed disability progression was noted in only 23% of patients completing M60 and the Kaplan-Meier estimate of the proportion of patients free from six-month confirmed disability progression (M0–M60) ranged from 60% to 71% (Table 1[b]). The proportion of patients (%) with no active T2 or gadolinium (Gd)-enhanced T1 lesions was higher for continuously treated patients versus placebo at M6 but values were comparable following the switch until M60 (Table 1[c]). The mean (SD) change in brain volume from M0 to M60 was −2.32% (2.61%) overall (n=129) and was comparable between dose groups (Table 1[d]).
After 60 months of treatment, 97.5% of patients experienced at least one AE (Table 2). Nasopharyngitis, headache, and influenza were the most frequently (>10%) reported AEs. Overall, 59 (21%) patients (5 / 1.25 mg: 25, 1.25 mg: 15, placebo/fingolimod: 19) had serious AEs (SAEs), of which 17 (6%) were in the core and 42 (15%) in the extension phase. The only SAEs that occurred in >1 patient in any group were bradycardia at treatment initiation (n=4), chest pain (n=3), macular edema (n=3, these cases were subsequently not confirmed), and two cases each of cholelithiasis, asthma, anxiety, MS relapse, palpitations, extra systoles, malignant melanoma and road accident. The most commonly reported AEs leading to study drug discontinuation were lymphopenia, increased alanine aminotransferase (ALT) (n=4 each, 1.4%), bradycardia and macular edema (n=3 each, 1.1%).
Discussion These results demonstrate that fingolimod treatment over five years is associated with continued low rates of MRI and clinical activity consistent with the six-month placebo-controlled phase. Relapse rate remained low at ~0.2/ year for the five years of continuous therapy, and more patients on continuous fingolimod remained relapse free after 60 months than in the switch group, although most of this is driven by the core phase differences. After switching from placebo to fingolimod, reduced disease activity was seen within the first six months and this was maintained for the remainder of the study. Brain volume loss (2.3%) over five years was consistent with that seen in fingolimod-treated patients in the two-year, Efficacy and Safety of Fingolimod in Patients with Relapsing– Remitting Multiple Sclerosis (FREEDOMS) study (0.4%/ year)3 and lower than that reported in untreated MS patients (0.6%–1.35% /year).9,10 Fingolimod treatment over five years was well tolerated and the observed safety profile was consistent with that reported previously.2–6 Somewhat higher rates of lymphopenia and leukopenia in continuously treated patients may reflect higher exposure to the drug than in switch patients. There were no new late-occurring or worsening safety events. Limitations of the present study are characteristic of long-term extensions of phase 2 and 3 studies, and include a discontinuation rate of >50% patients by the end of study, low overall sample size, absence of a control arm in the extension, lack of blinding beyond the M15 visit and retention bias if we assume that patients doing well were more likely to remain in the study. Nevertheless, these results demonstrate that patients who remain on fingolimod tolerate long-term therapy well and sustain a low level of disease activity as measured by relapses, disability progression, MRI lesion activity and loss of brain volume.
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Izquierdo et al. Table 1. Clinical and MRI outcomes. Placebo/fingolimod (N=93)a
Fingolimod 1.25 mg (N=94)
Fingolimod 5.0 mg (N=94)
All (N=281)
Clinical outcomes (a) Annualized relapse rateb from core baseline to end of study by time period (confirmed relapses only) Months 0–6 0.76 0.36 0.38 0.50 Months 6–12 0.21 0.25 0.16 0.20 Months 12–24 0.22 0.10 0.18 0.16 Months 24–36 0.18 0.21 0.17 0.19 Months 36–48 0.05 0.13 0.18 0.12 Months 48–60 0.06 0.08 0.11 0.08 Months 0–60 0.23 0.17 0.19 0.20 0.64 0.55 Hazard ratio (95% CI)c fingolimod vs placebo/fingolimod M 0-60 (0.40, 1.02) (0.33, 0.90) p valuesd 0.059 0.018 MRI: magnetic resonance imaging; CI: confidence interval. aPatients were on placebo up to Month 6. bAggregated annualized relapse rate is calculated for each treatment arm as (total number of relapses per treatment arm / total time at risk per treatment arm (days) × 365.25. cHazard ratios and p values are obtained from Cox proportional hazards model adjusted for treatment and number of relapses in previous two years prior to enrollment. dIndicates two-sided statistical significance. (b) Six-month confirmed disability progression on the EDSS scale, n(%) Confirmed 9 (22.5) 11 (22.9) 9 (22.5) 29 (22.7) progression (change from baseline ≥ +1) Progression is confirmed if observed at a regular visit and three and six months later. Change in EDSS is calculated as (Month 60)–(core baseline), i.e. negative values indicate improvement and positive values worsening. For a patient with EDSS more than or equal 5.5 at core baseline, an increase of 0.5 is counted as a one-unit step. KM estimates(SE), 0.66 (0.062) 0.71 (0.057), 0.60 (0.064), – (95% CI) of patients (0.541, 0.785) (0.603, 0.825) (0.474, 0.724) free from six-month confirmed disability progression at month 60 EDSS: Expanded Disability Status Scale; KM: Kaplan-Meier. The estimate is the proportion of patients without the event at the time point. 95% CI: 95% confidence interval for the Kaplan-Meier estimate. (c) Patients freee of new T2-weighted and gadolinium (Gd)-enhanced T1-weighted lesions,n(%) Month 6 38 (47.5%) 67 (77.0%) 67 (80.7%) 172 (68.8%) Month 12 40 (57.1%) 52 (67.5%) 51 (72.9%) 143 (65.9%) Month 24 44 (68.8%) 44 (69.8%) 44 (72.1%) 132 (70.2%) Month 36 44 (75.9%) 36 (65.5%) 44 (78.6%) 124 (73.4%) Month 48 45 (88.2%) 41 (78.8%) 36 (78.3%) 122 (81.9%) Month 60 40 (88.9%) 42 (87.5%) 35 (83.3%) 117 (86.7%) eA patient is defined as free of lesions if no new T2-weighted and no Gd-enhanced T1-weighted lesions are reported at a specific visit scan. New T2 lesions at a specific visit are assessed relative to the previous visit scan. The only exception was that new T2 lesions at Month 24 were assessed relative to the Month 12 scan. (d) Mean percentage change from core baseline in brain volume Months 0–6 –0.33 –0.25 –0.41 –0.33 Months 0–12 –0.70 –0.68 –0.68 –0.69 Months 0–24 –1.14 –1.10 –1.19 –1.14 Months 0–36 –1.58 –1.66 –1.63 –1.62 Months 0–48 –2.19 –2.13 –1.76 –2.03 Months 0–60 (n) –2.26 (42) –2.47 (45) –2.22 (42) –2.32 (129) The z-limit based percentage brain volume change is reported. n: number of patients with a change in brain volume assessment available at Month 60.
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Table 2. Adverse events (AEs) during months 0–60 (safety population n=281). Adverse events, n (%)
Placebo/fingolimod N=93
At least one AE 89 (95.7) Any serious AE 19 (20.4) Death 0 Study drug discontinued 20 (21.5) because of AE Most common AEs (>10% overall) Nasopharyngitis 29 (31.2) Headache 29 (31.2) Influenza 15 (16.1) Fatigue 20 (21.5) Back pain 19 (20.4) Lymphopenia 12 (12.9) URTI 14 (15.1) ALT increased 15 (16.1) Cough 10 (10.8) Diarrhea 10 (10.8) Arthralgia 16 (17.2) Depression 15 (16.1) Hypertension 9 (9.7) Bronchitis 8 (8.6) Leukopenia 8 (8.6) Nausea 8 (8.6) Insomnia 11 (11.8)
Fingolimod 1.25 mg N=94
Fingolimod 5.0 mg/1.25 mg N=94
All N=281
92 (97.9) 15 (16.0) 1 (1.1) 23 (24.5)
93 (98.9) 25 (26.6) 0 21 (22.3)
274 (97.5) 59 (21.0) 1 (0.4) 64 (22.8)
37 (39.4) 35 (37.2) 19 (20.2) 20 (21.3) 16 (17.0) 16 (17.0) 13 (13.8) 12 (12.8) 14 (14.9) 16 (17.0) 12 (12.8) 12 (12.8) 17 (18.1) 14 (14.9) 12 (12.8) 9 (9.6) 14 (14.9)
42 (44.7) 25 (26.6) 22 (23.4) 15 (16.0) 17 (18.1) 16 (17.0) 16 (17.0) 15 (16.0) 18 (19.1) 15 (16.0) 11 (11.7) 11 (11.7) 10 (10.6) 12 (12.8) 14 (14.9) 16 (17.0) 7 (7.4)
108 (38.4) 89 (31.7) 56 (19.9) 55 (19.6) 52 (18.5) 44 (15.7) 43 (15.3) 42 (14.9) 42 (14.9) 41 (14.6) 39 (13.9) 38 (13.5) 36 (12.8) 34 (12.1) 34 (12.1) 33 (11.7) 32 (11.4)
Adverse events could be reported more than once for each patient. AE: Adverse events; ALT: alanine aminotransferase; URTI: upper respiratory tract infection.
Acknowledgments The authors gratefully acknowledge Anupama Shrinivasan for medical writing assistance in developing the draft as per the authors’ directions, revising as per comments received from the authors and Terence Smith (both Medical Communications, Novartis Pharma) for coordinating author reviews. The final responsibility of content lies with the authors.
Funding This study was funded by Novartis Pharma AG; Clinicaltrials. gov: NCT00785083.
Conflicts of interest G Izquierdo has received honoraria for consultation from Biogen Idec, Merck Serono, Teva, Bayer, Novartis and Sanofi-Aventis. P O’Connor has received either personal compensation (for consulting, serving on a scientific advisory board, or speaking) or financial support for scholarly activities from pharmaceutical companies that develop products for MS, including Actelion, Biogen Idec., Celgene, Sanofi-Aventis, EMD Serono, Abbott Labs, Teva Pharmaceuticals, Bayer, Bio MS, Genentech, Lilly, Roche and Novartis. He has received consultation fees from the MS Society of Canada. Grant support has been received from the
MS Society of Canada, the National Institutes of Health (NIH) and Direct MS. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer, Biogen Idec, EMD, Merck, Genentech, GeNeuro, Genzyme, Novartis, Sanofi, Teva and Almirall. EW Radue received personal compensation from Bayer Schering, Biogen Idec, Novartis and Merck Serono for consulting and speaking services and financial support for research activities from Actelion, Basilea Pharmaceutica Ltd, Biogen Idec, Merck Serono and Novartis in the past two years. L Kappos: The University Hospital Basel, as employer of Prof Kappos, has received and dedicated to research support fees for board membership, consultancy or speaking, or grants, in the last three years from Actelion, Advancell, Allozyne, Bayer, Bayhill, Biogen Idec, BioMarin, CSLBehring, Eli Lilly, European Union, GeNeuro, Genmab, Gianni Rubatto Foundation, Glenmark, Merck Serono, MediciNova, Mitsubishi Pharma, Novartis, Novartis Research Foundation, Novonordisk, Peptimmune, Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, Swiss MS Society, Swiss National Research Foundation, Teva, UCB and Wyeth.
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Izquierdo et al. P von Rosenstiel, M Cremer, A de Vera and N Sfikas are employees of Novartis Pharma AG, Basel, Switzerland. G Francis is an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, and holds stock in Novartis.
References 1. Chun J and Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 2010; 33: 91–101. 2. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402–415. 3. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362: 387–401. 4. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006; 355: 1124–1140. 5. O’Connor P, Comi G, Montalban X, et al. Oral fingolimod (FTY720) in multiple sclerosis: Two-year results of a phase II extension study. Neurology 2009; 72: 73–79.
5 6. Comi G, O’Connor P, Montalban X, et al. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results. Mult Scler 2010; 16: 197–207. 7. IInternational Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline. Guideline for good clinical practice. http://www.ich.org/fileadmin/ Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_ R1/Step4/E6_R1__Guideline.pdf (accessed 11 November, 2013). 8. World Medical Association. Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. http://www.wma.net/en/30publications/10policies/b3/index. html(accessed 11 November, 2013 9. Anderson VM, Bartlett JW, Fox NC, et al. Detecting treatment effects on brain atrophy in relapsing remitting multiple sclerosis: Sample size estimates. J Neurol 2007; 254: 1588–1594. 10. Bermel RA and Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol 2006; 5: 158–170.
Five-year results from a phase 2 study of oral fingolimod in relapsing multiple sclerosis G Izquierdo, P O'Connor, X Montalban, P von Rosenstiel, M Cremer, A de Vera, N Sfikas, G Francis, EW Radue and L Kappos Mult Scler published online 30 November 2013 DOI: 10.1177/1352458513513059 The online version of this article can be found at: http://msj.sagepub.com/content/early/2013/11/30/1352458513513059
Published by: http://www.sagepublications.com
On behalf of: European Committee for Treatment and Research in Multiple Sclerosis
Americas Committee for Treatment and Research in Multiple Sclerosis
Pan-Asian Committee for Treatment and Research in Multiple Sclerosis
Latin American Committee on Treatment and Research of Multiple Sclerosis
Additional services and information for Multiple Sclerosis Journal can be found at: Email Alerts: http://msj.sagepub.com/cgi/alerts Subscriptions: http://msj.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Downloaded from msj.sagepub.com at UNIV ESTDL DE MARINGA on May 21, 2014
>> OnlineFirst Version of Record - Nov 30, 2013 What is This?
Downloaded from msj.sagepub.com at UNIV ESTDL DE MARINGA on May 21, 2014
513059 2013
MSJ0010.1177/1352458513513059Multiple Sclerosis JournalIzquierdo et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Short Report
Five-year results from a phase 2 study of oral fingolimod in relapsing multiple sclerosis
Multiple Sclerosis Journal 0(0) 1–5 © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458513513059 msj.sagepub.com
G Izquierdo1, P O’Connor2, X Montalban3, P von Rosenstiel4, M Cremer4, A de Vera4, N Sfikas4, G Francis5, EW Radue6 and L Kappos7
Abstract We present here results at 60 months (M), from the extension component of a phase 2, randomized, placebo-controlled, double-blind, six-month study evaluating oral fingolimod (1.25 mg or 5 mg daily) in relapsing multiple sclerosis. Placebo patients from the core study were re-randomized to fingolimod 1.25 mg or 5 mg in the extension. All patients received 1.25 mg fingolimod after the M24 visit. A total of 140/281 (49.8%) patients completed M60. Fingolimod treatment was associated with a low annualized relapse rate (0.2 relapses/ year), low MRI activity, and a modest rate of disability progression in those treated for five years. No new safety issues were reported. Keywords Fingolimod, sphingosine 1-phosphate receptor modulator, disease-modifying therapy, relapsing–remitting multiple sclerosis, phase 2, long term Date received: 14 October 2013; accepted: 24 October 2013
Introduction Fingolimod (FTY720, GilenyaTM, Novartis Pharma AG), a sphingosine 1-phosphate receptor (S1PR) modulator,1 was the first oral disease-modifying therapy (DMT) to be approved for the treatment of relapsing multiple sclerosis (MS) and is administered at a dose of 0.5 mg once daily. Phase 3 trials have demonstrated the efficacy of fingolimod in comparison to intramuscular interferon β-1a (Avonex®)2 and placebo.3 We report here the results at five years from the longterm extension of a six-month phase 2, randomized, placebo-controlled trial,4 involving two doses of fingolimod (1.25 mg, 5 mg) higher than the approved dose (0.5 mg).
Methods The first patient in Study FTY720D2201 (NCT00785083) was dosed in May 2003 and the Month (M) 60 visit for the last patient was May 2009. Follow-up is ongoing until 2016 in an umbrella extension study. The study design, patient populations and eligibility criteria of the core4 and extension phases of this phase 2 study have been reported
previously.5,6 In the optional dose-blinded extension, patients assigned to placebo were re-randomized to oncedaily fingolimod 1.25 or 5.0 mg; patients originally on fingolimod continued their same dose.5,6 Between M15 and M24, patients receiving fingolimod 5.0 mg were switched, in a blinded fashion, to the 1.25 mg dose, based on a benefit risk assessment. After M60, dosing was further reduced to 0.5 mg based on results of phase 3 studies. Patients provided written informed consent for participation and the 1Department
of Neurology,Virgen Macarena Hospital, Spain. Michael’s Hospital, Canada. 3Hospital Universitari Vall d’Hebron, Spain. 4Novartis Pharma AG, Switzerland. 5Novartis Pharmaceuticals Corporation, USA. 6MS MRI Evaluation Center, Switzerland. 7Department of Neurology, University Hospital, University of Basel, Switzerland. 2St
Corresponding author: Ludwig Kappos, Department of Neurology, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland. Email: [email protected]
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study conformed to the International Conference on Harmonization Guidelines for Good Clinical Practice7 and the Declaration of Helsinki.8 Visits were scheduled every three months up to M60. Clinical outcomes presented here include annualized relapse rates (ARR), time to-first-relapse, proportion of patients free of relapses, and six-month confirmed disability progression. Magnetic resonance imaging (MRI) scans were performed monthly until M6 and thereafter at M12, M18, M24, M36, M48 and M60. Results (patients free of MRI lesion activity and mean percentage change in brain volume [using the structural image evaluation using normalization of atrophy method, SIENA]) presented here include only patients with evaluable scans for the interval under consideration. Safety assessments were performed every three months. Statistical methods, power and sample size calculations have been published earlier.5,6 The study population was that of intention-to-treat and no imputation was made for missing data. Considering the length of the extension and the proportion of patients discontinuing (noncompleters), we also compared on-study behavior of completers and noncompleters in a post hoc analysis (see supplementary material).
Results Of the 281 patients recruited, 250 entered the extension and 140 patients (49.8%) completed the study at M60. Baseline demographic and disease characteristics were similar across treatment groups. Adverse events (AEs) (19.9%) and withdrawal of consent (14.6%) were the most common reasons of discontinuation. A low aggregate ARR (M0–M60) was sustained throughout the extension. The switch group experienced a two-thirds reduction in ARR within six months of the switch to fingolimod but showed a marginally higher ARR versus continuously treated patients in the extension (Table 1[a]). Over the entire study, risk of relapse was reduced and more continuously treated patients were relapse free (61%–68%) relative to switch patients, of whom 51% were relapse free. Six-month confirmed disability progression was noted in only 23% of patients completing M60 and the Kaplan-Meier estimate of the proportion of patients free from six-month confirmed disability progression (M0–M60) ranged from 60% to 71% (Table 1[b]). The proportion of patients (%) with no active T2 or gadolinium (Gd)-enhanced T1 lesions was higher for continuously treated patients versus placebo at M6 but values were comparable following the switch until M60 (Table 1[c]). The mean (SD) change in brain volume from M0 to M60 was −2.32% (2.61%) overall (n=129) and was comparable between dose groups (Table 1[d]).
After 60 months of treatment, 97.5% of patients experienced at least one AE (Table 2). Nasopharyngitis, headache, and influenza were the most frequently (>10%) reported AEs. Overall, 59 (21%) patients (5 / 1.25 mg: 25, 1.25 mg: 15, placebo/fingolimod: 19) had serious AEs (SAEs), of which 17 (6%) were in the core and 42 (15%) in the extension phase. The only SAEs that occurred in >1 patient in any group were bradycardia at treatment initiation (n=4), chest pain (n=3), macular edema (n=3, these cases were subsequently not confirmed), and two cases each of cholelithiasis, asthma, anxiety, MS relapse, palpitations, extra systoles, malignant melanoma and road accident. The most commonly reported AEs leading to study drug discontinuation were lymphopenia, increased alanine aminotransferase (ALT) (n=4 each, 1.4%), bradycardia and macular edema (n=3 each, 1.1%).
Discussion These results demonstrate that fingolimod treatment over five years is associated with continued low rates of MRI and clinical activity consistent with the six-month placebo-controlled phase. Relapse rate remained low at ~0.2/ year for the five years of continuous therapy, and more patients on continuous fingolimod remained relapse free after 60 months than in the switch group, although most of this is driven by the core phase differences. After switching from placebo to fingolimod, reduced disease activity was seen within the first six months and this was maintained for the remainder of the study. Brain volume loss (2.3%) over five years was consistent with that seen in fingolimod-treated patients in the two-year, Efficacy and Safety of Fingolimod in Patients with Relapsing– Remitting Multiple Sclerosis (FREEDOMS) study (0.4%/ year)3 and lower than that reported in untreated MS patients (0.6%–1.35% /year).9,10 Fingolimod treatment over five years was well tolerated and the observed safety profile was consistent with that reported previously.2–6 Somewhat higher rates of lymphopenia and leukopenia in continuously treated patients may reflect higher exposure to the drug than in switch patients. There were no new late-occurring or worsening safety events. Limitations of the present study are characteristic of long-term extensions of phase 2 and 3 studies, and include a discontinuation rate of >50% patients by the end of study, low overall sample size, absence of a control arm in the extension, lack of blinding beyond the M15 visit and retention bias if we assume that patients doing well were more likely to remain in the study. Nevertheless, these results demonstrate that patients who remain on fingolimod tolerate long-term therapy well and sustain a low level of disease activity as measured by relapses, disability progression, MRI lesion activity and loss of brain volume.
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Izquierdo et al. Table 1. Clinical and MRI outcomes. Placebo/fingolimod (N=93)a
Fingolimod 1.25 mg (N=94)
Fingolimod 5.0 mg (N=94)
All (N=281)
Clinical outcomes (a) Annualized relapse rateb from core baseline to end of study by time period (confirmed relapses only) Months 0–6 0.76 0.36 0.38 0.50 Months 6–12 0.21 0.25 0.16 0.20 Months 12–24 0.22 0.10 0.18 0.16 Months 24–36 0.18 0.21 0.17 0.19 Months 36–48 0.05 0.13 0.18 0.12 Months 48–60 0.06 0.08 0.11 0.08 Months 0–60 0.23 0.17 0.19 0.20 0.64 0.55 Hazard ratio (95% CI)c fingolimod vs placebo/fingolimod M 0-60 (0.40, 1.02) (0.33, 0.90) p valuesd 0.059 0.018 MRI: magnetic resonance imaging; CI: confidence interval. aPatients were on placebo up to Month 6. bAggregated annualized relapse rate is calculated for each treatment arm as (total number of relapses per treatment arm / total time at risk per treatment arm (days) × 365.25. cHazard ratios and p values are obtained from Cox proportional hazards model adjusted for treatment and number of relapses in previous two years prior to enrollment. dIndicates two-sided statistical significance. (b) Six-month confirmed disability progression on the EDSS scale, n(%) Confirmed 9 (22.5) 11 (22.9) 9 (22.5) 29 (22.7) progression (change from baseline ≥ +1) Progression is confirmed if observed at a regular visit and three and six months later. Change in EDSS is calculated as (Month 60)–(core baseline), i.e. negative values indicate improvement and positive values worsening. For a patient with EDSS more than or equal 5.5 at core baseline, an increase of 0.5 is counted as a one-unit step. KM estimates(SE), 0.66 (0.062) 0.71 (0.057), 0.60 (0.064), – (95% CI) of patients (0.541, 0.785) (0.603, 0.825) (0.474, 0.724) free from six-month confirmed disability progression at month 60 EDSS: Expanded Disability Status Scale; KM: Kaplan-Meier. The estimate is the proportion of patients without the event at the time point. 95% CI: 95% confidence interval for the Kaplan-Meier estimate. (c) Patients freee of new T2-weighted and gadolinium (Gd)-enhanced T1-weighted lesions,n(%) Month 6 38 (47.5%) 67 (77.0%) 67 (80.7%) 172 (68.8%) Month 12 40 (57.1%) 52 (67.5%) 51 (72.9%) 143 (65.9%) Month 24 44 (68.8%) 44 (69.8%) 44 (72.1%) 132 (70.2%) Month 36 44 (75.9%) 36 (65.5%) 44 (78.6%) 124 (73.4%) Month 48 45 (88.2%) 41 (78.8%) 36 (78.3%) 122 (81.9%) Month 60 40 (88.9%) 42 (87.5%) 35 (83.3%) 117 (86.7%) eA patient is defined as free of lesions if no new T2-weighted and no Gd-enhanced T1-weighted lesions are reported at a specific visit scan. New T2 lesions at a specific visit are assessed relative to the previous visit scan. The only exception was that new T2 lesions at Month 24 were assessed relative to the Month 12 scan. (d) Mean percentage change from core baseline in brain volume Months 0–6 –0.33 –0.25 –0.41 –0.33 Months 0–12 –0.70 –0.68 –0.68 –0.69 Months 0–24 –1.14 –1.10 –1.19 –1.14 Months 0–36 –1.58 –1.66 –1.63 –1.62 Months 0–48 –2.19 –2.13 –1.76 –2.03 Months 0–60 (n) –2.26 (42) –2.47 (45) –2.22 (42) –2.32 (129) The z-limit based percentage brain volume change is reported. n: number of patients with a change in brain volume assessment available at Month 60.
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Table 2. Adverse events (AEs) during months 0–60 (safety population n=281). Adverse events, n (%)
Placebo/fingolimod N=93
At least one AE 89 (95.7) Any serious AE 19 (20.4) Death 0 Study drug discontinued 20 (21.5) because of AE Most common AEs (>10% overall) Nasopharyngitis 29 (31.2) Headache 29 (31.2) Influenza 15 (16.1) Fatigue 20 (21.5) Back pain 19 (20.4) Lymphopenia 12 (12.9) URTI 14 (15.1) ALT increased 15 (16.1) Cough 10 (10.8) Diarrhea 10 (10.8) Arthralgia 16 (17.2) Depression 15 (16.1) Hypertension 9 (9.7) Bronchitis 8 (8.6) Leukopenia 8 (8.6) Nausea 8 (8.6) Insomnia 11 (11.8)
Fingolimod 1.25 mg N=94
Fingolimod 5.0 mg/1.25 mg N=94
All N=281
92 (97.9) 15 (16.0) 1 (1.1) 23 (24.5)
93 (98.9) 25 (26.6) 0 21 (22.3)
274 (97.5) 59 (21.0) 1 (0.4) 64 (22.8)
37 (39.4) 35 (37.2) 19 (20.2) 20 (21.3) 16 (17.0) 16 (17.0) 13 (13.8) 12 (12.8) 14 (14.9) 16 (17.0) 12 (12.8) 12 (12.8) 17 (18.1) 14 (14.9) 12 (12.8) 9 (9.6) 14 (14.9)
42 (44.7) 25 (26.6) 22 (23.4) 15 (16.0) 17 (18.1) 16 (17.0) 16 (17.0) 15 (16.0) 18 (19.1) 15 (16.0) 11 (11.7) 11 (11.7) 10 (10.6) 12 (12.8) 14 (14.9) 16 (17.0) 7 (7.4)
108 (38.4) 89 (31.7) 56 (19.9) 55 (19.6) 52 (18.5) 44 (15.7) 43 (15.3) 42 (14.9) 42 (14.9) 41 (14.6) 39 (13.9) 38 (13.5) 36 (12.8) 34 (12.1) 34 (12.1) 33 (11.7) 32 (11.4)
Adverse events could be reported more than once for each patient. AE: Adverse events; ALT: alanine aminotransferase; URTI: upper respiratory tract infection.
Acknowledgments The authors gratefully acknowledge Anupama Shrinivasan for medical writing assistance in developing the draft as per the authors’ directions, revising as per comments received from the authors and Terence Smith (both Medical Communications, Novartis Pharma) for coordinating author reviews. The final responsibility of content lies with the authors.
Funding This study was funded by Novartis Pharma AG; Clinicaltrials. gov: NCT00785083.
Conflicts of interest G Izquierdo has received honoraria for consultation from Biogen Idec, Merck Serono, Teva, Bayer, Novartis and Sanofi-Aventis. P O’Connor has received either personal compensation (for consulting, serving on a scientific advisory board, or speaking) or financial support for scholarly activities from pharmaceutical companies that develop products for MS, including Actelion, Biogen Idec., Celgene, Sanofi-Aventis, EMD Serono, Abbott Labs, Teva Pharmaceuticals, Bayer, Bio MS, Genentech, Lilly, Roche and Novartis. He has received consultation fees from the MS Society of Canada. Grant support has been received from the
MS Society of Canada, the National Institutes of Health (NIH) and Direct MS. X Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer, Biogen Idec, EMD, Merck, Genentech, GeNeuro, Genzyme, Novartis, Sanofi, Teva and Almirall. EW Radue received personal compensation from Bayer Schering, Biogen Idec, Novartis and Merck Serono for consulting and speaking services and financial support for research activities from Actelion, Basilea Pharmaceutica Ltd, Biogen Idec, Merck Serono and Novartis in the past two years. L Kappos: The University Hospital Basel, as employer of Prof Kappos, has received and dedicated to research support fees for board membership, consultancy or speaking, or grants, in the last three years from Actelion, Advancell, Allozyne, Bayer, Bayhill, Biogen Idec, BioMarin, CSLBehring, Eli Lilly, European Union, GeNeuro, Genmab, Gianni Rubatto Foundation, Glenmark, Merck Serono, MediciNova, Mitsubishi Pharma, Novartis, Novartis Research Foundation, Novonordisk, Peptimmune, Roche, Roche Research Foundation, Sanofi-Aventis, Santhera, Swiss MS Society, Swiss National Research Foundation, Teva, UCB and Wyeth.
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Izquierdo et al. P von Rosenstiel, M Cremer, A de Vera and N Sfikas are employees of Novartis Pharma AG, Basel, Switzerland. G Francis is an employee of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, and holds stock in Novartis.
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