Just Accepted by Current Medical Research & Opinion Brief Report Efficacy of fingolimod in patients with highly active relapsing– remitting multiple sclerosis T. Derfuss, N.K. Bergvall, N. Sfikas, D.L. Tomic doi: 10.1185/03007995.2015.1067191
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Abstract Objective: There is a need to identify effective switch therapies for patients with relapsing–remitting multiple sclerosis (RRMS) who experience high disease activity despite receiving disease-modifying therapy (DMT). The objective of this study was to assess the efficacy of fingolimod versus placebo in patients with RRMS who had experienced high disease activity despite previously receiving DMT, using post hoc analyses of two phase 3 trials: FREEDOMS (NCT00289978) and FREEDOMS II (NCT00355134). Research design and methods: Clinical and magnetic resonance imaging outcomes over 24 months were analysed in patients from FREEDOMS and FREEDOMS II who had received treatment in the previous year and had: 1) ≥ 1 relapse in the previous year and either ≥ 1 gadolinium (Gd)-enhancing T1 lesion or ≥ 9 T2 lesions at baseline and/or 2) as many or more relapses in the year before baseline as in the previous year (as per fingolimod’s EU label). Main outcome measures: The inclusion criteria were fulfilled by 249 and 257 patients in the fingolimod and placebo groups, respectively. Annualized relapse rates were reduced by 48% for fingolimod versus placebo (p < 0.001). Fingolimod reduced the risk of 3-month and 6-month confirmed disability progression by 34% (p = 0.031) and 45% (p = .016), respectively, versus placebo. Brain volume loss was reduced by 46% for fingolimod versus placebo (p < 0.001). The reduction in Gd-enhancing T1 lesion counts for fingolimod versus placebo was 65% (p < 0.001). Furthermore, fingolimod reduced the number of new or newly enlarged T2 lesions by 69% relative to placebo (p < 0.001). Limitation: The analyses are post hoc, but the population is specified by the European Medicines Agency in the label for fingolimod. Conclusions: Fingolimod demonstrated efficacy across all four key RRMS disease measures analysed in patients with high disease activity despite previous DMT.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
BRIEF REPORT Efficacy of fingolimod in patients with highly active relapsing–remitting multiple sclerosis T. Derfuss,a N.K. Bergvall,b N. Sfikas,b D.L. Tomicb
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a
Department of Biomedicine, University Hospital Basel, Basel, Switzerland
b
Novartis Pharma AG, Basel, Switzerland
Address for correspondence: Dr D.L. Tomic, Novartis Pharma AG, CH-4002 Basel, Switzerland. Tel: +41 613241111 ; [email protected]
Key words: Fingolimod, highly active RRMS, high disease activity, multiple sclerosis
[Short title: Fingolimod in patients with highly active RRMS]
1
Abstract Objective: There is a need to identify effective switch therapies for patients with relapsing–
Curr Med Res Opin Downloaded from informahealthcare.com by University of Otago on 07/03/15 For personal use only.
remitting multiple sclerosis (RRMS) who experience high disease activity despite receiving disease-modifying therapy (DMT). The objective of this study was to assess the efficacy of fingolimod versus placebo in patients with RRMS who had experienced high disease activity despite previously receiving DMT, using post hoc analyses of two phase 3 trials: FREEDOMS (NCT00289978) and FREEDOMS II (NCT00355134). Research design and methods: Clinical and magnetic resonance imaging outcomes over 24 months were analysed in patients from FREEDOMS and FREEDOMS II who had received treatment in the previous year and had: 1) ≥ 1 relapse in the previous year and either ≥ 1 gadolinium (Gd)-enhancing T1 lesion or ≥ 9 T2 lesions at baseline and/or 2) as many or more relapses in the year before baseline as in the previous year (as per fingolimod’s EU label). Main outcome measures: The inclusion criteria were fulfilled by 249 and 257 patients in the fingolimod and placebo groups, respectively. Annualized relapse rates were reduced by 48% for fingolimod versus placebo (p < 0.001). Fingolimod reduced the risk of 3-month and 6month confirmed disability progression by 34% (p = 0.031) and 45% (p = 0.016), respectively, versus placebo. Brain volume loss was reduced by 46% for fingolimod versus placebo (p < 0.001). The reduction in Gd-enhancing T1 lesion counts for fingolimod versus placebo was 65% (p < 0.001). Furthermore, fingolimod reduced the number of new or newly enlarged T2 lesions by 69% relative to placebo (p < 0.001).
2
Limitation: The analyses are post hoc, but the population is specified by the European Medicines Agency in the label for fingolimod. Conclusions: Fingolimod demonstrated efficacy across all four key RRMS disease measures analysed in patients with high disease activity despite previous DMT.
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Introduction The efficacy of fingolimod, the first oral therapy approved for the treatment of relapsing– remitting multiple sclerosis (RRMS), has been demonstrated in two phase 3, 24-month, placebo-controlled trials: FREEDOMS and FREEDOMS II1, 2. Previous analyses of data from the FREEDOMS trials, as well as the phase 3 TRANSFORMS study versus intramuscular interferon, suggest that subgroups of patients, with a wide spectrum of baseline and clinical characteristics, can potentially benefit from treatment with fingolimod3-5.
Fingolimod is approved in the EU for the treatment of patients with highly active RRMS, who include those with high disease activity despite previous disease-modifying therapy (DMT) with interferon, glatiramer acetate, natalizumab, dimethyl fumarate, teriflunomide or alemtuzumab6. These patients, specified by the European Medicines Agency in the label for fingolimod, are a clinically important population worldwide, requiring highly efficacious treatment where first-line therapy is not effective. We performed a post hoc analysis to estimate the efficacy of fingolimod on four key measures of RRMS disease, representing focal (predominantly neuroinflammatory) and diffuse (neuroinflammatory and neurodegenerative) damage, in patients with high disease activity despite previous DMT, using pooled data from FREEDOMS and FREEDOMS II.
3
Patients and methods Details of FREEDOMS and FREEDOMS II have been reported previously1, 2. FREEDOMS and FREEDOMS II were conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice, and the Declaration of Helsinki. Each
Curr Med Res Opin Downloaded from informahealthcare.com by University of Otago on 07/03/15 For personal use only.
trial site obtained institutional review board approval, and patients provided written informed consent before participation. The ClinicalTrials.gov identifiers for FREEDOMS and FREEDOMS II are NCT00289978 and NCT00355134, respectively.
A post hoc analysis was performed to assess the efficacy of the approved fingolimod dose (0.5 mg) versus placebo in patients from the FREEDOMS trials who had high disease activity despite previous DMT, according to the following criteria: 1) ≥ 1 relapse in the previous year and either ≥ 1 gadolinium (Gd)-enhancing T1 lesion or ≥ 9 T2 lesions at baseline and/or 2) as many or more relapses in the year before baseline as in the previous year.
Analyses of the primary and several secondary endpoints of the FREEDOMS trials were performed, and were conducted as pre-specified for the trials (i.e. statistical models and covariate selection). The annualized relapse rate (ARR; number of confirmed relapses per year) ratio for fingolimod versus placebo over 24 months was estimated using a negative binomial model, adjusted for treatment, relapses in the previous 2 years and study. Hazard ratios (HRs) for the risk of 3-month or 6-month confirmed disability progression (CDP) were derived using a Cox proportional hazard model, adjusted for treatment, baseline Expanded Disability Status Scale (EDSS) score, age and study. The mean percentage brain volume
4
change (PBVC) from baseline to month 24 and the mean number of Gd-enhancing T1 lesions at month 24 were assessed by analysis of co-variance regression models, adjusted for treatment, study and baseline normalized brain volume and for baseline Gd-enhancing T1 lesion count, respectively. Ratios of new or newly enlarged T2 lesions from baseline to month 24 were estimated using a negative binomial model, log-link, adjusted for treatment and study. In addition to pre-specified analyses, analyses were performed on all outcomes in
Curr Med Res Opin Downloaded from informahealthcare.com by University of Otago on 07/03/15 For personal use only.
which models were also adjusted for number of pre-study DMTs, most recently used DMT or number of Gd-enhancing T1 lesions.
Results A total of 506 patients were included in the analysis, 249 receiving fingolimod and 257 receiving placebo. With the exception of most recently used DMT (p = 0.009), there were no statistically significant differences in baseline demographic and clinical characteristics between the two groups (Table 1).
The ARR for patients receiving fingolimod was significantly lower than for those receiving placebo, equating to a relative reduction of 48% (p < 0.001; Figure 1a). The proportion of patients with 3-month CDP was reduced for patients on fingolimod (18.5%) compared with those on placebo (24.9%). The risk of 3-month CDP was significantly reduced by 34% in patients treated with fingolimod compared with those receiving placebo (p = 0.031); the corresponding value for 6-month CDP was 45% (p = 0.016; Figure 1b). A further analysis of 6-month CDP was performed to account for known variability in EDSS progression7. Using alternative criteria to define 6-month CDP (1.5 point change in EDSS score for patients with
5
a baseline score of 0 that was sustained at last observation), fingolimod was associated with a 54% (HR: 0.46; 95% CI: 0.25–0.84) reduction versus placebo.
Mean PBVC from baseline to month 24 was reduced by 46% for fingolimod versus placebo (p < 0.001; Figure 1c). The mean number of Gd-enhancing T1 lesions at month 24 was 65%
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lower for patients treated with fingolimod than for those treated with placebo (p < 0.001; Figure 1d). For new or newly enlarged T2 lesions at month 24, there was a 69% reduction (p < 0.001; Figure 1e) for fingolimod versus placebo.
In further analyses adjusting for additional baseline characteristics (number of pre-study DMTs, most recently used DMT or number of Gd-enhancing T1 lesions), in which differences between the treatment groups could influence the outcomes, results were near identical to those in the original analyses.
Discussion For many patients with multiple sclerosis, the effectiveness of first-line therapies, such as interferons and glatiramer acetate, is limited8 prompting those who continue to experience high disease activity to switch to alternative therapy. In one study, perceived limited effectiveness led to 29% of patients discontinuing treatment with interferons9. Unless switched to an effective second-line therapy, these patients usually experience continuous breakthrough disease10. However, some commonly used second-line therapies (e.g. natalizumab and immunosuppressive agents) have safety limitations and often cannot be used for extended periods of time11. Fingolimod has been shown to be superior to intramuscular
6
interferon beta-1a (IFNb-1a) in the treatment of RRMS12, including in patients with high disease activity despite previous DMT3, and has a fundamentally different mode of action from commonly used first-line DMTs. Consequently, switching from intramuscular IFNb-1a to fingolimod is associated with improvements in disease outcomes13. These factors might explain why fingolimod is considered highly efficacious for patients with high disease activity despite previous DMT; this efficacy is substantiated by this subgroup analysis. The
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results of this subgroup analysis are also in agreement with those of a retrospective analysis of data collected prospectively from MSBase that found that switching from injectable immunomodulators to fingolimod is associated with fewer relapses and more favourable disability outcomes, compared with switching to another injectable therapy, in patients with active RRMS14. Taken together, these findings suggest that fingolimod may be an appropriate first choice switch therapy for patients with active RRMS. Ongoing registry studies will determine whether the efficacy of fingolimod in randomized trials translates to reduced irreversible disability progression and other long-term treatment benefits in clinical practice.
Conclusion In patients with high disease activity despite previous DMT, fingolimod had significant efficacy in all four key measures of RRMS compared with placebo. The patients included in this post hoc analysis represent one of the groups specified in the EU label for fingolimod6, and are an important patient population for which effective therapies are required.
7
Transparency Declaration of funding: This study and report were funded by Novartis Pharma AG.
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Declaration of financial/other relationships: T. Derfuss serves on scientific advisory boards for Novartis Pharmaceuticals, Merck Serono, Biogen Idec, Genzyme, GeNeuro, Mitsubishi Pharma, Teva Pharmaceuticals, and Bayer Schering Pharma; he has received funding for travel and/or speaker honoraria from Biogen Idec, Genzyme, Novartis Pharmaceuticals, Merck Serono, and Bayer Schering Pharma, and receives research support from Biogen Idec, Novartis Pharmaceuticals, the European Union, the Swiss National Foundation, and the Swiss Multiple Sclerosis Society. N.K. Bergvall, N. Sfikas and D.L.Tomic are paid employees of Novartis Pharma AG. CMRO Peer Reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose.
Acknowledgements: The authors thank Dr Colin Glen and Dr Gemma Carter (Oxford PharmaGenesis) for medical writing support, editorial assistance, and collation and incorporation of comments from all authors. This support was funded by Novartis Pharma AG.
Previous presentation:
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This study was presented as a poster at the 66th American Academy of Neurology Annual
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Meeting between April 26 and May 3 2014 in Philadelphia, USA.
9
References 1.
Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol 2014;13:545–56.
2
Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral
Curr Med Res Opin Downloaded from informahealthcare.com by University of Otago on 07/03/15 For personal use only.
fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387–401. 3.
Cohen JA, Barkhof F, Comi G, et al. Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS. J Neurol 2013;260:2023–32.
4.
Devonshire V, Havrdova E, Radue EW, et al. Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol 2012;11:420–8.
5.
Goodin D, Jeffery D, Kappos L, et al. Fingolimod reduces annaulized relapse rate in patients with relapsing–remitting multiple sclerosis: FREEDOMS II study subgroup analysis. Poster presented the 65th AAN Annual Meeting, San Diego, USA, March 16–23 2013:PO7.102
6.
EMA. European Public Assessment Report for Gilenya, annex I, summary of product characteristics. 2011 (accessed March 2015); Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002202/WC500104528.pdf.
7.
Healy BC, Engler D, Glanz B, et al. Assessment of definitions of sustained disease progression in relapsing-remitting multiple sclerosis. Mult Scler Int 2013;2013:189624.
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8.
Derwenskus J. Current disease-modifying treatment of multiple sclerosis. Mt Sinai J Med 2011;78:161–75.
9.
Portaccio E, Zipoli V, Siracusa G, et al. Long-term adherence to interferon beta therapy in relapsing-remitting multiple sclerosis. Eur Neurol 2008;59:131–5.
10.
Castillo-Trivino T, Mowry EM, Gajofatto A, et al. Switching multiple sclerosis
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patients with breakthrough disease to second-line therapy. PLoS One 2011;6:e16664. 11.
Carrithers MD. Update on disease-modifying treatments for multiple sclerosis. Clin Ther 2014;36:1938–45
12.
Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402–15.
13.
Khatri B, Barkhof F, Comi G, et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol 2011;10:520–9.
14.
He A, Spelman T, Jokubaitis V, et al. Comparison of switch to fingolimod or interferon beta/glatiramer acetate in active multiple sclerosis. JAMA Neurol 2015:1– 10.
11
Tables and figures Table 1. Baseline demographics and clinical characteristics for patients with high disease activity despite previous DMT Characteristic
Placebo
Fingolimod
(N = 257)
(N = 249)
Female
74.7
76.3
Male
25.3
23.7
39.2 (8.4)
39.3 (8.8)
Since diagnosis
6.2 (5.5)
6.3 (5.6)
Since first symptom
10.2 (7.2)
10.0 (7.5)
Interferon beta
53.3
63.9
Glatiramer acetate
30.7
25.3
Natalizumab
5.1
0.8
Other MS medications
10.9
10.0
1 DMT
56.4
53.4
2 DMTs
23.3
31.7
≥ 3 DMTs
20.3
14.8
In the past year
1.6 (0.9)
1.5 (0.8)
In the past 2 years
2.4 (1.5)
2.3 (1.4)
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Sex, %
Age, years Duration of MS, years
Most recently used DMT, %
DMT used before study, %
Number of relapses, n
12
EDSS score, %
2.7 (1.4)
2.5 (1.3)
Number of Gd-enhancing T1 lesions
1.3 (3.0)
1.9 (6.6)
6267.5 (7922.3)
6118.5 (7914.6)
1507.0 (93.6)
1516.4 (83.0)
Total volume of T2 lesions, mm3 Brain volume, cm3
Values are mean (standard deviation) unless otherwise stated. DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; Gd, gadolinium; Curr Med Res Opin Downloaded from informahealthcare.com by University of Otago on 07/03/15 For personal use only.
MS, multiple sclerosis
13
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Figure 1.
Figure 1 caption. Estimated reductions in (a) Annualized relapse rate (ARR), (b) 6-month confirmed disability progression (CDP), (c) mean percentage brain volume change (PBVC), (d) mean number of gadolinium (Gd-) enhancing T1 lesions and (e) mean number of new or
14
newly enlarged T2 lesions for fingolimod versus placebo in patients with high disease
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activity despite previous disease-modifying therapy
15
Curr Med Res Opin Downloaded from informahealthcare.com by University of Otago on 07/03/15 For personal use only.
Abstract Objective: There is a need to identify effective switch therapies for patients with relapsing–remitting multiple sclerosis (RRMS) who experience high disease activity despite receiving disease-modifying therapy (DMT). The objective of this study was to assess the efficacy of fingolimod versus placebo in patients with RRMS who had experienced high disease activity despite previously receiving DMT, using post hoc analyses of two phase 3 trials: FREEDOMS (NCT00289978) and FREEDOMS II (NCT00355134). Research design and methods: Clinical and magnetic resonance imaging outcomes over 24 months were analysed in patients from FREEDOMS and FREEDOMS II who had received treatment in the previous year and had: 1) ≥ 1 relapse in the previous year and either ≥ 1 gadolinium (Gd)-enhancing T1 lesion or ≥ 9 T2 lesions at baseline and/or 2) as many or more relapses in the year before baseline as in the previous year (as per fingolimod’s EU label). Main outcome measures: The inclusion criteria were fulfilled by 249 and 257 patients in the fingolimod and placebo groups, respectively. Annualized relapse rates were reduced by 48% for fingolimod versus placebo (p < 0.001). Fingolimod reduced the risk of 3-month and 6-month confirmed disability progression by 34% (p = 0.031) and 45% (p = .016), respectively, versus placebo. Brain volume loss was reduced by 46% for fingolimod versus placebo (p < 0.001). The reduction in Gd-enhancing T1 lesion counts for fingolimod versus placebo was 65% (p < 0.001). Furthermore, fingolimod reduced the number of new or newly enlarged T2 lesions by 69% relative to placebo (p < 0.001). Limitation: The analyses are post hoc, but the population is specified by the European Medicines Agency in the label for fingolimod. Conclusions: Fingolimod demonstrated efficacy across all four key RRMS disease measures analysed in patients with high disease activity despite previous DMT.
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
BRIEF REPORT Efficacy of fingolimod in patients with highly active relapsing–remitting multiple sclerosis T. Derfuss,a N.K. Bergvall,b N. Sfikas,b D.L. Tomicb
Curr Med Res Opin Downloaded from informahealthcare.com by University of Otago on 07/03/15 For personal use only.
a
Department of Biomedicine, University Hospital Basel, Basel, Switzerland
b
Novartis Pharma AG, Basel, Switzerland
Address for correspondence: Dr D.L. Tomic, Novartis Pharma AG, CH-4002 Basel, Switzerland. Tel: +41 613241111 ; [email protected]
Key words: Fingolimod, highly active RRMS, high disease activity, multiple sclerosis
[Short title: Fingolimod in patients with highly active RRMS]
1
Abstract Objective: There is a need to identify effective switch therapies for patients with relapsing–
Curr Med Res Opin Downloaded from informahealthcare.com by University of Otago on 07/03/15 For personal use only.
remitting multiple sclerosis (RRMS) who experience high disease activity despite receiving disease-modifying therapy (DMT). The objective of this study was to assess the efficacy of fingolimod versus placebo in patients with RRMS who had experienced high disease activity despite previously receiving DMT, using post hoc analyses of two phase 3 trials: FREEDOMS (NCT00289978) and FREEDOMS II (NCT00355134). Research design and methods: Clinical and magnetic resonance imaging outcomes over 24 months were analysed in patients from FREEDOMS and FREEDOMS II who had received treatment in the previous year and had: 1) ≥ 1 relapse in the previous year and either ≥ 1 gadolinium (Gd)-enhancing T1 lesion or ≥ 9 T2 lesions at baseline and/or 2) as many or more relapses in the year before baseline as in the previous year (as per fingolimod’s EU label). Main outcome measures: The inclusion criteria were fulfilled by 249 and 257 patients in the fingolimod and placebo groups, respectively. Annualized relapse rates were reduced by 48% for fingolimod versus placebo (p < 0.001). Fingolimod reduced the risk of 3-month and 6month confirmed disability progression by 34% (p = 0.031) and 45% (p = 0.016), respectively, versus placebo. Brain volume loss was reduced by 46% for fingolimod versus placebo (p < 0.001). The reduction in Gd-enhancing T1 lesion counts for fingolimod versus placebo was 65% (p < 0.001). Furthermore, fingolimod reduced the number of new or newly enlarged T2 lesions by 69% relative to placebo (p < 0.001).
2
Limitation: The analyses are post hoc, but the population is specified by the European Medicines Agency in the label for fingolimod. Conclusions: Fingolimod demonstrated efficacy across all four key RRMS disease measures analysed in patients with high disease activity despite previous DMT.
Curr Med Res Opin Downloaded from informahealthcare.com by University of Otago on 07/03/15 For personal use only.
Introduction The efficacy of fingolimod, the first oral therapy approved for the treatment of relapsing– remitting multiple sclerosis (RRMS), has been demonstrated in two phase 3, 24-month, placebo-controlled trials: FREEDOMS and FREEDOMS II1, 2. Previous analyses of data from the FREEDOMS trials, as well as the phase 3 TRANSFORMS study versus intramuscular interferon, suggest that subgroups of patients, with a wide spectrum of baseline and clinical characteristics, can potentially benefit from treatment with fingolimod3-5.
Fingolimod is approved in the EU for the treatment of patients with highly active RRMS, who include those with high disease activity despite previous disease-modifying therapy (DMT) with interferon, glatiramer acetate, natalizumab, dimethyl fumarate, teriflunomide or alemtuzumab6. These patients, specified by the European Medicines Agency in the label for fingolimod, are a clinically important population worldwide, requiring highly efficacious treatment where first-line therapy is not effective. We performed a post hoc analysis to estimate the efficacy of fingolimod on four key measures of RRMS disease, representing focal (predominantly neuroinflammatory) and diffuse (neuroinflammatory and neurodegenerative) damage, in patients with high disease activity despite previous DMT, using pooled data from FREEDOMS and FREEDOMS II.
3
Patients and methods Details of FREEDOMS and FREEDOMS II have been reported previously1, 2. FREEDOMS and FREEDOMS II were conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice, and the Declaration of Helsinki. Each
Curr Med Res Opin Downloaded from informahealthcare.com by University of Otago on 07/03/15 For personal use only.
trial site obtained institutional review board approval, and patients provided written informed consent before participation. The ClinicalTrials.gov identifiers for FREEDOMS and FREEDOMS II are NCT00289978 and NCT00355134, respectively.
A post hoc analysis was performed to assess the efficacy of the approved fingolimod dose (0.5 mg) versus placebo in patients from the FREEDOMS trials who had high disease activity despite previous DMT, according to the following criteria: 1) ≥ 1 relapse in the previous year and either ≥ 1 gadolinium (Gd)-enhancing T1 lesion or ≥ 9 T2 lesions at baseline and/or 2) as many or more relapses in the year before baseline as in the previous year.
Analyses of the primary and several secondary endpoints of the FREEDOMS trials were performed, and were conducted as pre-specified for the trials (i.e. statistical models and covariate selection). The annualized relapse rate (ARR; number of confirmed relapses per year) ratio for fingolimod versus placebo over 24 months was estimated using a negative binomial model, adjusted for treatment, relapses in the previous 2 years and study. Hazard ratios (HRs) for the risk of 3-month or 6-month confirmed disability progression (CDP) were derived using a Cox proportional hazard model, adjusted for treatment, baseline Expanded Disability Status Scale (EDSS) score, age and study. The mean percentage brain volume
4
change (PBVC) from baseline to month 24 and the mean number of Gd-enhancing T1 lesions at month 24 were assessed by analysis of co-variance regression models, adjusted for treatment, study and baseline normalized brain volume and for baseline Gd-enhancing T1 lesion count, respectively. Ratios of new or newly enlarged T2 lesions from baseline to month 24 were estimated using a negative binomial model, log-link, adjusted for treatment and study. In addition to pre-specified analyses, analyses were performed on all outcomes in
Curr Med Res Opin Downloaded from informahealthcare.com by University of Otago on 07/03/15 For personal use only.
which models were also adjusted for number of pre-study DMTs, most recently used DMT or number of Gd-enhancing T1 lesions.
Results A total of 506 patients were included in the analysis, 249 receiving fingolimod and 257 receiving placebo. With the exception of most recently used DMT (p = 0.009), there were no statistically significant differences in baseline demographic and clinical characteristics between the two groups (Table 1).
The ARR for patients receiving fingolimod was significantly lower than for those receiving placebo, equating to a relative reduction of 48% (p < 0.001; Figure 1a). The proportion of patients with 3-month CDP was reduced for patients on fingolimod (18.5%) compared with those on placebo (24.9%). The risk of 3-month CDP was significantly reduced by 34% in patients treated with fingolimod compared with those receiving placebo (p = 0.031); the corresponding value for 6-month CDP was 45% (p = 0.016; Figure 1b). A further analysis of 6-month CDP was performed to account for known variability in EDSS progression7. Using alternative criteria to define 6-month CDP (1.5 point change in EDSS score for patients with
5
a baseline score of 0 that was sustained at last observation), fingolimod was associated with a 54% (HR: 0.46; 95% CI: 0.25–0.84) reduction versus placebo.
Mean PBVC from baseline to month 24 was reduced by 46% for fingolimod versus placebo (p < 0.001; Figure 1c). The mean number of Gd-enhancing T1 lesions at month 24 was 65%
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lower for patients treated with fingolimod than for those treated with placebo (p < 0.001; Figure 1d). For new or newly enlarged T2 lesions at month 24, there was a 69% reduction (p < 0.001; Figure 1e) for fingolimod versus placebo.
In further analyses adjusting for additional baseline characteristics (number of pre-study DMTs, most recently used DMT or number of Gd-enhancing T1 lesions), in which differences between the treatment groups could influence the outcomes, results were near identical to those in the original analyses.
Discussion For many patients with multiple sclerosis, the effectiveness of first-line therapies, such as interferons and glatiramer acetate, is limited8 prompting those who continue to experience high disease activity to switch to alternative therapy. In one study, perceived limited effectiveness led to 29% of patients discontinuing treatment with interferons9. Unless switched to an effective second-line therapy, these patients usually experience continuous breakthrough disease10. However, some commonly used second-line therapies (e.g. natalizumab and immunosuppressive agents) have safety limitations and often cannot be used for extended periods of time11. Fingolimod has been shown to be superior to intramuscular
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interferon beta-1a (IFNb-1a) in the treatment of RRMS12, including in patients with high disease activity despite previous DMT3, and has a fundamentally different mode of action from commonly used first-line DMTs. Consequently, switching from intramuscular IFNb-1a to fingolimod is associated with improvements in disease outcomes13. These factors might explain why fingolimod is considered highly efficacious for patients with high disease activity despite previous DMT; this efficacy is substantiated by this subgroup analysis. The
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results of this subgroup analysis are also in agreement with those of a retrospective analysis of data collected prospectively from MSBase that found that switching from injectable immunomodulators to fingolimod is associated with fewer relapses and more favourable disability outcomes, compared with switching to another injectable therapy, in patients with active RRMS14. Taken together, these findings suggest that fingolimod may be an appropriate first choice switch therapy for patients with active RRMS. Ongoing registry studies will determine whether the efficacy of fingolimod in randomized trials translates to reduced irreversible disability progression and other long-term treatment benefits in clinical practice.
Conclusion In patients with high disease activity despite previous DMT, fingolimod had significant efficacy in all four key measures of RRMS compared with placebo. The patients included in this post hoc analysis represent one of the groups specified in the EU label for fingolimod6, and are an important patient population for which effective therapies are required.
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Transparency Declaration of funding: This study and report were funded by Novartis Pharma AG.
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Declaration of financial/other relationships: T. Derfuss serves on scientific advisory boards for Novartis Pharmaceuticals, Merck Serono, Biogen Idec, Genzyme, GeNeuro, Mitsubishi Pharma, Teva Pharmaceuticals, and Bayer Schering Pharma; he has received funding for travel and/or speaker honoraria from Biogen Idec, Genzyme, Novartis Pharmaceuticals, Merck Serono, and Bayer Schering Pharma, and receives research support from Biogen Idec, Novartis Pharmaceuticals, the European Union, the Swiss National Foundation, and the Swiss Multiple Sclerosis Society. N.K. Bergvall, N. Sfikas and D.L.Tomic are paid employees of Novartis Pharma AG. CMRO Peer Reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose.
Acknowledgements: The authors thank Dr Colin Glen and Dr Gemma Carter (Oxford PharmaGenesis) for medical writing support, editorial assistance, and collation and incorporation of comments from all authors. This support was funded by Novartis Pharma AG.
Previous presentation:
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This study was presented as a poster at the 66th American Academy of Neurology Annual
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Meeting between April 26 and May 3 2014 in Philadelphia, USA.
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References 1.
Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol 2014;13:545–56.
2
Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral
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fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387–401. 3.
Cohen JA, Barkhof F, Comi G, et al. Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS. J Neurol 2013;260:2023–32.
4.
Devonshire V, Havrdova E, Radue EW, et al. Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol 2012;11:420–8.
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Goodin D, Jeffery D, Kappos L, et al. Fingolimod reduces annaulized relapse rate in patients with relapsing–remitting multiple sclerosis: FREEDOMS II study subgroup analysis. Poster presented the 65th AAN Annual Meeting, San Diego, USA, March 16–23 2013:PO7.102
6.
EMA. European Public Assessment Report for Gilenya, annex I, summary of product characteristics. 2011 (accessed March 2015); Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/002202/WC500104528.pdf.
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Healy BC, Engler D, Glanz B, et al. Assessment of definitions of sustained disease progression in relapsing-remitting multiple sclerosis. Mult Scler Int 2013;2013:189624.
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Derwenskus J. Current disease-modifying treatment of multiple sclerosis. Mt Sinai J Med 2011;78:161–75.
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Portaccio E, Zipoli V, Siracusa G, et al. Long-term adherence to interferon beta therapy in relapsing-remitting multiple sclerosis. Eur Neurol 2008;59:131–5.
10.
Castillo-Trivino T, Mowry EM, Gajofatto A, et al. Switching multiple sclerosis
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patients with breakthrough disease to second-line therapy. PLoS One 2011;6:e16664. 11.
Carrithers MD. Update on disease-modifying treatments for multiple sclerosis. Clin Ther 2014;36:1938–45
12.
Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402–15.
13.
Khatri B, Barkhof F, Comi G, et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol 2011;10:520–9.
14.
He A, Spelman T, Jokubaitis V, et al. Comparison of switch to fingolimod or interferon beta/glatiramer acetate in active multiple sclerosis. JAMA Neurol 2015:1– 10.
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Tables and figures Table 1. Baseline demographics and clinical characteristics for patients with high disease activity despite previous DMT Characteristic
Placebo
Fingolimod
(N = 257)
(N = 249)
Female
74.7
76.3
Male
25.3
23.7
39.2 (8.4)
39.3 (8.8)
Since diagnosis
6.2 (5.5)
6.3 (5.6)
Since first symptom
10.2 (7.2)
10.0 (7.5)
Interferon beta
53.3
63.9
Glatiramer acetate
30.7
25.3
Natalizumab
5.1
0.8
Other MS medications
10.9
10.0
1 DMT
56.4
53.4
2 DMTs
23.3
31.7
≥ 3 DMTs
20.3
14.8
In the past year
1.6 (0.9)
1.5 (0.8)
In the past 2 years
2.4 (1.5)
2.3 (1.4)
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Sex, %
Age, years Duration of MS, years
Most recently used DMT, %
DMT used before study, %
Number of relapses, n
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EDSS score, %
2.7 (1.4)
2.5 (1.3)
Number of Gd-enhancing T1 lesions
1.3 (3.0)
1.9 (6.6)
6267.5 (7922.3)
6118.5 (7914.6)
1507.0 (93.6)
1516.4 (83.0)
Total volume of T2 lesions, mm3 Brain volume, cm3
Values are mean (standard deviation) unless otherwise stated. DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; Gd, gadolinium; Curr Med Res Opin Downloaded from informahealthcare.com by University of Otago on 07/03/15 For personal use only.
MS, multiple sclerosis
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Figure 1.
Figure 1 caption. Estimated reductions in (a) Annualized relapse rate (ARR), (b) 6-month confirmed disability progression (CDP), (c) mean percentage brain volume change (PBVC), (d) mean number of gadolinium (Gd-) enhancing T1 lesions and (e) mean number of new or
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newly enlarged T2 lesions for fingolimod versus placebo in patients with high disease
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activity despite previous disease-modifying therapy
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