Therapeutics
Review: In relapsing–remitting multiple sclerosis, disease-modifying agents reduce annual relapse rates
CADTH Therapeutic Reviews. Management of relapsing–remitting multiple sclerosis [Internet]. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health;Oct 2013.
Clinical impact ratings: F ★★★★★✩✩ N ★★★★★★✩ Question In relapsing–remitting multiple sclerosis (RRMS), what are the relative efficacy and safety of disease-modifying agents (DMAs)?
Review scope
16 monotherapy RCTs (n = 10 553), DMAs did not differ from placebo or each other for SAEs.
Conclusions In relapsing–remitting multiple sclerosis, disease-modifying agents reduce annual relapse rates compared with placebo. Based on ≥ 2 trials, alemtuzumab reduces relapse rates more than interferon β-1a; glatiramer acetate and interferon β-1a or -1b do not differ. Source of funding: Not stated. For correspondence: Canadian Agency for Drugs and Technologies in Health, Ottawa, ON, Canada. E-mail [email protected]. ■
Included studies compared fingolimod, interferon β-1a and β-1b, natalizumab, glatiramer acetate, teriflunomide, dimethyl fumarate, or alemtuzumab, alone or in combination, with other DMAs or placebo in patients with RRMS. Trials of different types of MS in which > 50% of patients had RRMS were included. Studies of approved drugs that used formulations or doses not approved in Canada, follow-up or extension studies, and studies published only in abstract form were excluded. Outcomes included relapse and serious adverse events (SAEs).
Commentary
Most drugs approved by the US Food and Drug Administration are covered by insurance plans in the USA, although the greater expense of some recently approved oral agents (e.g., fingolimod and dimethyl fumarate) has resulted in drugs being tiered as first- and second-line treatments based on cost. Comparing MS DMAs and defining optimal initial treatment choices based on efficacy is difficult. Although drug approval is primarily based on ability to prevent clinical relapses, these are usually mild in MS. The primary concern of clinicians and patients is the risk for long-term irreversible disability, which is partially but imperfectly related to disease burden on magnetic resonance imaging (MRI) and measured in various ways (T2 lesion burden, T1 hypointensity burden, and brain atrophy). In general, DMA Main results effects on MRI outcomes are more robust than on relapse outcomes, Results for meta-analyses of direct treatment comparisons are in with some notable exceptions. The CADTH review showed that the Table. When direct and indirect comparisons were combined glatiramer acetate is less effective than interferon β-1a for reducing in Bayesian network meta-analysis, results were consistent. Across the number of patients with gadolinium-enhancing lesions and than interferon β-1b for reducing the number of new or enlarging T2-hyperintense lesions. Choice of drug may Direct comparisons of disease-modifying agent (DMA) monotherapies in depend on one’s perspective about the relative imporrelapsing–remitting multiple sclerosis* tance of relapse reduction and MRI lesion reduction. Comparisons Number of Annual relapse rate† Rate ratio (95% CI)† Newer drugs seem to be more effective than older trials (n) drugs for relative reduction in relapses compared with IFN β-1b vs placebo 1 (247) 0.78 vs 1.12 0.71 (0.61 to 0.81) placebo, but this must be viewed in the context of an IFN β-1a vs placebo 4 (1149) 0.14 vs 0.33 to 0.91 vs 1.28 Range 0.67 (0.59 to 0.78)‡ important decline in event rates in contemporary to 0.81 (0.67 to 0.96)‡ clinical trials, which probably reflects differences in Glatiramer acetate vs placebo 3 (1203) 0.29 vs 0.40 to 0.81 vs 1.21 0.51 (0.27 to 0.95)‡ severity of disease activity in enrolled patients rather than changes in the disease. This complicates the Natalizumab vs placebo 1 (942) 0.23 vs 0.73 0.32 (0.27 to 0.37) interpretation of differences in risk reduction. Fingolimod vs placebo 2 (957) 0.18 vs 0.40 to 0.50 vs 0.99 0.46 (0.38 to 0.54)‡ Alemtuzumab is approved for use in Europe but has Teriflunomide vs placebo 2 (1267) 0.37 vs 0.54 to 0.58 vs 0.81 Range 0.75 (0.61 to 0.92)‡ met challenges in the approval process in the USA (1). to 0.78 (0.64 to 0.95)‡ However, when compared with high-dose interferon Dimethyl fumarate vs placebo 2 (1540) 0.17 vs 0.36 to 0.22 vs 0.40 0.51 (0.44 to 0.60)‡ β-1a, the data seem convincing for superior effectiveIFN β-1b vs glatiramer acetate 2 (1420) 0.36 vs 0.34 to 0.37 vs 0.33 1.06 (0.94 to 1.20)‡ ness. Safety concerns about alemtuzumab remain, parIFN β-1a vs glatiramer acetate 3 (1438) 0.16 vs 0.11 to 0.50 vs 0.50 Range 0.97 (0.78 to 1.22)‡ ticularly an established risk for autoimmune disease (2) to 1.25 (0.85 to 1.85)‡ and theoretical risk for immunosuppression given the Dimethyl fumarate 1 (709) 0.22 vs 0.29 0.76 (0.62 to 0.93) long duration of CD4 T-cell suppression.
Review methods
MEDLINE and EMBASE/Excerpta Medica to Oct 2013; gray literature; the Internet; and reference lists were searched for English-language, randomized, controlled trials (RCTs). Experts were contacted. 30 RCTs (n = 18 896, mean age 29 to 41 y, 64% to 84% women, study duration 16 wk to ≥ 3 y) met the selection criteria: 27 evaluated DMA monotherapies and 4 DMA combination therapies. 18 RCTs reported adequate allocation concealment, 19 were double-blind, 26 were funded by drug manufacturers, and loss to follow-up varied from 0% to 33%. RCTs of combination DMAs each evaluated different combinations; their results are not reported here.
vs glatiramer acetate Alemtuzumab vs IFN β-1a
3 (1581)
0.08 vs 0.36 to 0.26 vs 0.52
Range 0.22 (0.14 to 0.35) to 0.44 (0.34 to 0.55)‡
Fingolimod vs IFN β-1a
1 (866)
0.16 vs 0.33
0.49 (0.38 to 0.63)
*IFN = interferon; other abbreviations defined in Glossary. Randomized controlled trials comparing different DMA forms, doses, or methods of administration are not reported in the Table. †Ranges are reported where separate analyses were done for different drug doses. ‡Data were pooled from direct treatment comparisons using a random-effects model.
18 March 2014 | ACP Journal Club | Volume 160 • Number 6 Downloaded From: http://annals.org/ by a University of California San Diego User on 12/20/2016
Brian G. Weinshenker, MD, FRCP(C) Mayo Clinic Rochester, Minnesota, USA References 1. Complete response letter for Lemtrada: www.drugs. com/nda/lemtrada_131230.html (accessed 8 Jan 2014). 2. Jones JL, Phuah CL, Cox AL, et al. J Clin Invest. 2009;119:2052-61. © 2014 American College of Physicians
JC5
Review: In relapsing–remitting multiple sclerosis, disease-modifying agents reduce annual relapse rates
CADTH Therapeutic Reviews. Management of relapsing–remitting multiple sclerosis [Internet]. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health;Oct 2013.
Clinical impact ratings: F ★★★★★✩✩ N ★★★★★★✩ Question In relapsing–remitting multiple sclerosis (RRMS), what are the relative efficacy and safety of disease-modifying agents (DMAs)?
Review scope
16 monotherapy RCTs (n = 10 553), DMAs did not differ from placebo or each other for SAEs.
Conclusions In relapsing–remitting multiple sclerosis, disease-modifying agents reduce annual relapse rates compared with placebo. Based on ≥ 2 trials, alemtuzumab reduces relapse rates more than interferon β-1a; glatiramer acetate and interferon β-1a or -1b do not differ. Source of funding: Not stated. For correspondence: Canadian Agency for Drugs and Technologies in Health, Ottawa, ON, Canada. E-mail [email protected]. ■
Included studies compared fingolimod, interferon β-1a and β-1b, natalizumab, glatiramer acetate, teriflunomide, dimethyl fumarate, or alemtuzumab, alone or in combination, with other DMAs or placebo in patients with RRMS. Trials of different types of MS in which > 50% of patients had RRMS were included. Studies of approved drugs that used formulations or doses not approved in Canada, follow-up or extension studies, and studies published only in abstract form were excluded. Outcomes included relapse and serious adverse events (SAEs).
Commentary
Most drugs approved by the US Food and Drug Administration are covered by insurance plans in the USA, although the greater expense of some recently approved oral agents (e.g., fingolimod and dimethyl fumarate) has resulted in drugs being tiered as first- and second-line treatments based on cost. Comparing MS DMAs and defining optimal initial treatment choices based on efficacy is difficult. Although drug approval is primarily based on ability to prevent clinical relapses, these are usually mild in MS. The primary concern of clinicians and patients is the risk for long-term irreversible disability, which is partially but imperfectly related to disease burden on magnetic resonance imaging (MRI) and measured in various ways (T2 lesion burden, T1 hypointensity burden, and brain atrophy). In general, DMA Main results effects on MRI outcomes are more robust than on relapse outcomes, Results for meta-analyses of direct treatment comparisons are in with some notable exceptions. The CADTH review showed that the Table. When direct and indirect comparisons were combined glatiramer acetate is less effective than interferon β-1a for reducing in Bayesian network meta-analysis, results were consistent. Across the number of patients with gadolinium-enhancing lesions and than interferon β-1b for reducing the number of new or enlarging T2-hyperintense lesions. Choice of drug may Direct comparisons of disease-modifying agent (DMA) monotherapies in depend on one’s perspective about the relative imporrelapsing–remitting multiple sclerosis* tance of relapse reduction and MRI lesion reduction. Comparisons Number of Annual relapse rate† Rate ratio (95% CI)† Newer drugs seem to be more effective than older trials (n) drugs for relative reduction in relapses compared with IFN β-1b vs placebo 1 (247) 0.78 vs 1.12 0.71 (0.61 to 0.81) placebo, but this must be viewed in the context of an IFN β-1a vs placebo 4 (1149) 0.14 vs 0.33 to 0.91 vs 1.28 Range 0.67 (0.59 to 0.78)‡ important decline in event rates in contemporary to 0.81 (0.67 to 0.96)‡ clinical trials, which probably reflects differences in Glatiramer acetate vs placebo 3 (1203) 0.29 vs 0.40 to 0.81 vs 1.21 0.51 (0.27 to 0.95)‡ severity of disease activity in enrolled patients rather than changes in the disease. This complicates the Natalizumab vs placebo 1 (942) 0.23 vs 0.73 0.32 (0.27 to 0.37) interpretation of differences in risk reduction. Fingolimod vs placebo 2 (957) 0.18 vs 0.40 to 0.50 vs 0.99 0.46 (0.38 to 0.54)‡ Alemtuzumab is approved for use in Europe but has Teriflunomide vs placebo 2 (1267) 0.37 vs 0.54 to 0.58 vs 0.81 Range 0.75 (0.61 to 0.92)‡ met challenges in the approval process in the USA (1). to 0.78 (0.64 to 0.95)‡ However, when compared with high-dose interferon Dimethyl fumarate vs placebo 2 (1540) 0.17 vs 0.36 to 0.22 vs 0.40 0.51 (0.44 to 0.60)‡ β-1a, the data seem convincing for superior effectiveIFN β-1b vs glatiramer acetate 2 (1420) 0.36 vs 0.34 to 0.37 vs 0.33 1.06 (0.94 to 1.20)‡ ness. Safety concerns about alemtuzumab remain, parIFN β-1a vs glatiramer acetate 3 (1438) 0.16 vs 0.11 to 0.50 vs 0.50 Range 0.97 (0.78 to 1.22)‡ ticularly an established risk for autoimmune disease (2) to 1.25 (0.85 to 1.85)‡ and theoretical risk for immunosuppression given the Dimethyl fumarate 1 (709) 0.22 vs 0.29 0.76 (0.62 to 0.93) long duration of CD4 T-cell suppression.
Review methods
MEDLINE and EMBASE/Excerpta Medica to Oct 2013; gray literature; the Internet; and reference lists were searched for English-language, randomized, controlled trials (RCTs). Experts were contacted. 30 RCTs (n = 18 896, mean age 29 to 41 y, 64% to 84% women, study duration 16 wk to ≥ 3 y) met the selection criteria: 27 evaluated DMA monotherapies and 4 DMA combination therapies. 18 RCTs reported adequate allocation concealment, 19 were double-blind, 26 were funded by drug manufacturers, and loss to follow-up varied from 0% to 33%. RCTs of combination DMAs each evaluated different combinations; their results are not reported here.
vs glatiramer acetate Alemtuzumab vs IFN β-1a
3 (1581)
0.08 vs 0.36 to 0.26 vs 0.52
Range 0.22 (0.14 to 0.35) to 0.44 (0.34 to 0.55)‡
Fingolimod vs IFN β-1a
1 (866)
0.16 vs 0.33
0.49 (0.38 to 0.63)
*IFN = interferon; other abbreviations defined in Glossary. Randomized controlled trials comparing different DMA forms, doses, or methods of administration are not reported in the Table. †Ranges are reported where separate analyses were done for different drug doses. ‡Data were pooled from direct treatment comparisons using a random-effects model.
18 March 2014 | ACP Journal Club | Volume 160 • Number 6 Downloaded From: http://annals.org/ by a University of California San Diego User on 12/20/2016
Brian G. Weinshenker, MD, FRCP(C) Mayo Clinic Rochester, Minnesota, USA References 1. Complete response letter for Lemtrada: www.drugs. com/nda/lemtrada_131230.html (accessed 8 Jan 2014). 2. Jones JL, Phuah CL, Cox AL, et al. J Clin Invest. 2009;119:2052-61. © 2014 American College of Physicians
JC5
