Efficacy and safety of BG-12 (dimethyl fumarate) and other disease-modifying therapies for the treatment of relapsing-remitting multiple sclerosis: a systematic review and mixed treatment comparison.

Just Accepted by Current Medical Research & Opinion Original article Efficacy and safety of BG-12 (dimethyl fumarate) and other disease modifying therapies for the treatment of relapsing-remitting multiple sclerosis: a systematic review and mixed treatment comparison Michael Hutchinson, Robert J Fox, Eva Havrdova, Nuwan C Kurukulasuriya, Sujata P Sarda, Sonalee Agarwal, Mohd Kashif Siddiqui, Ankush Taneja, Baris Deniz doi: 10.1185/03007995.2013.863755

Curr Med Res Opin Downloaded from informahealthcare.com by Memorial University of Newfoundland on 11/12/13 For personal use only.

Abstract Objective: Currently, direct comparative evidence or head-to-head data between BG-12 (dimethyl fumarate) and other disease-modifying treatments (DMTs) is limited. This study is a systematic review and data synthesis of published randomized clinical trials comparing the efficacy and safety of existing DMTs to BG-12 for Relapsing-Remitting Multiple Sclerosis (RRMS). Methods: A systematic review was conducted by searching MEDLINE, EMBASE, and the Cochrane Library for English-language publications from 1 January 1960 to 15 November 2012. Clinicaltrials.gov, metaRegister of Controlled Trials, and conference proceedings from relevant annual symposia were also hand searched. Two independent reviewers collected and extracted data, with discrepancies reconciled by a third reviewer. Included studies were randomized controlled trials (RCTs) of DMTs (interferon [IFN] beta-1a, IFN beta-1b, glatiramer acetate [GA], BG-12, fingolimod, natalizumab, and teriflunomide) in adults with RRMS. Mixed treatment comparisons were conducted to derive the relative effect size for the included treatments. Annualized relapse rate (ARR), disability progression, and safety outcomes were assessed. Results: BG-12 240 mg twice a day (BID) significantly reduces ARR compared to placebo (Rate Ratio: 0.529 [95% CI: 0.451 - 0.620]), IFNs (0.76 [95% CI: 0.639 - 0.904]), GA (0.795 [95% CI: 0.668 - 0.947]), and teriflunomide 7 mg and 14 mg (0.769 [95% CI: 0.610 - 0.970] and 0.775 [95% CI: 0.614 - 0.979]), and does not show a significant difference when compared to fingolimod. Only natalizumab was significantly superior to BG12 in reducing ARR. BG-12 also demonstrated favorable results for disability and safety outcomes. Conclusion: Based on indirect comparison, BG-12 offers an effective oral treatment option for patients with RRMS with an overall promising efficacy and safety profile compared to currently approved DMTs. Key limitations of the systematic review were the large heterogeneity in patients enrolled, and the variability in the definition of outcomes in included trials.

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Efficacy and safety of BG-12 (dimethyl fumarate) and other disease modifying therapies for the treatment of relapsing-remitting multiple sclerosis: a systematic review and mixed treatment comparison


Michael Hutchinson1, Robert J Fox2, Eva Havrdova3, Nuwan C Kurukulasuriya4, Sujata P Sarda4, Sonalee Agarwal4, Mohd Kashif Siddiqui5, Ankush Taneja5, Baris Deniz4

1

Newman Clinical Research Professor, St Vincent's University Hospital, University College Dublin, Ireland

2

Mellen Center for Multiple Sclerosis, Neurological Institute, and Lerner College of Medicine, Cleveland

Clinic, Cleveland, OH, USA 3

Department of Neurology, First Faculty of Medicine, Charles University in Prague, Czech Republic

4

Biogen Idec, Weston, MA, USA

5

Heron Health, Rajiv Gandhi IT Park, Chandigarh, UT, India

Corresponding Author: Name: Baris Deniz Address: Biogen Idec, 133 Boston Post Road, Weston, MA 02493 Email: [email protected] Fax: +1(866) 834-6881 Telephone: +1 (781) 464-1612 TYPE

OF

ARTICLE:

Original

article

1

Abstract Objective: Currently, direct comparative evidence or head-to-head data between BG-12 (dimethyl fumarate) and other disease-modifying treatments (DMTs) is limited. This study is a systematic review and data synthesis of published randomized clinical trials comparing the efficacy and safety of existing


DMTs to BG-12 for Relapsing-Remitting Multiple Sclerosis (RRMS). Methods: A systematic review was conducted by searching MEDLINE, EMBASE, and the Cochrane Library for English-language publications from 1 January 1960 to 15 November 2012. Clinicaltrials.gov, metaRegister of Controlled Trials, and conference proceedings from relevant annual symposia were also hand searched. Two independent reviewers collected and extracted data, with discrepancies reconciled by a third reviewer. Included studies were randomized controlled trials (RCTs) of DMTs (interferon [IFN] beta-1a, IFN beta-1b, glatiramer acetate [GA], BG-12, fingolimod, natalizumab, and teriflunomide) in adults with RRMS. Mixed treatment comparisons were conducted to derive the relative effect size for the included treatments. Annualized relapse rate (ARR), disability progression, and safety outcomes were assessed. Results: BG-12 240 mg twice a day (BID) significantly reduces ARR compared to placebo (Rate Ratio: 0.529 [95% CI: 0.451 - 0.620]), IFNs (0.76 [95% CI: 0.639 - 0.904]), GA (0.795 [95% CI: 0.668 0.947]), and teriflunomide 7 mg and 14 mg (0.769 [95% CI: 0.610 - 0.970] and 0.775 [95% CI: 0.614 0.979]), and does not show a significant difference when compared to fingolimod. Only natalizumab was significantly superior to BG-12 in reducing ARR. BG-12 also demonstrated favorable results for disability and safety outcomes. Conclusion: Based on indirect comparison, BG-12 offers an effective oral treatment option for patients with RRMS with an overall promising efficacy and safety profile compared to currently approved DMTs. Key limitations of the systematic review were the large heterogeneity in patients enrolled, and the variability in the definition of outcomes in included trials.

2

KEYWORDS: Multiple sclerosis, Relapsing-remitting, RRMS, Efficacy, Safety, Mixed treatment comparison


SHORT TITLE: Mixed Treatment Comparison of BG-12 with current DMTs in RRMS PREVIOUS PRESENTATION: Data from the current study has been presented in poster form at the American Academy of Neurology’s 65th annual meeting in San Diego, March 16-23 2013 WORD COUNT: 9358 words FIGURES: 5 TABLES: 1 SUPPLEMENTARY MATERIAL: 2 Figures and 2 Tables

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Introduction Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal degeneration1. MS most commonly presents with a relapsing-remitting course (RRMS) in 85% of cases, with the remaining 15% presenting with a steadily progressive disability


(primary progressive MS [PPMS])1; 2. Most patients with RRMS will eventually develop secondary progressive multiple sclerosis (SPMS) with gradually increasing disability over time with or without superimposed relapses. It is estimated that the median time to develop SPMS is 15 years 3. The management of MS involves using disease modifying therapies (DMTs) to reduce the frequency of relapse and the accumulation of inflammatory lesions within the CNS, with the aim of delaying onset of the SPMS phase (for which there is no adequate therapy)4. At present, there are ten DMTs approved in the United States (US) by the Food and Drug Administration (FDA) that are indicated for relapsing MS. These include beta interferons (IFNs beta; Avonex 1, Betaseron2, Extavia3, Rebif4), glatiramer acetate (GA; Copaxone 5), natalizumab (Tysabri6), teriflunomide (Aubagio ), mitoxantrone (Novantrone ) fingolimod (Gilenya )4, and BG-12 (dimethyl fumarate delayed-release 7

8

9

capsule; Tecfidera10). With the exception of mitoxantrone the recently approved agents teriflunomide and BG5

12, the same DMTs are also indicated for the treatment of relapsing MS in Europe . Across Europe and the US, GA and IFNs beta are used as first-line DMTs for relapsing MS , whereas natalizumab and fingolimod are typically 2

used as second-line therapies or in more severe disease . 2

1 2 3 4 5 6 7 8 9

Avonex is a registered trade name of Biogen Idec MA Inc, United States Betaseron is a registered trade name of Bayer Schering Pharma, Germany Extavia is a registered trade name of Novartis AG, Switzerland Rebif is a registered trade name of Ares Trading SA, Switzerland Copaxone is a registered trade name of Teva Pharmaceutical Industries Ltd, Israel Tysabri is a registered trade name of Elan Pharmaceuticals Inc, United States Aubagio is a registered trade name of Genzyme, a Sanofi company, United States Novantrone is a registered trade name of EMD Serono, Switzerland Gilenya is a registered trade name of Novartis AG, Switzerland

10

Tecfidera is a registered trade name of Biogen Idec MA Inc, United States

4

The majority of approved DMTs are injected or administered by intravenous infusion, which may be inconvenient for patients who would prefer an oral therapy. The recently approved DMTs fingolimod (FDA approved in 2010), teriflunomide (FDA approved September 2012), and BG-12 (FDA approved March 2013) are oral agents . It is anticipated that the development of more oral agents would be welcomed if they 4

demonstrate a similar or improved benefit to risk profile relative to the current injectable therapies 2.


Most DMTs have only been compared to placebo in Phase III trials, which makes direct head-to-head comparison of the results difficult. Mixed treatment comparisons (MTCs) are typically utilized in the absence of sufficient direct comparative evidence to help support access and reimbursement decisions. However, MTCs are also useful when direct evidence is available; these analyses can help leverage the differences in methodologies, and therefore inconsistencies in results, across individual trials by integrating the full evidence base. Thus, MTC analyses can help refine and strengthen the comparative evidence across therapeutic options. Due to the lack of head-to-head trials comparing BG-12 to other approved DMTs, with one trial having a reference arm but no head-to-head comparison6, an MTC was performed by assessing results from randomized controlled studies. The objective of this study was to conduct the first MTC comparing the efficacy and safety of BG-12 to approved DMTs for RRMS to inform future treatment decisions in clinical practice.

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Methods A systematic review was conducted to identify all randomized controlled trials (RCTs) examining the efficacy and safety of currently prescibed DMTs and the recently FDA-approved agent BG-12 in patients with RRMS. MTCs were perfomed to indirectly compare treatments across studies via a common comparator. The systematic review was conducted and reported in line with the PRISMA


guidelines7 and a full protocol for the systematic review detailing the patient population, interventions, and study design of interest is available upon request. The systematic review was managed using the HERON Systematic Review Database, a bespoke SQL-based internet database. Data sources Medline (including Medline-in-Process), EMBASE, and the Cochrane Library (existing Cochrane Reviews and CENTRAL Controlled Trials Register)

searched

were

for English-language publications from 1 January 1960 to 15 November 2012. Proceedings from relevant annual symposia held between 2009

and 2012 were hand-searched to capture unpublished data from ongoing trials (

European Committee for Treatment and Research

in Multiple Sclerosis, American Academy of Neurology, Americas Committee for Treatment and Research in Multiple Sclerosis, American Neurological Association, and European Federation of Neurological Societies). Other data sources, searched to identify trials in progress, included Clinicaltrials.gov and metaRegister of Controlled Trials (both searches conducted on 5 April 2012). The published clinical trial results for BG-12 were supplemented with data on file to allow for comparison across as many efficacy and safety outcomes as possible.

6

Study eligibility RCTs (double-blind, single-blind, and open-label) of DMTs in adult patients (≥18 years) of any race or gender with ≥80% patients with RRMS (without restriction on prior MS treatment) were included in the review. Clinical trials involving DMTs currently approved for RRMS treatment (IFN beta, GA, fingolimod, natalizumab, and teriflunomide) and recently FDA-approved BG-12 were included in the


review. Mitoxantrone was not compared as currently it is rarely used to treat relapsing MS due to severe adverse effects which limit the lifetime cumulative dose 4. Studies and treatment arms that involved non-licensed doses were excluded. For example, of the two studied doses of BG-12 (BG-12 240 mg twice a day [BID] and BG-12 240 mg thrice a day [TID]), only the BG-12 240 mg BID arm was included in the analysis as it is the licensed dose in the USA. To enable MTCs between the DMTs, both the interventions of interest and placebo were included as valid comparators. In order to avoid introducing heterogeneity into the review, studies with no subgroup data for the disease (e.g. a different subtype of MS) and age (e.g. children) were excluded. Clinical keywords and medical subject headings (MeSH terms) were used to search for disease (for example, multiple sclerosis, RRMS, SPMS, and relapsing multiple sclerosis (RMS) and interventions (for example, beta interferon, GA, natalizumab, fingolimod, teriflunomide, and BG-12 [dimethyl fumarate]). An example search strategy is provided in the supplementary material (Table S1), with all other search strategies available upon request. Study selection

7

The bibliographic details and abstracts of all citations identified through the literature search were downloaded into the HERON Systematic Review Database. A team of reviewers, information scientists specializing in evidence-based medicine, independently determined the eligibility of each publication by applying the defined set of selection criteria described above to each citation. Citations were first screened based on the title and abstract by two independent reviewers, with any discrepancies reconciled by a third independent reviewer. At this stage, citations that did not meet the eligibility


criteria for the review and duplicates of citations (due to overlap in the coverage of the databases) were excluded. Full-text copies of all references that potentially met the eligibility criteria after first screening were ordered. The eligibility criteria were then applied to the full-text papers by two different independent reviewers, with reconciliation of any differences conducted by a third independent reviewer. Data extraction Only one data set per study was compiled from all publications relating to that study to avoid doublecounting patients. After linking of multiple publications, studies included after the second stage of selection underwent data extraction using a specifically designed data extraction grid. Data were extracted in parallel by two independent reviewers, with any differences resolved by a third independent reviewer. Data extracted included, but was not limited to, study design, patient population characteristics, efficacy outcomes (annualized relapse rate [ARR], Expanded Disability Status Score [EDSS], disability progression, and proportion of patients with relapse), discontinuations, and AEs. Two efficacy outcomes were of interest in this analysis: ARR (measured at study end point) and 12week sustained disability progression (measured at 24 months).

8

For the safety outcomes, only the most common AEs (≥5% incidence in any treatment group) that have been reported in the published evidence for BG-12 were extracted. In addition to the AEs selected using this approach, AEs that occurred at an incidence of ≥3% in the total BG-12 group compared to the placebo group were also included (even if the overall incidence in the BG-12 arm was 40%) for a few of the pair-wise comparisons. MTC involves both direct and indirect comparison to generate a more precise estimate of the population. However, the heterogeneity observed in the direct meta-analysis would continue in the MTC analyses. Hence, to minimize the impact of heterogeneity on MTC, a random-effects model was used in this analysis. To show that consistency between direct meta-analyses and MTC is true and not derived by chance, the impact of heterogeneity on the primary outcomes using different baseline and disease characteristics as covariates were performed; the covariates used were publication year, study duration, mean age, disease duration, female percentage, relapse in prior 1 year, and EDSS score at baseline. To assess the impact of significant covariates on outcome, the adjusted and unadjusted MTC results were compared.

11

For all safety outcomes, the clinical trials analyzed were not designed to detect statistical differences between the treatment arms. As a result, the MTC was not expected to identify statistically significant differences either. Therefore, the safety results are not presented as comparative risk ratios but as annual incidence rates, and do not include p-values. Only events where a comparator had at least a 5% higher incidence of AEs than BG-12 and events where BG-12 had at least a 5% higher incidence


of AEs than any comparator were reported. The treatment-specific annual incidence of AEs was calculated using a weighted average across studies14. If an event occurs at a constant rate r per time unit t, then the probability that an event will occur during time t (provided the unit of time used in r and t are the same) is calculated as:

A probability is converted to a rate using:

The results of the MTCs were displayed as customized forest plot diagrams, comparing the intervention of interest (BG-12) to all other comparators included in the review, generated using STATA statistical software version 9.0 (StataCorp LP, Texas, USA).

12

Results Overview of identified studies The systematic review was conducted and reported in line with the PRISMA guidelines 7. The search of the literature databases yielded 7773 separate references. From these, 27 RCTs were identified as


appropriate to the review question and contributed to the quantitative analysis. Figure 1 depicts the flow of studies through the systematic review process, and the RCTs included in the analysis are described in Table 1. Two studies assessed BG-126; 15: one study compared BG-12 to placebo and GA to placebo6, while the second study compared only BG-12 with placebo15. The network of trials for mixed-treatment metaanalysis is depicted in Figure 2. In MTC placebo was used as the common comparator. Of the studies included in the review, more than half of the RCTs (n=14) were Phase III and three studies each were Phase IV and Phase II. The Phase of the remaining seven trials was unclear. The number of patients enrolled across the included studies ranged from 31 16 to 224417. The duration of the randomized phase varied across the included studies, ranging from 13 weeks18 to 260 weeks19. Included studies were considered of good quality in terms of reporting (Table S2, supplementary information), and more than 50% studies used an adequate method for allocation concealment and randomization (Figure S2, supplementary information). The majority of the studies (~90%) presented low risk of bias for baseline compatibility (93%), method of blinding (78%), withdrawals rate between treatment arms (81%), and statistical methodology (89%) (Figure S1, supplementary information).

13

Across all included RCTs, the patient population comprised adult patients with RRMS who had experienced at least one relapse within the preceding year or two relapses in the preceding 2 years, and had a mean EDSS score at baseline ranging from 1.9 20; 21 to 3.222; 23. The median age of recruited patients was 35 years with the majority of included studies reporting >65% female patients, however one study reported only 33% females in the IFN arm 16. The median disease duration reported in the RCTs ranged from 0.9 years in the IFN beta 1b 250 mcg EOD arm 24 to 10.6 years for patients in the


placebo arm25. Nine of the included studies provided information regarding prior treatment 6; 15; 17; 24-29 with a maximum of 56% of patients reported use of prior therapy 15; recruitment of treatment-naïve patients17; 24. All studies except four

28

. Two studies reported

16; 22; 30; 31

described exclusion of

patients previously treated with immunosuppressive therapy , or IFN, or GA specifically. Efficacy of DMTs Annualized relapse rate The results of the MTC for each active treatment versus BG-12 240 mg BID for ARR indicate that BG12 240 mg BID is statistically superior to the majority of comparators (Figure 3). BG-12 240 mg BID significantly reduces ARR compared with pooled IFN treatments (Rate Ratio: 0.760 [95% CI: 0.639 0.904]), GA 20 mg once daily (QD) (Rate Ratio: 0.795 [95% CI: 0.668 - 0.947]), teriflunomide 7 mg QD (Rate Ratio: 0.769 [95% CI: 0.610 - 0.970]), teriflunomide 14 mg QD (Rate Ratio: 0.775 [95% CI: 0.614 - 0.979]), and placebo (Rate Ratio: 0.529 [95% CI: 0.451 - 0.620]). The rate ratios equate to reductions in ARR for BG-12 of 24.0% compared to pooled IFN, 20.5% compared to GA, 23.1% compared to teriflunomide 7 mg QD, 22.5% compared to teriflunomide 14 mg QD, and 47.1% compared to placebo. Natalizumab 300 mg every 4 weeks (q4w) was the only therapy with a statistically significantly greater benefit in reducing ARR (54.1%) than BG-12 240 mg BID (Rate Ratio: 1.541 [95% CI: 1.234-1.924]). The MTC results also show that the 19.2% improvement in ARR with fingolimod 0.5 mg QD compared to BG-12 was not statistically significant (Rate Ratio: 1.192 [95% CI: 0.974-1.460]).

14

Disability progression The MTC results for 12-week sustained disability progression confirmed that BG-12 240 mg BID significantly reduced disability progression by 40.8% compared to placebo (HR: 0.592 [95% CI: 0.421-0.833]; Figure 4). Compared to other DMTs, BG-12 240 mg BID was numerically superior in terms of disability progression but statistical significance was not reached (pooled IFN HR: 0.818


[95% CI: 0.549 - 1.218]; GA 20 mg QD HR: 0.758 [95% CI 0.507 - 1.131]; teriflunomide 7 mg QD HR: 0.774 [95% CI: 0.478 - 1.253]; teriflunomide 14 mg QD HR: 0.828 [95% CI: 0.505 - 1.356]; fingolimod 0.5 mg QD HR: 0.745 [95% CI: 0.491 - 1.129] (Figure 4). The reduction in confirmed disability progression with BG-12 240 mg BID equated to 18.2% compared to pooled IFNs, 24.2% compared to GA, 22.6% compared to teriflunomide 7 mg, 17.2% compared to teriflunomide 14 mg, and 25.5% compared to fingolimod. As observed for ARR, natalizumab was numerically favorable when compared to BG-12 for disability progression which equated to a 7.0% improvement, however this difference did not reach statistical significance (HR: 1.070 [95% CI: 0.630 – 1.818]). Safety of DMTs A variety of specific AEs have been associated with the DMTs used in the treatment of RRMS. The annual incidence rates of AEs indicate that BG-12 240 mg BID has a higher annual incidence rate for abdominal pain (5.14%), diarrhea (7.62%), and flushing (19.97%) when compared to at least one other agent. For the other nine AEs (injection site reactions, flu-like symptoms, headache, fatigue, depression, influenza, ALT increased, leucopenia, and lower respiratory tract infection [RTI]), at least one comparator had a higher annual incidence rate than BG-12 240 mg BID (Figure 5).

15

Discussion The purpose of the current analysis was to indirectly compare the efficacy and safety of BG-12 with other approved DMTs in RRMS. MTCs were used, as an alternative analysis, due to the absence of comparative efficacy and safety data from more reliable sources such as head-to-head trials. This study demonstrated that BG-12 has a more favorable efficacy profile than IFN beta treatments, GA,


teriflunomide, and placebo. Only natalizumab had a superior efficacy profile for ARR compared to BG12, with the observed slight numerical advantage of fingolimod compared to BG-12 for ARR not reaching statistical significance. There was no significant difference between BG-12 and comparators, with the exception of placebo, for 12-week sustained disability progression at 24 months. A holistic review of the analyzed safety outcomes suggests that BG-12 has the potential to reduce treatment burden by reducing some highly prevalent events associated with existing therapies such as fatigue, depression, and flu-like symptoms. No new safety concerns for BG-12 compared to previously published data6; 15 have been highlighted in this review.

16

In this systematic review and analysis, natalizumab was the only DMT to demonstrate improved efficacy with respect to ARR compared to BG-12. This analysis also identified comparable efficacy between BG-12 and fingolimod. These results suggest that BG-12 could be a valid alternative treatment to all DMTs except natalizumab in terms of efficacy outcomes in this patient population. There were no statistical differences between BG-12 and the other active therapies with respect to their effect on disability progression. For the efficacy outcomes, several factors limited the derivation


of statistically conclusive results. First, the majority of trials were 2 years in duration, which may not be sufficient to detect statistically significant differences on disability progression; longer term data might be required for conclusive evidence on the efficacy of DMTs as disability progression occurs slowly over time. Second, the rate of development of neutralizing antibodies to IFNs and their potential impact on efficacy outcomes was not extracted from the RCTs, and hence not analyzed in the current study. This information could also affect efficacy comparisons of IFNs to other DMTs and within the IFN class itself. Finally, the burden of therapy administration and its potential impact on patient compliance and long-term efficacy was not analyzed in the current study as it was not reported in the RCTs included in the MTC. It can be hypothesized that as an oral agent, BG-12 would not be associated with injection- and/or infusion-related adverse events2, would reduce treatment burden, and be a valuable alternative therapy for patients who would prefer an oral treatment over an injected or infused product (e.g. IFN beta, GA, or natalizumab)32.

17

In terms of safety outcomes, the benefit to risk ratio of natalizumab and fingolimod may be limited by the association of natalizumab with progressive multifocal leukoencephalopathy in anti-JCV antibodypositive MS patients and the occurrence of bradyarrhythmia, atrioventricular block, macular edema, and infections reported with fingolimod 5; 33. In contrast, BG-12 is mainly associated with flushing and GI side-effects, and has a lower risk of infections such as RTI, influenza, and flu-like symptoms compared to fingolimod. In light of the potential AEs linked with the use of natalizumab and


fingolimod, BG-12 offers a valuable treatment alternative for patients with RRMS. A limitation of this AE analysis is that none of the clinical trial programs are powered to detect statistically significant differences in safety outcomes between treatment arms; a MTC was therefore not expected to show such a difference either and was not conducted as a result. An extension trial, ENDORSE, is currently underway to evaluate the long-term safety and efficacy of BG-12 in patients with RRMS34. Further, differences between data sources (i.e. trial publications), variation in patient population mix (naïve vs. experienced), physician/patient discretion on what is an AE, and high rates of AEs in placebo arms could have also affected the current safety analyses. Despite these limitations, the direction of effect of the results would not be expected to change as there would be no bias in how the variations occur across treatments.

18

There are several limitations that should be taken into consideration when interpreting the results of the current study. First, limited evidence was available for direct comparisons between the DMTs. Only nine of the total 27 included studies presented a head-to-head comparison of DMTs, with GA and IFN beta as common comparators. Since indirect comparisons do not provide the same level of evidence as direct (head-to-head) comparisons, they are typically used to support results from headto-head trials rather than stand-alone analyses. Further head-to-head data are expected over time as


new agents are studied, and this information will be important to validate the results from the current MTC analyses. Second, two trials were conducted over two decades ago 16; 22, potentially limiting their relevance to current practice. For example, from the early studies to present day, relapse rates have been declining, presumably due to changes in treatment patterns over time and the availability of more active treatments. Therefore, this long timeframe introduces additional heterogeneity that needs to be considered when interpreting the results. However, these studies were included to maximize the chance of indirect comparison with a great number of therapies.

19

Given that inter-individual and intra-individual variability is large in patients with RRMS35, there is often considerable heterogeneity observed between studies which requires consideration when conducting analyses such as MTCs. To account for this, a random effects analysis was applied. Further, covariate analyses were performed to evaluate the robustness of the MTC results and to determine the impact of different baseline characteristics on the major efficacy and tolerability outcomes (data not shown). The covariate analyses revealed that ‘publication year’ and ‘relapse in


prior 1 year’ were observed to be the significant covariates for ARR both in univariate and multivariate analysis in the MTC, with no considerable change in relative effect between unadjusted and adjusted models. It is unlikely that these results would translate into clinical relevance or would alter the outcomes. Additionally, there is variability in the definitions of outcomes across studies. For example, the definition of relapse was different between trials and included the following criteria: ‘a new or recurrent neurologic symptom lasting at least 24h confirmed by a medical examination’ 15; 26; 3638

, ‘a new or recurrent neurologic symptom lasting at least 48h with a change in the Kurtzke’s

functional scale (KFS) score’39 ‘any score change in EDSS’17, ‘a score change of 0.5 point in EDSS’24; 25; 27; 40-42

, ‘a score change of 1 point in EDSS’21;

28

, ‘a score change of 1 point in KFS score’43. It was

assumed that the treatment effects were similar across studies for a given therapy. It is also reasonable to assume that some level of heterogeneity exists across studies at random introduced by natural variation. Thus, the results presented here can be considered as a valid comparison of current DMT efficacy and safety and should be used to supplement, rather than replace, the results from head-to-head clinical trials.

20

Conclusions Based on the cumulative evidence on efficacy and safety, the BG-12 benefit to risk ratio in RRMS can be considered more favorable than that of IFNs, GA, and teriflunomide, and superior to that of fingolimod. We estimate a 47% reduction in ARR versus placebo and a reduction of 20% to 24% in the ARR versus GA, teriflunomide, and IFNs. A holistic review of the analyzed safety outcomes


suggests that BG-12 has the potential to reduce treatment burden by reducing some highly prevalent events associated with existing therapies such as injection-site reactions with injectable therapies and cardiac events for fingolimod, although BG-12 is associated with gastrointestinal and skin flushing events. The findings from this study further supplement and support the head-to-head clinical trial data for BG-12 in DEFINE15 and CONFIRM6. The current evidence indicates that BG-12 will be a useful oral alternative therapeutic option for patients with RRMS due to safety profile benefits and efficacy benefits observed in terms of relapse outcomes.

21

Transparency Declaration of funding This study was funded by Biogen Idec US. Biogen is developing BG-12 for patients with multiple sclerosis. The authors meet criteria for authorship as recommended by the International Committee


of Medical Journal Editors, and are fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development. MH, RJF, and EH contributed to the manuscript review. NK contributed to the interpretation of results and manuscript review. SA conceptualized the study design. BD contributed to study design and methodology, interpretation of results, and manuscript review. SS contributed to methodology, interpretation of results, and manuscript review. MKS and AT performed the data collection, analysis, and contributed to manuscript review. Declaration of financial/other relationships NK, SA, SPS, and BD have disclosed that they are employees of Biogen Idec. MH, RJF, and EH receive honoraria from Biogen Idec. EH is also supported by the Czech Ministry of Education (MSM 0021620849, PRVOUK-P26/LF1/4). MKS and AT are employees of HERON, a company that received funding from Biogen Idec to conduct this study.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgements With thanks to the evidence review team at HERON Health PVT for their assistance with data collection during the study. With thanks also to Ebony Samuels, Catherine Kielar, and Sarah Collington at HERON Evidence Development UK for their assistance with the preparation of the manuscript.

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23


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27


Tables

Table 1: List of studies included in the systematic review of the efficacy and safety of BG-12 and DMTs in RRMS Trial and primary study reference BG-12 CONFIRM trial 6

DEFINE trial 15

Phase of trial

Intervention

Comparator/s

N*

BG-12 240 mg BID

GA 20 mg QD (reference arm, not head-tohead comparator); Placebo

Phase III

1430

BG-12 240 mg BID

Placebo

Phase III

1237

Population

Patients aged 18 years to 55 years, with confirmed diagnosis of RRMS according to McDonald criteria, baseline EDSS between 0.0 and 5.0, with at least one relapse with in the 12 months prior to randomization with a brain MRI demonstrating lesion consistent with MS, or who show evidence of GdE lesion of the brain on an MRI performed within the 6 months prior to randomization Age 18 years to 55 years with confirmed diagnosis of RRMS according to McDonald criteria 1 to 4, EDSS between 0.0 and 5.0, with at least one relapse within the 12 months prior to randomization, a prior brain MRI demonstrating lesion consistent with MS, or evidence of GdE lesion of the brain on an MRI performed within the six weeks prior to randomization

Major outcomes assessed

ARR*, ARR-ST, CDPS3M, CDPS6M, PPR, PPR-F, EDSS score, MRI, QoL, safety, discontinuations ARR, ARR-ST, CDPS3M, CDPS6M, PPR*, PPR-F, EDSS score, MRI, QoL, safety, discontinuations

GA

BECOME trial 24

Calabrese 2011 20

BEYOND trial 17

Bornstein 1987 22

GA 20 mg QD

IFN beta-1b 250 mcg EOD

Phase IV

75

Patients between 18 years and 55 years of age with baseline EDSS score of 0-5.5, having one of the two following forms of demyelinating disease: (1) RRMS by revised McDonald`s criteria plus evidence of recent disease activity as shown by the development of one or more clinical and/or MRI attacks during the 6 previous months OR (2) a CIS characteristic of CNS demyelination (optic neuritis or transverse myelitis or brainstem attack) confirmed on examination with onset within the 6 prior months plus evidence of dissemination in time and space

GA 20 mg QD

IFN beta-1a 30 mcg once weekly; IFN beta-1a 44 mcg TIW

Phase IV

165

Patients aged 18 years to 55 years, RRMS according to the McDonald/Polman diagnostic criteria for MS, EDSS score of ≤5.0

GA 20 mg QD


Phase III

2244

GA 20 mg QD

Placebo

Unclear

50

Patients were treatment-naive with RRMS diagnosed using the 2001 McDonald and International Panel diagnostic criteria, age 18 years to 55 years with at least one relapse in the year before entry into the study, baseline EDSS score of 0 to 5 Fulfilling all the diagnostic criteria for definite MS with age: 20 years to 35 years and an above-average exacerbation rate, with at least two well-demarcated and well-documented episodes of exacerbation in the two years before admission, and score no

ARR, CDPS6M, PPR, PPR-F, EDSS score, MRI*, QoL, discontinuations

ARR, EDSS score, MRI, discontinuations

ARR, CDPS3M, PPR*, PPR-F, MRI, safety, discontinuations ARR, CDPS3M, PPR, PPR-F*, safety

28


Trial and primary study reference

Copolymer 1 Multiple Sclerosis trial

Intervention

Comparator/s

Phase of trial

N*

REGARD trial 39

higher than 6 on the Kurtzke Disability Status Scale Ambulatory patients aged 18 years to 45 years with clinically definite MS or laboratory supported definite MS, having EDSS score of 0 to 5.0, history of at least two clearly identified and documented relapses in the 2 years prior to entry and onset of the first relapse at least 1 year before randomization, with a period of neurologic stability and freedom from corticosteroid therapy of at least 30 days prior to entry


ARR*, CDPS3M, PPR, PPR-F, EDSS score, MRI, safety, discontinuations

GA 20 mg QD

Placebo

Phase III

251

GA 20 mg QD

Placebo

Unclear

239

Adult patients with a relapse remitting course, and diagnosis of MS for at least one year, having EDSS score of 0 to 5, with at least one documented relapse in previous 2 years and at least one enhancing lesion on their screening brain MRI

ARR, ARR-ST, PPR, PPR-F, EDSS score, MRI*, safety, discontinuations

GA 20 mg QD

IFN beta-1a 44 mcg TIW

764

IFN beta and GA naive patients with RRMS (diagnosed with McDonald criteria 2001), aged 18 years to 60 years, with EDSS score of 0 to 5.5 and at least one attack in the preceding 12 months, with clinical stability or neurological improvement during the 4 weeks before randomization

ARR, ARR-ST, CDPS6M, PPR, PPR-F, MRI*, safety, discontinuations

40

European/ Canadian glatiramer acetate trial41

Population

Phase IV

Fingolimod FREEDOMS trial

Fingolimod 0.5 mg QD

Placebo

Phase III

1272

FREEDOMS II trial


Placebo

Phase III

1083

Saida 2012


Placebo

Phase II

171


IFN beta-1a 30 mcg once weekly

Phase III

1292


Placebo

Phase III

1331

27

25

44

TRANSFORMS trial 28

IFN beta BRAVO trial 30

Adults aged 18 years to 55 years, diagnosed with RRMS according to the 2005 revised McDonald criteria, with one or more documented relapses in the previous year and two or more relapses in the previous 2 years, with a score of 0 to 5.5 on EDSS scale, IFN beta or GA therapy was stopped 3 or more months before randomization Patients aged 18 years to 55 years with an EDSS score of 0 5.5, and had experienced at least one relapse in the previous year or two relapses in the previous 2 years Patients with age of 18 years to 60 years, a diagnosis of MS according to the revised McDonald criteria and a relapsing course of the disease (relapsing–remitting or secondary progressive). Patients had to have had one or more relapses in the previous year 2 or more relapses in the previous 2 years, or at least 1 GdE T1-weighted brain lesion within the 30 days prior to study commencement Patients aged 18 years to 55 years, with diagnosis of RRMS, meeting the revised McDonald criteria, with at least one documented relapse during the previous year or at least 2 documented relapses during the previous 2 years, with score of 0 to 5.5 on the EDSS Patients diagnosed with RRMS using the revised McDonald criteria of 2005, have EDSS score 0 to 5.5, and have had at least one

ARR*, ARR-ST, CDPS3M, CDPS6M, PPR, PPR-F, EDSS score, MRI, QoL, safety, discontinuations ARR*, ARR-ST, CDPS3M, CDPS6M, PPR, PPR-F, MRI, safety, discontinuations

ARR, PPR, PPR-F, MRI*, safety, discontinuations

ARR*, ARR-ST, CDPS3M, PPR, PPR-F, EDSS score, MRI, QoL, safety, discontinuations

ARR*

29



Intervention

Comparator/s

Phase of trial

N*

Population


relapse in past 12 months or two relapses in past 24 months or had 1 relapse in past 12 months to 24 months with one documented T1-GdE lesion in the year prior to screening Etemadifar 2006


IFN beta-1a 44 mcg TIW; IFN beta-1b 250 mcg EOD

EVIDENCE trial



INCOMIN trial



Kappos 2010


MSCRG trial

90

Patients aged 15 years to 50 years with clinical-or laboratorysupported diagnosis of relapsing MS, with ≥ two relapses within the 2-year period to treatment initiation, EDSS ≤5

PPR, PPR-F, EDSS score, safety, discontinuations

677

IFN-naïve patients aged 18 years to 55 years with definite RRMS, having EDSS scores of 0 to 5.5, with at least two exacerbations of MS in the prior 2 years

ARR, ARR-ST, CDPS3M, CDPS6M, PPR, PPR-F*, EDSS score, MRI, safety, discontinuations

Unclear

188

Adult aged between 18 years to 50 years with clinically definite RRMS, EDSS score between 1 and 3.5, with two clinically documented relapses during the preceding 2 years and no relapse for at least 30 days prior to study entry

ARR, ARR-ST, CDPS3M, PPR, PPR-F*, EDSS score, MRI, safety, discontinuations

Placebo

Phase II

220

Diagnosis of RRMS

ARR, PPR, PPR-F, MRI*, safety, discontinuations


Placebo

Phase III

301

IFN beta-1a 22 mcg TIW; IFN beta-1a 44 mcg TIW

Placebo

Phase III

560

IMPROVE trial


Placebo

Phase III

180

Knobler 1993


Placebo

Unclear

31

Wroe 2005


Placebo

Unclear

98

IFNB MS trial


Placebo

Phase III

372

21

38

43

23

42

PRISMS trial 37

31

16

18

19

Unclear

Unclear

Patients aged 18 years to 55 years with definite MS for at least 1 year, with baseline Kurtzke EDSS of 1.0 to 3.5, with at least two documented exacerbations in the prior 3 years and no exacerbations for at least 2 months at study entry Adult patients with clinically definite or laboratory-supported definite RRMS of at least 1 year duration, with at least 2 relapses in the preceding 2 years, Kurtzke EDSS scores of 0 to 5.0 Patients aged 18 years to 60 years, diagnosed with RRMS according to revised McDonald criteria (2001), EDSS score less than or equal to 5.5, with disease duration >12 months, with presence of greater than one clinical event and brain GdE MRI lesions within 6 months prior to randomization Patients aged 18 years to 50 years clinically definite RRMS for not less than one year and not more than 15 years, with at least two clearly defined exacerbations 2 years prior to entry into the study, Kurtzke EDSS score of 0.0-5.5 Patients aged 18 years to 55 years, with diagnosis of clinically definite or laboratory supported RRMS for at least 1 year, a history of at least 2 clearly identified relapses within the preceding 24 months and no relapse, or neurological deterioration related to relapse, for at least 30 days prior to entry, having EDSS score of between 0 and 5.5 Patients aged 18 years to 50 years with clinically definite or laboratory-supported definite MS for more than 1 year, EDSS 5.5 or less, with at least 2 acute exacerbations in the previous 2 years, with clinical stability for at least 30 days before entry, patients had

ARR, CDPS6M*, PPR, PPR-F, EDSS score, MRI, safety, discontinuations ARR-ST, CDPS3M, PPR*, PPRF, EDSS score, MRI, safety, discontinuations EDSS score, MRI*, safety, discontinuations

ARR, PPR, PPR-F, safety, discontinuations

PPR, PPR-F, safety, discontinuations

ARR*, CDPS3M, PPR, PPR-F*, EDSS score, safety, discontinuations

30



Intervention

Comparator/s

Phase of trial

N*

Population


not received ACTH or prednisone during this period Natalizumab AFFIRM trial 26

Natalizumab 300 mg q4w

Placebo

Phase III

942

Adult patients (aged 18 years to 50 years) with a diagnosis of RRMS and a score of 0 to 5.0 on the EDSS. MRI showing lesions consistent with MS with at least one medically documented relapse within the 12 months before study initiation

ARR, ARR-ST, CDPS3M*,PPR*, PPR-F, EDSS score, MRI, QoL, safety, discontinuations

Teriflunomide O'Connor 2006 45

TEMSO trial 29

Teriflunomide, 7 mg QD Teriflunomide 14 mg QD

Placebo

Phase II

179

Teriflunomide, 7 mg QD Teriflunomide 14 mg QD

Placebo

Phase III

1088

MS patients aged 18 years to 65 years with an EDSS score of less than equal to six. Patients were required to have two documented relapses in the previous 3years and one clinical relapse during the preceding year Patients with 18 years to 55 years of age, met the McDonald criteria for a diagnosis of MS (recommended in 2001), and had a relapsing clinical course, with or without progression. Patients were required to have a score of 5.5 or lower on the EDSS, which ranges from 0 to 10, with higher scores indicating greater disability) and at least two clinical relapses in the previous 2 years or one relapse during the preceding year, but no relapses in the 60 days before randomization

ARR, PPR-F, MRI*, safety, discontinuations

ARR*, CDPS3M, PPR, PPR-F, MRI, safety, discontinuations

N* represents randomized population; * signifies primary outcome; ACTH: Adrenocorticotropin Hormone; ARR: Annualized Relapse Rate; ARR-ST: Annualized Steroid-Treated Relapse Rate; BID: Twice a Day; CIS: Clinically Isolated Syndrome; CDPS3M: Confirmed Disability Progression Sustained for 3 Months; CDPS6M: Confirmed Disability Progression Sustained for 6 Months; CNS: Central Nervous System; EDSS: Expanded Disability Status Scale; EOD: Every Other Day; GA: Glatiramer Acetate; GdE: Gadolinium-enhancing; IFN: Interferon; MRI: Magnetic Resonance Imaging; mcg: Microgram; mg: Milligram; MS: Multiple Sclerosis; PPR: Proportion of Patients with Relapse; PPR-F: Proportion of Patients Remaining Relapse Free; QD: Once Daily; q4w: Every 4 Weeks; QoL: Quality of Life; RRMS: Relapsing Remitting Multiple Sclerosis; TIW: Thrice a Week

31

Figure Legends Figure 1: Flow of studies through the systematic review process. CSR: Clinical Study Report; TID: Thrice a day.


Figure 2: Network diagram for MTC of BG-12 240 mg BID versus comparators for annualized relapse rate (A) and confirmed disability progression sustained for 3 months (B). * GA is a reference arm and not a head-to head comparator with BG-12 in the CONFIRM trial. BID: Twice a Day; GA: Glatiramer Acetate; IFN: Interferon; q4w: Every 4 Weeks; QD: Once Daily. Figure 3: Summary plot for MTC of BG-12 240 mg BID versus comparators for the efficacy outcome of annualized relapse rate. Customized forest plot diagram, comparing the intervention of interest (BG-12) to all other comparators included in the review. The point estimate treatment effect from each comparison is displayed on separate rows as a filled diamond ( ), with confidence intervals marked as a line extending either side of the diamond (- -). The vertical axis indicates where the intervention of interest and comparator has the same effect. Rate ratio

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