BJD British Journal of Dermatology. Summary. What s already known about this topic? What does this study add? CLINICAL TRIAL

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1 CLINICAL TRIAL BJD British Journal of Dermatology Matching-adjusted indirect comparison of efficacy in patients with moderate-to-severe plaque psoriasis treated with ixekizumab vs. secukinumab R.B. Warren, 1 A. Brnabic, 2 D. Saure, 2 R.G. Langley, 3 K. See, 2 J.J. Wu, 4 A. Schacht, 2 L. Mallbris 2 and A. Nast 5 1 Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Manchester, U.K. 2 Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A. 3 Division of Clinical Dermatology and Cutaneous Science, Dalhousie University, Halifax, NS, Canada 4 Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, U.S.A. 5 Division of Evidence-Based Medicine, Department of Dermatology, Venereology and Allergology, Charite Universit atsmedizin Berlin, Berlin, Germany Linked Comment: Paul. Br J Dermatol 218; 178:3 5. Summary Correspondence Richard B Warren. richard.warren@manchester.ac.uk Accepted for publication 14 November 217 Funding sources This study was sponsored by Eli Lilly and Company. Conflicts of interest R.B.W. has acted as a consultant and/or speaker for AbbVie, Amgen, Almirall, Boehringer Ingleheim, Celgene, Eli Lilly and Company, Janssen, Leo Pharma, Pfizer, Novartis and Xenoport. J.J.W. is an investigator for AbbVie, Amgen, Eli Lilly and Company, Janssen, Novartis and Regeneron. A.N. has received honoraria from Bayer, Boehringer Ingelheim and Novartis. The Division of Evidence-Based Medicine (Charite Universit atsmedizin Berlin, Berlin, Germany) has received research grants/research support from Eli Lilly and Company, Pfizer, GSK and MEDA. R.G.L. has been a principal investigator and/or served on advisory boards, and/or been a speaker for AbbVie, Amgen, Celgene, Janssen, Eli Lilly and Company, Leo, Merck, Novartis and Pfizer. A.B., D.S., K.S., A.S. and L.M. are employees of Eli Lilly and Company. DOI /bjd.161 Background Head-to-head randomized studies comparing ixekizumab and secukinumab in the treatment of psoriasis are not available. Objectives To assess efficacy and quality of life using matching-adjusted indirect comparisons for treatment with ixekizumab vs. secukinumab. Methods Psoriasis Area and Severity Index (PASI) improvement of at least 75%, 9% and % and Dermatology Life Quality Index (DLQI) /1 response rates for approved dosages of ixekizumab (1 mg at Week, then mg every two weeks for the first 12 weeks) and secukinumab (3 mg at, 1, 2, 3 and 4, then 3 mg every 4 weeks) treatment were compared using data from active (etanercept and ustekinumab) and placebo-controlled studies. Comparisons were made using the (BU) method and two modified versions of the Signorovitch (SG) method (SG total and SG separate). Subsequently, results based on active treatment common comparators were combined using generic inverse-variance meta-analysis. Results In the meta-analysis of studies with active comparators, PASI 9 response rates were 127% [95% confidence interval (CI) , P = 5], % (95% CI 21 1, P = 1) and 112% (95% CI , P = 6) higher and PASI response rates were 117% (95% CI , P < 1), 127% (95% CI 194, P < 1) and 131% (95% CI , P < 1) higher for ixekizumab compared with secukinumab using BU, SG total and SG separate methods. PASI 75 results were comparable when SG methods were used and favoured ixekizumab when the BU method was used. Week 12 DLQI /1 response rates did not differ significantly. Conclusions Ixekizumab had higher PASI 9 and PASI responses at week 12 compared with secukinumab using adjusted indirect comparisons. What s already known about this topic? Interleukin-17A antagonists are highly effective new therapies for the treatment of moderate-to-severe psoriasis; however, head-to-head studies are lacking. What does this study add? Efficacy and quality of life were compared using a matching-adjusted indirect comparison for ixekizumab and secukinumab treatment. In terms of response differences, ixekizumab had higher Psoriasis Area and Severity Index (PASI) 9 and PASI responses at week 12 compared with secukinumab. Dermatology Life Quality Index response rates did not differ. 164 British Journal of Dermatology (218) 178, pp The Authors. British Journal of Dermatology This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

2 Indirect comparison of ixekizumab and secukinumab, R.B. Warren et al. 165 Introduction During the past few decades, biologics have revolutionized the treatment of moderate-to-severe psoriasis, with higher efficacy and less organ toxicity than most of the conventional treatments. 1 Interleukin (IL)-17A has been shown to be a key cytokine in psoriasis pathogenesis, and recently, biologics targeting IL-17A have provided rapid improvement of psoriasis with high levels of skin clearance maintained over time and manageable safety profiles in phase III trials. 2 8 Reliable evidence on the comparative efficacy of two currently approved IL-17A antagonists, namely ixekizumab and secukinumab, which have both demonstrated superiority to placebo, etanercept and ustekinumab in randomized clinical trials, 2 8 may help to inform clinical and economic decisions regarding their use. In the absence of head-to-head trials, indirect comparisons through a common comparator provide a good approach to understanding the differences between these two treatments. 9 Although an indirect comparison is not a replacement for a head-to-head trial, accuracy is improved when a common active comparator is used with a method such as the previously described matching-adjusted indirect comparison (MAIC), which combines published and patient-level data that are matched for baseline characteristics. 9 Because the MAIC uses individual patient data (IPD), this approach is complementary to and can reduce biases found in network meta-analyses (NMAs), which have limitations that have been described elsewhere Matching on baseline characteristics helps to reduce imbalances from different trials that might impact the outcome (treatment effect modifiers). 9 Thus, if IPD is available and there is an imbalance regarding known effect modifiers that may impact the results across trials (especially across IPD and published trials), MAICs might be preferred over adjusted indirect comparisons (AICs) or NMAs. In this report, we indirectly compared efficacy and quality of life during the first 12 weeks of treatment with ixekizumab vs. secukinumab, using the MAIC method for phase III trials of patients with moderate-to-severe plaque psoriasis that included placebo, etanercept and/or ustekinumab (common comparators). Specifically, this method calculated weights for the patients treated with ixekizumab, for which we have patient-level data available, to match for the average baseline characteristics and/or treatment effect modifiers reported for patients treated with secukinumab (such as duration of psoriasis, previous systemic therapy and baseline weight), which could introduce bias resulting from imbalances across trials, and then applied those weights to the outcomes of interest. Finally, the weighted outcomes for patients treated with ixekizumab were used along with the outcomes from the patients treated with secukinumab for the calculation of the adjusted indirect comparison. 9 Materials and methods Inclusion and exclusion criteria for UNCOVER-1 (NCT ), UNCOVER-2 (NCT ), UNCOVER-3 (NC T ), IXORA-S (NCT25616), ERASURE (NCT ), FIXTURE (NCT ), FEATURE (NCT ), JUNCTURE (NCT ) and CLEAR (NCT274982) trials have been previously reported. 2 8 Common inclusion criteria for these studies included patients aged 18 years, a diagnosis of chronic plaque psoriasis 6 months prior to randomization, and psoriasis that was moderate-to-severe at randomization. At week 12, Psoriasis Area and Severity Index (PASI) 75, PASI 9 and PASI end points at week 12 were analysed using nonresponder imputation (NRI) in all studies. Quality of life was assessed using Dermatology Life Quality Index (DLQI) /1 status and missing data were imputed using the last observation carried forward (LOCF) for all studies, as primary secukinumab studies reported LOCF and not NRI. Systematic literature review for previous network metaanalyses Clinical efficacy and safety data of potential ixekizumab comparators for the treatment of moderate-to-severe plaque psoriasis were identified through an independent systematic review (the results of which have been previously reported) 1,14 using Ovid and grey literature searches of other databases specified by key Health Technology Assessment bodies (e.g. Gemeinsame Bundesausschuss, Canadian Agency for Drugs and Technologies in Health, Pharmaceutical Benefits Advisory Committee, Haute Autorite de Sante, and National Institute for Health and Care Excellence). The systematic literature review (SLR) was performed in line with recommended guidelines from the Cochrane Handbook of Systematic Reviews of Interventions. 15 For the previously reported SLR (data collected from January 199 to November 215, with an update from November 215 to November 216) 1,14 the following databases were searched in Ovid: Embase, Ovid MEDLINE, Ovid MEDLINE Daily Update, Ovid MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO, Econlit, ACP Journal Club, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, Database of Abstracts of Reviews of Effects, Health Technology Assessment, NHS Economic Evaluation Database and Database of Abstracts of Reviews of Effects. This analysis was carried out for previously reported NMAs; of the seven secukinumab studies identified, five met the criteria for selection in this MAIC. Search strategy and selection criteria for updated search, specifically for secukinumab studies Patient-level data were available for all ixekizumab studies, which are described below. To obtain aggregate data for secukinumab studies and check for any new studies since the previous search, an SLR of MEDLINE and Cochrane were carried out and updated in March 217. The search terms were secukinumab AND psoriasis AND trial. Reference lists were combined and duplicates were removed. Reviews, metaanalyses and abstracts that contained duplicate data from the 217 The Authors. British Journal of Dermatology British Journal of Dermatology (218) 178, pp

3 166 Indirect comparison of ixekizumab and secukinumab, R.B. Warren et al. primary manuscript were removed, as were disclosures with secondary analyses outside of the outcomes of interest. The following inclusion criteria were applied: (i) randomized, double-blind, phase III trial; (ii) either placebo or active control arm; (iii) moderate-to-severe plaque psoriasis (overall, no subgroups); and (iv) secukinumab treatment. Exclusion criteria Manuscripts/abstracts were excluded if they reported outcomes for only a subgroup of patients with moderate-tosevere psoriasis in the trial based on body region (e.g. nails, scalp, palmoplantar). A Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram is provided in Figure S1 (see Supporting Information). Outcome measures extracted AIC of the U.S. Food and Drug Administration (FDA)- approved dosages for the first 12 weeks of treatment [ixekizumab (1 mg at week, then mg every 2 weeks) and secukinumab (3 mg at weeks, 1, 2, 3 and 4, then 3 mg every 4 weeks)] relative to the common comparators etanercept 5 mg twice weekly, weight-based dosing of ustekinumab, and placebo, were conducted using the standard methods for indirect comparisons described by et al. 16 (BU) and a modified version of the Signorovitch (SG) method (balanced or weighted per treatment arm separately vs. overall as with original SG method), 9 which adjusts for respective baseline differences and/or any treatment effect modifiers. The SG comparison was carried out by calculating weights for the IPD based on mean values of covariates for total population (SG total) and on mean values of covariates for each treatment arm separately (SG separate). The weights were calculated in order to balance baseline characteristics/effect modifiers across studies (File S1; see Supporting Information). Calculated weights were then applied to the outcomes for the IPD and the AIC, which were calculated based on the weighted outcome for the IPD. For studies using etanercept as the common comparator, variables used for the weight calculation included age, sex, weight, duration of psoriasis, body surface area (BSA), Table 1 Baseline clinical characteristics from ixekizumab and secukinumab phase III trials before and after matching PBO ETN UST UNCOVER-1, -2 and -3 (IXE mg Q2W) Prematch total Postmatch total d Total (SEC 3 mg + PBO) b UNCOVER-2 and -3 (IXE mg Q2W) Prematch total Postmatch total d Total (SEC 3 mg + ETN) a IXORA-S (IXE mg Q2W) Prematch total Postmatch total d Total (SEC 3 mg + UST) c N Mean age, 455 (129) 448 (132) 448 (131) 453 (133) 442 (139) 442 (131) 437 (128) 449 (127) 449 (138) years (SD) Male sex, 1322 (676) 1158 (695) 454 (695) 973 (664) 69 (698) 456 (698) 174 (672) 87 (712) 481 (712) n (%) Mean duration 189 (121) 173 (113) 173 (122) 183 (121) 161 (19) 161 (122) 1 (118) 178 (116) 178 (122) of psoriasis, years (SD) Mean baseline 911 (23) 833 (27) 863 (23) 911 (23) 838 (194) 838 (211) 877 (223) 873 (226) 873 (211) weight, kg (SD) Mean baseline NA NA NR e 35 (73) 286 (62) 286 (62) 292 (61) 291 () 291 (63) BMI (SD) Mean 23 (81) 226 (12) 226 (95) 2 (77) 236 (16) 236 (99) 213 (84) 216 (84) 216 (83) baseline PASI score (SD) Mean baseline 274 (174) 326 (29) 326 (183) 267 (166) 3 (213) 3 (186) 291 (17) 323 (188) 323 (173) BSA, % (SD) Previous 1271 (65) 135 (621) 6 (621) 883 (3) 636 (643) 42 (643) 239 (923) 82 (675) 456 (675) systemic treatments, n (%) PsA, n (%) NA NA NR e 314 (214) 142 (144) 94 (144) 38 (147) 22 (182) 123 (182) BMI, body mass index; BSA, body surface area; ETN, etanercept; IXE, ixekizumab; PASI, Psoriasis Area and Severity Index; PBO, placebo; PsA, psoriatic arthritis; SEC, secukinumab; UST, ustekinumab; NR, not reported; NA, not available. a FIXTURE. b ERASURE, FEATURE, FIXTURE, JUNCTURE. c CLEAR. d Signorovitch method, weighting for mean values of covariates for total; postmatch total Ns are effective sample size. e Not reported in FEATURE study. British Journal of Dermatology (218) 178, pp The Authors. British Journal of Dermatology

4 Indirect comparison of ixekizumab and secukinumab, R.B. Warren et al. 167 psoriatic arthritis (PsA) and previous systemic psoriasis therapy; all of these variables except for PsA were used for studies where placebo was the common comparator (this variable was not available for all placebo-controlled studies). For studies where ustekinumab was the common comparator, age, sex, weight, duration of psoriasis, BSA, PsA, previous systemic psoriasis therapy and previous biological treatment failure were used. Variables were chosen based on the overlap for studies using the same comparator. Additional sensitivity analyses were conducted where BSA and weight were replaced by PASI and body mass index (BMI). Two patients treated with placebo from the UNCOVER trials were excluded from the MAIC approach owing to missing data for baseline weight and three patients were excluded owing to missing data for baseline BMI. Additionally, one patient from the ixekizumab Q2W group was excluded for missing data for baseline BMI. Furthermore, for the IXORA-S study, one patient from the ustekinumab arm had missing data for baseline BSA. The BU-adjusted indirect comparison method utilized the same patient population as the MAIC approach. Bootstrap estimates with iterations were used to calculate the variance of the weighted estimator in the SG comparison. This variance was used to calculate s and confidence intervals (CIs). 17 Risk difference (RD) and odds ratios (ORs) with associated 95% CI are presented below. Using the ixekizumab vs. secukinumab AIC, a meta-analysis was performed for the results from the MAIC using frequentist random and fixed effects meta-analyses. All statistical analyses were conducted using R version Placebo results were included as a sensitivity analysis. Results Selected baseline characteristics prematch and postmatch are reported in Table 1. Figure 1 illustrates the MAIC for PASI 75, PASI 9 and PASI response differences between either ixekizumab or secukinumab and each comparator over time at weeks 1, 2, 4, 8 and 12. PASI 75 and PASI 9 responses relative to etanercept were statistically significantly higher for ixekizumab vs. secukinumab as early as week 2. PASI responses relative to etanercept were statistically significantly higher for ixekizumab vs. secukinumab as early as week 4. Secukinumab Ixekizumab () Ixekizuamb () Ixekizumab () PASI 75 Response rate (%) (a) 2 PASI 75 (vs. PBO) (b) PASI 75 Response rate (%) 2 PASI 75 (vs. ETN) (c) PASI 75 Response rate (%) 2 PASI 75 (vs. UST) (d) PASI 9 Response rate (%) (g) PASI Response rate (%) 2 PASI 9 (vs. PBO) 2 PASI (vs. PBO) (e) PASI 9 Response rate (%) (h) PASI Response rate (%) 2 PASI 9 (vs. ETN) 2 PASI (vs. ETN) (f) PASI 9 Response rate (%) (i) PASI Response rate (%) 2 PASI 9 (vs. UST) 2 PASI (vs. UST) Fig 1. Psoriasis Area and Severity Index (PASI) 75 (a, b, c), PASI 9 (d, e, f) and PASI (g, h, i) response differences over time (nonresponder imputation) between ixekizumab and secukinumab, with (a, d, g) placebo (PBO), (b, e, h) etanercept (ETN) and (c, f, i) ustekinumab (UST) as the common comparator for the method, Signorovitch (SG) total or SG separate methods. 217 The Authors. British Journal of Dermatology British Journal of Dermatology (218) 178, pp

5 168 Indirect comparison of ixekizumab and secukinumab, R.B. Warren et al. Risk differences Generally, relative PASI responses at week 12 were higher for ixekizumab compared with secukinumab. In the combination of results from all trials with active comparators via meta-analysis, week-12 PASI 75 RDs were modestly higher for ixekizumab vs. secukinumab for all methods used; however, only the BU method demonstrated statistical significance (Fig. 2a). When evaluating the combination of results from all trials with active comparators, week-12 PASI 9 (1 126%) and PASI ( %) RDs were statistically significantly higher (P < 5) for ixekizumab vs. secukinumab for all methods used (Fig. 2b, c). RD results were even more favourable for ixekizumab when placebo was used as the common comparator (Fig. S2a; see Supporting Information). Odds ratios In the combination of results from all trials with active comparators, PASI 75 ORs favoured ixekizumab compared with secukinumab with a statistical significance of P < 5 for all methods (Fig. 3a). PASI 9 ORs also favoured ixekizumab; however, statistical significance (P < 5) was observed only when using the BU and SG separate methods (Fig. 3b). PASI ORs favoured ixekizumab, but not significantly (Fig. 3c). ORs for all relative PASI outcomes using placebo as the common comparator ratios favoured ixekizumab, but only demonstrated statistical significance for PASI 75 when the BU method was used (Fig. S2b; see Supporting Information). Similar OR and RD results for all relative PASI outcomes were observed in sensitivity analyses with each common comparator when matched for different baseline characteristics. In the meta-analysis of results from studies with active comparators, RDs for DLQI /1 responses were generally similar between ixekizumab and secukinumab, although they were numerically higher for ixekizumab when analysed using the BU method (Fig. 2d). A similar pattern was seen for ORs (Fig. 3d). Discussion In the absence of head-to-head randomized trials comparing the relative efficacy of ixekizumab vs. secukinumab, the SG MAIC method, 9 which adjusts for differences in baseline (a) PASI 75 (b) PASI 9 (c) Risk difference (%) PASI Risk difference (%) (d) Risk difference (%) DLQI / Risk difference (%) Fig 2. Risk differences and associated 95% confidence interval for: (a) Psoriasis Area and Severity Index (PASI) 75, (b) PASI 9 and (c) PASI (nonresponder imputation) and (d) Dermatology Life Quality Index (DLQI) /1 (last observation carried forward) response rates at week 12 in trials with etanercept (ETN) or ustekinumab (UST) as a comparator, and pooled frequentist meta-analysis results. IXE, ixekizumab; SEC, secukinumab; SG, Signorovitch method. British Journal of Dermatology (218) 178, pp The Authors. British Journal of Dermatology

6 Indirect comparison of ixekizumab and secukinumab, R.B. Warren et al. 169 (a) PASI 75 (b) PASI Odds ratio Odds ratio (c) PASI (d) DLQI / Odds ratio Odds ratio Fig 3. Odds ratios and associated 95% confidence interval for: (a) Psoriasis Area and Severity Index (PASI) 75, (b) PASI 9 and (c) PASI (nonresponder imputation) and (d) Dermatology Life Quality Index (DLQI) /1 (last observation carried forward) response rates at week 12 in trials with etanercept (ETN) or ustekinumab (UST) as a comparator, and pooled results. IXE, ixekizumab; SEC, secukinumab; SG, Signorovitch method. clinical characteristics and observed treatment effect modifiers across studies, may provide a less biased approach to the widely used and accepted AIC approach described by et al. 16 After adjusting for cross-trial differences in baseline characteristics, ixekizumab (UNCOVER-1, UNCOVER-2 and UNCOVER-3, and IXORA-S) was associated with significantly higher percentages of patients achieving clear or nearly clear skin (PASI 9 and PASI ) compared with secukinumab (FIXTURE, ERASURE, JUNC- TURE, FEATURE and CLEAR) at week 12 among patients with moderate-to-severe psoriasis. In the present meta-analysis, treatment of patients with moderate-to-severe psoriasis with either ixekizumab or secukinumab achieved high PASI 75 response rates with small differences when adjusting for baseline clinical characteristics and/or treatment effect modifiers. Both before and after adjusting for baseline characteristics and/or treatment effect modifiers, PASI 9 and PASI response rates were significantly higher for ixekizumab vs. secukinumab via etanercept. Across the different PASI end points, ixekizumab tended to provide a more rapid onset of action. This may be valuable to many patients with psoriasis, as surveys indicate that rapid improvement of disease and clearance of skin lesions are important treatment goals. 19,2 Interestingly, although there were significant differences in skin resolution at week 12, the proportion of patients for whom psoriasis had little or no impact on health-related quality of life was similar for ixekizumab and secukinumab. This was somewhat unexpected given previous reports of associations between skin clearance and quality of life. 2,21 23 A comparison of long-term efficacy and how this impacts long-term quality of life is needed. The higher percentages of patients achieving clear or nearly clear skin may translate into greater cost-efficiency, as a recently published analysis of FDA-approved biologics found, at least 217 The Authors. British Journal of Dermatology British Journal of Dermatology (218) 178, pp

7 17 Indirect comparison of ixekizumab and secukinumab, R.B. Warren et al. based on U.S. pricing, monthly cost per additional PASI responder was lowest in patients treated with ixekizumab vs. patients treated with secukinumab or other biologics. 14 A comparison of safety data was not performed because most adverse events were either too rare, potentially defined by different criteria, or potentially analysed via different methods in the different trials. In addition, meaningful safety comparisons would require long-term follow-up, which is challenging because most ixekizumab and secukinumab studies have different trial designs beyond 12 weeks. It is also possible that differences existed across trials in terms of how adverse events were collected (e.g. active vs. passive elicitation) and in the definition of treatment-emergent. 24 It is important to note that the PASI results were based on the nonresponder imputation, in which all patients who discontinued the study for any reason including adverse events were counted as nonresponders. Thus, the PASI results already combine elements of efficacy and tolerability. This study has several limitations. Even when matching on baseline characteristics and/or effect modifiers, and using an active comparator (etanercept or ustekinumab) to make relative comparisons, differences in trial populations, designs and conduct, along with the potential presence of unmeasured confounders may remain and can influence treatment effects; these issues are less likely to affect treatment comparisons within a head-to-head randomized trial. Although this comparison shows higher responses earlier for ixekizumab compared with secukinumab, peak responses for each drug may occur at different time points. UNCOVER trials have sufficiently different study designs compared with FIXTURE, ERA- SURE and JUNCTURE making longer-term comparisons beyond 12 weeks difficult. IXORA-S and CLEAR designs are more similar, but these trials are also significantly smaller, increasing the uncertainty of the indirect comparisons based only on these studies. Application of the SG or of the modified SG approach usually leads to a reduction of effective sample sizes and thus wider CIs. 9 Matching is dependent on aggregate data, and therefore varies by study. The approach of performing a meta-analysis of several MAIC networks might provide a more robust and reliable effect estimate. However, this approach is new and more research is necessary to investigate its strengths and limitations fully. This study also has several strengths. Active comparators (etanercept or ustekinumab), which are more informative than a placebo, were used in addition to placebo as common comparators for the indirect comparison. Placebo response rates (especially for PASI 9 or PASI ) are very low (nearly zero) across studies and are therefore noninformative with respect to variations in study design, and low responses in this group make CIs around the ORs unstable and difficult to interpret. Baseline differences between studies are one of the main challenges when using indirect comparisons, and using the modified SG approach allows us to reduce treatment differences that are attributable to differences in baseline characteristics. In the field of psoriasis, trials across compounds have similar inclusion and exclusion criteria, reporting of baseline characteristics and analyses of treatment effects, which allows for this approach to be used. Finally, the combined studies included large sample sizes allowing for a good estimation of the treatment difference between ixekizumab and secukinumab. This study provides evidence via indirect comparison to support the higher efficacy of ixekizumab compared with secukinumab through 12 weeks of treatment in patients with moderate-to-severe psoriasis with regard to PASI 9 and PASI (RDs) and PASI 75 and PASI 9 (ORs). Even with adjustment for cross-trial differences in baseline characteristics and treatment effect modifiers, ixekizumab was associated with higher relative PASI responses compared with secukinumab. Notably, the results of this study showed a rapid onset of action with higher percentages of patients treated with ixekizumab achieving higher levels of clearance (PASI 9) at week 2 compared with patients treated with secukinumab, both of which are important patient preferences in biological treatment. 19,2 Acknowledgments The authors thank Bridget Charbonneau for her writing support. References 1 Ferrandiz C, Carrascosa JM, Boada A. A new era in the management of psoriasis? The biologics: facts and controversies. Clin Dermatol 21; 28: Griffiths CE, Reich K, Lebwohl M et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 215; 386: Langley RG, Elewski BE, Lebwohl M et al. Secukinumab in plaque psoriasis results of two phase 3 trials. N Engl J Med 214; 371: Gordon KB, Blauvelt A, Papp KA et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med 216; 375: Blauvelt A, Prinz JC, Gottlieb AB et al. Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE). Br J Dermatol 215; 172: Paul C, Lacour JP, Tedremets L et al. Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE). J Eur Acad Dermatol Venereol 215; 29: Reich K, Pinter A, Lacour JP et al. Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study. Br J Dermatol 217; 177: Thacßi D, Blauvelt A, Reich K et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol 215; 73: 9. 9 Signorovitch JE, Wu EQ, Yu AP et al. Comparative effectiveness without head-to-head trials: a method for matching-adjusted indirect comparisons applied to psoriasis treatment with adalimumab or etanercept. Pharmacoeconomics 21; 28: British Journal of Dermatology (218) 178, pp The Authors. British Journal of Dermatology

8 Indirect comparison of ixekizumab and secukinumab, R.B. Warren et al Hartz S, Walzer S, Dutronc Y et al. Network meta-analysis to evaluate the efficacy of ixekizumab in the treatment of moderate-tosevere psoriasis. Value Health 216; 19:A Jabbar-Lopez ZK, Yiu ZZN, Ward V et al. Quantitative evaluation of biologic therapy options for psoriasis: a systematic review and network meta-analysis. J Invest Dermatol 217; 137: Reich K, Leonardi C, Papp K et al. Comment on Quantitative evaluation of biologic therapy options for psoriasis: a systematic review and network meta-analysis. J Invest Dermatol 217; 137: Schacht A, Dyachkova Y, Walton RJ. Critical evaluation of mixed treatment comparison meta-analyses using examples assessing antidepressants and opioid detoxification treatments. Int J Methods Psychiatr Res 213; 22: Al Sawah S, Foster SA, Burge R et al. Cost per additional responder for ixekizumab and other FDA-approved biologics in moderate-tosevere plaque psoriasis. J Med Econ 217; 2: Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Available at: ook.org (last accessed 13 December 217). 16 HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 1997; 5: Erder MH, Xie J, Signorovitch JE et al. Cost effectiveness of guanfacine extended-release versus atomoxetine for the treatment of attention-deficit/hyperactivity disorder: application of a matchingadjusted indirect comparison. Appl Health Econ Health Policy 212; 1: Ihaka R, Gentleman R. R: a language for data analysis and graphics. J Comput Graph Stat 1996; 5: Blome C, Gosau R, Radtke MA et al. Patient-relevant treatment goals in psoriasis. Arch Dermatol Res 216; 38: Kromer C, Schaarschmidt ML, Schmieder A et al. Patient preferences for treatment of psoriasis with biologicals: a discrete choice experiment. PLOS ONE 215; 1:e Takeshita J, Callis Duffin K, Shin DB et al. Patient-reported outcomes for psoriasis patients with clear versus almost clear skin in the clinical setting. J Am Acad Dermatol 214; 71: Torii H, Sato N, Yoshinari T et al. Dramatic impact of a Psoriasis Area and Severity Index 9 response on the quality of life in patients with psoriasis: an analysis of Japanese clinical trials of infliximab. J Dermatol 212; 39: Viswanathan HN, Chau D, Milmont CE et al. Total skin clearance results in improvements in health-related quality of life and reduced symptom severity among patients with moderate to severe psoriasis. J Dermatolog Treat 215; 26: Crowe B, Brueckner A, Beasley C, Kulkarni P. Current practices, challenges, and statistical issues with product safety labeling. Stat Biopharm Res 213; 5: Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher s website: Fig S1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram. Fig S2. (a) Risk differences and (b) odds ratios and associated 95% confidence interval for Psoriasis Area and Severity Index (PASI) 75, PASI 9 and PASI in trials with placebo as a comparator. File S1. Weight equation. 217 The Authors. British Journal of Dermatology British Journal of Dermatology (218) 178, pp