BJD C L I NI C A L T R I A L British Journal of Dermatology Adjusted treatment COMPArisons between guSelkumab and uStekinumab for treatment of moderate-to-severe plaque psoriasis: the COMPASS analysis* J. Diels,1 P. Thilakarathne,1 C. Cameron,2 S. McElligott,1 A. Schubert3 and L. Puig4 1 Janssen Research and Development LLC, Raritan, NJ, U.S.A. 2 Cornerstone Research Group Inc., Evidence Synthesis, Burlington, ON, Canada 3 Janssen-Cilag Polska, Warsaw, Poland 4 Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Linked Comment: Yiu. Br J Dermatol 2020; 183:202–203. Summary Correspondence Background Guselkumab is an interleukin-23 inhibitor indicated for the treatment Joris Diels. of moderate-to-severe plaque psoriasis in adults. Guselkumab has demonstrated E-mail: jdiels@ITS.JNJ.com additional benefit in patients with early inadequate response to ustekinumab. Long-term efficacy comparisons of guselkumab and ustekinumab are currently Accepted for publication 21 October 2019 lacking among ustekinumab-naive patients. Objectives To assess the relative efficacy of guselkumab and ustekinumab for main- Funding sources tenance therapy of moderate-to-severe plaque psoriasis, using individual patient This study was funded by Janssen Inc. data (IPD) from randomized controlled trials. Methods IPD for guselkumab from the VOYAGE 1 and 2 trials were pooled and Conflicts of interest compared with IPD for ustekinumab from the NAVIGATE trial. Multivariable J.D., P.T., A.S. and S.M. are employees of Janssen Inc. C.C. is an employee and shareholder of logistic regression analyses compared guselkumab 100 mg and ustekinumab 45 Cornerstone Research Group Inc. L.P. has received mg or 90 mg for the achievement and maintenance of Psoriasis Area and Severity consultancy and speaker’s honoraria from AbbVie, Index (PASI) 90, 75 and 100 responses up to 40 weeks. The regression models Almirall, Amgen, Baxalta, Biogen, Boehringer accounted for a range of clinically relevant covariates (e.g. age, sex, psoriasis Ingelheim, Celgene, Genro, Janssen, LEO Pharma, duration). Relative efficacy was expressed using odds ratios (ORs) and predicted Eli Lilly, Merck-Serono, MSD Mylan, Novartis, probability of treatment response associated with each intervention. Pfizer, Regeneron, Roche, Sandoz, Samsung Bioepis, Sanofi and UCB and participated in clinical trials Results Patients receiving guselkumab had significantly higher probabilities of sponsored by AbbVie, Almirall, Amgen, Boehringer achieving a PASI 90 response than patients receiving ustekinumab, at both week Ingelheim, Janssen, LEO Pharma, Eli Lilly, 16 [704% vs. 460%, OR 279, 95% confidence interval (CI) 222–345] and Novartis, Pfizer, Regeneron, Roche, Sanofi and week 40 (742% vs. 545%, OR 240, 95% CI 189–313]. Guselkumab was also UCB. The authors have no other relevant affilia- associated with a significantly increased likelihood of achieving both PASI 75 and tions or financial involvement with any organiza- PASI 100 responses at weeks 16 and 40, compared with ustekinumab. tion or entity with a financial interest in or financial conflict with the subject matter or mate- Conclusions Adjusted analyses leveraging IPD demonstrate that guselkumab has a rials discussed in the manuscript apart from those significantly higher probability of achieving and maintaining PASI treatment disclosed. responses through week 40 than ustekinumab does. *Plain language summary available online What’s already known about this topic? DOI 10.1111/bjd.18634 • The NAVIGATE trial demonstrated improved treatment responses in patients with moderate-to-severe plaque psoriasis who switched to guselkumab after inadequate responses to ustekinumab induction therapy. 276 British Journal of Dermatology (2020) 183, pp276–284 © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 13652133, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.18634 by Readcube (Labtiva Inc.), Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License COMPASS analysis: guselkumab vs. ustekinumab for plaque psoriasis, J. Diels et al. 277 What does this study add? • To date, no head-to-head randomized controlled trials have compared ustekinumab and guselkumab in a combination of biologic-naive and biologic-experienced patients. • The present study leveraged individual patient data from randomized controlled tri- als to compare guselkumab and ustekinumab maintenance therapy indirectly in a combination of biologic-naive and biologic-experienced patients. Psoriasis is a painful, disfiguring and chronic dermatological the efficacy of guselkumab vs. ustekinumab in a mix of ustek- condition characterized by autoimmune-mediated inflamma- inumab-naive and ustekinumab-experienced patients with tion of the skin.1,2 The most common form of the condition moderate-to-severe plaque psoriasis, using individual patient is psoriasis vulgaris, or plaque-type psoriasis, which affects data (IPD) from pivotal guselkumab RCTs (i.e. VOYAGE 1 and approximately 80–90% of patients.3 Plaque-type psoriasis is VOYAGE 2) and ustekinumab RCTs (i.e. NAVIGATE, PHOENIX characterized by raised red lesions on the skin that often cause 1 and PHOENIX 2). considerable pain and itchiness. These signs and symptoms can severely reduce health-related quality of life.4,5 Treatment Patients and methods of moderate-to-severe plaque psoriasis typically involves sys- temic therapy or phototherapy. Several biologic therapies have Overview of study populations been shown to have efficacy in this patient population. Interleukin (IL)-23 exerts an early effect in the pathogenesis Overviews of the NAVIGATE, VOYAGE and PHOENIX RCTs are of psoriasis via upstream regulation of the two key immune presented in the Appendix (see Supporting Information).12–16 axes in psoriasis: the IL-23/T helper cell 17 (Th17) axis, The ACCEPT trial of ustekinumab was not included because it which is responsible for the inflammatory cascade, and the did not have sufficient data beyond the induction period.17 In regulatory T cell (Treg)/Th17 axis, which contributes to the the current analysis, IPD from VOYAGE 1 and VOYAGE 2 were chronicity of the disease. From one side, IL-23 activates Th17 combined to form a pooled dataset for patients treated with cells to produce effector cytokines (i.e. IL-17, tumour necrosis guselkumab.13,14 IPD from NAVIGATE and PHOENIX 1 were factor-a and IL-22) that drive the inflammatory response and, included for patients treated with ustekinumab.12,15,16 Primary on the other side, IL-23 maintains the Th17 secretory pheno- analyses only included ustekinumab IPD from NAVIGATE,12 type leading to the chronic inflammation seen in psoriasis.6,7 while sensitivity analyses included IPD for patients treated with Inhibiting IL-23 is an effective strategy that downregulates the ustekinumab in the PHOENIX trials according to approved inflammatory cascade (IL-23/Th17 axis) and its perpetuation labelled dosing (i.e. 45 mg for patients weighing ≤ 100 kg, and (Treg/Th17 axis). Ustekinumab, an anti-IL-12/IL-23 mono- 90 mg for patients > 100 kg).15,16 In addition, NAVIGATE, clonal antibody that binds to the p40 subunit shared by IL-12 VOYAGE 1 and VOYAGE 2 were all conducted in a similar time- and IL-23, is indicated for the treatment of moderate-to-severe frame (i.e. initiated in 2014),12–14 making them more suitable plaque psoriasis and is consistently associated with the highest for comparison, whereas the PHOENIX trials were conducted rates of time on treatment in real-world settings.8–11 Guselku- earlier (i.e. initiated in 2005).15,16 mab is the first approved monoclonal antibody that inhibits IL-23 by targeting its p19 subunit with high specificity and Adjusting for treatment switching in the NAVIGATE and affinity.6 The more selective blockade of IL-23 via the p19 VOYAGE 2 trials subunit, as opposed to the dual blockade of IL-12/IL-23 via the p40 subunit, may provide additional clinical benefit.7 Primary analyses were performed using IPD from NAVIGATE The NAVIGATE study, a randomized controlled trial (RCT), for the ustekinumab cohort (n = 853) and from the VOYAGE provides data regarding the relative efficacy of guselkumab trials for the guselkumab cohort (n = 825).12–14 The ustek- compared with ustekinumab in patients who were inadequate inumab cohort included both responders (i.e. patients with an responders to ustekinumab [i.e. an Investigator’s Global IGA score of 0 or 1 at week 16) who received open-label Assessment (IGA) score ≥ 2 after 16 weeks of treatment].12 ustekinumab for 40 weeks, and inadequate responders (i.e. The VOYAGE 1 and VOYAGE 2 trials included patients with IGA ≥ 2 at week 16) who were randomized to continued or without prior biologic therapy (i.e. 216% and 204% of ustekinumab at week 16 (i.e. instead of switching to guselku- patients had prior biologic treatment in VOYAGE 1 and 2, mab). To adjust for treatment switching at week 16, inade- respectively).13,14 However, there are no head-to-head RCTs quate responders who continued ustekinumab were comparing guselkumab and ustekinumab in a broader patient reweighted to represent the outcome for patients who switched population of patients not treated previously with ustek- to guselkumab, through a commonly accepted method known inumab. The objective of the current study was to compare as inverse probability of censoring weighted (IPCW) analysis.18 © 2019 The Authors. British Journal of Dermatology British Journal of Dermatology (2020) 183, pp276–284 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. 13652133, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.18634 by Readcube (Labtiva Inc.), Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 278 COMPASS analysis: guselkumab vs. ustekinumab for plaque psoriasis, J. Diels et al. (a) NAVIGATE Open-label run-in period Randomized or open-label continuation period Follow-up period 1 1 weight = =0 weight = = 1/0.5 = 2 (probabilityUST) (probabilityUST) NR Guselkumab 100 mg (n=135) at Week 16 and 20, then Q8W R Ustekinumab Ustekinumab 45 mg or 90 mg (n=133) at Week 16, 28, and 40 Weeks 0, 4 (n=853) R Ustekinumab 45 mg or 90 mg (n=585) at Week 16, 28, and 40 Week 0 4 16 20 28 36 40 44 60 PE SE ® = Randomization; PE = Primary endpoint; SE = Secondary endpoint Q8W = every 8 weeks Responders R = IGA of 0 or 1; Nonresponders NR = IGA ≥ 2 (b) VOYAGE 1 Active-comparator period Placebo-comparator period Placebo-crossover period Guselkumab 100 mg at Weeks 0 and 4, then Q8W R Placebo Guselkumab 100 mg at Weeks 16 and 20, then Q8W Adalimumab 80 mg at Week 0 → 40 mg at Week 1, then Q2W Week 0 16 24 48 PE SE SE SE ® = Randomization; PE = Primary endpoint; SE = Secondary endpoint Q2W = every 2 weeks; Q8W = every 8 weeks (c) VOYAGE 2 Active-comparator period Placebo-controlled Placebo-crossover Randomized withdrawal and retreatment period period period 1 weight = = 1/0.5 = 2 (probabilityUST) Continue Guselkumab 100 mg Q8W NR Placebo → retreatment Guselkumab 100 mg at Weeks 0 and 4, then Q8W R R Continue Guselkumab 100 mg Q8W NR Continue Guselkumab 100 mg Q8W Placebo Guselkumab 100 mg R Placebo → retreatment R NR Initiate Guselkumab 100 mg 0, 4, then Q8W Adalimumab 80 mg at Week 0 → 40 mg at Week 1, then Q2W Placebo → Guselkumab R 100 mg, 0, 4, then Q8W• Week 0 16 24 28 48 PE SE SE SE ® = Randomization; PE = Primary endpoint; SE = Secondary endpoint Q2W = every 2 weeks; Q8W = every 8 weeks Responders R = 90% or greater improvement in Psoriasis Area and Severity Index (PASI 90); Nonresponders NR = < PASI 90 response Fig 1. Overview of study designs and approach to adjustments for crossovers in the VOYAGE 2 and NAVIGATE studies. (a) NAVIGATE. As nonresponding patients were randomly assigned to continue ustekinumab vs. switching to guselkumab, patients in both arms can be considered exchangeable, and outcomes for the nonresponding ustekinumab patients who continued on ustekinumab after randomization can be considered to constitute a valid counterfactual for the patients randomized to guselkumab. To estimate unbiased outcomes for the entire cohort and eliminate the impact of treatment switching at week 16, nonresponders who continued with ustekinumab were upweighted to represent the outcome for the patients switched to guselkumab as if they had continued ustekinumab. (b) VOYAGE 1. No adjustments for crossovers needed. (c) A similar approach as described for NAVIGATE was applied to VOYAGE 2 to deal with rerandomization of responding patients in the guselkumab arm at week 28 data. IGA, Investigator’s Global Assessment; R, randomized; UST, ustekinumab; W, week. In using this approach, we attempted to simulate a trial design Despite lacking long-term response rates for ustekinumab in where patients receiving ustekinumab in NAVIGATE all contin- patients who switched to guselkumab, we were able to esti- ued receiving ustekinumab (i.e. did not switch). mate missing information by leveraging information from British Journal of Dermatology (2020) 183, pp276–284 © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. 13652133, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.18634 by Readcube (Labtiva Inc.), Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License COMPASS analysis: guselkumab vs. ustekinumab for plaque psoriasis, J. Diels et al. 279 Fig 2. Hierarchy of evidence for comparing interventions; adapted from Coyle et al.26 AD, aggregated data; IPD, individual patient data; ITC, indirect treatment comparison; ITT, intention to treat; MAIC, matching-adjusted indirect comparison; NMA, network meta-analysis; RCT, randomized controlled trial. rerandomized patients who continued on ustekinumab. The Findings from all analyses were expressed in terms of both alternative approach of excluding nonresponder patients who odds ratios (ORs) and risk differences (RDs) with correspond- switched to guselkumab from our analysis would cause selec- ing 95% confidence intervals (CIs) to provide a more robust tion bias by including only responders, and overestimate analysis. Results were considered statistically significant if the response rates for ustekinumab (i.e. a half-cohort of nonre- 95% CI for ORs excluded the null value of 1 (and for RDs if sponders would have been left out). IPCW is expected to be the 95% CI excluded 0%). Inadequate responder imputation unbiased because of randomization, as nonresponding patients was used for missing data in the analyses. Multivariable logis- who continued using ustekinumab are treated as being similar tic models were also used to estimate the predicted probability to or exchangeable with patients who switched to guselku- of treatment response for each therapy up to week 40 of fol- mab. Due to the randomized nature of treatment switching at low-up. All analyses were performed using SAS software (ver- week 16, no adjustment for confounders was applied. In sion 94; SAS Institute Inc., Cary, NC, U.S.A.). VOYAGE 2, patients who achieved ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90 response) at week Sensitivity analysis using patients from PHOENIX 1 and 28 were rerandomized to either continued guselkumab or pla- PHOENIX 2 cebo.14 This rerandomization was accounted for via an approach that was similar to the adjustment for crossover Sensitivity analyses were performed using a second cohort of described for NAVIGATE (Fig. 1).12 patients who used ustekinumab, from the PHOENIX 1 and PHOENIX 2 trials.15,16 Only patients treated as per approved labelled dosing (i.e. ustekinumab 45 mg for patients weighing Approach for multivariable regression analysis ≤ 100 kg, or ustekinumab 90 mg for patients weighing > 100 Weighting was added to selected intervention arms as needed kg) were included. These analyses were performed to validate to account for the rerandomization of patient subgroups in findings from the primary analyses. NAVIGATE and VOYAGE 2.12,14 PASI 90, PASI 75 and PASI 100 response rates were analysed through 48 weeks of fol- Results low-up, using weighted multivariable logistic regression meth- ods to derive adjusted treatment comparisons between Overview of patient populations guselkumab and ustekinumab (Fig. 2). Covariates adjusted for in the analyses were prespecified and were selected based on Table 1 and Figure S1 (see Supporting Information) provide clinical relevance and discussions with clinical experts. an overview of patient demographics by intervention group Prognostic factors included sex (male vs. female), baseline age and trial for NAVIGATE, VOYAGE 1 and VOYAGE 2.12–14 Sta- (< 45 years, 45–64 years, ≥ 65 years), baseline bodyweight tistically significant differences were observed between the (< 70 kg, 70–79 kg, 80–89 kg, 90–99 kg, 100–109 kg, ≥ studies, with respect to sex (644–714% male, with higher 110 kg), psoriasis duration (< 15 years vs. ≥ 15 years), base- values in the VOYAGE studies); disease duration (468–553% line PASI score (< 16, 16–18, 18–19, 20–21, ≥ 22), baseline with duration ≥ 15 years, with higher values in the VOYAGE IGA score (< 4, 4), presence of psoriatic arthritis (yes vs. no), studies); prior therapies (285–421% of patients were treat- history of phototherapy (ever used vs. never used) and history ment naive, with higher values in the NAVIGATE study); and of prior therapies (systemic and biologic, biologic, systemic, history of phototherapy (512–584% ever used, with higher naive). values in the VOYAGE studies). The other patient © 2019 The Authors. British Journal of Dermatology British Journal of Dermatology (2020) 183, pp276–284 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. 13652133, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.18634 by Readcube (Labtiva Inc.), Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 280 COMPASS analysis: guselkumab vs. ustekinumab for plaque psoriasis, J. Diels et al. Table 1 Baseline patient characteristics by trial kg and prior phototherapy were both associated with a signifi- cantly lower likelihood of a PASI 90 response at week 40 (P VOYAGE NAVIGATE, < 005 vs. weight < 70 kg and no phototherapy, respectively). Characteristic 1 & 2, n (%)a n (%)b P-value Figure 4 presents a longitudinal plot of the predicted PASI 90 Sex response rates based on the multivariable regression model Male 589 (714) 549 (644) 0002 from the pooled VOYAGE and NAVIGATE trials. Female 236 (286) 304 (356) The predicted response rates account for differences Baseline age (years) between study populations and were found to align well with ˂ 45 432 (524) 475 (557) 023 45–64 352 (427) 330 (387) the observed rates from the individual studies (Appendix; see ≥ 65 41 (50) 48 (56) Supporting Information). Based on the regression analysis, sig- Baseline weight (kg) nificantly more patients treated with guselkumab achieved a < 70 125 (152) 173 (203) 006 PASI 90 response at week 40, compared with patients treated 70–79 146 (177) 148 (174) with ustekinumab. The predicted probability of achieving a 80–89 182 (221) 153 (179) PASI 90 response at week 40 was 742% for patients treated 90–99 165 (200) 152 (178) with guselkumab, compared with 544% for patients treated 100–109 92 (112) 112 (131) ≥ 110 115 (139) 115 (135) with ustekinumab (adjusted OR 240, 95% CI 189–313; Psoriasis disease duration (years) Fig. 4). The corresponding RD at week 40 was 197% (95% < 15 369 (447) 454 (532) < 0001 CI 147–241%). This difference was statistically significant in ≥ 15 456 (553) 399 (468) favour of guselkumab for weeks 16–48. Baseline PASI score < 16 240 (291) 264 (310) 068 16–17 134 (162) 134 (157) Psoriasis Area and Severity Index 75 and 100 responses 18–19 93 (113) 107 (126) 20–21 57 (69) 61 (72) Longitudinal plots of the observed and predicted response rates ≥ 22 301 (365) 286 (335) for PASI 75 and PASI 100 are presented in the Appendix (see IGA score Supporting Information); a summary of covariate effects is pro- <4 633 (767) 679 (795) 016 vided in the Appendix (see Supporting Information). Based on 4 192 (233) 174 (205) the multivariable regression analysis, the adjusted OR for the BSA (%) PASI 75 response at week 40 was 214 (95% CI 154–294) in < 20 309 (375) 345 (404) 021 favour of guselkumab (Fig. S3; see Supporting Information). ≥ 20 516 (625) 508 (596) Psoriatic arthritis The predicted probability of a PASI 75 response at week 40 was Yes 153 (185) 119 (140) 001 878% for guselkumab and 771% for ustekinumab, with a cor- No 672 (815) 734 (860) responding RD of 107% (95% CI 62–150%). Previous therapy Similarly, the adjusted OR for a PASI 100 response at week Naive 235 (285) 359 (421) < 0001 40 was 253 (95% CI 200–323) in favour of guselkumab Systemic use only 418 (507) 367 (430) (Fig. 5). The predicted probability of a PASI 100 response at Biologic use only 49 (59) 45 (53) week 40 was 497% for guselkumab and 281% for ustek- Systemic and 123 (149) 82 (96) biologic use inumab, with a corresponding RD of 216% (95% CI 167– Phototherapy 264%). The relative treatment effect (expressed as the OR) Never used 343 (416) 416 (488) 0003 was greater for higher PASI thresholds. Similar differences in Ever used 482 (584) 437 (512) PASI 75 and PASI 100 response rates between cohorts were observed for the entire maintenance treatment phase between PASI, Psoriasis Area and Severity Index; IGA, Investigator’s Global Assessment; BSA, body surface area; aguselkumab (N = 825 weeks 16 and 40. patients); bustekinumab (N = 853 patients). Sensitivity analyses characteristics that were assessed were comparable. Character- Multivariable logistic regression analyses for all PASI response istics of patients from the PHOENIX trials of ustekinumab are end points were repeated using ustekinumab IPD from the provided in the Appendix (see Supporting Information).15,16 PHOENIX trials; predicted and observed PASI response rates are presented in Figure 4 and the Appendix (see Supporting Information), respectively. Predicted treatment effects were The Psoriasis Area and Severity Index 90 response at 40 similar to those obtained in the primary analyses, with statisti- weeks cally significant differences in favour of guselkumab for the Figure 3 presents a forest plot summarizing the effects of the PASI 90 response (OR 263, 95% CI 185–370), the PASI 75 different covariates included in the multivariable model of the response (OR 214, 95% CI 139–333) and the PASI 100 PASI 90 response at week 40. PASI 90 response rates were response (OR 320, 95% CI 222–455; Fig. 5). The corre- generally consistent across covariates, although weight 90–99 sponding predicted probabilities of PASI responses were British Journal of Dermatology (2020) 183, pp276–284 © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. 13652133, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.18634 by Readcube (Labtiva Inc.), Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License COMPASS analysis: guselkumab vs. ustekinumab for plaque psoriasis, J. Diels et al. 281 Fig 3. Estimated covariate effects from logistic regression, Psoriasis Area and Severity Index 90 response at week 40. Treatment and covariate effects were estimated using multivariable logistic regression and are expressed as odds ratios with corresponding 95% confidence intervals. BSA, body surface area; IGA, Investigator’s Global Assessment; LCL, lower 95% confidence limit; OR, odds ratio; PASI, Psoriasis Area and Severity Index; PS, psoriatic; PSO, psoriasis; UCL, upper 95% confidence limit; areference value. © 2019 The Authors. British Journal of Dermatology British Journal of Dermatology (2020) 183, pp276–284 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. 13652133, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.18634 by Readcube (Labtiva Inc.), Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 282 COMPASS analysis: guselkumab vs. ustekinumab for plaque psoriasis, J. Diels et al. Fig 4. Predicted rates of a Psoriasis Area and Severity Index 90 treatment response for guselkumab and ustekinumab, based on data from the VOYAGE, NAVIGATE and PHOENIX trials, with 95% confidence intervals. Predicted rates were derived from the multivariable logistic regression model, as described in the study methods. CI, confidence interval; GUS, guselkumab; PASI, Psoriasis Area and Severity Index; UST, ustekinumab. 742% vs. 522% (PASI 90), 878% vs. 771% (PASI 75) and There was consistency in long-term results among analyses 497% vs. 236% (PASI 100; Fig. 5). using different data sources. The primary analyses included ustekinumab IPD from NAVIGATE,12 while sensitivity analyses included IPD for patients treated with ustekinumab in the Discussion PHOENIX trials, according to approved labelled dosing (i.e. To date, no head-to-head RCTs have compared ustekinumab 45 mg for patients weighing ≤ 100 kg, and 90 mg for and guselkumab in a combination of biologic-naive and bio- patients weighing > 100 kg).15,16 The primary analyses logic-experienced patients. The present study leveraged IPD focused on NAVIGATE,12 to reduce potential bias, as the time- from the NAVIGATE and VOYAGE trials to compare guselku- frame for that study was similar to that for VOYAGE 1 and mab and ustekinumab indirectly in a combination of biologic- VOYAGE 2 (i.e. it was initiated in 2014).13,14 It is reassuring naive and biologic-experienced patients.12–14 IPD analysis is that sensitivity analyses using IPD from the PHOENIX trials, the gold-standard methodology for comparing treatments in which were initiated in 2005,15,16 were consistent with the the absence of head-to-head RCTs.19,20 The current study primary analyses of PASI response rates. found that guselkumab was associated with significantly greater This is the first indirect treatment comparison of its kind to achievement of PASI 90, PASI 75 and PASI 100 responses than compare guselkumab and ustekinumab for induction and ustekinumab throughout 40 weeks of treatment, using IPD maintenance treatment in moderate-to-severe psoriasis in a from the NAVIGATE, VOYAGE 1 and VOYAGE 2 trials.12–14 combination of biologic-naive and biologic-experienced British Journal of Dermatology (2020) 183, pp276–284 © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists. 13652133, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.18634 by Readcube (Labtiva Inc.), Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License COMPASS analysis: guselkumab vs. ustekinumab for plaque psoriasis, J. Diels et al. 283 Fig 5. Adjusted comparisons for guselkumab vs. ustekinumab: achievement of Psoriasis Area and Severity Index (PASI) 90, 75 and 100 responses at week 40. Odds ratios from multivariable logistic regression analyses comparing guselkumab and ustekinumab for PASI response outcomes at 40 weeks of follow-up are shown. In both primary and secondary analyses, guselkumab was associated with a statistically significantly increased likelihood of treatment response. Predicted probabilities of response associated with each intervention are also provided for each outcome measure. CI, confidence interval. patients. The findings leveraged IPD from clinical trials of two for a wide range of clinically relevant patient characteristics; the treatments and adjusted for cross-trial differences by using fact that the results remained consistent across a number of multivariable regression. As we used a more methodologically analyses suggests that our findings are robust. Additionally, even rigorous form of indirect treatment comparison than naive though we used two different studies to provide patient data for indirect treatment comparisons,21 our study demonstrates the ustekinumab, with the two studies having been conducted at comparative effectiveness of guselkumab and ustekinumab in different times and using different study designs and patient the absence of a head-to-head clinical trial. populations, our findings were consistent, a result that further Clinical and real-world studies have shown that ustekinumab strengthens their credibility. Finally, comparing blinded arms is associated with sustained treatment response.22–25 However, for guselkumab with partly unblinded arms for ustekinumab the higher rates of PASI 90 response observed with guselkumab may have introduced information bias. However, the potential compared with ustekinumab up to week 40 in the present impact that such a bias might have had on the results is unclear; analysis suggest that guselkumab may be associated with rates in addition, the fact that results from the sensitivity analysis of sustained treatment response that are similar to or higher based on the PHOENIX trial confirmed long-term findings sug- than those for ustekinumab. Future studies are needed to assess gests that any impact was minimal. the long-term comparative efficacy of guselkumab relative to In summary, adjusted analyses leveraging IPD demonstrate ustekinumab and other treatments beyond 40 weeks. that guselkumab has a significantly higher probability of Multivariable regression analysis using IPD allowed adjust- achieving and maintaining PASI treatment responses through ment for the observed differences between patients from the week 40 than ustekinumab does. NAVIGATE trial and those from the VOYAGE trials.12–14 Given that only small differences were seen among patient characteris- tics before multivariable adjustments, and only a limited set of References covariates was predictive of PASI response, the alignment of the 1 Queiro R, Tejon P, Alonso S et al. Age at disease onset: a key factor results from both naive and adjusted comparisons estimates for understanding psoriatic disease. Rheumatology (Oxford) 2014; lends credibility to the findings of our analyses. Nonetheless, 53:1178–85. the following limitations of this study must be acknowledged. 2 World Health Organization. Global Report on Psoriasis. World Health Firstly, we could only adjust for differences between the Organization, 2016. 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Treatment switching: sta- logistic regression analyses of Psoriasis Area and Severity 75 tistical and decision-making challenges and approaches. Int J Technol and 100 responses at 40 weeks. Assess Health Care 2016; 32:160–6. Appendix Overviews of studies informing the adjusted 19 Phillippo D, Ades T, Dias S et al. Methods for population-adjusted treatment comparisons. indirect comparisons in submissions to NICE. Available at: http:// Powerpoint S1 Journal Club Slide Set. nicedsu.org.uk/wp-content/uploads/2018/08/Population-ad Video S1 Author video. British Journal of Dermatology (2020) 183, pp276–284 © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.