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Immunogenicity of Guselkumab Is Not Clinically Relevant in Patients with Moderate-to-Severe Plaque Psoriasis

Open ArchivePublished:March 06, 2019DOI:https://doi.org/10.1016/j.jid.2019.02.018

      Abbreviations:

      ADA (anti-drug antibody), IGA (Investigator’s Global Assessment), ISR (injection-site reaction), NAb (neutralizing antibody), PASI (Psoriasis Area and Severity Index), SGC (serum guselkumab concentration)
      To the Editor
      In two pivotal phase 3 studies (VOYAGE-1 [ClinicalTrials.gov ID NCT02207231] and VOYAGE-2 [ClinicalTrials.gov ID NCT02207244]), patients (n = 1,829) with moderate-to-severe plaque psoriasis were randomized to subcutaneous guselkumab 100 mg (weeks 0 and 4, then every 8 weeks), placebo with guselkumab crossover at week 16, or adalimumab with guselkumab crossover at week 28 or week 52. The design of VOYAGE-2 incorporated a randomized withdrawal and retreatment period for patients who achieved ≥90% improvement in the Psoriasis Area and Severity Index (PASI90) score at week 28. To assess guselkumab immunogenicity, we evaluated sera for anti-drug antibodies (ADAs), systemic exposure (serum drug concentrations), efficacy (Investigator’s Global Assessment [IGA], PASI), and safety (injection-site reactions [ISRs]). Through week 100, 8.5% of evaluable guselkumab-treated patients were ADA+. Neither ADA development nor guselkumab withdrawal and retreatment reduced systemic drug exposure or clinical efficacy or increased the occurrence of ISRs.
      Highly effective biologics targeting key inflammatory mediators have been developed for psoriasis (
      • Lee E.B.
      • Amin M.
      • Bhutani T.
      • Wu J.J.
      Emerging therapies in psoriasis: a systematic review.
      ). Guselkumab, a human IgG1λ mAb that selectively inhibits IL-23, a critical driver of pathogenic T cells, demonstrated significant efficacy in moderate-to-severe plaque psoriasis in two pivotal phase 3 studies (VOYAGE-1/VOYAGE-2) (
      • Blauvelt A.
      • Papp K.A.
      • Griffiths C.E.
      • Randazzo B.
      • Wasfi Y.
      • Shen Y.K.
      • et al.
      Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial.
      ,
      • Reich K.
      • Armstrong A.W.
      • Foley P.
      • Song M.
      • Wasfi Y.
      • Randazzo B.
      • et al.
      Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial.
      ).
      Development of ADAs against biologics reflects normal immune response to foreign proteins. ADA development can cause variable pharmacokinetics, ranging from prolonging mAb half-life to promoting rapid elimination of therapeutic protein/endogenous antibody complexes (
      • Lobo E.D.
      • Hansen R.J.
      • Balthasar J.P.
      Antibody pharmacokinetics and pharmacodynamics.
      ). ADAs can be associated with diminished efficacy and/or untoward side effects.
      We assessed ADA incidence and impact on guselkumab pharmacokinetics, clinical efficacy, and safety in VOYAGE-1 and VOYAGE-2 (
      • Blauvelt A.
      • Papp K.A.
      • Griffiths C.E.
      • Randazzo B.
      • Wasfi Y.
      • Shen Y.K.
      • et al.
      Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial.
      ,
      • Reich K.
      • Armstrong A.W.
      • Foley P.
      • Song M.
      • Wasfi Y.
      • Randazzo B.
      • et al.
      Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial.
      ). These ongoing phase 3, randomized, double-blind, placebo- and active comparator-controlled multicenter studies, which enrolled similar patient populations, are being conducted according to the principles of the Declaration of Helsinki and International Committee on Harmonisation Good Clinical Practices. The study protocols were approved by governing ethical bodies, and patients provided written informed consent. Methodology specific to this analysis is provided in Supplementary Patients and Methods online.
      Among 1,829 randomized patients, 1,721 received subcutaneous guselkumab, including 823 beginning at week 0, 398 at week 16 following placebo, and 500 after week 24 (VOYAGE-2) or week 48 (VOYAGE-1) following adalimumab (Supplementary Figure S1 online). Among 1,721 guselkumab-treated patients, 1,713 (99.5%) had evaluable samples for ADA assessment (Supplementary Table S1 online).
      Through up to 100 weeks of drug exposure, 8.5% (146/1,713) of guselkumab-treated patients with evaluable post-treatment serum samples were ADA+ (Supplementary Table S1). ADA titers were low in most patients: 76.0% (111/146) had titers ≤1:160, 11.6% (17/146) had titers of 1:320, 12.3% (18/146) had titers ≥1:640; one patient had the highest titer of 1:20,480. ADAs were transiently detected (i.e., only one to two post-treatment ADA+ samples through up to 100 weeks of drug exposure with a final ADA sample) in 45.2% (66/146) of ADA+ patients. At week 100, 134/146 ADA+ patients had samples available for ADA assessment: 72 were ADA , 45 had titers ≤1:160, and 17 had titers >1:160; only 15% (20/134) had their maximum titer detected at week 100. Nine of 146 (6.2%) ADA+ patients were neutralizing antibody (NAb)–positive (NAb+); 0.5% (9/1,713) of guselkumab-treated patients developed NAbs (Supplementary Table S2 online). While NAb+ samples can be detected across a broad range of ADA titers, those in this analysis tended to be associated with higher titers, indicating stronger ADA responses (data not shown). Because ADA incidence depends on assay methodology, sensitivity, and specificity; sample collection timing and handling; concomitant medications; and underlying diseases, any comparisons of guselkumab ADA incidence against other biologics must be interpreted cautiously.
      Serum guselkumab concentrations (SGCs) were comparable between ADA+ and ADA patients (inter-patient comparison) (Figure 1) and between samples obtained before versus after ADA development (intra-patient comparison). Among 137 ADA+ patients evaluable for assessing ADA effect on SGCs before and after ADA detection, 61 (44.5%) had numerically lower and 76 (55.5%) had numerically higher steady-state trough SGCs post-ADA formation.
      Figure thumbnail gr1
      Figure 1Median (IQR) serum guselkumab concentrations through week 100 by ADA status. Data are shown for VOYAGE-1 patients randomized to receive guselkumab (a) and placebo→guselkumab (b) and VOYAGE-2 patients randomized to guselkumab who were PASI90 responders (c) and nonresponders (d). ADA, anti-drug antibody; IQR, interquartile range; PASI90, ≥90% improvement in Psoriasis Area and Severity Index.
      Patients with higher steady-state trough SGCs have demonstrated more robust efficacy (

      Zhu Y, Xu Z, Wasfi Y, Randazzo B, Shen Y-K, Li S, et al. Use of phase 2 guselkumab exposure-response relationship in psoriasis to inform phase 3 dose selection. 26th European Academy of Dermatology and Venereology Congress, 13–17 September 2017, Geneva, Switzerland (Poster 1827).

      ). Herein, ADA development was not associated with diminished clinical efficacy: 88.4% (122/138) and 61.6% (85/138) of ADA+ patients achieved IGA = 0/1 (clear/minimal) and IGA = 0, respectively, at week 100 (Table 1). Most ADA+ patients continuing guselkumab maintained or achieved PASI90 post-ADA detection. Among 143 ADA+ patients evaluable for assessing ADA effect on efficacy before and after ADA detection, 136 (95.1%) achieved IGA = 0/1 and 132 (92.3%) achieved PASI90 post-ADA formation. Further, SGCs (Figure 1) and ADA incidence appeared similar between patients with lower versus higher clinical response. When combining VOYAGE-2 patients randomized to guselkumab and placebo→guselkumab, ADAs were detected through up to week 100 in 6.9% (45/506) of week 28 PASI90 responders and 8.9% (12/175) of nonresponders.
      Table 1Efficacy at week 100 by anti-drug antibody status (VOYAGE-1 and VOYAGE-2)
      Treatment Group/Response CriteriaADA Status
      ADA+ADA
      VOYAGE-1VOYAGE-2VOYAGE-1VOYAGE-2
      Guselkumab
       Guselkumab-treated patients with appropriate samples,
      Includes all patients who received guselkumab at any time and had one or more evaluable ADA samples obtained after their first guselkumab administration.
      n
      2939298453
       Patients with efficacy data available at week 100,
      Includes patients who had efficacy (IGA and PASI) data collected at week 100. Note that 8/146 ADA+ patients in the combined studies did not have efficacy assessed at week 100. These eight patients terminated study participation before week 100, because they were lost to follow-up (n = 5), elected to withdraw (n = 2), or due to an error reported by the site in calculating the length of the follow-up period (n = 1). None of these patients discontinued due to lack of efficacy or adverse events.
      n
      2736263411
      IGA = 0,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      16 (59.3)21 (58.3)140 (53.2)215 (52.3)
      IGA = 0/1,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      23 (85.2)33 (91.7)216 (82.1)335 (81.5)
      PASI100,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      13 (48.1)18 (50.0)129 (49.0)199 (48.4)
      PASI90,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      22 (81.5)31 (86.1)216 (82.1)322 (78.3)
      Placebo→guselkumab
       Guselkumab-treated patients with appropriate samples,
      Includes all patients who received guselkumab at any time and had one or more evaluable ADA samples obtained after their first guselkumab administration.
      n
      2019145212
       Patients with efficacy data available at week 100,
      Includes patients who had efficacy (IGA and PASI) data collected at week 100. Note that 8/146 ADA+ patients in the combined studies did not have efficacy assessed at week 100. These eight patients terminated study participation before week 100, because they were lost to follow-up (n = 5), elected to withdraw (n = 2), or due to an error reported by the site in calculating the length of the follow-up period (n = 1). None of these patients discontinued due to lack of efficacy or adverse events.
      n
      1918139189
      IGA = 0,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      13 (68.4)12 (66.7)80 (57.6)97 (51.3)
      IGA = 0/1,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      16 (84.2)17 (94.4)118 (84.9)159 (84.1)
      PASI100,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      12 (63.2)10 (55.6)75 (54.0)91 (47.6)
      PASI90,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      16 (84.2)16 (88.9)114 (82.0)151 (79.1)
      Adalimumab→guselkumab
       Guselkumab-treated patients with appropriate samples,
      Includes all patients who received guselkumab at any time and had one or more evaluable ADA samples obtained after their first guselkumab administration.
      n
      1623262197
       Patients with efficacy data available at week 100,
      Includes patients who had efficacy (IGA and PASI) data collected at week 100. Note that 8/146 ADA+ patients in the combined studies did not have efficacy assessed at week 100. These eight patients terminated study participation before week 100, because they were lost to follow-up (n = 5), elected to withdraw (n = 2), or due to an error reported by the site in calculating the length of the follow-up period (n = 1). None of these patients discontinued due to lack of efficacy or adverse events.
      n
      1622259187
      IGA = 0,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      7 (43.8)16 (72.7)146 (56.4)98 (52.4)
      IGA = 0/1,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      13 (81.3)20 (90.9)218 (84.2)158 (84.5)
      PASI100,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      6 (37.5)16 (72.7)136 (52.5)91 (48.7)
      PASI90,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      11 (68.8)19 (86.4)212 (81.9)151 (80.7)
      Total
       Guselkumab-treated patients with appropriate samples,
      Includes all patients who received guselkumab at any time and had one or more evaluable ADA samples obtained after their first guselkumab administration.
      n
      1461,567
       Patients with efficacy data available at week 100
      Includes patients who had efficacy (IGA and PASI) data collected at week 100. Note that 8/146 ADA+ patients in the combined studies did not have efficacy assessed at week 100. These eight patients terminated study participation before week 100, because they were lost to follow-up (n = 5), elected to withdraw (n = 2), or due to an error reported by the site in calculating the length of the follow-up period (n = 1). None of these patients discontinued due to lack of efficacy or adverse events.
      1381,448
      IGA = 0,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      85 (61.6)776 (53.6)
      OR (95% CI)
      OR (95% CI) for comparison of efficacy response rate between ADA+ and ADA− patients.
      1.39 (0.97–1.99)
      IGA = 0/1,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      122 (88.4)1,204 (83.1)
      OR (95% CI)
      OR (95% CI) for comparison of efficacy response rate between ADA+ and ADA− patients.
      1.55 (0.90–2.65)
      PASI100,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      75 (54.3)721 (49.8)
      OR (95% CI)
      OR (95% CI) for comparison of efficacy response rate between ADA+ and ADA− patients.
      1.20 (0.85–1.70)
      PASI90,
      Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA– patients, the denominator is the number of ADA− patients with efficacy data collected at week 100.
      n (%)
      115 (83.3)1,166 (80.5)
      OR (95% CI)
      OR (95% CI) for comparison of efficacy response rate between ADA+ and ADA− patients.
      1.21 (0.76–1.93)
      Abbreviations: ADA, anti-drug antibody; CI, confidence interval; IGA, Investigator’s Global Assessment; OR, odds ratio; PASI, Psoriasis Area and Severity Index.
      1 Includes all patients who received guselkumab at any time and had one or more evaluable ADA samples obtained after their first guselkumab administration.
      2 Includes patients who had efficacy (IGA and PASI) data collected at week 100. Note that 8/146 ADA+ patients in the combined studies did not have efficacy assessed at week 100. These eight patients terminated study participation before week 100, because they were lost to follow-up (n = 5), elected to withdraw (n = 2), or due to an error reported by the site in calculating the length of the follow-up period (n = 1). None of these patients discontinued due to lack of efficacy or adverse events.
      3 Data are provided as n (%). For ADA+ patients, the denominator is the number of ADA+ patients with efficacy data collected at week 100; for ADA patients, the denominator is the number of ADA patients with efficacy data collected at week 100.
      4 OR (95% CI) for comparison of efficacy response rate between ADA+ and ADA patients.
      Because ADA development was not associated with changes in SGCs, it is not surprising that ADA development did not reduce clinical efficacy. Further, some ADA+ patients were still IGA = 0/1 and/or PASI90 responders, while some ADA patients were nonresponders. Given that patients’ ADA status did not affect clinical response, guselkumab dose adjustment is not needed for ADA+ patients. Although NAb+ patients had slightly lower SGCs at week 100 than the overall population, the majority were IGA = 0/1 and PASI90 responders and none had guselkumab-related ISRs through up to week 100 (data not shown).
      In VOYAGE-2, 313 patients randomized to guselkumab or placebo→guselkumab were withdrawn from, and then retreated with, guselkumab prior to week 100 (Supplementary Table S3 online); 310 were evaluable for ADA assessment before and after retreatment, 196 of whom had serum samples available upon retreatment. The majority (88.3%, 173/196) of retreated patients had SGCs below the quantifiable level (<0.01 μg/ml) before retreatment, suggesting a drug-free state following washout. ADA incidence was only slightly higher in patients with guselkumab withdrawal+retreatment (10.2%, 32/313) versus continued guselkumab (6.8%, 25/368) (Supplementary Table S3); only approximately 1% (3/310) of withdrawn patients with evaluable samples newly developed ADA post-retreatment. While the clinical significance of slightly higher ADA+ incidence among the withdrawn+retreated patients is unclear, mean/median steady-state trough SGCs were 1.56/1.31 μg/ml after guselkumab retreatment versus 1.44/1.26 μg/ml at week 28 before withdrawal (Supplementary Table S4 online). All (32/32) withdrawn+retreated patients achieved IGA = 0/1, and 93.8% (30/32) achieved PASI90 post-retreatment.
      The combined incidence of ISRs was low. In VOYAGE-2, but not consistently in VOYAGE-1, the ISR incidence appeared slightly higher in ADA+ than ADA patients (Supplementary Table S5 online). Overall, 1.8% (25/1,425) and 0.4% (63/14,898) of guselkumab injections in ADA+ and ADA patients, respectively, were associated with ISRs. All ISRs were mild, except a 9-cm × 10-cm granuloma at the injection site during open-label treatment (serious ISR resolved after study agent discontinuation). Only two guselkumab retreatment injections were associated with ISRs (both mild). Because only small proportions of patients developed ADAs and injections had associated ISRs, results should be cautiously interpreted. Regardless of ADA status, no hypersensitivity, anaphylactic, or serum sickness-like reactions to guselkumab occurred through up to week 100 in either study. Rates of serious infections, infections requiring treatment, malignancies, and major adverse cardiovascular events were low and stable with extended guselkumab exposure (
      • Reich K.
      • Papp K.A.
      • Armstrong A.W.
      • Wasfi Y.
      • Li S.
      • Shen Y.-K.
      • et al.
      Safety of guselkumab in patients with moderate-to-severe psoriasis treated through 2 years: a pooled analysis from the randomised VOYAGE 1 and VOYAGE 2 studies.
      ).
      Thus, through up to week 100, development of ADA to guselkumab is not clinically relevant and clinical monitoring of ADA is not warranted. Decisions about guselkumab treatment should derive from clinical efficacy and safety evaluations. Evaluations for time periods longer than 2 years are needed to confirm these shorter-term findings.

      Data availability statement

      The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access Project site at http://yoda.yale.edu).

      Conflicts of Interest

      Yaowei Zhu, Joseph C. Marini, Michael Song, Bruce Randazzo, Yaung-Kaung Shen, Shu Li, and Honghui Zhou are employees of Janssen Research & Development, LLC, and own stock in Johnson & Johnson, of which Janssen Research & Development, LLC, is a subsidiary. This study was funded by Janssen Research & Development, LLC. Authors employed by Janssen were involved in the study design; data collection, analysis and interpretation; manuscript preparation; and decision to submit the article for publication.

      Acknowledgments

      The authors thank the patients, investigators, and study personnel who made these two phase 3 studies successful. We also thank Michelle L. Perate, a professional medical writer supported by Janssen, for assistance with manuscript preparation and submission. Work was performed in Spring House, PA, USA.

      Author Contributions

      Conceptualization: YZ and JCM. Methodology: YZ and JCM. Investigation: YZ and JCM. Formal analysis: YZ, Y-KS, and SL. Data interpretation: YZ, JCM, MS, BR, Y-KS, SL, and HZ; Writing: YZ. Review and editing: JCM, MS, BR, Y-KS, SL, and HZ. Approval for submission: YZ, JCM, MS, BR, Y-KS, SL, and HZ.

      Supplementary Patients and Methods

      Patients and study designs

      VOYAGE-1 (n = 837) and VOYAGE-2 (n = 992) enrolled patients with moderate-to-severe psoriasis (defined by IGA score ≥3, PASI score ≥12, and total body surface area involvement ≥10%) (
      • Blauvelt A.
      • Papp K.A.
      • Griffiths C.E.
      • Randazzo B.
      • Wasfi Y.
      • Shen Y.K.
      • et al.
      Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial.
      ,
      • Reich K.
      • Armstrong A.W.
      • Foley P.
      • Song M.
      • Wasfi Y.
      • Randazzo B.
      • et al.
      Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial.
      ). The study designs were identical through week 24 (Supplementary Figure S1). Patients were randomly assigned to receive subcutaneous injections of guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 825); placebo (weeks 0, 4, and 12, with crossover to guselkumab 100 mg at week 16 [placebo→guselkumab]; n = 422); or adalimumab (80 mg at week 0, 40 mg at week 1, then 40 mg every 2 weeks through week 23 in VOYAGE-2 or week 47 in VOYAGE-1 [adalimumab→guselkumab]; n = 582).
      In VOYAGE-2, patients randomized to guselkumab who achieved PASI90 response at week 28 were re-randomized (1:1) to either continue guselkumab every 8 weeks or withdraw from guselkumab. Withdrawn patients were retreated with guselkumab upon loss of ≥50% of the PASI improvement achieved at week 28 (Supplementary Figure S1). Patients randomized to placebo→guselkumab and adalimumab→guselkumab who achieved a PASI90 response at week 28 were withdrawn from guselkumab or adalimumab and were retreated with guselkumab or initiated guselkumab, respectively, upon loss of ≥50% of PASI improvement achieved at week 28. All PASI90 nonresponders continued or initiated guselkumab at week 28. All patients received guselkumab every 8 weeks starting at week 76. In VOYAGE-1, patients randomized to guselkumab or placebo→guselkumab continued guselkumab 100 mg every 8 weeks through week 100, and those randomized to adalimumab→guselkumab initiated guselkumab 100 mg at week 52 followed by every 8 weeks dosing through week 100.

      Interventions

      Guselkumab was supplied as a single-dose, sterile, preservative-free, clear, colorless to light-yellow solution in a 1-ml glass syringe with a 27-gauge, ½-inch fixed needle assembled in a passive needle-guard delivery system. The formulation comprises 100 mg/ml guselkumab, containing L-histidine, L-histidine monohydrochloride monohydrate, polysorbate-80, sucrose, and water for injection at pH 5.8 (http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/TREMFYA-pi.pdf).

      Sample collection

      Serum samples for immunogenicity evaluations were collected prior to any study agent administration at weeks 0, 4, 12, 16, 28, and 44 in both trials; weeks 52, 68, 84, and 100 in VOYAGE-1; and weeks 48, 52, 72, 76, and 100 in VOYAGE-2. Samples also were collected at the final visit from patients who terminated study participation.

      Bioanalytical methods

      The presence of ADAs to guselkumab was detected using a validated, sensitive, drug-tolerant electrochemiluminescence immunoassay using the Meso Scale Discovery platform (Gaithersburg, MD). This method employed an acid dissociation step to improve detection of anti-guselkumab antibodies in the presence of excess guselkumab in serum. The observed sensitivity was 3.1 ng/ml of ADAs in human serum absent of any guselkumab; 15 ng/ml of ADAs could be detected in the presence of up to 3,125 ng/ml (i.e., 3.125 μg/ml) of guselkumab in human serum samples. Of note, in VOYAGE-1 and VOYAGE-2, approximately 90.2% and 84.4%, respectively, of the post-guselkumab treatment serum samples obtained for ADA assessment had serum guselkumab concentrations (SGCs) <3.125 μg/ml. In addition, in VOYAGE-1 and VOYAGE-2, approximately 97.2% and 98.2% of the steady-state trough serum samples (i.e., samples collected ≥20 weeks after the first dose of guselkumab) obtained for ADA assessment had SGCs <3.125 μg/ml. Therefore, the vast majority of the samples obtained for ADA assessment had SGCs <3.125 μg/ml at the time when ADAs were evaluated, which allowed for the detection of ≥15 ng/ml of ADAs.
      Results from ADA analyses were classified as ADA+ or ADA. ADA+ samples were those with detectable ADA to guselkumab. Patients with ≥1 positive sample at any time point after guselkumab exposure were classified as ADA+. However, if patients had detectable ADAs in baseline (predose) samples, they were only considered ADA+ if the peak titer of the post-treatment sample was ≥2-fold higher than baseline. ADA samples were those without detectable ADA to guselkumab. Patients were designated as ADA when there was no positive sample at any time point evaluated after guselkumab exposure. However, if a patient had detectable ADA in a baseline (predose) sample, the patient was considered ADA if no post-treatment sample titers were ≥2-fold higher than baseline.
      Baseline was defined as the time point prior to guselkumab administration at week 0 for patients randomized to guselkumab, prior to guselkumab administration at week 16 for patients randomized to placebo→guselkumab, and prior to guselkumab administration at week 28 (VOYAGE-2) or week 52 (VOYAGE-1) for patients randomized to adalimumab→guselkumab.
      ADA+ serum samples from ADA+ patients were further characterized to determine their ability to neutralize the biological effects of guselkumab in vitro. The presence of neutralizing antibodies (NAbs) was assessed using a validated competitive ligand-binding assay based on Meso Scale Discovery electrochemiluminescence detection technology. Serum samples were determined to be NAb+ if demonstrating ≥22.46% inhibition of the electrochemiluminescent assay signal relative to the normalization control, reflective of neutralization of guselkumab binding to human IL-23. The NAb method incorporated an acid dissociation step to improve assay performance in the presence of excess guselkumab. The detection of 250 and 500 ng/ml of polyclonal NAb control was demonstrated in the presence of 3.08 and 5.03 μg/ml, respectively, of exogenous guselkumab in neat human serum. The NAb assay was less sensitive and drug-tolerant relative to the ADA assay. Of note, the presence of ADAs to adalimumab was not evaluated in these two studies.

      Serum guselkumab concentration evaluations

      Serum guselkumab concentrations were quantified using a validated electrochemiluminescence immunoassay. The lowest quantifiable concentration in a sample was 0.01 μg/ml (lower limit of quantification multiplied by the minimum required dilution of 1:10) (

      Zhu Y, Xu Z, Wasfi Y, Randazzo B, Shen Y-K, Li S, et al. Use of phase 2 guselkumab exposure-response relationship in psoriasis to inform phase 3 dose selection. 26th European Academy of Dermatology and Venereology Congress, 13–17 September 2017, Geneva, Switzerland (Poster 1827).

      ). This assay was capable of measuring both free drug and drug in complex with ADAs.

      Clinical efficacy and safety evaluations

      Efficacy was assessed via IGA and PASI scores, as detailed previously (
      • Blauvelt A.
      • Papp K.A.
      • Griffiths C.E.
      • Randazzo B.
      • Wasfi Y.
      • Shen Y.K.
      • et al.
      Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial.
      ,
      • Reich K.
      • Armstrong A.W.
      • Foley P.
      • Song M.
      • Wasfi Y.
      • Randazzo B.
      • et al.
      Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial.
      ). In the overall VOYAGE-1 and VOYAGE-2 trials, ISRs, hypersensitivity, anaphylaxis, serum sickness−like reactions, infections, malignancies, and major cardiovascular events were monitored as adverse events of special interest. For this analysis, ISRs were selected as the adverse events potentially most relevant to ADA development.

      Data analyses

      ADA status was assessed among all patients who received guselkumab at any time and had at least one evaluable ADA sample obtained after their first guselkumab administration. The proportion of patients with NAbs was determined among all ADA+ patients. Pharmacokinetic data were summarized among patients randomized to guselkumab and placebo→guselkumab (VOYAGE-1) or randomized to guselkumab (VOYAGE-2) who had post-treatment samples evaluable for SGCs. The proportions of patients with IGA = 0/1, IGA = 0, PASI90, and PASI100 responses at week 100 were determined by ADA status in both studies. The proportions of patients with ISRs through up to 100 weeks of drug exposure were summarized by ADA status within each study and for the combined studies. The effect of guselkumab treatment interruption on trough SGCs, IGA = 0/1 and PASI90 response, and the occurrence of ISRs were assessed in 32 of 313 patients in VOYAGE-2 who withdrew from, and were then retreated with, guselkumab, and were ADA+. No formal statistical analyses were conducted.
      Figure thumbnail fx1
      Supplementary Figure S1Study design through week 100 (VOYAGE-2).
      Supplementary Table S1Incidence of anti-drug antibody through up to 100 weeks of drug exposure (VOYAGE-1 and VOYAGE-2)
      Study/Treatment GroupGuselkumab-Treated Patients,
      Includes all patients who received guselkumab at any time.
      n
      Patients with Appropriate Samples,
      Patients had one or more evaluable ADA samples obtained after their first guselkumab administration and through up to 100 weeks of drug exposure.
      n
      Incidence of ADA through Week 100,
      Denominator is number of patients with appropriate samples for ADA through up to 100 weeks of drug exposure.
      n (%)
      VOYAGE-1
       Guselkumab32932729 (8.9)
       Placebo→guselkumab16516520 (12.1)
       Adalimumab→guselkumab28027816 (5.8)
       Overall
      Includes all treatment groups.
      77477065 (8.4)
      VOYAGE-2
       Guselkumab49449239 (7.9)
       Placebo→guselkumab23323119 (8.2)
       Adalimumab→guselkumab22022023 (10.5)
       Overall
      Includes all treatment groups.
      94794381 (8.6)
      Total1,7211,713146 (8.5)
      Abbreviation: ADA, anti-drug antibody.
      1 Includes all patients who received guselkumab at any time.
      2 Patients had one or more evaluable ADA samples obtained after their first guselkumab administration and through up to 100 weeks of drug exposure.
      3 Denominator is number of patients with appropriate samples for ADA through up to 100 weeks of drug exposure.
      4 Includes all treatment groups.
      Supplementary Table S2Neutralizing antibodies to guselkumab through up to 100 weeks of drug exposure (VOYAGE-1 and VOYAGE-2)
      StudyGuselkumab-Treated Patients with Appropriate Samples,
      Includes all patients who received guselkumab at any time and had one or more evaluable ADA samples obtained after their first guselkumab administration and through up to 100 weeks of drug exposure.
      n
      ADA+ Patients through Week 100, nIncidence of NAbs in ADA+ Patients,
      Denominator is number of patients who were ADA+ through up to 100 weeks of drug exposure.
      n (%)
      Incidence of NAbs in Study Population,
      Denominator is number of guselkumab-treated patients with appropriate samples for ADA through up to 100 weeks of drug exposure.
      n (%)
      VOYAGE-1
      Includes all treatment groups.
      770655 (7.7)5 (0.6)
      VOYAGE-2
      Includes all treatment groups.
      943814 (4.9)4 (0.4)
      Total1,7131469 (6.2)9 (0.5)
      Abbreviations: ADA, anti-drug antibody, NAb, neutralizing antibody.
      1 Includes all patients who received guselkumab at any time and had one or more evaluable ADA samples obtained after their first guselkumab administration and through up to 100 weeks of drug exposure.
      2 Denominator is number of patients who were ADA+ through up to 100 weeks of drug exposure.
      3 Denominator is number of guselkumab-treated patients with appropriate samples for ADA through up to 100 weeks of drug exposure.
      4 Includes all treatment groups.
      Supplementary Table S3Impact of withdrawal and retreatment on the incidence of anti-drug antibody through up to week 100 (VOYAGE-2)
      Withdrawn from and Retreated with Guselkumab after Week 28Continuous Guselkumab after Week 28
      Treatment Group
      Patients randomized to adalimumab were not included because they did not receive guselkumab before week 28.
      GuselkumabPlacebo→ GuselkumabGuselkumabPlacebo→ Guselkumab
      PASI90 response status at week 28PASI90 responders (randomized to placebo)PASI90 respondersPASI90 responders (randomized to guselkumab)PASI90 nonrespondersPASI90 nonresponders
      Patients who received guselkumab,
      Includes all patients in the guselkumab and placebo→guselkumab groups who received guselkumab at any time at or beyond week 28.
      n
      1741391939580
      Patients with appropriate samples,
      Patients who had one or more evaluable ADA samples obtained after their first guselkumab administration and through up to 100 weeks of drug exposure.
      n
      1741391939580
       ADA+,
      Data presented are n (%). Denominator is number of patients with appropriate samples for ADA through up to 100 weeks of drug exposure.
      n (%)
      19 (10.9)13 (9.4)13 (6.7)6 (6.3)6 (7.5)
       ADA,
      Data presented are n (%). Denominator is number of patients with appropriate samples for ADA through up to 100 weeks of drug exposure.
      n (%)
      155 (89.1)126 (90.6)180 (93.3)89 (93.7)74 (92.5)
      Patients who received guselkumab,
      Includes all patients in the guselkumab and placebo→guselkumab groups who received guselkumab at any time at or beyond week 28.
      n
      313368
      Patients with appropriate samples,
      Patients who had one or more evaluable ADA samples obtained after their first guselkumab administration and through up to 100 weeks of drug exposure.
      n
      313368
       ADA+,
      Data presented are n (%). Denominator is number of patients with appropriate samples for ADA through up to 100 weeks of drug exposure.
      ,
      Based on the limited data, the odds ratio (95% confidence interval) for patients treated intermittently versus continuously on the risk of developing ADAs is estimated to be 1.56 (95% confidence interval = 0.90–2.70).
      n (%)
      32 (10.2)25 (6.8)
       ADA,
      Data presented are n (%). Denominator is number of patients with appropriate samples for ADA through up to 100 weeks of drug exposure.
      n (%)
      281 (89.8)343 (93.2)
       Patients who developed ADA after retreatment,
      Data presented are n (%). Denominator is number of patients with appropriate samples for ADA through up to 100 weeks of drug exposure.
      n (%)
      3 (1.0)N/A
      Abbreviations: ADA, anti-drug antibody; N/A, not applicable; PASI, Psoriasis Area and Severity Index.
      1 Patients randomized to adalimumab were not included because they did not receive guselkumab before week 28.
      2 Includes all patients in the guselkumab and placebo→guselkumab groups who received guselkumab at any time at or beyond week 28.
      3 Patients who had one or more evaluable ADA samples obtained after their first guselkumab administration and through up to 100 weeks of drug exposure.
      4 Data presented are n (%). Denominator is number of patients with appropriate samples for ADA through up to 100 weeks of drug exposure.
      5 Based on the limited data, the odds ratio (95% confidence interval) for patients treated intermittently versus continuously on the risk of developing ADAs is estimated to be 1.56 (95% confidence interval = 0.90–2.70).
      Supplementary Table S4Impact of guselkumab withdrawal and retreatment on systemic exposure, clinical efficacy, and injection-site reactions in patients who were ADA+ (VOYAGE-2)
      VariableBefore WithdrawalAfter Retreatment
      n
      Withdrawn patients were retreated with guselkumab every 8 weeks prior to week 76 upon loss of ≥50% of the improvement in PASI achieved at week 28 or at week 76 if they did not meet this criteria at or before week 72. There were 32 patients in the guselkumab and placebo→guselkumab groups who were withdrawn and retreated with guselkumab and positive for ADA. Patients randomized to adalimumab were not included because they did not receive guselkumab before week 28.
      3232
      Trough concentrations (μg/ml)
      Before withdrawal: trough serum guselkumab concentrations observed at week 28. After withdrawal: maximum steady-state trough serum guselkumab concentration observed after retreatment with guselkumab.
       Mean (SD)1.44 (0.88)1.56 (1.08)
       Median (IQR)1.26 (0.79–1.86)1.31 (0.94–1.92)
       Range0.05–3.710.14–5.38
      IGA = 0/1,
      Efficacy response observed at week 100.
      n (%)
      32 (100)32 (100)
      PASI90,
      Efficacy response observed at week 100.
      n (%)
      32 (100)30 (93.8)
      Number of guselkumab injections with ISRs1 (mild)2 (mild)
      Abbreviations: ADA+, Anti-drug antibody–positive; IGA, Investigator’s Global Assessment; IQR, interquartile range; ISR, injection-site reaction; PASI, Psoriasis Area and Severity Index; SD, standard deviation.
      1 Withdrawn patients were retreated with guselkumab every 8 weeks prior to week 76 upon loss of ≥50% of the improvement in PASI achieved at week 28 or at week 76 if they did not meet this criteria at or before week 72. There were 32 patients in the guselkumab and placebo→guselkumab groups who were withdrawn and retreated with guselkumab and positive for ADA. Patients randomized to adalimumab were not included because they did not receive guselkumab before week 28.
      2 Before withdrawal: trough serum guselkumab concentrations observed at week 28. After withdrawal: maximum steady-state trough serum guselkumab concentration observed after retreatment with guselkumab.
      3 Efficacy response observed at week 100.
      Supplementary Table S5Injection-site reactions through up to 100 weeks of drug exposure by anti-drug antibody status (VOYAGE-1 and VOYAGE-2)
      Treatment Group/ISR StatusADA Status
      ADA+ADA
      VOYAGE-1VOYAGE-2VOYAGE-1VOYAGE-2
      Guselkumab
       Guselkumab-treated patients with appropriate samples,
      Includes all patients who received guselkumab at any time and had one or more evaluable ADA samples obtained after their first guselkumab administration and through up to 100 weeks of drug exposure.
      n
      2939298453
      Patients with ISRs,
      The denominator is the number of guselkumab-treated patients with evaluable ADA samples through up to 100 weeks of drug exposure.
      n (%)
      3 (10.3)8 (20.5)22 (7.4)30 (6.6)
       Total number of guselkumab injections3624063,5954,930
      Injections with ISRs
      For ADA+ and ADA− patients, the denominator is the total number of guselkumab injections with ISRs in ADA+ patients and ADA− patients, respectively.
      n (%)
      2 (0.6)11 (2.7)23 (0.6)26 (0.5)
       Total number of placebo injections7668827,6739,652
      Injections with ISRs
      For ADA+ and ADA− patients, the denominator is the total number of placebo injections with ISRs in ADA+ patients and ADA− patients, respectively.
      n (%)
      1 (0.1)4 (0.5)27 (0.4)23 (0.2)
      Placebo→guselkumab
       Guselkumab-treated patients with appropriate samples,
      Includes all patients who received guselkumab at any time and had one or more evaluable ADA samples obtained after their first guselkumab administration and through up to 100 weeks of drug exposure.
      n
      2019145212
      Patients with ISRs,
      The denominator is the number of guselkumab-treated patients with evaluable ADA samples through up to 100 weeks of drug exposure.
      ,
      For placebo→guselkumab and adalimumab→guselkumab groups, only include patients who had ISRs after crossover to guselkumab.
      n (%)
      1 (5.0)2 (10.5)4 (2.8)4 (1.9)
       Total number of guselkumab injections2131621,5571,693
      Injections with ISRs,
      For ADA+ and ADA− patients, the denominator is the total number of guselkumab injections with ISRs in ADA+ patients and ADA− patients, respectively.
      n (%)
      0 (0.0)9 (5.6)4 (0.3)3 (0.2)
       Total number of placebo injections3192372,2792,534
      Injections with ISRs,
      For ADA+ and ADA− patients, the denominator is the total number of placebo injections with ISRs in ADA+ patients and ADA− patients, respectively.
      n (%)
      1 (0.3)04 (0.2)3 (0.1)
      Adalimumab→guselkumab
       Guselkumab-treated patients with appropriate samples,
      Includes all patients who received guselkumab at any time and had one or more evaluable ADA samples obtained after their first guselkumab administration and through up to 100 weeks of drug exposure.
      n
      1623262197
      Patients with ISRs,
      The denominator is the number of guselkumab-treated patients with evaluable ADA samples through up to 100 weeks of drug exposure.
      ,
      For placebo→guselkumab and adalimumab→guselkumab groups, only include patients who had ISRs after crossover to guselkumab.
      n (%)
      1 (6.3)01 (0.4)5 (2.5)
       Total number of guselkumab injections961861,5531,570
      Injections with ISRs,
      For ADA+ and ADA− patients, the denominator is the total number of guselkumab injections with ISRs in ADA+ patients and ADA− patients, respectively.
      n (%)
      3 (3.1)04 (0.3)3 (0.2)
       Total number of placebo injections0770672
      Injections with ISRs,
      For ADA+ and ADA− patients, the denominator is the total number of placebo injections with ISRs in ADA+ patients and ADA− patients, respectively.
      n
      0003 (0.4)
      Total
       Guselkumab-treated patients with appropriate samples,
      Includes all patients who received guselkumab at any time and had one or more evaluable ADA samples obtained after their first guselkumab administration and through up to 100 weeks of drug exposure.
      n
      1461,567
      Patients with ISRs,
      The denominator is the number of guselkumab-treated patients with evaluable ADA samples through up to 100 weeks of drug exposure.
      ,
      For placebo→guselkumab and adalimumab→guselkumab groups, only include patients who had ISRs after crossover to guselkumab.
      n (%)
      15 (10.3)66 (4.2)
      Odds ratio (95% CI)
      Odds ratio (95% CI) for comparison of ISR incidence between ADA+ and ADA− patients.
      2.60 (1.45–4.69)
       Total number of guselkumab injections1,42514,898
      Injections with ISRs,
      For ADA+ and ADA− patients, the denominator is the total number of guselkumab injections with ISRs in ADA+ patients and ADA− patients, respectively.
      n (%)
      25 (1.8)63 (0.4)
      Odds ratio (95% CI)
      Odds ratio (95% CI) for comparison of ISR incidence between ADA+ and ADA− patients.
      4.20 (2.64–6.70)
       Total number of placebo injections2,28122,810
      Injections with ISRs,
      For ADA+ and ADA− patients, the denominator is the total number of placebo injections with ISRs in ADA+ patients and ADA− patients, respectively.
      n (%)
      6 (0.3)60 (0.3)
      Odds ratio (95% CI)
      Odds ratio (95% CI) for comparison of ISR incidence between ADA+ and ADA− patients.
      1.00 (0.43–2.32)
      Abbreviations: ADA, anti-drug antibody; CI, confidence interval; ISR, injection-site reaction.
      1 Includes all patients who received guselkumab at any time and had one or more evaluable ADA samples obtained after their first guselkumab administration and through up to 100 weeks of drug exposure.
      2 The denominator is the number of guselkumab-treated patients with evaluable ADA samples through up to 100 weeks of drug exposure.
      3 For ADA+ and ADA patients, the denominator is the total number of guselkumab injections with ISRs in ADA+ patients and ADA patients, respectively.
      4 For ADA+ and ADA patients, the denominator is the total number of placebo injections with ISRs in ADA+ patients and ADA patients, respectively.
      5 For placebo→guselkumab and adalimumab→guselkumab groups, only include patients who had ISRs after crossover to guselkumab.
      6 Odds ratio (95% CI) for comparison of ISR incidence between ADA+ and ADA patients.

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