Research JAMA Dermatology | Original Investigation Efficacy and Safety of Multiple Dupilumab Dose Regimens After Initial Successful Treatment in Patients With Atopic Dermatitis A Randomized Clinical Trial Margitta Worm, MD; Eric L. Simpson, MD; Diamant Thaçi, MD; Robert Bissonnette, MD; Jean-Philippe Lacour, MD; Stefan Beissert, MD; Makoto Kawashima, MD; Carlos Ferrándiz, MD, PhD; Catherine H. Smith, MD; Lisa A. Beck, MD; Kuo-Chen Chan, PhD; Zhen Chen, PhD; Bolanle Akinlade, MD; Thomas Hultsch, MD; Heribert Staudinger, MD, PhD; Abhijit Gadkari, PhD; Laurent Eckert, PhD; John D. Davis, PhD; Manoj Rajadhyaksha, PhD; Neil M. H. Graham, MB, BS, MD, MPH; Gianluca Pirozzi, MD, PhD; Neil Stahl, PhD; George D. Yancopoulos, MD, PhD; Marius Ardeleanu, MD Editorial page 119 IMPORTANCE The dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, Supplemental content moderate to severe atopic dermatitis (AD). OBJECTIVE To assess the efficacy and safety of different dupilumab regimens in maintaining response after 16 weeks of initial treatment. DESIGN, SETTING, AND PARTICIPANTS The Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (LIBERTY AD SOLO-CONTINUE) was a randomized, double-blind, phase 3 clinical trial conducted from March 25, 2015, to October 18, 2016, at 185 sites in North America, Europe, Asia, and Japan. Patients with moderate to severe AD who received dupilumab treatment and achieved an Investigator’s Global Assessment score of 0 or 1 or 75% improvement in Eczema Area and Severity Index scores (EASI-75) at week 16 in 2 previous dupilumab monotherapy trials (LIBERTY AD SOLO 1 and 2) were rerandomized in SOLO-CONTINUE. After completing SOLO-CONTINUE, patients were followed up for up to 12 weeks or enrolled in an open-label extension. Data were analyzed from December 5 to 12, 2016. INTERVENTIONS High-responding patients treated with dupilumab in SOLO were rerandomized 2:1:1:1 to continue their original regimen of dupilumab, 300 mg, weekly or every 2 weeks or to receive dupilumab, 300 mg, every 4 or 8 weeks or placebo for 36 weeks. MAIN OUTCOMES AND MEASURES Percentage change in EASI score from baseline during the SOLO-CONTINUE trial, percentage of patients with EASI-75 at week 36, and safety. RESULTS Among the 422 patients (mean [SD] age, 38.2 [14.5] years; 227 [53.8%] male), continuing dupilumab treatment once weekly or every 2 weeks maintained optimal efficacy, with negligible change in percent EASI improvement from SOLO 1 and 2 baseline during the SOLO-CONTINUE trial (−0.06%; P < .001 vs placebo); percent change with the other regimens dose-dependently worsened (dupilumab every 4 weeks, −3.84%; dupilumab every 8 weeks, −6.84%; placebo, −21.67%). More patients taking dupilumab weekly or every 2 weeks (116 of 162 [71.6%]; P < .001 vs placebo) maintained EASI-75 response than those taking dupilumab every 4 weeks (49 of 84 [58.3%]) or every 8 weeks (45 of 82 [54.9%]) or those taking placebo (24 of 79 [30.4%]). Overall adverse event incidences were 70.7% in the weekly or every 2 weeks group, 73.6% in the every 4 weeks group, 75.0% in the every 8 weeks group, and 81.7% in the placebo group. Treatment groups had similar conjunctivitis rates. Treatment-emergent antidrug antibody incidence was lower with more frequent dupilumab dose regimens (11.3% in the placebo group and 11.7%, 6.0%, 4.3%, and 1.2% in the dupilumab every 8 weeks, every 4 weeks, every 2 weeks, and weekly groups, respectively). CONCLUSIONS AND RELEVANCE In this trial, continued response over time was most consistently maintained with dupilumab administered weekly or every 2 weeks. Longer Author Affiliations: Author dosage intervals and placebo resulted in a diminution of response for both continuous and affiliations are listed at the end of this categorical end points. No new safety signals were observed. The approved regimen of 300 article. mg of dupilumab every 2 weeks is recommended for long-term treatment. Corresponding Author: Margitta Worm, MD, Klinik für Dermatologie, TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02395133 Venerologie und Allergologie, Charité Universitätsmedizin Berlin, JAMA Dermatol. 2020;156(2):131-143. doi:10.1001/jamadermatol.2019.3617 Charitéplatz 1, 10117 Berlin, Germany Published online December 26, 2019. (margitta.worm@charite.de). (Reprinted) 131 Downloaded From: https://jamanetwork.com/ on 10/09/2023 Research Original Investigation Dupilumab Dose Regimens After Successful Treatment in Patients With Atopic Dermatitis A topic dermatitis (AD) is a chronic inflammatory skin disease with eczematous lesions and intense pruritus1,2 Key Points associated with skin barrier dysfunction and immune Question Do dupilumab regimens less frequent than once weekly dysregulation mediated by type 2 inflammatory cytokines.3 Du- or every 2 weeks maintain long-term efficacy and safety? pilumab is a fully human VelocImmune-derived4,5 human Findings In this randomized clinical trial of 422 patients, monoclonal antibody against interleukin (IL) 4 receptor α that high-responding patients previously treated for 16 weeks with inhibits IL-4 and IL-13 signaling. Dupilumab is approved for pa- 300 mg of dupilumab weekly or every 2 weeks who continued tients 12 years or older in the United States with moderate to those regimens had the most consistent efficacy; patients taking severe AD inadequately controlled with topical prescription lower-dose regimens (every 4 or 8 weeks) or placebo had a therapies or when those therapies are not advisable; adults with dose-dependent reduction in response and no safety advantage. AD that is inadequately controlled with existing therapies Meaning The approved regimen (every 2 weeks) maintained in Japan; patients 12 years or older with moderate to severe AD clinical response and is therefore recommended for long-term who are candidates for systemic therapy in the European treatment. Union6,7; as an add-on treatment for patients 18 years or older with inadequately controlled chronic rhinosinusitis with na- sal polyps in the United States; and certain patients with asthma guidelines for Good Clinical Practice and applicable regula- in multiple countries.8-11 Efficacy and safety of dupilumab have tory requirements. Written informed consent was obtained also been found in a clinical trial of eosinophilic esophagitis,12 from each patient before the study, and all data were deiden- thus demonstrating the importance of IL-4 and IL-13 as key cy- tified. Institutional review boards and independent ethics com- tokines involved in multiple type 2 inflammatory diseases.13 mittees of each of the participating institutions reviewed and In previous studies,14-20 including 2 identically designed, approved the protocol, informed consent form, and patient in- 16-week, randomized, placebo-controlled, phase 3 mono- formation before study initiation. The Independent Data therapy studies in adults with moderate to severe AD and in- Monitoring Committee monitored patient safety. This trial adequate response to topical treatments (Study of Dupil- followed the Consolidated Standards of Reporting Trials umab Monotherapy Administered to Adult Patients With (CONSORT) reporting guideline. Moderate-to-Severe Atopic Dermatitis [LIBERTY AD SOLO 1, SOLO-CONTINUE was a randomized, double-blind, hereafter referred to as SOLO 1] and Study of Dupilumab Mono- placebo-controlled phase 3 clinical trial of dupilumab con- therapy Administered to Adult Patients With Moderate-to- ducted at 185 sites in North America, Europe, and Asia from Severe Atopic Dermatitis [LIBERTY AD SOLO 2, hereafter re- March 25, 2015, to October 18, 2016. Eligible participants were ferred to as SOLO 2])14 and phase 3 trials with concomitant dupilumab-treated patients who had achieved an Investiga- topical corticosteroids for 52 weeks or less, dupilumab signifi- tor’s Global Assessment (IGA) score of 0 or 1 or 75% or greater cantly improved clinical signs, itch, other symptoms, health- improvement in Eczema Area and Severity Index scores (EASI- related quality of life, and symptoms of anxiety and depres- 75) at week 16 of the preceding SOLO studies.14 Participants sion and was well tolerated. were rerandomized 2:1:1:1 on SOLO-CONTINUE day 1 (SOLO Once AD clinical response is achieved, it is unknown week 16) as follows: patients either continued their original whether control could be maintained with longer dosage in- SOLO regimen (ie, 300 mg of subcutaneous dupilumab weekly tervals or even treatment withdrawal. Psoriasis studies sug- or every 2 weeks) or were assigned to a less frequent regimen gest that intermittent administration of biologics can reduce (300 mg every 4 or 8 weeks) or placebo for 36 weeks (eFig- their efficacy and increase risk of antidrug antibodies (ADAs) ure 1 in Supplement 2). Randomization was stratified by re- or of safety issues.21-23 gion (North America, Europe, Asia, and Japan) and baseline IGA The objectives of Study to Confirm the Efficacy and Safety score (0, 1, or >1) using a central interactive voice response sys- of Different Dupilumab Dose Regimens in Adults With Atopic tem. Randomization was performed by a predefined random Dermatitis (LIBERTY AD SOLO-CONTINUE, hereafter referred to number sequence with block size of 5 within each combina- as SOLO-CONTINUE) were to evaluate maintenance of clinical tion of stratification factors (dose of dupilumab received in par- response and long-term safety of dupilumab monotherapy at ent study, region, and IGA scores). the original (300 mg every week or every 2 weeks) or less frequent SOLO-CONTINUE was blinded to all individuals until pre- regimens or drug withdrawal for an additional 36 weeks in specified unblinding except for the interactive voice re- patients treated with dupilumab who achieved predefined sponse system statistician (administered randomization se- treatment-success end points in SOLO 1 or 2. quence) and the independent data monitoring committee statistician and members, none of whom were involved in study design, management, or data analyses. For the every 2, 4, and 8 weeks regimens, matching placebo was adminis- Methods tered in the weeks that dupilumab was not administered. Study Design and Inclusion Criteria Blinded study-drug kits were coded with a medication num- This randomized clinical trial (study protocol in Supple- bering system. ment 1) was conducted in accordance with the ethical prin- Patients were required to apply moisturizers 2 or more ciples that have their origin in the Declaration of Helsinki24 and times daily throughout the study. Topical or systemic rescue are consistent with International Council for Harmonisation medications to control intolerable AD symptoms could be used 132 JAMA Dermatology February 2020 Volume 156, Number 2 (Reprinted) jamadermatology.com Downloaded From: https://jamanetwork.com/ on 10/09/2023 Dupilumab Dose Regimens After Successful Treatment in Patients With Atopic Dermatitis Original Investigation Research at investigator discretion. Patients discontinued use of the (disease severity), and SOLO-CONTINUE baseline as covari- study drug when using systemic rescue medication (eMethods ates. Sensitivity analyses were conducted for the coprimary in Supplement 2). end points (eMethods in Supplement 2). Safety, trough con- centrations of functional dupilumab, and treatment- End Points emergent ADAs were assessed using descriptive statistics. The continuous coprimary end point, based on percentage change in EASI score from SOLO baseline, assessed the differ- ence between SOLO-CONTINUE baseline (week 0) and SOLO- CONTINUE week 36. In SOLO, the continuous EASI end point Results was assessed as percentage change from the baseline EASI score Patient Disposition and Demographics (ie, baseline EASI score was considered 100%). In SOLO- A total of 1379 patients were randomized in SOLO (dupil- CONTINUE, the same method (ie, percentage change) and the umab weekly or every 2 weeks, n = 919; placebo, n = 460). At same reference point (SOLO baseline EASI score) were used, SOLO week 16, a total of 525 patients (38.1%) achieved EASI-75 but the continuous coprimary end point reported the addi- or had an IGA score of 0 or 1 (dupilumab weekly, 236 of 462 tional changes that occurred after SOLO (ie, during SOLO- [51.1%]; dupilumab every 2 weeks, 227 of 457 [49.7%]; pla- CONTINUE). The categorical coprimary end point was the per- cebo, 62 of 460 [13.5%]), of whom 475 met SOLO-CONTINUE centage of patients at week 36 who maintained EASI-75 from eligibility criteria and were enrolled. Of these, 53 placebo- SOLO-CONTINUE baseline (among patients with EASI-75 at treated SOLO patients did not meet the eligibility criteria; for SOLO week 16). Key secondary end points at week 36 in- the purposes of maintaining blinding, these patients were as- cluded percentages of patients with IGA scores maintained signed to a separate placebo cohort, not randomized in SOLO- within 1 point of SOLO-CONTINUE baseline, IGA scores of 0 CONTINUE, and not included in these analyses. Therefore, or 1 among patients with IGA scores of 0 or 1 at SOLO- 422 patients (mean [SD] age, 38.2 [14.5] years; 227 [53.8%] CONTINUE baseline, and a 3-point or greater worsening of Peak male) treated with dupilumab in SOLO were rerandomized in Pruritus Numerical Rating Scale (NRS) score from SOLO- SOLO-CONTINUE to either continue their original treatment CONTINUE baseline to week 35 among patients with SOLO- regimen (weekly, n = 89; every 2 weeks, n = 80) or to take du- CONTINUE baseline Peak Pruritus NRS scores of 7 or less. pilumab every 4 weeks (n = 86), dupilumab every 8 weeks A technical issue with the interactive voice response system (n = 84), or placebo (n = 83) in this intent-to-treat analysis collecting patient-reported pruritus data resulted in consid- (Figure 1). Treatment groups had similar baseline character- erable missing pruritus data at week 36; because Peak Pruri- istics (Table 1 and eTable 1 in Supplement 2). A total of 155 of tus NRS scores were stable in all dose groups by week 35, this 169 patients (91.7%) in the dupilumab weekly or every 2 weeks was deemed to be a suitable end-of-treatment time point for group, 76 of 86 patients (88.4%) in the every 4 weeks group, Peak Pruritus NRS analyses (eMethods in Supplement 2). 75 of 84 patients (89.3%) in the every 8 weeks group, and 69 Trough concentrations of functional dupilumab were as- of 83 patients (83.1%) in the placebo group completed study sessed in serum samples collected at SOLO-CONTINUE weeks treatment. 0, 4, 12, 24, and 36. Treatment-emergent ADAs were assessed at SOLO-CONTINUE baseline and week 36 (eMethods in Efficacy Supplement 2). Safety assessments included treatment- Eczema Area and Severity Index emergent adverse events (AEs), serious AEs, and AEs that led Patients who received dupilumab weekly or every 2 weeks dur- to study treatment withdrawal. ing SOLO and throughout SOLO-CONTINUE had nearly no diminution in efficacy during SOLO-CONTINUE. At SOLO- Statistical Analysis CONTINUE baseline (end of SOLO), patients taking dupil- Approximately 420 patients were expected to enroll based on umab weekly or every 2 weeks had EASI least squares mean SOLO sample sizes and anticipated response rates (eMethods improvement of 91.5% from SOLO baseline; EASI improve- in Supplement 2). To compare each dupilumab treatment group ment was maintained at 91.4% from SOLO-CONTINUE base- with placebo, significance was set to a 2-sided P < .05. To con- line to week 36 (−0.06% change from SOLO-CONTINUE base- trol for multiplicity, the coprimary and key secondary end line to week 36 [continuous coprimary end point]) (Figure 2A points were assessed in a hierarchical manner (eMethods in and eFigure 2 in Supplement 2). In contrast, patients as- Supplement 2). Other secondary and post hoc end points were signed to the placebo group in SOLO-CONTINUE had a 21.7% not controlled for multiplicity; their P values are nominal. decrease from the EASI improvement achieved in SOLO Categorical end points were analyzed using the Cochran- (Table 2 and Figure 2A). Differences in percentage change in Mantel-Haenszel test adjusted by randomization strata (dis- EASI score from SOLO baseline appeared to be dose depen- ease severity and region) and SOLO treatment regimens; pa- dent for treatment administration weekly or every 2 weeks tients were considered to be nonresponders from the time of compared with every 4 weeks and every 8 weeks (Table 2 and rescue medication use or withdrawal. For continuous end Figure 2A). Post hoc analyses showed no apparent difference points, data were treated as missing after rescue medication between dupilumab weekly and every 2 weeks in mainte- use or early discontinuation; missing data were imputed using nance of clinical response (eFigure 2B in Supplement 2). multiple imputation with analysis of covariance, with treat- Among patients with EASI-75 response at SOLO-CONTINUE ment group, SOLO treatment regimen, randomization strata baseline, significantly more dupilumab-treated patients main- jamadermatology.com (Reprinted) JAMA Dermatology February 2020 Volume 156, Number 2 133 Downloaded From: https://jamanetwork.com/ on 10/09/2023 Research Original Investigation Dupilumab Dose Regimens After Successful Treatment in Patients With Atopic Dermatitis Figure 1. CONSORT Diagram 1379 Patients randomized in parent studies 475 Patients enrolled in present study 422 Randomized (parent study dupilimab dosage: 199 every 2 wk; 223 every wk)a 83 Randomized to placebo (parent 84 Randomized to dupilumab every 86 Randomized to dupilumab every 169 Randomized to dupilumab every study dosage: 39 every 2 wk; 8 wk (parent study dosage: 39 4 wk (parent study dosage: 41 wk or every 2 wk (parent and 44 every wk) every 2 wk; 45 every wk) every 2 wk; 45 every wk) current study dosage: 89 every 82 Received intervention as 83 Received intervention as 86 Received intervention as 2 wk; 80 every wk) randomized randomized randomized 169 Received intervention as 1 Did not receive intervention 1 Did not receive intervention randomized as randomized as randomized 14 Did not complete treatment 9 Did not complete treatmentb 10 Did not complete treatment 14 Did not complete treatment 4 Adverse event 1 Adverse event 3 Adverse event 1 Lack of efficacy 1 Lack of efficacy 1 Protocol violation 1 Lack of efficacy 3 Protocol violation 1 Protocol violation 3 Consent withdrawn with 2 Study drug supply issue 2 Consent withdrawn with 1 Consent withdrawn with no reason provided 1 Lost to follow-up no reason provided no reason provided 1 Consent withdrawn with 3 Pregnancy 3 Consent withdrawn with 4 Study drug supply issue personal/administrative reason personal/administrative reason 2 Sponsor decision 1 Study drug supply issue 3 Study drug supply issue 1 Otherc 1 Lost to follow-up 1 Sponsor decision 1 Otherc 69 Completed treatment 75 Completed treatment 76 Completed treatment 155 Completed treatment a There were 53 placebo-treated patients from the Study of Dupilumab scores or Investigator’s Global Assessment scores of 0 or 1 at SOLO week 16 Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic and were excluded from per-protocol efficacy analyses but were included in Dermatitis (SOLO 1) and Study of Dupilumab Monotherapy Administered to the primary (intention-to-treat) analyses. Adult Patients With Moderate-to-Severe Atopic Dermatitis (SOLO 2) who met b One patient withdrew consent shortly after randomization and was not the eligibility criteria; for the purposes of maintaining blinding, these patients entered in the end of treatment page of the electronic data capture; therefore, were assigned to a separate placebo cohort, not randomized in Study to this individual was not counted in the subcategories for reason for Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in discontinuing study treatment. Adults With Atopic Dermatitis (SOLO-CONTINUE), and therefore not included c The categories with 1 patient overall were grouped together, including the in these analyses. Two randomized patients (placebo and dupilumab every categories of patient had been taking oral corticosteroids; therefore, study 8 weeks) withdrew before receiving the study drug. Two patients were drug injection could not be administered at week 36 and early rollover into erroneously randomized (placebo and dupilumab weekly or every 2 weeks); protocol of the open-label extension study. they had not achieved 75% improvement in Eczema Area and Severity Index tained this response at week 36 vs patients receiving placebo (cat- receiving dupilumab weekly or every 2 weeks (57 patients egorical coprimary end point) (Table 2 and eFigure 3 in Supple- [33.9%]; P < .001) or every 4 weeks (41 patients [49.4%]; P = .01) ment 2). There was an apparent dose-dependent response: the had a 3-point or greater worsening in Peak Pruritus NRS at week proportion of patients with EASI-75 was higher with the weekly 35 vs placebo (56 patients [70.0%]) (Table 2), with an apparently or every 2 weeks regimen (116 of 169 patients [71.6%]) than the dose-dependent response (eTable 2 in Supplement 2). Consis- every 4 weeks (49 of 86 patients [58.3%]; nominal P < .05) or tent with the continuous coprimary EASI end point, there was every 8 weeks (45 of 84 patients [54.9%]; nominal P = .01) regi- no overall loss of efficacy with dupilumab weekly or every mens (eTable 2 in Supplement 2). Similar maintenance of im- 2 weeks (baseline vs week 35) in percentage change in Peak provement was seen for patients with 50% and 90% improve- Pruritus NRS from SOLO baseline during SOLO-CONTINUE (0.1%; ment in EASI scores (Table 2). Sensitivity analyses confirmed the P < .001) (Table 2, Figure 2B, and eFigure 6 in Supplement 2), coprimary and key secondary outcomes (eTable 3 and eFigure 4 whereas there was a dose-dependent return of pruritus for the in Supplement 2). every 4 weeks (−8.6%; P < .001), every 8 weeks (−16.7%; P < .001), and placebo (−35.6%) groups, particularly after week 12 (Table 2, Pruritus Figure 2B, and eFigure 6 in Supplement 2). Other Peak Pruritus Improvements in pruritus were maintained with dupilumab in NRS end points had similar findings (Table 2 and eFigure 5 and a similar dose-dependent manner. Dupilumab weekly or every eFigure 7 in Supplement 2). 2 weeks resulted in Peak Pruritus NRS least squares mean im- provement of 62.2% from SOLO baseline to SOLO week 16; Other Clinical Efficacy End Points by SOLO-CONTINUE week 35, improvement from SOLO base- For IGA end points, all dupilumab regimens sustained re- line was 61.4% (eFigure 5 in Supplement 2). Fewer patients sponse significantly better than placebo (Table 2). For ex- 134 JAMA Dermatology February 2020 Volume 156, Number 2 (Reprinted) jamadermatology.com Downloaded From: https://jamanetwork.com/ on 10/09/2023 Dupilumab Dose Regimens After Successful Treatment in Patients With Atopic Dermatitis Original Investigation Research Table 1. SOLO-CONTINUE Baseline Characteristics (Full Analysis Set)a Dupilumab, 300 mg Placebo Every 8 wk Every 4 wk Weekly or Every Characteristic (n = 83) (n = 84) (n = 86) 2 wk (n = 169) Age, median (IQR), yb 37 (27.0-46.0) 35 (26.0-46.5) 36 (24.0-49.0) 36 (26.0-48.0) Race/ethnicity White 54 (65.1) 56 (66.7) 64 (74.4) 124 (73.4) Black/African American 7 (8.4) 8 (9.5) 4 (4.7) 7 (4.1) Asian 17 (20.5) 18 (21.4) 16 (18.6) 31 (18.3) Other 2 (2.4) 2 (2.4) 2 (2.3) 5 (3.0) Not reported or missing 3 (3.6) 0 0 2 (1.2) Sex Male 51 (61.4) 51 (60.7) 43 (50.0) 82 (48.5) Female 32 (38.6) 33 (39.3) 43 (50.0) 87 (51.5) Duration of AD at baseline, y <26 37 (44.6) 53 (63.1) 44 (51.2) 81 (47.9) ≥26 44 (53.0) 30 (35.7) 42 (48.8) 87 (51.5) Missing 2 (2.4) 1 (1.2) 0 1 (0.6) Abbreviations: AD, atopic dermatitis; EASI-75 or IGA score of 0 or 1 at baseline BSA, body surface area; DLQI, Dermatology Life Quality No 1 (1.2) 0 0 1 (0.6) Index; EASI, Eczema Area and Yes 82 (98.8) 84 (100) 86 (100) 168 (99.4) Severity Index; EASI-75, 75% or greater improvement in EASI from IGA score baseline; EQ-5D, EuroQol 0 8 (9.6) 9 (10.7) 10 (11.6) 18 (10.7) 5-Dimensional Scale; HADS, Hospital 1 55 (66.3) 55 (65.5) 58 (67.4) 111 (65.7) Anxiety and Depression Scale; IGA, Investigator’s Global 2 19 (22.9) 18 (21.4) 12 (14.0) 37 (21.9) Assessment; IQR, interquartile range; 3 1 (1.2) 2 (2.4) 6 (7.0) 3 (1.8) SOLO-CONTINUE, Study to Confirm 4 0 0 0 0 the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults EASI-75 at baseline With Atopic Dermatitis; No 4 (4.8) 2 (2.4) 2 (2.3) 7 (4.1) NRS, Numerical Rating Scale; Yes 79 (95.2) 82 (97.6) 84 (97.7) 162 (95.9) POEM, Patient-Oriented Eczema Measure; SCORAD, Scoring Atopic EASI score, mean (SD) 2.5 (2.31) 2.3 (2.33) 2.8 (3.31) 2.6 (2.92) Dermatitis. Percent change in EASI score from parent −91.2 (8.21) −90.8 (9.32) −91.2 (8.07) −91.3 (9.34) a Data are presented as number study baseline, mean (SD), % (percentage) of study participants Weekly Peak Pruritus NRS score, mean (SD) 2.8 (2.11) 2.7 (2.27) 3.1 (2.16) 2.8 (1.92) unless otherwise indicated. Baseline Percent BSA affected, mean (SD), % 8.1 (8.21) 7.9 (9.04) 9.3 (10.51) 7.9 (9.02) is per baseline of SOLO-CONTINUE. b SCORAD score, mean (SD) 16.8 (10.03) 17.1 (9.41) 17.5 (10.59) 17.1 (10.49) Median age is as per baseline of the current study; some patients had Total scores, mean (SD) birthdays between baseline of the POEM 6.1 (5.43) 6.8 (5.88) 6.1 (5.11) 6.4 (5.30) parent study and baseline of the DLQI 3.4 (4.25) 3.0 (3.76) 3.2 (3.93) 3.4 (4.21) current study. c HADSc 5.9 (6.36) 7.1 (6.87) 7.3 (7.53) 6.4 (5.94) Placebo, n = 78; 300 mg of d dupilumab every 8 weeks, n = 81; EQ-5D pain or discomfort 300 mg of dupilumab every None 60 (73.2) 60 (71.4) 63 (73.3) 126 (74.6) 4 weeks, n = 75; and 300 mg of dupilumab weekly or every 2 weeks, Moderate 21 (25.6) 24 (28.6) 23 (26.7) 42 (24.9) n = 164. Extreme 1 (1.2) 0 (0) 0 (0) 1 (0.6) d Placebo, n = 82. ample, among patients who had IGA scores of 0 or 1 at base- compared with dupilumab every 8 weeks, and more patients line, significantly more patients receiving dupilumab weekly receiving dupilumab weekly or every 2 weeks maintained their or every 2 weeks (89 of 126 patients [70.6%]; P < .001), every IGA scores of 0 or 1 compared with patients receiving 4 weeks (41 of 66 patients [62.1%]; P < .001), and every 8 weeks dupilumab every 8 weeks (eTable 2 in Supplement 2). For all (32 of 64 patients [50.0%]; P = .01) maintained their IGA scores other secondary efficacy end points, including flare rates and within 1 point of baseline at week 36 compared with placebo well-controlled weeks, dupilumab demonstrated signifi- (18 of 63 patients [28.6%]). A similar pattern was observed for cantly superior maintenance of efficacy vs placebo, with weekly other IGA end points (Table 2). In post hoc analyses, higher pro- or every 2 weeks administration consistently having greater portions of patients receiving dupilumab weekly or every 2 improvement than administration every 4 weeks and every 8 weeks maintained their IGA scores within 1 point of baseline weeks (Table 2 and eFigures 7, 8, 9, and 10 in Supplement 2). jamadermatology.com (Reprinted) JAMA Dermatology February 2020 Volume 156, Number 2 135 Downloaded From: https://jamanetwork.com/ on 10/09/2023 Research Original Investigation Dupilumab Dose Regimens After Successful Treatment in Patients With Atopic Dermatitis Figure 2. Maintenance of Improvement in Clinical and Patient-Reported Outcomes and Rescue Medication Use in the Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (SOLO-CONTINUE) A EASI B Peak pruritus NRS P <.001 for all dupilumab groups vs placebo Nominal P <.001 for all dupilumab groups vs placebo Dupilumab 300 mg Dupilumab 300 mg weekly or every 2 weeks Worsening weekly or every 2 weeks Improvement Dupilumab 300 mg Dupilumab 300 mg every 4 weeks every 4 weeks Dupilumab 300 mg Dupilumab 300 mg every 8 weeks every 8 weeks Placebo Placebo –25 –20 –15 –10 –5 0 5 –40 –35 –30 –25 –20 –15 –10 –5 0 5 LS Mean Percent Change in EASI Score, % LS Mean Percent Change in Peak Pruritus NRS Score, % C POEM D DLQI Nominal P <.001 for dupilumab weekly or every 2 weeks and every 4 weeks vs placebo Nominal P <.001 for all dupilumab groups vs placebo Nominal P = .02 for dupilumab every 8 weeks vs placebo Dupilumab 300 mg Dupilumab 300 mg weekly or every 2 weeks weekly or every 2 weeks Dupilumab 300 mg Dupilumab 300 mg every 4 weeks every 4 weeks Dupilumab 300 mg Dupilumab 300 mg every 8 weeks every 8 weeks Placebo Placebo –9 –8 –7 –6 –5 –4 –3 –2 –1 0 1 –4 –3 –2 –1 0 1 LS Mean Change in POEM Score LS Mean Change in DLQI Score E HADS F Rescue medication use Nominal P = .01 vs placebo 50 Placebo Dupilumab 300 mg Cumulative Patients Using 40 Dupilumab 300 mg weekly or every 2 weeks Rescue Medication, % every 8 weeks Dupilumab 300 mg 30 Dupilumab 300 mg every 4 weeks every 4 weeks 20 Dupilumab 300 mg Dupilumab 300 mg every 8 weeks weekly or every 2 weeks 10 Placebo 0 –2.0 –1.5 –1.0 –0.5 0 0.5 1.0 1.5 0 4 8 12 16 20 24 28 32 36 LS Mean Change in HADS Score Study Week Outcome measures included the Eczema Area and Severity Index (EASI), B, The LS mean percent change in Peak Pruritus NRS score from SOLO baseline Peak Pruritus Numerical Rating Scale (NRS), Patient-Oriented Eczema Measure during SOLO-CONTINUE: difference between SOLO-CONTINUE baseline and (POEM), Dermatology Life Quality Index (DLQI), and Hospital Anxiety and week 35. C, The LS mean change in POEM score from SOLO-CONTINUE Depression Scale (HADS) scores. A, Least squares (LS) mean percent change in baseline to week 36. D, The LS mean change in DLQI score from EASI score from baseline of Study of Dupilumab Monotherapy Administered to SOLO-CONTINUE baseline to week 36. E, The LS mean change in HADS score Adult Patients With Moderate-to-Severe Atopic Dermatitis (SOLO 1) or Study of from SOLO-CONTINUE baseline to week 36. F, Cumulative percentage of Dupilumab Monotherapy Administered to Adult Patients With patients using rescue medication from baseline in to week 36 in Moderate-to-Severe Atopic Dermatitis (SOLO 2) baseline during SOLO-CONTINUE. A-E, Negative values indicate a diminution of response. Error SOLO-CONTINUE: difference between SOLO-CONTINUE baseline and week 36. bars indicate SEs. Other Patient-Reported Symptoms provement from SOLO that was nominally significant for du- Dupilumab maintained response in Patient-Oriented Eczema pilumab weekly or every 2 weeks vs placebo; for example, for Measure (POEM), Dermatology Life Quality Index (DLQI), and POEM, dupilumab weekly or every 2 weeks showed signifi- Hospital Anxiety and Depression Scale (HADS): differences cant improvement (least squares mean change from baseline) (week 36 minus SOLO-CONTINUE baseline) showed further im- of 0.3 vs −7.0 for placebo (P < .001); for DLQI, dupilumab 136 JAMA Dermatology February 2020 Volume 156, Number 2 (Reprinted) jamadermatology.com Downloaded From: https://jamanetwork.com/ on 10/09/2023 Dupilumab Dose Regimens After Successful Treatment in Patients With Atopic Dermatitis Original Investigation Research Table 2. Dupilumab Efficacy Dupilumab, 300 mg Placebo Every 8 wk Every 4 wk Weekly or Every 2 wk End Point (n = 83) (n = 84) (n = 86) (n = 169) Coprimary end points Percent change in EASI score from SOLO baseline: −21.67 (3.13) −6.84 (2.43)a −3.84 (2.28)a −0.06 (1.74)a difference between SOLO-CONTINUE baseline and week 36, LS mean (SE) Patients with EASI-75 at week 36 among patients with 24/79 (30.4) 45/82 (54.9)b 49/84 (58.3)a 116/162 (71.6)a EASI-75 at SOLO-CONTINUE baseline, No./total No. (%) Key secondary end points Among patients with IGA score of 0 or 1 at SOLO-CONTINUE baseline, No./total No. (%) Patients with IGA score maintained within 1 point of 18/63 (28.6) 32/64 (50.0)c 41/66 (62.1)a 89/126 (70.6)a baseline at week 36 Patients with IGA score of 0 or 1 at week 36 9/63 (14.3) 21/64 (32.8)c 29/66 (43.9)a 68/126 (54.0)a c Patients with increase of ≥3 in Peak Pruritus NRS score from 56/80 (70.0) 45/81 (55.6) 41/83 (49.4) 57/168 (33.9)a SOLO-CONTINUE baseline to week 35 among patients with SOLO-CONTINUE baseline score ≤7, No./total No. (%) Other secondary end pointsd Percent change in EASI scores from SOLO-CONTINUE −6.61 (0.80) −1.75 (0.74)a −1.37 (0.74)a −0.09 (0.51)a baseline, LS mean (SE) Patients with EASI-50 at week 36 among patients with 33/83 (39.8) 46/84 (54.8) 52/86 (60.5)c 124/169 (73.4)a EASI-50 at SOLO-CONTINUE baseline, No./total No. (%) Percent change in Peak Pruritus NRS score from SOLO −35.6 (4.3) −16.7 (4.1)a −8.6 (4.0)a 0.1 (3.1)a baseline: difference between SOLO-CONTINUE baseline and week 35, LS mean (SE) Time to first event of IGA score ≥2 among patients with IGA score of 0 or 1 at SOLO-CONTINUE baseline No. of patients with an event 60 52 50 85 No. of patients censored 3 12 16 41 No. of days Mean (SD) 76.0 (62.02) 112.2 (85.98) 105.0 (89.14) 139.7 (99.95) Median (95% CI) 57 (56-58) 85 (59-113) 80 (55-85) 114 (85-169) Hazard ratio vs placebo (95% CI) NA 0.63 (0.43 to 0.92) 0.71 (0.49 to 1.05) 0.45 (0.32 to 0.64) Patients with IGA scores increased to 3 or 4 at week 36 among 42/63 (66.7) 31/64 (48.4)e 23/66 (34.8)a 33/126 (26.2)a patients with IGA score of 0 or 1 at SOLO-CONTINUE baseline, No./total No. (%) Percent change in SCORAD from SOLO baseline: difference −28.97 (3.68) −10.42 (2.99)a −2.21 (2.74)a −0.33 (2.09)a between SOLO-CONTINUE baseline and week 36, LS mean (SE) Percent BSA affected: change from SOLO-CONTINUE baseline, −9.16 (1.64) −2.74 (1.53)f −1.74 (1.46)a 1.27 (1.04)a LS mean (SE) Change from SOLO-CONTINUE baseline, LS mean (SE) POEM −7.0 (0.90) −2.8 (0.78)a −0.8 (0.73)a 0.3 (0.56)a DLQI −3.1 (0.52) −1.5 (0.46)c −0.3 (0.48)a 0.2 (0.33)a HADS −0.8 (0.60) −0.7 (0.52) −0.2 (0.54) 0.8 (0.39)c Annualized event rate of flares from SOLO-CONTINUE baseline through week 36g,h Total No. of flares 62 46 38 36 Total patient-years followed 54.7 56.9 58.2 112.1 Adjusted annualized rate (95% CI) 0.75 (0.47-1.21) 0.59 (0.36-0.96) 0.44 (0.26-0.73) 0.21 (0.13-0.35) Relative risk vs placebo (95% CI) NA 0.78 (0.45 to 1.36) 0.58 (0.33 to 1.03) 0.28 (0.17 to 0.49)a Well-controlled weeks before rescue medication use, 40.9 (30.35) 53.2 (32.95) 53.3 (35.86) 63.0 (32.36) mean (SD), %i Annualized event rate of skin infection treatment-emergent adverse events (excluding herpetic infections) through week 36 Total No. of events 10 7 1 4 Total patient-years of follow up 54.7 56.9 58.2 112.1 Adjusted annualized rate (95% CI) 0.12 (0.04-0.33) 0.09 (0.03-0.25) 0.01 (0.001-0.097) 0.02 (0.007-0.083) Relative risk vs placebo (95% CI) NA 0.71 (0.23-2.23) 0.10 (0.01-0.83)c 0.20 (0.06-0.72)c (continued) jamadermatology.com (Reprinted) JAMA Dermatology February 2020 Volume 156, Number 2 137 Downloaded From: https://jamanetwork.com/ on 10/09/2023 Research Original Investigation Dupilumab Dose Regimens After Successful Treatment in Patients With Atopic Dermatitis Table 2. Dupilumab Efficacy (continued) Dupilumab, 300 mg Placebo Every 8 wk Every 4 wk Weekly or Every 2 wk End Point (n = 83) (n = 84) (n = 86) (n = 169) Post hoc end pointsd Percent change in EASI score from SOLO baseline to SOLO-CONTINUE week 36, subgroups by original dose regimen in SOLO, LS mean (SE) Originally taking dupilumab, 300 mg, every 2 wk No. 39 39 41 80 LS mean (SE), % −72.73 (5.68) −82.80 (4.12) −85.35 (4.08) −90.75 (2.96)j Originally taking dupilumab, 300 mg, weekly No. 44 45 45 89 LS mean (SE), % −69.32 (3.38) −87.04 (3.24)a −88.70 (3.00)a −91.88 (2.13)a Percent change in EASI score from SOLO baseline to SOLO-CONTINUE week 36, subgroups by SOLO-CONTINUE baseline IGA and EASI, LS mean (SE) Subgroup with IGA score >1 at week 36, among patients with IGA score of 0 or 1 at SOLO-CONTINUE baseline No. 53 36 32 50 LS mean (SE), % −63.7 (8.08) −76.1 (9.14) −76.3 (8.12) −79.7 (7.60)c Subgroup with <75% improvement in EASI score from SOLO baseline at week 36, among patients with EASI-75 at baseline No. 34 14 19 17 LS mean (SE), % −43.9 (4.81) −47.4 (6.96) −57.8 (6.39)c −58.6 (6.68)c Patients who achieved EASI-90 at week 36 among patients with 10/55 (18.2) 16/49 (32.7) 33/56 (58.9)a 75/116 (64.7)a EASI-90 at SOLO-CONTINUE baseline, No./total No. (%) Percent change in Peak Pruritus NRS score from SOLO baseline to SOLO-CONTINUE week 35, subgroups by original dose regi- men in SOLO (weekly or every 2 wk), LS mean (SE) Originally taking dupilumab, 300 mg, every 2 wk No. 39 39 41 80 c k LS mean (SE), % −27.05 (7.57) −50.93 (6.41) −51.61 (6.31) −60.91 (4.75)a Originally taking dupilumab, 300 mg, weekly No. 44 45 45 89 LS mean (SE), % −33.32 (7.29) −38.68 (6.97) −50.64 (7.14) −59.59 (5.35)a Patients with improvement in Peak Pruritus NRS score from SOLO baseline to SOLO-CONTINUE week 35, No./total No. (%) ≥4 Pointsl 10/78 (12.8) 21/79 (26.6)c 27/82 (32.9)m 78/159 (49.1)a n c j ≥3 Points 15/82 (18.3) 28/82 (34.1) 34/84 (40.5) 95/166 (57.2)a a Patients who reported no sleep disturbance in the past 7 d at 18 (21.7) 30 (35.7) 41 (47.7) 103 (60.9)a week 36 (POEM item 2), No. (%) SCORAD Sleep Loss (scale, 0-10): change from SOLO baseline to −2.7 (0.3) −3.3 (0.3) −4.2 (0.2)a −4.3 (0.2)a SOLO-CONTINUE week 36, LS mean (SE) Patients who reported no pain or discomfort, EQ-5D item, at 13/63 (20.6) 25/64 (39.1)c 30/72 (41.7)c 78/138 (56.5)a week 36 among patients who reported moderate or severe pain or discomfort at SOLO baseline, No./total No. (%) e Abbreviations: DLQI, Dermatology Life Quality Index; EASI, Eczema Area and P = .009 vs placebo. Severity Index; EASI-50, proportion of patients with 50% or greater f P = .002 vs placebo. improvement in EASI from SOLO baseline; EASI-75, proportion of patients with g Safety analysis set: placebo, n = 82; dupilumab every 8 weeks, n = 84; 75% or greater improvement in EASI from SOLO baseline; EASI-90, proportion dupilumab every 4 weeks, n = 87; dupilumab weekly or every 2 weeks, n = 167. of patients with 90% or greater improvement in EASI from SOLO baseline; h EQ-5D, EuroQol 5-Dimensional Scale; HADS, Hospital Anxiety and Depression Flares were defined as worsening of disease requiring initiation or escalation Score; IGA, Investigator’s Global Assessment; SOLO-CONTINUE, Study to of rescue treatment. Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in i Defined as the proportion of patients who responded “yes” to the question: Adults With Atopic Dermatitis; LS, least squares; NA, not applicable; “Has your eczema been well-controlled over the last week?” and for whom NRS, Numerical Rating Scale; POEM, Patient-Oriented Eczema Measure; no rescue treatment was administered during that week. SCORAD, Scoring Atopic Dermatitis. j P ⱕ .003 vs placebo. a P < .001 vs placebo. k P = .006 vs placebo. b P = .004 vs placebo. l Patients with Peak Pruritus NRS scores of 4 or greater at SOLO baseline. c P < .05 vs placebo. m P = .005 vs placebo. d P values are nominal for all endpoints other than coprimary or key secondary. n Patients with Peak Pruritus NRS scores of 3 or greater at SOLO baseline. 138 JAMA Dermatology February 2020 Volume 156, Number 2 (Reprinted) jamadermatology.com Downloaded From: https://jamanetwork.com/ on 10/09/2023 Dupilumab Dose Regimens After Successful Treatment in Patients With Atopic Dermatitis Original Investigation Research weekly or every 2 weeks showed improvement of 0.2 vs −3.1 centage change in EASI score from SOLO baseline to week 36. for placebo (P < .001); and for HADS, dupilumab weekly or ev- For example, in the IGA greater than 1 subgroup, least squares ery 2 weeks showed improvement of 0.8 vs −0.8 for placebo mean (SE) percentage change in EASI score was −79.7 (7.60) (P = .01). Dupilumab every 4 weeks and every 8 weeks showed for the dupilumab weekly or every 2 weeks group vs −63.7 some attrition of response for these parameters but remained (8.08) for placebo (Table 2). nominally superior vs placebo for POEM and DLQI (Table 2 and Figure 2C-E). More dupilumab-treated patients vs patients re- Safety ceiving placebo reported no pain or discomfort at week 36; Treatment-emergent AEs occurred in 67 placebo-treated the proportion was greatest for administration weekly or ev- patients (81.7%) and 118 of 167 (70.7%) to 63 of 84 (75.0%) ery 2 weeks (dupilumab weekly or every 2 weeks, 78 of 138 pa- dupilumab-treated patients; the weekly or every 2 weeks group tients [56.5%], P < .001; every 4 weeks, 30 of 72 patients had the lowest rates (118 [70.7%]) (Table 3 and eTable 5 in [41.7%], P = .03; every 8 weeks, 25 of 64 patients [39.1%], Supplement 2). In all treatment groups, 14 of 420 patients P = .03; vs placebo, 13 of 63 patients [20.6%]) (Table 2). In ad- (3.3%) reported treatment-emergent serious AEs (Table 3 and dition, patients receiving treatment weekly or every 2 weeks eTable 6 in Supplement 2). A total of 5 patients (1.2%) perma- were more likely to report no sleep disturbances at week 36; nently discontinued study treatment because of treatment- for example, among patients receiving dupilumab weekly or emergent AEs (Table 3). Nasopharyngitis, injection-site reac- every 2 weeks, 103 of 169 patients (60.9%; P < .001) achieved tions, herpes simplex virus infection, and headache were the significant improvement in POEM item 2 compared with pla- most frequent treatment-emergent AEs, occurring at rates of cebo (18 of 83 patients [21.7%]) and significant improvement 2% or higher in the dupilumab weekly or every 2 weeks group in SCORAD sleep loss vs placebo (least squares mean [SE] than in the placebo group; AD and skin infections were the most change, −4.3 [0.2] for dupilumab weekly or every 2 weeks vs frequent treatment-emergent AEs, occurring at rates of 2% or −2.7 [0.3] for placebo; P < .001), with similar improvement seen higher in the placebo group than in the dupilumab groups among patients receiving dupilumab every 4 weeks vs pla- (Table 3 and eTables 7, 8, and 9 in Supplement 2). Conjuncti- cebo (Table 2). vitis incidences were low and similar across treatment groups (eg, 9 of 167 patients [5.4%] in the dupilumab weekly or every Rescue Treatment 2 weeks group and 4 of 82 patients [4.9%] in the placebo group) A higher cumulative percentage of placebo-treated patients (Table 3 and eTable 10 in Supplement 2). used rescue treatment by week 36; patients receiving dupil- umab weekly or every 2 weeks had the lowest percentage of Trough Dupilumab Concentrations rescue medication use (33 of 169 patients [19.5%]) compared Patients who continued to take dupilumab weekly or every with placebo (40 of 83 patients [48.2%]) (Figure 2F). Patients 2 weeks through week 36 maintained steady state serum con- receiving dupilumab weekly or every 2 weeks had fewer days centrations of dupilumab consistent with SOLO-CONTINUE of rescue medication use (31.80 days per patient-year [post hoc baseline concentrations, whereas the every 4 weeks group had end point]) than those receiving treatment every 4 weeks (57.97 4- to 9-fold lower concentrations and the every 8 weeks group days per patient-year), those receiving treatment every 8 weeks had 30- to 56-fold lower concentrations (eFigure 11 in Supple- (51.37 days per patient-year), and those receiving placebo (73.12 ment 2). This finding was consistent with the known pharma- days per patient-year). The most frequently used rescue medi- cokinetic profile for dupilumab.25 For patients rerandomized cations were topical corticosteroids (from 30 of 169 patients to placebo from dupilumab weekly or every 2 weeks, median [17.8%] for dupilumab weekly or every 2 weeks to 37 of 83 pa- dupilumab concentrations decreased below the lower limit of tients [44.6%] for placebo). Few patients required systemic res- quantification (0.078 mg/L) by SOLO-CONTINUE weeks 24 or cue treatment (mainly oral corticosteroids) (eTable 4 in Supple- 12, respectively. ment 2), with greatest use among those receiving placebo (systemic corticosteroids: 6 of 83 patients [7.2%]; systemic im- Antidrug Antibodies munosuppressants: 1 [1.2%]) and least among those receiv- Treatment-emergent ADAs during SOL O-CONTINUE ing dupilumab weekly or every 2 weeks (systemic corticoste- occurred in 9 of 80 individuals (11.3%) in the placebo group, roids, 3 of 169 patients [1.8%]). 9 of 77 (11.7%) in the dupilumab every 8 weeks group, 5 of 83 (6.0%) in the dupilumab every 4 weeks group, 3 of 70 (4.3%) Additional Post Hoc Subgroup Analyses in the dupilumab every 2 weeks group, and 1 of 83 (1.2%) in To evaluate response among patients who did not achieve the the dupilumab weekly group, indicating a higher incidence stringent IGA 0 or 1 scores or EASI-75 end points in SOLO- of immunogenicity with less frequent dosage intervals. CONTINUE, we conducted post hoc analyses of EASI in 2 sub- Because most treatment-emergent ADAs were low titer groups: patients with IGA scores greater than 1 at week 36 (<1000), there was no apparent effect of treatment- (among those with IGA scores of 0 or 1 at baseline) and pa- emergent ADAs on dupilumab exposure. No high treatment- tients without EASI-75 at week 36 (among those with EASI-75 emergent ADA titers (>10 000) were observed in SOLO- at baseline). In both subgroups, patients receiving dupil- CONTINUE. Few patients (placebo, n = 2; dupilumab every umab weekly or every 2 weeks or dupilumab every 4 weeks 8 weeks, n = 1) had moderate titer (range, 1000-10 000) (EASI-75 subgroup only) but not every 8 weeks had nomi- responses. Beyond what could be accounted for as differ- nally significantly greater improvements vs placebo in per- ences attributable to dose regimen, there were no apparent jamadermatology.com (Reprinted) JAMA Dermatology February 2020 Volume 156, Number 2 139 Downloaded From: https://jamanetwork.com/ on 10/09/2023 Research Original Investigation Dupilumab Dose Regimens After Successful Treatment in Patients With Atopic Dermatitis Table 3. Adverse Events (Safety Analysis Set) No. (%) of Participants Dupilumab, 300 mg Placebo Every 8 wk Every 4 wk Weekly or Every 2 wk Adverse Event (n = 82) (n = 84) (n = 87) (n = 167) Overall TEAEs ≥1 67 (81.7) 63 (75.0) 64 (73.6) 118 (70.7) Leading to permanent study treatment 3 (3.7)a 0 2 (2.3)b 0 discontinuation Leading to temporary study treatment 10 (12.2) 7 (8.3) 7 (8.0) 6 (3.6) discontinuation Deathc 0 0 1 (1.1) 0 Treatment-emergent SAEd 1 (1.2) 3 (3.6) 4 (4.6) 6 (3.6) MedDRA PT occurring in ≥2% of patients in any treatment group Dermatitis atopic 40 (48.8) 27 (32.1) 30 (34.5) 34 (20.4) Nasopharyngitis 11 (13.4) 11 (13.1) 11 (12.6) 32 (19.2) Upper respiratory tract infection 6 (7.3) 7 (8.3) 5 (5.7) 13 (7.8) Headache 2 (2.4) 3 (3.6) 5 (5.7) 8 (4.8) Abbreviations: MedDRA, Medical Herpes simplex virus infectione 0 4 (4.8) 1 (1.1) 7 (4.2) Dictionary for Regulatory Activities; PT, MedDRA preferred term; Asthma 3 (3.7) 4 (4.8) 2 (2.3) 4 (2.4) SAE, serious adverse event; Back pain 1 (1.2) 3 (3.6) 1 (1.1) 6 (3.6) TEAE, treatment-emergent Oral herpes infection 3 (3.7) 5 (6.0) 2 (2.3) 3 (1.8) adverse event. a Influenza 1 (1.2) 0 5 (5.7) 4 (2.4) Two patients discontinued Bronchitis 1 (1.2) 0 5 (5.7) 3 (1.8) participation in the study because of atopic dermatitis and 1 patient Urticaria 1 (1.2) 2 (2.4) 1 (1.1) 5 (3.0) because of acquired dacryostenosis. Arthralgia 1 (1.2) 0 2 (2.3) 5 (3.0) b One patient discontinued Pharyngitis 0 2 (2.4) 2 (2.3) 3 (1.8) participation in the study because of Diarrhea 3 (3.7) 1 (1.2) 1 (1.1) 4 (2.4) glioblastoma, disorientation, and Pruritus 2 (2.4) 1 (1.2) 2 (2.3) 3 (1.8) brain edema and 1 patient because Sinusitis 2 (2.4) 0 0 6 (3.6) of atopic dermatitis. c Blood creatine phosphokinase increased 2 (2.4) 1 (1.2) 3 (3.4) 1 (0.6) One death occurred during the 36-week treatment period Cough 1 (1.2) 0 1 (1.1) 4 (2.4) (on study day 187) in a 21-year-old Insomnia 1 (1.2) 1 (1.2) 0 4 (2.4) man in the dupilumab every Nasal congestion 0 0 1 (1.1) 4 (2.4) 4 weeks group because of a gunshot Contact dermatitis 2 (2.4) 2 (2.4) 1 (1.1) 1 (0.6) wound (homicide). The event was considered by the investigator to be Gastroenteritis 2 (2.4) 1 (1.2) 0 3 (1.8) not related to study drug use. Ligament sprain 0 2 (2.4) 0 2 (1.2) d The only SAE (MedDRA PT and Toothache 0 0 0 4 (2.4) system organ class) with incidence Abdominal pain 1 (1.2) 2 (2.4) 1 (1.1) 0 of 2% or greater in a treatment Basal cell carcinoma 0 2 (2.4) 1 (1.1) 0 group was basal cell carcinoma, Contusion 1 (1.2) 2 (2.4) 0 1 (0.6) which occurred in 2 patients in the dupilumab every 8 weeks group and Folliculitis 1 (1.2) 3 (3.6) 0 0 no other treatment groups. Hordeolum 1 (1.2) 0 3 (3.4) 0 e Herpes simplex cutaneous Hypertension 2 (2.4) 1 (1.2) 0 2 (1.2) infections with nonoral locations. Proteinuria 1 (1.2) 0 2 (2.3) 1 (0.6) f Includes any PTs that included the Rhinitis 2 (2.4) 1 (1.2) 1 (1.1) 1 (0.6) term conjunctivitis: conjunctivitis, Seasonal allergy 0 2 (2.4) 1 (1.1) 0 conjunctivitis bacterial, conjunctivitis viral, conjunctivitis allergic, and Tonsillitis 0 0 2 (2.3) 1 (0.6) atopic keratoconjunctivitis (for all Urinary tract infection 2 (2.4) 1 (1.2) 0 2 (1.2) conjunctivitis MedDRA PTs, see Viral infection 3 (3.7) 1 (1.2) 0 2 (1.2) eTable 10 in Supplement 2). Colitis 0 0 2 (2.3) 0 g Adjudicated; includes the following Eye allergy 0 0 2 (2.3) 0 MedDRA PTs: tinea versicolor, Ophthalmic herpes infection 2 (2.4) 1 (1.2) 0 1 (0.6) folliculitis, impetigo, skin bacterial infection, skin infection, abscess Musculoskeletal pain 2 (2.4) 1 (1.2) 0 1 (0.6) limb, localized infection, Vulvovaginal candidiasis 2 (2.4) 0 0 2 (1.2) staphylococcal skin infection, Fall 2 (2.4) 0 0 1 (0.6) subcutaneous abscess, and tinea Eye disorders with the PT conjunctivitisf 4 (4.9) 3 (3.6) 4 (4.6) 9 (5.4) cruris (eTable 8 in Supplement 2). h Nonherpetic skin infectionsg 8 (9.8) 5 (6.0) 1 (1.1) 4 (2.4) MedDRA high-level terms (see h eTable 7 in Supplement 2 for Injection-site reactions 7 (8.5) 6 (7.1) 6 (6.9) 18 (10.8) MedDRA PTs). 140 JAMA Dermatology February 2020 Volume 156, Number 2 (Reprinted) jamadermatology.com Downloaded From: https://jamanetwork.com/ on 10/09/2023 Dupilumab Dose Regimens After Successful Treatment in Patients With Atopic Dermatitis Original Investigation Research clinical consequences on efficacy or safety associated with of serious AEs was lower with dupilumab and the number treatment-emergent ADAs in the relatively small number of of clinically important herpetic infections (eczema herpeti- dupilumab-treated patients in SOLO-CONTINUE. cum and herpes zoster) was also lower for dupilumab vs placebo.14,20,29 Despite the waxing-and-waning nature of AD symptoms, continued treatment with dupilumab using the more fre- Discussion quent treatment regimens (weekly or every 2 weeks) ensured All dupilumab dose regimens were generally superior to placebo the most consistent maintenance of treatment effect that is sig- after 36 weeks of treatment in SOLO-CONTINUE. Continuing nificantly better than placebo (and at least numerically better treatment with dupilumab 300 mg weekly or every 2 weeks from than every 4 weeks and every 8 weeks) across all end points SOLO14 resulted in consistently greater maintenance of response— throughout the trial. In post hoc comparisons (eFigure 2B in numerically better than dupilumab every 4 weeks or every Supplement 2), dupilumab weekly did not appear to main- 8 weeks (nominally significant for some end points) and signifi- tain clinical response better than dupilumab every 2 weeks. cantly better than placebo for all end points—across multiple Because the dupilumab weekly or every 2 weeks group had the clinical end points and patient-reported outcomes (ie, pruritus, highest maintenance of clinical response and every 2 weeks symptoms of AD, sleep, pain or discomfort, quality of life, and is the approved dose, every 2 weeks is recommended for long- symptoms of anxiety and depression). For some continuous end term treatment. These findings also indicate that dupilumab points (eg, change in POEM, DLQI, and HADS scores), the dupi- weekly or every 2 weeks for 16 weeks is generally insufficient lumab weekly or every 2 weeks groups had further improvement for achievement of stable remission after cessation of dupil- above levels achieved in SOLO. The less frequent dupilumab dose umab therapy, as demonstrated by patients who received regimens had some dose-dependent reduction in efficacy. By dupilumab weekly or every 2 weeks in SOLO and then re- contrast, some binomial responder end points (eg, EASI-75) had ceived placebo during SOLO-CONTINUE; these patients expe- apparent attrition between baseline and week 36 for all treatment rienced significant diminution in efficacy during the 36- groups. Such attrition is inherent to this type of study, reflecting week SOLO-CONTINUE trial vs those treated with dupilumab combined effects of several factors, including the fluctuating weekly or every 2 weeks throughout SOLO and SOLO- nature of response arising from the relapsing-remitting nature CONTINUE. Similar findings have also been reported for long- of AD; intrinsic variability of the scoring instruments; the SOLO- term biologic treatment of psoriasis.30 Of importance, on the CONTINUE trial design, which started with 100% responders basis of our findings that dupilumab (and thereby IL-4 and IL-13 (ie, responder rates can only decrease); the nature of categori- blockade) can be beneficial in treating other type 2 inflamma- cal scales, which are typically less sensitive than continuous tory diseases (eg, asthma, chronic rhinosinusitis with nasal pol- scales; and the conservative nonresponder imputation methods yps, and eosinophilic esophagitis),6-12 whether continuous used to account for rescue and missing data for categorical end treatment is also required to maintain benefit in these set- points. Thus, both continuous and categorical end points are tings should be evaluated. Most of these studies6-11 involved needed to provide an accurate, complete picture of response patients with advanced and/or chronic disease; it is worth con- maintenance and to discern differences among treatment groups. sidering whether treatment of earlier-stage disease with IL-4 Overall, in dupilumab AD clinical trials, the most notable and IL-13 blockers such as dupilumab may result in long-term treatment-emergent AEs attributable to dupilumab were in- rebalancing of the immune system and termination or pos- jection-site reactions and conjunctivitis. 14-16,19,20 SOLO- sible reversal of the atopic march (ie, the progressive devel- CONTINUE found no new safety signals. Overall treatment- opment of additional type 2 inflammatory conditions, such as emergent AE incidence was higher with placebo than with asthma and/or allergic rhinitis, that often follows develop- dupilumab. Consistent with previous studies,14-16,19,20 skin in- ment of AD in children).13,31 fections and AD exacerbations were more frequent with pla- In general, treatment-emergent ADA incidence inversely cebo than with dupilumab. The patients receiving less fre- correlates with dose and treatment interval, consistent with quent dupilumab doses, particularly every 8 weeks, had greater other biologics.21-23 In SOLO-CONTINUE, treatment-emergent rates of skin infections, flares, and rescue medication use ADA incidences were lowest with dupilumab weekly or every than patients receiving dupilumab weekly or every 2 weeks. 2 weeks and were slightly higher with less frequent treat- Unlike previous studies,14-16,19,20 conjunctivitis incidences ment regimens. Because administration every 4 weeks or ev- were low (<6%) across all treatment groups. One possible ery 8 weeks did not provide an additional safety advantage and reason is that SOLO-CONTINUE patients were all high-level re- was numerically outperformed by administration weekly or sponders, who in general tend to have conjunctivitis less every 2 weeks, we believe that it is prudent to adhere to the frequently.26,27 In an in-depth analysis of conjunctivitis in mul- approved every 2 weeks regimen for adults and avoid less fre- tiple randomized clinical trials of dupilumab in AD, lower base- quent treatment regimens (every 4 weeks or every 8 weeks) line AD severity and higher levels of response were associ- for long-term maintenance of efficacy. ated with lower risk of conjunctivitis.28 In SOLO-CONTINUE, there were numerical imbalances that favored placebo for her- Limitations pes simplex infections and serious AEs in this relatively small One limitation of the study is that the SOLO-CONTINUE study, but this finding is not consistent with the larger overall population was restricted to SOLO patients who achieved experience in dupilumab phase 3 trials, wherein the number stringently defined responses (IGA scores of 0 or 1 or EASI-75). jamadermatology.com (Reprinted) JAMA Dermatology February 2020 Volume 156, Number 2 141 Downloaded From: https://jamanetwork.com/ on 10/09/2023 Research Original Investigation Dupilumab Dose Regimens After Successful Treatment in Patients With Atopic Dermatitis Therefore, caution should be taken when interpreting the re- efficacy achieved in SOLO and was significantly better than pla- sults of this study in the context of the overall population of cebo across all outcomes. Less frequent administration (ev- dupilumab-treated patients with AD. Because of the high ery 4 weeks or every 8 weeks) resulted in reduced efficacy, no disease burden in patients enrolled in SOLO, neither an IGA safety advantages, and numerically higher treatment- score of 0 or 1 nor EASI-75 captures the full extent of clini- emergent ADA incidences, whereas weekly administration had cally meaningful responses. A 50% improvement in EASI no apparent benefit over administration every 2 weeks. The scores, for example, may represent a more relevant treat- approved every 2 weeks treatment regimen is the lowest- ment outcome in this population of patients with moderate to dosage regimen associated with consistent maintenance of severe AD: with a median baseline EASI score of approxi- clinical response in this trial and is therefore recommended mately 30 in SOLO, 50% improvement represents more than for long-term treatment. However, therapeutic decisions are twice the minimal clinically important difference of 6.6 or often influenced by cost-benefit considerations, in which case greater in individuals.14,32 health care practitioners and other stakeholders involved in these decisions should carefully balance potential savings against suboptimal efficacy and long-term risks associated with discontinuous treatment paradigms. This study supports the Conclusions use of 300 mg of dupilumab weekly or every 2 weeks as ef- In SOLO-CONTINUE, monotherapy with dupilumab, 300 mg, fective regimens in adults with moderate to severe AD for long- weekly or every 2 weeks for 36 weeks maintained the clinical term maintenance of treatment response. ARTICLE INFORMATION Eckert, Davis, Rajadhyaksha, Graham, Stahl, Neokera, Pfizer Inc, Regeneron Pharmaceuticals, Accepted for Publication: September 2, 2019. Yancopoulos, Ardeleanu. Inc, Sienna, and Vitae and being a shareholder in Drafting of the manuscript: Thaçi, Bissonnette, Innovaderm Research. Dr Lacour reported receiving Published Online: December 26, 2019. Akinlade, Davis, Rajadhyaksha, Graham. grants and personal fees from Regeneron doi:10.1001/jamadermatol.2019.3617 Critical revision of the manuscript for important Pharmaceuticals, Inc and personal fees from Sanofi Open Access: This is an open access article intellectual content: All authors. during the conduct of the study and grants and distributed under the terms of the CC-BY-NC-ND Statistical analysis: Chan, Chen, Akinlade, Hultsch. personal fees from Novartis, Lilly, Galderma, License. © 2019 Worm M et al. JAMA Dermatology. Obtained funding: Graham, Pirozzi. Boehringer Ingelheim, Celgene, and LEO Pharma Author Affiliations: Division of Allergy and Administrative, technical, or material support: and grants from Janssen, AbbVie, Amgen, and Immunology, Klinik für Dermatologie, Venerologie Lacour, Ferrándiz Foraster, Beck, Chan, Akinlade, Pfizer outside the submitted work. Dr Beissert und Allergologie, Charité–Universitätsmedizin Staudinger, Davis, Graham. reported being an investigator with Regeneron Berlin, Berlin, Germany (Worm); Department of Supervision: Kawashima, Ferrándiz Foraster, Smith, Pharmaceuticals, Inc during the conduct of the Dermatology, Oregon Health & Science University, Beck, Hultsch, Staudinger, Davis, Graham, Pirozzi, study; serving on the member advisory board for Portland (Simpson); Institute and Comprehensive Ardeleanu. AbbVie, Celgene, Novartis, BMS, MSD, Actelion, Center for Inflammation Medicine, University of Conflict of Interest Disclosures: Dr Worm Janssen-Cilag, LEO Pharma, UCB Pharma, Menlo Lübeck, Lübeck, Germany (Thaçi); Innovaderm reported receiving honoraria for consulting and and Therapeutics; and receiving speaker Research, Montreal, Quebec, Canada (Bissonnette); lecture activity from Regeneron Pharmaceuticals, honorarium from AbbVie, Celgene, Novartis, Department of Dermatology, Nice University Inc and Sanofi during the conduct of the study and Actelion, Janssen-Cilag, and La Roche-Posay. Hospital, Nice, France (Lacour); Klinik und Poliklinik outside the submitted work and receiving personal Dr Smith reported receiving departmental funding für Dermatologie, Universitätsklinikum, Technische fees from Regeneron Pharmaceuticals, Inc, Sanofi, for commercially sponsored clinical trials that Universität Dresden, Dresden, Germany (Beissert); ALK-Abello, Allergopharma GmbH & Co, Allergy involved dupilumab from Regeneron Tokyo Women's Medical University, School of Therapeutics Plc, HAL Allergy B.V., LEO Pharma, Pharmaceuticals, Inc, Pfizer, Roche, AbbVie and Medicine, Tokyo, Japan (Kawashima); Servicio de Mylan Germany GmbH, and Novartis outside the Novartis. Dr Beck reported receiving grants from Dermatología, Hospital Universitario Germans Trias submitted work. Dr Simpson reported grants, Regeneron Pharmaceuticals, Inc during the conduct i Pujol, Universidad Autónoma de Barcelona, personal fees, and nonfinancial support from of the study and grants and personal fees from Badalona, Spain (Ferrándiz); St John's Institute of Regeneron Pharmaceuticals, Inc, during the Regeneron Pharmaceuticals, Inc, AbbVie, Pfizer, Dermatology, Guys and St Thomas’ Foundation conduct of the study; grants and personal fees from and LEO Pharma, personal fees from Sanofi, Trust, King’s College, London, United Kingdom AbbVie, Eli Lilly, Galderma, LEO Pharma, Pfizer, Allakos, Arena Pharma, AstraZeneca, Connect (Smith); Department of Dermatology, University of Genentech, MedImmune, and Anacor; grants from Biopharma, Novan, Incyte, Lilly, Novartis, UCB, and Rochester Medical Center, Rochester, New York Kyowa Hakko Kirin, Chugai, Merck, Novartis, Tioga Vimalan outside the submitted work. Dr Chen (Beck); Regeneron Pharmaceuticals, Inc, Vanda, Amgen, and Celgene; and personal fees reported being an employee and shareholder of Tarrytown, New York (Chan, Chen, Akinlade, from Sanofi Genzyme, Boehringer Ingelheim, Regeneron Pharmaceuticals, Inc. Dr Akinlade Gadkari, Davis, Rajadhyaksha, Graham, Stahl, Dermavant, Forte Bio Rx, Menlo Therapeutics, reported being an employee and shareholder of Yancopoulos, Ardeleanu); Sanofi Genzyme, Pierre Fabre Dermo Cosmetique, Valeant, and Regeneron Pharmaceuticals, Inc. Dr Hultsch Cambridge, Massachusetts (Hultsch); Sanofi, Roivant outside the submitted work. Dr Thaçi reported being a full-time employee at Sanofi when Bridgewater, New Jersey (Staudinger, Pirozzi); reported receiving grants and personal fees from the clinical studies were performed. Dr Staudinger Sanofi, Chilly-Mazarin, France (Eckert). Sanofi and Regeneron Pharmaceuticals, Inc during reported being an employee of and holding stock the conduct of the study and grants and personal and/or stock options in Sanofi Genzyme during the Author Contributions: Drs Worm and Chen had conduct of the study and outside the submitted full access to all the data in the study and take fees from AbbVie, Novartis, Pfizer, LEO Pharma, Eli Lilly, Almirall, Janssen-Cilag, Bristol-Myers Squibb, work. Dr Gadkari reported being an employee and responsibility for the integrity of the data and the shareholder of Regeneron Pharmaceuticals, Inc accuracy of the data analysis. and Dignity and grants from Morphosis outside the submitted work. Dr Bissonnette reported serving as during the conduct of the study and outside the Concept and design: Thaçi, Kawashima, Akinlade, submitted work. Dr Eckert reported being an Hultsch, Staudinger, Davis, Graham, Pirozzi, an investigator, consultant, advisory board member, and speaker for and/or receiving employee of and holding stock or stock options in Ardeleanu. Sanofi during the conduct of the study and outside Acquisition, analysis, or interpretation of data: honoraria from Antiobix, Aquinox Pharma, Asana, Astellas, Brickell Biotech, Dermavant, Dermira, the submitted work. Dr Davis reported being an Worm, Simpson, Thaçi, Bissonnette, Lacour, employee and shareholder of Regeneron Beissert, Ferrándiz Foraster, Smith, Beck, Chan, Dignity Sciences, Galderma, Glenmark, GSK-Stiefel, Hoffman-La Roche Ltd., Kiniksa, LEO Pharma, Pharmaceuticals, Inc, Inc during the conduct of the Chen, Akinlade, Hultsch, Staudinger, Gadkari, study and outside the submitted work. 142 JAMA Dermatology February 2020 Volume 156, Number 2 (Reprinted) jamadermatology.com Downloaded From: https://jamanetwork.com/ on 10/09/2023 Dupilumab Dose Regimens After Successful Treatment in Patients With Atopic Dermatitis Original Investigation Research Dr Rajadhyaksha reported being an employee and immunoglobulin genes generate antibodies as a placebo-controlled, randomized phase III clinical shareholder of Regeneron Pharmaceuticals, Inc efficiently as normal mice. Proc Natl Acad Sci U S A. trial (LIBERTY AD CAFÉ). Br J Dermatol. 2018;178 during the conduct of the study. Dr Graham 2014;111(14):5153-5158. doi:10.1073/pnas.1324022111 (5):1083-1101. doi:10.1111/bjd.16156 reported being an employee and shareholder of 6. Dupilumab [package insert]. Tarrytown, NY: 20. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Regeneron Pharmaceuticals, Inc. Dr Pirozzi Regeneron Pharmaceuticals, Inc; 2019. Long-term management of moderate-to-severe atopic reported being an employee of and holding stock or 7. Dupilumab: Summary of Product Characteristics. dermatitis with dupilumab and concomitant topical stock options in Sanofi outside the submitted work. European Medicines Agency. Published 2017. corticosteroids (LIBERTY AD CHRONOS): a 1-year, Dr Stahl reported receiving being and employee https://www.ema.europa.eu/documents/product- randomised,double-blinded,placebo-controlled,phase and shareholder of Regeneron Pharmaceuticals, Inc information/dupixent-epar-product-information_ 3 trial. Lancet. 2017;389(10086):2287-2303. during the conduct of the study. Dr Yancopoulos en.pdf. Accessed August 8, 2019. doi:10.1016/S0140-6736(17)31191-1 reported being an employee, shareholder, and 21. Brezinski EA, Armstrong AW. Off-label biologic 8. WenzelS,CastroM,CorrenJ,etal.Dupilumabefficacy member of the board of directors of Regeneron regimens in psoriasis: a systematic review of andsafetyinadultswithuncontrolledpersistentasthma Pharmaceuticals, Inc during the conduct of the despite use of medium-to-high-dose inhaled efficacy and safety of dose escalation, reduction, study. Dr Ardeleanu reported being an employee corticosteroids plus a long-acting β2 agonist: and interrupted biologic therapy. PloS One. 2012;7 and shareholder of Regeneron Pharmaceuticals, Inc a randomised double-blind placebo-controlled pivotal (4):e33486. doi:10.1371/journal.pone.0033486 during the conduct of the study and outside the phase 2b dose-ranging trial. Lancet. 2016;388(10039): 22. Hsu L, Armstrong AW. Anti-drug antibodies in submitted work. No other disclosures were 31-44. doi:10.1016/S0140-6736(16)30307-5 psoriasis: a critical evaluation of clinical significance reported. and impact on treatment response. Expert Rev Clin 9. Castro M, Corren J, Pavord ID, et al. Dupilumab Funding/Support: This study was funded by Sanofi efficacy and safety in moderate-to-severe Immunol. 2013;9(10):949-958. doi:10.1586/ and Regeneron Pharmaceuticals, Inc. uncontrolled asthma. N Engl J Med. 2018;378(26): 1744666X.2013.836060 2486-2496. doi:10.1056/NEJMoa1804092 23. Maini RN, Breedveld FC, Kalden JR, et al. Role of the Funder/Sponsor: Data were collected 10. Rabe KF, Nair P, Brusselle G, et al. Efficacy and Therapeutic efficacy of multiple intravenous by the investigators and analyzed by the sponsors. safety of dupilumab in glucocorticoid-dependent infusions of anti-tumor necrosis factor alpha All authors interpreted the data, assisted in drafting severe asthma. N Engl J Med. 2018;378(26): monoclonal antibody combined with low-dose and critically revising the manuscript, provided final weekly methotrexate in rheumatoid arthritis. approval, and take responsibility for the accuracy, 2475-2485. doi:10.1056/NEJMoa1804093 Arthritis Rheum. 1998;41(9):1552-1563. doi:10. completeness, and adherence to the protocol of 11. Bachert C, Mannent L, Naclerio RM, et al. Effect 1002/1529-0131(199809)41:9<1552::AID-ART5>3. the data and analyses. All investigators had of subcutaneous dupilumab on nasal polyp burden 0.CO;2-W confidentiality agreements with the study in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA. 2016; 24. World Medical Association. World Medical sponsors. Manuscript drafts were prepared with 315(5):469-479. doi:10.1001/jama.2015.19330 Association Declaration of Helsinki: ethical the assistance of medical writers, funded by the principles for medical research involving human sponsors. 12. Hirano I, Dellon ES, Hamilton JD, et al. subjects. JAMA. 2013;310(20):2191-2194. Data Sharing Statement: See Supplement 3. Dupilumab efficacy in adults with active doi:10.1001/jama.2013.281053 eosinophilic esophagitis: a randomized, Additional Contributions: Medical writing and placebo-controlled phase 2 trial. Gastroenterology. 25. Kovalenko P, DiCioccio AT, Davis JD, et al. editorial assistance was provided by Vicki Schwartz, doi:10.1053/j.gastro.2019.09.042 Exploratory population PK analysis of dupilumab, a PhD, Manuela Pigors, PhD, and Juliet Bell, PhD, fully human monoclonal antibody against IL-4Rα, in 13. Gandhi NA, Pirozzi G, Graham NMH. atopic dermatitis patients and normal volunteers. Excerpta Medica, funded by Sanofi Genzyme and Commonality of the IL-4/IL-13 pathway in atopic Regeneron Pharmaceuticals, Inc. Miriam Kore, CPT Pharmacometrics Syst Pharmacol. 2016;5(11): diseases. Expert Rev Clin Immunol. 2017;13(5): 617-624. doi:10.1002/psp4.12136 PharmD, directed and provided oversight and 425-437. doi:10.1080/1744666X.2017.1298443 critical feedback to clinical operations for the 26. Uchio E, Miyakawa K, Ikezawa Z, Ohno S. Systemic 14. Simpson EL, Bieber T, Guttman-Yassky E, et al; and local immunological features of atopic dermatitis dupilumab program, Lillian Brener, MSc, and Mbole SOLO 1 and SOLO 2 Investigators. Two phase 3 trials patients with ocular complications. Br J Ophthalmol. Ekaney, MSc and MSc, coordinated the clinical of dupilumab versus placebo in atopic dermatitis. 1998;82(1):82-87. doi:10.1136/bjo.82.1.82 operations for the dupilumab program, and Linda N Engl J Med. 2016;375(24):2335-2348. doi:10. Williams, RPh, provided organizational and editorial 1056/NEJMoa1610020 27. Thyssen JP, Toft PB, Halling-Overgaard AS, assistance during publication development and Gislason GH, Skov L, Egeberg A. Incidence, 15. Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab prevalence, and risk of selected ocular disease in critically reviewed the manuscript for clarity and treatment in adults with moderate-to-severe atopic adults with atopic dermatitis. J Am Acad Dermatol. consistency, at Regeneron Pharmaceuticals, Inc. dermatitis. N Engl J Med. 2014;371(2):130-139. 2017;77(2):280-286.e1. doi:10.1016/j.jaad.2017.03.003 Dianne Barry, PhD, and El-Bdaoui Haddad, PhD, doi:10.1056/NEJMoa1314768 Sanofi, provided organizational and editorial 28. Akinlade B, Guttman-Yassky E, de Bruin-Weller M, assistance during publication development and 16. Thaçi D, Simpson EL, Beck LA, et al. Efficacy et al. Conjunctivitis in dupilumab clinical trials. Br J critically reviewed the manuscript for clarity and and safety of dupilumab in adults with Dermatol. 2019;181(3):459-473. doi:10.1111/bjd.17869 moderate-to-severe atopic dermatitis inadequately consistency. All contributors were compensated 29. Eichenfield LF, Bieber T, Beck LA, et al. controlled by topical treatments: a randomised, through their company salaries. We thank the Infections in dupilumab clinical trials in atopic placebo-controlled, dose-ranging phase 2b trial. patients and their families for their participation in dermatitis: a comprehensive pooled analysis. Am J Lancet. 2016;387(10013):40-52. doi:10.1016/S0140- this study, our colleagues for their support. 6736(15)00388-8 Clin Dermatol. 2019;20(3):443-456. doi:10.1007/ s40257-019-00445-7 REFERENCES 17. Simpson EL, Gadkari A, Worm M, et al. Dupilumab therapy provides clinically meaningful improvement 30. Dávila-Seijo P, Dauden E, Carretero G, et al; 1. Paller AS, Kabashima K, Bieber T. Therapeutic in patient-reported outcomes (PROs): a phase IIb, BIOBADADERM Study Group. Survival of classic and pipeline for atopic dermatitis: end of the drought? randomized, placebo-controlled, clinical trial in adult biological systemic drugs in psoriasis: results of the J Allergy Clin Immunol. 2017;140(3):633-643. patients with moderate to severe atopic dermatitis BIOBADADERM registry and critical analysis. J Eur doi:10.1016/j.jaci.2017.07.006 (AD). J Am Acad Dermatol. 2016;75(3):506-515. Acad Dermatol Venereol. 2016;30(11):1942-1950. doi:10.1016/j.jaad.2016.04.054 doi:10.1111/jdv.13682 2. Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387(10023):1109-1122. doi:10.1016/S0140-6736 18. Tsianakas A, Luger TA, Radin A. Dupilumab 31. Paller AS, Spergel JM, Mina-Osorio P, Irvine AD. (15)00149-X treatment improves quality of life in adult patients The atopic march and atopic multimorbidity: Many with moderate-to-severe atopic dermatitis: results trajectories, many pathways. J Allergy Clin Immunol. 3. Bieber T. Atopic dermatitis. N Engl J Med. 2008; from a randomized, placebo-controlled clinical trial. 2019;143(1):46-55. doi:10.1016/j.jaci.2018.11.006 358(14):1483-1494. doi:10.1056/NEJMra074081 Br J Dermatol. 2018;178(2):406-414. doi:10.1111/ 32. Schram ME, Spuls PI, Leeflang MMG, 4. Macdonald LE, Karow M, Stevens S, et al. Precise bjd.15905 Lindeboom R, Bos JD, Schmitt J. EASI, (objective) and in situ genetic humanization of 6 Mb of mouse 19. De Bruin-Weller M, Thaçi D, Smith CH, et al. SCORAD and POEM for atopic eczema: immunoglobulin genes. Proc Natl Acad Sci U S A. Dupilumab with concomitant topical corticosteroid responsiveness and minimal clinically important 2014;111(14):5147-5152. doi:10.1073/pnas.1323896111 treatment in adults with atopic dermatitis with an difference. Allergy. 2012;67(1):99-106. doi:10.1111/j. 5. Murphy AJ, Macdonald LE, Stevens S, et al. 1398-9995.2011.02719.x inadequate response or intolerance to ciclosporin A Mice with megabase humanization of their or when this treatment is medically inadvisable: jamadermatology.com (Reprinted) JAMA Dermatology February 2020 Volume 156, Number 2 143 Downloaded From: https://jamanetwork.com/ on 10/09/2023