TY - JOUR
T1 - Efficacy and Safety of Multiple Dupilumab Dose Regimens after Initial Successful Treatment in Patients with Atopic Dermatitis
T2 - A Randomized Clinical Trial
AU - Worm, Margitta
AU - Simpson, Eric L.
AU - Thaçi, Diamant
AU - Bissonnette, Robert
AU - Lacour, Jean Philippe
AU - Beissert, Stefan
AU - Kawashima, Makoto
AU - Ferrándiz, Carlos
AU - Smith, Catherine H.
AU - Beck, Lisa A.
AU - Chan, Kuo Chen
AU - Chen, Zhen
AU - Akinlade, Bolanle
AU - Hultsch, Thomas
AU - Staudinger, Heribert
AU - Gadkari, Abhijit
AU - Eckert, Laurent
AU - Davis, John D.
AU - Rajadhyaksha, Manoj
AU - Graham, Neil M.H.
AU - Pirozzi, Gianluca
AU - Stahl, Neil
AU - Yancopoulos, George D.
AU - Ardeleanu, Marius
N1 - Funding Information:
reported receiving honoraria for consulting and lecture activity from Regeneron Pharmaceuticals, Inc and Sanofi during the conduct of the study and outside the submitted work and receiving personal fees from Regeneron Pharmaceuticals, Inc, Sanofi, ALK-Abello, Allergopharma GmbH & Co, Allergy Therapeutics Plc, HAL Allergy B.V., LEO Pharma, Mylan Germany GmbH, and Novartis outside the submitted work. Dr Simpson reported grants, personal fees, and nonfinancial support from Regeneron Pharmaceuticals, Inc, during the conduct of the study; grants and personal fees from AbbVie, Eli Lilly, Galderma, LEO Pharma, Pfizer, Genentech, MedImmune, and Anacor; grants from Kyowa Hakko Kirin, Chugai, Merck, Novartis, Tioga Vanda, Amgen, and Celgene; and personal fees from Sanofi Genzyme, Boehringer Ingelheim, Dermavant, Forte Bio Rx, Menlo Therapeutics, Pierre Fabre Dermo Cosmetique, Valeant, and Roivant outside the submitted work. Dr Thaçi reported receiving grants and personal fees from Sanofi and Regeneron Pharmaceuticals, Inc during the conduct of the study and grants and personal fees from AbbVie, Novartis, Pfizer, LEO Pharma, Eli Lilly, Almirall, Janssen-Cilag, Bristol-Myers Squibb, and Dignity and grants from Morphosis outside the submitted work. Dr Bissonnette reported serving as an investigator, consultant, advisory board member, and speaker for and/or receiving honoraria from Antiobix, Aquinox Pharma, Asana, Astellas, Brickell Biotech, Dermavant, Dermira, Dignity Sciences, Galderma, Glenmark, GSK-Stiefel, Hoffman-La Roche Ltd., Kiniksa, LEO Pharma, Neokera, Pfizer Inc, Regeneron Pharmaceuticals, Inc, Sienna, and Vitae and being a shareholder in Innovaderm Research. Dr Lacour reported receiving grants and personal fees from Regeneron Pharmaceuticals, Inc and personal fees from Sanofi during the conduct of the study and grants and personal fees from Novartis, Lilly, Galderma, Boehringer Ingelheim, Celgene, and LEO Pharma and grants from Janssen, AbbVie, Amgen, and Pfizer outside the submitted work. Dr Beissert reported being an investigator with Regeneron Pharmaceuticals, Inc during the conduct of the study; serving on the member advisory board for AbbVie, Celgene, Novartis, BMS, MSD, Actelion, Janssen-Cilag, LEO Pharma, UCB Pharma, Menlo and Therapeutics; and receiving speaker honorarium from AbbVie, Celgene, Novartis, Actelion, Janssen-Cilag, and La Roche-Posay. Dr Smith reported receiving departmental funding for commercially sponsored clinical trials that involved dupilumab from Regeneron Pharmaceuticals, Inc, Pfizer, Roche, AbbVie and Novartis. Dr Beck reported receiving grants from Regeneron Pharmaceuticals, Inc during the conduct of the study and grants and personal fees from Regeneron Pharmaceuticals, Inc, AbbVie, Pfizer, and LEO Pharma, personal fees from Sanofi, Allakos, Arena Pharma, AstraZeneca, Connect Biopharma, Novan, Incyte, Lilly, Novartis, UCB, and Vimalan outside the submitted work. Dr Chen reported being an employee and shareholder of Regeneron Pharmaceuticals, Inc. Dr Akinlade reported being an employee and shareholder of Regeneron Pharmaceuticals, Inc. Dr Hultsch reported being a full-time employee at Sanofi when the clinical studies were performed. Dr Staudinger reported being an employee of and holding stock and/or stock options in Sanofi Genzyme during the conduct of the study and outside the submitted work. Dr Gadkari reported being an employee and shareholder of Regeneron Pharmaceuticals, Inc during the conduct of the study and outside the submitted work. Dr Eckert reported being an employee of and holding stock or stock options in Sanofi during the conduct of the study and outside the submitted work. Dr Davis reported being an employee and shareholder of Regeneron Pharmaceuticals, Inc, Inc during the conduct of the study and outside the submitted work.
Funding Information:
Additional Contributions: Medical writing and editorial assistance was provided by Vicki Schwartz, PhD, Manuela Pigors, PhD, and Juliet Bell, PhD, Excerpta Medica, funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Miriam Kore, PharmD, directed and provided oversight and critical feedback to clinical operations for the dupilumab program, Lillian Brener, MSc, and Mbole Ekaney, MSc and MSc, coordinated the clinical operations for the dupilumab program, and Linda Williams, RPh, provided organizational and editorial assistance during publication development and critically reviewed the manuscript for clarity and consistency, at Regeneron Pharmaceuticals, Inc. Dianne Barry, PhD, and El-Bdaoui Haddad, PhD, Sanofi, provided organizational and editorial assistance during publication development and critically reviewed the manuscript for clarity and consistency. All contributors were compensated through their company salaries. We thank the patients and their families for their participation in this study, our colleagues for their support.
Funding Information:
Funding/Support: This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc.
Publisher Copyright:
© 2020 American Medical Association. All rights reserved.
PY - 2020/2
Y1 - 2020/2
N2 - Importance: The dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, 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 dosage intervals and placebo resulted in a diminution of response for both continuous and categorical end points. No new safety signals were observed. The approved regimen of 300 mg of dupilumab every 2 weeks is recommended for long-Term treatment. Trial Registration: ClinicalTrials.gov identifier: NCT02395133.
AB - Importance: The dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, 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 dosage intervals and placebo resulted in a diminution of response for both continuous and categorical end points. No new safety signals were observed. The approved regimen of 300 mg of dupilumab every 2 weeks is recommended for long-Term treatment. Trial Registration: ClinicalTrials.gov identifier: NCT02395133.
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U2 - 10.1001/jamadermatol.2019.3617
DO - 10.1001/jamadermatol.2019.3617
M3 - Article
C2 - 31876900
AN - SCOPUS:85077217391
VL - 156
SP - 131
EP - 143
JO - A. M. A. archives of dermatology and syphilology
JF - A. M. A. archives of dermatology and syphilology
SN - 2168-6068
IS - 2
ER -