1. Nemolizumab with concomitant topical therapy in adolescents and adults with moderate-to-severe atopic dermatitis (ARCADIA 1 and ARCADIA 2): results from two replicate, double-blind, randomised controlled phase 3 trials.
- Author
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Silverberg JI, Wollenberg A, Reich A, Thaçi D, Legat FJ, Papp KA, Stein Gold L, Bouaziz JD, Pink AE, Carrascosa JM, Rewerska B, Szepietowski JC, Krasowska D, Havlíčková B, Kalowska M, Magnolo N, Pauser S, Nami N, Sauder MB, Jain V, Padlewska K, Cheong SY, Fleuranceau Morel P, Ulianov L, and Piketty C
- Subjects
- Adolescent, Adult, Female, Humans, Male, Middle Aged, Young Adult, Administration, Topical, Adrenal Cortex Hormones administration & dosage, Adrenal Cortex Hormones therapeutic use, Calcineurin Inhibitors administration & dosage, Calcineurin Inhibitors therapeutic use, Double-Blind Method, Drug Therapy, Combination, Severity of Illness Index, Treatment Outcome, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized therapeutic use, Dermatitis, Atopic drug therapy, Pruritus drug therapy
- Abstract
Background: Nemolizumab, an interleukin (IL)-31 receptor subunit α antagonist, inhibits the IL-31 pathway of itch and skin inflammation in atopic dermatitis. Two international phase 3 studies were done to assess the efficacy and safety of nemolizumab in atopic dermatitis. In this Article we report results for the 16-week initial treatment period of both trials., Methods: ARCADIA 1 and ARCADIA 2 were identical 48-week randomised, double-blind, placebo-controlled phase 3 trials in adult and adolescent participants (aged ≥12 years) with moderate-to-severe atopic dermatitis, associated pruritus, and inadequate response to topical steroids. Participants were enrolled from 281 clinics, hospitals, and academic centres in 22 countries across both trials, and were randomly assigned (2:1) to receive nemolizumab 30 mg subcutaneously (baseline loading dose 60 mg) or matching placebo once every 4 weeks with background topical corticosteroids (TCS) with or without topical calcineurin inhibitors (TCI; ie, TCS-TCI background treatment). Randomisation was done via interactive response technology and stratified by baseline disease and pruritus severity. Study staff and participants were masked throughout the study, with outcome assessors masked until database lock. Coprimary endpoints at week 16 post-baseline were Investigator's Global Assessment (IGA) success (score of 0 [clear skin] or 1 [almost clear skin] with a ≥2-point improvement from baseline) and at least 75% improvement in Eczema Area and Severity Index score from baseline (EASI-75 response). Outcome rates were compared between groups with the Cochran-Mantel-Haenszel test adjusting for randomisation strata. The key secondary endpoints were the proportion of participants with Peak Pruritus Numerical Rating Scale (PP-NRS) score improvement of at least 4 points at weeks 1, 2, 4, and 16; PP-NRS score below 2 at weeks 4 and 16; Sleep Disturbance Numerical Rating Scale score improvement of at least 4 points at week 16; EASI-75 response plus PP-NRS score improvement of at least 4 points at week 16; and IGA success plus PP-NRS score improvement of at least 4 points at week 16. Efficacy analyses were done on an intention-to-treat basis; safety analyses included all participants who received one dose of nemolizumab or placebo. Both studies are completed (ClinicalTrials.gov: ARCADIA 1, NCT03985943 and ARCADIA 2, NCT03989349)., Findings: Between Aug 9, 2019, and Nov 2, 2022, 1728 participants were enrolled across both trials: 1142 were allocated to nemolizumab plus TCS-TCI (620 in ARCADIA 1 and 522 in ARCADIA 2) and 586 to placebo plus TCS-TCI (321 in ARCADIA 1 and 265 in ARCADIA 2). ARCADIA 1 included 500 (53%) male participants and 441 (47%) female participants, and ARCADIA 2 included 381 (48%) male participants and 406 (52%) female participants. Mean age ranged from 33·3 (SD 15·6) years to 35·2 (17·0) years across the treatment groups. Both trials met the coprimary endpoints; at week 16, a greater proportion of participants receiving nemolizumab plus TCS-TCI versus placebo plus TCS-TCI had IGA success (ARCADIA 1: 221 [36%] of 620 vs 79 [25%] of 321, adjusted percentage difference 11·5% [97·5% CI 4·7-18·3], p=0·0003; ARCADIA 2: 197 [38%] of 522 vs 69 [26%] of 265, adjusted difference 12·2% [4·6-19·8], p=0·0006) and an EASI-75 response (ARCADIA 1: 270 [44%] vs 93 [29%], adjusted difference 14·9% [7·8-22·0], p<0·0001; ARCADIA 2: 220 [42%] vs 80 [30%], adjusted difference 12·5% [4·6-20·3], p=0·0006). Significant benefits were observed with nemolizumab for all key secondary endpoints including improvement in itch, as early as week 1, and sleep improvement by week 16. The safety profile was similar between nemolizumab plus TCS-TCI and placebo plus TCS-TCI. In the safety sets, 306 (50%) of 616 participants (ARCADIA 1) and 215 (41%) of 519 participants (ARCADIA 2) who received nemolizumab plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in six [1%] and 13 [3%], respectively); and 146 (45%) of 321 (ARCADIA 1) and 117 (44%) of 263 (ARCADIA 2) who received placebo plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in four [1%] and three [1%], respectively). Ten serious treatment-emergent adverse events possibly related to nemolizumab were reported in five (1%) participants in ARCADIA 2. No deaths occurred., Interpretation: Nemolizumab plus TCS-TCI was efficacious and showed statistically and clinically significant improvements in inflammation and itch in adults and adolescents with moderate-to-severe atopic dermatitis. Nemolizumab might offer a valuable extension of current therapies if approved., Funding: Galderma., Competing Interests: Declaration of interests JIS has received honoraria as a consultant or advisory board member for AbbVie, Aldena, Amgen, AOBiome, Arcutis, Arena, Asana, Aslan, Attovia, BiomX, Biosion, Bodewell, Boehringer-Ingelheim, Bristol Myers Squibb, Cara, Castle Biosciences, Celgene, Connect Biopharma, Corevitas, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Kiniksa, LEO Pharma, MyOr Diagnostics, Nektar, Novartis, Optum, Pfizer, RAPT Therapeutics, Recludix, Regeneron, Sanofi-Genzyme, Shaperon, Target RWE, and Union Therapeutics; and his institution has received grants from Galderma, Incyte, and Pfizer. AW has received grants or contracts from AbbVie, Aileens, Almirall, Amgen, Beiersdorf, Bioderma, BioProject, Bristol Myers Squibb, Chugai, Galapagos, Galderma, Glenmark, GSK, Hans Karrer, Janssen, Maruho, MedImmune, MSD, Mylan, Novartis, Pfizer, Pierre Fabre, Regeneron, Sandoz, Sanofi-Aventis, and UCB; payment or honoraria from AbbVie, Aileens, Almirall, Amgen, Beiersdorf, Bioderma, Galderma, Glenmark, LEO Pharma, L'Oreal, Maruho, Novartis, Pfizer, Pierre Fabre, Regeneron, Sanofi-Aventis, and UCB; and support for attending meetings or travel from AbbVie, LEO Pharma, and Pierre Fabre. He has also participated on a data safety monitoring board or advisory board for Alentis Therapeutics and BioProject; served as Secretary and Executive Board member of the International Society of Atopic Dermatitis and Vice Chair of the European Task Force on Atopic Dermatitis; and received medical writing support for clinical trial reports from AbbVie, Almirall, Galderma, LEO Pharma, Eli Lilly, L'Oreal, Merck, Novartis, Pfizer, Pierre Fabre, Regeneron, Sanofi-Aventis, and UCB. AR has served as an investigator or participated in advisory boards for AbbVie, Alvotech, Amgen, AnaptysBio, Biotherapy, Bristol Myers Squibb, Celgene, Celltrion, Dermira, Galderma, Inflarx, Janssen, Kiniksa, Kymab, LEO Pharma, Novartis, Pierre Fabre, Pfizer, Trevi Therapeutics, and UCB; and has received honoraria from Chema Rzeszow, Eli Lilly, LEO Pharma, Novartis, Sandoz, and Takeda. DT is a lecturer or consultant for AbbVie, Almirall, Amgen, Boehringer-Ingelheim, Bristol Myers Squibb, Celltrion, Galderma, Janssen-Cilag, Kyowa Kirin, LEO Pharma, Eli Lilly, Novartis, Regeneron, Sandoz, Target RWE, and UCB; and has received grants from AbbVie, LEO Pharma, and Novartis (paid to his institution). FJL has received honoraria as a consultant, advisory board member, or speaker for Almirall, Celgene, Eli Lilly, Galderma, Menlo Therapeutics, Novartis, Pelpharma, Pfizer, Sanofi, Trevi Therapeutics, and Vifor Pharma; has received support for participating in scientific meetings from Amgen, AbbVie, Celgene, Eli Lilly, Galderma, Janssen-Cilag, LEO Pharma, Novartis, Pelpharma, Pfizer, and Sanofi; and has served as the principal investigator in clinical studies for Amgen, Almirall, DS Biopharma, Eli Lilly, Galderma, Incyte, Kiniksa, Menlo Therapeutics, LEO Pharma, Pfizer, and Trevi Therapeutics. KAP has served as a consultant, scientific advisor, investigator, scientific officer, or speaker for Pfizer, AbbVie, Acelyrin, Akros, Alumis, Amgen, Arcutis, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Can-Fite BioPharma, Celltrion, Concert Pharmaceuticals, CorEvitas, Dermavant, Dermira, Dice Pharmaceuticals, Dice Therapeutics, Eli Lilly, Evelo Biosciences, Forbion, Galderma, Horizon Therapeutics, Incyte, Janssen, Kymab, Kyowa Hakka Kirin, LEO Pharma, Meiji Seika Pharma, Mitsubishi Pharma, Nimbus Therapeutics, Novartis, Reistone, Sandoz, Genzyme (subsidiary of Sanofi Aventis), Sun Pharma, Takeda, Tarsus Pharmaceuticals, UCB, and Zai Lab. LSG has received grants, contracts, consulting fees, payment, or honoraria for scientific or educational work from Galderma, AbbVie, Pfizer, Incyte, Arcutis, LEO Pharma, Dermavan, and Eli Lilly; and is an investigator for Allergan and Galderma. J-DB has received speaker fees from AbbVie, AstraZeneca, Galderma, Janssen, LEO Pharma, Eli Lilly, Novartis, Pfizer, and Sanofi, consulting fees from Eli Lilly and Neovacs, a research grant from Astra Zeneca, Sanofi, and Therakos, and travel grants from AbbVie, Janssen, and Sanofi; and has served on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, Galderma, Janssen, LEO Pharma, Eli Lilly, Novartis, Pfizer, and Sanofi. AEP has received grants or contracts from Amgen, Medac Pharma, and Pfizer, acted as an investigator, speaker, and advisor for or received educational support or research funding from Sanofi, Eli Lilly, Pfizer, LEO Pharma, AbbVie, Galderma, Novartis, Janssen, Boehringer Ingelheim, Bristol Myers Squibb, UCB, Amgen, Almirall, Artax Biopharma, and Medac Pharma. JMC has received honoraria as a consultant, advisory board member, or speaker, or has served as the principal investigator in clinical studies, for Almirall, Celgene, Eli Lilly, Galderma, Novartis, Pfizer, Sanofi, Amgen, AbbVie, Janssen-Cilag, LEO Pharma, UCB, Boehringer Ingelheim, Bristol Myers Squibb, and Sandoz. BR has served as an investigator for Galderma. JCS has received consulting fees or honoraria from Galderma, AbbVie, Almirall, Eli Lilly, Janssen, LEO Pharma, Novartis, Pierre-Fabre, Pfizer, Sanofi-Genzyme, Trevi, and UCB; has served as President of the Polish Dermatological Society; and has served as an investigator for AbbVie, Amgen, Bristol Myers Squibb, Galapagos, Galderma, Incyte, InflaRx, Janssen, Kliniksa, Kymab, Menlo Therapeutics, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Trevi Therapeutics, and UCB Pharma. DK has served as an investigator for Galderma. BH is an investigator for Galderma. MK has served as an investigator for Galderma. NM is a consultant or speaker for AbbVie, Almirall, Apogee, Boehringer Ingelheim, Bristol Myers Squibb, Dr Wolff, Eli Lilly, La Roche-Posay, LEO Pharma, Novartis, Pfizer, Sanofi, and UCB; and has served as an investigator for Galderma. SP has served as an investigator for Galderma. NN has served as an investigator for Galderma. MBS has received honoraria as a consultant, advisory board member, or speaker from Amgen, AbbVie, Arcutis, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Galderma, Incyte Pharma, Janssen, L'Oréal Canada, LEO Pharma, Merck, Novartis, Pfizer, Sanofi, Sun Pharmaceuticals, and UCB Canada; support for attending meetings or travel from Galderma, Janssen, and Pfizer; has served as the principal investigator in clinical studies for Alumis, Amgen, AbbVie, Bristol Myers Squibb, Dermavant, Evelo, Galderma, Inycte, Janssen, LEO Pharma, Meiji Pharma, Moberg Pharma, Novartis, Pfizer, Reistone Biopharma, Sanofi, and Ventyx Biosciences; and is Treasurer for the Canadian Dermatology Association, Treasurer for the Ontario Medical Association section of Dermatology, and Secretary for the Dermatology Association of Ontario. VJ has consulted or advised for or received research funding for speakers bureaus from Pediapharm, Aralez, Sanofi, Regeneron, Bausch, Novartis, Medexus, ALK-Abelló, Celgene, LEO Pharma, Mylan, Amgen, AbbVie, Pfizer, AstraZeneca, GSK, Covis Pharma, and Incyte; and has received research grants from Eli Lilly, Pfizer, Galderma, AstraZeneca, Arcutis, Sanofi, LEO Pharma, Amgen, AbbVie, GSK, Allakos, Novartis, Janssen, and Kymab. KP has served as an investigator for Galderma. SYC, PFM, LU, and CP are employees of Galderma., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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