Tralokinumab Plus Topical Corticosteroids as Needed Provides Progressive and Sustained Efficacy in Adults with Moderate-to-Severe Atopic Dermatitis Over a 32-Week Period: An ECZTRA 3 Post Hoc Analysis

Abstract

Background: The efficacy and safety of tralokinumab, a fully human monoclonal antibody that specifically neutralizes interleukin-13, plus topical corticosteroids (TCS) as needed were evaluated over 32 weeks in the phase III ECZTRA 3 trial. Significantly more tralokinumab- versus placebo-treated patients achieved the primary endpoints of Investigator's Global Assessment (IGA) score of 0/1 and 75% improvement in Eczema Area and Severity Index (EASI-75) and all confirmatory endpoints at Week 16.

Objective: This post hoc analysis investigated the impact of tralokinumab plus TCS on atopic dermatitis (AD) severity, symptoms, and health-related quality of life (QoL) over the entire 32-week treatment period of ECZTRA 3, including all patients initiated on tralokinumab irrespective of the response achieved at Week 16.

Methods: Patients were randomized 2:1 to receive subcutaneous tralokinumab 300 mg or placebo every 2 weeks (q2w) with TCS as needed for an initial 16 weeks. At Week 16, patients who achieved the clinical response criteria (IGA 0/1 and/or EASI-75) with tralokinumab were re-randomized 1:1 to tralokinumab q2w or every 4 weeks (q4w), with TCS as needed, for another 16 weeks. Patients not achieving the clinical response criteria with tralokinumab received tralokinumab q2w plus TCS from Week 16. All patients randomized to tralokinumab in the initial treatment period were pooled for this analysis, irrespective of response at Week 16 or dosing regimen beyond Week 16.

Results: Continued tralokinumab (q2w, N = 164; q4w, N = 69) plus TCS treatment provided progressive improvements from Week 16 onwards in AD signs, with 70.2% (177/252) of patients achieving EASI-75 and 50.4% (127/252) achieving EASI-90 at Week 32. Improvements in patient-reported outcomes were observed within the first few weeks of tralokinumab q2w plus TCS treatment and were sustained throughout the 32-week period. At Week 32, patients initiated on tralokinumab q2w plus TCS achieved a relative improvement versus baseline of 70.8% (standard error (SE), 2.4) in eczema-related sleep interference numeric rating scale (NRS) and 66.8% (SE, 3.1) in Dermatology Life Quality Index (DLQI). Mean TCS use during Weeks 16-32 ranged from 9.2 to 13.6 g (SE, 1.2-2.0) q2w. Most patients (89.9% (222/247)) initiated on tralokinumab q2w plus TCS achieved a meaningful improvement in at least one of the three disease domains, including AD signs (EASI-50), symptoms (pruritus NRS improvement ≥ 3), and QoL (DLQI improvement ≥ 4) at Week 16. Of patients initiated on tralokinumab q2w plus TCS, 53.4% (132/247) achieved a clinically meaningful improvement in all three domains at Week 16 (vs. placebo, 28.5% (35/123); p < 0.001).

Conclusions: Continued tralokinumab treatment plus TCS as needed provides progressive and sustained improvements in AD signs, symptoms, and health-related QoL over 32 weeks.

Clinical trial registration: NCT03363854; study start date: 22 February 2018; primary completion date: 8 March 2019; study completion date: 26 September 2019.

Conflict of interest statement

JIS reports personal fees from AbbVie, Afyx, AnaptysBio, Aobiome, Arena, Asana, Aslan, BioMX, Bluefin, Bodewell, Boehringer Ingelheim, Celgene, Connect Biopharma, Dermavant, Dermira, DS Biopharma, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Kiniksa, Kymab, LEO Pharma, Luna, Menlo, Novartis, Pfizer, RAPT, Realm, Regeneron, and Sanofi Genzyme, grants and/or personal fees from Galderma, GlaxoSmithKline and Pfizer, and stock/stock options from AbbVie, Arcutis, and Eli Lilly outside the submitted work. DNA has been an investigator, consultant, advisory board member, speaker for and/or received honoraria from AbbVie, Actelion, Amgen, Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Stiefel, Sun Pharma, UCB, and Valeant. MZ is a consultant, investigator, and/or speaker for AbbVie, All Free Care/Sun, Anaptys Bio, Arcutis, Bausch Health, Cara, Concert, Dermavant, Edessa Biotech, Eli Lilly and Company, EPI Health, Fit Bit, Galderma, Genentech, Incyte, LEO Pharma, Level-Ex, L’Oréal, LUUM, Menlo, Novartis, Oculus, Ortho Derm, Peloton, Pfizer, Regeneron, Sanofi, Trevi, and UCB, is a part owner of AsepticMD, and has worked with LEO Pharma and other companies with atopic dermatitis drugs that have received FDA approval or are expected to receive FDA approval in the next year. SK reports consulting for AbbVie, Amgen Inc, Aralez Pharmaceuticals Canada Inc, Bausch Health, Celgene Corporation, Eli Lilly and Company, Galderma SA, Johnson & Johnson, La Roche-Posay, Novartis International AG, Pfizer Inc, Sanofi Genzyme, and UCB; conducting clinical trials that have received funding from AbbVie, Amgen Inc, Bausch Health, Corbus Pharmaceuticals Holdings Inc, Eli Lilly and Company, Janssen Pharmaceuticals, LEO Pharma, Merck & Co, Novartis, Pfizer Inc, and UCB; receiving grant funding from LEO Pharma A/S and Novartis International AG; and serving as co-chair of the Canadian PSOLAR steering committee; and has received salary support from the Michael Smith Foundation for Health Research. JG is a consultant and/or speaker for and/or receives honoraria from AbbVie, Almirall, Eli Lilly, LEO Pharma, Pfizer, Regeneron, and Sanofi Genzyme, and has provided expert testimony to AbbVie and LEO Pharma. AP reports acting as an investigator, speaker, or advisor for AbbVie, Almirall-Hermal, Amgen, Biogen Idec, BioNTec, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, GlaxoSmithKline, Hexal, Janssen, LEO Pharma, MC2, Medac, Merck Serono, Mitsubishi, MSD, Novartis, Pascoe, Pfizer, Regeneron, Roche, Sandoz Biopharmaceuticals, Sanofi Genzyme, Schering-Plough, Tigercat Pharma, and UCB Pharma. AEP has acted as an advisor/speaker/investigator for or received educational support from AbbVie, Almirall, Amgen, Anaptys Bio, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Galderma, Janssen, La Roche-Posay, LEO Pharma, Lilly, Novartis, Pfizer, Sanofi, and UCB. AC has served as a scientific adviser and/or clinical study investigator for AbbVie, Almirall, Fresenius Kabi, Janssen, LEO Pharma, Lilly, Novartis, Sanofi Genzyme, and UCB Pharma, and as paid speaker for AbbVie, Almirall, Janssen, LEO Pharma, Lilly, Novartis, and Sanofi Genzyme. SB is an investigator or speaker for AbbVie, Almirall, Chiesi, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi-Genzyme, UCB Pharma. TM and AMT are employees of and hold stock in LEO Pharma. SW is co-principal investigator of the German atopic eczema registry TREATgermany; has received institutional research grants from La Roche-Posay, LEO Pharma, and Sanofi Deutschland GmbH; has performed consultancies for AbbVie, Almirall, Eli Lilly, GlaxoSmithKline, Kymab, LEO Pharma, Novartis, Pfizer, Regeneron, and Sanofi Genzyme; has lectured at educational events sponsored by AbbVie, Almirall, Eli Lilly, Galderma, LEO Pharma, Pfizer, Novartis, Regeneron, and Sanofi Genzyme; has received work-related travel support from AbbVie, LEO Pharma, and Sanofi Genzyme; and is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of psoriasis and atopic eczema.

© 2022. The Author(s).

Figures

Fig. 1

Trial design. AD atopic dermatitis, q2w every 2 weeks, q4w every 4 weeks, TCS topical corticosteroid

Fig. 2

EASI response rates at Weeks 16 and 32. Composite estimand (primary analysis): Patients who received rescue medication were considered non-responders. Patients with missing data were imputed as non-responders. EASI Eczema Area and Severity Index, EASI-50 at least 50% improvement in EASI, EASI-75 at least 75% improvement in EASI, EASI-90 at least 90% improvement in EASI, q2w every 2 weeks, q4w every 4 weeks, TCS topical corticosteroid

Fig. 3

Distribution of percentage improvement in EASI from baseline in all patients initiated on tralokinumab q2w at a Week 4, b Week 16, and c Week 32. a,b Tralokinumab q2w + TCS (n = 252), full analysis set. LOCF applied for patients using rescue medication/discontinuing study medication during the initial period (last observation available prior to using rescue medication/discontinuing study medication during the initial period). c Tralokinumab q2w/q4w + TCS (n = 252), full analysis set. LOCF applied for patients using rescue medication (during Weeks 16–32) or discontinuing study medication (last observation available prior to using rescue medication (during Weeks 16–32) or discontinuing study medication) and for patients with missing data for other reasons at Week 32 (last observation available). EASI Eczema Area and Severity Index, EASI-50 at least 50% improvement in EASI, EASI-75 at least 75% improvement in EASI, EASI-90 at least 90% improvement in EASI, LOCF last observation carried forward, q2w every 2 weeks, q4w every 4 weeks, TCS topical corticosteroids

Fig. 4

Least squares mean percentage improvement by visit in a weekly average of worst daily pruritus NRS, b weekly average in eczema-related sleep NRS, and c DLQI. Hypothetical estimand: treatments were reassigned at Week 16 and the placebo arm was only followed up to Week 16. The tralokinumab arm was followed beyond Week 16 and the different dosing (q2w or q4w) was ignored. Rescue medication was reset at Week 16. Data collected after permanent discontinuation of study medication or initiation of rescue medication were not included. In case of no post-baseline assessments before initiation of rescue medication, the Week 2 change was imputed as 0. Repeated-measurements model: Endpoint = Treatment*Week + Baseline*Week + Region + Baseline IGA. Compound symmetry was assumed for the covariance matrix. *p < 0.05 vs. placebo + TCS; **p < 0.01 vs. placebo + TCS; ***p < 0.001 vs. placebo + TCS. DLQI Dermatology Life Quality Index, IGA Investigator’s Global Assessment, NRS numeric rating scale, q2w every 2 weeks, q4w every 4 weeks, SE standard error, TCS topical corticosteroids

Fig. 5

Composite endpoint response rates at Week 16. DLQI Dermatology Life Quality Index, EASI Eczema Area and Severity Index, EASI-50 at least 50% improvement in EASI, NRS numeric rating scale, q2w every 2 weeks, TCS topical corticosteroids

Fig. 6

TCS use from baseline to Week 32 by visit. Assuming no TCS was used from non-returned tubes. Hypothetical estimand: treatments were reassigned at Week 16 and the placebo arm was only followed up to Week 16. The tralokinumab arm was followed beyond Week 16 and the different dosing (q2w or q4w) was ignored. Rescue medication was reset at Week 16. Data collected after permanent discontinuation of study medication or initiation of rescue medication were not included. In case of no post-baseline assessments before initiation of rescue medication, the Week 2 change was imputed as 0. Repeated-measurements model: Endpoint = Treatment*Week + Baseline*Week + Region + Baseline IGA. Compound symmetry was assumed for the covariance matrix. *p < 0.05 vs. placebo + TCS; **p < 0.01 vs. placebo + TCS; ***p < 0.001 vs. placebo + TCS. IGA Investigator’s Global Assessment, q2w every 2 weeks, q4w every 4 weeks, SE standard error, TCS topical corticosteroids