Presented at the Revolutionizing Atopic Dermatitis (RAD), Virtual Meeting, June 13, 2021

Comparison of Efficacy of Targeted Therapies without Topical Corticosteroids for Moderate to Severe Atopic Dermatitis: Systematic Review and Network Meta-analysisJonathan I Silverberg1; H Chih-ho Hong2; Jacob P Thyssen3; Brian M Calimlim4; Avani D Joshi4; Henrique D Teixeira4; Eric B Collins5; Marjorie M Crowell5; Scott J Johnson5; April W Armstrong6

1Department of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington DC, United States; 2Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada; and Probity Medical Research, Surrey, British Columbia, Canada; 3Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Denmark; 4AbbVie Inc., North Chicago, Illinois, United States; 5Medicus Economics LLC, Boston, Massachusetts, United States; 6Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States

INTRODUCTION• Targeted therapies for patients with moderate to severe atopic

dermatitis (AD) have been recently evaluated in multiple randomized controlled trials (RCTs), but comparative efficacy evidence among these therapies is lacking

• Reported here are network meta-analysis (NMA) results comparing efficacy measures of skin clearance and itch among targeted therapies as monotherapy without concomitant topical corticosteroids (TCS)

METHODSSYSTEMATIC LITERATURE REVIEW• We conducted a systematic literature review (SLR) that searched the

Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, Global Resource of Eczema Trials database, and clinical trial registries in October 2020

• English-language RCTs (phase III and IV) with ≥8 weeks of systemic immunomodulatory treatment for moderate to severe AD were included, as well as data from two upadacitinib trials (Measure Up 1 [NCT03569293], Measure Up 2 [NCT03607422])

• The SLR adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-Analyses guidelines

• All studies selected by the SLR and included in the NMA were critically appraised for methodological quality using validated tools in accordance with NICE recommendations1

• Studies were evaluated on multiple domains of bias: random sequence generation, allocation concealment, blinding of participants, blinding of investigators, blinding of outcome assessors, incomplete outcome data, selective reporting, and other potential sources of bias that may affect internal or external validity and generalizability of the study findings to the general population

NETWORK META-ANALYSIS• Prespecified efficacy outcomes were: Investigator Global Assessment

score of 0 or 1 (clear or almost clear) with a ≥2-point reduction from baseline (IGA 0 / 1), ≥75% and ≥90% improvement in Eczema Area and Severity Index (EASI) from baseline (EASI-75, EASI-90), and ≥4-point improvement in Pruritus Numerical Rating Scale from baseline (∆NRS≥4)

• Bayesian NMA2 was performed for each outcome evaluated at the primary endpoint timepoint of each trial (week 12 for abrocitinib, week 16 for all other therapies)

• Fixed-effects and random-effects models, both with and without baseline risk-adjustment, were fit

• Odds ratio (OR), placebo-unadjusted response rate, number needed-to-treat (NNT), and surface under the cumulative ranking curve (SUCRA) scores were estimated

– NNT is the estimated number of patients that would need to be treated with the interventional therapy in order to observe one additional responder relative to placebo

– SUCRA is the estimated probability of which therapy is found to be the most favorable by the NMA for a given outcome. SUCRA would be 100% when a therapy is certain to be the best and 0% when a therapy is certain to be the worst

• Statistical significance among therapies was assessed by OR 95% credible intervals excluding 1

RESULTSSLR RESULTS• The SLR results are summarized in Figure 1• The NMA analyzed 11 unique phase 3 placebo-controlled trials

encompassing 6,254 patients in 28 arms across five targeted therapies (abrocitinib, baricitinib, dupilumab, tralokinumab, upadacitinib) (Figure 2)

RESULTS (CONTINUED) Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram

* The discrepancy between the numbers of records (n=6) and number of unique studies (n=9) is because three of the records each published the findings from two included studies.

Figure 2. Network meta-analysis diagram

NMA RESULTS• Fit statistics and diagnostics supported fixed-effect models for all

outcomes analyzed• For IGA 0 / 1, response rates were greatest for upadacitinib 30 mg, followed

by upadacitinib 15 mg, abrocitinib 200 mg, and dupilumab 300 mg (Figure 3)

• For ∆NRS≥4, response rates were greatest for upadacitinib 30 mg, followed by abrocitinib 200 mg, upadacitinib 15 mg, and dupilumab 300 mg (Figure 3)

• For EASI-75 and EASI-90, response rates were greatest for upadacitinib 30 mg, followed by abrocitinib 200 mg, upadacitinib 15 mg, and dupilumab 300 mg (Figure 4)

Figure 3. IGA 0 / 1 vs ΔNRS≥4 response rate estimates and 95% credible intervals at primary endpoint timepoint (Bayesian NMA fixed-effects results)

Endpoints were measured at the primary endpoint timepoint for each trial (week 12 for abrocitinib, week 16 for all other targeted therapies).*Represents the sample size pooled across included studies.ΔNRS≥4, Pruritus Numerical Rating Scale reduction of ≥4 points from baseline; EASI, Eczema Area and Severity Index

Figure 4. EASI-75 and EASI-90 response rate estimates and 95% credible intervals at primary endpoint timepoint (Bayesian NMA fixed-effects results)

Endpoints were measured at the primary endpoint timepoint for each trial (week 12 for abrocitinib, week 16 for all other targeted therapies). EASI, Eczema Area and Severity Index; IGA, Investigator Global Assessment for Atopic Dermatitis

• For EASI-75, EASI-90, and ∆NRS≥4, NTT and SUCRA estimates were most favorable for upadacitinib 30 mg, followed by abrocitinib 200 mg, upadacitinib 15 mg, and dupilumab 300 mg (Table 1)

• For IGA 0 / 1, NNT and SUCRA estimates were most favorable for upadacitinib 30 mg, followed by upadacitinib 15 mg, abrocitinib 200 mg, and dupilumab 300 mg (Table 1)

Table 1. Number needed-to-treat and SUCRA at primary endpoint evaluation (Bayesian NMA fixed-effects results)

EASI-75 EASI-90 IGA 0 / 1 ΔNRS≥4

NNT (95% CrI) SUCRA NNT (95% CrI) SUCRA NNT (95% CrI) SUCRA NNT (95% CrI) SUCRA

Dupilumab 300 mg 3.2 (2.3 - 4.9) 55.6% 5.1 (2.9 - 10.6) 50.2% 4.3 (2.7 - 7.9) 60.3% 4.1 (2.6 - 8.2) 54.7%

Tralokinumab 300 mg 6.2 (3.8 - 11.5) 19.1% 8.2 (3.9 - 19.9) 25.0% 12.1 (6.0 - 29.3) 15.7% 8.9 (4.5 - 21.2) 17.0%

Baricitinib 2 mg 5.6 (3.4 - 10.7) 23.2% 8.2 (3.9 - 20.8) 23.8% 7.5 (3.9 - 17.4) 30.6% 7.0 (3.6 - 17.4) 25.1%

Baricitinib 4 mg 4.5 (2.8 - 8.5) 36.4% 5.8 (2.9 - 14.2) 44.0% 5.6 (3.0 - 12.9) 46.3% 4.7 (2.7 - 11.0) 47.1%

Abrocitinib 100 mg 3.2 (2.1 - 5.9) 53.9% 5.3 (2.4 - 15.4) 46.3% 6.4 (3.1 - 17.0) 38.6% 4.6 (2.6 - 10.6) 47.0%

Abrocitinib 200 mg 2.0 (1.6 - 2.9) 85.8% 2.8 (1.6 - 6.0) 82.5% 3.4 (2.0 - 6.8) 73.3% 2.8 (1.9 - 5.5) 82.3%

Upadacitinib 15 mg 2.2 (1.8 - 3.0) 77.9% 2.9 (1.9 - 5.0) 79.8% 2.6 (1.9 - 4.2) 85.3% 3.0 (2.1 - 5.4) 77.7%

Upadacitinib 30 mg 1.7 (1.5 - 2.1) 98.3% 2.0 (1.5 - 3.2) 98.4% 1.9 (1.5 - 2.7) 99.9% 2.2 (1.7 - 3.4) 98.9%

Placebo 0.0% 0.0% 0.0% 0.0%

Endpoints were measured at the primary endpoint timepoint for each trial (week 12 for abrocitinib, week 16 for all other targeted therapies). NNT is estimated relative to placebo, with higher efficacy indicated by lower NNT values. SUCRA scores are based on the overall ranking of a therapy from the NMA, with higher SUCRA scores indicating a greater likelihood that a therapy is the top ranked therapy in the network. ΔNRS≥4, Pruritus Numerical Rating Scale reduction of ≥4 points from baseline; CrI, credible interval; EASI, Eczema Area and Severity Index; IGA, Investigator Global Assessment for Atopic Dermatitis; NMA, network meta-analysis; NNT, Number needed-to-treat; SUCRA, Surface Under the Cumulative Ranking curve

• For IGA 0 / 1, estimates were most favorable for upadacitinib 30 mg, followed by upadacitinib 15 mg, abrocitinib 200 mg, and dupilumab 300 mg; upadacitinib 30 mg demonstrated significant differences vs. all other therapies based on OR (Figure 5)

• For EASI-75, EASI-90, and ∆NRS≥4, estimates were most favorable for upadacitinib 30 mg, followed by abrocitinib 200 mg, upadacitinib 15 mg, and dupilumab 300 mg (Figure 5)

LIMITATIONSSome heterogeneity was observable in baseline characteristics and placebo response rates across the analyzed trials. Adjusted models were tested but were not selected based on relevant fit statistics

CONCLUSIONSAmong targeted therapies used as monotherapy without concomitant TCS, upadacitinib 30 mg appears to be the most efficacious therapy for patients with moderate to severe AD, followed by abrocitinib 200 mg, upadacitinib 15 mg, and dupilumab 300 mg.

REFERENCES1. National Institute for Health and Care Excellence (NICE). Guide to the

methods of technology appraisal. Process and methods [PMG9]. Available at: https://www.nice.org.uk/process/pmg9/. Published 2013.

2. Dias, S., et al., NICE DSU Technical Support Document 2: A Generalised Linear Modelling Framework for Pairwise and Network Meta-Analysis of Randomised Controlled Trials. Technical Support Document in Evidence Synthesis. 2011: National Institute for Health and Clinical Excellence.

ACKNOWLEDGEMENTS• Medical writing support was provided by Marric Buessing, PhD,

Medicus Economics LLC, Boston, MA, United States; this support was funded by AbbVie.

• Systematic literature review was provided by Kimberley Maxwell, Georghia Michael, Manpreet Sambi, Helen Baldwin, Fiona Robinson, Robin Marwick, Diana Petrina and Sabrina Smith; this support was funded by AbbVie.

DISCLOSURES• AbbVie Inc., funded this study and participated in the study design;

study research; collection, analysis and interpretation of data; and writing, reviewing and approving of this publication. All authors had access to the data, and participated in the development, review, and approval, and in the decision to submit this publication. No honoraria or payments were made for authorship.

• JI Silverberg is an advisor, speaker, or consultant for AbbVie, Asana Biosciences, Dermavant, Galderma, GlaxoSmithKline, Glenmark, Kiniksa, LEO Pharma, Lilly, Menlo Therapeutics, Novartis, Pfizer, Realm Pharma, and Regeneron-Sanofi. He is also a researcher for GlaxoSmithKline.

• HC Hong is a researcher, consultant, and / or advisor for AbbVie, Amgen, Arcutis, Bausch Health, Boehringer Ingelheim, Bristol-Meyers Squibb, Celgene, Dermira, Dermavant, DS Biopharma, Galderma, GlaxoSmithKline, Janssen, LEO Pharma, Lilly, MedImmune, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, and UCB.

• JP Thyssen is an advisor, investigator, and speaker for AbbVie, Eli Lilly, Leo Pharma, Pfizer, Regeneron, and Sanofi-Genzyme.

• BM Calimlim, AD Joshi, and HD Teixeira are full-time, salaried employees of AbbVie Inc. and own AbbVie stock or stock options.

• EB Collins, MM Crowell, and SJ Johnson are employees of Medicus Economics LLC, which was paid fees by AbbVie to conduct the research in this study.

• AW Armstrong reported receiving grants and personal fees from AbbVie, Eli Lilly, Leo Pharma, and Novartis Pharmaceuticals Corp; personal fees from Boehringer Ingelheim / Parexel, Bristol-Myers Squibb, Celgene, Dermavant, Janssen Pharmaceuticals Inc, Merck, Modernizing Medicine, Ortho Dermatologics, Pfizer Inc, Regeneron Pharmaceuticals, Sanofi Genzyme, Science 37 Inc, Genentech, GlaxoSmithKline, and Valeant; and grants from Dermira, Janssen-Ortho Inc, Kyowa Hakko Kirin, and UCB Pharma outside the submitted work.

Figure 5. Odds ratios for all outcomes at primary endpoint evaluation (Bayesian NMA fixed-effects results)

Endpoints were measured at the primary endpoint timepoint for each trial (week 12 for abrocitinib, week 16 for all other targeted therapies). Odds ratio values are presented as the column therapy vs. the row therapy. Values greater than 1 favor the column therapy; values less than 1 favor the row therapy.EASI, Eczema Area and Severity Index; IGA, Investigator Global Assessment for Atopic Dermatitis; ΔNRS≥4, Pruritus Numerical Rating Scale reduction of ≥4 points from baseline. © AbbVie Inc. 2021