Long-term Efficacy of Baricitinib in Adults With Moderate to Severe Atopic Dermatitis Who Were Treatment Responders or Partial Responders: An Extension Study of 2 Randomized Clinical Trials

Abstract

Importance: Baricitinib, an oral selective Janus kinase inhibitor, improved the clinical signs and symptoms of moderate to severe atopic dermatitis in the 16-week, phase 3 monotherapy studies, BREEZE-AD1 and BREEZE-AD2. Long-term efficacy has not yet been examined.

Objective: To evaluate the long-term (68-week) efficacy of baricitinib in adults with moderate to severe atopic dermatitis who were treatment responders or partial responders in BREEZE-AD1 and BREEZE-AD2.

Design, setting, and participants: Patients completing BREEZE-AD1/BREEZE-AD2 entered the ongoing, multicenter, double-blind, long-term extension study BREEZE-AD3. The study was initiated on March 28, 2018. Data were analyzed on December 13, 2019.

Interventions: Responders and partial responders (patients achieving validated Investigator Global Assessment for Atopic Dermatitis [vIGA-AD] score of 0 or 1 [0,1], or 2) at BREEZE-AD1/BREEZE-AD2 completion remained on originally assigned treatment for 52 weeks (68 total weeks of continuous therapy).

Main outcomes and measures: The primary end point was the proportion of patients achieving a vIGA-AD score of 0,1 at weeks 16, 36, and 52 of BREEZE-AD3. Secondary end points included the proportion of patients achieving 75% or more improvement in the Eczema Area and Severity Index [EASI75] score and 4-point or more improvement in the itch numeric rating scale (NRS), using originating study baseline data. Itch data were collected during the first 16 weeks in BREEZE-AD3. The last originating study visit was the first BREEZE-AD3 visit; therefore, data are presented for continuous weeks of therapy, including the 16-week originating study period. Missing data were imputed by last observation carried forward. Modified intention-to-treat analysis was used.

Results: Of the responder/partial responder population, the proportion of patients treated with baricitinib, 4 mg (n = 70) (mean [SD] age, 36.7 [15.5] years; 42 [60%] were men), achieving vIGA-AD (0,1) at week 16 was 45.7% (BREEZE-AD3 baseline) and, at week 68, 47.1%. Improvement of 75% or more in the EASI score was 70.0% at week 16 and 55.7% at week 68. The proportion of patients achieving an itch NRS improvement greater than or equal to 4 points at week 16 was 52.5% and, at week 32, 45.9%. Of the responder/partial responder population, the proportion of patients treated with baricitinib, 2 mg (n = 54) (mean [SD] age, 32.8 [12.7] years; 28 [51.9%] were men), achieving vIGA-AD (0,1) at week 16 was 46.3% and, at week 68, 59.3%. Improvement in the EASI75 score was 74.1% at week 16 and 81.5% at week 68. The proportion of patients achieving an itch NRS improvement greater than or equal to 4 points at week 16 was 44.2% and, at week 32, 39.5%.

Conclusions and relevance: In this long-term double-blind extension study of 2 randomized clinical trials, baricitinib, 4 and 2 mg, demonstrated sustained long-term efficacy in patients with moderate to severe atopic dermatitis.

Trial registration: ClinicalTrials.gov Identifier: NCT03334435.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Silverberg has received grants and/or personal fees from AbbVie, AFYX Therapeutics, Arena Pharmaceuticals, Asana BioSciences, Bluefin, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly and Company, Galderma, GlaxoSmithKline, Incyte, Kiniksa, LEO Pharma, Luna Pharma, Menlo Therapeutics, Novartis, Pfizer, RAPT Therapeutics, Regeneron, and Sanofi. Dr Simpson has been a paid investigator for Eli Lilly and Company, Galderma, LEO Pharma, Merck, Pfizer, and Regeneron and a consultant with honorarium for AbbVie, Boehringer Ingelheim, Dermavant, Eli Lilly and Company, Incyte, LEO Pharma, Pfizer, Pierre Fabre Dermo Cosmetique, Regeneron, and Sanofi Genzyme. Dr Wollenberg has received grants as an investigator, honoraria, and/or consulting fees from AbbVie, Almirall, Anacor Pharmaceuticals, Beiersdorf, Eli Lilly and Company, Galapagos NV, Galderma, LEO Pharma, MedImmune, Novartis, Pfizer, Pierre Fabre, Regeneron, and Sanofi Genzyme. Dr Bissonnette is an advisory board member, consultant, speaker, and/or an investigator for and/or has received honoraria or grants from AbbVie, Antiobix, Aquinox Pharmaceuticals, Arcutis, Asana BioSciences, Astellas, Boehringer Ingelheim, Brickell Biotech, Dermavant, Dermira, Dignity Sciences, Eli Lilly and Company, Galderma, Glenmark Pharmaceuticals, GSK-Stiefel, Hoffman-LaRoche Ltd, Kiniksa, LEO Pharma, NeoKera, Pfizer, Ralexar Therapeutics, Regeneron, Sanofi Genzyme, Sienna Biologics, and Vitae Pharmaceuticals and is an employee and shareholder of Innovaderm Research. Dr Kabashima has received grants, honoraria, or consulting fees from Japan Tobacco, LEO Pharma, Maruho, Mitsubishi Tanabe Pharma, Procter & Gamble, Ono Pharmaceutical, Taiho Pharmaceutical, and Torii Pharmaceutical. Ms DeLozier, Dr Sun, and Ms Cardillo are employees and shareholders of Eli Lilly and Company. Dr Nunes is a former employee of Eli Lilly and Company and is a current employee and shareholder of Janssen. Dr Reich has served as advisor and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Affibody, Almirall, Amgen, Biogen, Boehringer Ingelheim, Celgene, Covagen, Eli Lilly and Company, Forward Pharma, Fresenius Medical Care, Galapagos NV, GlaxoSmithKline, Janssen Cilag, Kyowa Kirin, LEO Pharma, Medac, Merck Sharp & Dohme, Miltenyi Biotec, Novartis, Ocean Pharma, Pfizer, Samsung Bioepis, Sanofi, Takeda, UCB Pharma, Valeant Pharmaceuticals, XBiotech, and XenoPort.

Figures

Figure 1.. CONSORT Diagram for Patients Who Entered BREEZE-AD3 as Responders or Partial Responders

Patients who had a validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 were considered responders; those with a score of 2 were considered partial responders. No rescue therapy was used in these groups during the originating study (BREEZE-AD1/BREEZE-AD2). aFor baricitinib, 4 mg, the other reason was the investigator’s decision owing to the patient’s work commitments.

Figure 2.. Validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 (vIGA-AD [0,1]), 75% Improvement From Originating Study Baseline in Eczema Area and Severity Index (EASI75), and Mean EASI Change From Baseline Responses Through 68 Weeks of Continuous Treatment for Patients Who Entered BREEZE-AD3 as Responders or Partial Responders

Patients who had a vIGA-AD score of 0 or 1 were considered responders; those with a score of 2 were considered partial responders. No rescue therapy was used in these groups during the originating study (BREEZE-AD1/BREEZE-AD2). LOCF indicates last observation carried forward; NRI, nonresponder imputation. Error bars indicate 95% CI (A-D) or SD (E,F). aData for the modified intent-to-treat population are shown as weeks of continuous therapy, which includes the 16-week treatment period in the originating studies.

Figure 3.. Improvement for All Patients Who Received Continuous Baricitinib, 4 mg, Through BREEZE-AD1/BREEZE-AD2 and BREEZE-AD3

A, Validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 (vIGA-AD [0,1]). B, 75% Improvement in Eczema Area and Severity Index (EASI75). C, Itch numeric rating scale greater than or equal to 4-point (NRS ≥4) improvement. Missing data were imputed using nonresponder imputation (NRI). Error bars indicate 95% CI; ITT, intent-to-treat; and mITT, modified ITT. aResponse during weeks 0 to 16 was censored only at the time of the drug discontinuation; ITT population included all patients as randomized during the study. Data after study treatment discontinuation were imputed as NRI. bmITT in BREEZE-AD3 included all patients receiving 1 or more dose of baricitinib in BREEZE-AD3.

Figure 4.. Patient-Reported Outcomes Through 32 Weeks of Continuous Treatment for Patients Who Entered BREEZE-AD3 as Responders or Partial Responders

Responders and partial responders were patients who had a validated Investigator Global Assessment for Atopic Dermatitis score of 0,1 or 2 and never received rescue therapy during the originating study (BREEZE-AD1/BREEZE-AD2). Error bars indicate 95% CIs. Findings shown for Atopic Dermatitis Sleep Scale (ADSS) item 2 improvement of 1.5 points or more; itch numeric rating scale (NRS) improvement of 4 points or more, and skin pain NRS improvement of 4 points or more. A, Last observation carried forward (LOCF) for baricitinib, 4 mg: ADSS item 2, n = 28; itch NRS, n = 61; skin pain NRS, n = 55. B, Nonresponder imputation (NRI) for baricitinib, 4 mg: ADSS, n = 28; itch NRS, n = 61; skin pain NRS, n = 55. C, LOCF for baricitinib, 2 mg: ADSS, n = 19; itch NRS, n = 43; NRS, skin pain, n = 40. D, NRI for baricitinib, 2 mg: ADSS, n = 19; itch NRS, n = 43; skin pain NRS, n = 40. aIn patients with an originating study baseline ADSS item 2 score greater than or equal to 1.5. bIn patients with an originating study baseline skin pain NRS score greater than or equal to 4. cIn patients with an originating study baseline itch NRS score greater than or equal to 4. dData for the modified intent-to-treat population are shown as weeks of continuous therapy, which includes the 16-week treatment period in the originating studies.