Efficacy and safety of ivarmacitinib in patients with moderate-to-severe atopic dermatitis, with or without comorbid allergies

Efficacy and safety of ivarmacitinib in patients with moderate-to-severe atopic dermatitis, with or without comorbid allergies MATERIALS AND METHODS Study design and patients For this post-hoc analysis, data on M-SAD patients with or without comorbid allergies were extracted from the phase 3 trial of ivarmacitinib. The detailed methodologies of the phase 3 trial (NCT04875169) have been previously published.13 In brief, patients aged 12 to 75 years with M-SAD for a minimum duration of one year, who had an inadequate response or intolerance to topical corticosteroids or calcineurin inhibitors or required systemic therapy within the past six months, were randomized in a 1:1:1 ratio to receive oral ivarmacitinib 4 mg, ivarmacitinib 8 mg, or placebo once daily for 16 weeks, followed by an ivarmacitinib-treatment extension for 52 weeks. The ethical committees at each site approved the trial. All patients signed informed consents. Definition of comorbid allergies The comorbid allergies were defined as any allergy-related disease, including but not limited to allergic rhinitis, asthma, food allergies, seasonal allergies, animal allergies, drug allergies, dust allergies, allergic conjunctivitis, mite allergies, chemical allergies, arthropod sting allergies, papular urticaria, plant allergies, excipient- or preservative-related allergic reactions, allergic sinusitis, allergic dermatitis, allergic bronchitis, rubber allergies, and fungal allergies. Outcomes In this post-hoc analysis, outcomes included the proportion of patients achieving: at least 75% and 90% improvements from baseline in Eczema Area and Severity Index (EASI) score (EASI-75 and EASI-90 responses, respectively), an Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with a ≥ 2 grade improvement from baseline (IGA response), and ≥4-point improvement from baseline in the Worst Itch Numeric Rating Scale (WI-NRS) score (WI-NRS 4 response). Changes from baseline in Dermatology Life Quality Index (DLQI) score and Patient-Oriented Eczema Measure (POEM) score were also assessed. The efficacy assessments were conducted from baseline to week 16 (W16). In addition, adverse events (AEs) were recorded for safety assessment. Statistical analysis Missing data for binary efficacy variables were imputed using non-responder imputation (NRI), while missing data for other variables were not imputed. Statistical comparisons were performed using the one-way analysis of variance test, least significant difference test, χ2 test, or Fisher's exact test. A P-value of less than 0.05 was considered statistically significant. RESULTS Figure 1. Treatment responses. The EASI-75 (A), EASI-90 (B), IGA (C), and WI-NRS 4 (D) response rates within 16 weeks were compared between the ivarmacitinib 4 mg or 8 mg groups and the placebo group. #P < 0.05, ##P < 0.01, and ###P < 0.001 for the ivarmacitinib 4 mg group versus the placebo group. *P < 0.05, **P < 0.01, and ***P < 0.001 for the ivarmacitinib 8 mg group versus the placebo group. Dark-colored markers represent statistical significance between groups in patients with comorbid allergies, while light-colored markers represent statistical significance between groups in patients without comorbid allergies. EASI-75 or -90, Eczema Area and Severity Index (at least 75% or 90% improvement); IGA, Investigator Global Assessment; WI-NRS, Worst Itch Numeric Rating Scale. Figure 2. Patient-reported outcomes. Changes from baseline in DLQI (A) and POEM (B) total scores within 16 weeks were compared between the ivarmacitinib 4 mg or 8 mg groups and the placebo group. #P < 0.05, ##P < 0.01, and ###P < 0.001 for the ivarmacitinib 4 mg group versus the placebo group. **P<0.01, ***P<0.001 for the ivarmacitinib 8 mg group versus the placebo group. Dark-colored markers represent statistical significance between groups in patients with comorbid allergies, while light-colored markers represent statistical significance between groups in patients without comorbid allergies. DLQI, Dermatology Life Quality Index; POEM, Patient-Oriented Eczema Measure. Table 1. Baseline characteristics of M-SAD patients with or without comorbid allergies. Characteristics With comorbid allergies Without comorbid allergies Ivarmacitinib 8 mg (n = 60) Ivarmacitinib 4 mg (n = 64) Placebo (n = 58) Ivarmacitinib 8 mg (n = 52) Ivarmacitinib 4 mg (n = 49) Placebo (n = 53) Age (years) Mean±SD 27.8±11.9 29.7±14.2 27.8±13.4 35.4±18.0 34.8±17.7 32.1±15.5 <18 years 10 (16.7) 11 (17.2) 12 (20.7) 9 (17.3) 8 (16.3) 8 (15.1) 18-64 years 50 (83.3) 52 (81.3) 45 (75.9) 38 (73.1) 38 (77.6) 43 (81.1) ≥65 years 0 (0.0) 1 (1.6) 2 (3.4) 5 (9.6) 3 (6.1) 2 (3.8) Gender Female 21 (35.0) 26 (40.6) 24 (41.4) 18 (34.6) 16 (32.7) 18 (34.0) Male 39 (65.0) 38 (59.4) 34 (58.6) 34 (65.4) 33 (67.3) 35 (66.0) BMI (kg/m2) Mean±SD 24.9±6.2 24.2±4.8 25.9±5.9 24.2±4.5 23.3±3.7 23.1±4.2 <25 kg/m2 35 (58.3) 44 (68.7) 34 (58.6) 34 (65.4) 35 (71.4) 40 (75.5) ≥25 kg/m2 25 (41.7) 20 (31.3) 24 (41.4) 18 (34.6) 14 (28.6) 13 (24.5) Smoker 10 (16.7) 9 (14.1) 5 (8.6) 8 (15.4) 9 (18.4) 14 (26.4) Concomitant allergic diseases Asthma 24 (40.0) 18 (28.1) 18 (31.0) 0 (0.0) 0 (0.0) 0 (0.0) Allergic rhinitis 25 (41.7) 34 (53.1) 28 (48.3) 0 (0.0) 0 (0.0) 0 (0.0) Other allergic diseases 31 (51.7) 30 (46.9) 23 (39.7) 0 (0.0) 0 (0.0) 0 (0.0) Duration of AD (years) Mean±SD 16.2±11.5 11.4±10.9 14.3±13.6 8.1±7.9 8.0±12.2 7.9±8.3 <10 years 17 (28.3) 39 (60.9) 27 (46.6) 35 (67.3) 38 (77.6) 37 (69.8) ≥10 years 43 (71.7) 25 (39.1) 31 (53.4) 17 (32.7) 11 (22.4) 16 (30.2) EASI score Mean±SD 32.9±14.0 29.8±11.0 27.7±10.4 26.2±9.1 29.0±11.9 27.6±10.8 ≥16 and ≤25 20 (33.3) 24 (37.5) 29 (50.0) 30 (57.7) 25 (51.0) 28 (52.8) >25 40 (66.7) 40 (62.5) 39 (50.0) 22 (42.3) 24 (49.0) 25 (47.2) IGA score 3 31 (51.7) 37 (57.8) 32 (55.2) 35 (67.3) 27 (55.1) 33 (62.3) 4 29 (48.3) 27 (42.2) 26 (44.8) 17 (32.7) 22 (44.9) 20 (37.7) WI-NRS score, mean±SD 7.6±1.8 7.8±1.6 7.8±1.5 7.3±1.7 7.8±1.3 7.4±1.7 DLQI score†, mean±SD 15.7±7.5 15.2±7.3 14.0±5.6 14.6±6.3 15.8±6.9 15.7±7.4 POEM score, mean±SD 22.0±5.5 21.2±5.2 20.4±5.4 20.0±6.1 20.9±6.8 20.7±5.8 Data are n (%) or mean±SD. There was no significant difference among groups. †Patients aged ≥16 years completed the DLQI assessment, while those aged <16 years completed the CDLQI assessment. AD, atopic dermatitis; BMI, body mass index; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; IGA, Investigator’s Global Assessment; M-SAD, moderate-to-severe atopic dermatitis; POEM, Patient-Oriented Eczema Measure; SD, standard deviation; WI-NRS, Worst Itch Numeric Rating Scale. Table 2. Adverse events. Items With comorbid allergies Without comorbid allergies Ivarmacitinib 8 mg (n = 60) Ivarmacitinib 4 mg (n = 64) Placebo (n = 58) Ivarmacitinib 8 mg (n = 52) Ivarmacitinib 4 mg (n = 49) Placebo (n = 53) Adverse events 40 (66.7) 44 (68.8) 39 (67.2) 34 (65.4) 34 (69.4) 33 (62.3) Severe adverse events 1 (1.7) 2 (3.1) 2 (3.4) 1 (1.9) 1 (2.0) 1 (1.9) Treatment-related adverse events 21 (35.0) 25 (39.1) 17 (29.3) 18 (34.6) 22 (44.9) 15 (28.3) Severe treatment-related adverse events 0 (0.0) 2 (3.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Adverse events leading to discontinuation 2 (3.3) 3 (4.7) 1 (1.7) 2 (3.8) 0 (0.0) 5 (9.4) Most frequently reported adverse events* Elevated blood creatine phosphokinase 8 (13.3) 4 (6.3) 1 (1.7) 4 (7.7) 4 (8.2) 0 (0.0) Folliculitis 6 (10.0) 1 (1.6) 1 (1.7) 2 (3.8) 0 (0.0) 2 (3.8) Upper respiratory tract infection 7 (11.7) 5 (7.8) 6 (10.3) 6 (11.5) 7 (14.3) 6 (11.3) Urine protein Detection 5 (8.3) 1 (1.6) 1 (1.7) 3 (5.8) 3 (6.1) 7 (13.2) Hyperlipidemia 3 (5.0) 1 (1.6) 0 (0.0) 5 (9.6) 1 (2.0) 1 (1.9) Fever 3 (5.0) 4 (6.3) 3 (5.2) 0 (0.0) 1 (2.0) 1 (1.9) Cough 3 (5.0) 2 (3.1) 0 (0.0) 0 (0.0) 2 (4.1) 1 (1.9) Decreased red blood cell count 3 (5.0) 0 (0.0) 1 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) Elevated blood uric acid, 2 (3.3) 3 (4.7) 3 (5.2) 1 (1.9) 2 (4.1) 3 (5.7) Diarrhea 2 (3.3) 3 (4.7) 2 (3.4) 3 (5.8) 1 (2.0) 1 (1.9) Hyperuricemia 1 (1.7) 1 (1.6) 3 (5.2) 3 (5.8) 1 (2.0) 2 (3.8) Acne 2 (3.3) 2 (3.1) 0 (0.0) 5 (9.6) 2 (4.1) 2 (3.8) Elevated blood lactate dehydrogenase 2 (3.3) 1 (1.6) 1 (1.7) 0 (0.0) 1 (2.0) 0 (0.0) Conjunctivitis 0 (0.0) 2 (3.1) 1 (1.7) 2 (3.8) 2 (4.1) 0 (0.0) Elevated alanine aminotransferase 0 (0.0) 2 (3.1) 2 (3.4) 1 (1.9) 1 (2.0) 1 (1.9) Data are n (%). There was no significant difference between ivarmacitinib and placebo. *Adverse events in at least 2% of patients across groups are reported.