Safety of Lebrikizumab in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis: An Integrated Analysis of Eight Clinical Trials.

BACKGROUND: Lebrikizumab is a monoclonal antibody that binds with high affinity to interleukin (IL)-13, thereby blocking the downstream effects of IL-13 with high potency. OBJECTIVES: To report integrated safety of lebrikizumab in adults and adolescents with moderate-to-severe atopic dermatitis from phase 2 and 3 studies. METHODS: Five double-blind, randomized placebo-controlled studies; one randomized open-label study; one adolescent open-label, single-arm study; and one long-term safety study were summarized in two datasets: (1) placebo-controlled week 0-16 (All-PC Week 0-16) in patients who received lebrikizumab 250 mg every 2 weeks (LEBQ2W) versus placebo and (2) patients who received any dose of lebrikizumab at any time during the studies (All-LEB). Exposure-adjusted incidence rates (IR)/100 patient-years (PY) are provided. RESULTS: A total of 1720 patients received lebrikizumab (1637.0 PY exposure). In All-PC Week 0-16, the frequency of treatment-emergent adverse events (TEAEs) was similar between treatment groups; most events were nonserious and mild or moderate in severity. The most frequently reported TEAEs were atopic dermatitis (placebo) and conjunctivitis (LEBQ2W). Frequencies of conjunctivitis cluster were 2.5% (placebo) and 8.5% (LEBQ2W), and all events were mild or moderate (All-LEB 10.6%, IR, 12.2). Frequencies of injection site reactions were 1.5% (placebo) and 2.6% (LEBQ2W; All-LEB 3.1%, IR, 3.3). Frequencies of adverse events leading to treatment discontinuation were 1.4% (placebo) and 2.3% (LEBQ2W; All-LEB 4.2%, IR, 4.5). CONCLUSION: The safety profile for lebrikizumab consisted of TEAEs that were mostly nonserious, mild or moderate in severity, and did not lead to treatment discontinuation. The safety profile was similar in both adults and adolescents. CLINICALTRIALS: GOV: NCT02465606, NCT02340234, NCT03443024, NCT04146363, NCT04178967, NCT04250337, NCT04250350, NCT04392154 Safety of lebrikizumab in adults and adolescents with moderate-to-severe atopic dermatitis: an integrated analysis of eight clinical trials (MP4 34165 KB).

Atopic dermatitis (AD) is a common chronic (persistent) skin disease that occurs in up to 7% of adults and approximately 20% of children. Lebrikizumab is a monoclonal antibody that goes against interleukin-13, which is overexpressed in patients with AD. Lebrikizumab is given by injection and is being studied to treat AD. It has been tested in several studies in both adults and adolescents (patients age ≥ 12 ­ < 18 years). In some of those studies, patients used lebrikizumab by itself, and in other studies patients used lebrikizumab in combination with low-to-moderate strength topical (rubbed on the skin) corticosteroid medicines. We examined the safety of lebrikizumab by combining the data from eight of those studies and analyzing the data in two datasets. The first dataset compared the safety of lebrikizumab 250 mg injected every 2 weeks with placebo (no drug in the injection) in four 16-week studies in which neither patient nor physician knew whether lebrikizumab or placebo was being injected. The second dataset included four additional studies and examined the safety of lebrikizumab in all patients receiving at least 1 injection of lebrikizumab at any dose. A total of 1720 patients took lebrikizumab. In the first dataset the frequency of adverse events was similar between lebrikizumab and placebo, and most events that did occur were mild or moderate in severity and were not serious. The most common adverse event in patients treated with placebo was atopic dermatitis, and in patients treated with lebrikizumab it was conjunctivitis. Frequencies of adverse events in the conjunctivitis cluster, which included a search for the terms of conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, and giant papillary conjunctivitis, were 2.5% in placebo and 8.5% in lebrikizumab, and all events were mild or moderate. Frequencies of injection site reactions were 1.5% in placebo and 2.6% in lebrikizumab, and frequencies of adverse events that led to patients stopping treatment were 1.4% in placebo and 2.3% in lebrikizumab. In the second dataset, the rate of these adverse events did not increase with longer duration of lebrikizumab. The safety profile for lebrikizumab consisted of adverse events that were mostly nonserious, mild or moderate in severity, and did not lead to stopping treatment. The safety profile was similar in both adults and adolescents.

Efficacy and safety of lebrikizumab in moderate-to-severe atopic dermatitis: 52-week results of two randomized double-blinded placebo-controlled phase III trials.

BACKGROUND: Lebrikizumab is a novel, high-affinity monoclonal antibody that selectively binds to interleukin (IL)-13. OBJECTIVES: To evaluate the efficacy and safety of lebrikizumab monotherapy in adolescent and adult patients with moderate-to-severe atopic dermatitis (AD) over 52 weeks of treatment in ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967). METHODS: Patients who responded to lebrikizumab 250 mg every 2 weeks (Q2W) at the end of the 16-week induction period were re-randomized 2 : 2 : 1 to receive lebrikizumab Q2W, lebrikizumab 250 mg every 4 weeks (Q4W) or placebo Q2W (lebrikizumab withdrawal) for 36 additional weeks. Response at week 16 was defined as achieving a 75% reduction in Eczema Area Severity Index (EASI 75) or an Investigator's Global Assessment (IGA) of 0 or 1, with a ≥ 2-point improvement and no rescue medication use. Multiple imputation was used to handle missing data. Intermittent use of topical therapy was permitted during the maintenance period. RESULTS: After 52 weeks, an IGA of 0 or 1 with a ≥ 2 point improvement was maintained by 71.2% of patients treated with lebrikizumab Q2W, 76.9% of patients treated with lebrikizumab Q4W and 47.9% of patients in the lebrikizumab withdrawal arm. EASI 75 was maintained by 78.4% of patients treated with lebrikizumab Q2W, 81.7% of patients treated with lebrikizumab Q4W and 66.4% of patients in the lebrikizumab withdrawal arm at week 52. Across treatment arms, proportions of patients using any rescue therapy were 14.0% (ADvocate1) and 16.4% (ADvocate2). During the combined induction and maintenance periods of ADvocate1 and ADvocate2, 63.0% of lebrikizumab-treated patients reported any treatment emergent adverse event, with most events (93.1%) being mild or moderate in severity. CONCLUSIONS: After a 16-week induction period with lebrikizumab Q2W, lebrikizumab Q2W and Q4W maintained similar improvement of the signs and symptoms of moderate-to-severe AD, with a safety profile consistent with previously published data.

Efficacy and safety of baricitinib in combination with topical corticosteroids in patients with moderate-to-severe atopic dermatitis with inadequate response, intolerance or contraindication to ciclosporin: results from a randomized, placebo-controlled, phase III clinical trial (BREEZE-AD4).

BACKGROUND: Baricitinib, an oral selective Janus kinase (JAK)1 and JAK 2 inhibitor, was shown to improve the signs and symptoms of moderate-to-severe atopic dermatitis (AD). OBJECTIVES: To evaluate the efficacy and safety of baricitinib with background topical corticosteroids (TCS) in patients with moderate-to-severe AD and inadequate response, intolerance or contraindication to ciclosporin A (CA). METHODS: In this double-blind, randomized, placebo-controlled, phase III study, patients were randomized 1: 1: 2: 1 to placebo (N = 93), baricitinib 1 mg (N = 93), 2 mg (N = 185) or 4 mg (N = 92) with background TCS. The primary endpoint was the proportion of patients receiving baricitinib 4 mg or 2 mg (+ TCS) vs. placebo + TCS who achieved ≥ 75% improvement from baseline in the Eczema Area and Severity Index (EASI 75) at week 16. RESULTS: Baricitinib 4 mg + TCS was superior to placebo + TCS for EASI 75 (4 mg: 32%, placebo: 17%, P = 0·031) at week 16 and for improvements in itch, skin pain and number of night-time awakenings owing to itch. Improvements were maintained through 52 weeks of treatment. Treatment-emergent adverse events (TEAEs) were more common with baricitinib than placebo (+ TCS); most were mild or moderate. The most frequent TEAEs with baricitinib 4 mg + TCS were nasopharyngitis, herpes simplex, influenza and headache. No deaths or deep vein thromboses were reported. CONCLUSIONS: Baricitinib 4 mg + TCS improved the signs and symptoms of moderate-to-severe AD through 52 weeks of treatment in patients with inadequate response, intolerance or contraindication to CA. The safety profile was consistent with previous studies of baricitinib in moderate-to-severe AD. What is already known about this topic? Ciclosporin A is indicated for the treatment of atopic dermatitis that is refractory to topical therapies. However, its use is limited by safety concerns and it may not provide adequate response for some patients. Baricitinib, an oral selective Janus kinase (JAK)1 and JAK2 inhibitor, has been shown to improve the signs and symptoms of moderate-to-severe atopic dermatitis as a monotherapy or in combination with topical corticosteroids. What does this study add? Baricitinib combined with background low- or moderate-potency topical corticosteroids provided improvements in the signs and symptoms of moderate-to-severe atopic dermatitis through 1 year of treatment in patients with a contraindication, intolerance or failure to respond to ciclosporin A. The most common treatment-emergent adverse events with baricitinib 4 mg were nasopharyngitis, herpes simplex, influenza and headache. The safety profile was consistent with previous studies in patients with moderate-to-severe atopic dermatitis.