Ebglyss

Pharmacotherapeutic group: other dermatological preparations, agents for dermatitis, excluding corticosteroids, ATC code: D11AH10 Mechanism of action Lebrikizumab is an immunoglobulin (IgG4) monoclonal antibody that binds with high affinity to interleukin (IL)‑13 and selectively inhibits IL‑13 signalling through the IL‑4 receptor alpha (IL‑4Rα)/ IL-13 receptor alpha 1 (IL‑13Rα1) heterodimer, thereby inhibiting the downstream effects of IL‑13. Inhibition of IL‑13 signalling is expected to be of benefit in diseases in which IL‑13 is a key contributor to the disease pathogenesis. Lebrikizumab does not prevent the binding of IL‑13 to the IL‑13 receptor alpha 2 (IL‑13Rα2 or decoy receptor), which allows the internalisation of IL‑13 into the cell. Pharmacodynamic effects In lebrikizumab clinical studies, lebrikizumab reduced the levels of serum periostin, total immunoglobulin E (IgE), CC chemokine ligand (CCL)17 [thymus and activation-regulated chemokine (TARC)], CCL18 [pulmonary and activation-regulated chemokine (PARC)], and CCL13 [monocyte chemotactic protein-4 (MCP-4)]. The decreases in the type 2 inflammation mediators provide indirect evidence of inhibition of the IL-13 pathway by lebrikizumab. Immunogenicity Anti-drug antibodies (ADA) were commonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed. Clinical efficacy and safety Adults and adolescents with atopic dermatitis The efficacy and safety of lebrikizumab as monotherapy (ADvocate-1, ADvocate-2) and with concomitant TCS (ADhere) were evaluated in three randomised, double-blind, placebo-controlled pivotal studies in 1062 adults and adolescents (aged 12 to 17 years and weighing ≥40 kg) with moderate-to-severe atopic dermatitis, defined by an Eczema Area and Severity Index (EASI) ≥ 16, Investigator's Global Assessment (IGA) ≥ 3, and a body surface area (BSA) involvement of ≥ 10%. Patients enrolled into the three studies previously had an inadequate response to topical medication or determination that topical treatments are otherwise medically inadvisable. In all three studies, patients received an initial dose of 500 mg of lebrikizumab (two 250 mg injections) at weeks 0 and 2, followed by 250 mg every other week (Q2W) until week 16, or matching placebo in a 2:1 ratio. In ADhere, study patients also received concomitant low-to-mid potency TCS or TCI on active lesions. Patients were permitted to receive rescue treatment at the discretion of the investigator to control intolerable symptoms of atopic dermatitis. Patients requiring systemic rescue treatment were discontinued from study treatment. Patients achieving IGA 0 or 1 or at least a 75% reduction in EASI (EASI 75) without having received any rescue therapy were re-randomised in a blinded manner to (i) lebrikizumab 250 mg Q2W; (ii) lebrikizumab 250 mg every 4 weeks (Q4W); or (iii) matching placebo up to 52 weeks. In ADvocate-1 and 2, patients not achieving IGA 0 or 1 or EASI 75 at week 16, or who received rescue medication prior to week 16, were entered into an Escape Arm and treated with open-label lebrikizumab 250 mg Q2W through Week 52. In ADvocate-1 and ADvocate-2, after completing the 52-week study, and in ADhere, after completing the 16-week study, patients were offered the option to continue treatment in a separate long-term extension study (ADjoin). Endpoints In all three studies, the co-primary endpoints were the percentage of patients with IGA 0 or 1 (“clear” or “almost clear”), with a ≥2-point reduction from baseline, and the percentage of patients achieving EASI 75 from baseline to week 16. Key secondary endpoints (adjusted for multiplicity) included the percentage of patients who achieved at least a 90% reduction in EASI (EASI 90), percentage of patients with at least 4-point improvement from baseline in Pruritus Numerical Rating Scale (Pruritus NRS), percentage of patients with at least 4-point improvement from baseline in Dermatology Life Quality Index (DLQI) and interference of itch on sleep (Sleep-Loss Scale), which is a patient-reported, single-item, daily scale measuring the extent of interference of itch on sleep over the last night on a 5-point Likert scale. An additional secondary endpoint (not adjusted for multiplicity) included the change from baseline in Patient Oriented Eczema Measure (POEM). Patients Baseline characteristics The monotherapy studies ADvocate-1 and ADvocate-2 enrolled 424 and 427 patients, respectively, and across studies the mean age was 35.8, the mean weight was 77.1 kg, 49.9% were female, 63.7% were white, 22.6% were Asian, and 9.9% were black, 12.0% were adolescents (12 to 17 years). Overall, 61.5% of patients had a baseline IGA of 3 (moderate atopic dermatitis), 38.5% of patients had a baseline IGA of 4 (severe atopic dermatitis), and 54.8% of patients had received prior systemic treatment. The mean baseline EASI was 29.6, the mean baseline Pruritus NRS was 7.2 and the mean baseline DLQI was 15.5. The concomitant TCS study ADhere enrolled 211 patients and the mean age was 37.2, the mean weight was 76.2 kg, 48.8% were female, 61.6% were white, 14.7% were Asian, and 13.3% were black, 21.8% were adolescents. In this study, 69.2% of patients had a baseline IGA of 3 (moderate atopic dermatitis), 30.8% of patients had a baseline IGA of 4 (severe atopic dermatitis), and 47.4% of patients had received prior systemic treatment. The mean baseline EASI was 27.3, the mean baseline Pruritus NRS was 7.1 and the mean baseline DLQI was 14.4. Clinical response Monotherapy studies (ADvocate-1 and ADvocate-2) – induction period, weeks 0-16 In ADvocate-1 and ADvocate-2, a significantly greater proportion of patients randomised to lebrikizumab 250 mg Q2W achieved IGA 0 or 1 with a ≥2-point improvement from baseline, EASI 75, EASI 90, and an improvement of ≥4 points in Pruritus NRS and DLQI compared to placebo at week 16 (see Table 2). In both monotherapy studies, lebrikizumab reduced daily worst itch severity compared to placebo, as measured by the percent change from baseline in Pruritus NRS, already at week 1 of treatment. The improvement in Pruritus NRS occurred in conjunction with improvements in skin inflammation related to atopic dermatitis and quality of life. Table 2 . Efficacy results of lebrikizumab monotherapy at week 16 in ADvocate-1 and Advocate‑2 ADvocate-1 ADvocate-2 Week 16 Placebo N=141 LEB 250 mg Q2W N=283 Placebo N=146 LEB 250 mg Q2W N=281 IGA 0 or 1, % a 12.7 43.1*** 10.8 33.2*** EASI 75, % b 16.2 58.8*** 18.1 52.1*** EASI 90, % b 9.0 38.3*** 9.5 30.7*** Pruritus NRS (≥ 4-point improvement), % c 13.0 45.9*** 11.5 39.8*** DLQI (Adults) (≥ 4-point improvement), % d 33.8 75.6*** 33.6 66.3*** LEB = lebrikizumab; N = number of patients. a Patients with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points from baseline on a 0-4 IGA scale. b Patients with a 75% or 90% reduction in EASI from Baseline to Week 16, respectively. c The percentage is calculated relative to the number of patients with a baseline Pruritus NRS ≥4. d The percentage is calculated relative to the number of patients with a baseline DLQI ≥4. *** p<0.001 versus placebo. In the two studies, fewer patients randomised to lebrikizumab needed rescue treatment (topical corticosteroids, systemic corticosteroids, immunosuppressants) as compared to patients randomised to placebo (14.7% versus 36.6%, respectively, across both studies). Monotherapy Studies (ADvocate-1 and ADvocate-2) – maintenance period, weeks 16-52 To evaluate maintenance of response, 157 patients from ADvocate-1 and 134 patients from ADvocate-2 treated with lebrikizumab 250 mg Q2W, who achieved IGA 0 or 1 or EASI 75 at week 16 without topical or systemic rescue treatment, were re-randomised in a blinded manner 2:2:1 to an additional 36-week treatment of (i) lebrikizumab 250 mg Q2W, or (ii) lebrikizumab 250 mg Q4W, or (iii) matching placebo for a cumulative 52-week study treatment (see Table 3). Table 3 . Efficacy results of lebrikizumab monotherapy at week 52 in patients responding to treatment at week 16 in ADvocate-1 and ADvocate-2 (pooled analysis) ADvocate-1 and ADvocate-2 (pooled) Week 52 Placebo d (LEB Withdrawal) N=60 LEB 250 mg Q4W N=118 IGA 0 or 1, % a 47.9 76.9** EASI 75, % b 66.4 81.7* EASI 90, % b 41.9 66.4** Pruritus NRS (≥ 4-point improvement), % c 66.3 84.7 a Patients with IGA 0/1 with a ≥2-point improvement from baseline at week 16 who continued to exhibit IGA 0/1 with a ≥2-point improvement at week 52. b Patients who achieved EASI 75 at week 16 and continued to exhibit EASI 75 at week 52, or patients who achieved EASI 75 at Week 16 and exhibited EASI 90 at week 52, respectively. c The percentage is calculated relative to the number of patients with a baseline Pruritus NRS ≥4. d Patients responding to lebrikizumab 250 mg Q2W at week 16 (IGA 0 or 1 or EASI 75) and re-randomised to placebo. *p<0.05; ** p<0.01 versus placebo. Among patients who received lebrikizumab during the induction period and continued lebrikizumab 250 mg Q2W open-label treatment up to week 52 in the Escape Arm, 58% achieved EASI 75 and 28% achieved IGA 0 or 1 with a ≥2-point improvement from baseline at week 52 in ADvocate-1 and ADvocate-2 (pooled). Monotherapy Studies (ADvocate-1 and ADvocate-2) ‑ Long-Term Extension (ADjoin), weeks 52 – 152 Maintenance of clinical response was evaluated in patients who achieved IGA 0 or 1 or EASI 75 at week 16 without topical or systemic rescue treatment, completed 52 weeks of lebrikizumab monotherapy in ADvocate-1 or ADvocate-2, and continued treatment in the 100-week extension study ADjoin. (Figure 1). Figure 1. IGA 0 or 1, EASI 75, and Pruritus NRS in week 16 treatment responders who completed week 52 in ADvocate-1 and ADvocate-2 and were treated with lebrikizumab 250 mg Q4W in ADjoin * * Missing data imputed using Markov Chain-Monte Carlo multiple imputation. ** Only in patients with pruritus NRS score ≥ 4 at baseline. Pruritus was evaluated only for the first year of ADjoin. Concomitant TCS Study (ADhere), weeks 0 - 16 In ADhere, from baseline to week 16, a significantly greater proportion of patients randomised to and dosed with lebrikizumab 250 mg Q2W + TCS achieved IGA 0 or 1, EASI 75, and improvements of ≥ 4 points in the Pruritus NRS and DLQI compared to placebo + TCS (see Table 4). Table 4. Efficacy results of lebrikizumab combination therapy with TCS at week 16 in ADhere ADhere Week 16 Placebo + TCS N=66 LEB 250 mg Q2W + TCS N=145 IGA 0 or 1, % a 22.1 41.2* EASI 75, % b 42.2 69.5*** EASI 90, % b 21.7 41.2** Pruritus NRS (≥ 4-point improvement), % c 31.9 50.6* DLQI (Adults) (≥ 4-point improvement), % d 58.7 77.4* a Patients with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points from baseline on a 0-4 IGA scale. b Patients with a 75% or 90% reduction in EASI from Baseline to week 16, respectively. c The percentage is calculated relative to the number of patients with a baseline Pruritus NRS ≥ 4. d The percentage is calculated relative to the number of patients with a baseline DLQI ≥4. * p<0.05; **p<0.01; *** p<0.001 versus placebo. In ADhere, patients who received lebrikizumab 250 mg Q2W+TCS from week 0 to 16 used high potency TCS as rescue medication less often as compared to patients who received placebo + TCS (1.4% and 4.5%, respectively). Concomitant TCS Study (ADhere) - Long-Term Extension (ADjoin), weeks 16 to 116 Clinical response was maintained among patients who achieved IGA 0 or 1 or EASI 75 at week 16 in ADhere and continued treatment with lebrikizumab 250 mg Q4W in the 100-week extension study ADjoin. Clinical response in patients not adequately controlled with, intolerant to, or for whom ciclosporin is not medical advisable (ADvantage) The ADvantage study evaluated the efficacy of lebrikizumab compared to placebo in adults and adolescents (aged ≥12 to <18 years and weighing ≥40 kg) with moderate-to-severe atopic dermatitis treated concomitantly with TCS who were not adequately controlled with ciclosporin or for whom ciclosporin was not medically advisable. A total of 331 patients were enrolled and the mean age was 33.8 years, 52.9% were male, 93.7% identified as white, and adolescents comprised 11.8% of the patient population. At baseline, mean EASI was 28.1, mean Pruritus NRS score was 6.9, and 38.7% of patients had IGA of 4. Overall, 53.2% were previously exposed to ciclosporin (see Table 5). Table 5. Efficacy results of lebrikizumab combination therapy with TCS at week 16 in ADvantage ADvantage Week 16 Placebo + TCS N=111 LEB 250 mg Q2W + TCS N=220 EASI 75, % a 40.8 68.4*** IGA 0 or 1, % b 24.5 42.0** EASI 90, % c 20.8 42.9*** Pruritus NRS (≥ 4-point improvement), % d 29.7 49.9* DLQI (Adults) (≥ 4-point improvement), % e 69.6 78.0 a Patients with a 75% reduction in EASI from baseline to week 16, respectively. b Patients with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points from baseline on a 0-4 IGA scale. c Patients with a 90% reduction in EASI from baseline to week 16, respectively. d The percentage is calculated relative to the number of patients with a baseline Pruritus NRS ≥4. e The percentage is calculated relative to the number of patients with a baseline DLQI ≥4. * p<0.05; **p<0.01; *** p<0.001 versus placebo. p-values for IGA 0 or 1, EASI 90, Pruritus NRS, and DLQI are nominal. Other patient-reported outcomes In both monotherapy studies (ADvocate-1 and ADvocate-2) and in the concomitant TCS studies (ADhere and ADvantage) lebrikizumab 250 mg Q2W significantly improved POEM and interference of itch on sleep (Sleep-Loss Scale) at week 16 compared to placebo. Adolescents (12 to 17 years of age) In the monotherapy studies ADvocate 1 and ADvocate 2, the mean age of adolescent patients was 14.6 years, the mean weight was 68.2 kg, and 56.9% were female. In these studies, 63.7% had a baseline IGA of 3 (moderate atopic dermatitis), 36.3% had a baseline IGA of 4 (severe atopic dermatitis), and 47.1% had received prior systemic treatment. In the concomitant study with TCS ADhere, the mean age of adolescent patients was 14.6 years, mean weight was 62.2 kg, and 50.0% were female. In this study, 76.1% had a baseline IGA of 3 (moderate atopic dermatitis), 23.9% had a baseline IGA of 4 (severe atopic dermatitis), and 23.9% had received prior systemic treatment. The efficacy results at week 16 in adolescent patients are presented in Table 6. Table 6. Efficacy results of lebrikizumab monotherapy in ADvocate-1, ADvocate‑2 and lebrikizumab combination therapy with TCS in ADhere at week 16 in adolescent patients ADvocate-1 ADvocate-2 ADhere Week 16 Placebo N=18 LEB 250 mg Q2W N=37 Placebo N=17 LEB 250 mg Q2W N=30 Placebo + TCS N=14 LEB 250 mg Q2W + TCS N=32 IGA 0 or 1, % a 22.2 48.6 5.9 44.1** 28.6 57.3 EASI 75, % a 22.2 62.2** 12.0 61.7** 57.1 88.0* EASI 90, % a 16.7 45.9* 6.1 34.3* 28.6 55.1 Pruritus NRS (≥ 4-point improvement), % b 22.8 54.3* 0.3 42.1 13.8 45.8 a At Week 16, patients with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥ 2 points from baseline on a 0-4 IGA scale, or a 75% or 90% reduction in EASI from baseline to week 16, respectively. b The percentage is calculated relative to the number of patients with a baseline Pruritus NRS ≥4. * p<0.05; **p<0.01 versus placebo. Adolescent patients treated with lebrikizumab and lebrikizumab + TCS achieved clinically meaningful improvements in disease severity and maintained response up to week 52. Additional data from the single-arm ADore study with lebrikizumab in 206 adolescents support the efficacy of lebrikizumab in adolescent patients up to 52 weeks of treatment. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with lebrikizumab in one or more subsets of the paediatric population in atopic dermatitis (see section 4.2 for information on paediatric use).