Predicting success with reduced dosing frequency of tralokinumab in patients with moderate-to-severe atopic dermatitis.

Approved tralokinumab maintenance dosing regimens for treatment of moderate-to-severe atopic dermatitis (AD) include 300 mg every 2 weeks (Q2W) and every 4 weeks (Q4W). Clinicians may consider tralokinumab Q4W for patients whose skin has become clear or almost clear at week 16 with initial Q2W dosing. To identify predictive factors associated with maintained response after switching to tralokinumab Q4W, evaluate recapture of treatment response after relapse on Q4W, and assess treatment-emergent immunogenicity with tralokinumab Q4W. These post hoc analyses utilized machine learning to identify predictive factors for maintained treatment response at week 52 using data from the week 16 responder population of the phase III ECZTRA 1 and 2 trials, i.e. patients who met Investigator's Global Assessment of clear/almost clear skin (IGA 0/1) and/or ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab Q2W monotherapy. Top-ranked factors were then assessed individually and together to identify factors associated with a similar maintained efficacy at week 52 between patients rerandomized to tralokinumab Q2W or Q4W monotherapy at week 16. Additionally, the probability of recapturing IGA 0/1 and/or EASI 75 response after relapse was assessed in patients on tralokinumab Q4W transferred to the open-label arm. The two top-ranked predictive factors for maintained response at week 52 were IGA score at week 16 (76.1%) and worst daily pruritus numeric rating scale (NRS) < 3 at week 16 (56.5%). Patients whose AD reached stable clinical response scores of both IGA 0/1 and worst daily pruritus NRS < 3 from weeks 12-16 with tralokinumab Q2W similarly maintained IGA 0/1 response at week 52 regardless of dosing regimen beyond week 16 (72.0% of patients on Q2W and 72.2% of those on Q4W). Of patients who relapsed on Q4W, 94.6% recaptured treatment response after returning to Q2W dosing. The immunogenicity potential of tralokinumab was low, and patients with positive antidrug antibodies did not show loss of efficacy or higher incidences of adverse events. These data suggest that Q4W is an effective dosing regimen for most patients who achieved stable disease control as shown by clear/almost clear skin and no itch to mild itch over 4 consecutive weeks on the initial regimen of tralokinumab Q2W.

Weidinger S ，Bewley A ，Hong HC ，Silvestre JF ，Peris K ，Wollenberg A ，Ivens U ，Soehoel A ，Steffensen LA ，Tindberg AM ，Simpson EL ... -  《-》

Long-term management of moderate-to-severe atopic dermatitis with lebrikizumab and concomitant topical corticosteroids: a 68-week randomized double-blind placebo-controlled phase III trial in Japan (ADhere-J).

Moderate-to-severe atopic dermatitis (AD) affects the quality of life of patients. More treatment options are urgently needed to manage this chronic disease. Lebrikizumab is a monoclonal antibody that binds to interleukin-13, a key mediator in AD pathogenesis. In Japanese patients, lebrikizumab has been evaluated through week 16 in the randomized placebo-controlled phase III ADhere-J study. To evaluate the long-term efficacy and safety of lebrikizumab in combination with topical corticosteroids (TCS) in the ADhere-J study. Patients aged ≥12 years weighing ≥ 40 kg with moderate-to-severe AD and receiving either subcutaneous lebrikizumab 250 mg -every 2 weeks (Q2W)/every 4 weeks (Q4W) or placebo during the 16-week induction period were evaluated during the long-term maintenance period from week 16 to week 68. Responders achieved the co-primary endpoints at week 16: an Investigator's Global Assessment score of 0 or 1 [IGA (0,1)] with ≥ 2-point improvement from baseline and/or ≥ 75% improvement from baseline in Eczema Area and Severity Index (EASI 75). In this analysis, week 16 responders received lebrikizumab 250 mg Q2W or Q4W combined with TCS during the maintenance period (maintenance primary population; MPP); week 16 per-protocol nonresponders received lebrikizumab Q2W with TCS (maintenance escape population; MEP). Major endpoints included IGA (0,1) with ≥ 2-point improvement from baseline and EASI 75 through week 68. Other outcomes included quality of life, itch and serum thymus and activation-regulated chemokine. The trial was registered with ClinicalTrials.gov (NCT04760314). At week 68, 66-81% of 103 patients in the MPP and 32-38% of 168 patients in the MEP achieved IGA (0,1) with ≥ 2-point improvement from baseline. EASI 75 was maintained by 83-89% of patients in the MPP, while 71-80% of patients in the MEP achieved this outcome by week 68. Across treatment arms, patients in the MPP tended to maintain improvements recorded at week 16, while patients in the MEP steadily improved across the maintenance period. No new safety signals were reported, and most treatment-emergent adverse events were mild or moderate in severity in both populations. Safety outcomes were consistent with previous reports for lebrikizumab treatment in global studies. These results support the use of lebrikizumab in combination with TCS for the treatment of moderate-to-severe AD in the Japanese population in the long term.

Katoh N ，Tanaka A ，Takahashi H ，Shimizu R ，Kataoka Y ，Torisu-Itakura H ，Morisaki Y ，Yamamoto C ，Igawa K ... -  《-》

Long-Term Disease Control and Minimal Disease Activity of Head and Neck Atopic Dermatitis in Patients Treated with Tralokinumab up to 4 Years.

There is a need for long-term atopic dermatitis (AD) treatments that can effectively improve AD involvement of the head and neck (H&N) region (referred to as H&N AD). Tralokinumab, a high-affinity monoclonal antibody that neutralizes interleukin-13, is approved for the treatment of moderate-to-severe AD. Recent real-world studies have observed the effectiveness of tralokinumab for H&N AD. Here, data from phase III parent trials, ECZTRA 1 and ECZTRA 2, and the long-term extension trial, ECZTEND, were used to assess impacts of long-term tralokinumab treatment on H&N AD and the association between improvements in H&N AD and patient quality of life, and to evaluate whether a proportion of patients developed paradoxical H&N erythema. These post hoc analyses included data from all patients initiated on tralokinumab in ECZTRA 1 or ECZTRA 2. Patients were treated up to 4 years (i.e., up to 52 weeks in ECZTRA 1 or ECZTRA 2 plus up to 152 weeks in ECZTEND). Outcomes included body region subscores of the Eczema Area and Severity Index (EASI; H&N, upper limbs, trunk, lower limbs) and the Dermatology Life Quality Index (DLQI). Correlations between H&N EASI and DLQI were assessed with Spearman's correlation coefficient (ρ). The incidence of paradoxical H&N erythema (defined as H&N EASI erythema increasing from baseline to a score of 3, while all other regional EASI subscores are 0 or 1, during two or more consecutive visits) was also assessed. Overall, 1192 patients who were initiated on tralokinumab in ECZTRA 1 and ECZTRA 2, of whom 523 patients opted to continue in ECZTEND, were analyzed. Percentages of patients who had H&N EASI ≤ 1 increased from 12.2% at parent trial baseline to 87.2% by week 152 of ECZTEND. Improvements in EASI subscore outcomes from parent trial baseline were comparable across body regions throughout all timepoints of the study. At parent trial week 16, H&N EASI was moderately correlated with total DLQI (ρ = 0.47), with the strongest numerical correlations observed for DLQI questions regarding skin discomfort (ρ = 0.43) and embarrassment due to skin (ρ = 0.40). During up to 4 years of treatment, seven tralokinumab-treated patients exhibited paradoxical H&N erythema, five of whom improved to absent or mild H&N EASI erythema with continued tralokinumab treatment. Tralokinumab provided progressive and sustained improvements in H&N AD, with H&N EASI 0/1 observed in nearly 90% of patients treated up to 4 years. Improvements in H&N EASI were similar to improvements observed for other body regions and were associated with improvements in patient quality of life, particularly for skin discomfort and self-consciousness/embarrassment due to skin. NCT03131648 (ECZTRA 1); study start date: 30 May, 2017; primary completion date: 7 August, 2018; study completion date: 10 October, 2019. NCT03160885 (ECZTRA 2); study start date: 12 June, 2017; primary completion date: 4 September, 2019; study completion date: 14 August, 2019. NCT03587805 (ECZTEND); study start date: 18 March, 2018; data cut-off date: 30 April, 2022; primary completion date: 3 July, 2024; study completion date: 3 July, 2024.

Chovatiya R ，Ribero S ，Wollenberg A ，Park CO ，Silvestre JF ，Hong HC ，Seneschal J ，Saeki H ，Thyssen JP ，Øland CB ，Gjerum L ，Maslin D ，Blauvelt A ... -  《-》

Patients with Moderate-to-Severe Atopic Dermatitis Maintain Stable Response with No or Minimal Fluctuations with 1 Year of Lebrikizumab Treatment.

Lebrikizumab is a novel monoclonal antibody with established efficacy in patients with moderate-to-severe atopic dermatitis (AD) in multiple Phase 3 trials. One of the ultimate treatment goals for patients with moderate-to-severe AD is to achieve stable disease control without concern for planning future life events. In ADvocate1 and ADvocate2, lebrikizumab-treated patients meeting the protocol-defined response criteria at Week 16 were re-randomized 2:2:1 to receive lebrikizumab every 2 weeks (Q2W), lebrikizumab every 4 weeks (Q4W), or placebo Q2W (lebrikizumab withdrawal) for 36 additional weeks. In this post hoc analysis, we evaluated the proportions of patients with no or minimal fluctuations of efficacy during the 36-week maintenance period and plotted individual patient trajectories. We defined no or minimal fluctuations as achieving and maintaining the defined endpoint (≥ 75% improvement in the Eczema Area and Severity Index [EASI 75], ≥ 90% improvement in EASI, Pruritus Numeric Rating Scale [NRS] ≥ 4-point improvement, or Pruritus NRS ≥ 3-point improvement) for ≥ 80% of the study visits. If patients used rescue medication, discontinued treatment, or transferred to the escape arm, data collected at or after the event were imputed as non-response. The proportions of lebrikizumab responders who maintained EASI 75 with no or minimal fluctuations were 70.8% (lebrikizumab Q2W), 71.2% (lebrikizumab Q4W), and 60.0% (lebrikizumab withdrawal). Of the patients with baseline Pruritus NRS ≥ 4 and who achieved ≥ 4-point improvement at Week 16, 66.1% (lebrikizumab Q2W), 62.7% (lebrikizumab Q4W), and 55.2% (lebrikizumab withdrawal) maintained ≥ 4-point Pruritus NRS improvement with no or minimal fluctuations. Patients who met the response criteria at Week 16 and continued treatment with lebrikizumab Q2W or Q4W demonstrated a stable response with no or minimal fluctuations of efficacy in measures of skin and itch up to Week 52. NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2).

Silverberg JI ，Wollenberg A ，Stein Gold L ，Del Rosso J ，Yosipovitch G ，Lio P ，Carrascosa JM ，Gallo G ，Ding Y ，Xu Z ，Casillas M ，Pierce E ，Agell H ，Ständer S ... -  《-》

Efficacy and safety of upadacitinib versus dupilumab in adults and adolescents with moderate-to-severe atopic dermatitis: week 16 results of an open-label randomized efficacy assessor-blinded head-to-head phase IIIb/IV study (Level Up).

Atopic dermatitis (AD) is a chronic skin disease characterized by intense itch and eczematous skin lesions. Some patients with AD continue to experience flares and substantial clinical burden, despite ongoing systemic treatment. To assess the efficacy and safety of once-daily upadacitinib (UPA), initiated at 15 mg and dose-escalated to 30 mg based on clinical response, compared with dupilumab (DUPI) as per its label, and present the week 16 primary analysis results. Level Up is a phase IIIb/IV global randomized open-label efficacy assessor-blinded study evaluating UPA vs. DUPI in adolescents and adults with moderate-to-severe AD who had an inadequate response to systemic therapy or when use was inadvisable. Patients were randomized to UPA or DUPI for 16 weeks of treatment (period 1). Patients on UPA were started on 15 mg and dose-escalated to 30 mg if they did not achieve an Eczema Area and Severity Index reduction of at least 50% (EASI 50) or a ≥ 4-point Worst Pruritus Numerical Rating Scale (WP-NRS) improvement on or after week 4, or an EASI reduction of at least 75% (EASI 75) on or after week 8. The primary endpoint was simultaneous achievement of an EASI reduction of at least 90% (EASI 90) and WP-NRS 0/1 at week 16. Ranked secondary endpoints included skin and itch responses at varying response levels and timepoints. Safety measures were assessed throughout the study. Superior efficacy in achieving simultaneous EASI 90 and WP-NRS 0/1 response at week 16 was demonstrated with UPA vs. DUPI (19.9% vs 8.9%, respectively; P < 0.001). UPA showed superiority over DUPI for all ranked secondary endpoints, with post hoc analyses exhibiting higher itch response rates as early as day 2. No new safety signals were identified in this period. Treatment of moderate-to-severe AD with UPA, initiated at 15 mg and dose-escalated based on clinical response, demonstrated superiority over DUPI per its label for the primary endpoint of simultaneous achievement of near-complete skin clearance (EASI 90) and little-to-no itch (WP-NRS 0/1) at week 16, with all ranked secondary endpoints demonstrating superiority at varying skin and itch response levels and timepoints. No new safety signals were identified vs. the previously reported safety profiles of UPA and DUPI.

Silverberg JI ，Bunick CG ，Hong HC ，Mendes-Bastos P ，Stein Gold L ，Costanzo A ，Ibrahim N ，Sancho C ，Wu X ，Han Y ，Levy G ，Altman K ，Calimlim B ，Eyerich K ... -  《-》