FormalPara Key Summary Points

Patients with moderate-to-severe atopic dermatitis (AD) experience debilitating signs and symptoms, including skin lesions, itch, and sleep disturbance due to itch, and their severity can have a detrimental impact on quality of life (QoL).

In this article, we report the sustained impact of lebrikizumab monotherapy over 52 weeks and between visits on itch and sleep loss symptoms, as assessed by Patient-Oriented Eczema Measure (POEM), in patients with moderate-to-severe AD.

Patients reported stable and improved response of AD symptoms (itch and sleep disturbance) with continuous lebrikizumab treatment, regardless of dose, as assessed by POEM. Weekly POEM responses for itch and sleep disturbance remained stable between injections and visits and continued to improve from Week 16 to 52 in lebrikizumab-treated patients, demonstrating consistent improvement over time for key AD symptoms.

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects an estimated 2% to 7% of adults worldwide [1,2,3,4,5]. Patients with moderate-to-severe AD experience debilitating signs and symptoms, including skin lesions, itch, and sleep disturbance due to itch, and their severity can have a detrimental impact on quality of life (QoL) [6,7,8]. The burden of AD is not always captured by physician-reported measures of disease severity, as assessments are completed only when patients visit the clinic. Between visits, patients may still experience burdensome symptoms, and measures that use patient diaries, such as Patient Oriented Eczema Measure (POEM), may provide insight into disease progression and how patients are affected between visits to the clinic. POEM is a patient-reported instrument used to assess disease severity from a patients’ perspective [9, 10]. POEM is recommended for use in clinical trials by the Harmonising Outcome Measures for Eczema group [9, 11].

Treatments that can maintain symptom improvement in AD, like itch and sleep disturbance, can have a positive impact on patient quality of life [6, 8]. In patients with moderate-to-severe AD in two Phase 3 studies (ADvocate1 and ADvocate2), lebrikizumab demonstrated improvement in the cutaneous signs and key symptoms that represents a high burden on the QoL of patients, such as itch and sleep disturbance [12, 13]. Lebrikizumab is an IgG4 monoclonal antibody that selectively binds with high affinity and slow off-rate to interleukin (IL)-13 and inhibits IL-13 signaling through the IL-4 receptor alpha (IL-4Rα)/IL-13 receptor alpha 1 (IL-13Rα1) pathway, thereby blocking the downstream effects of IL-13 with high potency. The clinical profile of lebrikizumab further corroborates the evidence that IL-13 has a dominant role in AD signs and symptoms [12].​

This publication combines data from two Phase 3 trials (ADvocate1 and ADvocate2) to report the sustained impact of lebrikizumab monotherapy, over 52 weeks and between visits, on the frequency of itch and sleep loss symptoms, as assessed by Patient-Oriented Eczema Measure (POEM), in patients with moderate-to-severe AD.

Methods

Study Design

ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) were identically designed 52-week randomized, double-blind, parallel-group, placebo-controlled, monotherapy Phase 3 trials [12]. Eligible patients included adults (≥ 18 years old) and adolescents (≥ 12 to < 18 years old and weighing ≥ 40 kg) with moderate-to-severe AD that met an Eczema Area and Severity Index Score (EASI) of ≥ 16, an Investigator’s Global Assessment (IGA) score of ≥ 3, and a body surface area (BSA) involvement of ≥ 10% and had chronic AD for > 1 year for which topical treatment was no longer advisable or was insufficient at controlling symptoms of AD.

At baseline, patients were randomized 2:1 to either monotherapy lebrikizumab 250 mg (loading dose of 500 mg given at baseline and Week 2) or placebo by subcutaneous (SC) injection every 2 weeks (Q2W). At week 16, LEB Q2W responder patients (patients achieving IGA (0/1) with a ≥ 2-point improvement or EASI 75 without rescue medication) were re-randomized in a 2:2:1 ratio to receive LEB Q2W, LEB 250 mg every 4 weeks (LEB Q4W), or placebo for an additional 36 weeks. The analyses discussed here focus on pooled data across ADvocate1 and ADvocate2 studies, from week 16 LEB Q2W responders, in the maintenance period from Week 16 to 52 who were re-randomized to continue LEB Q2W or to move to LEB Q4W.

ADvocate1 and ADvocate2 studies were approved by the appropriate institutional review boards or ethics committee situated across the 100 study sites in the US, Canada, Europe, and the Asia/Pacific area. Both studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.

POEM Measure

POEM is a 7-item, validated, questionnaire used by patients to assess their daily intensity of disease symptoms over the last week. Patients used their electronic diary once per week to report the frequency of their symptoms by responding to the seven questions on skin dryness, itching, flaking, cracking, sleep loss, bleeding, and wee**. Response categories include “No days,” “1–2 days,” “3–4 days,” “5–6 days,” and “Every day” with corresponding scores of 0, 1, 2, 3, and 4, respectively. The total possible score ranges from 0 to 28, with a high score indicative of increased severity [9, 11]. As POEM is a patient-reported outcome, recorded by patients weekly, it enables continuous assessment of itch and sleep disturbance between clinician visits and doses.

While POEM was reported weekly, the scheduled clinic visits in the maintenance period were every 4 weeks. Control of itch and sleep symptoms between visits was defined as patients having 0 (no days) or 1 (≤ 2 days) response on POEM Items 1 and 2 from Week 16 to Week 52. Item 1 asked, “Over the last week, on how many days has your skin been itchy because of the eczema?”. Item 2 asked, “Over the last week, on how many nights has your sleep been disturbed because of the eczema?”. Data were pooled across both ADvocate1 and ADvocate2 studies.

Statistical Analyses

Analyses were performed on the pooled modified primary maintenance population from ADvocate1 and ADvocate2, excluding 14 patients from ADvocate2 (from a single study site) whose eligibility criteria of having moderate-to-severe AD could not be confirmed. Descriptive analyses were performed using observed data, excluding data collected after rescue medication use or treatment discontinuation.

Results

At Week 16 (rerandomization visit), the total POEM score was 8.6 and 7.7 for patients treated with lebrikizumab Q2W and Q4W, respectively. Lebrikizumab week 16 responders treated with lebrikizumab Q2W and Q4W in the maintenance period reported a mean POEM Item 1 (Itch) score of 3.8 and 3.7 and a mean POEM Item 2 (Sleep) score of 3.0 and 2.9 at baseline, respectively. At Week 16, the mean POEM Item 1 (Itch) score was 2.2 for both groups, and the mean POEM Item 2 (Sleep) score was 1.2 and 1.1, respectively. Patient responses to POEM Item 1 (Itch) and POEM Item 2 (Sleep) at baseline and Week 16 are shown in Table 1. At Week 52, total POEM score was 5.8 and 7.0 for the Q2W and Q4W groups, respectively.

Table 1 The proportion of patients reporting scores of 0, 1, 2, 3, or 4 for POEM Item 1 and POEM Item 2 at baseline and Week 16
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POEM Item 1 (Itch)

At Week 16, in the lebrikizumab Q2W and Q4W treatment arms, 35.9% (n = 37/103) and 39.3% (n = 42/107) responded 0 or 1 to Item 1 of POEM (Itch) and 12.6% (n = 13/103) and 12.1% (n = 13/107) of patients responded 0 to Item 1 of POEM (Itch).

For patients responding 0 or 1 to Item 1 of POEM, response was maintained at Week 24 [32.3% (n = 30/93) and 31.9% (n = 30/94)], Week 32 [51.3% (n = 41/80) and 34.1% (n = 29/85)], Week 40 [46.1% (n = 35/76) and 44.4% (n = 36/81)], and Week 48 [46.3% (n = 31/67) and 50.7% (n = 37/73)] for the lebrikizumab Q2W and Q4W treatment arms, respectively. Likewise, for patients responding 0 to Item 1 of POEM, response was sustained and improved at Week 24 [11.8% (n = 11/93) and 14.9% (n = 14/94)], Week 32 [22.5% (n = 18/80) and 12.9% (n = 11/85)], Week 40 [19.7% (n = 15/76) and 13.6% (n = 11/81)], and Week 48 [17.9% (n = 12/67) and 17.8% (n = 13/73)].

By Week 52, 44.6% (n = 29/65) and 48.0% (n = 36/75) of patients responded 0 or 1 to Item 1 of POEM (Itch) and 21.5% (n = 14/65) and 18.7% (n = 14/75) responded 0 to Item 1 of POEM (Itch) for the lebrikizumab Q2W and Q4W treatment arms, respectively (Fig. 1a, b).

Fig. 1
figure 1

Patient-reported response rates for itch over time: a POEM Item 1 (Itch) “≤ 2 days” (0/1) and b POEM Item 1 (Itch) “No days” (0). Patients recorded responses via electronic diary. Patient study visits occurred every 4 weeks from Week 16 to Week 52. LEB lebrikizumab, LEBQ2W lebrikizumab 250 mg every 2 weeks, LEBQ4W lebrikizumab 250 mg every 4 weeks, Nx number of patients

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POEM Item 2 (Sleep)

At Week 16, in the lebrikizumab Q2W and Q4W treatment arms, 66.0% (n = 68/103) and 72.6% (n = 77/106) of patients responded 0 or 1 to Item 2 of POEM (Sleep) and 37.9% (n = 39/103) and 44.3% (n = 47/106) responded 0 to Item 2 of POEM (Sleep).

For patients responding 0 or 1 to Item 2 of POEM, response was maintained and improved at Week 24 [65.6% (n = 61/93) and 74.5% (n = 70/94)], Week 32 [72.5% (n = 58/80) and 75.0% (n = 63/84)], Week 40 [78.7% (n = 59/75) and 81.5% (n = 66/81)], and Week 48 [80.3% (n = 53/66) and 75.0% (n = 54/72)] for the lebrikizumab Q2W and Q4W treatment arms, respectively. Likewise, for patients, responding 0 to Item 2 of POEM, response was sustained at Week 24 [44.1% (n = 41/93) and 50.0% (n = 47/94)], Week 32 [50.0% (n = 40/80) and 45.2% (n = 38/84)], Week 40 [56.0% (n = 42/75) and 59.3% (n = 48/81)], and Week 48 [54.5% (n = 36/66) and 61.1% (n = 44/72)].

By Week 52, 83.1% (n = 54/65) and 78.4% (n = 58/74) responded 0 or 1 to Item 2 of POEM (Sleep), and 67.7% (n = 44/65) and 59.5% (n = 44/74) of patients responded 0 to Item 2 of POEM (Sleep) for the lebrikizumab Q2W and Q4W treatment arms, respectively (Fig. 2a, b) (Fig. 1).

Fig. 2
figure 2

Patient-reported response rates for sleep disturbance due to eczema over time: a POEM Item 2 (Sleep) “≤ 2 days” (0/1) and b POEM Item 2 (Sleep) “No days” (0). Patients recorded responses via electronic diary. Patient study visits occurred every 4 weeks from Week 16 to Week 52. LEB lebrikizumab, LEBQ2W lebrikizumab 250 mg every 2 weeks, LEBQ4W lebrikizumab 250 mg every 4 weeks, Nx number of patients

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Discussion

In this study, patients reported a stable and continuous improvement in itch and sleep disturbance (as assessed by POEM) for up to 52 weeks of continuous lebrikizumab treatment for both Q4W and Q2W dose regimens. Despite current treatments for moderate-to-severe AD, itch and sleep symptoms remain a significant burden for patients [14]. Therefore, patients require a stable and reliable treatment that will consistently alleviate this burden [15].

Treatment efficacy is typically reported by physicians during a clinic visit. Due to the nature of AD, patients may experience fluctuations in response in between clinic visits and across doses as well as go longer between clinic visits when treated with biologics [16]. This study reports stable response of itch and sleep disturbance in patients treated with lebrikizumab 250 mg every 2 weeks or every 4 weeks after responding to 16 weeks of lebrikizumab treatment every 2 weeks, respectively, using POEM. POEM Item 1 and POEM Item 2 were reported, which asked patients to report the number of days they experienced itch or sleep disturbance, respectively. We reported patients with 0 days and up to 2 days of disturbance for both POEM items. These analyses demonstrated that even between visits and doses, patients reported stable response of symptoms related to itch and sleep disturbance. In particular, these results show that symptoms do not worsen between doses, demonstrating the stability of effect. Maintenance of control of symptoms, like itch and sleep disturbance, improves the QoL of patients with AD [6]. The reduction of these symptoms is important enough that new systemic medications and nanotechnologies are being explored to address symptom control in a variety of ways [17]. In addition, for patients with moderate-to-severe AD, maintaining weekly control of symptoms can lead to reduced burden on everyday tasks, resulting in improved work productivity [18]. Patients in both treatment arms maintained stable response and showed improvements from Week 16 to Week 52, with a large proportion of patients reporting that itch and sleep symptoms were reduced to < 2 days and even 0 days. A larger proportion of patients reported sleep disturbance was reduced to < 2 days and even 0 days compared to itch symptoms. Given the chronicity of AD and its relapsing nature, patients showed a robust and sustained response in symptoms related to itch and sleep disturbance and, importantly, did not suffer extended fluctuating or worsening of symptoms between visits. In addition, both doses maintained similar levels of response over time, translating into a more convenient patient-friendly option.

The assessment of response is not only related to assessing EASI or skin improvement but also related to itch (which is the most burdensome symptom reported by patients) and sleep loss (also reported by patients) [19]. Additionally, previous studies related to lebrikizumab report measures of itch and sleep loss using the Pruritus Numerical Rating Scale (NRS) and the Sleep Loss Scale, respectively, and studies have shown that POEM correlates well with the previously reported Pruritus NRS, which demonstrates consistency in the reported measures [20].

Limitations

The current analysis was not designed to compare treatment arms. Additionally, longer term data, beyond 52 weeks, may provide deeper insights into how control of key symptoms of AD, such as itch and sleep disturbance, is maintained and how it impacts the QoL of patients. Additionally, these data are reported using POEM, which is a patient-reported outcome, and by the nature of being subjective, data from POEM are prone to bias [21].

Conclusion

Weekly POEM responses for itch and sleep disturbance remained stable between doses and visits, and continued to improve from Week 16 to Week 52 in lebrikizumab-treated patients, demonstrating consistent improvement over time for key AD symptoms.