Efficacy of Lebrikizumab on Pruritus: A Narrative Review

Abstract

Atopic dermatitis (AD) is a chronic, relapsing, and heterogeneous skin disease characterized by eczematous morphology and intense pruritus, significantly impacting the quality of life of affected individuals. A primary cytokine implicated in AD is interleukin-13 (IL-13), which directly drives pruritus skin sensitization, contributing to pruritus. Lebrikizumab, a high-affinity IgG4 monoclonal antibody, targets IL-13 to block inflammatory and neuronal sensitization processes. This review aims to provide a comprehensive summary of lebrikizumab's efficacy in managing pruritus in patients with AD, focusing on data from the ADvocate 1&2, ADjoin, ADmirable, and ADhere studies. Clinical trials have demonstrated rapid and sustained improvements in pruritus outcomes, with significant relief observed within days of treatment initiation and maintained over long periods. Lebrikizumab has shown efficacy across diverse populations, including adolescents, the elderly, and skin of color. By effectively targeting IL-13, lebrikizumab offers a valuable treatment option for moderate-to-severe AD, providing significant and sustained pruritus relief, skin clearance, and quality of life improvements.

Key Summary Points

Pruritus is the most burdensome symptom of atopic dermatitis (AD), significantly impairing quality of life and sleep for affected patients.

Lebrikizumab, a high-affinity anti–IL-13 monoclonal antibody, provides rapid and sustained pruritus relief in moderate-to-severe AD, with improvements observed within days and maintained for up to 2 years.

Long-term lebrikizumab therapy leads to deep and stable pruritus responses, with a subset of patients maintaining pruritus improvement and quality of life even after treatment withdrawal.

Efficacy of lebrikizumab is consistent across diverse populations, including adolescents, elderly patients, and individuals with skin of color.

Compared to other systemic therapies, lebrikizumab demonstrates a favorable safety profile and robust, durable pruritus control, supporting its role as a valuable treatment option for moderate-to-severe AD.

Introduction

Atopic dermatitis (AD) is a chronic, relapsing skin disease that manifests with typical eczematous morphology and intense pruritus [1]. This disease affects a significant portion of the global population (up to 30% of children and 2–18% of adults), depending on the region [2, 3]. The hallmark symptom of AD is pruritus, reported as the most burdensome aspect of the disease across all severity levels—mild, moderate, and severe [4, 5]. The impact of pruritus on patients' quality of life represents a global concern, as it disrupts sleep, leading to daytime sleepiness, reduced functional activity, and overall health deterioration [6, 7].

The etiology of AD is complex, involving genetic, environmental, and immunological factors [8]. Interleukin-13 (IL-13) has been implicated as the primary cytokine in AD that drives skin inflammation and barrier abnormalities. It contributes directly to pruritus by upregulating pruritus-relevant gene expression in sensory neurons, enhancing neuronal responses to pruritus stimuli, and lowering the pruritus threshold of sensory neurons [9].

Due to its chronic nature, AD requires long-term management and care, including the avoidance of triggers like allergens and irritants, proper skin care and moisturizing, prescription topical therapy, and phototherapy [10, 11]. While these management strategies are effective in treating the signs, they do not address the underlying systemic inflammation related to altered expression of IL-13 [12]. In patients with AD, there is evidence that IL-13 is highly expressed in both lesional and non-lesional areas of the skin [13, 14], and pruritus can be generalized rather than localized to lesional areas of the skin. Consequently, long-term management cannot rely solely on topical therapies when they are insufficient to control the disease, or therapies targeting primarily pruritus without addressing the skin disease pathophysiology. Systemic therapies are essential for effectively managing the underlying systemic inflammation that leads to AD [15].

In recent years, the development of systemic therapies, such as Janus kinase (JAK) inhibitors and biologics, has provided new therapeutic options for AD. JAK inhibitors, including baricitinib, abrocitinib, and upadacitinib, are known for their rapid and effective action in reducing skin inflammation and pruritus [16]. However, they come with safety concerns, including the need for laboratory test monitoring and a black box warning in the United States (US) due to potential risks [17]. Similarly, the European Medicines Agency has issued guidance restricting the use of JAK inhibitors in certain patient populations, advising against their use in those aged 65 years and older, those with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, and those with malignancy risk factors, including current or past cancer [18]. On the other hand, biologics, including monoclonal antibodies like lebrikizumab, dupilumab, tralokinumab, and nemolizumab, target specific cytokines involved in the pathophysiology of AD. These targeted therapies offer a more precise approach to managing the disease, allowing long-term treatment strategies [15].

Lebrikizumab is a novel monoclonal antibody that selectively binds with high affinity and slow off-rate to IL-13, thereby blocking the downstream effects of IL-13 with high potency [19]. By selectively binding to IL-13, lebrikizumab helps to modulate the inflammatory processes that contribute to the symptoms of AD, including skin inflammation and pruritus [9]. To date, lebrikizumab has been approved as a monotherapy treatment in the US, Canada, the European Union, the United Kingdom, Japan, Saudi Arabia, and Brazil for the treatment of moderate-to-severe AD in adults and adolescents aged 12 years and older who weigh at least 40 kg and are candidates for systemic therapy [20].

The pruritus–scratch cycle is a critical aspect of AD that significantly impacts disease progression and patient quality of life. Pruritus is defined as an uncomfortable sensation on the skin that causes a desire to scratch [21]. Scratching temporarily relieves pruritus through the activation of pain-sensory fibers that can inhibit pruritus at the spinal cord level [22]. However, chronic pruritus can drive persistent scratching responses that cause mechanical disruption of the skin. This cycle involves crosstalk between multiple host cellular networks, including the stromal, immune, and sensory nervous systems [21]. In AD, the central symptom is chronic pruritus, often referred to as the ‘itch that rashes,’ where the urge to scratch is uncontrollable [23].

The aim of this review is to provide a comprehensive summary of the efficacy of lebrikizumab in managing pruritus in patients with AD. This review will focus on data from the ADvocate1&2, ADhere, ADjoin, and ADmirable clinical trials. Additionally, we will explore the efficacy of lebrikizumab in specific populations of interest, including adolescents, the elderly, and skin of color [24, 25]. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

The ADvocate 1&2 monotherapy clinical trials were identically designed, randomized, double-blind, placebo-controlled, phase 3 studies in which adult and adolescent patients with moderate-to-severe AD who achieved a clinical response—defined as an Investigator Global Assessment score of 0 or 1 (IGA 0/1) or a 75% improvement in Eczema Area and Severity Index (EASI75), and without the use of rescue medication—at Week 16 were re-randomized to receive subcutaneous injections of lebrikizumab 250 mg every 4 weeks (Q4W), every 2 weeks (Q2W), or placebo (lebrikizumab withdrawal) for the maintenance period from Weeks 16 to 52 [25]. The ADhere clinical trial was a 16-week randomized, double-blinded, placebo-controlled, phase 3 study that included adult and adolescent patients with moderate-to-severe AD in which patients were randomized to subcutaneous lebrikizumab 250 mg Q2W or placebo in combination with topical corticosteroids (TCS) for 16 weeks [26]. Patients who completed participation in ADvocate 1&2, ADhere, and other lebrikizumab phase 3 studies were offered the opportunity to enroll in the long-term ADjoin study, where efficacy outcomes were assessed up to Week 110 [27]. Additionally, the ADmirable clinical trial was a phase 3b, open-label, 24-week study to evaluate the efficacy and safety of lebrikizumab in adult and adolescent patients with moderate-to-severe AD and skin of color (Fitzpatrick phototypes IV–VI) [28].

What is the Role of IL-13 in AD Pruritus?

Several type 2 cytokines, including IL-4 and IL-31, are involved in the pathophysiology of AD, but increasing evidence supports a pivotal role of IL-13 in driving the inflammatory processes associated with the disease. These cytokines also play an important role in mediating and modulating the predominantly non-histaminergic pruritus pathways that are responsible for pruritus in AD [29]. Note that H1 antihistamines do not provide relief for pruritus in patients with AD [30].

The non-histaminergic pruritus pathway in AD is largely driven by IL-13 and other type 2 cytokines such as IL-4, IL-31, and IL-33, and thymic stromal lymphopoietin [30]. These cytokines are not only key drivers of inflammation in AD but are also found to be elevated in the lesional and non-lesional skin of affected individuals compared to control [31, 32]. Indeed, IL-13 plays a central role in the pathogenesis of pruritus in AD. The receptors for IL-13 signaling, IL-13Rα1 and IL-4Rα, are expressed in human dorsal root ganglia, the cell bodies of peripheral sensory neurons. Although IL-13 itself is not a pruritogen, it has been shown to directly stimulate and sensitize sensory neurons to pruritogens by driving nerve fiber outgrowth and branching, and increasing neuronal excitability, thereby contributing to the sensation of pruritus (Fig. 1) [33, 34].

Fig. 1.

IL-13 drives pruritus sensitization in AD. IL-13 activates IL-13Rα1 and IL-4Rα receptors, which are expressed in human sensory neurons. Although IL-13 itself is not a pruritogen, it directly stimulates and sensitizes sensory neurons to pruritogens, thereby contributing to the sensation of pruritus

IL-4 contributes to pruritus by disrupting the epidermal barrier, promoting inflammation, and sensitizing sensory neurons. It is released by hematopoietic cells and decreases the expression of proteins like filaggrin, loricrin, and involucrin in keratinocytes, leading to barrier dysfunction [35]. IL-4 signals through the IL-4Rα/IL/13Rα1 receptor complex on non-hematopoietic cells and the IL-4Rα/common γ-chain complex on hematopoietic cells, activating downstream pathways such as JAK/STAT. IL-31 acts as a pruritogen by binding to its receptor IL-31RA/OSMRβ on various cells, including keratinocytes, nerve endings, and dorsal root ganglia. It signals through pathways like JAK/STAT, contributing to pruritus and neurogenic inflammation [36].

Patients with AD often experience pruritus in non-lesional skin, and IL-13 is the only cytokine consistently found to be elevated in non-lesional skin [29]. IL-13 gene expression in lesional and non-lesional skin was shown to be greater than IL-4 and IL-31 in patients with AD [32]. The elevation of IL-31 in non-lesional skin is controversial, while IL-4 is not elevated in non-lesional skin [32, 37]. Also, in serum, IL-13 levels have been described to be sevenfold higher than in healthy controls; instead, IL-4 levels were not significantly different in the serum of patients with AD versus healthy controls [38]. This highlights the importance of systemic therapies, such as targeted biologics, in managing AD when topical therapies are insufficient. Therapeutic agents, including lebrikizumab, have demonstrated efficacy in blocking pruritus signaling in vitro and in vivo. For instance, an experiment utilizing human dorsal root ganglia cells demonstrated that blockade of IL-13 with lebrikizumab inhibited neuronal excitability and transcriptional downstream of pruritus-related targets [34].

In summary, type 2 cytokines, IL-4, IL-31, and IL-13, play a role, which is pivotal for IL-13 in driving the inflammatory processes and non-histaminergic pruritus associated with AD. Elevated levels of IL-13 in lesional and non-lesional skin contribute significantly to the pathogenesis of pruritus by sensitizing sensory neurons to pruritogens. This mechanism highlights the ineffectiveness of H1 antihistamines in providing relief for AD-related pruritus, as pruritus is predominantly mediated through non-histaminergic pathways. Therapeutic agents like lebrikizumab, which target IL-13, have been shown to block pruritus signaling. By effectively targeting IL-13, lebrikizumab offers a valuable treatment option for patients with moderate-to-severe AD, addressing both the inflammatory and sensory components of the disease and significantly improving patient quality of life.

How Quickly can Lebrikizumab Treatment have an Observed Impact on Pruritus in AD?

In clinical trials of moderate-to-severe AD, the efficacy of lebrikizumab in alleviating pruritus has been assessed using the Pruritus Numeric Rating Scale (NRS), a patient-reported measure [39]. The Pruritus NRS is an 11-point scale where patients rate the severity of their worst pruritus over the past 24 h, with 0 indicating “No itch” and 10 indicating “Worst itch imaginable” [39]. Patients with AD treated with lebrikizumab have reported significant improvements in pruritus outcomes within days of receiving their first dose. In the ADvocate1 study, daily diary data revealed a significantly greater percentage change from baseline in Pruritus NRS scores as early as day 2 with lebrikizumab Q2W compared to placebo [least squares mean (LSM) − 9.8% vs. − 2.3% respectively, p = 0.002]. Similarly, in the ADvocate2 study, a significantly greater improvement was seen by day 10 with lebrikizumab Q2W compared to placebo (LSM − 12.7% vs. − 3.3% respectively, p = 0.005) (Fig. 2) [40]. These early improvements highlight lebrikizumab’s rapid onset of action in alleviating pruritus symptoms and confirm that lebrikizumab’s impact on itch is more direct, decreasing neuronal excitability by downregulating IL-13 signaling [34], and is not mediated by the suppression of inflammation. Weekly averages further demonstrated that patients in both ADvocate 1&2 studies experienced significantly greater percentage changes from baseline in Pruritus NRS scores during the first week of lebrikizumab treatment [41]. Post-baseline weekly Pruritus NRS scores were calculated by averaging the daily scores from the previous 7 days for patients with ≥ 1 non-missing values. This rapid response provides timely relief and improves both the quality of sleep and of life in patients with AD with pruritus.

Fig. 2.

Early improvements in pruritus by lebrikizumab in the ADvocate studies. Daily diary data showed that patients who received lebrikizumab 250 mg Q2W experienced a significantly greater LSM percentage change from baseline in Pruritus NRS scores compared to those who received placebo, as early as day 2 in ADvocate 1 (highlighted in the red rectangle) and as early as day 10 in ADvocate 2. Data is shown as mean. *P < 0.05; **P < 0.01; ***P < 0.001 vs. placebo. Q2W lebrikizumab 250 mg every 2 weeks, LSM least squares mean, NRS numeric rating scale

The minimal clinically important difference (MCID) for Pruritus NRS is defined as a 3-point improvement from baseline. This was achieved by significantly more lebrikizumab-treated patients compared to placebo-treated patients by Week 2 in ADvocate1 and by Week 4 in ADvocate2. Approximately 50% of patients who received lebrikizumab reported this outcome by Week 16, compared to only 14–19% of patients who received placebo. Furthermore, patients treated with lebrikizumab reported no or minimal pruritus (Pruritus NRS score of 0 or 1) from Week 4 onwards, with approximately 20% of lebrikizumab-treated patients achieving this outcome by Week 16, compared to just 5% of placebo-treated patients [40].

What is the Long-Term Effect of Lebrikizumab on Pruritus Outcomes in AD?

The long-term efficacy of lebrikizumab in managing pruritus has been well-documented in patients with moderate-to-severe AD, with improvements maintained beyond the initial 16 weeks of treatment, in the maintenance period of the ADvocate 1&2 clinical trials (Weeks 16–52), and in the ADjoin long-term extension study up to Week 104. During this period, intermittent use of TCS/topical calcineurin inhibitor (TCI) was allowed, but the majority of patients did not receive any topical therapy. Moreover, 88% of patients in the lebrikizumab Q4W treatment arm, 90% of patients in the lebrikizumab Q2W treatment arm, and 87% in the lebrikizumab withdrawal arm did not use TCS during the maintenance period of ADvocate 1&2 (Fig. 3) (Simpson, unpublished).

Fig. 3.

Use of TCS in patients treated with lebrikizumab during the maintenance period of ADvocate 1&2 (Week 16–52). Proportion of lebrikizumab IGA (0,1) or EASI 75 responders at Week 16 of ADvocate1 and ADvocate2 who did not use TCS during the ADvocate1 and ADvocate2 maintenance period. EASI 75 at least 75% improvement in Eczema Area and Severity Index, IGA (0,1) Investigator Global Assessment score 0 or 1, N number of patients in the analysis population, Q4W every 4 weeks, Q2W every 2 weeks, TCS topical corticosteroid

At Week 52, amongst the lebrikizumab Week 16 responders, 73% of patients who received lebrikizumab Q4W and 72% of patients who received lebrikizumab Q2W reported an MCID [42]. Additionally, these patients experienced significant relief, with those receiving lebrikizumab Q4W and Q2W reporting 12 and 11 pruritus-free days per month, respectively, or approximately 3 days per week, with no or minimal pruritus [42].

By Week 104, this positive response continued, with 86% of patients who received lebrikizumab Q4W and 85% of patients who received lebrikizumab Q2W maintaining a ≥ 3-point improvement in Pruritus NRS, based on the population of Week 16 skin responders [43]. Additionally, among these Week 16 skin responders, 55% of patients who received lebrikizumab Q4W and 57% of patients who received lebrikizumab Q2W reported Pruritus NRS scores of 0 or 1 by Week 104 [44] (Simpson, unpublished).

Separately, for patients who had achieved a 4-point improvement in Pruritus NRS at Week 16, this response was sustained through Week 104, with 90% of patients who received lebrikizumab Q4W and 100% of patients who received lebrikizumab Q2W maintaining their improvement [45]. Thus, these data point out the significant and sustained impact of lebrikizumab on pruritus reduction in patients with AD over the long term, providing consistent relief and improving overall quality of life.

The majority of patients who achieved a skin response also maintained a stable long-term response with no or minimal fluctuations in pruritus with lebrikizumab monotherapy for up to one year, and without any use of rescue medication. In the ADvocate 1&2 studies, the proportions of lebrikizumab responders who maintained EASI 75 or deeper for the majority of study visits in the maintenance period were 71% in the lebrikizumab Q4W treatment arm and 71% in the lebrikizumab Q2W treatment arm [46]. Importantly, stability was assessed using individual patient-level data, not population averages. This analysis evaluated the extent to which each patient sustained their response over time, with “stability with minimal fluctuations” defined as maintaining the same level of response at ≥ 80% of visits, and “stability with no fluctuations” defined as maintaining it at 100% of visits [46].

Week 16 responders who reported at least a 3-point improvement from baseline in Pruritus NRS at Week 16 demonstrated sustained benefits. Specifically, 72% of patients who received lebrikizumab Q4W and 65% of patients who received lebrikizumab Q2W maintained at least a 3-point improvement from baseline in Pruritus NRS for at least 80% of the study visits from Week 16 to Week 52 [46]. Similarly, among patients who reported at least a 4-point improvement from baseline in Pruritus NRS, 63% of those receiving lebrikizumab Q4W and 66% of those receiving lebrikizumab Q2W maintained this level of improvement for the majority of study visits during the same period (Fig. 4) [46].

Fig. 4.

Proportions of patients maintaining Pruritus NRS ≥ 3 or ≥ 4-point improvement for ≥ 80% of study visits (up to Week 52). Patients had baseline Pruritus NRS ≥ 3 or ≥ 4 and achieved a ≥ 3 or ≥ 4-point improvement at Week 16 in the ADvocate 1 and 2 studies. Data collected after rescue medication use (any topical/systemic therapy), treatment discontinuation, and moving to the escape arm were imputed as non-response. LEB lebrikizumab, NRS numeric rating scale, Q4W every 4 weeks, Q2W every 2 weeks

Similar stability of the response to lebrikizumab is further evidenced in the withdrawal/placebo arm. After lebrikizumab discontinuation, during the maintenance period (Weeks 16–52), 60% of patients maintained a stable EASI 75 with no or minimal fluctuations for the majority of study visits, and without any use of rescue medication. Similarly, 55% of these patients maintained a stable 4-point improvement in Pruritus NRS from baseline with no or minimal fluctuations at an individual basis (Fig. 4) [46].

Furthermore, the long-term efficacy of lebrikizumab was demonstrated over a period of 104 weeks. Among patients treated with lebrikizumab Q4W and Q2W, 96% and 92% respectively, maintained a stable EASI 75 response or higher for the majority (80–100%) of attended visits from Week 16 to Week 104. For the more stringent EASI 90 outcome measure, 81% of patients in the lebrikizumab Q4W treatment arm and 79% in the lebrikizumab Q2W treatment arm maintained a stable response for at least 80% of attended visits (Silverberg, unpublished).

In terms of pruritus, 94% of patients treated with lebrikizumab Q4W and 89% of patients treated with lebrikizumab Q2W maintained a stable 3-point or greater improvement in Pruritus NRS for the majority of study visits from Week 16 to Week 104. When looking at more stringent response criteria, 88% in the lebrikizumab Q4W group and 87% in the lebrikizumab Q2W group maintained a stable 4-point or greater improvement with no or minimal fluctuations in pruritus over the same 2-year period. These findings highlight the stability of lebrikizumab in maintaining pruritus improvement over an extended duration in patients with AD (Silverberg, unpublished).

This analysis is distinct because it focuses on the stability of efficacy in patients treated with lebrikizumab for moderate-to-severe AD over an extended period. Unlike conventional regulatory and clinical trial endpoints that are cross-sectional, this study emphasizes the longitudinal dimension of long-term stable disease control and minimal fluctuations in efficacy, which is extremely relevant in a chronic disease characterized by alternating periods of unpredictable flares. The visualization of stability data helps translate population-based results to individual patient outcomes, showing that lebrikizumab can provide robust and sustained responses for both skin clearance and pruritus relief.

Lebrikizumab’s ability to induce and maintain stable deep response up to therapy-free remission may be explained by its potential disease-modifying properties [47]. This finding is particularly significant when considering that a subset of patients were able to maintain clinical benefits and long-lasting, deep, and stable pruritus relief without receiving any concomitant rescue therapies, including TCS, and with a significant impact on the overall quality of life [48]. Among Week 16 skin responders who remained in the withdrawal arm through Week 52, 32% achieved Pruritus NRS 0/1, further supporting the durability of response and potential for disease modification. Indeed, lebrikizumab responders in the withdrawal arm who achieved Pruritus NRS 0/1 at Week 52 also reported a substantial improvement in quality of life, with mean DLQI scores decreasing from 10.5 at baseline to 1.3 at Week 52 [48].

How Effective is Lebrikizumab in Relieving Pruritus in AD Populations of Special Interest?

Lebrikizumab has demonstrated efficacy in improving pruritus across various populations of special interest, including adolescents, the elderly, and patients with skin of color (Table 1).

Table 1.

Proportion of patients achieving ≥ 4-point improvement in Pruritus NRS at Week 16 across populations of special interest

Population	Trial	Lebrikizumab (%)	Placebo (%)
Adolescents	ADvocate	49	13
Adolescents	ADhere	46	14
Elderly	ADvocate	46	12
Asian	ADvocate	36	6
Black/African American	ADvocate	42	17
Skin of color	ADmirablea	56	NA

^aPlacebo data for ADmirable is not available due to open-label design

Adolescents

In the lebrikizumab ADvocate 1&2 clinical trials, adolescent patients with moderate-to-severe AD aged ≥ 12 to < 18 years and weighing at least 40 kg were also included (n = 67 lebrikizumab, n = 35 placebo). Starting from Week 4, a significantly greater proportion of adolescent patients receiving lebrikizumab reported at least a 4-point improvement from baseline in Pruritus NRS compared to those receiving placebo. By Week 16, 49% of adolescent patients who received lebrikizumab Q2W reported a 4-point improvement in Pruritus NRS, compared to only 13% of those who received placebo [49]. In the ADhere clinical trial (adolescents: n = 32 lebrikizumab + TCS, n = 14 placebo + TCS), 46% of adolescent patients who received lebrikizumab Q2W with concomitant TCS reported a 4-point improvement, compared to 14% of patients who received TCS only, although this was not statistically significant [26, 49].

Elderly

A total of 98 patients with moderate-to-severe AD and age ≥ 60 years participated in the ADvocate 1&2 clinical trials (n = 70 lebrikizumab, n = 28 placebo). Improvement in pruritus was observed at Week 16 in elderly patients, among whom 46% of those who received lebrikizumab Q2W reported a 4-point improvement in Pruritus NRS, compared to 12% of those who received placebo [50].

Skin of Color

AD can vary in severity across different racial and ethnic groups, with patients with skin of color often reporting a higher burden of pruritus compared to white patients. An analysis of data from the CorEvitas AD Registry, which includes clinical sites throughout the US and Canada, showed that Black and Hispanic patients reported significantly higher mean pruritus over the past 7 days compared to White patients [51]. A post hoc subgroup analysis of the ADvocate 1&2 studies showed no significant differences among treatment arms for the proportion of patients reporting at least a 4-point improvement in Pruritus NRS across Asian, Black/African American, White, or Hispanic Latino patients [52].

From a post hoc analysis of ADvocate 1&2, a higher proportion of patients who received lebrikizumab reported at least a 4-point improvement in Pruritus NRS scores compared to those who received a placebo by Week 16. Specifically, 36% of Asian patients treated with lebrikizumab achieved this improvement, compared to only 6% of those on placebo. Similarly, 42% of Black/African American patients reported this 4-point improvement compared to 17% of those on placebo [52].

In the open-label study ADmirable, a study specifically designed to assess lebrikizumab in patients with skin of color and moderate-to-severe AD, patients received lebrikizumab as per US label through Week 24. The Week 16 results show that 66% and 56% of patients reported at least 3- and 4-point improvements, respectively, in Pruritus NRS [28]. This response was maintained through Week 24, with 60% of patients continuing to report a ≥ 4-point improvement in Pruritus NRS after 6 months of continuous treatment.

Why is Efficacy on Pruritus Important for Patients with AD?

Pruritus is the most burdensome symptom of AD, with effects that extend beyond physical discomfort. It frequently disrupts sleep, leading to daytime fatigue, impaired functioning, and reduced quality of life [53–55].

The consequences of pruritus are not limited to personal discomfort and reduced quality of life. There are also significant economic implications. Increased absenteeism and presenteeism in the workplace are common among individuals suffering from AD, as the persistent pruritus and its effects on sleep make it difficult for them to perform optimally [56, 57]. Additionally, the direct healthcare resource utilization associated with managing AD and its symptoms further adds to the economic burden [56]. The broad impacts on patients' lives highlight the necessity for treatments that effectively address the debilitating symptom of pruritus.

The rapid and significant impact of lebrikizumab is observed within the first weeks of treatment including improvements in pruritus [40, 41]. Lebrikizumab not only improved pruritus but also reduced the interference of pruritus on sleep and enhanced the quality of life for patients with moderate-to-severe AD, as demonstrated in ADvocate 1&2 [58, 59]. Indeed, significantly greater proportions of pruritus responders had a clinically meaningful improvement in measures related to quality of life [Dermatology Life Quality Index (DLQI) scores (0/1), DLQI ≤ 5 total score, and ≥ 4-point DLQI improvement] compared to pruritus non-responders, where pruritus responders were defined as having a weekly mean ≥ 4-point reduction in Pruritus NRS from baseline to Week 16 [58]. By effectively managing pruritus, lebrikizumab not only alleviates the immediate discomfort but also contributes to better sleep quality, improved daytime functioning, and overall enhanced quality of life for patients.

How does the Efficacy of Lebrikizumab on Symptoms of Pruritus Fit Within the Broader Context of Available Biologic Therapies for AD?

Biologic therapies targeting type 2 cytokines have transformed the treatment landscape for moderate-to-severe AD. Among these, lebrikizumab has demonstrated rapid and sustained efficacy in reducing pruritus, with improvements observed as early as Day 2 and maintained through Week 104. To contextualize its performance, a network meta-analysis compared lebrikizumab 250 mg Q2W with dupilumab 300 mg Q2W and tralokinumab 300 mg Q2W. At Week 4, lebrikizumab showed comparable odds of achieving a ≥ 4-point reduction in Pruritus NRS versus dupilumab (OR 0.67, 95% CrI 0.38–1.18) and superior odds compared to tralokinumab (OR 0.37, 95% CrI 0.19–0.70) [60]. By Week 16, lebrikizumab remained comparable to dupilumab (OR 0.79, 95% CrI 0.48–1.24) and continued to outperform tralokinumab (OR 0.39, 95% CrI 0.23–0.63) [60].

Clinical trials of dupilumab, an IL-4 receptor blocker, have shown that 41–40% of patients in SOLO 1 and 36–39% in SOLO 2 achieved a ≥ 4-point improvement in Pruritus NRS by Week 16 [61]. Long-term extension studies demonstrated sustained benefits, with 64% of patients maintaining this level of improvement by Week 76 [62]. For tralokinumab, an IL-13-specific monoclonal antibody, 20% and 25% of adult patients achieved a ≥ 4-point reduction in Pruritus NRS by Week 16 in the ECZTRA 1 and ECZTRA 2 trials, respectively [63]. The IL-31 receptor blocker nemolizumab, recently approved in combination with TCS/TCI, demonstrated early onset of pruritus relief, with ≥ 4-point reductions in peak Pruritus NRS achieved by 27% and 26% of patients at Week 4 in the ARCADIA 1 and 2 trials, respectively, and by 43% and 41% at Week 16 [64].

What is the Safety Profile of Lebrikizumab in Patients with AD?

The safety of lebrikizumab has been extensively evaluated across multiple clinical trials involving adults and adolescents with moderate-to-severe AD and has been shown to be consistent across 10 global trials and 2271 patient-years of exposure [65]. Two comprehensive analyses provide consistent evidence supporting the favorable tolerability of lebrikizumab (one systematic review and meta-analysis [66], and one integrated safety analysis [65]).

Across the analyzed global trials, the incidence of treatment-emergent adverse events (TEAEs) was similar between Q2W lebrikizumab and placebo groups, with most events being mild or moderate in severity. Serious adverse events (SAEs) were also comparable between Q2W lebrikizumab and placebo groups (1.1% vs. 1.8%) [65]. The most commonly reported adverse drug reactions associated with lebrikizumab include conjunctivitis (10%), injection site reactions (3%), and herpes zoster (< 1%) [67]. Importantly, the rate of AE leading to trial discontinuation was low, with 2.2% in Q2W lebrikizumab-treated patients compared to 1.7% in placebo groups [65].

Future Research and Limitations

While lebrikizumab has demonstrated significant efficacy in achieving skin clearance in patients with AD, it also has proven to be effective in providing significant relief from pruritus. One of the primary challenges in assessing pruritus is its qualitative nature. Pruritus is a subjective symptom that can vary widely among patients, making it difficult to quantify accurately. The current method of collecting pruritus data through daily diary entries can be burdensome for patients, leading to potential issues with missing data, especially in the long term [68]. Future studies should explore alternative methods for capturing pruritus data that are less intrusive and more reliable.

Wearable devices such as actigraphy offer a non-invasive approach to monitoring pruritus-related activity and sleep disruption in research settings. While cost-effective and suitable for long-term observation, actigraphy has limitations in accurately capturing pruritus severity and may be influenced by external factors like movement and environment, making it less applicable for routine clinical use [69].

Additionally, the nature of pruritus in AD is complex, with different types of pruritus sensations such as stinging and burning. Understanding the specific characteristics of pruritus experienced by patients and how lebrikizumab affects these different types of pruritus will be crucial for optimizing treatment strategies. Further research is needed to elucidate the mechanisms underlying these various pruritus sensations and to determine the most effective ways to address them.

Conclusion

Lebrikizumab is an approved treatment option for managing patients with moderate-to-severe AD, and is strongly recommended with a high level of evidence by the recently updated AAD guidelines [70]. The rapid onset of action, with significant improvements in pruritus observed within the first days of treatment, highlights its potential to provide timely relief for patients with AD suffering from this debilitating symptom. The long-term efficacy of lebrikizumab is well-documented, with deep and stable pruritus responses sustained up to 2 years of treatment. This stability in response highlights the durability of the therapeutic effects of lebrikizumab, offering consistent pruritus relief and enhancing the quality of life for patients with AD. A remarkable and unique feature of lebrikizumab is the extent of maintaining pruritus improvement for up to 1 year in a subset of patients that discontinued treatment after the initial 16-week induction period, suggestive of lebrikizumab disease-modifying properties.

Furthermore, lebrikizumab has demonstrated efficacy across various populations of special interest, including adolescents, the elderly, and patients with skin of color. This broad applicability ensures that diverse patient groups can benefit from its therapeutic effects. By selectively targeting IL-13 with a high binding affinity and slow dissociation rate, lebrikizumab, directly and indirectly, impacts molecular pathways underlying the pathognomonic skin manifestations and pruritus of AD. Taken together, lebrikizumab represents an effective and valuable treatment for AD, providing significant and sustained relief from pruritus and improving the overall well-being of patients.

Author Contributions

Gil Yosipovitch, Brian S. Kim, Sonja Ständer, Sarina B. Elmariah, Vimal H. Prajapati, Kenji Kabashima, Gaia Gallo, Maria Jose Rueda, Evangeline Pierce, Yuxin Ding, and Shawn Kwatra contributed to the conception and design of the review, provided critical intellectual input to manuscript drafts, critically revised the manuscript, and approved the final version for submission.

Funding

The journal’s Rapid Service Fee and Open Access Fee were funded by Eli Lilly.

Data Availability

Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at http://www.vivli.org.

Declarations

Conflict of Interest

Gil Yosipovitch has participated as a Consultant or Board Member for Sanofi, Regeneron, Galderma, Pfizer, Novartis, Eli Lilly, AbbVie, Arcutis, Vifor, Kamari, Kiniksa, Trevi Therapeutics, Pierre Fabre, LEO Pharma, Escient Health, Celldex, and GSK. He has received research support from Pfizer, Sanofi, Regeneron, LEO, Eli Lilly, Kiniksa, Novartis, Escient, Bellus, Galderma, and Celldex. Brian S. Kim is co-founder of Alys Pharmaceuticals; he has served as a consultant for 23andMe, ABRAX Japan, AbbVie, Amgen, Attovia Therapeutics, Cara Therapeutics, Clexio Biosciences, Eli Lilly and Company, Escient Pharmaceuticals, Evommune, Galderma, LEO Pharma, Micreos, Novartis, Pfizer, Recens Medical, Regeneron, Sanofi, Septerna, Teva, Trevi Therapeutics, Triveni Bio; he has stock in ABRAX Japan, Alys Pharamaceuticals, Attovia Therapeutics, Locus Biosciences, Recens Medical and Triveni Bio; he holds a patent for the use of JAK1 inhibitors for chronic pruritus. Sonja Ständer was speaker and/or consultant and/or investigator and/or has received research funding from Almirall S. A., Amgen Inc., Amgen Europe GmbH, Celldex Therapeutics Inc., Clexio Biosiences Ltd., Focus-Insight Healthtech Group Co. Ltd., Galderma Laboratorium GmbH, Galderma R&D LLC., Galderma S.A., GSK R&D Ltd., Incyte Corporation, Klirna Biotech Inc., Leo Pharma, Lilly Deutschland GmbH, Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, Sanofi-Aventis R&D, Sanofi Genzyme Corporation, TouchIME, Vifor Pharma Deutschland GmbH P. G. Unna Academy. Sarina B. Elmariah has served as an advisory board member, consultant or received honoraria from Celldex, Galderma, Eli Lilly, New Frontier Bio, Novartis, Pfizer, Regeneron, and Sanofi. Vimal H. Prajapati has been an advisor, consultant, and/or speaker for: AbbVie, Actelion, Amgen, Apogee Therapeutics, Aralez, Arcutis, Aspen, Bausch Health, BioJAMP/JAMP Pharma, BioScript Solutions, Boehringer Ingelheim, Bristol Myers Squibb, Canadian Psoriasis Network, Celgene, Celltrion, Cipher, CorEvitas, Eczema Society of Canada, Eli Lilly, Galderma, GlaxoSmithKline, Homeocan, Incyte, J&J Innovative Medicine, Janssen, Johnson & Johnson, LEO Pharma, Medexus, Novartis, Organon, Paladin, Pediapharm, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, Tribute, and UCB; investigator for: AbbVie, AnaptysBio, Apogee Therapeutics, Apollo Therapeutics, Arcutis, Arena, Asana, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Concert, CorEvitas, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, J&J Innovative Medicine, Janssen, LEO Pharma, Nektar Therapeutics, Nimbus Lakshmi, Novartis, Pfizer, RAPT Therapeutics, Regeneron, Reistone, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, and Vyne Therapeutics; and received grants from: AbbVie, Bausch Health, Janssen, LEO Pharma, Novartis, and Sanofi Genzyme. Kenji Kabashima has received consulting fees, honoraria, grant support, and/or lecture fees from AbbVie, Amgen, Eli Lilly, Kyowa Kirin, Japan Tobacco, LEO Pharma, Maruho, Mitsubishi Tanabe, Ono Pharmaceutical, Pfizer, Procter & Gamble, Sanofi, Regeneron, Taiho, and TORII Pharmaceutical. Gaia Gallo, Maria Jose Rueda, Evangeline Pierce, and Yuxin Ding are employees and shareholders of Eli Lilly and Company. Shawn Kwatra is an advisory board member or consultant for AbbVie, Amgen, Arcutis Biotherapeutics, Aslan Pharmaceuticals, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, Dermavant, Galderma, Incyte Corporation, Johnson & Johnson, Leo Pharma, Novartis Pharmaceuticals Corporation, Pfizer, Regeneron Pharmaceuticals, and Sanofi and has served as an investigator for Galderma, Incyte, Pfizer, and Sanofi.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.