Reimbursement Review

Lebrikizumab (Ebglyss)

Sponsor: Eli Lilly Canada Inc.

Therapeutic area: Atopic dermatitis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance; SC = subcutaneous.

Introduction

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory, and noncontagious skin disease that is commonly associated with other atopic expressions, such as asthma, allergic rhinitis, and food allergy.¹ The burden of disease and its impact on quality of life may be profound, particularly in the case of moderate-to-severe AD.² Itch or pruritus; soreness, pain, or tenderness; and skin dryness are the signs and symptoms most frequently cited as having a clinical impact.³ Itch, the major symptom, has a negative impact on quality of life and is associated with mental distress and an increased risk for suicidal thoughts.¹ Depression, anxiety, and sleep disturbance are frequently reported comorbidities.^2,3 Moreover, AD can result in embarrassment related to appearance and can have a negative impact on a patient’s self-esteem and social life.¹ Patients with AD are at increased risk of skin infections because of excessive rubbing or scratching.¹ Exacerbations, or flares, are an integral part of the disease course and generally indicate a worsening of AD that requires escalation or intensification of treatment.⁴

AD has no impact on approximately 15% to 20% of children and approximately 1% to 3% of adults worldwide; in high-income countries, AD affects around 20% of children and up to 10% of adults.^1,5 Approximately 50% of adult patients have moderate-to-severe disease based on clinical disease severity scales.⁶

Initial treatment for most patients with AD is emollients (moisturizers) plus topical anti-inflammatory therapy, including topical corticosteroids (TCS) and topical calcineurin inhibitors.⁷ For patients with more severe AD or with AD that is refractory to topical therapy, advanced treatments, including phototherapy and systemic treatment, are considered. According to clinical practice guidelines from the American Academy of Dermatology and the American Academy of Allergy, Asthma & Immunology, biologics, and particularly dupilumab, are considered first-line systemic therapy.^7,8 Other options include tralokinumab (another biologic) and oral Janus kinase (JAK) inhibitors (upadacitinib, abrocitinib).^7,8 According to the clinical expert consulted, off-label immunomodulators (cyclosporine, methotrexate, mycophenolate, and azathioprine) are generally only used when mandated by a medication payer as step-through therapy or when the previously mentioned biologics and JAK inhibitors fail or are contraindicated. These drugs were not listed as first-line systemic therapies in the 2023 American Academy of Dermatology clinical practice guidelines due to the lower certainty of evidence for newer drugs, the potential for serious adverse events (SAEs), the need for stringent laboratory monitoring, and the lack of regulatory approval for use in AD.⁷

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of lebrikizumab (Ebglyss) 250 mg per 2 mL subcutaneous (SC) injection for the treatment of moderate-to-severe AD in adults and adolescents 12 years and older with a body weight of at least 40 kg, whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Perspectives of Patients, Clinicians and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups that responded to calls for input from Canada’s Drug Agency (CDA-AMC) and the clinical expert consulted by CDA-AMC for the purpose of this review.

Patient Input

Three patient groups provided input to this submission. Eczema Quebec gathered information through review of scientific literature, informal conversations with patients, The Skin I'm In 2022 Update (a joint report by Eczema Quebec and the Canadian Skin Patient Alliance [CSPA]), expert opinion from the Centre of Excellence for Atopic Dermatitis at the McGill University Health Centre, 9 written patient testimonials, interviews with 14 patients, and feedback from 3 patient-group discussions. The CSPA gathered information from previous submissions to CDA-AMC, data from the Canadian Institute for Health Information on AD-related emergency department visits, hospitalizations from 2016 to 2020 (reported in The Skin I'm In), and guidelines. The Eczema Society of Canada (ESC) gathered information through a survey and through one-on-one interviews from more than 3,000 patients with AD and their caregivers who live in Canada.

According to the input from patient groups, symptoms of patients with AD include inflamed, painful, dry, and itchy skin that cracks, oozes, bleeds, and, in some cases, involves thickening and/or infections of the skin. Conditions associated with AD include asthma, seasonal and environmental allergies, food intolerances, sleep disorders, anxiety, and depression. Patient groups stated that physical manifestations and visibility of the disease contribute to psychological distress through stigmatization, which impacts a patient’s self-esteem, professional commitments, and social engagements.

Based on patient-group input, the burden of AD also extends to caregivers and family members. Caregivers reported feelings of anxiety, depression, helplessness, guilt, frustration, and a lack of control over the situation. Caregivers and family members also shared that their own health and emotional wellness, lifestyle, sleep, intimacy, social activities, and family dynamics were affected by the disease. Further, the cost of treatment and other skincare products can place financial stress not only on the patient, but also on the family.

Important desired outcomes reported by patient groups included the following: better, fast, and long-term control of the disease; reduction of flares; relief from itch; reduction of skin symptoms; pain and discomfort relief; improved psychological status; improved daily and social activities; increased productivity; improved emotional well-being; improved sleep quality; and the ability to maintain intimate relationships. In addition, treatments should be affordable or covered by insurance, and should be easy to use (i.e., not administered by injection or topically).

Access to health care presents another challenge to patients with AD. Canada has a low ratio of dermatologists to the population, making specialized care difficult to obtain, particularly in remote areas. Additionally, 36% of caregivers reported feeling a lack of support from the health care system and 30% reported financial challenges related to managing their child’s disease.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

According to the clinical expert consulted for this review, there is an unmet need for more treatment options for people who are refractory to or do not tolerate current biologic treatments for AD, as well as for people who are concerned about the safety profile of oral JAK inhibitors, particularly people with comorbidities and those who are older.

Patients with moderate-to-severe AD that is refractory to topical therapy are most likely to respond to treatment with lebrikizumab, according to the clinical expert. The clinical expert anticipates that lebrikizumab’s use will be similar to that of other systemic medications that allow the concomitant use of emollients and topical anti-inflammatory treatments (e.g., corticosteroids). Given the clinical experience with dupilumab and the evidence supporting its use, the expert anticipates that lebrikizumab will be considered a second-line biologic after dupilumab and may be chosen for patients for whom dupilumab is contraindicated, ineffective, or not tolerated.

In clinical practice, clinicians generally use a gestalt assessment of improvement in clinical signs and a patient’s history of change in symptoms (e.g., itch) and quality of life, the clinical expert explained. Clinicians only use the tools used in clinical trials (e.g., Eczema Area and Severity Index [EASI] score) if mandated by a medication payer to obtain coverage. According to the clinical expert, a meaningful response to treatment would be an improvement of approximately 50% to 75% in signs and symptoms; the specific proportion likely differs by clinician and by patient. The improvement should include a reduction in the severity and frequency of symptoms and is often accompanied by an improvement in quality of life and the ability to perform household, work, and/or school activities. A reduction in skin infections and disease flares is also important.

The clinical expert indicated that lebrikizumab should be discontinued if it is inadequately effective, if the patient experiences intolerable adverse effects, or if the patient wishes to interrupt or discontinue therapy. The clinical expert noted that in most instances, a specialist (dermatologist, allergist, pediatrician) would be required to treat a patient with AD with a biologic, although in areas where access to specialty care is difficult, some family physicians could gain comfort with biologics for AD.

Clinician-Group Input

CDA-AMC received inputs from 2 clinician groups for this review. The Canadian Dermatology Association (CDA) submitted input from 3 clinicians from its Pharmacy and Therapeutics Advisory Board, and the Dermatology Association of Ontario (DAO) submission included input from 11 clinicians.

Clinician groups and the clinical expert consulted by CDA-AMC agreed that a lack of adequate response to treatment, incomplete effectiveness, adverse effects related to treatments, a lack of feasibility of some treatments, and relapses are unmet needs of patients with AD. One of the clinician groups added that challenges in access to care, multitiered treatment regimens, treatment intolerance or contraindications, and comorbid bacterial skin infections are unmet needs as well.

The CDA and the clinical expert consulted by CDA-AMC agree that the goals of treatment are improving quality of life and maximizing efficacy and safety. Regarding the place of lebrikizumab in therapy, the DAO and the clinical expert consulted by CDA-AMC indicate that lebrikizumab will not cause a shift in the treatment paradigm and would be considered another treatment option. In contrast, the CDA stated that lebrikizumab contributes to an important shift in the current treatment paradigm toward a new era of focus on novel disease mechanisms that target and modify disease and have favourable safety and efficacy profiles.

According to the DAO, adult patients with moderate-to-severe AD who have failed topical therapies and those who have failed or do not have access to phototherapy would be best suited for treatment with lebrikizumab. The CDA stated that patients best suited for treatment with lebrikizumab would be those with uncontrolled moderate-to-severe AD who are candidates for systemic therapy or who meet criteria for biologic therapy. The CDA noted that dupilumab is indicated for patients with other severe forms of atopic or allergic conditions, such as severe asthma or eosinophilic esophagitis; thus, dupilumab may be chosen for these patients instead of the interleukin (IL)-13 inhibitors, such as lebrikizumab, which are not approved for use in patients with these conditions.

The DAO noted that a patient’s response to treatment would be assessed with the Investigator Global Assessment (IGA), EASI, Pruritus Numerical Rating Scale (NRS), and Dermatology Life Quality Index (DLQI) scoring systems at 4 to 6 months and annually thereafter. The CDA stated that the assessment of a patient’s response would be based on a clinical exam, the patient’s history, physician-reported clinical scoring systems (EASI, body surface area [BSA], IGA), and patient-reported outcomes (DLQI, Children’s DLQI [CDLQI], and Pruritus NRS). The CDA added that in clinical practice, due to time limitations, only some of the scoring systems are used.

The clinician groups reported that adverse events (AEs) and a lack of efficacy should be considered when deciding to discontinue the treatment.

Based on clinician-group input, the treatment and monitoring of patients on lebrikizumab should be limited to specialists trained in this area, which would include those from the fields of dermatology, allergy, immunology, or pediatrics.

Drug Program Input

The drug programs identified issues related to relevant comparators; considerations for the initiation, renewal, discontinuation, and prescribing of therapy; and system and economic issues. For more information, refer to Table 4.

Clinical Evidence

Systematic Review

Description of Studies

Three double-blind, randomized controlled trials (RCTs) met the inclusion criteria for the systematic review (ADvocate 1, ADvocate 2, and ADhere).^9-11 The objective of the ADvocate 1 (N = 424) and ADvocate 2 (N = 427) studies was to evaluate the safety and efficacy of lebrikizumab as monotherapy in patients with moderate-to-severe AD. Eligible patients were adults or adolescents (aged 12 years to less than 18 years and weighing more than 40 kg) who had a diagnosis of chronic AD that was rated as moderate to severe, based on an EASI score of at least 16, an IGA score of at least 3, and AD covering a BSA of 10% or more. All patients had a history of inadequate response to topical therapies for AD. Both studies included a 16-week induction period (parallel design), followed by a 36-week maintenance period (randomized withdrawal design). The double-blind studies randomized patients in a ratio of 2:1 to receive a lebrikizumab 500 mg SC loading dose at week 0 and week 2 and then 250 mg SC every 2 weeks up to week 16, or placebo for the 16-week induction period. At week 16, patients in the lebrikizumab group who responded to treatment (i.e., an IGA score of 0 or 1 or at least a 75% reduction in EASI score [EASI-75], and who did not receive rescue therapy) were randomly reassigned in a ratio of 2:2:1 to double-blind lebrikizumab 250 mg every 2 weeks until week 36, lebrikizumab 250 mg every 4 weeks until week 36, or placebo for the 36-week maintenance period.

The objective of the ADhere study was to compare the safety and efficacy of lebrikizumab in combination with low-to-midpotency TCS with placebo plus TCS in patients with moderate-to-severe AD. The study was a 16-week randomized, double-blind, parallel-design trial (N = 211). Adults or adolescents (aged 12 years to less than 18 years and weighing more than 40 kg) with moderate-to-severe AD (EASI score of ≥ 16, IGA score of ≥ 3, AD coverage of a BSA of 10% or more) were eligible to enrol. Patients were randomized in a 2:1 ratio to receive a 500 mg lebrikizumab SC loading dose at week 0 and week 2 followed by 250 mg SC once every 2 weeks up to week 16 plus TCS, or placebo plus TCS for the 16-week treatment period.

In all 3 trials, the coprimary outcomes were the proportion of patients with an IGA score of 0 or 1 and at least a 2-point reduction from baseline to week 16, and the proportion of patients with an EASI-75 response at week 16. The IGA measures the investigator’s global assessment of the patient’s overall severity of AD at that visit, based on a static, numeric 5-point scale that ranges from 0 (clear) to 4 (severe). The EASI is a composite index based on the physician’s assessment of 4 clinical signs of the disease (erythema, infiltration and/or papulation, excoriation, and lichenification) and the extent of BSA involved at that visit. It is scored from 0 to 72, with higher scores indicating greater disease severity and/or extent of disease. Other key outcomes reported were the proportion of patients with a Pruritus NRS score of at least 4 points at baseline who reported at least a 4-point reduction from baseline at week 16, and the change from baseline to week 16 in the Patient-Oriented Eczema Measure (POEM) score, the DLQI total score, or the CDLQI total score.

The patients enrolled in the trials had a mean age that ranged from 34.2 years (standard deviation [SD] = 16.4) to 37.5 years (SD = 19.9) per treatment group. In the ADvocate 1, ADvocate 2, and ADhere studies, 13%, 11%, and 22% of patients, respectively, were adolescents. There were roughly equal proportions of females and males in the studies. On average, the patients enrolled in the study had been diagnosed with AD for 20 or more years; most patients (59% to 73%) were classified as having disease of moderate severity based on an IGA score of 3 at baseline, whereas 27% to 41% of patients were classified as having severe AD (i.e., an IGA score of 4). Almost all patients enrolled had previously used TCS (97% to 100%), and 33% to 46% of patients had received topical calcineurin inhibitors. Systemic therapies had been previously received by 43% to 56% of patients, and 12% to 24% of patients had used phototherapy before enrolment in the trials.

Efficacy Results

Induction Period

At week 16, the proportion of patients with an IGA score of 0 or 1 and at least a 2-point reduction from baseline favoured the lebrikizumab groups over the placebo groups in all 3 studies. In the ADvocate 1 study, 43.1% and 12.7% of patients attained an IGA 0 or 1 response in the lebrikizumab and placebo groups, respectively, with a risk difference (RD) of 29.7% (95% confidence interval [CI], 21.6% to 37.8%; P < 0.001). In the ADvocate 2 study, 33.2% and 10.8% of patients attained an IGA 0 or 1 response (RD = 21.9%; 95% CI, 14.2% to 29.6%; P < 0.001) in the lebrikizumab and placebo groups, respectively. The IGA 0 or 1 response also favoured lebrikizumab plus TCS over placebo plus TCS in the ADhere study (41.2% versus 22.1%; RD = 18.3%; 95% CI, 5.1% to 31.5%; P = 0.01).

In all 3 studies, a higher proportion of patients reported an EASI-75 response at week 16 in the lebrikizumab groups than in the placebo groups. An EASI-75 response was attained by 58.8% and 16.2% of patients in the lebrikizumab and placebo groups, respectively, in the ADvocate 1 study (RD = 42.0%; 95% CI, 33.3% to 50.6%; P < 0.001), and by 52.1% and 18.1% of patients, respectively, in the ADvocate 2 study (RD = 33.3%; 95% CI, 24.4% to 42.2%; P < 0.001). In the ADhere study, 69.5% and 42.2% of patients attained an EASI-75 response at week 16 (RD = 26.4%; 95% CI, 12.1% to 40.8%; P < 0.001) in the lebrikizumab plus TCS and placebo plus TCS groups, respectively.

The severity of itch was assessed using the Pruritus NRS, for which patients rated their worst itch symptoms over the previous 24 hours from 0, indicating no itch, to 10, indicating the worst itch imaginable. Among patients who had a Pruritus NRS score of 4 or more at baseline, 45.9% and 13.0% in the lebrikizumab and placebo groups, respectively, reported at least a 4-point reduction at week 16 in the ADvocate 1 study (RD = 32.9%; 95% CI, 24.6% to 41.3%; P < 0.001). The proportion of Pruritus NRS responders was 39.8% and 11.5% in the lebrikizumab and placebo groups, respectively, in the ADvocate 2 study (RD = 28.3%; 95% CI, 20.0% to 36%; P < 0.001), favouring lebrikizumab. In the lebrikizumab plus TCS group in the ADhere study, 50.6% of patients met the Pruritus NRS response criteria, as did 31.9% of patients in the placebo plus TCS group (RD = 19.2%; 95% CI, 4.3% to 34.1%; P = 0.02).

A secondary outcome in the pivotal trials was the change from baseline in the POEM score; the 7-item, self-reported POEM questionnaire was used to assess the frequency of disease symptoms (skin dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) over the previous week. It is scored from 0 to 28, with a higher score indicating worse disease severity.¹² A minimal important difference (MID) of 3.4 points was identified as the threshold for a clinically relevant between-group difference.¹³ The ADvocate 1 study reported a least squares (LS) mean difference of |||| |||||| |||| ||| |||| || ||||) in the POEM score change from baseline to week 16 for lebrikizumab versus placebo. The LS mean difference was |||| |||||| |||| ||| |||| || ||||| for the lebrikizumab versus placebo groups in the ADvocate 2 study, and the ADhere study reported a LS mean difference of −4.0 points (95% CI, −6.3 to −1.7 points) for lebrikizumab plus TCS versus placebo plus TCS. Of note, this outcome was potentially biased due to the extent of missing data and the analysis methods used to handle missing data. Moreover, the change in POEM score was not part of the graphical testing strategy used to control the family-wise type I error rate, and thus this outcome should be interpreted as supportive evidence only.

In the 3 pivotal trials, the DLQI was used to measure health-related quality of life (HRQoL) in patients 17 years and older, and the CDLQI was used for those who were aged 12 to 16 years. These instruments are scored from 0 to 30, with higher scores indicating poorer HRQoL. MIDs of 4 points for the DLQI and 6 points for the CDLQI were selected as the thresholds for clinically relevant between-group differences.^14,15 In the ADvocate 1 study, the LS mean difference in the change from baseline to week 16 in the DLQI total score for lebrikizumab versus placebo was −5.8 points (95% CI, −7.1 to −4.5 points; P < 0.001), and in the ADvocate 2 study, the LS mean difference was −4.9 points (95% CI, −6.3 to −3.5 points; P < 0.001) for lebrikizumab versus placebo. The ADhere study reported a LS mean difference in the change from baseline in DLQI score of −3.3 points (95% CI, −5.3 to −1.3 points; P = 0.001) for the lebrikizumab plus TCS group versus the placebo plus TCS group. These analyses included 75% to 86% of patients randomized to a treatment group who were 17 years or older at the start of the studies.

Among adolescents aged 12 to 16 years, the LS mean difference in the change from baseline in the CDLQI was |||| |||||| |||| ||| ||||| || ||||| in the ADvocate 1 study, |||| |||||| |||| ||| |||| || |||| in the ADvocate 2 study, and −4.6 points (95% CI, −7.2 to −2.0 points) in the ADhere study for the lebrikizumab versus placebo groups at week 16. The change in CDLQI was not controlled for the type I error rate, and thus the outcome should be interpreted as supportive evidence only. Also of note, the number of patients per treatment group was small, ranging from 5 to 11 patients in the placebo groups and from 17 to 26 patients in the lebrikizumab groups.

Maintenance Period

At week 16 of the ADvocate 1 and ADvocate 2 studies, patients in the lebrikizumab group who met the treatment response criteria were rerandomized to placebo or to lebrikizumab every 4 weeks or lebrikizumab every 2 weeks for the maintenance period. This review focuses on the results of the lebrikizumab every-4-weeks groups to be consistent with the Health Canada–recommended maintenance dosing. The ADvocate 1 study reported that 79.2% of patients in the lebrikizumab every-4-weeks group maintained an EASI-75 response at week 52, compared with 61.3% of patients who were switched to placebo (RD = ||||| |||| ||| |||| || |||||). In the ADvocate 2 study, 84.7% and 72.0% of patients maintained an EASI-75 response in the lebrikizumab every 4 weeks and placebo (i.e., lebrikizumab withdrawal) groups, respectively, (RD = ||||| |||| || |||| || |||||||

Harms Results

Induction Period

During the induction period of the trials, the proportion of patients in the ADvocate 1, ADvocate 2, and ADhere studies who experienced 1 or more treatment-emergent adverse events (TEAEs) was 46% versus 52%, 53% versus 66%, and 43% versus 35% in the lebrikizumab and placebo groups, respectively. The most common AEs in the lebrikizumab groups were conjunctivitis, headache, and nasopharyngitis.

The frequency of SAEs was generally low, with 2.1% versus 0.7%, 0.7% versus 2.8%, and 1.4% versus 1.5% reporting an SAE in the lebrikizumab versus placebo groups of the ADvocate 1, ADvocate 2, and ADhere studies, respectively. One patient who received placebo died of a myocardial infarction in the ADvocate 2 study. No other deaths were reported.

During the induction period in the ADvocate 1, ADvocate 2, and ADhere studies, 1.1% versus 0.7%, 3.2% versus 2.8%, and 2.1% versus 0% of patients in the lebrikizumab versus placebo groups, respectively, stopped treatment due to AEs.

Conjunctivitis-related AEs, which was a notable harm, were reported by 4.8% to ||||| of patients in the lebrikizumab groups and by 0.0% to 3.5% of patients in the placebo groups. The RD for conjunctivitis in the lebrikizumab versus placebo groups was |||| |||| ||| ||| || ||||| in the ADvocate 1 study, |||| |||| ||| ||| || ||||| in the ADvocate 2 study, and |||| |||| ||| ||| || |||| in the ADhere study.

Maintenance Period

During the maintenance period, ||| |||||| |||| ||| ||| |||||| ||| of patients experienced a TEAE in the lebrikizumab every-4-weeks group versus the placebo (i.e., lebrikizumab withdrawal) group in the ADvocate 1 and ADvocate 2 trials, respectively. A total of | patients reported an SAE, including |||||||| |||||| in the lebrikizumab every-4-weeks group of the ADvocate 1 study, and ||||||| |||||| in the placebo group and |||||||| |||||| in the lebrikizumab every-2-weeks group of the ADvocate 2 study. No deaths were reported during the maintenance period.

Between week 16 and week 52, 1 patient each in the lebrikizumab every-4-weeks groups of the ADvocate 1 and ADvocate 2 studies stopped treatment due to AEs. No patients in the placebo groups stopped therapy due to AEs during the maintenance period. Overall, conjunctivitis was reported || |||| |||||| ||||| ||| ||||| |||||| ||||| of patients in the lebrikizumab every-4-weeks versus placebo (lebrikizumab withdrawal) groups, respectively, of the ADvocate 1 and ADvocate 2 studies.

Critical Appraisal

No major concerns were identified with the randomization, allocation concealment, blinding, or statistical methods used in the trials included in the systematic review. The key outcomes tested (EASI-75, Pruritus NRS, POEM, and DLQI) were important to patients and had evidence to support their validity and reliability in patients with AD or other dermatologic conditions. The primary estimand for EASI-75, IGA, Pruritus NRS, and DLQI outcomes was used to analyze patients who discontinued due to lack of efficacy or who required rescue therapy as nonresponders, and multiple imputation methods were used to impute data for patients who discontinued for other reasons. These methods should address any potential bias due to the differential use of rescue treatments in the lebrikizumab and placebo groups.

The key limitations of the change in POEM, DLQI, and CDLQI were related to missing data. The analyses of the change in POEM and CDLQI scores were based on the supportive (hypothetical) estimand and the mixed model for repeated measures (MMRM), which assumed that data are missing at random. These outcomes were not based on the true intention-to-treat (ITT) population, as they excluded patients with missing data at baseline. In addition, there were differences between the groups in the frequency of missing outcome data at week 16, and it is unclear if the missing-at-random assumption is valid. Similar issues were noted with regard to missing data for the change in DLQI scores. Due to the missing data imputation methods and the extent and differential rate of missing data, there is potential for bias in the change in POEM and CDLQI scores. The changes in POEM and CDLQI scores were not part of the graphical testing strategy used to control the family-wise type I error rate; therefore, these results should be interpreted as supportive evidence only.

The 52-week data from the ADvocate trials were limited by the enriched population, carry-over effects of lebrikizumab in the placebo group, and the small sample size. At week 16 of the ADvocate studies, patients treated with lebrikizumab who met the response criteria were rerandomized to 1 of 3 groups. This represents an enriched population, and thus the 1-year treatment effects of lebrikizumab may be overestimated compared with what would be observed in an unselected population. Given the long half-life of lebrikizumab (24.5 days¹⁶), it is reasonable to assume that there are substantial carry-over effects for patients who switched from lebrikizumab to placebo, which may impact efficacy assessments, as well as the frequency of harms.

The clinical expert consulted for this review did not identify any major limits to the generalizability of the findings of the trials, and the baseline characteristics of patients enrolled were generally consistent with those who may receive systemic treatments for AD in clinical practice. However, the expert noted that the studies excluded some patients with comorbidities who may receive lebrikizumab for AD. Due to these exclusions, the safety and efficacy of lebrikizumab is uncertain for patients with chronic conditions that may require treatment with oral corticosteroids, acute or chronic infections, severe mental or physical illnesses, or a history of immunosuppression. Given that 11% to 22% of patients enrolled were adolescents, the results are mainly reflective of adult patients. The dosing of lebrikizumab during the induction period of the trials was consistent with the Health Canada–recommended dose; however, the clinical expert anticipates that most patients using lebrikizumab will also use TCS as needed. The concurrent use of TCS was prohibited in the ADvocate studies, and thus the magnitude of effects observed in the ADhere study may be more consistent with what may occur in clinical practice. Also, the generalizability of the 52-week efficacy and safety data may be limited, given the enriched population and the carry-over effects of lebrikizumab in patients who switched to placebo. The results at 52 weeks are reflective of the effects of lebrikizumab maintenance therapy, not of lebrikizumab withdrawal among patients who initially tolerate and respond to treatment during the 16-week induction period.

GRADE Summary of Findings and Certainty of the Evidence

For the pivotal studies identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess the certainty of the evidence for outcomes considered to be most relevant to CDA-AMC expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^17,18

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment for the proportion of patients with an IGA 0 or 1 response, EASI-75 response, or at least a 4-point improvement on the Pruritus NRS were based on thresholds informed by the clinical expert consulted for this review. The certainty of evidence assessments for the change in POEM, DLQI, and CDLQI scores were based on thresholds identified in the literature, and the certainty assessments for SAEs and conjunctivitis were based on the presence or absence of any (nonnull) effect.

For the GRADE assessments, findings from the ADvocate 1, ADvocate 2, and ADhere studies were considered together and summarized narratively by outcome, because these studies were similar in population, interventions, design, and outcome measures.

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• the proportion of patients with an IGA score of 0 or 1 and at least a 2-point reduction from baseline

• the proportion of patients with an EASI-75 response

• the proportion of patients who reported at least a 4-point reduction in Pruritus NRS score

• the change from baseline in POEM score

• the change from baseline in DLQI and CDLQI total scores

• SAEs and conjunctivitis AEs.

Table 2: Summary of Findings for Lebrikizumab Versus Placebo for Patients With Moderate-to-Severe Atopic Dermatitis

AE = adverse event; aRD = adjusted risk difference; CDLQI = Children’s Dermatology Life Quality Index; CI = confidence interval; DLQI = Dermatology Life Quality Index; EASI-75 = at least a 75% reduction in EASI score; IGA = Investigator Global Assessment; LEB = lebrikizumab; LS = least squares; NR = not reported; NRS = Numeric Rating Scale; PBO = placebo; POEM = Patient-Oriented Eczema Measure; RCT = randomized controlled trial; RD = risk difference; SAE = serious adverse event; TCS = topical corticosteroids.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aThe IGA measures the investigator’s global assessment of the patient’s overall severity of AD at that visit, based on a static, numeric 5-point scale ranging from 0 (clear) to 4 (severe). Based on clinical expert input, the threshold for a clinically important between-group difference was 100 per 1,000 for the proportion of patients with an IGA score of 0 or 1 and at least a 2-point reduction from baseline.

^bThe EASI is a composite index, based on the physician’s assessment of 4 clinical signs of the disease (erythema, infiltration and/or papulation, excoriation, and lichenification) and the extent of BSA involved at that visit. It is scored from 0 to 72, with higher scores indicating greater disease severity and/or extent of disease. Based on clinical expert input, the threshold for a clinically important between-group difference was 100 per 1,000 for the proportion of patients with at least an EASI-75 response.

^cEASI-75 response at week 52: rated down 1 level for serious imprecision. The CI for differences between groups included the potential for little to no difference (based on the threshold for a clinically important between-group difference of 100 per 1,000 for the proportion of patients who maintained at least an EASI-75 response at week 52).

^dThe Pruritus NRS is a patient-reported, single-item, daily, 11-point scale. The scale is used by patients to rate their worst itch severity over the previous 24 hours, with 0 indicating no itch and 10 indicating the worst itch imaginable. Based on clinical expert input, the threshold for a clinically important between-group difference was 100 per 1,000 for the proportion of patients with at least a 4-point reduction from baseline. This outcome was analyzed for the subgroup of patients who had a Pruritus NRS score of 4 or higher at baseline.

^eThe POEM is a 7-item, patient-reported questionnaire used to assess the frequency of disease symptoms in adults and children over the previous week. The patients respond to 7 questions on skin dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping. The total score ranges from 0 to 28, with a high score indicating worse disease severity. The MID of 3.4 points was selected as the threshold for a clinically important between-group difference based on the literature and clinical expert input.^12,13

^fChange in POEM score at week 16: rated down 2 levels for very serious study limitations. The extent of missing data was large and the method for accounting for missing data was potentially biased. Note that there was no control for the type I error rate for this end point, so outcomes should be interpreted as supportive evidence only.

^gThe DLQI (for patients 16 years and older) and CDLQI (for those younger than 16 years) are patient-reported, 10-item, HRQoL questionnaires that cover 6 domains (symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment) over the previous week. The total score ranges from 0 (no impact of skin disease on quality of life) to 30 (maximum impact on quality of life). MIDs of 4 points for the DLQI and 6 points for the CDLQI were selected as the thresholds for clinically important between-group differences based on the literature and clinical expert input.^15,19-21

^hChange in DLQI at week 16: rated down 1 level for serious imprecision (the CI for differences between groups included the potential for little to no difference based on an MID of 4 points) and rated down 1 level for serious study limitations (due to missing data). Also considered was the possibility of inconsistency, given that the point estimate for 1 of the 3 trials falls below the MID, although a decision was made not to rate down for inconsistency.

^IChange in CDLQI at week 16: rated down 1 level for serious imprecision (the CI for differences between groups included the potential for little to no difference based on a MID of 6 points) and rated down 2 levels for very serious study limitations. The extent of missing data was large and the method for accounting for missing data was potentially biased. Note that there was no control for the type I error rate for this end point, so outcomes should be interpreted as supportive evidence only.

^jSAE at week 16: rated down 2 levels for very serious indirectness (follow-up duration limited to 16 weeks, which may be insufficient to detect uncommon SAEs or those that develop over time; the clinical expert noted that worsening AD may be reported as an SAE, whereas this more accurately reflects lack of efficacy) and rated down 1 level for serious imprecision (the CI for differences between groups includes the possibility of no difference, benefit [fewer harms], or increased harms).

^kSAE at week 52: rated down 2 levels for very serious indirectness (AEs were reported for an enriched population of patients who had received lebrikizumab 250 mg every-2-weeks induction therapy and met the treatment response criteria at week 16; the AEs reported in the placebo group may be confounded due to the carry-over effects of lebrikizumab before the switch to placebo; follow-up duration and sample size may be insufficient to detect uncommon SAEs or those that develop over time) and rated down 1 level for serious imprecision (the CI for differences between groups includes the possibility of no difference, benefit [fewer harms], or increased harms).

^lConjunctivitis at week 16: rated down 1 level for serious indirectness (the clinical expert stated that dermatologists may not have sufficient expertise to distinguish between eye disorders with a similar presentation, so the reported conjunctivitis-related AEs may be flawed).

^mConjunctivitis at week 52: rated down 2 levels for very serious indirectness (the clinical expert stated that dermatologists may not have sufficient expertise to distinguish between eye disorders with a similar presentation, so the reported conjunctivitis-related AEs may be flawed; AEs were reported for an enriched population of patients who had received lebrikizumab 250 mg every-2-weeks induction therapy and met the treatment response criteria at week 16; the AEs reported in the placebo group may be confounded due to the carry-over effects of lebrikizumab before the switch to placebo) and rated down 2 levels for very serious imprecision (the CI for differences between groups includes the possibility of no difference, benefit [fewer harms], or increased harms).

Sources: Clinical study report (CSR) for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere,⁹ additional information supplied by sponsor.²²

Long-Term Extension Study

Description of Study

One long-term extension study was summarized to provide evidence on the long-term (100-week) efficacy and safety of lebrikizumab among patients with moderate-to-severe AD who were enrolled in the ADvocate 1, ADvocate 2, ADhere, ADore, and ADopt-VA studies (parent trials).²³ This study was conducted at 199 centres that enrolled 999 patients in Australia, Bulgaria, Canada, Estonia, France, Germany, Latvia, Lithuania, Mexico, Poland, Singapore, South Korea, Spain, Taiwan, Ukraine, and the US. This report presents interim safety data from the ADjoin study and limited efficacy data at week 40 for a subset of patients who completed the 16-week ADhere study (i.e., up to 56 weeks of lebrikizumab treatment). |||| |||| |||||||| || |||||| ||| |||||| |||| |||| ||||||||| ||||| || ||||||| ||| |||||||| |||| ||| |||||||| || ||| ||||||| |||||||| ||||| |||||||

Efficacy Results

Efficacy outcomes were assessed up to || ||||| (week 16 to week 104). Evaluation of efficacy in the interim report was conducted on a subset of the main cohort, which included || |||||||||||| who were responders to lebrikizumab plus TCS in the ADhere study.

At week 40, the proportion of patients with an IGA score of 0 or 1 was ||||| in the lebrikizumab 250 mg every-4-weeks group and ||||| in the lebrikizumab 250 mg every-2-weeks group.

At week 40, the mean (standard error [SE]) percent change from baseline in EASI score in the lebrikizumab 250 mg every-4-weeks and lebrikizumab 250 mg every-2-weeks groups were |||||| ||||| ||| |||||| |||||| respectively. The proportion of patients with an EASI-75 response at week 40 in the lebrikizumab 250 mg every-4-weeks and lebrikizumab 250 mg every-2-weeks groups was ||||| ||| |||||| respectively.

Among patients who had a Pruritus NRS score of 4 or more points at baseline, the proportion of patients who reported an improvement of at least 4 points at week 40 in the lebrikizumab 250 mg every-4-weeks and lebrikizumab 250 mg every-2-weeks groups was ||||| ||| |||||| respectively.

The mean (SE) percent change in POEM score from baseline to week 40 in the lebrikizumab 250 mg every-4-weeks and lebrikizumab 250 mg every-2-weeks groups was |||||| |||||| ||| |||||| ||||||, respectively.

Harms Results

Overall, || |||||||| (|| || ||| |||||||| |||||| ||||||||||) discontinued study treatment due to AEs. Discontinuation due to an AE was noted in || |||||| || ||| ||||| |||||||| ||| || | |||||| || ||| |||||||||| ||||||||.

One death due to natural causes occurred in the lebrikizumab 250 mg every-2-weeks group.

The most frequently reported TEAEs were in the infections and infestations system organ class, with COVID-19 (|||| in lebrikizumab 250 mg every-4-weeks group and |||| in the lebrikizumab 250 mg every-2-weeks group) and nasopharyngitis (|| in lebrikizumab 250 mg every-4-weeks group and |||| in the lebrikizumab 250 mg every-2-weeks group) being the most common TEAE. A similar proportion of patients in the lebrikizumab 250 mg every-2-weeks group (||||) and the lebrikizumab 250 mg every-4-weeks group (||||) reported an AE of atopic dermatitis exacerbation. The proportion of patients experiencing 1 or more AEs in the conjunctivitis cluster (narrow terms) was similar in both the lebrikizumab 250 mg every-4-weeks group (||||) and the lebrikizumab 250 mg every-2-weeks group (||||).

Critical Appraisal

Internal Validity

There is no randomized comparison to another treatment or a placebo, which limits the ability to draw inferences on the effects of lebrikizumab in the study population. The patients were aware they were receiving active treatment, so their expectations of treatment may have influenced their reporting of subjective patient-reported outcomes, such as the POEM, and subjective AEs or investigator-reported IGA and EASI responses, which are measures that require subjective judgments. Discontinuation rates were |||| in the lebrikizumab every-4-weeks and ||||| in the lebrikizumab every-2-weeks groups. Among patients from the ADhere study (efficacy assessment), the rates of discontinuation are ||||| in the every-4-weeks group and ||||| in every-2-weeks group. Thus, there is potential bias due to missing data. All analyses were conducted descriptively without statistical comparisons between the cohorts or adjustment for multiple comparisons.

External Validity

Only responders in the ADhere study were included in the efficacy assessment. Patients were excluded if, during their participation in the parent trial, they developed an SAE deemed to be related to lebrikizumab, developed an AE that was deemed to be related to lebrikizumab and led to study treatment discontinuation, or had conditions in the parent trial that led to investigator-initiated or sponsor-initiated withdrawal from the study. This is a select population, so the results apply only to patients who initially tolerate and respond to lebrikizumab. The proportion of patients with concomitant TCS use and systemic rescue therapy was higher in the every-4-weeks group than in the every-2-weeks group. The effect of these differences between groups on the efficacy results remains unclear.

Indirect Comparisons

Description of Studies

The sponsor-submitted indirect treatment comparison (ITC) first conducted a systematic literature review (SLR) to identify evidence for inclusion in a network meta-analysis (NMA). The relative efficacy of lebrikizumab (with or without TCS) from the ADvocate 1, ADvocate 2, J2T-DM-KGAF, ADhere, ADhere-J, ADopt-VA, and ADvantage trials was indirectly compared to alternative treatments for AD using a Bayesian NMA. Comparators of interest for the sponsor-submitted NMA included abrocitinib, dupilumab, and upadacitinib. All networks in the sponsor-submitted NMA also included baricitinib and tralokinumab as comparators.²⁴ However, baricitinib does not have Health Canada approval for the treatment of AD, and tralokinumab is not currently reimbursed by public drug plans in Canada. As such, results comparing lebrikizumab to baricitinib or tralokinumab were not included in this report. Outcomes of interest included EASI response, IGA 0 or 1 response, a reduction of greater than or equal to 4 points in the Pruritus NRS at week 16, and a reduction of greater than or equal to 4 points in Pruritus NRS at week 4.²⁴

Efficacy Results

The SLR identified a total of ||||| citations. A total of || unique studies identified by the SLR were assessed for eligibility to be included in the NMAs. Three studies of lebrikizumab that were not identified as part of the SLR were also assessed for inclusion. In total, || studies were eligible for inclusion in the NMAs: || monotherapy studies and || combination therapy studies.²⁴

Networks were generated for all eligible interventions as monotherapy and combination therapy for the outcomes of EASI response, IGA 0 or 1 response, and Pruritus NRS response at time points of interest. In all cases, the baseline risk-adjusted random-effects model was selected as the favoured model, based on the deviance information criterion and residual deviance.²⁴

Primary Analysis

EASI response (week 16): In the primary analysis for EASI response at week 16 in the monotherapy network, there was insufficient evidence to show a difference between lebrikizumab and dupilumab 300 mg every 2 weeks or abrocitinib 100 mg daily. Abrocitinib 200 mg daily (probit difference, ||||| |||| |||||||| |||||||| |||||| |||||| ||||||), upadacitinib 15 mg daily (probit difference ||||| |||| |||| |||||| ||||||), and upadacitinib 30 mg daily (probit difference ||||| |||| |||| |||||| ||||||) were favoured over lebrikizumab.²⁴

|| ||| ||||||| |||||||| ||| |||| |||||||| || |||| || || ||| ||||||||||| ||||||| |||||||| ||||| ||| |||||||||||| |||||||| || |||| | |||||||||| ||||||| |||||||||||| |||| ||| ||| ||| || ||| |||||||||| |||||||||||||

IGA response of 0 or 1 (week 16): In the primary analysis for an IGA 0 or 1 response at week 16 in the monotherapy network, there was insufficient evidence to show a difference between lebrikizumab and dupilumab 300 mg every 2 weeks, abrocitinib 100 mg daily or 200 mg daily, or upadacitinib 15 mg daily. Upadacitinib 30 mg daily was favoured over lebrikizumab (odds ratio [OR], |||| |||| |||| ||||| ||||||.²⁴

|| ||| ||||||| |||||||| ||| ||| ||| |||||||| || |||| || || ||| ||||||||||| ||||||| |||||||| ||||| ||| |||||||||||| |||||||| || |||| | |||||||||| ||||||| |||||||||||| |||| ||| ||| ||| || ||| |||||||||| ||||||||||| |||||| ||| |||||||||||| || || ||||| |||| |||| ||||| ||| |||||||| |||| |||||||||||| |||| ||| |||| |||| |||| |||| ||||| |||||||||

A reduction of greater than or equal to 4 points in Pruritus NRS (week 16): In the primary analysis for Pruritus NRS response at week 16 in the monotherapy network, there was insufficient evidence to show a difference between lebrikizumab and dupilumab 300 mg every 2 weeks, abrocitinib 100 mg daily or 200 mg daily, or upadacitinib 15 mg daily. Upadacitinib 30 mg daily was favoured over lebrikizumab (OR, |||| |||| |||| ||||| |||||).²⁴

|| ||| ||||||| |||||||| ||| ||||||||||||| ||| |||||||| || |||| || || ||| ||||||||||| ||||||| |||||||| ||||| ||| |||||||||||| |||||||| || |||| | |||||||||| ||||||| |||||||||||| |||| ||| ||| ||||||||||| ||| || ||||| |||| |||| ||| |||||||||||| || || ||||| |||| |||| ||||||||| ||| || ||||| | ||||| |||| ||| |||| |||| |||| |||| ||||| ||||||| ||||||||||| ||| || ||||| |||| ||| |||| |||| |||| |||| ||||| ||||||| ||| |||||||||||| || || ||||| |||| ||| |||| |||| |||| |||| ||||| |||||| |||| |||||||| |||| |||||||||||| |||| ||||||

A reduction of greater than or equal to 4 points in Pruritus NRS (week 4): In the primary analysis for Pruritus NRS response at week 4 in the monotherapy network, there was insufficient evidence to show a difference between lebrikizumab and dupilumab 300 mg every 2 weeks or abrocitinib 100 mg daily. Abrocitinib 200 mg daily (||| |||| |||| |||| ||||| ||||]), upadacitinib 15 mg daily (||| |||| |||| |||| ||||| ||||]), and upadacitinib 30 mg daily (||| |||| |||| |||| ||||| |||||| were favoured over lebrikizumab.²⁴

|| ||| ||||||| |||||||| ||| ||||||||||||| ||| |||||||| || |||| | || ||| ||||||||||| ||||||| |||||||| ||||| ||| |||||||||||| |||||||| || |||| | |||||||||| ||||||| |||||||||||| |||| ||| ||| ||||||||| ||| || ||||| | ||||| |||| |||| ||||||||||| ||| || ||||| |||| |||| ||| ||||||||||| ||| || ||||| |||| |||| |||||||||||| || || ||||| |||| ||| |||| |||| |||| |||| ||||| |||||| ||| |||||||||||| || || ||||| |||| ||| |||| |||| |||| ||| ||||| |||||| |||| |||||||| |||| |||||||||||| |||| ||||||

Secondary Analysis

Phase III studies only in monotherapy networks: ||||||||| |||||||| |||| ||||||||| ||||||||| |||| ||||| ||| ||||||| || ||| ||||||||||| ||||||||| | ||||| || || |||||| |||| |||||||| || ||| |||||||| |||| |||| ||||| ||| |||||||| || ||| |||| |||||||| ||| |||||||||| |||||| ||||||| ||||| ||| |||||||| || ||| |||| ||||| ||| ||| ||||||| |||| |||||||||| |||| ||| ||||||| ||||||||| ||| ||| ||||||||| |||||||||| ||| |||||| ||||||| ||||| |||||||| ||| |||||||| |||| ||| ||| ||||| || ||||||| ||| ||||||| |||| |||||||||| |||| ||| ||||||| ||||||||| || ||| ||| ||| |||||||| |||||||| |||||||||||| || || ||||| ||| |||| |||||||| |||| |||||||||||| |||| |||| |||| |||| |||| || |||||||||

Meta-regression analysis: ||||||||| |||||||| ||||| ||||||||||||||| || |||||| ||| |||||||| |||||||| |||| ||||||||| ||| ||||||||||| ||| ||||||||||| ||||||| |||||||| ||| ||| |||||||| || |||| ||||| || |||| || ||| ||| ||| |||||||| || |||| |||| ||| ||||||||| |||||||| | ||||||| ||||||||||||||| || |||| |||||||| || |||| || |||||||| ||| |||||||| |||| |||| ||||| ||| |||||||||| ||||| ||| || ||||||||||| |||||||||| || ||| ||||||| ||||| ||| |||||| ||||||| ||||||| |||||| |||||| ||||||| |||||| |||| |||||||| ||||| || ||| ||||| |||||||| ||||||||| ||||||| |||| |||||||||| |||| ||| ||||||| ||| ||||||||| ||||||||| |||| ||||||||||| ||| || |||||| |||||||||||| || || |||||| ||| |||||||||||| || || ||||| |||||||| |||| |||||||||||| ||| |||||||||||| |||||||| || |||| | |||||||||| ||||||| |||||||||||| ||| ||||| ||||||||||| ||| ||| ||| |||||||| || ||| ||||||||||| |||||||| | |||||| ||||||| ||||| |||||||| ||| ||| |||||||||| || |||||||| |||| || ||| ||||| || | || |||| || |||||||| ||| |||||||| || ||| ||||||||| |||||| ||| ||||||| |||| |||||||||| |||| ||| ||||||| ||||||||| |||| |||||||||||| || || ||||| |||||||| |||| |||||||||||| ||| |||||||||||| |||||||| || |||| | |||||||||| ||||||| |||||||||||| ||| ||||| |||||||||||||||| ||| ||||||||||| ||||||| |||||||| ||| ||||| ||||||| ||||| |||||||| ||| |||||||| |||| ||||| ||| ||| ||||||||| ||||| || ||||| |||| ||| |||| |||||||||| || |||||||| ||| |||||| ||||||| |||||| ||||||||||| ||| ||||||| |||| |||||||||| |||| ||| ||||||| ||| ||||||||| ||||||||| |||||||| ||||| ||| |||||||||||| |||||||| || |||| | |||||||||| ||||||| |||||||||||| |||| ||| ||| |||||||||||| || || ||||| |||| |||||||||| ||| ||||||||| ||| |||||| ||||||| ||||| |||||||| ||| |||||||| ||| |||||||| ||| |||||||| || ||| ||||||||| |||||| ||||||| |||| |||||| |||||||||| |||| ||| ||||||| ||||||||| |||||||| ||||| ||| |||||||||||| |||||||| || |||| | |||||||||| ||||||| |||||||||||| |||| ||| ||| |||||||||||| || || ||||| |||| |||

Harms Results

Harms were not evaluated in the sponsor-submitted NMA.

Critical Appraisal

The sponsor-submitted NMA was informed by an SLR that included comprehensive searches (updated in April 2023) of multiple databases, conference proceedings, clinical trial databases, and health-technology assessment websites. Additionally, the risk-of-bias assessment conducted by the sponsor did not indicate a serious risk of bias in the included studies. However, it should be noted that methods for risk-of-bias appraisals were incompletely reported (i.e., it is not clear how many reviewers were involved and whether they worked independently). As such, the risk for bias and error in the appraisals could not be ascertained. Further, the risk-of-bias appraisal was undertaken at the study level, rather than at the level of the reported effects. Appraisals undertaken at the study level do not account for differences in the risk of bias that can exist across reported results (within and across outcomes) within trials.²⁵ Additionally, there is a risk of bias due to missing results in the networks, because trials of relevant comparator treatments without a placebo control group were excluded. ||| ||| ||||||||| |||||||| ||||||| ||||| | |||||| |||| |||||||| |||| ||| ||||||||| ||| |||| |||||||

A feasibility assessment was conducted, evaluating potential heterogeneity in study design; patient baseline characteristics; interventions; and outcomes, time points, and placebo response. The sponsor noted that some heterogeneity was observed across studies in both the monotherapy and combination therapy networks. Studies for abrocitinib used a 12-week time of assessment, as opposed to the 16 weeks used for other trials. The effect of the difference in time of assessment was not evaluated in the NMA and remains unknown. There were differences in age across studies, with the mean age ranging from |||| ||||| || |||| years. There was also heterogeneity in the proportion of patients |||| ||| |||||||| |||||| || ||||||| ||| |||| |||||||| |||||| || ||||| |||||| ||||||||| || ||| ||||||||||| ||||||| |||||||| ||||||| ||||||| || ||||||||||||| || ||||| |||||| ||| |||||||| ||||||||||||||| |||| |||||||| || ||||||||| |||||||| |||| ||| |||||| |||| || |||| |||||| ||| |||||||||| |||| ||||| || |||||| ||| |||| ||||||||||| ||||| || ||||||| Adjustment for baseline EASI and IGA responses did not bring about improvements in model fit, and conclusions were considered to be comparable to the primary analysis. Other differences were noted by the CDA-AMC review team in weight and ethnicity across studies, although the impact of these differences remains unclear. The sponsor also noted heterogeneity in other features, such as race and time since AD diagnosis, although it is not clear whether these are important treatment-effect modifiers. No formal search for potential treatment-effect modifiers was conducted; instead, the sponsor relied on internal clinical opinion, only including AD severity measured by EASI and IGA, and weight, which the clinical expert consulted by CDA-AMC agreed with, although there was a risk of bias in the selection of treatment-effect modifiers, and it was not clear whether the list was comprehensive. Additionally, the sponsor highlighted differences in the ||||| |||||||| ||| ||||||||| || ||| ||||||||| || ||| ||||||||||| ||||||| ||||||| |||||| |||||||. Differences in TCS treatment may have biased the reported response rates and limited the reliability of comparing responses in patients receiving the active interventions; however, baseline risk-adjusted analysis models were included to mitigate the potential for bias. No scenario analyses were conducted to compare the difference between adjusted and unadjusted results; thus, it is unclear what effect not adjusting for baseline risk had on the results. Overall, the notable heterogeneity in the baseline characteristics raises concern about the plausibility of the transitivity assumption, so the resulting effect estimates may not be valid.

Baricitinib and tralokinumab were included as comparators in the NMAs; however, the use of baricitinib for AD is limited in Canada, given the lack of a specific indication for AD and the availability of more efficacious and tolerable JAK inhibitors (i.e., abrocitinib, upadacitinib). Tralokinumab, although indicated for AD, received a do not reimburse recommendation from CDA-AMC and is not reimbursed in Canada. As such, comparative results for these treatments were not included in this report.

Outcomes included in the NMA were relevant to the treatment of AD in Canada, although the clinical expert consulted by CDA-AMC highlighted the fact that EASI scores are generally not calculated in routine clinical practice. Additionally, outcomes of importance to this review, including harms and HRQoL, were not included in the NMA.

In all random-effects analyses, results were associated with wide 95% credible interval (CrIs), with most estimates crossing the 0 or 1 threshold, suggesting notable imprecision in the results and precluding conclusions to be drawn about which treatment is favoured. For some comparisons in the monotherapy ||| ||||||||||| ||||||| |||||||| |||||| |||||||||||| |||||| ||||||||| ||| || ||||| | ||||| || ||||| ||| ||||||||||| ||| || ||||| || |||||| there was generally insufficient evidence to demonstrate a difference between treatments for most outcomes. Further, abrocitinib 200 mg daily, upadacitinib 15 mg daily, and upadacitinib 30 mg daily (± TCS) were favoured over lebrikizumab (± TCS) for most outcomes but were also associated with wide 95% CrIs. Overall, this imprecision limits the interpretability of the treatment effect of lebrikizumab relative to other comparators. Furthermore, this NMA was primarily restricted to adults, so it is unclear whether the results may be generalized to adolescents with AD.

Studies Addressing Gaps in the Evidence From the Systematic Review

Description of Studies

The sponsor submitted 4 studies that provided additional data to cover gaps in the systematic review evidence:

• ADvantage, a phase III, 52-week (16-week double-blind induction period followed by a 36-week open-label maintenance period), RCT designed to address uncertainty regarding the efficacy and safety of lebrikizumab, specifically in patients whose AD is not adequately controlled with cyclosporine or for whom cyclosporine is not medically advisable (N = 331).

• ADopt-VA, a 16-week, phase III, randomized, double-blind, placebo-controlled, parallel-group trial designed to address uncertainty regarding the impact of lebrikizumab on vaccine immune responses. This trial also provides evidence of the efficacy and safety of lebrikizumab (N = 247).

• ADhere-J, a 68-week (16-week induction period plus a 52-week maintenance period), phase III, randomized, double-blind, placebo-controlled, parallel-group study designed to address uncertainty regarding the efficacy and safety of lebrikizumab, specifically for patients in Japan (N = 268).

• ADore, a 52-week, open-label, single-arm study designed to address uncertainty regarding the efficacy and safety of lebrikizumab, specifically among adolescent patients (N = 206 received treatment, 172 completed the treatment period).

The ADvantage Study

Results

A summary of efficacy results for patients randomized to lebrikizumab plus TCS relative to placebo plus TCS at week 16 is provided here.

• EASI-75: 68.4% versus 40.8%, P < 0.0001, || | |||||| ||| || |||||| |||||

• IGA 0 or 1 and an improvement of at least 2 points: 42.0% versus 24.5%, ||||||||| || | |||||| ||| || ||||| |||||

• Pruritus NRS improvement of at least 4 points: 49.9% versus 29.7%, ||||||||| || | |||||| ||| || ||||||||||

• POEM mean (SD) change from baseline: ||||| ||||| |||||| |||| |||||| ||||||||| || |||| |||||||||| | ||||| ||| || |||||| |||||

• DLQI mean (SD) change from baseline: |||| ||||| |||||| |||| ||||||||||| || |||| |||||||||| | ||||| ||| || ||||||| ||||||

• CDLQI mean (SD) change from baseline: |||| ||||| |||||| |||| |||||| |||||||| || |||| |||||||||| | ||||| ||| ||| ||||||| ||||||

In terms of safety, a summary of harms results for patients randomized to lebrikizumab plus TCS relative to placebo + TCS at week 16 is provided here.

• Proportion of patients with at least 1 AE: 61.8% versus 53.2%

• Proportion of patients with at least 1 SAE: |||| |||||| ||||

• Proportion of patients with at least 1 AE leading to study drug discontinuation: 0.9% versus 1.8%

• Proportion of patients with conjunctivitis AE: ||||| |||||| |||||

Up to week 52, harm results for patients randomized to lebrikizumab plus TCS were reported as ||| for patients with at least 1 AE, |||| for patients with at least 1 SAE, and |||| for patients with at least 1 AE leading to study drug discontinuation.

Critical Appraisal

Because few adolescents were enrolled in this study, generalizability to this age group is limited. No control for multiplicity was included for the analyses of the secondary efficacy end points; therefore, the study is at risk of type I error (false-positive results) for all end points except EASI-75 response. Dosage of maintenance therapy was 250 mg every 2 weeks, which is not consistent with the Health Canada product monograph, which recommends 250 mg every 4 weeks after 16 weeks. In the lebrikizumab group versus the placebo group, |||| ||| |||| discontinued the study which might increase risk of bias due to missing outcomes data.

The ADopt-VA Study

Results

The efficacy results reported in the ADopt-VA study that correspond to patients randomized to lebrikizumab versus placebo at week 16 are provided here.

• EASI-75: 58.0% versus 32.7%, P < 0.001, || | |||||| ||| || |||||| |||||

• IGA 0 or 1 and an improvement of at least 2 points: 40.6% versus 18.9%, P < 0.001, || | |||||| ||| || |||||| |||||

• A Pruritus NRS improvement of at least 4 points: ||||| |||||| |||||| |||||||| || | |||||| ||| || ||||| |||||

• POEM LS mean change from baseline (SE): −9.4 (0.8) versus −6.6 (0.8), |||||| || |||| |||||||||| | ||||| ||| || |||||| ||||||

In terms of safety, a summary of the harms for patients randomized to lebrikizumab versus placebo at week 16 is provided here.

• Proportion of patients with at least 1 AE: 38.4% versus 34.4%

• Proportion of patients with at least 1 SAE: 0.8% versus 0.8%

• Proportion of patients with at least 1 AE leading to study drug discontinuation: 2.4% versus 4.1%

• Proportion of patients with conjunctivitis AE: |||| |||||| |||

Critical Appraisal

There is an increased risk of type I error (false-positive results) for all end points. The results of this study may not be generalizable to adolescent patients. The use of TCS was |||| in lebrikizumab group and ||||| in the placebo group, and its effect on the results is not clear. The discontinuation rate was ||| in the placebo group and |||| in the lebrikizumab group, which might increase the risk of bias due to missing outcomes data.

The ADhere-J Study

A total of ||| |||||||||||| in the ADhere-J study completed the induction period, including patients receiving placebo, patients in the lebrikizumab every-4-weeks group, and patients in the lebrikizumab every-2-weeks group. Responders in the lebrikizumab every-4-weeks group continued on with 250 mg lebrikizumab every 4 weeks. Responders in the lebrikizumab every-2-weeks group were randomly allocated to receive 250 mg lebrikizumab every 2 weeks or 250 mg lebrikizumab every 4 weeks. The nonresponders and those who used rescue therapy in the induction period moved to the escape arm and received 250 mg lebrikizumab every 2 weeks. In the placebo group, responders continued to receive placebo, whereas nonresponders and those who used rescue therapy in the induction period moved to the escape arm and received a loading dose of 500 mg lebrikizumab at week 16 and week 18.

Results

A summary of the efficacy results for the induction period corresponding to patients randomized to placebo plus TCS versus lebrikizumab every 2 weeks plus TCS at week 16 is provided here.

• EASI-75: 13.4% versus 51.2%, P < 0.001

• IGA 0 or 1 and an improvement of at least 2 points: 6.1% versus 33.4%, P < 0.001

• A Pruritus NRS improvement of at least 4 points: 3.3% versus 32.7%, P < 0.001

• DLQI LS mean (SE) change from baseline: ||| |||| ||||| |||||| |||| |||||||||||

• CDLQI LS mean (SE) change from baseline: ||| |||| ||||| |||||| |||| |||||||||||

• POEM LS mean (SE) change from baseline: |||| ||||| |||||| |||| |||||| | |||||||

||| ||| ||||||||||| ||||||| ||||||| ||||| || |||||||| |||||||| |||| || |||||||| || |||| || ||||| ||| |||||||| || |||||||| ||| ||||||||| || |||||||||||| ||||| | ||||| ||||||||| ||||||| ||| |||| |||||||| || |||||||||||| ||||| | ||||| ||||||||||| |||||||.

Harm results for induction period in the placebo versus lebrikizumab every-2-weeks plus TCS groups:

• Proportion of patients with at least 1 AE: 63.4% versus 75.6%

• Proportion of patients with at least 1 SAE: 2.4% versus 0.8%

• Proportion of patients with AEs leading to study drug discontinuation: ||| || |||||| ||||

• Proportion of patients with conjunctivitis AE: ||| ||||| |||||| |||||

• Harm results for the maintenance blinded period: || |||||||| |||||||| || |||||||||||| ||||| | ||||| ||||||||||| ||||||||

• Proportion of patients with at least 1 AE: ||| |||||

• Proportion of patients with at least 1 SAE: ||| ||

• Proportion of patients with AEs leading to study drug discontinuation: ||| ||

• Proportion of patients with conjunctivitis AE: ||| |||||

Critical Appraisal

This study is limited to patients in Japan, and generalizability to patients in Canada is uncertain. Not all patients in the induction phase received the Health Canada–recommended dose. High-potency TCS use was ||||| in the placebo group, |||| in the lebrikizumab every-4-weeks group, and |||| in the lebrikizumab every-2-weeks group; the effect of this difference on the results is unclear. DLQI, CDLQI, and POEM were not included in multiplicity testing and are at risk of type I error. For the maintenance period, discontinuation was |||| in the placebo group versus |||| in the lebrikizumab every-2-weeks responder and/or every-4-weeks plus TCS group. The impact of missing data on the findings is unclear.

The ADore Study

Results

The efficacy results reported in the ADore study at week 52 are summarized here.

• EASI-75 (Markov chain Monte Carlo multiple imputation [MCMC-MI] analysis): 81.9%

• IGA 0 or 1 and an improvement of at least 2 points (MCMC-MI analysis): 62.6%

• DLQI mean (SE) change from baseline (MCMC-MI): −8.9 (0.9), N = 35

• CDLQI mean (SE) change from baseline (MCMC-MI): −6.5 (0.5), N = 168.

The harms results reported in the ADore study at week 52 are summarized here.

• Proportion of patients with at least 1 AE: 65%

• Proportion of patients with at least 1 SAEs: 2.4%

• Proportion of patients with at least 1 AE leading to study treatment discontinuation: 2.4%

• Proportion of patients with conjunctivitis AE: 6.8%

• One death (0.5%), the cause of which was reported as cardiac arrest.

Critical Appraisal

There is a risk of bias in the measurement of the outcomes due to the open-label design and the subjectivity of the outcomes. There is no comparator, which limits the ability to determine causal inferences. Maintenance therapy doses were not consistent with the Health Canada product monograph. There is a ||||| ||||||||||||||| rate, which might contribute to the risk of bias due to missing outcome data.

Key Take Aways for Studies Addressing Gaps in the Evidence

In patients with moderate-to-severe AD who received induction therapy with lebrikizumab 250 mg every 2 weeks (with or without TCS), the results of the supplementary trials (ADvantage, ADhere-J, and ADopt-VA) were generally consistent with the findings of the pivotal trials. The efficacy findings favoured lebrikizumab over placebo for EASI-75, IGA 0 or 1, and a Pruritus NRS score of at least 4 points at 16 weeks in the RCTs addressing gaps in the evidence (ADvantage, ADhere-J, and ADopt-VA).

In terms of harms results at week 16, in the ADvantage study, a higher proportion of patients in the lebrikizumab group than in the placebo group reported TEAEs and serious TEAEs. In the ADopt-VA study, the proportion of patients with TEAEs and the proportion of patients with at least 1 AE leading to study drug discontinuation were higher in the lebrikizumab group than in the placebo group. In the ADhere-J study, the proportion of patients who reported TEAEs and the proportion of patients with 1 or more AEs leading to study drug discontinuation were higher in the lebrikizumab every-2-weeks group than in the placebo group. In the open-label ADore study, 2.4% of patients reported at least 1 AE leading to permanent discontinuation from the study treatment, including 1 death.

Some of the limitations of the ADvantage study include uncertain generalizability to adolescent patients, dosage inconsistency with the Health Canada–recommended dose, lack of control for multiplicity for secondary efficacy end points (increasing the risk of type I errors), and risk of bias due to missing outcomes data. In the ADopt-VA study, there is an increased risk of type I error, uncertain generalizability to adolescent patients, between-group differences in the use of TCS, and risk of bias due to missing outcome data. In the ADhere-J study, there was uncertain generalizability to patients in Canada, the dosage was inconsistent with the Health Canada–recommended dose for the induction period, there were between-group differences in the use of high-potency TCS, there was an increased risk of type I error for DLQI, CDLQI, and POEM scores, and there were between-group differences in discontinuations during the maintenance period.

Conclusions

In patients with moderate-to-severe AD that was not adequately controlled with topical therapies, 3 pivotal RCTs demonstrated that lebrikizumab induction therapy provided a clinically relevant improvement in physician-assessed signs of AD and reduced patient-reported symptoms of itch relative to placebo, measured based on EASI-75 response, IGA 0 or 1 response, or Pruritus NRS response at week 16. The benefits were observed when lebrikizumab was used as monotherapy and in combination with TCS. Lebrikizumab may improve HRQoL and reduce other symptoms of AD at 16 weeks compared with placebo, but the evidence is less certain.

There was no direct evidence comparing lebrikizumab to other biologics or JAK inhibitors used to treat AD in Canada; however, the sponsor submitted indirect evidence from an NMA that assessed the short-term comparative efficacy. The results of the NMA were inconclusive for lebrikizumab compared with dupilumab and abrocitinib, with most estimates affected by serious imprecision. The NMA results suggest that upadacitinib may be favoured over lebrikizumab for the proportion of patients with an EASI or Pruritus NRS response, although differences were not consistently detected, and the clinical relevance of any differences is unclear.

Lebrikizumab may increase the short-term risk of conjunctivitis relative to placebo. The NMA did not assess any safety end points, so the comparative safety of lebrikizumab is unknown. The longer-term safety and efficacy of lebrikizumab derived from the RCTs and extension study is uncertain due to limitations with the data. These limitations include an enriched population, carry-over effects for the 52-week data in the pivotal trials (i.e., effect estimates apply to lebrikizumab maintenance therapy relative to lebrikizumab withdrawal among patients who tolerate the treatment and initially experience a response), and the lack of a comparator group for the extension study.

The supplementary evidence available from the sponsor-submitted trials addressing the gaps was generally consistent with the findings of the pivotal trials, including in patients whose AD was not adequately controlled with cyclosporine or for whom cyclosporine was not medically advisable. No new safety signals were detected in the single-arm study in adolescents.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of lebrikizumab 250 mg per 2 mL SC injection in adult and adolescent patients aged 12 years and older for the treatment of moderate-to-severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Disease Background

The contents of this section have been informed by materials submitted by the sponsor and clinical expert input. The following information has been summarized and validated by the CDA-AMC review team.

AD is a chronic, relapsing, inflammatory, and noncontagious skin disease that is commonly associated with other atopic expressions, such as asthma, allergic rhinitis, and food allergy.¹ Approximately 90% of patients with AD develop the disease within the first 5 years of life.¹ Risk factors for the development of AD are family history of atopy (a major risk factor), and a genetic defect in the filaggrin gene.^1,26 Although AD primarily affects the skin, accumulating evidence suggests that it is a systemic disease with both atopic and nonatopic comorbidities.²⁷ Patients with AD are at an increased risk of skin infections because of excessive rubbing or scratching.¹ Exacerbations, or flares, are an integral part of the disease course, and generally indicate a worsening of AD that requires the escalation or intensification of treatment.⁴ Flares can be aggravated or triggered by endogenous factors, including alteration of skin microbiota, skin barrier dysfunction, dysregulation of cytokine production, stressful life events, and hormonal changes, or by environmental factors, such as allergen exposure, hot and humid or dry and cold environments, sweating, sun exposure, or clothing made from irritable fibres.⁴

AD impacts approximately 15% to 20% of children and approximately 1% to 3% of adults worldwide; in high-income countries, AD affects around 20% of children and up to 10% of adults.^1,5 Approximately 50% of adult patients have moderate-to-severe disease, based on clinical disease severity scales.⁶

AD can adversely impact all aspects of life and the productivity of patients and their families, especially in its severe state.^3,28 The burden of disease and its impact on quality of life may be profound, particularly in cases of moderate-to-severe AD.² An SLR that focused on the burden of AD in adolescents and adults reported that itch or pruritus; soreness, pain, or tenderness; and skin dryness were the signs and symptoms most frequently cited as having a clinical impact.³ Itch, the major symptom, has a negative impact on quality of life and is associated with mental distress and an increased risk for suicidal thoughts.¹ Depression, anxiety, and sleep disturbance are frequently reported comorbidities.^2,3 Patients may experience significant sleep disturbance leading to lack of concentration, lethargy, and increased absenteeism.^2,3 Moreover, AD can result in embarrassment related to appearance and can have a negative impact on self-esteem and a patient’s social life.¹ During adolescence, when individuals are developing their identity, body-image and self-image are particularly important, and AD may impact these patients to a greater degree than patients in other age groups.²⁹

A clinical diagnosis of AD is based on the patient’s medical history and an evaluation of morphology, the distribution of skin lesions, and associated signs and symptoms.³⁰ Numerous tools have been developed to assess disease severity in AD, such as the EASI, Pruritus NRS, POEM, SCORing Atopic Dermatitis (SCORAD), and IGA; although not all have been validated.² These severity measures are primarily used in the research setting and are not generally practical for the measurement of disease severity in routine clinical practice.²⁷

Standards of Therapy

The contents of this section have been informed by materials submitted by the sponsor and clinical expert input. The following information has been summarized and validated by the CDA-AMC review team.

Initial treatment for most patients with AD is emollients (moisturizers) plus topical anti-inflammatory therapy, including TCS and topical calcineurin inhibitors.⁷ For patients with more severe AD or with AD that is refractory to topical therapy, advanced treatments, including phototherapy and systemic treatment, are considered. Ultraviolet B phototherapy can be tried, but its efficacy is not as well established, and it is often not feasible, requiring 2 or 3 clinic visits per week for about 10 to 14 weeks.⁷ Additionally, phototherapy cannot be used for the long term, so it cannot be relied upon as a long-term solution for people with more chronic AD.

As discussed in the clinical practice guidelines issued by the American Academy of Dermatology and the American Academy of Allergy, Asthma and Immunology, biologics, and particularly dupilumab, are considered first-line systemic therapy.^7,8 Other options include tralokinumab (another biologic) and oral JAK inhibitors (upadacitinib, abrocitinib).^7,8 Because of potential safety concerns with the JAK inhibitor drug class, upadacitinib and abrocitinib are generally not considered first-line systemic therapies for AD.⁷ Regulators have included warnings for all JAK inhibitors based on safety data from other populations with tofacitinib (another JAK inhibitor), which was associated with an increased risk of major cardiovascular AEs, thrombosis, cancer, and death.⁷ According to the clinical expert consulted, off-label immunomodulators (cyclosporine, methotrexate, mycophenolate, and azathioprine) are generally only used when mandated by a medication payer as step-through therapy or when the previously mentioned biologics and JAK inhibitors fail or are contraindicated. These drugs were not listed a first-line systemic therapies in the 2023 American Academy of Dermatology clinical practice guidelines due to their certainty of evidence being lower than for newer drugs, the potential for SAEs, the need for stringent laboratory monitoring, and lack of regulatory approval for use in AD.⁷

The clinical expert noted that all therapies treat the underlying inflammation of AD; they do make symptoms better, but that is secondary to treating the inflammation. Goals of treatment include reducing the symptoms of AD, particularly itch; reducing the visible signs of AD; improving quality of life, sleep quality and work productivity. Reducing potential adverse effects is important. Because AD is a chronic disease, maintaining low levels of disease activity and reducing flares is important.

Drug Under Review

The key characteristics of lebrikizumab, dupilumab, abrocitinib, and upadacitinib are summarized in Table 3. Of note, although tralokinumab is approved for the treatment of AD in Canada, it is not currently reimbursed by any publicly funded drug plan and so was not considered a relevant comparator for this review.

Lebrikizumab is approved by Health Canada for the treatment of moderate-to-severe AD in adults and adolescents aged 12 years and older with a body weight of at least 40 kg, whose disease is not adequately controlled with topical prescription therapies or for whom those therapies are inadvisable.¹⁶ Lebrikizumab can be used with or without TCS.¹⁶ The product monograph also states that lebrikizumab may be used in combination with topical calcineurin inhibitors for problem areas, such as the face, neck, and intertriginous and genital areas.¹⁶

Lebrikizumab is available as a 250 mg per 2 mL solution in a prefilled pen or prefilled syringe with needle shield for SC injection.¹⁶ The recommended initial dose is 500 mg (two 250 mg injections) at week 0 and week 2, followed by 250 mg (1 injection) every 2 weeks until week 16. Once a clinical response is achieved, the recommended maintenance dose is 250 mg every-4-weeks starting at week 16. The product monograph states that continued therapy beyond 16 weeks should be carefully considered in a patient who does not show a treatment benefit within this time period.¹⁶

Lebrikizumab is an immunoglobulin G4 (IgG4) monoclonal antibody that binds with high affinity and a slow off-rate to IL-13, and inhibits IL-13 signalling through the IL-4 receptor alpha (IL-4RAlpha) and IL-13 receptor alpha 1 (IL-13RAlpha1) pathways, thereby blocking the downstream effects of IL-13.¹⁶

Lebrikizumab has not been previously reviewed by CDA-AMC. The sponsor’s reimbursement request is the same as the Health Canada indication.³¹

Lebrikizumab was under review by Health Canada when this report was drafted and received a Notice of Compliance on June 24, 2024. Lebrikizumab was approved in 2024 by the FDA for adults and adolescents with moderate-to-severe AD for the same indication as in Canada. The European Medicines Agency (EMA) authorized lebrikizumab for adults and adolescents with moderate-to-severe AD for whom treatment applied directly to the skin cannot be used or is not sufficient.

Table 3: Key Characteristics of Lebrikizumab, Dupilumab, Abrocitinib, and Upadacitinib

AD = atopic dermatitis, EASI-75 = at least a 75% reduction in Eczema Area and Severity Index score; IL = interleukin, JAK = Janus kinase, MACE = major adverse cardiovascular events, SC = subcutaneous, STATs = signal transducers and activators of transcription; TCS = topical corticosteroids.

^aHealth Canada–approved indication.

Source: Lebrikizumab Product Monograph,¹⁶ Dupilumab Product Monograph,³² Abrocitinib Product Monograph,³³ Upadacitinib Product Monograph,³⁴ Sponsor’s Summary of Clinical Evidence.³⁵

Perspectives of Patients, Clinicians, and Drug Programs

Patient-Group Input

This section was prepared by the CDA-AMC review team based on the input provided by patient groups. The full original patient inputs received by CDA-AMC have been included in the Perspectives of Patients, Clinicians, and Drug Programs section of this report.

Three patient groups provided input to this submission. Eczema Quebec gathered information through review of scientific literature, informal conversations with patients, The Skin I'm In 2022 Update: A National Report of the Patient and Caregiver Experience With Atopic Dermatitis (a joint report by Eczema Quebec and the CSPA), expert opinion from the Centre of Excellence for Atopic Dermatitis at the McGill University Health Centre, 9 written patient testimonials, interviews with 14 patients, and feedback from 3 patient-group discussions. The CSPA gathered information from previous submissions to CADTH, data from the Canadian Institute for Health Information on AD-related emergency department visits, hospitalizations from 2016 to 2020 (reported in The Skin I'm In), and guidelines. ESC gathered information through a survey, and one-on-one interviews with more than 3,000 patients with AD and their caregivers who live in Canada.

According to the patient-group input, the symptoms experienced by patients with AD include inflamed, painful, dry, and itchy skin that cracks, oozes, bleeds, and, in some cases, involves thickening and/or infections of the skin. ESC noted that 62% of survey respondents with moderate AD and 87% of survey respondents with severe AD reported having scars or marks on their skin from scratching. Conditions associated with AD include asthma, seasonal and environmental allergies, food intolerances, sleep disorders, anxiety, and depression. Often, patients with AD experience flares, which are periods of worsening of the disease and its symptoms, and periods of remissions. Itch is frequently reported as the most burdensome symptom and has been described as uncontrollable, incapacitating, debilitating, and bugs crawling all over, leading to disrupted sleep, fatigue, decreased functionality, and significant impacts on daily life, work, and school.

According to ESC, 72% of adult respondents with moderate AD and 95% of respondents with severe AD reported feeling itchy multiple times each day, whereas 44% of ESC survey respondents with severe AD reported feeling itchy all the time. Furthermore, 71% and 42% of adult survey respondents with moderate or severe AD rated their overall itch as 7 out of 10 and 10 out of 10 (the worst itch imaginable), respectively. Also, 54% of adult survey respondents with severe AD reported rarely being able to control their urge to scratch their skin. According to ESC, 69% of survey respondents with moderate AD and 87% of survey respondents with severe AD reported that itch negatively impacts stress. ESC added that feelings of depression and anxiety, as well as poor self-esteem, low energy, and, in some extreme cases, suicidal thoughts can be common among the patients with more severe AD. Based on the Eczema Quebec and CSPA joint report, 89% of survey respondents acknowledged the significant impact of the emotional and psychological burden of AD on their quality of life. ESC reported that 63% of survey respondents with moderate AD and 86% of survey respondents with severe AD reported that itch negatively impacted their sleep, and 50% of survey respondents with severe AD reported experiencing sleep loss 8 nights per month or more.

Patient groups stated that physical manifestations and the visibility of the disease contribute to psychological distress through stigmatization, which impacts a patient’s self-esteem, professional commitments, and social engagements. ESC reported that 32% of adult survey respondents with moderate or severe AD had missed work events due to their disease, and 30% had to change careers or give up certain activities. Eczema Quebec stated that access to health care presents another challenge to patients with AD; Canada's low ratio of dermatologists to the population makes specialized care difficult to obtain, particularly in remote areas.

Eczema Quebec and CSPA cited data from the Canadian Institute for Health Information that showed the frequency of hospitalization and emergency department visits for patients with AD.

Based on patient-group input, the burden of AD also extends to caregivers and family members. Caregivers reported feelings of anxiety, depression, helplessness, guilt, frustration, and a lack of control over the situation. Caregivers and family members also shared that their own health and emotional wellness, lifestyle, sleep, intimacy, social activities, and family dynamics were affected by the disease. Further, the cost of treatment and other skincare products can place financial stress not only on patients, but also on the family. ESC noted that 55% of caregivers of a teenager with moderate-to-severe AD reported experiencing sleep loss, 69% of caregivers reported experiencing anxiety related to managing a youth with moderate-to-severe AD, and 25% reported experiencing depression related to their child’s moderate-to-severe AD. Additionally, 62% of caregivers reported that time management was a challenge when trying to care for a child with moderate-to-severe AD; 63% reported experiencing physical, mental, or emotional stress; 36% reported feeling a lack of support from the health care system; and 30% reported financial challenges related to managing their child’s disease.

ESC noted that adolescents with AD can suffer significantly with itch and pain; however, the impact goes far beyond those symptoms. ESC reported that the daily life of 52% of families with a patient who has moderate-to-severe disease are negatively impacted by AD, according to survey data. In the same moderate-to-severe disease data, 70% of youth reported loss of sleep, 30% reported difficulty participating in sports or physical activities, and 21% reported avoiding social activities. ESC reported that 30% of teenagers experienced anxiety related to their AD and 20% of adolescents with moderate-to-severe disease missed school days specifically due to their AD, with 23% of those respondents missing 10 or more days of school per year and 12% missing 20 or more days of school per year. The caregiver-reported rate of bullying of children with moderate-to-severe AD was 14%.

In terms of experience with currently available treatments, the patient groups reported that topical treatments that are not eligible for reimbursement and necessary nongeneric products contribute to the financial burden of managing AD. The efficacy level and adverse effects of current treatments, the inconvenience of product use, and the high cost or unavailability of newer therapies were reported as important concerns. According to ESC, 87% of adult respondents with moderate AD reported that their disease is not well controlled; moreover, 74% and 24% of respondents have lived without adequate treatment for “more than a year” and “a decade or longer,” respectively.

Important desired outcomes reported by the patient groups were better, fast, and long-term control of the disease; reduction of flare; relief from itch; reduction of skin symptoms; pain and discomfort relief; improved psychological status; improved daily and social activities; increased productivity; improved emotional well-being; improved sleep quality; and the ability to maintain intimate relationships. In addition, treatments should be affordable or covered by insurance and should be easy to use (i.e., not administered by injection or topically).

Clinician Input

Input From Clinical Expert Consulted by CDA-AMC

All CDA-AMC review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of AD.

Unmet Needs

The clinical expert stated there is an unmet need for more treatment options for people who are refractory to or do not tolerate current biologic treatments and for people who are concerned about the safety profile of oral JAK inhibitors, such as those with comorbidities or who are older.

Place in Therapy

The clinical expert did not expect lebrikizumab to cause a shift in the treatment paradigm; rather, it would be another biologic medication used to treat patients with moderate-to-severe AD whose disease is not adequately controlled with topical therapy. Lebrikizumab is not the first treatment to address the underlying disease process and inflammation; its mechanism of action is similar to other biologics, particularly tralokinumab. The clinical expert anticipates that the use of lebrikizumab will be similar to that of other systemic medications that allow the concomitant use of emollients and topical anti-inflammatory treatments (e.g., corticosteroids). Given the clinical experience with and the evidence supporting the use of dupilumab, the expert anticipated that lebrikizumab would be considered a second-line biologic after dupilumab, and that it may be chosen for patients for whom dupilumab is contraindicated, ineffective, or not tolerated.

The clinical expert stated that it would be appropriate for patients to try topical anti-inflammatory medications (e.g., TCS or topical calcineurin inhibitors) and dupilumab before initiating lebrikizumab. Topical anti-inflammatory treatments are almost always used in the first-line setting and can be effective even in severe cases. However, when patients are refractory, systemic treatment should be considered. According to the clinical expert and clinical practice guidelines,⁷ dupilumab, is recommended as the first-line systemic treatment option, based on its efficacy and safety profile. Other options, such as tralokinumab and lebrikizumab, are reserved for second-line therapy.

Patient Population

Patients with moderate-severe AD refractory to topical therapy are most likely to respond to treatment with lebrikizumab, according to the clinical expert. Patients who are refractory to treatment with dupilumab are most in need of a new intervention such as lebrikizumab. There are no known disease characteristics among patients with moderate-severe AD refractory to topical therapy that differentiate potential lebrikizumab responders from nonresponders.

Clinician examination and history, including assessment of the impact of AD on quality of life, would establish which patients are suitable for treatment with lebrikizumab. No laboratory tests or other diagnostic tools would be necessary. No companion diagnostic test is required. Most cases of AD are not difficult to diagnose, and misdiagnosis is rare. Occasionally, tests such as skin biopsy or patch testing can help differentiate AD from other mimickers, but these are not necessary in the vast majority of cases.

Assessing the Response Treatment

In clinical practice, clinicians generally use a gestalt assessment of improvement in clinical signs and a patient’s history of change in symptoms (e.g., itch) and quality of life, the clinical expert stated. Clinicians only use the tools used in clinical trials (e.g., EASI score) if mandated by a medication payer to obtain coverage. The outcomes used in clinical trials are often reflective of what would be considered in a clinician’s gestalt response, but they are cumbersome and not meant for use in routine clinical practice.

According to the clinical expert, a meaningful response to treatment would be an approximately 50% to 75% improvement in signs and symptoms; the specific proportion likely differs by clinician and by patient. The improvement should include a reduction in the severity and frequency of symptoms, often accompanied by improvement in quality of life and the ability to perform household, work, and/or school activities. Disease flares should also be reduced (fewer episodes of intense itching and widespread and severe eruptions). For patients who are prone to secondary skin infections, any treatment that reduces the inflammation of AD and improves the skin barrier should result in fewer infections.

Discontinuing Treatment

The clinical expert indicated that lebrikizumab would be discontinued if it is inadequately effective, as judged by the gestalt response to treatment. If patients are satisfied with treatment, even if an arbitrary cut-off like EASI-75 is not met, they might continue with treatment.

Patients may discontinue treatment if AEs are intolerable. Lebrikizumab has been associated with conjunctivitis, but this adverse effect is usually mild and transient; if conjunctivitis is severe and/or refractory to eyedrops, lebrikizumab could be discontinued. Other unanticipated SAEs, like severe allergy, could lead to discontinuation.

The clinical expert stated that some patients do not like the idea of being on a medication indefinitely. In such cases, patients and their physicians can use shared decision-making to decide whether to stop lebrikizumab to see if the dermatitis recurs; if it does, lebrikizumab would likely be restarted.

Prescribing Considerations

The clinical expert indicated that in most instances, a specialist (dermatologist, allergist, pediatrician) would be required to treat a patient with AD with a biologic. This can be done in a community setting, hospital clinic, or specialty clinic. Family physicians are adept at diagnosing AD but are likely not comfortable prescribing biologic therapy. In areas where access to specialty care is difficult, some family physicians could gain comfort with biologics for AD, because minimal clinical monitoring is required.

Clinician-Group Input

This section was prepared by the CDA-AMC review team based on the input provided by clinician groups. The full original clinician-group inputs received by CDA-AMC have been included in the Perspectives of Patients, Clinicians, and Drug Programs section of this report.

CDA-AMC received inputs from 2 clinician groups for this review. The CDA submitted input from 3 clinicians from their Pharmacy and Therapeutics Advisory Board, and the DAO submission included input from 11 clinicians.

Clinician groups and the clinical expert consulted by CDA-AMC agreed that a lack of adequate response to treatment, incomplete effectiveness, the adverse effects of treatments, a lack of feasibility of some of treatments, and relapses are unmet needs of patients with AD. One of the clinician groups added that challenges in access to care, multitiered treatment regimens, treatment intolerance or contraindications, and comorbid bacterial skin infections are unmet needs as well.

The CDA and the clinical expert consulted by CDA-AMC agree that the goals of treatment are to improve quality of life and maximize efficacy and safety. Regarding the place of lebrikizumab in therapy, the DAO and the clinical expert consulted by CDA-AMC indicate that lebrikizumab will not cause a shift in the treatment paradigm and would fit into the current paradigm as another treatment option. In contrast, the CDA indicated that lebrikizumab contributes to an important shift in the current treatment paradigm toward a new era of focus on novel disease mechanisms that target and modify disease and have favourable safety and efficacy profiles.

According to the DAO, adult patients with moderate-to-severe AD who have failed topical therapies and those who have failed or do not have access to phototherapy would be best suited to treatment with lebrikizumab. The CDA stated that patients best suited for treatment with lebrikizumab would be those with uncontrolled moderate-to-severe AD who are candidates for systemic therapy or who meet criteria for biologic therapy. The CDA noted that dupilumab is indicated for patients with other severe forms of atopic or allergic conditions, such as severe asthma, or eosinophilic esophagitis; thus, dupilumab may be chosen for these patients instead of the IL-13 inhibitors, which are not indicated for these conditions.

The DAO noted that a patient’s response to treatment would be assessed with the IGA, EASI, Pruritus NRS, and DLQI scoring systems at 4 to 6 months and annually thereafter. The CDA stated that assessment of a patient’s response would be based on a clinical exam, patient history, physician-reported clinical scoring systems (EASI, BSA, IGA) and patient-reported outcomes (DLQI, CDLQI, and Pruritus NRS). The CDA added that in clinical practice, due to time limitations, only some of the scoring systems are used.

Clinician groups reported AEs and poor efficacy of treatment as factors that should be considered when deciding whether to discontinue the treatment.

Based on clinician-group input, the treatment and monitoring of patients on lebrikizumab should be limited to specialists trained in this area, which would include the fields of dermatology, allergy, immunology, or pediatrics.

Drug Program Input

The drug programs provide input on each drug being reviewed through the CDA-AMC reimbursement review process by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CDA-AMC are summarized in Table 4.

Table 4: Summary of Drug-Plan Input and Clinical Expert Response

AD = atopic dermatitis; CDEC = Canadian Drug Expert Committee; EASI = Eczema Area and Severity Index; EASI-75 = at least a 75% reduction in Eczema Area and Severity Index score; JAK = Janus kinase; pCPA = pan-Canadian Pharmaceutical Alliance; SC = subcutaneous; TCS = topical corticosteroids.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of lebrikizumab 250 mg per 2 mL solution for SC injection in the treatment of moderate-to-severe AD in adults and adolescents aged 12 years and older with a body weight of at least 40 kg, whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The focus will be placed on comparing lebrikizumab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of lebrikizumab is presented in 4 sections, with the CDA-AMC-conducted critical appraisal of the evidence included at the end of each section. The first section, the Systematic Review, includes pivotal studies and RCTs that were selected in accordance with the sponsor’s systematic review protocol. The CDA-AMC assessment of the certainty of the evidence in this first section, using the GRADE approach, follows the critical appraisal of the evidence. The second section includes a sponsor-submitted long-term extension study. The third section includes indirect evidence from the sponsor. The fourth section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

Clinical evidence from the following are included in the CDA-AMC review and appraised in this document:

• 3 pivotal studies identified in the systematic review

• 1 long-term extension study

• 1 ITC

• 4 additional studies addressing gaps in evidence.

Systematic Review

The contents of this section have been informed by materials submitted by the sponsor. The following information has been summarized and validated by the CDA-AMC review team.

Description of Studies

Characteristics of the included studies are summarized in Table 5.

The objective of the ADvocate 1 and ADvocate 2 studies was to evaluate the safety and efficacy of the 250 mg lebrikizumab SC injection as monotherapy in patients with moderate-to-severe AD. Both were randomized, double-blind, placebo-controlled studies that included a 16-week induction period (parallel design), followed by a 36-week maintenance period that used a randomized withdrawal design. Eligible patients were adults or adolescents (aged 12 years to less than 18 years and weighing more than 40 kg) who had a diagnosis of chronic AD that was rated as moderate-to-severe based on an EASI score of at least 16, an IGA score of at least 3, and AD covering a BSA of 10% or more.

Table 5: Details of the Studies Included in the Systematic Review

ACQ-5 = Asthma Control Questionnaire; AD = atopic dermatitis; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; EASI-50 = at least a 50% reduction in EASI score; EASI-75 = at least a 75% reduction in EASI score; EASI-90 = at least a 90% reduction in EASI score; IGA = Investigator Global Assessment; LD = loading dose; NA = not applicable; NRS = Numeric Rating Scale; POEM = Patient-Oriented Eczema Measure; PROMIS = Patient-Reported Outcomes Measurement Information System; RCT = randomized controlled trial; SC = subcutaneous; SCORAD = SCORing Atopic Dermatitis; TCS = topical corticosteroids.

^aPrimary and secondary outcomes are listed according to the statistical analysis plan for the European Medicines Agency.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere,⁹ Sponsor’s Summary of Clinical Evidence.³⁵

The ADvocate 1 study was conducted in Australia, Canada, Europe, South Korea, and the US, and a total of 424 patients were randomized, including 23 patients from Canada. The ADvocate 2 study randomized 427 patients (including 58 from Canada) from Asia, Europe, and North America. The study schematic for the ADvocate 1 and ADvocate 2 studies is shown in Figure 1. Using an electronic data capture system, the studies randomized patients in a ratio of 2:1 to receive 250 mg lebrikizumab or placebo once every 2 weeks for the 16-week induction period. Randomization was stratified by region (Europe, the US, or the rest of the world), age (adolescent or adult), and disease severity (IGA score of 3 or 4). At week 16, patients who responded to treatment (defined as either an IGA score of 0 or 1 or an EASI-75 response in patients who did not receive rescue therapy) were randomly reassigned in a ratio of 2:2:1 to double-blind lebrikizumab 250 mg every 2 weeks, lebrikizumab 250 mg every 4 weeks, or placebo for the 36-week maintenance period. Separate randomizations were used for patients who responded to lebrikizumab and patients who responded to placebo. Patients who did not meet the response criteria at week 16 or who required rescue therapy during the induction phase were enrolled in the escape arm and received open-label lebrikizumab 250 mg every 2 weeks through to week 52. In addition, rerandomized patients who did not maintain at least a 50% reduction in EASI score from baseline (EASI-50) during the maintenance phase were assigned to the escape arm.

Patients who completed the ADvocate 1 or ADvocate 2 study were eligible to enrol in the extension study (ADjoin).

Figure 1: Study Design of the ADvocate 1 and ADvocate 2 Studies

D/C = discontinue; EASI-50 = at least a 50% reduction in Eczema Area and Severity Index score; LEB = lebrikizumab; Q2W = every 2 weeks; Q4W = every 4 weeks.

Source: CSR for ADvocate 1.¹¹

The objective of the ADhere study was to evaluate the safety and efficacy of the lebrikizumab in combination with TCS compared with placebo plus TCS in patients with moderate-to-severe AD. The study was a 16-week randomized, double-blind, placebo-controlled, parallel-design trial. Adults or adolescents (aged 12 years to less than 18 years weighing more than 40 kg) with moderate-to-severe AD (EASI score of ≥ 16, IGA score of ≥ 3, AD covering a BSA of 10% or more) were eligible to enrol. Patients were randomized in a 2:1 ratio to receive 250 mg lebrikizumab SC once every 2 weeks in addition to TCS or placebo plus TCS for the 16-week treatment period. An electronic data capture system was used to allocate patients to treatment, and randomization was stratified by region (Europe, the US, or the rest of the world), age (adolescent or adult), and disease severity (IGA score of 3 or 4). A total of 211 patients were randomized, including 22 patients from Canada. The study was conducted at 54 centres in Canada, Germany, Poland, and the US.

Patients who completed the ADhere study were eligible to enter the extension study (ADjoin).

Populations

Inclusion and Exclusion Criteria

All 3 studies used similar inclusion and exclusion criteria and enrolled adults and adolescents with chronic AD, defined by the American Academy of Dermatology consensus criteria,³⁹ for at least 1 year before the screening visit and with disease that was classified as moderate-to-severe (EASI score of ≥ 16, IGA score of ≥ 3, and AD covering a BSA of 10% or more) (Table 5). Patients were also required to have a history of inadequate response to topical medications or to be in a position in which topical treatments are medically inadvisable.

In the ADvocate 1 and ADvocate 2 studies, patients were excluded if they had previously received dupilumab, tralokinumab, or lebrikizumab, and were required to stop all other AD therapies before randomization. For the ADhere study, patients who had received tralokinumab were not excluded from the trial and those who had received dupilumab were eligible, provided the drug was stopped 8 weeks before study entry. In all trials, patients underwent a 1-week washout period for topical treatments and a 4-week to 6-month washout period for other AD treatments (refer to the Interventions section for details) to be eligible for either study.

Other key exclusion criteria for the 3 trials were uncontrolled chronic disease that might require bursts of oral corticosteroids or may interfere with the study assessments of clinical status, active chronic or acute infection requiring recent systemic treatment, HIV, hepatitis, or cirrhosis, and a history of or suspected immunosuppression.

Additional inclusion and exclusion criteria were applied at week 16 in the ADvocate 1 and ADvocate 2 trials. To quality for rerandomization for the maintenance phase, patients had to meet the treatment response criteria and had to have achieved an IGA score of 0 or 1 or EASI-75 at week 16. Patients who did not meet the response criteria at week 16 or who required rescue therapy during the induction phase were eligible to enter the escape arm of the studies.

Interventions

The ADvocate 1 and ADvocate 2 Studies

In the ADvocate 1 and ADvocate 2 studies, patients were randomized to receive double-blind lebrikizumab 250 mg or placebo SC once every 2 weeks for the 16-week induction period. Patients in the lebrikizumab group received a 500 mg lebrikizumab loading dose at week 0 and week 2, and then 250 mg every 2 weeks until week 14. The lebrikizumab or placebo injections were supplied as 2-mL prefilled syringes with a preassembled needle safety device. The placebo solution was identical in appearance and content to the active solution, except for lebrikizumab.

At week 16, patients who responded to treatment were randomly reassigned in a ratio of 2:2:1 to double-blind lebrikizumab 250 mg every 2 weeks, lebrikizumab 250 mg every 4 weeks, or placebo for the maintenance period. Separate randomizations were used for lebrikizumab responders (maintenance primary population) and placebo responders (maintenance secondary population). Responders who received placebo during the first 16 weeks of the study and who were randomly reassigned to 1 of the lebrikizumab arms received loading doses of lebrikizumab 500 mg at week 16 and week 18, and then received lebrikizumab 250 mg every 2 or 4 weeks, depending on the randomized treatment group. To maintain blinding during the induction and maintenance phases, all patients received the same number of injections through a combination of active and placebo injections. All doses of the study drug were administered at the study centres during the induction period and were self-administered after week 16.

Both studies provided access to escape therapy if the study treatments did not adequately control the AD. Patients who did not meet the response criteria at week 16 or who received topical or systemic rescue therapy during the first 16 weeks were enrolled in the escape arm and received open-label lebrikizumab 250 mg SC every 2 weeks through to week 52 (including a blinded loading dose if the patient had not received lebrikizumab previously). In addition, rerandomized patients who failed to maintain an EASI-50 response during the maintenance phase were assigned to the escape arm and received open-label lebrikizumab 250 mg every 2 weeks. Patients who did not achieve an EASI-50 response after 8 weeks in the escape arm were terminated from the study.

Concomitant medications to treat AD were prohibited during the induction period of the trials unless they were part of rescue therapy. Rescue therapy started with topical therapies first (e.g., midpotency TCS) and, if symptoms were not controlled, systemic treatments could be initiated (e.g., oral corticosteroids, phototherapy, cyclosporine). The study drug was stopped if systemic rescue therapy was required, but these patients continued to attend study visits for assessments of safety and efficacy. During the maintenance period, the intermittent use of topical rescue medications was permitted, including by patients in the escape arm. The short-term use of systemic rescue therapies was determined on a case-by-case basis after consultation with the medical monitor. In both studies, all patients were required to use nonmedicated topical moisturizers daily.

Patients receiving specific AD therapies before the study underwent a washout period before randomization. The washout period was as follows: 1 week for TCS, calcineurin inhibitors, and phosphodiesterase type 4 inhibitors; 4 weeks for systemic immunosuppressive drugs (e.g., corticosteroids, cyclosporine, mycophenolate-mofetil, interferon gamma, JAK inhibitors, azathioprine, and methotrexate) and for phototherapy or photochemotherapy; 6 months for B-cell-depleting biologics (e.g., rituximab); 16 weeks or 5 half-lives for other biologics; and 1 week for prescription moisturizers.

The ADhere Study

In the ADhere study, patients were randomized to receive double-blind lebrikizumab 250 mg or placebo SC once every 2 weeks in combination with TCS for 16 weeks. Loading doses of 500 mg lebrikizumab at week 0 and week 2 were administered to patients randomized to lebrikizumab, followed by 250 mg every 2 weeks thereafter. To maintain blinding, the study drug was supplied as identical-looking prefilled syringes containing 2 mL of either lebrikizumab or placebo (vehicle), and all patients received the same number of injections. All patients were prescribed a midpotency TCS (triamcinolone acetonide 0.1% cream) plus a low-potency TCS (hydrocortisone 1% cream) for use in sensitive areas. The use of topical calcineurin inhibitors was allowed for sensitive areas only. TCS were initiated at baseline, and patients were allowed to taper, stop, or reinitiate TCS as needed. Using an electronic diary, patients recorded the topical AD therapies they used daily. All patients were required to use a nonmedicated topical moisturizer daily.

The ADhere study had the same washout criteria for prior AD treatments as the ADvocate studies, with 1 exception. Patients who had previously received dupilumab were eligible for the ADhere study provided treatment had stopped 8 weeks before the start of the trial. Patients who had received tralokinumab previously were not excluded from the ADhere study.

Rescue therapy for patients who experienced a clinical worsening of symptoms that were intolerable consisted of high-potency TCS or systemic therapy (e.g., oral corticosteroids, phototherapy, and cyclosporine). Patients who required systemic rescue therapy stopped their study drug but continued the scheduled study visits and underwent assessments for safety and efficacy.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 6 and is followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence, as well as any outcomes identified as important to this review, according to the clinical expert consulted by CDA-AMC and input from patient and clinician groups and public drug plans. Using the same considerations, the CDA-AMC review team selected end points that were considered to be most relevant to the CDA-AMC expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. The efficacy outcomes selected for assessment using GRADE are shown in Table 6. Other supportive efficacy outcomes were reported in the Results section only. Select notable harms outcomes considered important for the CDA-AMC expert committee deliberations were also assessed using GRADE.

All the outcomes listed in Table 6 were identified as clinically important measures by the clinical expert consulted by CDA-AMC. The patient-group input also identified AD severity, symptoms (particularly itch), and HRQoL as key outcomes. Moreover, EASI, DLQI and CDLQI, POEM, and Pruritus NRS scores were identified as part of the core outcome set for clinical trials of AD.⁴⁰ For outcomes in which there were multiple analyses for the same instrument (e.g., change from baseline and proportion of responders), only 1 measure was selected for GRADE. IGA response and EASI-75 response were selected, as they were coprimary end points. The proportion of patients with a Pruritus NRS 4-point response was selected to be consistent with the outcomes reported in the ITC. Conjunctivitis was identified by the clinical expert as a common and potentially troublesome adverse effect of some AD medications, and the risk of SAEs was an important end point, given that most patients will require long-term treatment to manage their disease.

All 3 studies had a separate statistical analysis plan for submission to the EMA and to the FDA. The EMA submission included 2 coprimary end points and 15 major secondary end points for the ADvocate 1 and ADvocate 2 studies, and 2 coprimary end points and 8 major secondary end points for the ADhere trial. The FDA submission considered a single primary end point (IGA 0 or 1 response) and 8 major secondary end points for the ADvocate 1 and ADvocate 2 studies, and a single primary end point and 4 major secondary end points for the ADhere study. The sponsor focused on the results in the EMA submission in its clinical summary, and the same approach was used in the CDA-AMC review.

Evidence for validity, reliability, and responsiveness of the outcome measures of interest is summarized in Table 8.

Investigator Global Assessment

A coprimary end point for all 3 studies was the percentage of patients with an IGA score of 0 or 1 and an improvement of greater than or equal to 2 points from baseline at week 16. The IGA measures the investigator’s global assessment of the patient’s overall severity of AD at that visit, based on a static, numeric 5-point scale that ranges from 0 (clear) to 4 (severe) (Table 7). A score was selected using descriptors that best described the overall appearance of the lesions at a given time point. The CSRs state that assessors were trained and certified by the sponsor before conducting this assessment and that a single assessor was assigned to each patient for as many visits as possible. No MID was identified for adult or adolescent patients with AD.

Based on input from the clinical expert consulted for this review, an absolute difference of at least 10% between the lebrikizumab and placebo groups was considered clinically important with respect to the proportion of patients achieving an IGA score of 0 or 1.

Table 6: Outcomes Summarized From the Studies Included in the Systematic Review

CDLQI = Children’s Dermatology Life Quality Index; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index score; EASI-75 = at least a 75% reduction in Eczema Area and Severity Index score; EASI-90 = at least a 90% reduction in Eczema Area and Severity Index score; GRADE = Grading of Recommendations Assessment, Development, and Evaluation; IGA = Investigator Global Assessment; NA = not applicable; NRS = Numeric Rating Scale; POEM = Patient-Oriented Eczema Measure; SAE = serious adverse event.

^aThe outcomes in the table are described according to the statistical plan for the European Medicines Agency (EMA). Outcomes listed as primary and major secondary were adjusted for multiple comparisons. Other outcomes were not controlled for multiplicity.

^bPrimary end point according to the statistical plan for the FDA.

^cMajor secondary outcome according to the statistical plan for the FDA, which was adjusted for multiple comparisons.

^dOther outcome that was not adjusted for multiple comparisons according to the statistical plan for the EMA or the FDA.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere.⁹

Table 7: Investigator Global Assessment Scoring

Source: CSR for ADhere.⁹

Eczema Area and Severity Index

The percentage of patients who attained a reduction greater than or equal to 75% from baseline in EASI score at week 16 was used as the coprimary end point in the 3 trials. The EASI assesses the extent of disease at 4 body regions, and measures 4 clinical signs at the visit, each on a scale of 0 to 3: erythema, edema or papulation, excoriation, and lichenification. The EASI confers a maximum score of 72, with higher values indicating more severe disease and/or more extensive disease. The EASI evaluates 2 dimensions of AD: disease extent and clinical signs. Assessors were trained and certified by the sponsor before conducting this assessment. The overall MID has been reported to be 6.6 based on a study of mainly adults and an unknown number of adolescents with AD.¹³

The studies also reported the percentage of patients who achieved at least a 90% reduction from baseline in EASI score (EASI 90) and the percent change from baseline in EASI score at week 16.

The clinical expert consulted for this review identified at least a 10% difference between groups in the proportion of patients who achieved an EASI-75 response as a clinically important difference.

Pruritus NRS

The Pruritus NRS is a patient-reported, single-item, daily, 11-point scale. The scale is used by patients to rate their worst itch severity over the previous 24 hours, with 0 indicating no itch and 10 indicating the worst itch imaginable. Patients were asked to record their assessment daily in an electronic diary. In adults, a change from baseline of2 to 4 points may be considered an important within-person change.^41,42 According to the CSR, a 4-point change was selected for the responder analysis as a conservative assessment of clinical impact.

At least a 10% difference between groups in the proportion of patients who reported a Pruritus NRS 4-point response was identified as a clinically important difference, according to the clinical expert consulted.

DLQI and CDLQI

In the pivotal trials, patients aged 17 years and older completed the DLQI and those aged 12 to 16 years completed the text version of the CDLQI and continued to complete the CDLQI for the duration of the study.

The DLQI is a patient-reported, 10-item, HRQoL questionnaire for adults that covers 6 domains (symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment). The recall period of this scale is the previous week. Response categories include not at all, a little, a lot, and very much, with corresponding scores of 0, 1, 2, and 3; unanswered (or not relevant) responses were scored as 0. The 10 questions are scored from 0 to 3, giving a possible total score range of 0 (no impact of skin disease on quality of life) to 30 (maximum impact on quality of life). A DLQI total score of 0 or 1 is considered to have no effect on a patient’s HRQoL, and a 4-point change from baseline is considered to be the minimal clinically important difference threshold.^14,43 Estimates of the MID have ranged from 2.2 to 6.9, but no information about MID was found specifically for adult patients with AD.^19-21

The CDLQI questionnaire is based on the adult version (DLQI) and is designed and validated in patients with dermatological conditions who are aged 3 to 16 years. It is available in text and cartoon versions. The questionnaire consists of 10 items addressing the patient’s perception of the impact of their skin disease on various aspects of their quality of life over the previous week, including dermatology-related symptoms and feelings, leisure, school, friendships, sleep, and the impact of treatment. The total score ranges from 0 to 30, with a higher score indicating a poorer HRQoL.^15,44,45 In adolescents, a reduction in CDLQI score of 6 to 8 points has been suggested as the clinically relevant threshold for a within-person change in patients with moderate-to-severe AD.¹⁵

Based on input from the clinical expert consulted and a review of the literature, a MID of 4 points for the DLQI and 6 points for the CDLQI were selected as the clinically important threshold for GRADE.^14,15

Patient-Oriented Eczema Measure

The POEM is a 7-item, self-reported questionnaire used to assess the frequency of disease symptoms in adults and children over the previous week. Patients use an electronic diary to respond to 7 questions on skin dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping. Response categories include no days, 1 to 2 days, 3 to 4 days, 5 to 6 days, and every day, with corresponding scores of 0, 1, 2, 3, and 4.⁴⁶ The total possible score ranges from 0 to 28, with a high score indicating worse disease severity.¹² The MID in AD has been estimated to be 3.4 to 5.0 points in adults and to be 3.0 to 3.9 points in children.^12,13,47 Based on expert input, an MID of 3.4 points was selected as the threshold for a clinically relevant difference.

Table 8: Summary of Outcome Measures and Their Measurement Properties

AD = atopic dermatitis; AUC = area under the curve; CDLQI = Children’s Dermatology Life Quality Index; CI = confidence interval; CV = coefficient of variation; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; EASI-50 = at least a 50% reduction in EASI score; EASI-75 = at least a 75% reduction in EASI score; EASI-90 = at least a 90% reduction in EASI score; HRQoL = health-related quality of life; ICC = intraclass correlation coefficient; IGA = Investigator Global Assessment; MID = minimal important difference; NRS = Numeric Rating Scale; PCS = Pruritus Categorical Scale; PGADS = Patient Global Assessment of Disease Status; POEM = Patient-Oriented Eczema Measure; SCORAD = SCORing Atopic Dermatitis; SD = standard deviation; VAS = visual analogue scale.

Statistical Analysis

The 3 studies used similar statistical methods to analyze the data for the induction phase (Table 9). The Cochran-Mantel-Haenszel test stratified by geographic region (US versus Europe versus the rest of the world), age group (adolescent versus adult), and disease severity (IGA 3 versus IGA 4) was used to compare treatment groups for categorical end points (e.g., EASI-75 response). The common RD adjusted for stratification factors was reported, with 95% CI calculated using the Mantel-Haenszel-Sato method. The major secondary continuous efficacy end points were analyzed using an analysis of covariance model, with treatment group, baseline value, and stratification factors as covariates (e.g., change from baseline in DLQI score). The LS mean and 95% CI for the difference between groups was reported. Continuous efficacy outcomes with multiple measures (i.e., change from baseline in POEM score) were analyzed using an MMRM that included treatment, baseline value, visit, the interaction of baseline values-by-visit and treatment-by-visit, and the stratification factors.

For the induction phase, all 3 studies used a hybrid estimand for the primary and major secondary end points, and defined a second, supportive estimand for categorical end points (composite) and continuous end points (hypothetical) (Table 10). The estimand defined how missing data and intercurrent events (i.e., the use of rescue therapy or the stoppage of treatment due to AEs or for other reasons) were handled in the analyses (Table 11). Table 9 outlines the primary and/or supportive estimand used for each of the efficacy outcomes of interest to this review. For the change in POEM score, there was no imputation for missing data, and the MMRM used assumed that all missing data were missing at random (i.e., missingness can be explained by associations with observed data). For the IGA 0 or 1, EASI-75, and EASI-90, and at least 4-point Pruritus NRS responder analyses, a tipping point analysis was run as a sensitivity analysis only if the results of the primary analyses were statistically significant. In this analysis, all patients who used rescue medication or discontinued treatment due to lack of efficacy were imputed as nonresponders. Multiple iterations were run in which the probability of response was varied for other intercurrent events or missing data to determine if there was a tipping point, where the results were no longer statistically significant.

For the maintenance phase in the ADvocate 1 and ADvocate 2 studies, the proportion of patients who maintained an EASI-75 response at week 52 was analyzed using a Cochran-Mantel-Haenszel test stratified by region and the maintenance primary estimand (hybrid strategy) (Table 10). Two supportive estimands were defined (hybrid and composite strategies) (Table 12) that used alternate approaches for missing data.

The studies’ protocols stated that subgroup analyses were to be conducted based on age group, sex, race, baseline IGA score, and region. The statistical analysis plans also list the following subgroups to be tested: ethnicity, weight category, body mass index category, duration since AD onset category, baseline Pruritus NRS score (< 4 versus ≥ 4), and prior use of systemic treatments. The sponsor identified 1 subgroup of interest in the protocol for their systematic review: patients using lebrikizumab in combination with TCS.

Table 9: Statistical Analyses of Efficacy End Points

CDLQI = Children’s Dermatology Life Quality Index; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; EASI-75 = at least a 75% reduction in EASI score; EASI-90 = at least a 90% reduction in EASI score; IGA = Investigator Global Assessment; MCMC-MI = Markov chain Monte Carlo multiple imputation; NRI = nonresponder imputation; NRS = Numeric Rating Scale; POEM = Patient-Oriented Eczema Measure; vs. = versus.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere.⁹

Table 10: Estimands for the Studies Included in the Systematic Review

ICE = intercurrent event.

^aRescue medications during the ADvocate 1 and ADvocate 2 studies included any topical treatments (e.g., midpotency TCS) or systemic therapies (e.g., oral corticosteroids, phototherapy, and cyclosporine). Rescue therapy in the ADhere study included high-potency TCS or systemic AD therapies (e.g., oral corticosteroids, phototherapy, and cyclosporine). Note that in the ADhere study, all patients were prescribed low-to-midpotency TCS for use as needed during the trial.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere.⁹

Table 11: Analysis of Primary and Supportive Estimands — Induction Period

ICE = intercurrent event; MCMC-MI = Markov chain Monte Carlo multiple imputation; MMRM = mixed model repeated measures.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere.⁹

Table 12: Analysis of Primary and Supportive Estimands — Maintenance Period

ICE = intercurrent event; MCMC-MI = Markov chain Monte Carlo multiple imputation.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2.¹⁰

Control of Type I Error Rate

According to the statistical analysis plan for the EMA, a graphical approach was used to control the overall type I error rate at a 2-sided alpha of 0.05 for all primary and major secondary end points in the induction period of the ADvocate 1 and ADvocate 2 studies (13 outcomes in total). A hierarchical approach was used for the maintenance phase, in which the major secondary end points were tested in a prespecified order, and for each of the lebrikizumab every-2-weeks and every-4-weeks groups, the outcome of interest to this review (i.e., EASI-75 at week 52) was tested first; subsequent end points were tested only if the results were statistically significant at a 2-sided alpha of 0.05. For the FDA, a graphical approach was also used to control the overall type I error rate at a 2-sided alpha of 0.05 for the primary and 8 major secondary end points for the induction period of the ADvocate 1 and ADvocate 2 studies.

In the ADhere study, a prespecified, multiple testing, gatekeeping approach was used for all primary and major secondary end points to control the overall type I error rate at a 2-sided alpha of 0.05. There were separate gatekeeping approaches for the EMA and the FDA. The primary and major secondary end points were tested in the following sequential order for the EMA:

• IGA 0 or 1 with an improvement of at least 2 points at week 16 (coprimary)

• EASI-75 at week 16 (coprimary)

• EASI-90 at week 16

• percent change in EASI score at week 16

• an improvement of at least 4 points in Pruritus NRS score at week 16

• percent change in Pruritus NRS at week 16

• an improvement of at least 4 points in Pruritus NRS score and EASI-75 at week 16

• change in DLQI total score at week 16

• an improvement of at least 4 points in DLQI total score at week 16

• change in Sleep Loss Scale score at week 16.

The sequence for testing for the FDA was as follows:

• IGA 0 or 1 with an improvement of at least 2 points at week 16 (primary)

• EASI-75 at week 16

• an improvement of at least 4 points in Pruritus NRS score at week 16

• an improvement of at least 4 points in Pruritus NRS score and EASI-75 at week 16

• EASI-90 at week 16.

Sample Size

For the ADvocate studies, a sample size of 96 patients for lebrikizumab and 48 patients for placebo was estimated to have at least 90% power to detect a statistically significant difference between groups for IGA 0 or 1 and EASI-75 responses at week 16, based on a chi-square distribution with a 2-sided significance of 0.05. The CSR stated that the planned sample size was increased to 400 patients to ensure that sufficient safety information was collected and that there was an adequate number of patients for the maintenance phase of the trials. The power estimates were based on data from the phase II study (DRM06-AD01),⁵⁵ which reported an EASI-75 and IGA 0 or 1 response rate of ||||| ||| ||||| for lebrikizumab and |||| ||| ||||| for placebo, respectively. || ||||| |||||||||||| |||| |||||||| ||| ||| ||||||||||| ||||||

For the ADhere study, a sample size of 225 patients was planned (randomized in a ratio of 2:1 to lebrikizumab and placebo) to have at least 95% power to test the superiority of lebrikizumab for the coprimary end points based on a 2-sided Fisher’s exact test with an alpha of 0.05. These estimates assumed 16-week IGA 0 or 1 and EASI-75 response rates of 38% and 58%, respectively, for lebrikizumab plus TCS and of 13% and 20% for placebo plus TCS. ||| |||||||| ||||| |||| ||||| || | ||||| ||| ||||| ||| |||||||||||| |||||||||||||| | |||||| || |||||||||| ||| |||||||| |||||| ||| || ||| ||||||||| ||||||||||

Analysis Populations

Efficacy analyses for the induction period were conducted in the ITT population of the ADvocate 1 study and the modified ITT population of the ADvocate 2 and ADhere studies (Table 13). In the ADvocate 2 and ADhere trials, the modified ITT population excluded patients from a study site that was closed due to critical audit findings that threatened the validity of the data. The safety analyses were based on all randomized patients who received at least 1 dose of the study drug in the ADvocate 1 study (safety population), and in the modified safety population in the ADvocate 2 and ADhere studies that excluded patients from the closed study site.

The maintenance period efficacy and safety analyses of interest to this review were based on the maintenance primary population or the modified maintenance primary population in the ADvocate studies. These populations included patients who had received lebrikizumab during the induction phase and who were rerandomized and received at least 1 dose of the study drug during the maintenance phase. For patients who entered the escape arm after week 16, only information gathered before escape was included.

Table 13: Analysis Populations of the Studies Included in the Systematic Review

AE = adverse event; ITT = intention to treat; mITT = modified intention to treat; SAE = serious adverse event.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere.⁹

Results

Patient Disposition

Patient disposition during the induction phase is shown in Table 14 and during the maintenance phase is shown in Table 15 for the studies included in the systematic review.

In the ADvocate 1 study, 536 patients were enrolled, 112 patients (|||) were excluded at the screening stage, and 424 patients were randomized (|||). Of these patients, ||| ||| || stopped treatment during the induction phase in the placebo and lebrikizumab groups, respectively. Lack of efficacy (||), withdrawal by patient (||), and protocol violations (||) were the most common reasons for discontinuation in the placebo group, whereas protocol violations (||) were the most common reason in the lebrikizumab group. More patients in the placebo group entered the escape arm than the lebrikizumab group (||| |||||| |||) during the first 16 weeks. A total of 157 (|||) patients from the lebrikizumab group met the response criteria at week 16 and were rerandomized. |||| |||||||| || ||| ||| of patients discontinued treatment during the maintenance phase in the placebo group (i.e., lebrikizumab withdrawal), the lebrikizumab every-4-weeks group, and the lebrikizumab every-2-weeks group, respectively.

The ADvocate 2 study screened 606 patients, of which 179 patients (|||) failed to meet the screening criteria or were excluded due to protocol violations at a study site. A total of 427 patients (|||) were randomized and analyzed. In the placebo group, ||| of patients stopped treatment during the induction phase, compared with || of patients in the lebrikizumab group. The most common reasons for stopping treatment included withdrawal by the patient |||), AEs (||), and lack of efficacy (||) in the placebo group, and AEs (||) and protocol violations (||) in the lebrikizumab group. The CSR reported that ||| |||||| ||| of patients in the placebo and lebrikizumab groups, respectively, entered the escape arm during the first 16 weeks. A total of 134 (|||) of patients from the lebrikizumab group met the response criteria at week 16 and were rerandomized. During the maintenance phase, |||| || ||| || of patients stopped treatment in the placebo group (i.e., lebrikizumab withdrawal), the lebrikizumab every-4-weeks group, and the lebrikizumab every-2-weeks group, respectively.

The ADhere study screened 312 patients, of which 211 patients were randomized and analyzed |||||| The proportion of patients who stopped treatment during the first 16 weeks was ||| in the placebo group and || in the lebrikizumab group. The most common reasons for stopping treatment included withdrawal by the patient |||| and protocol violations (|||) in the placebo group, and AEs |||||, lack of efficacy |||||, and withdrawal by the patient |||| in the lebrikizumab group.

In the ADvocate 2 and ADhere studies, a study site was identified |||| ||| ||||| |||||||| |||||||||| |||| |||||||| || |||||||| ||||| ||||||||| ||| |||| |||| |||| |||| ||| |||||| ||||||||||| ||| |||||||| |||| |||| |||| |||| |||||||| |||| ||| |||||||| ||| |||||| |||||||||| ||||| ||||||||| |||| |||||||| ||||| ||| |||||||| |||| || ||||||| ||| |||||||| || ||| |||||||| ||| ||| |||||||| |||||| |||||||||||| ||||| |||||||| ||| |||||||| |||| ||| |||||||| ||||| ||||. In total, 18 patients |||| from the ADvocate 2 study and 17 patients |||| from the ADhere study were excluded.

Table 14: Summary of Patient Disposition From the Studies Included in the Systematic Review — Induction Period

ITT = intention to treat; LEB = lebrikizumab; mITT = modified intention to treat; NA = not applicable; NR = not reported; PBO = placebo; TCS = topical corticosteroids.

^aData presented are for the modified ITT population, which excludes data from a study site with critical audit findings.

^bData for the ADvocate 2 and ADhere studies are for the modified safety population, which excludes data from a study site with critical audit findings.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere.⁹

Table 15: Summary of Patient Disposition From the ADvocate 1 and ADvocate 2 Studies — Maintenance Period Primary Population

LEB = lebrikizumab; MPP = maintenance primary population; NA = not applicable; NR = not reported; PBO = placebo.

^aData reported are for the maintenance primary population that included all patients randomized to lebrikizumab at baseline who were responders at week 16 and were rerandomized at the start of the maintenance period. All patients received at least 1 dose of the study drug in the maintenance period.

^bThe modified MPP population excludes data from the study site with critical audit findings.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2.¹⁰

Baseline Characteristics

The characteristics outlined in Table 16, Table 17, and Table 18 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

The baseline characteristics of the patients enrolled were similar between groups within studies, and generally comparable across the trials. The mean age per treatment group ranged from 34.2 years (SD = 16.4) to 37.5 years (SD = 19.9) across the studies. In the ADvocate studies, ||| || ||| of patients were adolescents, compared to ||| || ||| in the ADhere study. There were roughly equal proportions of females and males in the studies. Most patients identified as white (||| || |||), but ||| || ||| of patients identified as Asian and || || ||| identified as Black or African American. People of other races made up a smaller proportion of those enrolled. Of note, there was a higher proportion of patients who identified as Asian in the placebo groups than in the lebrikizumab groups in the ADvocate 1 (||| |||||| |||) and ADhere (||| |||||| |||) studies. On average, patients enrolled in the study had been diagnosed with AD for 20 or more years, with most patients (||| || |||) classified as having disease of moderate severity based on an IGA score of 3 at baseline, whereas ||| || ||| were classified as having severe AD (i.e., IGA score of 4). The mean BSA affected ranged from 38.2% (SD = 20.8) to 47.8% (SD = 23.9).

Table 16: Summary of Baseline Characteristics From the Studies Included in the Systematic Review — Induction Period

AD = atopic dermatitis; BSA = body surface area; CDLQI = Children Dermatology Life Quality Index; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; IGA = Investigator Global Assessment; ITT = intention to treat; LEB = lebrikizumab; mITT = modified intention to treat; NRS = Numeric Rating Scale; PBO = placebo; POEM = Patient-Oriented Eczema Measure; SD = standard deviation; TCS = topical corticosteroids.

^aNumber of patients with nonmissing Pruritus NRS scores at baseline was as follows: |||||||| | ||| | ||| |||||||| ||| | ||| |||||||| |||||||| || ||| | ||| |||||||| ||| | ||| |||||||| ||||||| ||| | || |||||||| ||| | ||| ||||||||

^bNumber of patients with nonmissing DLQI scores at baseline was as follows: |||||||| | ||| | |||| ||| | |||| |||||||| || ||| | |||| ||| | |||| ||||||| ||| | ||| ||| | ||||

^cNumber of patients with nonmissing CDLQI scores at baseline was as follows: |||||||| | ||| | ||| ||| | ||| |||||||| || ||| | ||| ||| | ||| ||||||| ||| | ||| ||| | |||

^dNumber of patients with nonmissing POEM scores at baseline was as follows: |||||||| | ||| | ||| |||||||| ||| | ||| |||||||| |||||||| || ||| | ||| |||||||| ||| | ||| |||||||| ||||||| ||| | || |||||||| ||| | ||| ||||||||

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere,⁹ Sponsor’s Summary of Clinical Evidence.³⁵

Most patients enrolled had previously used TCS |||| || ||||| and ||| || ||| of patients had used topical calcineurin inhibitors. Before enrolment, ||| || ||| of patients had received phototherapy (Table 17). The proportion of patients who had received systemic therapies previously was ||| |||||| |||| ||| |||||| |||| ||| ||| |||||| ||| in the lebrikizumab versus placebo groups of the ADvocate 1, ADvocate 2, and ADhere studies, respectively. In the ADvocate studies, the most common systemic therapies were oral corticosteroids (||| || |||) and cyclosporine (|| || |||). Patients who had previously received dupilumab and tralokinumab were excluded from the ADvocate trials ||| || || || ||| |||||||| ||||| |||||| ||||||||||. In the ADhere study, |||| |||| |||| || ||| || of patients had received oral corticosteroids, cyclosporine, dupilumab, JAK inhibitors, or tralokinumab, respectively. ||| |||||||||| || |||||||| ||| ||| |||||||| ||||| |||||||||| ||| ||||||||| ||||||| ||||||| |||||| |||||| |||||| |||||| ||| |||||||| || ||||| ||||||||| ||||||||||| |||| ||||| ||| |||||||||||| |||| |||||| |||| ||| |||||||| ||||||||||||||| |||| |||||| |||| || ||| |||||||||||| ||| ||||||| ||||||| |||||||||||||

After rerandomization at week 16, the baseline characteristics of patients who continued in the maintenance primary population are shown in Table 18. There was some variation noted between groups in mean age, racial and sex distribution, mean body weight (and body weight categories), baseline IGA score, and baseline EASI score.

Table 17: Summary of AD Treatment History at Baseline for the Studies Included in the Systematic Review

AD = atopic dermatitis; IFN = interferon; ITT = intention to treat; LEB = lebrikizumab; mITT = modified intention to treat; NA = not applicable; NR = not reported; PBO = placebo; TCS = topical corticosteroids.

^aIn the ADvocate 1 and ADvocate 2 studies, patients were excluded if they had previously received dupilumab or tralokinumab.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere,⁹ Sponsor’s Summary of Clinical Evidence.³⁵

Table 18: Summary of Baseline Characteristics From the ADvocate 1 and ADvocate 2 Studies — Maintenance Period (Maintenance Primary Population)

AD = atopic dermatitis; EASI = Eczema Area and Severity Index; IGA = Investigator Global Assessment; LEB = lebrikizumab; NRS = Numeric Rating Scale; PBO = placebo; SD = standard deviation.

^aData for the maintenance primary population of patients who initially received lebrikizumab and met the treatment response criteria at week 16 (EASI-75 or IGA 0 or 1). Patients were rerandomized at week 16 and received at least 1 dose of the study drug during the maintenance phase.

^bData presented for the ADvocate 2 study are for the modified maintenance primary population (MPP), which included patients in the MPP as described for the ADvocate 1 study but excluded patients from a study site with critical audit findings.

^cDisease characteristics were recorded at the baseline visit for the study (day 1).

^dPruritus NRS data in the ADvocate 1 study are based on ||| ||| ||| || ||||||||| ||| ||| |||||||| | ||||| ||||| || ||| || ||| || |||||||| || ||| |||| ||| |||||| ||| ||| |||||| ||||||| ||||||||||||

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ Sponsor’s Summary of Clinical Evidence.³⁵

Exposure to Study Treatments

During the induction period of the trials, the mean duration of exposure ranged from ||||| |||| ||| | ||||| || ||||| |||| ||| | ||||| || ||| ||||||| ||||||| ||| |||| ||||| |||| ||| | ||||| || ||||| |||| ||| | ||||| || ||| |||||||||||| |||||| (Table 19). Patients were considered adherent to therapy if they received at least ||| of the study drug doses while enrolled in the study. During the induction period, ||| || |||| of patients were classified as adherent.

Table 19: Summary of Patient Exposure From the Studies Included in the Systematic Review — Induction Period (Safety Population)

LEB = lebrikizumab; PBO = placebo; SD = standard deviation; TCS = topical corticosteroids.

^aData for the ADvocate 2 and ADhere studies were based on the modified safety population, which excludes data from the study site with critical audit findings.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere,⁹ Sponsor’s Summary of Clinical Evidence.³⁵

Table 20: Summary of Patient Exposure From the ADvocate 1 and ADvocate 2 Studies — Maintenance Period (MPP)

LEB = lebrikizumab; PBO = placebo; SD = standard deviation.

^aData presented for the ADvocate 2 study are for the modified maintenance primary population (MPP), which included patients in the MPP except for patients from the study site with critical audit findings.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ Sponsor’s Summary of Clinical Evidence.³⁵

|||||| ||| ||||||||||| |||||| ||| |||| |||||||| || |||||||| ||| ||||| |||| ||| | ||||| ||| ||||| |||| ||| | ||||| || ||| |||||||| | |||||| ||| ||||| |||| ||| | ||||| ||| ||||| |||| ||| | ||||| || ||| |||||||| | |||||| ||| ||| ||||||| ||| |||||||||||| ||||| ||||||| |||||||||||| (Table 20). ||| |||||||| ||| ||| ||||||||| ||||||||| |||||||||

At the start of the ADhere study, all patients were prescribed low- and midpotency corticosteroids for use as needed. ||| ||| | ||||||| |||||||| |||||| |||| ||| ||| (Table 21). || ||||||||| ||| ||| ||| || |||||||| || ||| ||||||| ||| |||||||||||| ||||||| ||||||||||||| |||||||| ||||| ||||||| ||||||||||| |||||||||| |||||| ||| ||||||

Table 21: Concomitant Topical AD Treatments — The ADhere Study (mITT)

AD = atopic dermatitis; LEB = lebrikizumab; PBO = placebo; TCS = topical corticosteroids.

Sources: CSR for ADhere,⁹ Sponsor’s Summary of Clinical Evidence.³⁵

During the induction phase of the pivotal trials, more patients in the placebo group used rescue therapy than in the lebrikizumab group (Table 22). In the ADvocate 1 study, 33.3% versus 11.0% of patients used rescue treatments in the placebo and lebrikizumab groups, respectively, as did 39.7% versus 18.5% of patients, respectively, in the ADvocate 2 study. Most of these patients used topical treatments; less than 8% of patients used systemic therapies. In the ADhere study, 4.5% versus 1.4% of patients used high-potency TCS in the placebo and lebrikizumab groups, respectively, and 7.6% versus 3.4% of patients used systemic therapies.

During the maintenance period, ||||| |||||| ||||| of patients used rescue treatments in the placebo (lebrikizumab withdrawal) versus lebrikizumab every-4-weeks groups, respectively, in the ADvocate 1 study, as did ||||| |||||| ||||| of patients in the ADvocate 2 study (Table 23).

Table 22: Types of Rescue Therapy in the Studies Included in the Systematic Review — Induction Period

AD = atopic dermatitis; ITT = intention to treat; LEB = lebrikizumab; mITT = modified intention to treat; NA = not applicable; PBO = placebo; TCS = topical corticosteroids.

^aAll patients in the ADhere study were required to use mild or moderate TCS at the start of the study and were allowed to taper, stop, and restart use as needed throughout the 16-week trial. Low-potency topical calcineurin inhibitors were allowed for sensitive areas. High-potency TCS were designated as rescue therapy.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere.⁹

Table 23: Types of Rescue Therapy in the ADvocate 1 and ADvocate 2 Studies — Maintenance Period

AD = atopic dermatitis; LEB = lebrikizumab; PBO = placebo.

Sources: CSR for J2T-DM-KGAB (Table KGAB.4.11); CSR for J2T-DM-KGAC (Table KGAC.4.11).

Efficacy

Disease Severity

At week 16, the proportion of patients with an IGA score of 0 or 1 and at least a 2-point reduction from baseline favoured the lebrikizumab groups over the placebo groups in all 3 studies (Table 24). For the ADvocate 1 study, 43.1% versus 12.7% of patients attained an IGA 0 or 1 response in the placebo and lebrikizumab groups, respectively, with a RD of 29.7% (95% CI, 21.6 to 37.8) favouring lebrikizumab (P < 0.001). Similar results were reported for the ADvocate 2 study (33.2% versus 10.8%; RD = 21.9%; 95% CI, 14.2 to 29.6; P < 0.001 for the lebrikizumab versus placebo groups, respectively). The IGA 0 or 1 response rate also favoured lebrikizumab plus TCS over placebo plus TCS in the ADhere study (41.2% versus 22.1%; RD = 18.3%; 95% CI, 5.1 to 31.5; P = 0.01).

A higher proportion of patients attained an EASI-75 response at week 16 in the lebrikizumab than in the placebo groups in the ADvocate 1 study (58.8% versus 16.2%; RD = 42.0%; 95% CI, 33.3 to 50.6; P < 0.001) and in the ADvocate 2 study (52.1% versus 18.1%; RD = 33.3%; 95% CI, 24.4 to 42.2; P < 0.001). In the ADhere study, 69.5% versus 42.2% of patients attained an EASI-75 response (RD = 26.4%; 95% CI, 12.1 to 40.8; P < 0.001) in the lebrikizumab plus TCS and placebo plus TCS groups, respectively (Table 24). For the EASI-90 response threshold, the results favoured lebrikizumab over placebo at week 16 in all 3 studies.

From a baseline EASI score of 28.8 (SD = 11.3) and 31.0 (SD = 12.9) in the lebrikizumab and placebo groups, respectively, the ADvocate 1 study reported a LS mean difference in the EASI percent change from baseline to week 16 of ||||| |||| ||| ||||| || ||||||, favouring the lebrikizumab group (P < 0.001) (Table 24). Similar findings were reported for the ADvocate 2 study, with a LS mean difference of |||||| |||| ||| ||||| || |||||; P < 0.001) favouring the lebrikizumab group over the placebo group, and for the ADhere study, with a LS mean difference of −23.6% (95% CI, −33.6% to −13.7%; P < 0.001), favouring the lebrikizumab plus TCS over placebo plus TCS group.

During the maintenance period, the ADvocate 1 study reported that 79.2% of patients in lebrikizumab every-4-weeks group maintained an EASI-75 response at week 52 compared with 61.3% of patients who were switched to placebo ||| || ||||| |||| ||| |||| || ||||||. In the ADvocate 2 study, 84.7% versus 72.0% maintained an EASI-75 response in the lebrikizumab every-4-weeks and placebo (i.e., lebrikizumab withdrawal) groups, respectively, ||| || ||||| |||| || |||| || |||||| (Table 25).

Of note, the every-2-weeks maintenance dose of lebrikizumab is not consistent with the recommended dosing in the product monograph and has been included in the data tables as supplemental information only.

Symptom Severity

Among patients who had a Pruritus NRS score of 4 or more points at baseline, the proportion of patients who reported at least a 4-point reduction in their Pruritus NRS score at week 16 was higher in the lebrikizumab groups than in the placebo groups (Table 26). These results were based on ||| |||||| |||| ||| |||||| |||| ||| ||| |||||| ||| of patients randomized in the lebrikizumab versus placebo groups of the ADvocate 1, ADvocate 2, and ADhere studies, respectively. In the ADvocate 1 study, 45.9% versus 13.0% of patients reported at least a 4-point reduction in their Pruritus NRS score in the lebrikizumab versus placebo groups, respectively, with a RD of 32.9% (95% CI, 24.6% to 41.3%; P < 0.001). The proportion of Pruritus NRS responders was 39.8% versus 11.5% in the ADvocate 2 study (RD = 28.3%; 95% CI, 20.0% to 36.5%; P < 0.001), favouring the lebrikizumab groups over the placebo groups (). In the ADhere study, 50.6% of patients in the lebrikizumab plus TCS group met the response criteria, compared with 31.9% in the placebo plus TCS group (RD = 19.2%; 95% CI, 4.3% to 34.1%; P = 0.02).

Table 24: Summary of Key Disease Severity Results From the Studies Included in the Systematic Review — Induction Period

CI = confidence interval; EASI = Eczema Area and Severity Index; EASI-75 = at least a 75% reduction in EASI score; EASI-90 = at least a 90% reduction in EASI score; IGA = Investigator Global Assessment; ITT = intention to treat; LEB = lebrikizumab; LS = least squares; mITT = modified intention to treat; PBO = placebo; RD = risk difference; SD = standard deviation; SE = standard error; TCS = topical corticosteroids; vs. = versus.

^a|| |||| |||| ||| ||||| || |||||| ||||| |||||||| ||| |||||||||||||| ||||||| |||||||| ||| ||||| ||||||||||| |||||| ||||||| |||||||| ||| ||||| || |||||| ||| ||| |||||||| ||||| || | |||||||||| |||||||| ||| ||||| || ||| ||||||| |||||||| |||||||| ||||||||| ||| |||||||| |||||| ||||||| || |||||||||||| ||| || |||| || |||||||| ||| |||||| ||| || ||||||||| |||| ||||||| ||| ||||| ||||||| |||||||

^b|||||| |||| |||||||||| |||| ||| ||||| || ||| ||| |||| |||||||| ||| |||||||||||||| ||||||| |||||||| ||| ||||| ||||||||||| |||||| ||||||| |||||||| ||| ||||| || |||||| ||| ||| ||| ||||||| |||||||| |||||||| ||||||||| ||| |||||||| |||||| ||||||| || |||||||||||| ||| || |||| || |||||||| ||| |||||| ||| || ||||||||| |||| ||||||| ||| ||||| ||||||| ||||||

^cP value was not controlled for multiple testing.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere.⁹

Table 25: Summary of EASI-75 Response Results From the ADvocate 1 and ADvocate 2 Studies — Maintenance Period

CI = confidence interval; EASI-75 = at least a 75% reduction in Eczema Area and Severity Index score; LEB = lebrikizumab; MPP = maintenance primary population; PBO = placebo; RD = risk difference.

^aAmong patients who reported an EASI-75 response at week 16 and were rerandomized to placebo, lebrikizumab 250 mg every 2 weeks, or lebrikizumab 250 mg every 4 weeks.

^b|||||| |||| |||||||||| |||| ||| ||||| || ||| ||| |||| |||||||| ||| |||||||||||||| |||||| |||||||| ||| ||| ||||||| ||||||||||| |||||||| |||||||| ||||||||| ||| |||||||| |||||||| |||||| |||||||| |||||||||||| ||| || |||| || |||||||| || ||||||| ||| |||||| ||| ||| |||||| ||| || ||||||||| |||||||| ||| |||||||| ||||||| |||||| ||||||| || |||||||||||| ||| || ||||| ||||||| ||| |||||| ||| || |||||||| ||||||| ||| |||| || |||||| ||||| ||||||| ||||||

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2.¹⁰

Table 26: Summary of Symptom Severity Results From the Studies Included in the Systematic Review — Induction Period

CI = confidence interval; ITT = intention to treat; LEB = lebrikizumab; LS = least squares; mITT = modified intention to treat; NRS = Numeric Rating Scale; PBO = placebo; POEM = Patient-Oriented Eczema Measure; SD = standard deviation; SE = standard error; TCS = topical corticosteroids; vs. = versus.

^a|| |||| |||| ||| ||||| || |||||| ||||| |||||||| ||| |||||||||||||| ||||||| |||||||| ||| ||||| ||||||||||| |||||| ||||||| |||||||| ||| ||||| || |||||| ||| ||| |||||||| ||||| || | |||||||||| |||||||| ||| ||||| || ||| ||||||| |||||||| ||||||||

^bCommon RD (95% CI) based on the Cochran-Mantel-Haenszel test adjusted for stratification factors (region, age group [adolescent vs. adult], baseline IGA score [3 vs. 4]) and the primary (hybrid) estimand (patients who received rescue therapy or discontinued due to lack of efficacy had values set to baseline, with Markov chain Monte Carlo multiple imputation for other missing data).

^c|| |||| |||||||||| |||| ||| ||||| || |||| ||||| |||| |||||||||| ||| |||||||||| |||||||| |||||| |||||| |||||||| |||||||||||||| |||||||||||| |||||||||||||||||| |||||||||||| |||||||||| ||||||| ||| |||||| |||||||| ||| |||||| ||| ||||||||||

^dP value was not controlled for multiple testing.

Sources: CSR for ADvocate 1,¹¹ CSR for ADvocate 2,¹⁰ CSR for ADhere,⁹ additional information supplied by sponsor.²²

The percent change from baseline in Pruritus NRS scores at week 16 favoured the lebrikizumab groups over the placebo groups in the ADvocate 1 study (|| |||| |||||||||| |||||| |||| ||| ||||| || ||||||||||||), the ADvocate 2 study (|||||| |||| ||| ||||| || ||||||| | ||||||), and the ADhere study (−15.2%; 95% CI, −27.7% to −2.7%; P = 0.02) (Table 26).

The POEM symptom frequency scale is scored from 0 to 28, with a high score indicating more severe disease.¹² A MID of 3.4 points was selected as the threshold for a clinically relevant difference.¹³ The analyses at week 16 excluded |||| || |||| || |||||||| ||| |||||| ||| |||| || |||| |||| ||||||| |||| ||||| || ||||| || |||||||| ||| ||||||||| |||||.The change in POEM score was not part of the graphical testing strategy used to control the family-wise type I error rate.

The ADvocate 1 study reported a LS mean difference in the change from baseline to week 16 in POEM scores of |||| |||||| |||| ||| |||| || ||||| | ||||||| for lebrikizumab versus placebo. The LS mean difference was |||| |||||| |||| ||| |||| || ||||| | ||||||| in the ADvocate 2 study for lebrikizumab versus placebo, and the ADhere study reported a LS mean difference of −4.0 points (95% CI, −6.3 to −1.7 points; P < 0.001) for lebrikizumab plus TCS versus placebo plus TCS.

Health-Related Quality of Life

In the pivotal trials, the DLQI was used to measure HRQoL in patents 17 years and older, and the CDLQI was used for those aged 12 to 16 years. The instruments are scored from 0 to 30, with higher scores indicating poorer HRQoL. The change in CDLQI was not part of the graphical statistical testing strategy to control the family-wise type I error rate. MIDs of 4 points for the DLQI and 6 points for the CDLQI were selected as the clinically relevant threshold of change.^14,15

In the ADvocate 1 study, the LS mean difference in the change in baseline in the DLQI was −5.8 points (95% CI, −7.1 to −4.5 points; P < 0.001) for lebrikizumab versus placebo at week 16, and in the ADvocate 2 study, it was −4.9 points (95% CI, −6.3 to −3.5 points; P < 0.001). The ADhere study reported a LS mean difference in the change from baseline in the DLQI of −3.3 points (95% CI, −5.3 to −1.3 points; P = 0.001) for lebrikizumab plus TCS versus placebo plus TCS. These analyses included 75% to 86% of patients initially randomized in the trials (Table 27).

The number of patients per treatment group included in the analysis of CDLQI was small, ranging from 5 to 11 patients in the placebo groups and from 17 to 26 patients in the lebrikizumab groups. The LS mean difference in the change from baseline in the CDLQI was −7.0 points (95% CI, −10.1 to −3.9 points; P < 0.001) in the ADvocate 1 study, −4.2 points (95% CI, −9.1 to 0.6 points; P = 0.085) in the ADvocate 2 study, and −4.6 points (95% CI, −7.2 to −2.0 points; P = 0.001) in the ADhere study for the lebrikizumab groups versus the placebo groups at week 16.

Table 27: Summary of HRQoL Results From the Studies Included in the Systematic Review — Induction Period