Reimbursement Review

Lebrikizumab (Ebglyss)

Sponsor: Eli Lilly Canada Inc.

Therapeutic area: Atopic dermatitis

What Is Atopic Dermatitis?

• Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease. It is characterized by pruritus and eczematous skin lesions, pain, tenderness, and skin dryness. Approximately 90% of patients develop AD within the first 5 years of life; however, the disease may persist into adulthood. Most adult patients with AD have mild disease, and approximately 50% have moderate to severe disease.

• AD affects approximately 15% to 20% of children and 1% to 3% of adults worldwide. International survey data suggest that the prevalence of AD in Canada was approximately 4% among adults in 2016 and approximately 15% among children in 2019.

What Are the Treatment Goals and Current Treatment Options for AD?

• Improving visible clinical signs of the disease, itch, and quality of life, as well as establishing long-term control of AD, are among important treatment goals.

• Sustained symptom control, improved quality of life, reduction of flares, fewer treatment side effects, and access to therapies that are affordable, minimize reliance on topical treatments, and do not require injection were identified as important outcomes in the patient group input. Clinician group input highlighted improving sleep and quality of life, reducing severity and frequency of flares, and minimizing treatment burden and safety concerns among the key outcomes.

• Treatment typically begins with topical anti-inflammatory therapies, including topical corticosteroids (TCSs), calcineurin inhibitors, PDE inhibitors, and JAK inhibitors. If these treatments are ineffective, subsequent options include UVB phototherapy and systemic therapies, such as immunomodulators, biologic therapies, and JAK inhibitors.

What Is Ebglyss and Why Did Canada’s Drug Agency Conduct This Review?

• Ebglyss (lebrikizumab) is a drug that is administrated through subcutaneous injection. Health Canada has approved Ebglyss 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 when those therapies are not advisable. Ebglyss can be used with or without TCSs.

• Canada’s Drug Agency (CDA-AMC) reviewed Ebglyss to inform a recommendation to the participating public drug programs on whether it should be reimbursed for the Health Canada–approved indication.

  • CDA-AMC previously reviewed Ebglyss and issued a recommendation not to reimburse. Since then, new relevant evidence has become available and new input was received from interested parties.

How Did CDA-AMC Evaluate Ebglyss?

• CDA-AMC reviewed the clinical evidence on the beneficial and harmful effects of Ebglyss, as well as the economic evidence, versus other treatments used in 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 when those therapies are not advisable. Ebglyss can be used with or without TCSs. Off-label immunosuppressant therapies (methotrexate, cyclosporine, mycophenolate mofetil, or azathioprine), dupilumab, abrocitinib, and upadacitinib were considered relevant treatments to compare with Ebglyss when reviewing the clinical evidence. The focus of the Clinical Review is to evaluate the new clinical evidence submitted for this resubmission.

• CDA-AMC identified equity and ethical considerations relevant to Ebglyss and AD.

• The review was informed by materials submitted by the sponsor, which included clinical and economic evidence.

• The review was also informed by 2 patient group submissions and 3 clinician group submissions in response to our call for input as well as by input from the participating public drug programs concerning issues that may impact their ability to implement a recommendation.

• Two dermatologists with representation from Ontario were consulted as part of the review process.

What Were the Findings?

Clinical Evidence

• Studies previously reviewed during the initial Reimbursement Review of Ebglyss included 3 pivotal, double-blind randomized controlled trials (RCTs) that evaluated the safety and efficacy of Ebglyss versus placebo in adults and adolescents (aged 12 years and older) with moderate to severe AD who had history of inadequate response to topical AD therapies (ADvocate 1, ADvocate 2, and ADhere). Moreover, 1 long-term extension (LTE) study (ADjoin) that provided longer-term safety data (N = 979), as well as 40-week efficacy data for a subset of patients who completed 1 of the parent trials (N = 86), was included. One network meta-analysis (NMA) was included to estimate the relative efficacy of Ebglyss versus abrocitinib, dupilumab, and upadacitinib in the short-term treatment of adults and adolescents with moderate to severe AD. Also, a summary of 4 studies submitted by the sponsor to address gaps in the systematic review evidence (ADvantage, ADopt, ADhere-J, and ADore) were included.

• In the final recommendation previously issued by the Canadian Drug Expert Committee based on the initial review of Ebglyss, the committee acknowledged that, in the 3 RCTs, lebrikizumab induction therapy showed a clinically relevant improvement in physician-assessed Eczema Area and Severity Index (EASI) and Investigator’s Global Assessment (IGA), as well as reduced patient-reported symptoms of itch relative to placebo at 16 weeks in adults and adolescents with moderate to severe AD with a history of inadequate response to topical AD therapies. However, the Canadian Drug Expert Committee identified several evidence gaps in the initial submission, including insufficient evidence to address unmet patient needs, uncertainty in comparative effectiveness of Ebglyss versus other treatments, uncertainty in the evidence regarding longer-term safety and efficacy, and lack of evidence on health-related quality of life (HRQoL) of Ebglyss relative to other treatments.

• In this resubmission, CDA-AMC reviewed the following clinical evidence:

  • no new phase III RCTs

  • evidence from the LTE, ADjoin, with a longer duration of follow-up (up to 100 weeks at the data cut-off █████ ███ ████

  • one updated NMA reporting additional outcomes and 2 new matching-adjusted indirect comparison (MAICs) of Ebglyss versus abrocitinib, upadacitinib, and dupilumab, providing longer-term comparative evidence at 52 weeks.

• The results of the ADjoin LTE study suggested that efficacy of Ebglyss appeared to be sustained up to 100 weeks, with no new safety events identified. Most common harms observed were consistent with pivotal trials. The clinical experts consulted by CDA-AMC agreed that 100 weeks is sufficient to assess long-term efficacy, safety, and treatment relapse. However, the study lacked a comparator group to assess the benefits and harms of Ebglyss compared to another relevant treatment, limiting the ability to make causal interpretations about the treatment effects of Ebglyss in the studied population. Other serious methodological limitations included the potential for bias in the measurement of subjective outcomes due to the open-label design, lack of statistical analysis, missing data, as well as a limited number of patients receiving the recommended maintenance dose.

• In the updated NMA, upadacitinib may be favoured over lebrikizumab for percent change from baseline in EASI at week 16. For overall adverse events (AEs) at week 16, results favoured lebrikizumab in the monotherapy network and generally favoured comparators in the combination network (combined with TCSs). In the unanchored MAICs, lebrikizumab may be favoured over abrocitinib 100 mg for at least a 75% reduction in EASI score (EASI-75), IGA 0 or 1, and at least a 90% reduction in EASI score (EASI-90), and over dupilumab for IGA 0 or 1 at week 52. For overall AEs at week 52, results favoured lebrikizumab versus upadacitinib 30 mg and abrocitinib (100 mg and 200 mg). Although some analyses suggested potential differences in efficacy and safety, due to serious imprecision and methodological limitations, no firm conclusions could be drawn from the indirect treatment comparisons regarding the comparative effects of Ebglyss versus abrocitinib, upadacitinib, and dupilumab across efficacy outcomes, HRQoL, or harms.

Economic Evidence

• Ebglyss is available as a single-dose prefilled pen and a single-dose prefilled syringe with needle shield containing 250 mg/2mL of solution for SC injection. At the submitted price of $1,949.90 per prefilled pen or prefilled syringe with needle shield, the annual cost of Ebglyss is expected to be $37,048 per patient in the first year and $25,349 in subsequent years, based on the Health Canada–recommended dosage.

• Key clinical efficacy in the economic analysis (i.e., treatment response as 75% improvement in the EASI at week 16) was derived from a sponsor-submitted NMA, which compared Ebglyss plus TCSs to dupilumab plus TCSs, upadacitinib (15 mg and 30 mg) plus TCSs, and abrocitinib (100 mg and 200 mg) plus TCSs. According to the Clinical Review, there was insufficient evidence to show a difference between Ebglyss plus TCSs and any comparator for EASI-75 response at week 16. Comparative safety in the model was based on a naive comparison using AE data from published literature. According to the Clinical Review of the updated NMA including safety analysis, point estimates favoured the comparators over Ebglyss plus TCSs for overall AEs at week 16 in the combination-therapy networks. However, the effect estimates were imprecise, with 95% confidence intervals including the potential that either Ebglyss or the comparators could be favoured or that there was no difference between these treatments. Overall, there was insufficient evidence to show a difference between Ebglyss plus TCSs and any comparators plus TCSs for EASI-75 response and safety at week 16.

• The sponsor conducted 2 additional MAICs. However, the data from these additional MAICs were not incorporated in the cost-utility analysis. According to the Clinical Review, comparative analyses of Ebglyss versus dupilumab, abrocitinib, and upadacitinib using an updated NMA and 2 MAICs were inconclusive and affected by serious imprecision and methodological limitations. Although some analyses suggested potential differences in efficacy, the uncertainty resulted in very low confidence in any conclusions regarding comparative effects for efficacy outcomes, HRQoL, or harms.

• Based on evidence reviewed for this submission, there is no robust evidence to suggest that Ebglyss provides greater health benefit than relevant comparators. If decision-makers determine there are no differences in health outcomes between Ebglyss and relevant comparators, then the total cost of Ebglyss to the health system should not exceed that of the least costly advanced treatment for the indicated population.

• CDA-AMC estimates that the budget impact of reimbursing Ebglyss 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 when those therapies are not advisable, will be approximately $127 million over the first 3 years of reimbursement compared to the amount currently spent on comparators, with an estimated expenditure of $472 million on Ebglyss over this period. The actual budget impact of reimbursing Ebglyss is uncertain due to uncertainty in the market share of relevant comparators. The economic feasibility must be addressed, given the incremental budget impact of reimbursing Ebglyss is predicted to be greater than $40 million in year 1 and year 3 and the magnitude of uncertainty in the estimated budget impact.

Background

Introduction

The objectives of this report are as follows:

• Review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of lebrikizumab 250 mg/2 mL solution for subcutaneous (SC) injection in the treatment of moderate to severe atopic dermatitis (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 in clinical practice in Canada and identifying gaps in the current evidence (Table 1).

• Review and critically appraise the economic information submitted by the sponsor, including a cost-effectiveness analysis and budget impact analysis. The focus of the Economic Review is aligned with the scope of the Clinical Review, unless otherwise stated. For most reviews, a base case is developed by Canada’s Drug Agency (CDA-AMC), informed by clinical expert input, the available clinical evidence, and the best interpretation of the economic evidence based on the information provided by the sponsor.

• Lebrikizumab was initially reviewed 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 when those therapies are not advisable. the Canadian Drug Expert Committee (CDEC) issued a recommendation not to reimburse on October 9, 2024. The recommendation was based on evidence assessed in the Clinical Review report for the initial submission. The executive Summary of Clinical Evidence reviewed in the initial submission is presented in the Clinical Evidence from the Initial Lebrikizumab Review section of this report. Key reasons for the recommendation included the following:

  • Insufficient evidence was submitted that lebrikizumab would address the unmet needs of patients because of the uncertainty around the benefit of lebrikizumab versus appropriate comparators and in patients who received prior dupilumab or JAK inhibitor treatment.

  • No evidence was submitted that directly compared lebrikizumab to currently available treatments for AD and the certainty of evidence from the submitted indirect treatment comparisons (ITCs) was limited.

  • The safety and effects on health-related quality of life (HRQoL) of lebrikizumab relative to other treatments for AD were unknown because no comparative evidence was submitted.

  • Longer-term safety and efficacy were uncertain because of limitations of the study designs and analysis with the available evidence.

• On October 27, 2025, the sponsor resubmitted lebrikizumab for review with indirect comparative efficacy and safety of lebrikizumab relative to other advanced AD therapies and with longer-term efficacy and safety evidence. The new sponsor-submitted evidence is assessed in this Clinical Review report.

Table 1: Information on the Application Submitted for Review and on the CDA-AMC Review

AE = adverse event; CDA-AMC = Canada’s Drug Agency; 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; IGA = investigator Global Assessment; IgG4 = immunoglobulin G4; IST = immunosuppressive treatment; NOC = Notice of Compliance; NRS = Numeric Rating Scale; POEM = Patient‑Oriented Eczema Measure; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

Submission History for the Drug Under Review

CDA-AMC has not previously reviewed lebrikizumab through the reimbursement review process for other indications.

Sources of Information

The contents of the Reimbursement Review report are informed by materials submitted by the sponsor, input received from interested parties (patient groups, clinician groups, and drug programs), and input from clinical experts consulted for this review.

Calls for patient group and clinician group input are issued for each Reimbursement Review. Two patient group submissions were received from Canadian Skin Patient Alliance in collaboration with Eczéma Québec, and the Eczema Society of Canada. Three clinician group submissions were received from the Fraser Health Dermatology Group, Atlantic Dermatology Group, and a group of clinicians who frequently serve Indigenous patients and communities. Canadian Skin Patient Alliance gathered information from previous submissions to CDA-AMC and incorporated Canadian Institute for Health Information data on AD-related emergency department visits and hospitalizations from 2016 to 2020, as reported in The Skin I’m In, 2022, and relevant guidelines. Additional information was obtained through a national survey conducted from June 28 to July 18, 2025, in partnership with Harris Poll Canada, which surveyed 1,055 adults living in Canada with AD. The Eczema Society of Canada collected survey data from more than 3,000 individuals in Canada living with AD, as well as their caregivers and family members. Additional information for this submission was gathered through questionnaires and one-on-one interviews. The Fraser Health Dermatology Group submitted input from 3 clinicians, and the Atlantic Dermatology Group submission included input from 7 clinicians.

The full submissions received are available on the project landing page in the consolidated input document. The drug programs provide input on each drug being reviewed through the reimbursement review process by identifying issues that may impact their ability to implement a recommendation.

Input from patient and clinician groups is considered throughout the review, including in the selection of outcomes to include in the Clinical Review and in the interpretation of the clinical and economic evidence. Relevant patient and clinician group input is summarized in the Disease Background, Current Management, and Unmet Needs and Existing Challenges sections.

Each review team includes at least 1 clinical expert with expertise regarding 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. Two dermatologists with expertise in the diagnosis and management of AD participated as part of the review team, with representation from Ontario.

Disease Background

AD is a chronic, relapsing, inflammatory, noncontagious skin disease.¹ It is characterized by pruritus and eczematous skin lesions.¹ AD is commonly associated with other atopic conditions, including asthma, allergic rhinitis, and food allergy.¹ Approximately 90% of patients develop AD within the first 5 years of life; however, the disease may persist into adulthood.^1,2 Risk factors for the development of AD are family history of atopy (major risk factor) and genetic defect in the filaggrin gene.^1,2 Although AD primarily affects the skin, evidence supports its classification as a systemic inflammatory disease with atopic and nonatopic comorbidities.² Patients with AD are at increased risk of skin infections due to scratching and barrier disruption.¹ Exacerbations or “flares” are a defining feature of AD and generally indicate a worsening of AD that requires escalation or intensification of treatment.³ Flares may be triggered by endogenous factors or environmental exposures.³ AD affects approximately 15% to 20% of children and 1% to 3% of adults worldwide,^1,4 with a lifetime prevalence rate of up to 17%.^5,6 Prevalence is higher in high-income countries, affecting up to 20% of children and 10% of adults.^1,4 International survey data suggest that the prevalence of AD in Canada was approximately 4% among adults in 2016 and approximately 15% among children in 2019.^7,8 Most adult patients with AD have mild disease, and approximately 50% have moderate to severe disease, based on clinical disease severity scales.^9,10

AD can adversely impact all aspects of life and productivity of the patients and their families, especially when it is severe.¹¹ A systematic literature review (SLR) assessing the burden of AD in adolescents and adults reported that itch, pain, tenderness, and skin dryness were the symptoms most frequently associated with clinically meaningful impact.⁹ Patients experience severe itch, which reduces quality of life and increases the risk of psychological distress, including suicidal thoughts; depression, anxiety, and sleep disturbance commonly co-occur.^1,9,11 AD also affects concentration, daily functioning, self-esteem, and social interactions, with adolescents experiencing greater impact due to the developmental importance of body image and identity.¹² Diagnosis of AD is based on medical history and clinical examination, including assessment of lesion morphology, distribution, and associated symptoms.¹³ Disease severity may be assessed using validated tools, such as the Eczema Area and Severity Index (EASI) and Investigator Global Assessment (IGA).¹¹ These tools are primarily used in research and clinical trials and are not routinely applied in everyday practice.^2,11

Patient group input: Patients with moderate to severe AD experience persistent itch, pain, sleep disturbance, and visible skin changes that substantially impair daily functioning, emotional well-being, and social participation. These ongoing symptoms and frequent flares contribute to substantial physical, psychological, and quality of life burden for both patients and caregivers.

Current Management

Treatment Goals

According to the clinician experts consulted by the review team, improving visible clinical signs of the disease, itch, and quality of life, as well as establishing long-term control of AD, are among important treatment goals.

Patient group input: Patients highlighted the need for treatments that reliably reduce itch, improve sleep, prevent flares and complications (including secondary infections), promote rapid skin healing, and restore daily functioning. They emphasized outcomes such as sustained symptom control, improved quality of life, reduction of flares, fewer side effects, and access to therapies that are affordable and practical to use, that minimize reliance on topical treatments, and that do not require injections.

Clinician input: Clinician groups indicated that the key goals of treatment for moderate to severe AD are rapid and sustained relief of pruritus, clearance or marked improvement of skin lesions, and reduction in the frequency and severity of flares to achieve durable disease control. They further emphasized improving sleep, overall quality of life, and patients’ ability to maintain normal daily activities, including work and school, while minimizing treatment burden and safety concerns.

Current Treatment Options

For individuals aged 12 years and older with moderate to severe AD, treatment typically begins with topical anti-inflammatory therapies, including topical corticosteroids (TCSs), calcineurin inhibitors, PDE inhibitors, JAK inhibitors, and aryl hydrocarbon receptor agonists. The latter 3 topical therapies are currently available for patients via private drug coverage only. If disease control remains inadequate following an appropriate trial of topical therapy (generally at least 4 weeks), management options include continued or alternative topical treatment — particularly when patients prefer to avoid advanced therapies — or escalation to advanced treatments such as UVB phototherapy or systemic therapy.

The clinical experts noted that UVB phototherapy is generally administered in specialized clinics 2 to 3 times per week for approximately 10 to 12 weeks. Although home-based phototherapy units are available, their use is limited by high cost and concerns regarding safety in the absence of regular clinical monitoring. Access to clinic-based phototherapy is also restricted in many regions of Canada due to limited availability of phototherapy units, making this option impractical for some patients.

Systemic treatment options include conventional immunomodulators, biologic therapies, and JAK inhibitors. Conventional immunomodulators (e.g., methotrexate, azathioprine, cyclosporine, mycophenolate) are not approved in Canada for AD but are used off-label in clinical practice, typically when newer therapies are not reimbursed or when step-therapy requirements must be met for reimbursement. Approved biologic therapies include dupilumab, lebrikizumab, tralokinumab, and nemolizumab. Approved JAK inhibitors include abrocitinib and upadacitinib. The clinical experts noted that biologics and JAK inhibitors may be used as first-line systemic treatments, although clinicians may prefer dupilumab due to its established long-term efficacy and safety profile. Dupilumab is the only biologic therapy currently reimbursed by public drug plans in Canada, after there is an inadequate response to at least 1 conventional systemic immunomodulatory drug. Nemolizumab received a recommendation of reimburse with conditions by CDEC in March 2026 (note that, at the time this submission was filed, nemolizumab had not received Health Canada approval). The clinical experts noted that JAK inhibitors are generally used as second-line systemic options in patients with an inadequate response to biologic therapy, although they may be used earlier in selected cases. Safety warnings and immunosuppressive effects may limit their use and contribute to hesitancy among clinicians and patients. All of the systemic treatments described are immunomodulatory and target the underlying immune dysregulation central to the pathogenesis of AD. These treatment approaches are supported by recent American Academy of Dermatology clinical practice guidelines.^14-16

Key characteristics of lebrikizumab are summarized with other treatments available for AD refer to the Supplemental Material document, Appendix 1, Table 1.

Unmet Needs and Existing Challenges

Patient group input: Input from the patient groups underscored major unmet needs related to persistent symptoms, inadequate or nondurable relief with current therapies, burdensome treatment routines, and flares that continue to disrupt sleep, daily functioning, and mental well-being. They also noted challenges with side effects from current treatments, limited access to phototherapy and specialist care, concerns about long-term steroid use, and inequitable access due to cost and reimbursement barrier, highlighting the need for more effective, well-tolerated, and accessible treatment options.

Clinician input: Clinician groups indicated that key unmet needs in moderate to severe AD include lack of adequate or durable response to currently available systemic therapies, incomplete skin clearance even with the most efficacious drugs, and adverse effects, such as conjunctivitis with dupilumab and herpes zoster, acne, and headache with JAK inhibitors. The Atlantic Dermatology Group noted that phototherapy can be difficult to access because it requires frequent clinic visits. They also indicated that access constraints may limit individualized treatment selection and the ability to switch therapies in cases of loss of response or adverse events (AEs).

The clinical experts stated that, despite the availability of multiple treatment options, a subset of patients with AD that remains inadequately controlled or are unable to tolerate existing therapies. Tolerability issues further limit treatment options. Conjunctivitis is a common AE associated with biologic therapies, including dupilumab, lebrikizumab, and tralokinumab, while dupilumab is also associated with head and neck dermatitis. The clinical experts highlighted that, for JAK inhibitors, immunosuppression-related AEs, such as infections, may lead to treatment discontinuation. Although 2 JAK inhibitors are listed on public formularies, some patients are unable to use this class due to comorbid conditions or contraindicated concomitant medications. Conventional immunosuppressants are generally less effective, are not suitable for long-term use (in the case of cyclosporine), or are associated with frequent AEs and the need for regular laboratory monitoring, which can limit tolerability. Phototherapy represents another treatment option; however, it is often insufficiently effective, as is not used for long-term control, may cause sunburn-like reactions, and is largely inaccessible to most patients in Canada.

Considerations for Using the Drug Under Review

Contents in this section have been informed by input from the clinical experts consulted for the purpose of this review and from clinician groups, as well as the reimbursement conditions proposed by the sponsor (refer to the Supplemental Material document, Appendix 1, Table 2). The implementation questions from the public drug programs and corresponding responses from the clinical experts consulted for this review are summarized in the Supplemental Material document, Appendix 1, Table 3. The following has been summarized by the review team.

Place in Therapy

The clinical experts consulted for this review indicated that lebrikizumab would not cause a paradigm shift in the treatment of AD. It may be used as a first-line systemic therapy after patients have trialled all classes of topical therapies. The clinical experts noted that dupilumab would likely remain the preferred option due to its longer clinical track record, although some physicians may prefer lebrikizumab as a first-line biologic because it appears to be associated with a lower incidence of conjunctivitis and has not been reported to cause the facial erythema observed with dupilumab. The clinical experts emphasized that patients should not be required to trial dupilumab (or other biologics or JAK inhibitors) before receiving lebrikizumab. Additionally, in the opinion of the clinical experts, it is unreasonable to require a trial of conventional immunosuppressants before the use of lebrikizumab because there is limited evidence supporting their efficacy and safety in AD and they are associated with many AEs. The clinical experts noted that, for these reasons, they are only conditionally recommended — or, in some cases, not recommended — in North American treatment guidelines.^15-17

The clinical experts noted that lebrikizumab may offer a meaningful treatment option for patients who have an inadequate response to dupilumab and could achieve disease control with this therapy. In 1 clinical expert’s experience, about 10% of patients have inadequate response to dupilumab treatment after 16 weeks, while the other clinical expert estimated this percentage at about 30% to 40%. Biologic therapies can typically be used as monotherapy or in combination with topical anti-inflammatory treatments. The clinical experts noted that lebrikizumab is often used in combination with topical therapy, as patients’ AD is not usually completely cleared with lebrikizumab. Clinical experts stated that a combination of biologics with JAK inhibitors is uncommon and is reserved for severe disease. Combination use of biologics and phototherapy is also rare.

Clinician group input: According to clinician group input, lebrikizumab should be used as a first-line advanced systemic therapy for moderate to severe AD, alongside dupilumab and oral JAK inhibitors. They indicated that lebrikizumab should be initiated once topical therapies are inadequate, rather than being reserved for second-line use. They further noted that all advanced systemic therapies should be equally accessible, so that treatment choice is guided by disease characteristics, comorbidities, prior treatment experience, and patient preference.

Clinicians and clinical experts agreed that lebrikizumab has a favourable safety profile, efficacy comparable to existing first-line options, and a possibly lower incidence of conjunctivitis in clinical practice relative to dupilumab.

Patient Population

The clinical experts consulted for this review noted that patients with AD that is refractory to topical therapy should be eligible for lebrikizumab treatment. The experts noted that patients with moderate to severe AD refractory to topical therapy are in need of treatment. In particular, patients who have disease refractory to or are unable to tolerate dupilumab need safe options after trialling dupilumab, and these choices should not be limited to oral JAK inhibitors and older immunomodulators. The clinical experts added that studies, particularly from the US, have shown that people from marginalized communities, including lower socioeconomic status and racialized communities, are more likely to have severe and persistent AD. They highlighted that, in Canada, patients living in rural areas face barriers to care. Access to specialists is limited and advanced treatments are typically only prescribed by specialists. Phototherapy is often unavailable or inaccessible in rural areas. The clinical experts noted that patients in rural areas may have challenges with using conventional immunosuppressants, as they require more frequent blood and clinical monitoring.

The clinical experts generally agreed with the initial reimbursement conditions proposed by the sponsor. However, the clinical experts noted that EASI scoring is primarily a research tool and is not used routinely outside of payer requirements, whereas the IGA is more commonly applied in clinical practice. Experts also highlighted that some patients with moderate to severe disease may have an EASI score below 16; 6.6 is a commonly cited cut-off for EASI for moderate disease, and relaxing the EASI threshold could help prevent undertreatment.

Clinician group input: Input from the clinician groups indicated that lebrikizumab is best suited for adults and adolescents aged 12 years and older with moderate to severe AD that is inadequately controlled with topical therapies or for whom such therapies are not advisable. The clinicians and clinical experts agreed that no companion diagnostic testing is required for lebrikizumab. They further noted that no biomarkers or specific clinical characteristics have been identified that reliably predict treatment response.

Assessing the Response to Treatment

The clinical experts stated that the treatment response can be assessed based on at least a 75% reduction in EASI score (EASI-75) or an IGA improvement of 2 points or more, which are considered reasonable standards of response. A Dermatology Life Quality Index (DLQI) improvement of 4 points or more may also be used to assess meaningful patient benefit. Regarding the renewal criteria proposed by the sponsor, the clinical experts noted that requiring patients to attend visits every 6 months on an ongoing basis poses a challenge. Once it is established that a patient’s disease responds to treatment at 4 to 6 months, annual assessments are generally sufficient. They added that more frequent follow-ups would place an unnecessary burden on the health care system, particularly given limited access to dermatologists. The clinical experts indicated that biologic treatments are preferable to conventional immunosuppressants. In contrast to newer drugs, conventional immunosuppressants require visits to dermatologists every 1 to 3 months.

Clinician group input: Input from the clinician groups indicated that treatment response in clinical practice is usually assessed using patient general satisfaction, together with physician’s global assessment. Clinicians indicated that other standardized outcomes for AD include achieving clear (score of 0) or almost clear skin (score of 1) on the IGA, at least a 4-point improvement in the Pruritus Numerical Rating Scale (NRS), at least a 4-point improvement in the Sleep Numerical Rating Scale, and a 50% to 75% improvement in the EASI.

Discontinuing Treatment

The clinical experts agreed with the Health Canada product monograph about discontinuation conditions, including hypersensitivity and helminth infections. Clinical experts indicated that discontinuation of lebrikizumab should be based on inadequate treatment efficacy or intolerable AEs. Experts also highlighted that, in their experience, discontinuation of lebrikizumab is not associated with acute disease rebound or flare; however, any clinical effect will wane upon discontinuation.

Clinician group input: Clinician groups identified AEs and poor efficacy — specifically, failure to achieve at least a 25% reduction in EASI score at week 16 or at least a 50% reduction in EASI score (EASI-50) at week 24 — as factors that should be considered when deciding to discontinue the treatment.

Prescribing Considerations

The clinical experts consulted for this review noted that lebrikizumab can be prescribed by a dermatologist, allergist, pediatrician, or clinical immunologist, or in consultation with 1 of these specialists. However, in areas where specialty care cannot be readily accessed, primary care doctors with sufficient expertise and comfort in the clinical area could prescribe lebrikizumab.

Clinician group input: Based on clinician groups’ input, treatment and monitoring of patients on lebrikizumab should be limited to dermatologists, allergists, or clinical immunologists. Lebrikizumab would be prescribed in outpatient dermatology, allergy, or immunology clinics.

Clinical Review From the Initial Lebrikizumab Submission

This section presents the executive summary of Clinical Review from the initial lebrikizumab submission.

Clinical Evidence

Systematic Review

Description of Studies

Three double-blind randomized controlled trials (RCTs) met the inclusion criteria for systematic review (ADvocate 1, ADvocate 2, and ADhere studies).^18-20 The objective of ADvocate 1 (N = 424) and ADvocate 2 (N = 427) studies were 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 younger 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, IGA score of at least 3, and AD covering a body surface area (BSA) of 10% or more. All patients had 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 studies randomized patients in a ratio of 2:1 to receive lebrikizumab 500 mg SC loading dose at week 0 and 2, and then 250 mg SC every 2 weeks or placebo, in a double-blind design, for the 16-week induction period. At week 16, patients in the lebrikizumab group who responded to treatment (i.e., with an IGA score of 0 or 1 or EASI-75, 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.

The objective of the ADhere study was to evaluate the safety and efficacy of the lebrikizumab in combination with low to midpotency TCS, compared 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 younger than 18 years, weighing more than 40 kg) with moderate to severe AD (EASI score ≥ 16, IGA score ≥ 3, AD covered a BSA of 10% or more) were eligible to enrol. Patients were randomized 2:1 to receive 500 mg lebrikizumab SC loading dose at week 0 and 2, then 250 mg SC once every 2 weeks in addition to TCS, or placebo plus TCS for the 16-week treatment period.

In all 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 ranging 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 Children’s DLQI (CDLQI) total score.

The patients enrolled in the trials had a mean age that ranged from 34.2 years (standard deviation [SD] = 16.4 years) to 37.5 years (SD = 19.9 years) 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, with most patients (59% to 73%) classified as having disease of moderate severity based on an IGA score of 3 at baseline, whereas 27% to 41% were classified as having severe AD (i.e., 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 were 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 versus the placebo groups in all 3 studies. For the ADvocate 1 study, 43.1% versus 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% versus 10.8% attained an IGA 0 or 1 response (RD = 21.9%; 95% CI, 14.2% to 29.6%; P < 0.001) for the lebrikizumab versus placebo groups. The IGA 0 or 1 response also favoured lebrikizumab plus TCS versus 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 versus placebo groups. An EASI-75 response was attained by 58.8% versus 16.2% of patients in the lebrikizumab versus placebo groups, respectively, in the ADvocate 1 study (RD = 42.0%; 95% CI, 33.3% to 50.6%; P < 0.001), and 52.1% versus 18.1% of patients (RD = 33.3%; 95% CI, 24.4% to 42.2%; P < 0.001) in the ADvocate 2 study. In the ADhere study, 69.5% versus 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 score, where patients rated their worst itch symptoms over the past 24 hours from 0, indicating “No itch” to 10, indicating “Worst itch imaginable.” Among patients who had a Pruritus NRS score of 4 or more points at baseline, 45.9% versus 13.0% in the lebrikizumab versus 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 patients who responded to the Pruritus NRS 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 lebrikizumab. In the lebrikizumab plus TCS group in the ADhere study, 50.6% met the Pruritus NRS 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).

A secondary outcome in the pivotal trials was the change from baseline in the POEM score, a 7-item, self-reported questionnaire used to assess the frequency of disease symptoms (skin dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) over the last week. It is scored from 0 to 28, with a higher score indicative of worse disease severity.²¹ A minimal important difference (MID) of 3.4 points was identified as the threshold for a clinically relevant between-group difference.²² The ADvocate 1 study reported a least squares (LS) mean difference of −7.3 points (95% CI, −8.9 points to −5.7 points) in the POEM score change from baseline to week 16 for lebrikizumab versus placebo. The LS mean difference was −6.0 points (95% CI, −7.7 points to −4.3 points) 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 points to −1.7 points) for the lebrikizumab plus TCS versus placebo plus TCS groups. 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; thus, this outcome should be interpreted as supportive evidence only.

In the pivotal trials, the DLQI was used to measure HRQoL in patients aged 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 poor HRQoL. An MID of 4 points for the DLQI and 6 points for the CDLQI were selected as the threshold for clinically relevant between-group difference.^23,24 In the ADvocate 1 study, the LS mean difference in the change in baseline to week 16 in the DLQI total score was −5.8 points (95% CI, −7.1 points 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 points to −3.5 points; P < 0.001) for the lebrikizumab versus placebo groups. The ADhere study reported an LS mean difference in the change from baseline in the DLQI of −3.3 points (95% CI, −5.3 points 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 aged 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 −7.0 points (95% CI, −10.1 points to −3.9 points) in the ADvocate 1 study, −4.2 points (95% CI, −9.1 points to 0.6 points) in the ADvocate 2 study, and −4.6 points (95% CI, −7.2 points 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 type I error rate and thus 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 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, lebrikizumab every 4 weeks, or lebrikizumab every 2 weeks for the maintenance period. This review focused 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 = 17.9%; 95% CI, −2.3% to 38.1%). 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 (RD = 12.8%; 95% CI −9.5% to 35.1%).

Harms Results

Induction Period

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

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

Conjunctivitis-related AEs, which was also a notable harm, was reported by 4.8% to 11.0% of patients in the lebrikizumab groups and 0% to 3.5% of patients in the placebo groups. The RD for conjunctivitis in the lebrikizumab versus placebo groups was 6.0% (95% CI, 1.4% to 10.6%) for the ADvocate 1 study, 7.6% (95% CI, 2.9% to 12.3%) for the ADvocate 2 study, and 4.8% (95% CI, 1.3% to 8.3%) in the ADhere study.

Maintenance Period

During the maintenance period, 52% versus 47%, and 51% versus 54% of patients experienced a TEAE in the lebrikizumab every 4 weeks versus placebo (i.e., lebrikizumab withdrawal) groups in the ADvocate 1 and ADvocate 2 trials, respectively. A total of 5 patients reported an SAE, including 2 patients (3.2%) in the lebrikizumab every 4 weeks group of the ADvocate 1 study and 1 patient (3.6%) in the placebo group, and 2 patients (3.9%) in the lebrikizumab every 2 weeks group of the ADvocate 2 study. No deaths were reported during the maintenance period.

Between weeks 16 and 52, 1 patient in each of 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 in 6.3% versus 6.3%, and 14.5% versus 10.7% of patients in the lebrikizumab every 4 weeks versus placebo (lebrikizumab withdrawal) groups of the ADvocate 1 and ADvocate 2 studies, respectively.

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 dermatological conditions. The primary estimand used for the EASI-75, IGA, Pruritis NRS, and DLQI outcomes analyzed patients who discontinued due to lack of efficacy or who required rescue therapy as those who did not respond to treatment, and used multiple imputation methods to impute data for patients who discontinued due to 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, which assumed 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 whether 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 change 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, carryover effects of lebrikizumab in the placebo group, and small sample size. At week 16 of the ADvocate studies, patients treated with lebrikizumab who met the response criteria were rerandomized to 3 groups. This represents an enriched population, and, thus, the 1-year treatment effects of lebrikizumab may overestimate the effects compared to those that would be observed in an unselected population. Given the long half-life of lebrikizumab (24.5 days²⁵), it is reasonable to assume there are substantial carryover 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 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 only 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 TCSs as needed. Concurrent use of TCSs 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 carryover effects of lebrikizumab in patients who switched to placebo. The results at 52 weeks are reflective of the effects of lebrikizumab maintenance therapy compared with 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 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 most relevant to inform the CDA-AMC expert committee deliberations, and a final certainty rating was determined, as outlined by the GRADE Working Group.^26,27

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 in Pruritus NRS was 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 were based on thresholds identified in the literature; the certainty assessments for SAEs and conjunctivitis were based on the presence or absence of any (non-null) effect.

For the GRADE assessments, findings from the ADvocate 1, ADvocate 2, and ADhere studies were considered together and summarized narratively per 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:

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

• proportion of patients with an EASI-75 response

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

• change from baseline in the POEM score

• change from baseline in the DLQI and CDLQI total score

• SAEs, conjunctivitis AEs.

Table 2: Summary of Findings for Lebrikizumab vs. 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 = Eczema Area and Severity Index; EASI-75 = at least a 75% reduction in EASI score; IGA = Investigator’s Global Assessment; LEB = lebrikizumab; LS = least squares; MID = minimal important difference; NR = not reported; NRS = numeric rating scale; PBO = placebo; POEM = Patient-Oriented Eczema Measure; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; RCT = randomized controlled trial; RD = risk difference; SAE = serious adverse event; TCS = topical corticosteroids; vs. = versus.

Note: Study limitations (which refers 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 body surface area 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 an EASI-75 score from baseline.

^cEASI-75 response at week 52: −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 past 24 hours, with 0 indicating “No itch” and 10 indicating “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 last 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 indicative of 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.^21,22

^fChange in POEM score at week 16: −2 for levels for very serious study limitations. The extent of missing data was large and the method for accounting for missing data was potentially biased. There was no control of type I error rate for this end point; thus, it should be interpreted as supportive evidence only.

^gThe DLQI (for those aged 16 years and older) and CDLQI (for those aged younger than 16 years) are patient-reported, 10-item, health-related quality of life questionnaires that cover 6 domains (symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment) over the last week. The total score ranges from 0 (no impact of skin disease on quality of life) to 30 (maximum impact on quality of life). The MID of 4 points for the DLQI and 6 points for the CDLQI were selected as the threshold for a clinically important between-group difference based on the literature and clinical expert input.^24,28-30

^hChange in DLQI at week 16: −1 level for serious imprecision (the CI for differences between groups included the potential for little to no difference based on a MID of 4 points) and −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: −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 −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. There was no control of type I error rate for this end point; thus, it should be interpreted as supportive evidence only.

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

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

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

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

Source: Clinical Study Report for ADvocate 1,²⁰ CSR for ADvocate 2,¹⁹ CSR for ADhere.¹⁸ Additional information supplied by sponsor.³¹

Long-Term Extension Study

Description of Study

One long-term extension (LTE) study was summarized to provide evidence regarding 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).³² 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). Data from patients in the ADjoin study who rolled over from the ADopt-VA study, which is ongoing and blinded, were not included in the interim Clinical Study Report.

Efficacy Results

Efficacy outcomes were assessed for up to 88 weeks (weeks 16 to 104). Evaluation of efficacy in the interim report was conducted on a subset of the main cohort, which included 86 participants who responded to lebrikizumab plus TCS in the ADhere study.

At week 40, the proportion of patients with an IGA score of 0 or 1 was 67.6% in the lebrikizumab 250 mg every 4 weeks group and 71.7% in lebrikizumab 250 mg every 2 weeks group.

At week 40, the mean change from baseline in the EASI score in lebrikizumab 250 mg every 4 weeks and lebrikizumab 250 mg every 2 weeks groups was −88.9% (standard error [SE] = 2.7%) and −88.4% (SE = 2.9%), 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 81.2% and 85.9%, 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 67.5% and 61.5%, respectively.

The mean 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 −64.0% (SE = 28.0%) and −69.1% (SE = 23.4%), respectively.

Harms Results

Overall, 29 patients (3% of the modified safety population) discontinued study treatment due to AEs. Discontinuation due to an AE was noted in 24 (3.5%) of 687 adult patients and in 5 (1.7%) of 292 adolescent patients.

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 (7.1% in lebrikizumab 250 mg every 4 weeks group and 7.6% in the lebrikizumab 250 mg every 2 weeks group) and nasopharyngitis (5% in lebrikizumab 250 mg every 4 weeks group and 4.9% in the lebrikizumab 250 mg every 2 weeks group) being the most common TEAEs. A similar proportion of patients in the lebrikizumab 250 mg every 2 weeks group (2.6%) and the lebrikizumab 250 mg every 4 weeks group (4.3%) reported an AE of AD exacerbation. The proportion of patients experiencing 1 or more AEs in the conjunctivitis cluster (narrow terms) were similar in both the lebrikizumab 250 mg every 4 weeks group (3.5%) and the lebrikizumab 250 mg every 2 weeks group (3.7%).

Critical Appraisal

Internal Validity

There is no randomized comparison to another treatment or to 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. Thus, their expectations of treatment may have influenced reporting of subjective patient-reported outcomes, such as POEM, and subjective AEs, or investigator-reported IGA and EASI, which are measures that require subjective judgments. Discontinuation rates were 8.5% in the lebrikizumab every 4 weeks and 15.6% in the lebrikizumab every 2 weeks. Among the participants from the ADhere study (efficacy assessment), the rates of discontinuation were 13.8% in the every 4 weeks group and 17.5% in the 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 those who responded to 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 related to lebrikizumab; developed an AE deemed related to lebrikizumab that led to study treatment discontinuation; or had conditions that led to investigator-initiated or sponsor-initiated withdrawal from the study. This is a selected population, consisting only of patients who initially tolerated and responded to lebrikizumab. The proportion of patients with concomitant TCS use and systemic rescue therapy was higher in the every 4 weeks group compared to 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 ITC first conducted an 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 via 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.³³ 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. Hence, results comparing lebrikizumab to baricitinib or tralokinumab were not included in this report. Outcomes of interest included EASI response, IGA 0 or 1 response, and a 4-point or more reduction in Pruritus NRS at week 16, and a 4-point or more reduction in Pruritus NRS at week 4.³³

Efficacy Results

The SLR identified a total of 8,392 citations. A total of ██████ unique studies identified by the SLR were assessed for eligibility to be included in 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 NMAs: 22 monotherapy studies, and ██ ███████████ ███████ ███████.³³

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.³³

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 and abrocitinib 100 mg daily. Abrocitinib 200 mg daily (probit difference, ██████ ███ ████ █████ ██ ████████ and upadacitinib 15 mg daily (probit difference ██████ ███ ████ █████ ██ ██████ and 30 mg daily (probit difference, ██████ ███ ████ █████ ██ ██████ were favoured over lebrikizumab.³³

In the primary analysis for EASI response at week 16 in the combination-therapy network, there was insufficient evidence to show a difference between lebrikizumab plus TCS and any of the comparator treatments.³³

IGA 0 or 1 response (week 16): In the primary analysis for 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] = 2.73; 95% credible interval [CrI], 1.67 to 4.32).³³

In the primary analysis for IGA 0 or 1 response at week 16 in the combination-therapy network, there was insufficient evidence to show a difference between lebrikizumab plus TCS and any of the comparator treatments, except for upadacitinib 30 mg daily plus TCS, which was favoured over lebrikizumab plus TCS (OR = █████ ███ ████ ████ ██ █████.³³

At least 4-point reduction 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 = 1.87; 95% CrI, 1.10 to 3.01).³³

In the primary analysis for Pruritus NRS response at week 16 in the combination-therapy network, there was insufficient evidence to show a difference between lebrikizumab plus TCS and abrocitinib 100 mg daily plus TCS, and upadacitinib 15 mg daily plus TCS. Dupilumab 300 mg every 2 weeks plus TCS (OR █████ ███ ████ ████ ██ ██████, abrocitinib 200 mg daily plus TCS (OR = █████ ███ ████ ████ ██ ████), and upadacitinib 30 mg daily plus TCS (OR █████ ███ ████ ████ ██ ████) were favoured over lebrikizumab plus TCS.³³

At least 4-point reduction 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, and abrocitinib 100 mg daily. Abrocitinib 200 mg daily (███ ████ ████ ████ █████ █████), upadacitinib 15 mg daily (███ █████ ███ ████ ████ ██ ████]), and upadacitinib 30 mg daily ████ █████ ███ ████ ████ ██ █████ were favoured over lebrikizumab.³³

In the primary analysis for Pruritus NRS response at week 4 in the combination-therapy network, there was insufficient evidence to show a difference between lebrikizumab plus TCS and dupilumab 300 mg every 2 weeks plus TCS, abrocitinib 100 mg daily plus TCS, and abrocitinib 200 mg daily plus TCS. Upadacitinib 15 mg daily plus TCS (OR = █████ ███ ████ ████ ██ ████) and upadacitinib 30 mg daily plus TCS (OR = █████ ███ ███ ████ ██ ████) were favoured over lebrikizumab plus TCS.³³

Secondary Analysis

Phase III studies only — monotherapy networks: Secondary analyses were conducted, including only phase III studies in the monotherapy networks. A total of ██ ██████ were included in these networks. In the EASI network, the unadjusted random-effects model was selected as the best model, and the results were consistent with the primary analysis. For the remaining end points, the random-effects model adjusted for baseline risk was the model of choice, and results were consistent with the primary analysis. In the IGA 0 or 1 response network, upadacitinib 15 mg daily was also favoured over lebrikizumab (OR = █████ ███ ████ ████ ██ ██████.³³

Meta-regression analysis: Secondary analyses using meta-regression to adjust for baseline severity were conducted for monotherapy and combination-therapy networks for the outcomes of EASI score at week 16 and IGA 0 or 1 response at week 16.³³ In the monotherapy network, a network meta-regression of EASI response at week 16 adjusted for baseline mean EASI score was conducted. There was no substantial difference in deviance information criterion between fixed-effects and random-effects models, although random-effects models were selected based on the lower residual deviance. Results were consistent with the primary and secondary analyses, with abrocitinib 200 mg daily, upadacitinib 15 mg daily, and upadacitinib 30 mg daily favoured over lebrikizumab and insufficient evidence to show a difference between lebrikizumab and other treatments. For IGA 0 or 1 response in the monotherapy network, a random-effects model adjusted for the proportion of patients with an IGA score of 4 or more at baseline was selected as the preferred model. The results were consistent with the primary analysis, with upadacitinib 30 mg daily favoured over lebrikizumab and insufficient evidence to show a difference between lebrikizumab and other treatments.³³

In the combination-therapy network, the fixed-effects model adjusted for baseline EASI score was the preferred model, as there were too many parameters to complete the random-effects model. Regardless, the results were consistent with the primary and secondary analyses. However, there was insufficient evidence to show a difference between lebrikizumab plus TCS and upadacitinib 15 mg daily plus TCS.³³

For IGA severity, the random-effects model adjusted for baseline IGA severity was selected as the preferred model. Results were mostly consistent with the primary analysis. However, there was insufficient evidence to show a difference between lebrikizumab plus TCS and upadacitinib 15 mg daily plus TCS.³³

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 to 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 was not indicative of serious risk of bias in the included studies. However, it should be noted that methods for risk of bias appraisal were incompletely reported (i.e., it is not clear how many people reviewed, were involved, and whether they worked independently). As a result, the risk of 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.³⁴ 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. Per the submitted excluded studies list, 2 trials were excluded from the syntheses for this reason.

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 16 weeks for other trials. The effect of the difference in time of assessment was not evaluated in the NMA and remains unknown. There were also differences in age across studies, with the mean age ranging from ████ █████ ██ ████ years. There was also heterogeneity in the proportion of patients with IGA response (█████ ██ ███████ and EASI response (█████ ██ █████ across studies). In the combination-therapy network, similar sources of heterogeneity in study design and baseline characteristics were observed (3 crossover studies; mean age range, ████ ██ ████ █████; those who responded to the IGA [%], █████ ██ ██████ and those who responded to the EASI, █████ ██ ██████. Adjustment for baseline EASI and IGA did not improve model fit, and conclusions were considered 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 unclear 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, including only 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 unclear whether the list was comprehensive. Additionally, the sponsor also highlighted differences in the type, potency, and frequency of TCS treatment in the combination-therapy network across studies. Differences in TCS treatment may bias reported response rates and limit the reliability of comparing responses on 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; hence, 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 recommendation of do not reimburse from CDA-AMC and is not reimbursed in Canada. Therefore, comparative results versus 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 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% CrIs, with most estimates crossing the 0 or 1 threshold, suggesting notable imprecision in the results and precluding conclusions concerning which treatment is favoured. For some comparisons in the monotherapy and combination-therapy networks (i.e., lebrikizumab versus dupilumab 300 mg every 2 weeks [with or without TCS] and abrocitinib 100 mg daily [with or without TCS]), 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 (with or without TCS) were favoured over lebrikizumab (with or without TCS) for most outcomes but were also associated with wide 95% CrIs. Overall, this imprecision limits the interpretability of the treatment effect of lebrikizumab relevant to other comparators. Furthermore, this NMA was primarily restricted to adults. Thus, 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 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 to address the uncertainty regarding the impact of lebrikizumab on vaccine immune responses, which also provides additional 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 to address uncertainty regarding the efficacy and safety of lebrikizumab specifically in patients residing in Japan (N = 268)

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

ADvantage Study

Results

The following summarizes efficacy results for patients randomized to the lebrikizumab plus TCS group relative to placebo plus TCS at week 16:

• EASI-75 was 68.4% versus 40.8%, █████████ ███████ ███ ██ ██████ █████

• IGA score of 0 or 1 and at least 2-point improvement was 42.0% versus 24.5%, █████████ █ ██████ ███ ██ █████ █████

• Pruritus NRS at least 4-point improvement was 49.9% versus 29.7%, █████████ █ ██████ ███ ██ ██████████

• |████ ████ ████ ██████ ████ █████████ █████ █████ ██████ ████ ██████ █████████ ██ ████ ██████████ █ █████ ███ ██ ██████ █████

• DLQI mean change from baseline was −9.5 (SD = 7.4) versus −8.1 (SD = 7.6); ██████ ██ ████ ██████████ █ █████ ███ ██ ███████ ██████

• |█████ ████ ████ ██████ ████ █████████ ████ █████ ██████ ████ ██████ ████████ ██ ████ ██████████ █ █████ ███ ███ ███████ ██████

In terms of safety, the following summarizes harms results for patients randomized to lebrikizumab plus TCS group relative to placebo plus TCS group at week 16:

• Proportion of patients with at least 1 AE was █████ ██████ █████

• Proportion of patients with at least 1 SAE was 1.4% versus 0.9%.

• Proportion of patients with at least 1 AE leading to study drug discontinuation was ████ ██████ ████

• Proportion of patients with conjunctivitis AE was █████ ██████ █████

Up to week 52, harms results for patients randomized to the lebrikizumab plus TCS group 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 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 for EASI-75. Dosage of maintenance therapy was 250 mg every 2 weeks, which is inconsistent with the Health Canada product monograph which recommends 250 mg every 4 weeks after 16 weeks. In the lebrikizumab group versus the placebo group ████ and ████ discontinued the study, which might increase risk of bias due to missing outcomes data.

ADopt-VA Study

Results

The following provides the efficacy results reported in ADopt-VA that correspond to patients randomized to lebrikizumab compared to placebo at week 16:

• EASI-75 was 58.0% versus 32.7% (RD = 25.3%; 95% CI, 12.6% to 38.0%; P < 0.001).

• IGA score of 0 or 1 and at least 2-point improvement, 40.6% versus 18.9% (RD = 21.7%; 95% CI, 10.3% to 33.2%; P < 0.001).

• Pruritus NRS at least 4-point improvement was 51.7% versus 33.2% (RD = 19.2%; 95% CI, 4.0% to 34.3%; P = 0.014).

• POEM LS mean change from baseline (−9.4 [SE = 0.8] versus −6.6 [SE = 0.8]; LS mean difference = −2.8; 95% CI, −5.0 to −0.5; P = 0.014).

In terms of safety, the following summarizes the harms for patients randomized to lebrikizumab compared to placebo at week 16:

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

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

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

• Proportion of patients with conjunctivitis AEs was ████ versus 0%.

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 8.8% in the lebrikizumab group versus 14.8% in the placebo group, and its effect on the results is not clear. The discontinuation rate was 27% in the placebo group versus 9.6% in the lebrikizumab group, which might increase the risk of bias due to missing outcomes data.

ADhere-J Study

A total of 282 participants in the ADhere-J study completed the induction period, including patients receiving placebo, patients in the lebrikizumab every 4 weeks treatment group, and patients in the lebrikizumab every 2 weeks treatment group. Those who responded to treatment in the lebrikizumab every 4 weeks treatment group continued receiving treatment with 250 mg lebrikizumab every 4 weeks. Those who responded to treatment in the lebrikizumab every 2 weeks treatment group were randomly allocated to receive 250 mg lebrikizumab every 2 weeks or 250 mg lebrikizumab every 4 weeks. Those who did not respond to treatment or 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, those who responded to treatment continued to receive placebo, while those who did not respond to treatment or 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

The following summarizes the efficacy results for the induction period corresponding to patients randomized to placebo plus TCS relative to lebrikizumab every 2 weeks plus TCS at week 16:

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

• IGA score of 0 or 1 and at least 2-point improvement was 6.1% versus 33.4%, P < 0.001.

• Pruritis NRS 4-point improvement or higher was 3.3% versus 32.7%, P < 0.001.

• |████ ██ ████ ████ ██████ ████ ████████ ███ ████ █████ ██████ ████ ███████████

• |█████ ██ ████ ████ ██████ ████ ████████ ███ ████ █████ ██████ ████ ███████████

• |█████ ██ ████ ████ ██████ ████ █████████ ████ █████ ██████ ████ ██████ █ ███████

For the maintenance blinded period, 74.9% of patients achieved EASI-75 response at week 52 among the subgroup of patients who responded to lebrikizumab every 2 weeks induction therapy and were switched to lebrikizumab every 4 weeks maintenance therapy.

Harms results for the induction period in the placebo group versus the lebrikizumab every 2 weeks plus TCS group were the following:

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

• Proportion of patients with at least 1 SAEs was 2.4% versus 0.8%.

• Proportion of patients with AE leading to study drug discontinuation was 0% versus 1.6%.

• Proportion of patients with conjunctivitis AE ███ █████ ██████ █████

Harms results for the maintenance blinded period in patients switched to lebrikizumab every 4 weeks maintenance dosage were the following:

• Proportion of patients with at least 1 AE was █████

• Proportion of patients with at least 1 SAE was 0%.

• Proportion of patients with AE leading to study drug discontinuation was 0%.

• Proportion of patients with conjunctivitis AE was 3.0%.

Critical Appraisal

This study is limited to patients residing in Japan only, 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 17.1% in the placebo group, 3.7% in the lebrikizumab every 4 weeks group, and 4.9% 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 group or every 4 weeks plus TCS group. The impact of missing data on the findings is unclear.

ADore Study

Results

The following summarizes the efficacy results reported in the ADore study at week 52:

• EASI-75 (Markov Chain Monte Carlo multiple imputation [MCMC-MI] analysis) was 81.9%.

• IGA score of 0 or 1 and at least 2-point improvement (MCMC-MI analysis) was 62.6%.

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

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

The following summarizes harms results reported in the ADore study at week 52:

• Proportion of patients with at least 1 AE was 65%.

• Proportion of patients with at least 1 SAEs was 2.4%.

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

• The proportion of patients with conjunctivitis AEs was 6.8%.

• One death (0.5%) was reported, due to cardiac arrest.

Critical Appraisal

There is risk of bias in the measurement of the outcomes due to the open-label design and subjectivity of the outcomes. There is no comparator, which limits causal inferences. The maintenance therapy dose was inconsistent with the Health Canada product monograph. There is a 16.5% discontinuation rate, which might contribute to risk of bias due to missing outcome data.

Key Takeaways 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 when compared to placebo for EASI-75 response, IGA 0 or 1 response, and Pruritus NRS at least 4-point improvement at 16 weeks.

In terms of harms results at week 16, in the ADvantage study, a higher proportion of patients in the lebrikizumab group compared with 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 compared to the placebo group. In the ADhere-J study, the proportion of patients who reported TEAEs, and patients with 1 or more AEs leading to study drug discontinuation, were higher in the every 2 weeks group versus 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 included uncertain generalizability to adolescent patients, dosage inconsistency with the Health Canada–recommended dose, lack of control for multiplicity for secondary efficacy end points (thus, increased risk of type I error), and risk of bias due to missing outcomes data. In the ADopt-VA study, there was 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; dosage inconsistency with the Health Canada–recommended dose for the induction period; between-group differences in the use of high-potency TCS; increased risk of type I error for DLQI, CDLQI and POEM; and between-group differences in discontinuations during the maintenance period.

Clinical Review From the Lebrikizumab Resubmission

Methods

The review team considered a sponsor-submitted LTE and ITCs. Relevant patients and interventions were defined by the treatment of moderate to severe atopic dermatitis 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 and the recommended dosage in the product monograph. Patients using TCSs for their AD were considered a potentially important subgroup for informing the reimbursement recommendation. Relevant comparators were drugs and nondrug treatments used in clinical practice in Canada to treat patients described in the indication under review. These included off-label immunosuppressive treatments (methotrexate, cyclosporine, mycophenolate mofetil, or azathioprine), as well as dupilumab, abrocitinib, and upadacitinib. An LTE of pivotal studies and RCTs (detailed in the initial submission and found in the Clinical Evidence from the Initial Lebrikizumab Review section in the Clinical Evidence of the main report) was included, regardless of whether there was a comparison group. ITCs submitted by the sponsor were included when they were believed to fill an identified gap in the systematic review evidence presented in the initial submission of lebrikizumab.

Included outcomes are those in the initial submission and were selected for review considering the sponsor’s Summary of Clinical Evidence, clinical expert input, and patient and clinician group input. They were considered relevant to expert committee deliberations, and they were selected in consultation with committee members:

• percentage of patients with an IGA score of 0 or 1 and a reduction of at least 2 points from baseline

• percentage of patients with EASI-75 response

• percentage of patients with a Pruritus NRS score of at least 4 points at baseline who report a 4-point or more reduction from baseline

• change from baseline in POEM score

• change from baseline in DLQI total score

• change from baseline in CDLQI total score

• percentage of patients randomly reassigned having achieved EASI-75 at week 16 who continue to exhibit EASI-75 (EASI-75 calculated relative to baseline EASI)

• percentage of patients with an SAE

• percentage of patients with conjunctivitis

• percentage of patients achieving at least a 90% reduction in EASI score (EASI-90)

• percentage change in EASI from baseline

• percentage change in Pruritus NRS score from baseline.

Methods for data extraction and risk of bias appraisal are in the Supplemental Material document, Appendix 2.

Clinical Evidence

In this report, the following sources of evidence submitted by the sponsor are reviewed and appraised:

• 1 LTE study

• 3 ITCs.

Systematic Review

There are no updates to the systematic review section for resubmission of lebrikizumab, and the results from the initial submission can be found in the Clinical Evidence from the Initial Lebrikizumab Review section.

LTE Study

Description of Study

One LTE study (ADjoin) was summarized to provide evidence regarding the long-term (100-week) efficacy and safety of lebrikizumab among patients with moderate to severe AD who were enrolled in the parent trials, including ADvocate 1 and ADvocate 2 (lebrikizumab monotherapy trials in adults), ADhere (lebrikizumab plus TCSs in adults), ADore (lebrikizumab in adolescents, with concomitant TCS permitted), and ADopt-VA (lebrikizumab’s effect on vaccine immune responses in adults).

In the initial submission, interim safety data and limited efficacy data at week 40 were reported based on the data cut-off of July 6, 2022. In this review, updated safety and efficacy results of up to 100 weeks from the latest data cut-off ██████ ███ █████ are presented.

Population

Participants were eligible if they had previously received lebrikizumab in a parent trial and had adequately completed both treatment and the final visit of that study. Participants were excluded if, during the parent trial, they experienced a lebrikizumab-related SAE or an AE leading to treatment discontinuation that posed an unacceptable risk, or if they met protocol-defined criteria for permanent discontinuation or withdrawal (e.g., noncompliance or inability to complete assessments) related to lebrikizumab.

Inclusion and exclusion criteria for direct entry into the ADjoin study (without participation in a parent trial; Addendum ███ of the trial protocol) were consistent with those for the parent trials that contributed patients to the ADjoin study. Additionally, patients could not have received a dose of lebrikizumab in any prior clinical study. An additional inclusion criterion (Addendum ███ of the trial protocol), for existing patients receiving open-label lebrikizumab in the ADjoin study at selected US sites, was the capability and willingness to self-administer lebrikizumab after receiving training.

The ADjoin study’s main cohort included all patients who entered via the parent trials or by direct entry who received at least 1 dose of lebrikizumab. The cohorts of interest for the present submission were defined as follows:

• main cohort (all participants who entered ADjoin from a parent study or via direct entry and received at least 1 dose of lebrikizumab)

• participants in the ADhere study who responded to treatment (participants who met the criteria for response at week 16 based on EASI-75 or IGA 0 or 1 response without receiving rescue therapy during the ADhere trial)

• participants in the ADvocate 1 and ADvocate 2 studies who responded to treatment (participants who met the criteria for response at week 16 based on EASI-75 or IGA 0 or 1 response and did not enter the rescue therapy arms during the ADvocate 1 and ADvocate 2 trials).

Interventions

Patients received lebrikizumab for up to 100 weeks after completing the parent trial. Patients in the ADjoin study’s main cohort were assigned to either blinded lebrikizumab 250 mg SC every 2 weeks or lebrikizumab 250 mg SC every 4 weeks based on the group to which they were randomly assigned for the maintenance blinded period of the parent trial. Lebrikizumab loading doses were administered to patients who received placebo in the parent trial at the time of enrolment and at week 2, followed by 250 mg lebrikizumab every 2 weeks. Placebo injections were used to maintain blinding of dosing frequency.

Patients who had direct entry were assigned to 500 mg lebrikizumab administered at baseline and week 2 (loading dose) followed by 250 mg lebrikizumab every 2 weeks.

Participants in the ADhere study who responded to treatment were randomly assigned 1:2 to receive 250 mg lebrikizumab every 4 weeks or every 2 weeks in combination with TCS.

The use of concomitant medications for other medical conditions (e.g., hypertension, diabetes, acute infections) was permitted during this study. Intermittent use of topical rescue medications (e.g., TCS, topical calcineurin inhibitors, and PDE inhibitors) for AD was permitted for the treatment of disease flares during the trial.

Outcomes

The primary end point of the ADjoin study was the proportion of patients who discontinued study treatment due to AEs through the last treatment visit. The secondary end points were the proportion of patients with an IGA score of 0 or 1 at each visit, and proportion of patients achieving a response of EASI-75 from baseline of the parent trial at each visit. Additional secondary outcomes considered relevant to this review included percentage change from baseline in EASI total score (EASI-90, EASI-50), BSA change from baseline, and POEM percentage change from baseline up to 100 weeks. Pruritus NRS percentage change from baseline, Pruritus NRS 4-point improvement, Sleep Loss Scale percentage change from baseline, and Sleep Loss Scale 2-point improvement were measured up to 52 weeks.

Statistical Analysis

All outcomes were summarized using descriptive analyses. Missing data were imputed for the efficacy end points using MCMC-MI and last observation carried forward (LOCF) methods. For the MCMC-MI method, all data collected after treatment discontinuation due to lack of efficacy were set to the patient’s baseline value, and data collected after treatment discontinuation due to other reasons were set to missing; MCMC-MI was then used to impute all missing data. For the LOCF method (supportive estimand), all data collected after treatment discontinuation were set to missing; LOCF was then used to impute all missing data. Observed data (i.e., no imputation for missing data) were used for the analysis of POEM scores. All analyses were conducted descriptively, without adjustment for multiple comparisons.

The modified ITT analysis set included all patients assigned to treatment, excluding patients from 1 study site, who were excluded following clinical site audits. Patients were analyzed in the groups to which they were assigned. The modified safety analysis set included all patients who received at least 1 dose of lebrikizumab, excluding patients from the same site.

The primary estimand for the ADjoin study was the proportion of modified safety population participants who discontinued from study treatment due to AEs through the last treatment visit of the reporting period. The secondary estimand for the ADjoin study was the proportion of patients with modified ITT who met the clinical requirements for response and who did not discontinue due to lack of efficacy.

Critical Appraisal

Internal Validity

The analyses were conducted in an enriched population, consisting only of patients who had previously responded to and tolerated lebrikizumab during induction therapy, which introduces selection bias. Consequently, the observed outcomes primarily reflect a comparison between continued lebrikizumab maintenance doses among those who initially responded to treatment, rather than providing a comprehensive assessment of long-term efficacy and safety in an unselected population. The clinical experts consulted by CDA-AMC agreed that 100 weeks is sufficient time to assess the long-term efficacy, safety, and treatment relapse. However, the study lacked a comparator group to assess the benefits and harms of lebrikizumab compared to another relevant treatment, limiting the ability to make causal interpretations about the treatment effects of lebrikizumab in the studied population. Although patients were blinded to dosing arms, they were likely aware they were receiving active therapy. This may have introduced reporting bias for the subjective outcomes such as POEM, Sleep Loss improvement, and AEs or investigator-reported IGA and EASI. This introduces the potential for expectation-related reporting bias, which may favour improved outcomes. In addition, treatment discontinuation was relatively frequent, with higher withdrawal rates observed in the lebrikizumab every 2 weeks group compared with the every 4 weeks group. These levels of discontinuation introduce the potential for bias related to missing data. Moreover, differences in the use of concomitant TCS were observed in the cohort of participants in the ADhere study who responded to treatment, with a greater proportion of patients in the lebrikizumab every 4 weeks group receiving TCS and systemic rescue treatments compared with the every 2 weeks group. The impact of these imbalances on the observed efficacy outcomes is unclear. All outcomes were summarized using descriptive analyses, with no formal statistical comparisons conducted between treatment groups, precluding drawing conclusions from the findings.

External Validity

The outcomes evaluated in the LTE study and reported in this review are considered important by patients with AD and aligned with their treatment goals. The analyses were restricted to patients who had demonstrated a clinical response in the parent studies; individuals were not eligible for inclusion if they had experienced an SAE considered related to lebrikizumab, an AE leading to treatment discontinuation, or other conditions that resulted in investigator-initiated or sponsor-initiated withdrawal during the parent trial. Consequently, the long-term treatment effects reflect outcomes only in patients who both responded to and tolerated lebrikizumab, limiting the generalizability of the findings to the broader patient population. The recommended maintenance dose of lebrikizumab is 250 mg every 4 weeks starting at week 16. However, the majority of patients included in the ADjoin study (more than 80%) received lebrikizumab 250 mg every 2 weeks. Therefore, only a small proportion of the participants in the LTE study received the recommended maintenance dose.

The 100-week duration was deemed sufficient to assess long-term efficacy, safety, and treatment relapse by the clinical experts consulted by CDA-AMC. The results suggested that lebrikizumab’s efficacy appears to be sustained over long-term treatment and no new safety events were identified. However, multiple study design limitations introduce uncertainty in the LTE study results, including the absence of a comparator group, lack of statistical testing, the potential for bias in the measurement of subjective outcomes due to the open-label design, missing data, and a limited number of patients receiving the recommended maintenance dose.

Results

Details of patient disposition and baseline characteristics of the patients are in the Supplemental Material document, Appendix 5, Figure 1 [redacted], Figure 2 [redacted], and Figure 3 [redacted].

Patient Disposition

Main Cohort

A total of ███ patients entered the ADjoin study via the ADvocate 1 and ADvocate 2 studies, ███ via the ADhere and ADopt-VA studies, ███ via the ADore study, and ██ via direct entry. A total of 1,175 patients were randomized to different doses (ITT population). Following the exclusion of 22 patients due to a critical audit finding at 2 sites, 1,153 participants constituted the modified ITT. Of these, 141 (12.2%) were assigned to the lebrikizumab 250 mg SC every 4 weeks group and 1,012 (87.7%) to the every 2 weeks group. █████ ███ ████ ██████ ███ █████ ██ ███████████████ ███ ███ ███ ███ ██ ███ ████████████ █████ █ █████ █████ ███ █████ █ █████ ██████ █████████████ ███ ████ ██████ ██████ ███ ███████████████ ██ ████ ██████ ███ ███ ██ ██████████ ██ █████████ █ ██ █████ █ █████ ███ ████ █ ██ █████ █ █████ █████████ ██████ █████████████ ███ ██ ███ ████████████ █████ █ █████ ██████ ████ █████████ ███████ █████████ ████ ███ █████████ ████ ████ ██ ██ ███ ████ ██████ █████.

Cohort of Participants in the ADhere Study Who Responded to Treatment

A total of 86 patients from the ADhere study met the treatment response criteria and continued in the ADjoin study. Of those, 29 patients (█████) were rerandomized to the lebrikizumab every 2 weeks group and 57 (█████) to the every 4 weeks group. Of these, █████ of patients in the lebrikizumab every 4 weeks group and █████ in the lebrikizumab every 2 weeks group discontinued treatment. ███ ████ ██████ ██████ ███ ███████████████ ███ ██████████ ██ ███ ███████ ██ █████████████ █████ █ █████ █████ ███████ ███ ████ ██ ██████ ██ ██ ███ ████████████ █████ █ █████ █████ ████████.

Cohort of Participants in the ADvocate 1 and ADvocate 2 Studies Who Responded to Treatment

A total of 181 patients from the ADvocate 1 and ADvocate 2 studies met the treatment response criteria and continued in the ADjoin study. Of those, 99 patients (██████ were rerandomized to the lebrikizumab every 4 weeks group and 82 (██████ to the every 2 weeks group. Among the patients who responded to treatment in the ADvocate 1 and 2 studies, █████ of patients in the lebrikizumab every 4 weeks group and █████ in the lebrikizumab every 2 weeks group discontinued treatment. ███ ████ ██████ ██████ ███ ███████████████ ███ ██████████ ██ ████████████ ██ ████ ██████ █████ █ ██ █████ █ █████ ███ ████ █ ██ █████ █ █████ ███████.

Baseline Characteristics

The baseline disease and demographic characteristics of the patients enrolled in the ADjoin study at the parent trial baseline, based on the interim Clinical Study Report, are presented in the Supplemental Material document, Appendix 5, Table 5. In the main ADjoin study cohort, the mean age of participants was approximately ██ █████. Adolescents (aged 12 years to younger than 18 years) constituted █████ of the overall population, compared ████ █████ █████ ███ ████ ██████ in the cohort of participants in the ADhere study who responded to treatment and █████ █████ ███ ████ ██████ in the cohort of participants in the ADvocate 1 and ADvocate 2 studies who responded to treatment. The mean duration of time since AD onset was ████ ██████ ████ ██████ ████ █████ for the main ADjoin study cohort, the cohort of participants in the ADhere study who responded to treatment, and the cohort of participants in the ADvocate 1 and ADvocate 2 studies who responded to treatment, respectively. Similar percentages of females and males were included in all cohorts. In the main ADjoin study cohort, most participants were █████ ████████ ████████ ██ █████ ███████ ███ █████ ██ ███████ ████████ ████████ In the cohort of participants in the ADhere study who responded to treatment, those proportions were █████ ██████ ████ █ █████ ██ ███████ █████████ ███ ███ █████. In the cohort of participants in the ADvocate 1 and ADvocate 2 studies who responded to treatment, ███ ████████ ████ ██████ █████ ████ ██████ ███ ████ █ ████ █████ ██ ███████ ████████. In the main cohort, ██ ███████ patients receiving lebrikizumab every 4 weeks and ███ ███████ patients receiving lebrikizumab every 2 weeks ███ █████ ███ ██ █████████████████ ██ ████████████████ ██████ ███ █ █████ ██ ███ ███████ ████████ ████████ ████████ ███████████████ █████████ ███ ███ ███████ ██████████ ██ █████████████████ ████ ███ ████████.

Exposure to Study Treatments

Details of patients’ treatment exposure and/or adherence and use of concomitant medications, subsequent treatments, and/or rescue therapies in each of the included studies (i.e. Adjoin, ADhere Responders Cohort, and Advocate 1 and 2 Responders Cohort) are found in the Supplemental Material document, Appendix 5.

█████ ███ ████ ██████ █████████ ██████ ████████████ ████████ ████ ███████ ██ ████████████ █████ █ █████ ███ █ ████ █████ ████ ██████ ████ ███ ██ ████████████ █████ █ █████ ███ █ ████ ██ █████ ████ ██████ █████ ██ ███ ████████████ █████ █ █████ ██████ ████ ██████████ ███ ██████████ █████ ██████████ ███ ████ ████████ ████████ ███ █ █████ ██ █████ ███ █████ ███ █████ ███ ███ ████ ██ █████████ █████████████ ██ ███ ████████████ █████ █ █████ ██████ █████ ████████████ █████ ███████████ █████ ███████████ ███ ████ █████████ ████████ ███ ██ █████ ██ █████ ███ █████ ████ ███ ███ ████ ██ █████████ ████████████.

█████ ███ ████ ███████ █████ ██ ████████ ██ ███ ████████████ █████ █ █████ █████ ███ █████ ██ ████████ ██ ███ ████████████ █████ █ █████ █████ ███████ ██ ███ █████████ █████████ ████ ████████ ██████ ██ ████████████.

███ ██████████ ████ ████ █████ ██ █████ ██ ██████ █████████ ██████ ███ █████ ██ █████ ██ ████████ ███ █████████ ███████.

Concomitant Medications and Co-Interventions

Common concomitant AD treatments (used in 10% or more of patients) were TCS in the main cohort (███ ██ ████████) and the cohort of participants in the ADhere study who responded to treatment (███ ██ ████████), and the cohort of participants in the ADvocate 1 and ADvocate 2 studies who responded to treatment (███ ██ ████████). Given that the ADjoin study is an LTE of the ADhere protocol, the majority (█████ ███ ████████████ █████ █ █████ ██████ ███ █████ ███ ████████████ █████ █ █████ █████) of the cohort of participants in the ADhere study who responded to treatment recorded concomitant TCS use (refer to the Supplemental Material document, Table 6).

Efficacy

Detailed results for outcomes relevant to this review are in the Supplemental Material document, Appendix 5.

Results from week 100 and from week 52 of the ADjoin study (i.e., after exposure to lebrikizumab in the preceding studies) are presented for the modified ITT population.

Key results include the following at the data cut-off of █████ ███ █████:

• In the main cohort, the response rate of IGA 0 or 1 at week 100 was 80.1% and 60.6% in the lebrikizumab every 4 weeks and every 2 weeks groups, respectively. ██████████ ███████ ████ █████ ████ ███ ████████ ████ ████ ████ ████ ███ ██ ███ ███████ ██ ██████████ ████ ██████ ██████ ██ ██████ ███ ████████ ███ ██████ ██ ███████

• In the main cohort, the lebrikizumab every 4 weeks group achieved an EASI-75 response rate of █████ at week 100, and the every 2 weeks group achieved an EASI-75 response rate of █████ at week 100. ██████████ ███████ ████ █████ ████ ███ ████████ ████ ████ ████ ████ ███ ██ ███ ███████ ██ ██████████ ████ ██████ ██████ ██ ██████ ███ ████████ ███ ██████ ██ ███████.

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Harms

Detailed results for harms are presented in the Supplemental Material document, Appendix 5. Key results for the main cohort up to week 100 at data cut-off █████ ███ ████ include the following:

• The incidence of TEAEs was █████ ██████ ████% in the lebrikizumab every 4 weeks and every 2 weeks groups, respectively.

• The most frequent TEAEs of lebrikizumab were: █████ ██ █████ █ ██ ███████ ███████████████ █████ ██ ███████ ██ █████ ██ ██████ █████ ███████████ █████ █████████ █████ ██ ██████ ███ ██████████████ █████ ██ ████.

• The incidence of SAEs was ████ ██████ ████ in the every 4 weeks and every 2 weeks groups, respectively.

• AEs leading to permanent discontinuation of study treatment occurred in ████ ███ ████ of patients in the every 4 weeks and every 2 weeks groups, respectively.

• Most frequent AEs of special interest were reported as follows:

  • Conjunctivitis: ████ ██ ███ █████ █ █████ █████ ██ ██ ██ ███ █████ █ █████ █████

  • Allergic conjunctivitis ████ ██ ███ █████ █ █████ █████ ██ ██ ███ ████ █████ █ █████ █████

• Two deaths occurred in the lebrikizumab every 2 weeks group – 1 due to natural causes and the other due to metastatic pancreatic carcinoma.

Indirect Evidence

Multiple placebo-controlled, phase III clinical trials have been conducted to determine the safety and efficacy of lebrikizumab in patients with AD. The sponsor conducted ITCs to establish the relative efficacy and safety of lebrikizumab compared to key comparators in the treatment of adults and adolescents with moderate to severe AD.

Description of ITCs

One sponsor-submitted updated NMA and 2 new matching-adjusted indirect comparisons (MAICs) that could address some of the evidence gaps previously identified by CDEC were reviewed and critically appraised in the review.

Network Meta-Analysis

The objective of the sponsor-submitted NMA was to estimate the relative efficacy, safety, and quality of life for lebrikizumab, both monotherapy and in combination with TCS, during the induction period (baseline to weeks 12 to 16) versus approved systemic regimens in adults and adolescents with moderate to severe AD.

Study Selection and Review Methods

To inform the original NMA, the sponsor conducted a clinical SLR (up to May 2022) of RCTs in patients with moderate to severe AD. Following feasibility assessment, 38 studies were deemed eligible and included in the NMA, including 22 monotherapy studies ███ ██ ███████ ██████████ ████████████ ███████ ██ ███████████ ████ ███. The sponsor conducted an updated literature search through November 2024, which identified 41 records, including 6 new studies in adults or adolescents with moderate to severe AD. Three of these were lebrikizumab studies already incorporated in the original NMA using Eli Lilly data on file (the ADhere-J, ADopt-VA, and ADvantage trials) and did not contribute additional data beyond the Clinical Study Reports. Tralokinumab results from pooled ECZTRA 1 and ECZTRA 2 trials were digitized to inform a week 4 analysis. To address limited evidence in the postcyclosporine subgroup, targeted searches of health technology assessment websites (UK National Institute for Health and Care Excellence [NICE], CDA-AMC, Pharmaceutical Benefits Advisory Committee) were conducted; however, no usable subgroup data were identified due to redactions. Two newly identified nemolizumab trials (the ARCADIA 1 and ARCADIA 2 trials) were excluded because a CDA-AMC recommendation for this comparator was not yet available. Therefore, after feasibility assessment, the evidence networks remained unchanged, with 38 included studies.

Details of the systematic review methods, study selection, included studies, and studies previously reviewed in the original NMA are provided in the Supplemental Material, Appendix 6.

Additional outcomes included in the updated NMA included the following:

• Percent change from baseline in EASI score, with an MID of plus or minus 6.6 based on the previous NMA publication³⁵

• DLQI 0 or 1 response and change in baseline in DLQI score

• Safety outcomes: overall AEs, severe AEs, discontinuation due to AEs, and discontinuation due to lack of efficacy.

These additional outcomes were assessed at week 16, with week 12 evidence used in some networks — where considered appropriate by the sponsor — including abrocitinib monotherapy studies. These outcomes were generally well reported across the included studies, with the exception of the DLQI 0 or 1 response outcome. The sponsor noted that, although DLQI 0 or 1 response is more readily interpretable than change from baseline in DLQI, key comparators were omitted from the network for this outcome. Consequently, the sponsor considered change from baseline in DLQI to be sufficient for the NMA. Across eligible monotherapy studies, data were generally well reported for percent change from baseline in EASI (19 of 22) and DLQI (15 of 22), ███████ ███ ███ ██ ████ ███████ ███ ███ ██ ████ ████████████████ ███ ██ ███ ███ ██ ████ ███████████████ ███ ██ ████ ██ ████████ ███ ██ ████ ██ █████████ ████ █ ██ █ ████████ ███ ████████ ██ ████ █ ██ ██ ███████ ███ ██████ ███ ██ █ ██ ██ ████████████ ████████ ███████████ ███████ █████ ████ ████████ ████ ████████ ██████ ████ ████████ ██ ████ ███ ███ ██ ███ ███ ████ ███ ██ ████ ███████ ███ ███ ██ ████ ███████ ███ ███ ██ ████ ████████████████ ███ ██ ███ ███ ██ ████ ███ ████████████████ ███ ██ ████ ██ ████████ ██ ██ ████ ███ ████ █ ██ █ ████████ ███ ██████ ███ ████ ████ ████████ ██ ████ █ ██ ██ ████████ ████████ ███████████████ ███ ██ ███ ███ ████ ██ ████████ ████ █████████ ███ ███ █████ █████ ████████ ██████ ███████ ████████ ████████████ ███████████ ██ ███████████ ██████████.

NMA Analysis Methods and Summary of Included Studies

Details on the NMA methods and the included studies are provided in the Supplemental Material, Appendix 6.

For continuous outcomes, including percent change from baseline in EASI and change from baseline in DLQI, a normal likelihood with an identity link was specified, in accordance with the recommendations in NICE Decision Support Unit Technical Support Document 3³⁶ for NMA of continuous outcomes. Fixed-effects and random-effects models, with and without baseline risk adjustment, were fitted for each network. According to the sponsor, informative priors were not required for these outcomes, as the use of vague priors allowed for reliable estimation of the between-study variance parameters.

Critical Appraisal of the NMA

The sponsor-submitted updated NMA was informed by an updated SLR that included comprehensive searches through November 2024 of multiple databases, conference proceedings, clinical trial databases, and health technology assessment websites. The methods used for this updated NMA were the same as those used in the initial submission; therefore, many of the critical appraisal considerations identified in the initial submission also apply to this updated NMA. The sponsor’s risk of bias assessment did not indicate serious risk of bias in the included studies. However, the appraisal was conducted at the study level rather than at the level of reported effects. Appraisals undertaken at the study level do not account for differences in the risk of bias that can exist across reported results. 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. However, the magnitude and direction of this bias are unknown. Per the submitted excluded studies list, 2 trials were excluded from the syntheses for this reason.

Baricitinib and tralokinumab were included in the NMA as comparators; 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 recommendation of do not reimburse from CDA-AMC and is not reimbursed by public drug plans in Canada. Therefore, comparative results versus these treatments were not included in this report. Two identified nemolizumab trials (the ARCADIA 1 and ARCADIA 2 trials) were not included in the NMA. Nemolizumab received a positive recommendation from CDA-AMC for the treatment of moderate to severe AD; however, at the time this resubmission was received, the final recommendation for nemolizumab had not yet been issued. Additionally, the sponsor-submitted NMA did not report baseline proportions of prior conventional immunosuppressant exposure, precluding assessment of its impact on comparative estimates.

A feasibility assessment examined heterogeneity in study design, baseline characteristics, interventions, outcomes, time points, and placebo response. The sponsor noted that some heterogeneity was observed across studies in both the monotherapy and combination-therapy (with TCS) networks. Studies for abrocitinib assessed outcomes at week 12, whereas the other trials assessed outcomes at week 16. The effect of the difference in time of assessment was not evaluated in the NMA and remains unknown. There was also heterogeneity in the proportion of patients with IGA scores of 0 or 1 at baseline (█████ ██ ███████ and EASI score at baseline (████ ██ ████ across studies). In the combination therapy with TCS network, similar sources of heterogeneity in study design and baseline characteristics were observed (mean age range, 14.9 to 39.1 years; those who responded to IGA at baseline █████ ██ ██████ and those who responded to EASI at baseline, █████ ██ ███████. Other differences were noted by the CDA-AMC review team include 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 unclear whether these are important treatment-effect modifiers. Additionally, the sponsor also highlighted differences in the type, potency, and frequency of TCS treatment in the combination therapy with TCS network across studies. Differences in TCS treatment could bias reported response rates and limit the reliability of comparisons between active interventions. Additionally, it is unclear whether HRQoL results are generalizable to adolescents with AD, because DLQI findings primarily apply to adults, and adolescents typically complete the CDLQI. However, clinical experts consulted by CDA-AMC agreed that these differences were unlikely to have a meaningful impact on the results.

The additional outcomes included in the updated NMA were percent change from baseline in EASI and DLQI at week 16, as well as harms outcomes. The clinical experts consulted by CDA-AMC considered these outcomes relevant to the treatment of AD in Canada. Overall, the notable heterogeneity in baseline characteristics raises concerns regarding the plausibility of the transitivity assumption, which limits the validity of the resulting effect estimates. In all random-effects analyses, results were associated with wide 95% CrIs, with most estimates crossing the 0 or 1 threshold, suggesting notable imprecision in the results and precluding conclusions concerning which treatment is favoured. Overall, this imprecision limits the interpretability of the treatment effect of lebrikizumab relevant to other comparators.

Efficacy and Harms Results of the Updated NMA

Key efficacy results of the updated NMA are summarized in Table 3.

For percent change from baseline in EASI, more positive values indicate less improvement (i.e., a less favourable outcome), whereas more negative values indicate greater improvement. In the primary analysis of percent change from baseline in EASI at week 16, comparing lebrikizumab versus upadacitinib 30 mg, the point estimates with 95% CrIs favoured upadacitinib in both the monotherapy and combination (with TCS) networks (mean difference, ███████ ███ ████ █████ ██ ██████ and mean difference, ███████ ███ ████ █████ ██ ██████).

Point estimates favoured the comparators over lebrikizumab for dupilumab 300 mg, abrocitinib 200 mg, and upadacitinib 15 mg in both the monotherapy and combination networks. In contrast, the point estimate for abrocitinib 100 mg favoured lebrikizumab over abrocitinib in the monotherapy network but favoured abrocitinib 100 mg in the combination network. However, the effect estimates were imprecise, with 95% CrIs including the potential that either lebrikizumab or the comparators could be favoured or that there was no difference between the treatments.

In the primary analysis for change from baseline in DLQI at week 16, point estimates favoured dupilumab 300 mg and abrocitinib 200 mg over lebrikizumab in both the monotherapy and combination-therapy networks. The point estimate for abrocitinib 100 mg favoured lebrikizumab in both the monotherapy and combination-therapy network. However, the effect estimates for all comparators were imprecise, with 95% CrIs including the potential that either lebrikizumab or the comparators could be favoured or that there was no difference between the treatments. Comparisons versus upadacitinib 15 mg and 30 mg for change from baseline in DLQI at week 16 were not available.

Table 3: Redacted

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Key safety results from the updated NMA are summarized in Table 4. In the analysis of overall AEs at week 16, point estimates with 95% CrIs for overall AEs favoured lebrikizumab over all active comparators in the monotherapy network, whereas, in the combination-therapy network, point estimates generally favoured the comparators over lebrikizumab plus TCS, except for the comparison versus abrocitinib 200 mg and upadacitinib 30 mg plus TCS, which favoured lebrikizumab plus TCS. For SAEs and severe AEs at week 16, point estimates generally favoured lebrikizumab in both networks for most comparisons. However, the effect estimates were imprecise, with 95% CrIs including the potential that either lebrikizumab or the comparators could be favoured or that there was no difference between the treatments. NMAs for discontinuation outcomes produced estimates with considerable uncertainty due to low or absent event rates across the included studies at week 16.

Table 4: Redacted

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Matching-Adjusted ITCs

The longer-term safety and efficacy of lebrikizumab versus relevant comparators beyond week 16 was limited, presenting an important gap in the initially submitted evidence. To address this limitation, the sponsor conducted longer-term controlled analyses, including 2 unanchored MAICs, to assess the efficacy and safety of lebrikizumab versus relevant comparators at week 52. An unanchored approach was used because a common comparator (placebo) was not available beyond week 16 across the included studies, precluding anchored indirect comparisons at approximately 52 weeks.

Description of MAIC Versus JAK Inhibitors

Study Selection and Review Methods

MAIC versus JAK inhibitors (upadacitinib and abrocitinib): The sponsor conducted an unanchored MAIC to compare lebrikizumab with the JAK inhibitors upadacitinib and abrocitinib at week 52 of treatment. To ensure alignment with the analysis objective and minimize heterogeneity in concomitant therapy, eligibility was restricted to studies reporting approximately 52-week outcomes for monotherapy without concomitant TCS. Given that the pivotal phase III evidence base for each JAK inhibitor in this setting is limited and well-defined, a formal database search was not undertaken. Data extraction was performed by 1 analyst and independently cross-checked by a second person who reviewed to support accuracy and consistency. The sponsor stated that all included studies were phase III, randomized, double-blind trials and were considered methodologically robust. A formal risk of bias assessment was not conducted.

The analysis compares individual patient data (IPD) from patients treated with lebrikizumab in the ██████ ███ ███ █████ ██ to published aggregate data from patients treated with upadacitinib and abrocitinib. For upadacitinib, ██████ ███ ███ █████ ██ were the only monotherapy studies with outcomes reported at week 52. Efficacy and safety aggregate data at week 52 were extracted from publicly available sources. For abrocitinib, long-term outcomes at the target time horizon were available only through the ██████ ███ ███ █████ ██ study. To maximize comparability with the lebrikizumab and upadacitinib monotherapy studies, the analysis was restricted to the abrocitinib monotherapy LTE study population. This population included patients who were initially randomized to abrocitinib monotherapy in the parent monotherapy studies and who continued abrocitinib in the ██████ ███ ███ █████ ██ study without the use of TCS at any point. Consequently, both efficacy and safety outcomes for abrocitinib were derived exclusively from this monotherapy extension subgroup rather than the broader extension cohorts. The outcomes for this subpopulation were reported over a shorter follow-up window (week 48), reflecting 12 weeks of treatment in the ██████ ███ ███ █████ ██ studies followed by 36 weeks of continued treatment in the ██████ ███ ███ █████ ██ study. Outcomes of interest at week 52 included EASI-75 response, IGA 0 or 1 response, EASI-90 response, and safety outcomes.

MAIC versus dupilumab: The sponsor conducted an unanchored MAIC to estimate the comparative efficacy and safety of lebrikizumab versus dupilumab at week 52. A formal database search to identify eligible studies was not described, as the analysis relied on the single, well-defined dupilumab maintenance evidence source and the available lebrikizumab IPD. The sponsor stated that all included studies were pivotal phase III randomized, double-blind trials and were considered methodologically robust. A formal critical appraisal or risk of bias assessment tool was not reported.

Efficacy and safety results for dupilumab were obtained from public reporting of the SOLO-CONTINUE maintenance study, in which the baseline corresponds to week 16 of treatment. Information on discontinuations due to AEs was supplemented from trial registry records when required. Lebrikizumab outcomes were derived from IPD from the ADvocate 1 and ADvocate 2 trials. To improve comparability across studies, the lebrikizumab IPD were restricted to patients who met the maintenance-phase entry criteria used in the SOLO-CONTINUE study. This included adults who achieved an induction response at week 16 (EASI-75 and/or IGA score of 0 or 1). Outcomes were then assessed through week 52 (week 36 in the SOLO-CONTINUE study). Outcomes of interest at week 52 included EASI-75 response, IGA 0 or 1 response, and safety outcomes. In addition to the MAIC, the sponsor conducted a simulated treatment comparison as a supportive analysis. The simulated treatment comparison was conducted using a binomial regression predicting the outcomes of interest in the IPD from the ADvocate trials.

Analysis Methods of MAICs

For additional information on the MAIC analysis methods, refer to the Supplemental Material document, Appendix 6.

MAICs Versus JAK Inhibitors (Upadacitinib and Abrocitinib)

The sponsor conducted 2 separate unanchored MAICs to compare lebrikizumab with upadacitinib ██████ ███ ███ █████ ██ █████ and abrocitinib ██████ ███ ███ █████ trial of abrocitinib monotherapy LTE study subgroup). An unanchored approach was used because a continuous common comparator (placebo) was not available beyond week 16 across the contributing studies, which precluded anchored indirect comparisons at the approximately 52-week time horizon. Lebrikizumab IPD from the ██████ ███ ███ █████ were reweighted to match the published baseline characteristics of each comparator population using covariates available in aggregate form. Selection of prognostic factors and potential treatment-effect modifiers was informed by a targeted literature search, supplemented by empirical analyses of IPD in the ██████ ███ ███ ███ trials. Because effect modification was difficult to assess at week 52 without a concurrent placebo group, placebo-controlled data at week 16 were used to explore treatment-covariate interactions and main effects, with complementary analyses at week 52 that did not require this distinction. In the base case, the upadacitinib comparison adjusted for age, sex, white race, body mass index, baseline IGA 4 status, baseline EASI, and baseline POEM. The abrocitinib comparison adjusted for age, sex, baseline disease severity (IGA and EASI) scores ██████ ███ ███ studies rerandomized those who responded at week 16, unlike the comparator studies. To align designs, those who did not respond in the ██████ ███ ███ studies were included and assigned a participation weight of 0.8 (reflecting an assumed 20% allocation to placebo), in addition to MAIC weighting.

MAIC Versus Dupilumab

An unanchored MAIC was conducted using lebrikizumab IPD from the ADvocate trials and dupilumab aggregate data from the SOLO-CONTINUE trial. Dupilumab data were derived from publicly available study reporting, with discontinuations due to AEs supplemented from trial registry information when needed. The analysis evaluated maintenance outcomes through week 52. In the SOLO-CONTINUE trial, week 16 functioned as the maintenance baseline because only those who responded in week 16 (EASI-75 and/or IGA score of 0 or 1) entered the maintenance phase. Placebo groups were present in both the ADvocate maintenance phase and the SOLO-CONTINUE study. However, placebo was managed differently after week 16, which limited its suitability as a common comparator and supported the unanchored approach. To improve comparability, a SOLO-CONTINUE–like subset of patients was derived from the ADvocate IPD to align with the week 16 maintenance entry criteria of the SOLO-CONTINUE study. The subpopulation was further restricted to the relevant maintenance regimen for lebrikizumab (250 mg every 4 weeks). Selection of prognostic factors and potential treatment-effect modifiers was informed using 2 approaches: a targeted literature search, and empirical analyses of the SOLO-CONTINUE–like subset of the ADvocate study data to identify candidate prognostic factors. Matching was limited to covariates reported in aggregate form for the SOLO-CONTINUE trial. This included age, sex, and white versus all other races, as well as week 16 EASI and week 16% BSA affected. Sensitivity analyses evaluated alternative severity measures at week 16, including DLQI, POEM, and IGA, when available. The IPD from the ADvocate trials were then reweighted using a propensity score-based MAIC weighting approach to match the SOLO-CONTINUE study baseline characteristics. The dupilumab comparator was the pooled maintenance group in the SOLO-CONTINUE study (dupilumab administered weekly or every 2 weeks).

Summary of Included Studies

MAICs Versus JAK Inhibitors (Upadacitinib and Abrocitinib)

The evidence included the ██████ ███ ███ ████ trials (lebrikizumab), the ██████ ███ ███ ████ trials (upadacitinib) which rerandomized patients to different active treatment doses after week 16, and the ██████ ███ ███ ████ LTE study (abrocitinib). The ██████ ███ ███ ████ trials were phase III, randomized, double-blind trials, whereas the ██████ ███ ███ ████ study was a phase III LTE study. Across studies, efficacy outcomes included EASI-75, EASI-90, and IGA 0 or 1 response, and safety outcomes included TEAEs, serious AEs, and AEs leading to discontinuation. Key sources of heterogeneity included differences in follow-up across the included studies. Outcomes were assessed at week 52 in the ██████ ███ ███ ████ but at week 48 in the abrocitinib monotherapy LTE study subgroup. Additional heterogeneity was observed in outcome measurement (Validated IGA in the ██████ ███ ███ ███ studies rather than IGA) and safety reporting ███████████ ███ ███ █████ ███ ███ ████ incidence rates per 100 person-years and included patients who switched from placebo at week 16). Additionally, trial designs differed meaningfully. ██████ ███ ███ trials rerandomized those who responded to treatment at week 16 to different maintenance regimens (lebrikizumab every 2 weeks, lebrikizumab every 4 weeks), while those who did not respond to treatment continued taking lebrikizumab every 2 weeks. In contrast, patients assigned to active upadacitinib or abrocitinib generally continued their originally assigned regimen, with placebo crossover to active treatment occurring at week 16 in the ██████ ███ ███ ████ trial and week 12 in the ██████ ███ ███ ████ study. Lebrikizumab was administered as an SC injection (500 mg loading dose at baseline and week 2, followed by 250 mg every 2 weeks during induction and 250 mg every 2 or 4 weeks during maintenance), whereas upadacitinib (15 mg or 30 mg once daily) and abrocitinib (100 mg or 200 mg once daily) were administered orally.

Baseline patient characteristics were broadly comparable in terms of age and overall disease severity (refer to the Supplemental Material document, Appendix 6). However, differences in the distribution of key characteristics and, importantly, in the availability of baseline variables across studies informed the matching approach. Reweighting achieved balance on the selected covariates. However, it reduced the effective sample size from ██████ ██ to ██████ ██ for the upadacitinib comparison, and from ██████ ██ to ██████ ██ for the abrocitinib comparison, reflecting imperfect population overlap. MAICs were conducted separately for each binary outcome, with results summarized using absolute effects (RD), relative effects (risk ratio [RR], odds ratio [OR]), and incidence rate ratio.

MAIC Versus Dupilumab

All included studies informing the MAIC versus dupilumab were phase III, randomized, double-blind trials in adults with moderate to severe AD. The analysis used lebrikizumab IPD from the ADvocate 1 and ADvocate 2 trials and published aggregate data for dupilumab from the SOLO-CONTINUE study. The MAIC focused on maintenance outcomes throughout approximately 52 weeks. In the SOLO-CONTINUE study, maintenance eligibility was based on week 16 response (EASI-75 and/or IGA 0 or 1), and week 16 served as the effective baseline for the maintenance population. Outcomes assessed included EASI-75, IGA 0 or 1 response, overall AEs, and discontinuations due to AEs. A formal risk of bias assessment was not reported for the included studies in the sponsor-submitted MAIC report. Key sources of heterogeneity included differences in study structure after week 16 and limitations in the baseline variables available for matching. Although placebo groups were present during maintenance, placebo was handled differently beyond week 16, which supported an unanchored approach. The IPD from the ADvocate trials were restricted to the subset of patients aligned to week 16 maintenance entry criteria in the SOLO-CONTINUE study and to the relevant maintenance regimen.

Baseline characteristics were summarized at week 16 and are presented in the Supplemental Material document, Appendix 6. Matching was limited to covariates available in aggregate for the SOLO-CONTINUE study, including age, sex, white versus all other races, week 16 EASI score, and percent BSA at week 16 ██████████████ █████ ███ ████████████████ █████ ██████████████ █████ ███ ██████████████ ███████████████████ █████ █████████████████ █████ ███ ██ ██ ███ ███████ ██. For each binary outcome, the MAIC reported relative effects using RRs (primary), RDs, and ORs.

Critical Appraisal of MAICs

The sponsor-submitted unanchored MAICs had a number of limitations that challenge the interpretation of the internal and external validity of the findings. In the absence of head to head trials, 2 MAICs were conducted to compare efficacy and safety of lebrikizumab (from the ████████ █ ████ ██████) relative to upadacitinib (████ ███ ███████ ██ █ ███ █ ████████ ███████████ █████ ███ ████ ██████ █████), and dupilumab (from the █████████████ █████). Although the ████████ and ███████ ██ trials were designed to remain blinded, interpretation of longer-term outcomes is limited by postinduction treatment changes. In the ████████ trial, those who responded to treatment were rerandomized at week 16 (including a placebo maintenance group), and in the ███████ ██ trial, patients in the placebo group crossed over to active treatment with upadacitinib at week 16. Abrocitinib results were informed by the ████ ██████ monotherapy LTE following the 12-week ████ ████ trials, in which patients receiving placebo switched to abrocitinib treatment at week 12. These design features may have reduced effective blinding across the trials and could bias study end points. The sponsor-submitted MAICs did not report baseline proportions of prior conventional immunosuppressant exposure, precluding assessment of its impact on comparative estimates.

The sponsor provided an adequate rationale for conducting the MAICs. Eligibility criteria for the MAIC populations were described and were generally consistent with the analysis objective, such as longer-term outcomes at approximately 52 weeks. However, in both MAIC analyses, no systematic review was conducted to identify eligible studies, which increases the risk that relevant data sources (e.g., updated analyses or subgroup publications) were not captured. The sponsor also did not report a formal risk of bias assessment for the included studies. The abrocitinib evidence in the MAIC was restricted to a selected ████ ██████ monotherapy extension subgroup (patients initially randomized to abrocitinib monotherapy who continued abrocitinib without TCS), which may introduce selection bias. In addition, outcomes for this subgroup were assessed at week 48, which does not align with the 52-week time horizon for other comparisons. However, the clinical experts consulted did not consider this difference to be a concern.

Heterogeneity in the inclusion and exclusion criteria, patients baseline characteristics, and outcomes measured in the trials were reported and reviewed by the authors as part of the assessment of feasibility. The methodology for matching and adjustment was in line with NICE Decision Support Unit Technical Support Document 18.³⁸ Unanchored MAICs were conducted, which require the strong assumption that all relevant prognostic factors and treatment-effect modifiers are identified, measured, and adequately adjusted for, because there is no common comparator to mitigate residual confounding. The list of potential treatment-effect modifiers was identified based on a targeted literature review, a clinical expert’s opinion, and supplemented by empirical assessment using lebrikizumab IPD. The clinical experts consulted by CDA-AMC for this review agreed that the adjustment factors were found to be generally reasonable. Prior treatment history could not be adjusted for because it was not available in aggregate data across comparator sources. The clinical experts consulted noted that, although this factor was considered important, its omission was unlikely to introduce meaningful bias.

For the MAIC versus upadacitinib, the final list of factors used in the adjustment included age, sex, white race, body mass index, IGA 4 status at baseline, baseline EASI, and baseline POEM. For the MAIC versus abrocitinib, the base-case adjustment included age, sex, baseline IGA, and baseline EASI. For the MAIC versus dupilumab, matching was based on covariates available for the SOLO-CONTINUE maintenance study population, including age, sex, white versus all other races, as well as EASI and percent BSA at week 16. Further, the sponsor introduced an additional design-alignment assumption by including participants in the ADvocate 1 and ADvocate 2 studies who did not respond to treatment and applying a participation weight (0.8) intended to reflect an assumed placebo allocation. This adds uncertainty because it depends on assumptions that cannot be verified, specifically, how those who did not respond to treatment would have reacted under a placebo-like pathway and whether that aligns with how those who did not respond to treatment and crossover were handled in the comparator trials. Residual differences in prognostic factors and treatment-effect modifiers may not have been fully addressed in the MAIC analyses. However, the direction of any resulting bias remains uncertain.

Several important sources of heterogeneity remain that cannot be fully accounted for through reweighting. In the MAIC versus upadacitinib and abrocitinib, follow-up time points differed, with outcomes assessed at week 52 in the ████████ ███ ███████ ██ trials and at week 48 in the ████ ██████ trial, and the outcome measurement also differed, as the ███████ ██ trials used the Validated IGA rather than IGA used in the other comparator trials. However, the clinical experts consulted indicated that these differences in assessment time points and IGA scale were unlikely to introduce meaningful bias in the comparative estimates. Trial designs also diverged meaningfully after induction. In particular, the ████████ trials rerandomized patients who responded to treatment at week 16 to different maintenance regimens (including every 2 weeks and every 4 weeks), whereas patients receiving active upadacitinib or abrocitinib generally continued their assigned regimen, with placebo crossover occurring to active treatment. These differences cannot be adjusted by weighting. In addition, for the comparison versus upadacitinib, the sponsor relied on publicly available sources and digitized or combined results for some outcomes, which introduces additional risk of extraction error. In the MAIC versus dupilumab, the lebrikizumab evidence was derived from ████████ patients assigned to the recommended maintenance regimen of lebrikizumab 250 mg every 4 weeks over weeks 16 to 52.

The sponsor presented baseline characteristics before and after weighting and reported reductions in ███, indicating imperfect overlap between index and comparator populations. In the MAIC versus JAK inhibitors, ███ █████████ ████ ███ ██ █████ ██████████████ ████ for the upadacitinib comparison and to █████ ██████████████ ████ for the abrocitinib comparison. The reduction in the effective sample size reflects the heterogeneity between the trials among the variables, including in the weighting process. For the MAIC versus dupilumab, matching was limited to covariates available for the SOLO-CONTINUE maintenance population (including demographics and week 16 disease severity measures), and ███ █████████ ████ ███ ██ ████ ██████████████ █████ again reflecting imperfect population overlap and increased uncertainty. Restricting the lebrikizumab population who responded to treatment to a week 16 maintenance subset improves design alignment with the SOLO-CONTINUE study but narrows the estimand and limits generalizability to the full induction population, including patients who do not achieve a response at week 16 or who follow alternative treatment pathways in practice.

In the MAIC versus JAK inhibitors (upadacitinib and abrocitinib), efficacy was assessed using EASI-75, EASI-90, and IGA 0 or 1 response outcomes, while, in the MAIC versus dupilumab, it was assessed using EASI-75 and IGA 0 or 1 response at week 52. Harms in both MAICs were assessed using overall AEs and discontinuations due to AEs up to approximately week 52. In the MAIC versus JAK inhibitors, upadacitinib safety was summarized using incidence rates and included patients who switched from placebo at week 16, which complicates attribution of harms over a nominal 52-week horizon and limits comparability with lebrikizumab maintenance regimens derived from the ████████ ██████. Across both unanchored MAICs at approximately week 52, lebrikizumab may be favoured over abrocitinib 100 mg for EASI-75 and IGA 0 or 1 response and over dupilumab for IGA 0 or 1 response, while most other comparisons and harms remain uncertain due to methodological limitations and imprecision in the effect estimates. Overall, while the sponsor-submitted unanchored MAICs provide longer-term comparative estimates for lebrikizumab over the relative comparators, interpretation is limited by the unanchored design, between-trial heterogeneity, and reductions in effective sample size after weighting.

Efficacy and Harms Results of MAIC Versus JAK Inhibitors (Upadacitinib and Abrocitinib)

Key efficacy results of the MAIC of lebrikizumab 250 mg every 2 weeks or every 4 weeks versus upadacitinib and abrocitinib are summarized in Table 5.

In the analysis at week 52, the effect estimates lebrikizumab was favoured over abrocitinib 100 mg for EASI-75 response (RR = ██████ ███ ███ █████ ██ ███████ IGA 0 or 1 response (RR ██████ ███ ███ █████ ██ ███████ and EASI-90 response (RD = ██████ ███ ███ ████ ██ ██████. For all other comparisons at week 52 across EASI-75, EASI-90, and IGA 0 or 1 responses (relative to upadacitinib 15 mg and 30 mg and abrocitinib 200 mg), the point estimates were imprecise, with 95% CIs including the potential that either lebrikizumab or the comparators could be favoured or that there was no difference between the treatments.

Key safety results of the MAIC versus upadacitinib and abrocitinib are summarized in Table 6. In the analysis of TEAEs at week 52, the effect estimates favoured lebrikizumab versus upadacitinib 30 mg (incidence rate ratio = ██████ ███ ███ █████ ██ ███████ abrocitinib 100 mg (RR = ██████ ███ ███ █████ ██ █████), and abrocitinib 200 mg (RR = ██████ ███ ███ █████ ██ █████). For AEs leading to treatment discontinuation, the effect estimates favoured lebrikizumab over all comparators. For serious AEs, the effect estimates favoured lebrikizumab versus abrocitinib 200 mg. For the remaining comparisons, the effect estimates were imprecise, with 95% CIs including the potential that either lebrikizumab or the comparators could be favoured or that there was no difference between the treatments.

Table 5: Redacted

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Table 6: Redacted

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Efficacy and Harms Results of MAIC Versus Dupilumab

Key efficacy and safety results of the MAIC versus dupilumab are summarized in Table 7.

At week 52, the effect estimates favoured lebrikizumab 250 mg every 4 weeks over dupilumab 300 mg for achieving an IGA 0 or 1 response (RR = 1.334; 95% CI, 1.022 to 1.742). For EASI-75 response and overall AEs, the effect estimates were imprecise, with CIs including the potential that either lebrikizumab or the comparators could be favoured or that there was no difference between the treatments. The supportive simulated treatment comparison results were generally consistent with the corresponding MAIC findings; however, in most analyses, they were slightly more conservative, with point estimates closer to 1.

Table 7: Summary of MAIC Efficacy and Safety Results for Lebrikizumab vs. Dupilumab at Week 52

AE = adverse event; Cl = confidence interval; EASI-75 = at least a 75% reduction in Eczema Area and Severity Index score; IGA = Investigator’s Global Assessment; RR = risk ratio; vs. = versus.

Source: Sponsor-submitted MAIC vs. dupilumab. Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Studies Addressing Gaps in the Systematic Review Evidence

No studies addressing gaps were included in the resubmission.

Discussion

Lebrikizumab was initially reviewed for the treatment of adults with moderate to severe AD and received a recommendation of do not reimburse from CDEC on October 9, 2024. The drug was resubmitted by the sponsor for review on the basis of the availability of new evidence. Based on the evidence from the initial review, CDEC concluded that, in the short-term, treatment with lebrikizumab improved the severity of AD and reduced itch symptoms compared with placebo in adults and adolescents with moderate to severe AD. However, based on the evidence reviewed in the initial meeting and the reconsideration meeting, CDEC could not determine whether lebrikizumab would address the unmet needs of patients because of the uncertainty around the benefit of lebrikizumab versus appropriate comparators and in patients who received prior dupilumab or JAK inhibitor treatment. Additionally, CDEC noted uncertain comparative efficacy evidence due to methodological limitations with the indirect evidence and unknown safety and effects on HRQoL relative to other treatments for AD due to lack of submitted evidence. As well, longer-term safety and efficacy was uncertain because of limitations of the study designs and analysis in the initially submitted evidence.

As such, the sponsor filed a resubmission based on new clinical evidence to address the issues identified by CDEC in the previous recommendation. This report summarizes long-term efficacy and safety data for lebrikizumab in adults with AD from the ADjoin study (N = 1,153). The study was reviewed in the initial submission, but this report includes longer follow-up data for up to 100 weeks from patients who were enrolled in the parent studies. All patients received lebrikizumab every 2 or 4 weeks, alone or in combination with TCS.

The sponsor submitted 3 ITCs: an updated NMA comparing lebrikizumab with upadacitinib, abrocitinib, and dupilumab at week 16; and 2 new MAICs comparing lebrikizumab with upadacitinib, abrocitinib, and dupilumab through week 52.

Efficacy

Input from 2 patient groups received for this review highlighted the key unmet needs for patients with moderate to severe AD, including the need for treatments that reliably reduce itch; improve sleep; prevent flares and complications (including secondary infections); promote rapid skin healing; and restore daily functioning. Clinician groups also emphasized the overall quality of life and ability to maintain normal daily activity, and the clinical experts consulted by CDA-AMC indicated that a clear unmet need for additional therapies that improve both efficacy and tolerability compared to existing treatments for moderate to severe AD still remains.

Clinician groups and the clinical experts consulted by CDA-AMC noted that it is appropriate to use lebrikizumab as first-line advanced therapy in patients with inadequate response to topical therapies. The use of lebrikizumab as first-line advanced therapy was studied in 3 RCTs (ADvocate 1, ADvocate 2, and ADhere), which were previously reviewed and appraised by CDA-AMC in the initial lebrikizumab review. In these studies, lebrikizumab induction therapy showed a clinically relevant improvement in physician-assessed EASI and IGA and reduced patient-reported symptoms of itch relative to placebo at 16 weeks in adults and adolescents with moderate to severe AD who had a history of inadequate response to topical AD therapies. There is high-certainty evidence that lebrikizumab results in an increase in the proportion of patients with IGA response, EASI-75 response, and at least 4-point reduction in Pruritus NRS score at week 16, compared with placebo. There is low-certainty evidence that lebrikizumab may result in a reduction in POEM and DLQI scores at week 16, compared with placebo. The evidence is very uncertain about the effect of lebrikizumab on the change in CDLQI at week 16, compared with placebo.

In the current resubmission review, findings from the ADjoin LTE study suggest that response rate of IGA 0 or 1, EASI-75, and EASI-90 at week 100 in patients receiving lebrikizumab were maintained. The response rates for Pruritic NRS and POEM appeared to be maintained at week 52. However, several methodological considerations, which were similarly highlighted in the initial submission, introduce uncertainty regarding the long-term efficacy results of lebrikizumab. The LTE study data involved an enriched population comprising patients who had previously responded to and tolerated lebrikizumab, suggesting potential selection bias and limiting the applicability of the results to a broader patient population. Multiple design limitations impact interpretation of LTE study results, including the absence of a comparator group and the potential for bias arising from the lack of blinding (patients were blinded to dose) for subjective study outcomes (IGA, EASI, Pruritus NRS, POEM, Sleep Loss score) and missing data. In the absence of a comparator arm, the findings from the efficacy analyses from the LTE remain uncertain, as the noncomparative design does not allow conclusions to be drawn about the comparative efficacy of lebrikizumab versus any comparators for the treatment of moderate to severe AD.

In the absence of controlled head to head trials comparing lebrikizumab with other systemic treatments for AD, the sponsor submitted 3 ITCs in this resubmission: an updated NMA and 2 unanchored MAICs (versus JAK inhibitors and dupilumab). The updated NMA assessed short-term efficacy and safety outcomes through week 16, focusing on additional outcomes in this resubmission: percent change from baseline in EASI and DLQI, as well as safety outcomes. In both the monotherapy and combination-therapy (concurrent TCS) networks, point estimates and 95% CrIs favoured upadacitinib 30 mg daily over lebrikizumab for the change from baseline in EASI. For all other comparisons, the results were associated with wide CrIs, which commonly crossed the null, precluding firm conclusions about which treatment may be favoured. A comparison of lebrikizumab versus upadacitinib for change from baseline in DLQI was not available. Key limitations of the NMA included heterogeneity in trial designs and baseline characteristics, timing of outcome assessments, and variation in the type and intensity of the TCS use, all of which likely contributed to imprecision and reduced confidence in the estimated relative effects of lebrikizumab versus other systemic treatments. The updated NMA was conducted using the same methods as the initially submitted NMA; these limitations were similarly noted in the initial submission.

Two unanchored MAICs evaluated longer-term outcomes through approximately week 52. The MAIC of lebrikizumab versus JAK inhibitors outcomes included EASI-75, EASI-90, IGA score of 0 or 1, and safety outcomes, while the MAIC versus dupilumab outcomes included EASI-75, IGA score of 0 or 1, and safety outcomes. In the MAIC versus JAK inhibitors, lebrikizumab was favoured over abrocitinib 100 mg for key maintenance efficacy outcomes (EASI-75, IGA score of 0 or 1, and EASI-90). In the MAIC of lebrikizumab versus dupilumab, point estimates for IGA score of 0 or 1 favoured lebrikizumab. However, across both MAICs, results for efficacy and harm estimates were imprecise (i.e., wide CIs), precluding definitive conclusions. Confidence in these findings is further limited by important methodological constraints, including residual confounding risk, reductions in effective sample size after weighting, and differences in study design across trials.

In the final recommendation issued in 2024, the committee highlighted an unmet need for treatment options in patients with AD who are refractory to or intolerant of existing biologic therapies, such as dupilumab. However, the clinical trials included in the initial review did not require enrolled patients to have an inadequate response or intolerance to prior biologics or JAK inhibitors, which is the subpopulation identified as having an unmet need. Input received from clinician groups and the clinical experts consulted for the current review anticipated that lebrikizumab would share the same place of therapy as existing biologics (e.g., dupilumab) in the treatment of AD. The input noted the potential use of lebrikizumab as first-line advanced therapy. The input also highlighted that some patients experience refractory disease or intolerance to existing advanced therapy. The clinical experts noted lebrikizumab could be considered for such patients as second-line or subsequent-line advanced therapy, in addition to its potential for first-line use. This evidence gap previously identified by CDEC remains, as no new comparative evidence for the clinical benefit of lebrikizumab in this subpopulation was included in this resubmission.

Harms

The longer-term safety findings from the ADjoin LTE study are uncertain due to several methodological limitations, as previously discussed. Despite these limitations, no new safety signals were identified in LTE study, and the frequency of reported AEs in the LTE study was generally consistent with that observed in the pivotal trials. The updated NMA and MAICs generally favoured lebrikizumab over active comparators for overall AEs, although the aforementioned important methodological limitations limit confidence in these findings.

Ethics and Equity Considerations

Moderate to severe AD is a chronic condition associated with substantial physical, psychological, and social burden, highlighting the ethical importance of access to effective and tolerable treatments. Patient input highlighted the substantial impact of ongoing symptoms and frequent flares of AD on daily functioning, emotional well-being, social participation, and caregiver burden. Patients emphasized the importance of access to treatments for AD that provide sustained symptom control, improve quality of life, minimize AEs, reduce reliance on topical therapies, and are practical and acceptable to use, including concerns related to injectable therapies. Ethical concerns also arise when patients have limited options due to contraindications to JAK inhibitors or reliance on conventional immunosuppressive therapies that carry greater safety risks or require more frequent monitoring than biologics. These treatments may impose disproportionate burdens, such as repeated appointments and laboratory testing, which can pose challenges for both patients and the health care system.

The study populations in the RCTs and LTE study were predominantly white. Representation was lower for other racialized groups: Black or African American (6.4% to 13.6%), Asian (12.4% to 30.1%), and Indigenous (0% to 3.4%). While these proportions appear broadly consistent with the demographic distribution of the population in Canada, the low representation of these racialized groups in the trials may affect generalizability of the efficacy and safety findings for lebrikizumab in these patients. The clinical experts noted that access to phototherapy and specialist care is limited in Canada, particularly in rural and remote regions, where travel burden, time commitment, and availability of services restrict treatment options. Further, although dupilumab is currently the only publicly funded biologic in Canada, access to other advanced therapies such as lebrikizumab is limited for patients without private insurance, raising concerns about socioeconomic inequities and out of pocket costs. For individuals unable to use JAK inhibitors or conventional immunosuppressive therapies, these coverage gaps may further narrow available treatment choices.

Conclusion

Lebrikizumab has previously been reviewed for treatment of moderate to severe AD by CDA-AMC. Following a review of the evidence from the initial submission, including 3 pivotal studies, 1 LTE study, 1 NMA comparing the efficacy and safety of lebrikizumab versus relevant comparators, and 4 studies addressing gaps in evidence, CDEC issued a recommendation not to reimburse on October 9, 2024. Based on evidence from the 3 pivotal studies, lebrikizumab induction therapy showed a clinically relevant improvement in physician-assessed EASI and IGA and reduced patient-reported symptoms of itch relative to placebo at 16 weeks in adults and adolescents with moderate to severe AD who had a history of inadequate response to topical AD therapies. Key reasons for the committee’s recommendation to not reimburse were uncertainty around the benefit of lebrikizumab versus appropriate comparators and in patients who received prior dupilumab or JAK inhibitor treatment in the absence of robust direct and indirect comparative evidence, unknown safety and efficacy on HRQoL relative to other treatments for AD in the absence of evidence, and uncertain longer-term safety and efficacy due to methodological limitations of the available evidence.

As a part of this resubmission, evidence from the LTE (ADjoin study) with a longer duration of follow-up was reviewed, which suggested that the efficacy of patient-important outcomes, including EASI and IGA 0 or 1 response, appeared to be maintained up to 100 weeks. However, the evidence was uncertain due to the open-label, noncomparative design, which precludes firm conclusions on the long-term effects of lebrikizumab. There were no new safety signals from the LTE study, and most common harms were consistent with those reported in the parent trials. The updated NMA showed inconclusive results for lebrikizumab compared with dupilumab and abrocitinib at week 16, with most estimates affected by serious imprecision. The NMA findings suggested that upadacitinib may be favoured over lebrikizumab for percent change from baseline in EASI at week 16. For overall AEs at week 16, results favoured lebrikizumab over comparators in the monotherapy network and generally favoured comparators over lebrikizumab plus TCSs in the combination-therapy network. However, heterogeneity and other methodological limitations introduce uncertainty in the comparative effects. Similarly, the unanchored MAICs suggested that lebrikizumab may be favoured over abrocitinib 100 mg for EASI-75 response, IGA 0 or 1 response, and EASI-90 response, and over dupilumab for IGA 0 or 1 response at week 52. For overall AEs at week 52, results favoured lebrikizumab versus upadacitinib 30 mg and abrocitinib (100 mg and 200 mg). However, these findings were also affected by imprecision and other methodological limitations. Overall, limitations of the NMA and MAICs (e.g., heterogeneity across study methods and populations) result in very low confidence in comparative estimates for lebrikizumab versus upadacitinib, abrocitinib, or dupilumab across efficacy outcomes, HRQoL, and harms, and no definitive conclusions can be drawn.

The current submission sought to address previously identified evidence gaps through the inclusion of LTE study data, an updated NMA with additional outcomes at 16 weeks, and unanchored MAICs for 52 week data. Overall, many methodological limitations and resulting uncertainty identified in the initial review remain relevant to the current submission. Clinical expert input received for this resubmission suggested that lebrikizumab has a place in first-line advanced therapy as well as a potential role in patients with an inadequate response or intolerance to other advanced therapies. The evidence gap in patients with an inadequate response to or intolerance of prior biologics or JAK inhibitors was previously identified by CDEC and remains, as no new comparative evidence for the clinical benefit of lebrikizumab in these patients was included in this resubmission.

Economic Review

Methods

The review team appraised the pharmacoeconomic evidence submitted by the sponsor on the cost-effectiveness and budget impact of lebrikizumab, in combination with TCS, compared to dupilumab 300 mg, upadacitinib (15 mg and 30 mg), and abrocitinib (100 mg and 200 mg) 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 when those therapies are not advisable.

Summary of the Submitted Economic Evaluation

The sponsor submitted a cost-utility analysis to estimate the cost-effectiveness of lebrikizumab, in combination with TCS, from the perspective of a public health care payer in Canada over a lifetime horizon (70 years). The modelled population comprised adults (aged 18 years and older) and adolescents (aged 12 years to younger than 18 years, weighing ≥ 40 kg) with moderate to severe AD and was based on the participants in the ADvocate 1 and ADvocate 2 trials. The sponsor’s base-case analysis included costs related to drug acquisition, administration, disease management, and AEs.

In the sponsor’s base case, lebrikizumab plus TCS was dominated by abrocitinib 100 mg. Apart from dupilumab, lebrikizumab plus TCS was associated with fewer total quality-adjusted life-years than all comparators. Lebrikizumab plus TCS was also more costly than all comparators apart from upadacitinib 30 mg and dupilumab, which was associated with higher total quality-adjusted life-years than lebrikizumab. Additional information about the sponsor’s submission is summarized in the Supplemental Material document, Appendix 10.

CDA-AMC identified several key issues with the sponsor’s analysis (refer to Table 8; full details are provided in the Supplemental Material document, Appendix 11).

Table 8: Key Issues With the Sponsor’s Economic Submission

AD = atopic dermatitis; AE = adverse event; CDA-AMC = Canada’s Drug Agency; ITC = indirect treatment comparison; NMA = network meta-analysis; TCS = topical corticosteroid; vs. = versus.

Note: Full details of the issues identified by CDA-AMC are provided in the Supplemental Material document, Appendix 11.

CDA-AMC Assessment of Cost-Effectiveness

In the absence of head to head trials comparing lebrikizumab with other systemic treatments for AD, the sponsor submitted 3 ITCs: an updated NMA and 2 unanchored MAICs (versus JAK inhibitors and dupilumab). The updated NMA assessed short-term efficacy (i.e., change from baseline in EASI and DLQI) and safety outcomes through week 16, while the MAICs evaluated longer-term outcomes through approximately week 52. According to the updated NMA, in both the monotherapy and combination-therapy (concurrent TCS) networks, point estimates favoured upadacitinib 30 mg daily over lebrikizumab for the change from baseline in EASI. In the MAIC versus JAK inhibitors, point estimates favoured lebrikizumab over abrocitinib 100 mg for key maintenance efficacy outcomes (EASI-75, IGA 0 or 1 response, and EASI-90). In the MAIC versus dupilumab, point estimates favoured lebrikizumab for IGA 0 or 1 response. Across all analyses, results were consistently associated with wide CIs that commonly crossed the null, precluding definitive conclusions about relative efficacy. The updated NMA and MAICs generally favoured lebrikizumab over active comparators for overall AEs, although important methodological limitations limit confidence in these findings. Key limitations identified by the CDA-AMC clinical team included heterogeneity in trial designs and baseline characteristics, timing of outcome assessments, variation in TCS use, residual confounding risk, reductions in effective sample size after weighting in the MAICs, and differences in study design across trials. These methodological constraints and the substantial imprecision in effect estimates precluded conclusions on the comparative effectiveness and safety of lebrikizumab compared to dupilumab, upadacitinib (15 mg and 30 mg), and abrocitinib (100 mg and 200 mg) 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 when those therapies are not advisable.

Key efficacy inputs for the economic model were derived from the sponsor-conducted NMA, with treatment response defined as EASI-75 at week 16. According to the Clinical Review, there was insufficient evidence to show a difference between lebrikizumab plus TCS and any comparator for EASI-75 response at week 16. In the sponsor's economic analysis, lebrikizumab was dominated (i.e., more costly and less effective) and did not appear on the cost-effectiveness frontier. Given the uncertainty in comparative effectiveness and safety, the cost-effectiveness of lebrikizumab plus TCS compared to dupilumab plus TCS, upadacitinib (15 mg and 30 mg) plus TCS, and abrocitinib (100 mg and 200 mg) plus TCS is highly uncertain. If decision-makers determine there are no differences in health outcomes between lebrikizumab and relevant comparators, then the total cost of lebrikizumab plus TCS to the health system should not exceed that of the least costly advanced treatment for the indicated population.

Summary of the Budget Impact

The sponsor submitted a budget impact analysis to estimate the 3-year (2027 to 2029) budget impact of reimbursing lebrikizumab for use in the treatment of adult and adolescent patients aged 12 years and older with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The sponsor assumed that the payer would be CDA-AMC–participating public drug plans and derived the size of the eligible population using an epidemiologic approach. The price of lebrikizumab was aligned with the price included in the sponsor’s economic evaluation, while the prices of comparators were based on the publicly available list prices. Additional information pertaining to the sponsor’s submission is provided in the Supplemental Material document, Appendix 12.

CDA-AMC identified a number of issues with the sponsor’s estimated budget impact and made changes to model parameters and assumptions in consultation with clinical experts to derive the CDA-AMC base case (refer to the Supplemental Material document, Appendix 12). CDA-AMC estimated that by year 3 of reimbursement, 83,239 patients would be eligible for lebrikizumab; of these, 6,576 patients are expected to receive lebrikizumab. The estimated incremental budget impact of reimbursing lebrikizumab is predicted to be approximately $127 million over the first 3 years, with an expected expenditure of $472 million on lebrikizumab. The actual budget impact will depend on the market share of relevant comparators.

Conclusion

Based on the Clinical Review, limitations of the NMA and MAICs (e.g., heterogeneity across study methods and populations) result in very low confidence in comparative estimates for lebrikizumab versus upadacitinib, abrocitinib, or dupilumab across efficacy outcomes, HRQoL, or harms, and no definitive conclusions can be drawn. In the sponsor’s economic analysis, lebrikizumab was dominated and did not appear on the cost-effectiveness frontier. Given the uncertainty in the clinical evidence, the cost-effectiveness of lebrikizumab plus TCS compared with dupilumab plus TCS, upadacitinib (15 mg and 30 mg) plus TCS, and abrocitinib (100 mg and 200 mg) plus TCS in the indicated population is uncertain. If decision-makers determine there are no differences in health outcomes between lebrikizumab plus TCS and relevant comparators, then the total cost of lebrikizumab plus TCS to the health system should not exceed that of the least costly advanced treatment for the indicated population.

The budget impact of reimbursing lebrikizumab to the public drug plans in the first 3 years is estimated to be approximately $127 million. The 3-year expenditure on lebrikizumab (i.e., not accounting for current expenditure on comparators) is estimated to be $472 million. The estimated budget impact is highly uncertain due to uncertainty in the market share of relevant comparators.

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