Drugs, Health Technologies, Health Systems
Indication: As an add-on maintenance treatment in adult patients with chronic obstructive pulmonary disease (COPD) characterized by raised blood eosinophils inadequately controlled by the combination of an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), or on a combination of a LABA and a LAMA if ICS is not appropriate
Sponsor: Sanofi-Aventis Canada Inc.
Final recommendation: Reimburse with conditions
Summary
What Is the Reimbursement Recommendation for Dupixent?
Canada’s Drug Agency (CDA-AMC) recommends that Dupixent should be reimbursed by public drug plans as an add-on maintenance treatment in adult patients with chronic obstructive pulmonary disease (COPD) characterized by raised blood eosinophils inadequately controlled by the combination of an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), or on a combination of a LABA and a LAMA if ICS is not appropriate, if certain conditions are met.
Which Patients Are Eligible for Coverage?
Dupixent should only be covered to treat adults diagnosed with COPD who have obstructed airflow confirmed by lung function testing, whose disease has been stable while receiving optimized inhaler therapy for at least 3 months, who have experienced at least 2 moderate COPD exacerbations or 1 severe exacerbation within the past 12 months (with at least 1 occurring after the patient had been receiving optimized inhaler therapy for 3 months), and who have elevated blood eosinophil levels. Optimized inhaler therapy must consist of ICS, LABA, and LAMA combination therapy or a LABA in combination with a LAMA if the use of an ICS is inappropriate.
What Are the Conditions for Reimbursement?
Dupixent should be prescribed by, or in consultation with, a respirologist. Dupixent should only be reimbursed if the cost of Dupixent is reduced.
Why Did CDA-AMC Make This Recommendation?
Evidence from 2 clinical trials showed that Dupixent, when added to optimized inhaler treatment, reduced the number of moderate or severe COPD exacerbations compared with placebo in adults with COPD who had elevated blood eosinophil levels and continued to have exacerbations despite optimized inhaler treatment.
Dupixent meets the need for an effective treatment that reduces the number of moderate or severe COPD exacerbations when used as an add-on treatment to optimized inhaler therapy in adults with uncontrolled COPD characterized by elevated blood eosinophil levels.
Based on the CDA-AMC assessment of the health economic evidence, Dupixent does not represent good value to the health care system at the public list price. A price reduction is therefore required.
Based on public list prices, Dupixent is estimated to cost the public drug plans approximately $576 million over the next 3 years. At the submitted price, the economic feasibility of adoption must be addressed.
Additional Information
What Is COPD?
COPD is a chronic lung disease that makes it hard to breathe and gets worse over time, causing symptoms like breathlessness, cough, and fatigue and leading to exacerbations that can severely affect daily activities and may require hospitalization. In some patients, a type of airway inflammation called type 2 inflammation is present and is linked to more frequent exacerbations and poorer outcomes. COPD is common in adults aged older than 40 years, affecting about 9% of people aged 35 years or older in Canada, and it is 1 of the leading causes of death worldwide.
Unmet Needs in COPD
Many people with COPD continue to have exacerbations and troubling symptoms even when using optimized inhaler treatment, and no current therapy can stop or reverse the progression of the disease. There is a need for treatments that better prevent exacerbations and improve breathing, daily functioning, and the ability to work for patients whose COPD remains uncontrolled while receiving optimized inhaler therapy.
How Much Does Dupixent Cost?
Treatment with Dupixent is expected to cost approximately $27,078 per patient annually.
The Canadian Drug Expert Committee (CDEC) recommends that dupilumab be reimbursed as an add-on maintenance treatment in adult patients with COPD characterized by raised blood eosinophils inadequately controlled by the combination of an ICS, a LABA, and a LAMA, or on a combination of a LABA and a LAMA if ICS is not appropriate, only if the conditions listed in Table 1 are met.
Two double-blind, phase III randomized controlled trials (RCTs) (the BOREAS trial [N = 939] and the NOTUS trial [N = 935]) demonstrated that in adult patients with COPD characterized by elevated blood eosinophil levels (≥ 300 cells/µL) and moderate to severe airflow obstruction despite receiving triple inhaler therapy (an ICS, a LABA, and a LAMA) or dual inhaler therapy (a LABA and a LAMA) if an ICS is not appropriate, dupilumab treatment for 52 weeks resulted in a clinically meaningful reduction in the rate of moderate or severe COPD exacerbations compared to placebo, when used in addition to best supportive care. In the 2 trials, the adjusted annualized rate of moderate or severe COPD exacerbations over the 52-week intervention period was lower in the dupilumab group compared with the placebo group. In the BOREAS trial, the annualized rate of moderate or severe COPD exacerbations was 0.78 (95% CI, 0.64 to 0.93) in the dupilumab group versus 1.10 (95% CI, 0.93 to 1.30) in the placebo group with a relative risk (RR) of 0.70 (95% CI, 0.58 to 0.86; P < 0.001). In the NOTUS trial, the annualized rate of moderate or severe COPD exacerbations was 0.86 (95% CI, 0.70 to 1.06) in the dupilumab group versus 1.30 (95% CI, 1.05 to 1.60) in the placebo group with an RR of 0.66 (95% CI, 0.54 to 0.82; P < 0.001). Furthermore, dupilumab was well tolerated and no new safety concerns were identified.
Patients identified a need for additional COPD treatments that reduce symptoms and exacerbations, improve lung function, slow or prevent disease progression, minimize side effects, and improve health-related quality of life (HRQoL). CDEC concluded that dupilumab meets their need for a drug that reduces moderate or severe COPD exacerbations and has manageable side effects.
Using the sponsor-submitted price for dupilumab and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio for dupilumab as an add-on to background therapy was $720,337 per quality-adjusted life-year (QALY) gained compared with background therapy alone. At this incremental cost-effectiveness ratio, dupilumab as an add-on to background therapy is not cost-effective at a $50,000 per QALY gained willingness-to-pay threshold for adults with COPD characterized by raised blood eosinophils inadequately controlled by the combination of an ICS, a LABA, and a LAMA, or on a combination of a LABA and a LAMA if ICS is not appropriate. A price reduction is required for dupilumab as an add-on to background therapy to be considered cost-effective at a $50,000 per QALY gained threshold.
Table 1: Reimbursement Conditions and Reasons
Reimbursement condition | Reason | Implementation guidance |
|---|---|---|
Initiation | ||
1. Dupilumab should be reimbursed only if all the following conditions are met: 1.1. adult diagnosed with COPD 1.2. postbronchodilator FEV1:FVC ratio < 0.70, and postbronchodilator FEV1 predicted to be ≤ 70% 1.3. their disease has been stabilized for at least 3 months while receiving continuous, optimized background therapy consisting of either ICS, LABA, and LAMA combination therapy or a LABA in combination with a LAMA if an ICS is contraindicated; patients must have a documented history of ≥ 2 moderate COPD exacerbations or ≥ 1 severe exacerbation within the past 12 months, and at least 1 of these moderate or severe exacerbations must have occurred after the patient completed the 3-month stabilization period on optimized background therapy 1.4. blood eosinophil count ≥ 300 cells/µL (0.3 × 109/L). | The BOREAS and NOTUS trials demonstrated that when used in addition to best supportive care, dupilumab resulted in clinically meaningful benefits compared to placebo in adult patients with COPD characterized by elevated blood eosinophil levels inadequately controlled by the combination of an ICS, a LABA, and a LAMA or by a combination of a LABA and a LAMA if ICS is not appropriate, as per the characteristics outlined. | Condition 1.1: The BOREAS trial included patients aged 40 to 80 years and the NOTUS trial included patients aged 40 to 85 years. While there was insufficient evidence to support the use of dupilumab for the treatment of COPD in adults outside these age ranges, CDEC considered it appropriate to allow reimbursement of dupilumab in adults aged 18 years or older based on the treating physician’s clinical judgment. Condition 1.2: Spirometry is predominantly performed in specialty respiratory clinics or hospitals; therefore, there may be limitations in access to this test for some patients. Patients with postbronchodilator FEV1 predicted to be ≤ 30% were excluded from the pivotal trials. CDEC considered clinical expert input and noted that it is appropriate to allow reimbursement of dupilumab in these patients based on the treating physician’s clinical judgment. Condition 1.3: As per the trials, moderate exacerbation is defined as an AECOPD that requires either systemic corticosteroids (intramuscular, IV, or oral) and/or antibiotics. Severe exacerbation is defined as an AECOPD requiring hospitalization or observation for > 24 hours in an emergency department or urgent care facility. If ICSs are contraindicated, not tolerated, or considered inappropriate, background therapy should consist of LABA plus LAMA combination therapy. An ICS may be considered inappropriate for patients with conditions such as intractable dysphonia, recurrent Candida infections, or frequent lower respiratory tract infections or in those at high risk for pneumonia or bacterial colonization of the airway. Condition 1.4: This is based on blood eosinophil counts performed in the past 12 months. |
2. A baseline assessment of the number and severity of COPD exacerbation in the past 12 months must be completed before initiation of dupilumab treatment. | A baseline assessment of the number and severity of COPD exacerbations is needed to assess response to therapy. | — |
Renewal | ||
3. The effects of dupilumab should be assessed every 12 months to determine whether reimbursement should continue. | This allows sufficient time for patients and clinicians to assess response. | — |
4. For renewal after initial authorization, reimbursement of dupilumab should be renewed if there are any of the following: 4.1. a reduction in the number of moderate or severe COPD exacerbation within the previous 12 months compared to the baseline, unless the lack of a reduction is explained by a medical comorbidity 4.2. a reduction in the severity of COPD exacerbations despite the same number of COPD exacerbations within the previous 12 months compared to the baseline, unless the lack of a reduction is explained by a medical comorbidity. | The BOREAS and NOTUS trials demonstrated that dupilumab treatment resulted in a clinically meaningful reduction in the annualized rate of moderate or severe exacerbations compared to placebo at 52 weeks, when used in addition to best supportive care. | Determination of whether COPD exacerbations are attributable to a medical comorbidity (e.g., respiratory tract infection) should be based on the treating physician’s clinical judgment. |
5. For subsequent renewal, the physician must provide proof that there has been no increase in the number of moderate or severe COPD exacerbations within the previous 12 months compared to baseline, unless any such increase is explained by a medical comorbidity. | To account for the progressive nature of COPD such that patients may continue to experience exacerbations despite receiving optimized therapy over time. | — |
Prescribing | ||
6. Dupilumab should be prescribed by or in consultation with a respirologist. | This ensures that dupilumab is prescribed only for appropriate patients and adverse effects are managed in an optimized and timely manner. | CDEC noted that in communities with limited access to respirologists, physicians with expertise in treating COPD may need to be considered by jurisdictions to prescribe dupilumab. |
Pricing | ||
7. A reduction in price. | The ICER for dupilumab as an add-on to background therapy is $720,337 per QALY gained compared to background therapy only. A price reduction of at least 90% would be required for dupilumab used in combination with background therapy to achieve an ICER of $50,000 per QALY gained compared to background therapy only. | — |
Feasibility of adoption | ||
8. The economic feasibility of adoption of dupilumab as an add-on to background therapy must be addressed. | At the submitted price, the incremental budget impact of dupilumab as an add-on to background therapy is expected to be greater than $40 million after the first year of funding. | — |
AECOPD = acute exacerbation of COPD; BD = bronchodilator; CDEC = Canadian Drug Expert Committee; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in the first second; FVC = forced vital capacity; ICER = incremental cost-effectiveness ratio; ICS = inhaled corticosteroid; LABA = long-acting beta2-agonist; LAMA = long-acting muscarinic antagonist; QALY = quality-adjusted life-year.
Reconsideration request: The sponsor and the public drug plans requested a minor reconsideration of the initial draft recommendation to reimburse dupilumab with conditions for the treatment of COPD. During the minor reconsideration discussion, a subpanel of the committee discussed the issues raised by the sponsor and the drug plans in their request for reconsideration. The sponsor proposed changes to the renewal criteria and implementation guidance related to the initiation criteria. The drug plans proposed changes to the initiation and prescribing criteria, as well as to the corresponding implementation guidance. CDEC also discussed feedback from patient groups, clinical groups, and the clinical experts consulted by CDA-AMC on the initial draft recommendation.
Unmet needs: CDEC discussed that no current treatment can fully eliminate COPD exacerbations, an important outcome identified by patients and clinicians. There is an unmet need for treatment in patients with COPD who continue to experience exacerbations despite receiving triple inhaler therapy with an ICS, a LABA, and a LAMA or dual inhaler therapy with a LABA and a LAMA if an ICS is not appropriate. Dupilumab is the first advanced therapy approved as an add-on maintenance treatment for adult patients with COPD characterized by elevated blood eosinophil levels inadequately controlled by the combination of an ICS, a LABA, and a LAMA or by a combination of a LABA and a LAMA if an ICS is not appropriate. Based on the submitted evidence, CDEC concluded that dupilumab meets the need for an effective treatment for reducing moderate or severe COPD exacerbations compared to placebo when used as an add-on treatment to triple or dual inhaler therapy in adults with uncontrolled COPD characterized by elevated blood eosinophil levels.
Efficacy: CDEC discussed that evidence from the BOREAS and NOTUS trials was of high certainty (as assessed using Grading of Recommendations Assessment, Development and Evaluations [GRADE] methodology) and that dupilumab results in a clinically important decrease in the annualized rate of moderate or severe COPD exacerbations compared with placebo when used as an add-on treatment. There is moderate certainty evidence that dupilumab likely results in little to no clinically meaningful difference in lung function at weeks 12 or 52 (as assessed using prebronchodilator forced expiratory volume in the first second [FEV1]) or in HRQoL at week 52 (as assessed using St. George’s Respiratory Questionnaire [SGRQ] scores) when compared to placebo.
Comparative evidence: No direct or indirect comparative evidence for the efficacy and safety of dupilumab versus other add-on COPD therapies available in clinical practice was submitted. CDEC discussed that roflumilast and azithromycin may be used as add-on maintenance treatments for patients with uncontrolled COPD despite the use of triple inhaler therapy in clinical practice, but they are associated with limited efficacy and safety concerns. CDEC noted that the appropriate place in therapy of dupilumab relative to roflumilast and chronic azithromycin as an add-on treatment is unclear. It is unknown whether dupilumab offers a benefit compared with azithromycin or roflumilast as an add-on treatment in the absence of comparative evidence. CDEC considered input from clinical experts consulted for this review that there are no appropriate comparators to dupilumab as add-on treatments for COPD. Based on the placebo-controlled RCT evidence, the committee considered that dupilumab meets the unmet needs highlighted in the treatment of COPD.
Long-term safety: Harms results for up to 52 weeks were available from the BOREAS and NOTUS trials. CDEC discussed that the adverse events (AEs) associated with dupilumab appeared to be manageable and were consistent with the known safety profile of dupilumab in treating other disease states based on the 52-week RCT results. Further, the evidence suggests that dupilumab may result in little to no difference in the proportions of patients with treatment-emergent AEs (TEAEs) of special interest (e.g., clinically symptomatic eosinophilia, severe injection site reactions) when compared with placebo at week 52. However, the committee discussed that a longer duration of follow-up is needed to adequately capture the long-term safety profile of dupilumab in patients with COPD, particularly for rare AEs (e.g., helminth infections).
Initiation of treatment: In reviewing the reconsideration requests, the CDEC subpanel discussed whether patients with postbronchodilator FEV1 predicted to be less than 30% should be eligible for dupilumab treatment. The subpanel noted that the efficacy and safety of dupilumab in these patients are unknown because these patients were excluded from the pivotal trials. However, the subpanel recognized that patients with very low lung function are among those at highest risk for poor outcomes with exacerbations. The subpanel also acknowledged that according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) clinical practice guidelines, the choice of treatment is determined by exacerbation history and symptoms rather than severity of airflow limitation. Therefore, the subpanel considered it reasonable to allow reimbursement for this subpopulation of patients. Further, the subpanel discussed revisions to the initiation criteria to clarify the original intent of the committee and the addition of implementation guidance related to contraindications to ICS and the baseline assessment of COPD exacerbations.
Renewal of treatment: In reviewing the reconsideration requests, the CDEC subpanel discussed whether treatment response should be assessed based on the number of COPD exacerbations relative to the prior year or relative to baseline. The subpanel discussed that there is limited evidence from the submission to guide treatment discontinuation. Input from the clinical experts and feedback from patients and clinicians emphasized that COPD is a progressive disease and exacerbation frequency fluctuates, and applying a year-to-year comparison may risk premature discontinuation for patients who have achieved and maintained a clinically meaningful response. For renewal after initial authorization, the subpanel considered it reasonable to renew reimbursement if there is a decrease in the number of moderate or severe COPD exacerbations within the previous 12 months compared to baseline, unless the lack of a decrease is explained by a comorbidity. Further, the subpanel acknowledges that some patients may experience the same number of moderate or severe exacerbations in the previous year compared to baseline but with reduced severity of exacerbations; these patients should remain eligible for renewal of reimbursement. This approach aligns with the input received from the clinical experts regarding what constitutes a clinically meaningful response. For subsequent renewal, the subpanel considered it reasonable to renew reimbursement if there is no increase in the number of moderate or severe COPD exacerbations within the previous 12 months compared to the baseline. This is to acknowledge that COPD is a progressive disease in which exacerbations may continue to occur despite optimized therapy.
Prescribing condition: In considering the reconsideration requests, the CDEC subpanel discussed whether dupilumab should be prescribed by, or in consultation with, a respirologist. The sponsor input and the patient group input raised concerns that requiring respirologist involvement could delay access, particularly in regions with limited specialist availability. However, to support appropriate prescribing and the ongoing management of patients receiving dupilumab, the subpanel felt that respirologist oversight is appropriate. This position was supported by clinical expert input and clinician group feedback. The subpanel acknowledged that access to respirologists varies in Canada. In communities with limited access to respirologist care, the subpanel considered it reasonable to allow physicians with expertise in treating COPD to prescribe dupilumab.
Uncertainty in the health economic analysis: The economic analysis assumes a mortality benefit associated with the reduction of exacerbations based on real-world evidence. However, the committee noted that based on evidence from the BOREAS and NOTUS trials alone, there is no evidence of a mortality benefit associated with dupilumab. Given the absence of robust evidence, the link between dupilumab and a reduction in mortality for patients with COPD is uncertain. The economic analysis may therefore overestimate the benefit of dupilumab.
COPD is a progressive inflammatory lung condition characterized by airflow obstruction, hyperinflation, and systemic effects, often associated with chronic bronchitis and emphysema. It manifests with dyspnea, wheezing, cough, sputum production, fatigue, and activity limitation, with exacerbations leading to worsened lung function, increased morbidity, and substantial health care costs. COPD affects approximately 8.7% of Canadians aged 35 years or older. COPD is associated with comorbidities such as cardiovascular disease, osteoporosis, malnutrition, and metabolic syndrome, and up to 40% of patients exhibit type 2 inflammation — characterized by elevated blood eosinophil levels — which correlates with worse outcomes. Standard therapy aims to reduce symptoms, prevent exacerbations, improve quality of life, and extend survival. Nondrug interventions such as smoking cessation, pulmonary rehabilitation, and noninvasive ventilation play critical roles in improving outcomes, but they remain underutilized due to accessibility challenges. Pharmacologic treatment follows guideline-based recommendations, with mild cases managed using a single inhaled LAMA or LABA. Patients with moderate to severe disease receive dual bronchodilator therapy (a LABA and a LAMA) if they are at low risk for exacerbations, while those at high risk require triple therapy with an ICS, a LABA, and a LAMA. Additional therapies such as macrolides and roflumilast are reserved for specific populations, though concerns regarding antibiotic resistance and adverse effects limit their widespread use. Despite available treatments, COPD exacerbations remain common, and no currently approved therapies have demonstrated a significant reduction in exacerbations for patients already receiving triple therapy.
Dupilumab received a Notice of Compliance on October 21, 2025, from Health Canada “as an add-on maintenance treatment in adult patients with COPD characterized by raised blood eosinophils inadequately controlled by the combination of an ICS, a LABA, and a LAMA, or on a combination of a LABA and a LAMA if ICS is not appropriate.” Dupilumab is a recombinant human monoclonal immunoglobulin G4 monoclonal antibody that inhibits interleukin (IL)-4 and IL-13 and both IL-4 and IL-13 signalling through the type II receptor (IL-4R-alpha and IL-13R-alpha). It is available as a 300 mg per 2 mL single-use syringe or pen for subcutaneous (SC) injection, and the dosage recommended in the product monograph is 300 mg by SC injection once every 2 weeks.
To make its recommendation, the committee considered the following information:
a review of 2 phase III, placebo-controlled RCTs in adult patients with COPD characterized by elevated blood eosinophil levels inadequately controlled by the combination of an ICS, a LABA, and a LAMA or by the combination of a LABA and a LAMA if an ICS is not appropriate
patients’ perspectives gathered by 2 patient groups, the Chronic Obstructive Pulmonary Disease Association (COPD Canada) and the Lung Health Foundation
input from public drug plans that participate in the reimbursement review process
2 clinical specialists with expertise diagnosing and treating patients with COPD
input from 1 clinician group, the Canadian Thoracic Society
a review of the pharmacoeconomic model and report submitted by the sponsor
information submitted as part of the sponsor and the drug plans’ request for reconsideration (described subsequently)
feedback on the draft recommendation.
Two patient groups, COPD Canada and the Lung Health Foundation, provided input for this review. COPD Canada gathered responses from an email survey conducted in November 2024 with 61 participants, while the Lung Health Foundation collected data through an online survey of 27 patients across Canada conducted between December 2022 and December 2024, along with additional feedback from 7 individuals in Ontario. None of the patients had experience with the drug under review. Both groups highlighted the substantial burden of COPD on daily life, with effects on fundamental activities such as breathing, working, and socializing. Shortness of breath, fatigue, and coughing were among the most debilitating symptoms, leading to difficulties in performing routine tasks and contributing to feelings of isolation. Patients emphasized the need for treatments that alleviate physical symptoms while improving overall quality of life. While current therapies offer some benefits (such as reduced shortness of breath and improved exercise capacity), residual symptoms and side effects remain problematic. The input underscored the need for additional COPD treatments that minimize side effects, enhance treatment outcomes, and improve quality of life. Access to medications through public drug plans was also identified as a crucial concern for many older patients.
The clinical experts consulted for this review highlighted that despite the availability of triple therapy with an ICS, a LABA, and a LAMA, many patients with COPD continue to experience exacerbations, and no current treatment fully eliminates them. According to the clinical experts, COPD remains a progressive disease with irreversible lung damage, and while smoking cessation and pulmonary rehabilitation offer some benefits, they do not halt disease progression. Poor inhaler technique, disease severity, and comorbidities often limit the real-world effectiveness of inhaled medications, leading to suboptimal treatment adherence and symptom control. The clinical experts noted that given these limitations, there is an unmet need for additional therapies that improve exacerbation prevention, symptom relief, and long-term treatment adherence. Dupilumab is considered an add-on therapy for patients who continue to experience exacerbations despite optimal inhaler therapy. It targets type 2 inflammation — characterized by elevated blood eosinophil levels — through systemic effects, complementing rather than replacing current treatments. The clinical experts emphasized that dupilumab should be reserved for patients with type 2 inflammation who remain at high risk for exacerbations despite triple therapy, aligning with clinical trial criteria.
The clinical experts suggested that the ideal patient population for dupilumab includes those with COPD and type 2 inflammation, particularly those with eosinophil levels of at least 300 cells/µL and a history of moderate to severe exacerbations. The clinical experts emphasized the importance of spirometry to confirm the COPD diagnosis, as misdiagnosis rates are high. According to the clinical experts, treatment response is primarily assessed by reductions in the number or severity of exacerbations, improvement in quality of life, symptom relief, and improvements in functional capacity. The clinical experts noted that a lack of reduction in the number of exacerbations within a year, unless this is attributed to a comorbidity, may indicate a lack of benefit, though improvements in validated COPD measures may still justify continued treatment. According to the clinical experts, discontinuation should also be considered when serious adverse effects occur. Dupilumab should be prescribed by respiratory specialists to ensure appropriate patient selection and monitoring occur.
One group, the Canadian Thoracic Society, provided input for this review, with a total of 5 clinicians contributing. In alignment with the clinical experts consulted for this review, the clinician group emphasized preventing exacerbations, improving symptoms, and optimizing treatment for patients with COPD. Also, the clinician group aligned with the clinical experts in identifying unmet needs, highlighting the importance of phenotyping patients with COPD to personalize treatment, and recognizing the need for additional therapies for those experiencing exacerbations despite optimized inhaled therapy. Both groups agreed that dupilumab should be reserved for patients with type 2 inflammation, specifically those with blood eosinophil counts of 300 cells/µL or higher, and prescribed by respirologists managing COPD.
The clinician group stated that dupilumab would be the first biologic therapy available for COPD and could represent a paradigm shift by providing a targeted approach for patients with persistent exacerbations. They recommended that patients receive at least 6 months of treatment before considering discontinuation unless side effects necessitate earlier cessation. Additionally, they advised that the first doses should be administered in a clinical setting to ensure proper technique and patient tolerance, with subsequent doses potentially given at home.
Input was obtained from the drug programs that participate in the reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a recommendation for dupilumab:
relevant comparators
considerations for initiation of therapy
considerations for continuation or renewal of therapy
considerations for discontinuation of therapy
considerations for prescribing of therapy
generalizability of trial populations to the broader populations in the jurisdictions
system and economic issues.
The clinical experts consulted for the review provided advice on the potential implementation issues raised by the drug programs (refer to Table 2).
Table 2: Responses to Questions From the Drug Programs
Drug program implementation questions | Clinical expert response |
|---|---|
Relevant comparators | |
The efficacy and safety of dupilumab were assessed in 2 multinational, randomized, double-blind, placebo-controlled, phase III trials (the BOREAS and NOTUS trials). Each trial was designed and conducted to investigate the efficacy and safety of dupilumab 300 mg administered by SC injection every 2 weeks over 52 weeks in patients with uncontrolled COPD (i.e., ≥ 2 moderate exacerbations or ≥ 1 severe exacerbation in the previous year and MRC Dyspnoea Scale grade ≥ 2, with higher grades indicating greater symptom severity) and moderate to severe airflow obstruction (i.e., postbronchodilator FEV1 > 30% to ≤ 70% of predicted) despite receiving maximum best supportive care background therapy, including an ICS, a LABA, and a LAMA (unless ICSs were contraindicated). The primary end point of both trials was the annualized rate of AECOPD over the 52-week treatment period compared to placebo. In both studies, dupilumab 300 mg every 2 weeks led to a significant and clinically relevant reduction in the annualized rate of moderate or severe AECOPD during the 52-week intervention period (a 30% reduction in the BOREAS trial and a 34% reduction in the NOTUS trial compared with placebo). The key secondary end points were prebronchodilator FEV1 over 12 weeks compared to placebo; HRQoL, assessed by the change from baseline to week 52 in SGRQ scores and evaluating respiratory symptoms; and changes in prebronchodilator FEV1 over 52 weeks compared to placebo. Both trials were placebo controlled. The trials did not compare dupilumab add-on therapy to add-on therapy with azithromycin, N-acetylcysteine, or roflumilast.a | This is a comment from the drug plans to inform CDEC deliberations. According to the clinical experts, azithromycin, though used to reduce exacerbations, is an off-label treatment, poses risks such as QTc prolongation and antibiotic resistance, and does not target underlying inflammation. Roflumilast, a PDE4 inhibitor, is limited by modest efficacy, GI intolerance, and lack of reimbursement by the jurisdictions. While other biologic drugs like benralizumab, mepolizumab, and tezepelumab have been studied in COPD, none have demonstrated substantial clinical benefits. The clinical experts noted that there is no evidence to show that N-acetylcysteine confers benefit when added on to contemporary first-line COPD therapy, and it is rarely used in this context in clinical practice in Canada. The clinical experts commented that there are no appropriate comparators to dupilumab for COPD treatment. |
Roflumilast is not covered by any jurisdictions in Canada; however, roflumilast is rarely used and may not be considered a relevant comparator. | This is a comment from the drug plans to inform CDEC deliberations. The clinical experts noted that roflumilast is not a relevant comparator of dupilumab for patients with uncontrolled COPD associated with type 2 inflammation, characterized by elevated blood eosinophil levels. |
Considerations for initiation of therapy | |
Inclusion criteria for the BOREAS and NOTUS trials were:
Drug program implementation questions:
| The clinical experts suggested that not all inclusion criteria from the trials should be required for dupilumab eligibility in clinical practice, and there are no other parameters to consider. According to the clinical experts, the key considerations are as follows:
CDEC agreed with the clinical experts that smoking history, MRC Dyspnoea Scale grade, and presence of chronic bronchitis symptoms should not be required for the reimbursement of dupilumab treatment. CDEC noted that there is no evidence to support the efficacy of dupilumab in patients who have baseline postbronchodilator FEV1 predicted to be ≤ 30% or ≥ 70%. Nonetheless, CDEC noted that it is reasonable to allow reimbursement of dupilumab with postbronchodilator FEV1 predicted to be ≤ 70%. The committee noted that type 2 inflammation should be determined based on a blood eosinophil count of ≥ 300 cells/μL, as per trial design. |
Would dupilumab be considered in patients who fall outside the target populations of the clinical trials (e.g., those with a history of or a current diagnosis of asthma, those outside the age ranges used in trials)? | The clinical experts suggest that dupilumab could be considered for patients outside the strict inclusion criteria of the BOREAS and NOTUS trials. The clinical experts noted the following conditions should not preclude treatment of COPD with dupilumab: a history or current diagnosis of asthma, as type 2 inflammation remains the key factor for treatment response; age; and low FEV1. While an FEV1 > 70% may raise concerns, exceptions could be made for patients with emphysema-dominant COPD, such as those with alpha-1 antitrypsin deficiency. According to the clinical experts, given that dupilumab is already approved in Canada for asthma, patients with COPD with asthma-COPD overlap may already qualify for treatment. Other trial criteria that are not directly tied to dupilumab’s mechanism of action or to the clinical phenotype most likely to benefit (i.e., age and FEV1 thresholds) should not necessarily restrict treatment eligibility. CDEC agreed with the clinical experts that adult patients outside of the age ranges of patients included in the trials and patients with a history or current diagnosis of asthma should not be precluded from reimbursement of dupilumab treatment. CDEC noted there is no evidence to support the efficacy of dupilumab in patients who have baseline postbronchodilator FEV1 predicted to be > 70%. |
Considerations for continuation or renewal of therapy | |
It was noted in the sponsor’s submission that the onset of treatment effects with dupilumab as an add-on treatment to current best supportive care was apparent within 2 weeks of initiation of dupilumab treatment and was maintained at week 52. A return to baseline levels of COPD symptoms, including a higher number of exacerbations, lower prebronchodilator FEV1, and higher SGRQ scores, was noted after dupilumab treatment discontinuation, supporting the need for long-term dupilumab therapy. In addition to the primary benefit of reducing the frequency of moderate or severe exacerbations, the sponsor noted that dupilumab was associated with a statistically significant and clinically relevant improvement in patients’ lung function, as demonstrated by statistically significant improvements in prebronchodilator FEV1 at week 12 and week 52 compared to placebo. It was also associated with improved health status or HRQoL. Drug program implementation questions:
| The clinical experts noted that in clinical practice, treatment response to dupilumab in COPD is determined by a reduction in exacerbation frequency, improved quality of life, a reduction in COPD symptoms, or improved functional capacity. The clinical experts further indicated that patients who do not show a reduction in exacerbations may still be considered as having a disease response if they demonstrate meaningful improvements in other validated COPD outcomes, such as a SGRQ score decrease of at least 4 points, a CAT score decrease of at least 2 points, or a 6-minute walk distance increase of at least 30 m. The clinical experts suggested that follow-up should occur at approximately 12 weeks to assess early treatment response, with ongoing monitoring over the first year to evaluate long-term benefit. CDEC agreed with the clinical experts that therapeutic response to dupilumab treatment should be assessed every 12 months based on exacerbation rate given that dupilumab demonstrated clinical benefits in reducing exacerbations at 52 weeks relative to placebo. CDEC noted that the clinical trials did not suggest a clinically meaningful response based on SGRQ scores and that CAT and 6-minute walk test scores were not outcome measures used in the trials. |
Considerations for discontinuation of therapy | |
The sponsor noted that in the BOREAS and NOTUS trials, consistent benefit was seen across subgroups of baseline biomarkers (including biomarkers of type 2 inflammation), with a trend toward numerically greater improvements with higher type 2 biomarker levels. Benefits of dupilumab were consistently observed in the overall population, in patients with potentially higher morbidity and mortality outcomes, and in populations of patients who currently smoke or previously smoked, according to the sponsor. What would be considered an absence of clinical benefit or loss of response? | The clinical experts pointed out that an absence of clinical benefit or a loss of disease response to dupilumab would be determined by the treating physician based on adverse side effects (such as uncontrolled uveitis or severe infusion reactions), though no standardized clinical algorithm exists. Additionally, inability to achieve key treatment goals — including reducing exacerbation frequency, improving quality of life, decreasing COPD symptoms, or increasing functional capacity — would indicate a lack of disease response, unless worsening is attributable to a medical comorbidity. The clinical experts noted that these criteria align with those already used by Canadian public drug program formularies to assess treatment response for dupilumab and other biologic drugs in asthma patients. CDEC noted that it would be appropriate to consider discontinuation of dupilumab treatment upon intolerable adverse events, or upon an increase in the number of clinically significant COPD exacerbations within the previous 12 months compared to the baseline, unless they are explained by a medical comorbidity. |
As per the indication, the patient should currently be using triple therapy (an ICS, a LABA, and a LAMA) or dual therapy (a LABA plus a LAMA) if an ICS is contraindicated. What duration of triple (or dual) therapy should be required before initiating add-on therapy with dupilumab? | CDEC agreed with the clinical experts noted that the required duration of triple (or dual) therapy before considering add-on therapy with dupilumab should be at least 3 months, as per the inclusion criteria of the BOREAS and NOTUS trials. According to the clinical experts, prior studies have shown that any benefit or lack of benefit of triple therapy on exacerbation risk can typically be assessed within 12 weeks. Therefore, because an individual patient’s COPD exacerbation rate remains stable over time in the absence of treatment changes, a severe exacerbation occurring within the first 3 months suggests a continued high risk for exacerbations despite ongoing triple therapy, warranting consideration of add-on therapy like dupilumab. |
Considerations for prescribing of therapy | |
Dosing of dupilumab is 300 mg by SC injection every 2 weeks. | This is a comment from the drug plans to inform CDEC deliberations. |
The sponsor stated that both spirometry and blood eosinophil tests are widely available across Canada. However, spirometry is only performed in specialty respiratory clinics or hospitals; therefore, some patients may face limitations in accessing this test. | This is a comment from the drug plans to inform CDEC deliberations. |
Generalizability | |
Could dupilumab be considered in patients with uncontrolled COPD who do not have type 2 inflammation? | CDEC agreed with the clinical experts that dupilumab should not be reimbursed in patients who do not have type 2 inflammation, due to the lack of evidence regarding its efficacy and safety in these patients. |
System and economic issues | |
The drug programs stated the results of the sponsor’s base-case analysis of the estimated incremental cost-effectiveness ratio and the budget impact analysis for CDEC’s consideration. | This is a comment from the drug plans to inform CDEC deliberations. |
AECOPD = acute exacerbation of COPD; CAT = COPD Assessment Test; CDEC = Canadian Drug Expert Committee; COPD = chronic obstructive pulmonary disease; FeNO = fractional exhaled nitric oxide; FEV1 = forced expiratory volume in the first second; FVC = forced vital capacity; GI = gastrointestinal; HRQoL = health-related quality of life; ICS = inhaled corticosteroid; LABA = long-acting beta2-agonist; LAMA = long-acting muscarinic antagonist; mMRC = Modified Medical Research Council; MRC = Medical Research Council; PDE4 = phosphodiesterase type 4; SC = subcutaneous; SGRQ = St. George's Respiratory Questionnaire.
Note: mMRC grades ≥ 1 are equivalent to MRC grades ≥ 2.
aCanadian clinical experts indicated that roflumilast and azithromycin are rarely used in the maintenance treatment of COPD (due to adverse events, safety concerns, and microbial resistance concerns).
bModerate exacerbations were recorded by the investigator and defined as AECOPD that required either systemic corticosteroids (intramuscular, IV, or oral) and/or antibiotics. One of the 2 required moderate exacerbations had to require the use of systemic corticosteroids.
cSevere exacerbations were recorded by the investigator and defined as AECOPD requiring hospitalization or observation > 24 hours in emergency department/urgent care facility.
The sponsor-conducted systematic literature review identified 2 multicentre, multinational, double-blind, identically designed, placebo-controlled RCTs (the BOREAS trial [N = 939]; and the NOTUS trial, a confirmatory study [N = 935] of the BOREAS trial) for inclusion. The RCTs assessed the efficacy and safety of dupilumab relative to placebo in adults with uncontrolled COPD (i.e., at least 2 moderate exacerbations or 1 severe exacerbation in the previous year and Medical Research Council [MRC] Dyspnoea Scale grades ≥ 2, which are equivalent to modified MRC [mMRC] scores ≥ 1); moderate to severe airflow obstruction (i.e., a postbronchodilator FEV1 > 30% to ≤ 70% of predicted) despite receiving maximum standard of care background therapy, including an ICS, a LABA, and a LAMA (unless an ICS was contraindicated); and evidence of type 2 inflammation (with blood eosinophil counts ≥ 300 cells/µL). The study population consisted of patients aged 40 to 80 years in the BOREAS trial and aged 40 to 85 years in the NOTUS trial who currently smoke or previously smoked (with a smoking history of at least 10 pack-years) and who did not have either a history of or current diagnosis of asthma. In each study, patients were randomized in a 1:1 ratio to receive SC dupilumab 300 mg every 2 weeks plus best supportive care or placebo plus best supportive care for a 52-week randomized study intervention period, followed by a 12-week safety post-intervention follow-up period.
The annualized rate of moderate (requiring either systemic corticosteroids and/or antibiotics) or severe (requiring hospitalization or observation for more than 24 hours in an emergency department or urgent care facility) COPD exacerbations, prebronchodilator FEV1 (at week 12 and week 52), SGRQ total score, and TEAEs of special interest were outcomes of interest to this review. At baseline, all patients in each study had a history of smoking, with 30% of patients currently smoking. The proportion of patients with moderate airflow limitation (i.e., GOLD grade 2; a predicted postbronchodilator FEV1 between ≥ 50% and < 80%) was █████ ██ █████ across the treatment arms in the BOREAS and NOTUS trials. The proportion of patients with severe airflow limitation (i.e., GOLD grade 3; a predicted postbronchodilator FEV1 between ≥ 30% and < 50%) was █████ ██ ██████ A total of ██ ██████ patients in the BOREAS trial and a total of ██ ██████ patients in the NOTUS trial had airflow limitation categorized as very severe (i.e., GOLD grade 4; a predicted postbronchodilator FEV1 < 30%).
As the primary end point in both trials, the adjusted annualized rate of moderate or severe COPD exacerbations over the 52-week intervention period in the intention-to-treat (ITT) population was lower in the dupilumab group as compared with the placebo group: 0.78 (95% CI, 0.64 to 0.93) versus 1.10 (95% CI, 0.93 to 1.30), respectively, with an RR of 0.70 (95% CI, 0.58 to 0.86, P < 0.001) in the BOREAS trial; and 0.86 (95% CI, 0.70 to 1.06) versus 1.30 (95% CI, 1.05 to 1.60), respectively, with an RR of 0.66 (95% CI, 0.54 to 0.82; P < 0.001) in the NOTUS trial. The absolute differences between groups were ██████ ████ ███ ██████ ██ ███████ in the BOREAS trial, and ██████ ████ ███ ██████ ██ ██████) in the NOTUS trial.
The least squares (LS) mean change from baseline to week 12 in prebronchodilator FEV1 in the ITT population was an increase of 0.160 L in the dupilumab group versus 0.077 L in the placebo group (between-group LS mean difference = 0.083 L; 95% CI, 0.042 L to 0.125 L; P < 0.001) in the BOREAS trial, and an increase of 0.139 L in the dupilumab group versus 0.057 L in the placebo group (between-group LS mean difference = 0.082 L; 95% CI, 0.040 L to 0.124 L; P < 0.001) in the NOTUS trial.
The LS mean change from baseline to week 52 in prebronchodilator FEV1 in the ITT population was an increase of 0.153 L in the dupilumab group versus 0.070 L in the placebo group (between-group LS mean difference = 0.083 L; 95% CI, 0.038 L to 0.128 L; P < 0.001) in the BOREAS trial, and an increase of 0.115 L in the dupilumab group versus 0.054 L in the placebo group (between-group LS mean difference = 0.062 L; 95% CI, 0.011 L to 0.113 L; P = 0.02) in the NOTUS trial.
The LS mean change from baseline to week 52 in SGRQ total score was −9.7 in the dupilumab group versus −6.4 in the placebo group (between-group LS mean difference = −3.4; 95% CI, −5.5 to −1.3; P = 0.002) in the BOREAS trial, and −9.8 in the dupilumab group versus −6.4 in the placebo group (between-group LS mean difference = −3.4; 95% CI, −5.8 to −0.9; nominal ██ ██████) in the NOTUS trial.
In the BOREAS and NOTUS trials, similar proportions of patients reported any TEAE in the dupilumab and placebo groups (77% of patients in the dupilumab group versus 76% in the placebo group in the BOREAS trial, and 67% of patients in the dupilumab group versus 66% in the placebo group in the NOTUS trial). The most common TEAEs associated with dupilumab in either study were nasopharyngitis, upper respiratory tract infections, COVID-19, headache, diarrhea, and back pain. In the BOREAS trial, treatment-emergent serious AEs were reported in 14% of patients in the dupilumab group and 16% of patients in the placebo group. In the NOTUS trial, treatment-emergent serious AEs were reported in 13% of patients in the dupilumab group and 16% of patients in the placebo group. The most common treatment-emergent serious AE was █████ ████████████ ██ ████ ███ ██ ███ ██ █████ ███ █████████ █████████ ██ ████ █████████ ███ ███ ██████████ ██ ██ ██████ ██ ███ ███ ███████████ █████████. █████████ █████ ██ ██████ ████████ █████ ██ ██████ ███ ████████ █████████ █████ ██ █████ ████ ███ ████ ██████████ ████████ ███████ ██████████. Withdrawal due to TEAEs (3% to 4%) was uncommon in the studies.
In the BOREAS trial, overall, ██ patients died during the on-study period, defined as from treatment initiation to the end of study, ███████ in each intervention group. In the NOTUS trial, overall, ██ patients died during the on-study period, ██ ██████ in the dupilumab group and ███████ in the placebo group.
In the BOREAS trial, the proportions of patients who experienced any TEAEs of special interest were generally comparable between the groups: ████ ██████ ████ with dupilumab and placebo, respectively. █████████ ████ █████████ were more frequently reported in the dupilumab group as compared to the placebo group (████ ██████ █████.
In the NOTUS trial, the proportion of patients with any TEAE of special interest was numerically higher in the dupilumab group compared to the placebo group █████ ██████ █████ respectively. The between-group difference was mostly driven by the AEs of special interest of ███████ █████████ ███████████ █████ ███████ █████ ███ ███ ███ ██ █████████ ████ ████████ ███ ██████████████ ███████████ █████ ████████ █████.
The BOREAS and NOTUS trials ensured allocation concealment through an interactive voice- or web-response system. Randomization was stratified based on COPD prognosis factors, though the BOREAS trial did not account for smoking status; however, its distribution remained balanced between the 2 treatment groups (patients who currently smoke accounted for 29% of participants in the dupilumab group and 31% in the placebo group). Baseline characteristics were generally comparable between groups, except for notably higher serum immunoglobulin E levels in the dupilumab arms compared with the placebo arms in both studies, a difference the clinical experts deemed unlikely to affect COPD-related outcomes. Blinding was maintained, yet patients might have inferred their treatment allocation based on symptom changes, potentially biasing subjective efficacy outcomes in favour of dupilumab and safety outcomes in favour of placebo. Objective measures, such as COPD exacerbation rates and prebronchodilator FEV1, had a low risk of bias. Sample size calculations were appropriate, though the NOTUS trial investigators reduced the trial’s week 52 end point population due to an interim analysis. The primary reason for discontinuation was patient withdrawal (5% to 6% in the BOREAS trial and 4% to 5% the NOTUS trial), with small between-group differences unlikely to affect results. Missing data in key end points were handled through the restricted maximum likelihood method, and sensitivity analyses confirmed robust findings. Multiplicity control appeared adequate, minimizing type I error risk. A negative binomial regression model was prespecified for COPD exacerbation counts, showing similar results using the Poisson regression in both trials. While subgroup analyses based on eosinophil counts were prespecified, the lack of sample size consideration and multiplicity control limits the reliability of these findings. The trials’ year-long duration minimized seasonal confounding, and the SGRQ total score’s minimal important difference estimate (4 points) was considered clinically meaningful, despite originating from within-group changes rather than direct between-group comparisons.
The BOREAS and NOTUS trials were multinational RCTs, with ██ ███ ██ patients in Canada, respectively. The clinical experts noted that trial eligibility criteria and the baseline characteristics of the enrolled patients broadly reflected the population in Canada that would be eligible for dupilumab, though in practice, individuals outside the specified age ranges or with asthma may still be considered for treatment. The dupilumab dosing regimen in each study aligned with the draft product monograph, and concomitant medications used (ICSs, LABAs, LAMAs, rescue therapies, and systemic corticosteroids) mirrored standard COPD management in Canada, according to the clinical experts. The primary efficacy outcomes — annualized exacerbation rate, prebronchodilator FEV1, and HRQoL — were clinically meaningful, with the clinical experts emphasizing that all exacerbations, regardless of severity, matter to patient health and health care utilization. The clinical experts noted that the 52-week randomized treatment period and the 12‑week postrandomization safety follow-up were adequate to assess the efficacy of dupilumab. However, the clinical experts felt that a longer duration of follow-up would be required to capture the long-term safety of dupilumab, particularly for potential rare AEs, such as helminth infections. Of note, the sponsor stated that dupilumab has been available in Canada since 2017, and it has been approved for use in patients as young as 6 months since 2023. The BOREAS and NOTUS trials were the sole phase III RCTs submitted for review, with no head-to-head or indirect comparisons against other active therapies (azithromycin and roflumilast) provided. Nonetheless, the absence of comparative evidence is unlikely to be a concern given that, based on clinical expert input, there are currently no appropriate comparators of dupilumab available for the treatment of uncontrolled COPD associated with type 2 inflammation in Canada.
For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE methodology was used to assess the certainty of evidence for the outcomes considered most relevant to the expert committee deliberations, and final certainty ratings were determined as outlined by the GRADE Working Group. Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (i.e., internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, or publication bias.
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:
annualized rate of moderate or severe COPD exacerbations
mean change from baseline in prebronchodilator FEV1 to week 12 and to week 52
HRQoL assessed with SGRQ total score
TEAEs of special interest.
Findings from the BOREAS and NOTUS trials were considered together and summarized narratively per outcome because these studies were similar in population, interventions, design, and outcome measures. Table 3 presents the GRADE summary of findings for dupilumab versus placebo in adult patients with COPD characterized by elevated blood eosinophil levels inadequately controlled by the combination of an ICS, a LABA, and a LAMA, or by a combination of a LABA and a LAMA if an ICS is not appropriate.
Table 3: Summary of Findings for Dupilumab vs. Placebo as an Add-On Maintenance Treatment in Adult Patients With COPD Characterized by Elevated Blood Eosinophil Levels Inadequately Controlled by the Combination of an ICS, a LABA, and a LAMA or by a Combination of a LABA and a LAMA if an ICS Is Not Appropriate
Outcome and follow-up | Patients, N (studies) | Result | Certainty | What happens |
|---|---|---|---|---|
Primary efficacy outcome | ||||
Annualized event rate of moderate or severe COPD exacerbations Follow-up: 52 weeks | 1,874 (2 RCTs) | The BOREAS trial
The NOTUS trial
| High | Dupilumab results in a clinically important decrease in the annualized rate of moderate or severe COPD exacerbations when compared with placebo. |
Lung function | ||||
Prebronchodilator FEV1 LS mean change from baseline Follow-up: 12 weeks | 1,860 (2 RCTs) | The BOREAS trial
The NOTUS trial
| Moderatea | Dupilumab likely results in little to no clinically meaningful difference in prebronchodilator FEV1 when compared with placebo at 12 weeks. |
Prebronchodilator FEV1 LS mean change from baseline Follow-up: 52 weeks | 1,650 (2 RCTs) | The BOREAS trial
The NOTUS trial
| Moderatea | Dupilumab likely results in little to no clinically meaningful difference in prebronchodilator FEV1 when compared with placebo at 52 weeks. |
Health-related quality of life (SGRQ) | ||||
SGRQ total score (0 [best HRQoL] to 100 [worst HRQoL]), LS mean change from baseline, points Follow-up: 52 weeks | 1,604 (2 RCTs) | The BOREAS trial
The NOTUS trial
| Moderateb | Dupilumab likely results in little to no clinically meaningful difference in SGRQ score improvement when compared with placebo. |
Harms | ||||
Proportion of patients with treatment-emergent AEs of special interestc (95% CI) Follow-up: 52 weeks | 1,872 (2 RCTs) | The BOREAS trial ██████████ ██ ███ █████ ███ ██ ███ ███ ███████████████ ██ ███ █████ ███ ██ ███ ███ ██████████████████ █ █████ ███ █████ █████ ██ █████ ██ ██ ████ ███ The NOTUS trial ██████████ ██ ███ █████ ███ ██ ███ ███ ███████████████ ██ ███ █████ ███ ██ ██ ███ ██████████████████ ██ ████ ███ █████ █████ ██ █████ ██ ██ ████ ███ ██████ | Lowd | Dupilumab may result in little to no difference in proportion of patients with treatment-emergent AEs of special interest when compared with placebo. |
AE = adverse event; CI = confidence interval; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in the first second; HRQoL = health-related quality of life; ICS = inhaled corticosteroids; LABA = long-acting beta2-agonist; LAMA = long-acting muscarinic antagonist; LS = least square; MID = minimal important difference; RCT = randomized controlled trial; SE = standard error; SGRQ = St. George’s Respiratory Questionnaire; vs. = versus.
Notes: Study limitations (i.e., 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.
In this table, the data presented for the BOREAS trial are from the data cut-off of February 8, 2023 (last patient end of treatment visit). The data presented for the NOTUS trial are the primary efficacy analyses results based on the interim analysis data cut-off of September 29, 2023.
aThe level of certainty was rated down 1 level for serious imprecision. A difference of 0.1 L between the groups was identified by the clinical expert consulted for this review as a threshold of clinical importance for this outcome. The point estimates suggested little to no difference, and the 95% CIs for the between-group difference crossed the MID threshold in the BOREAS and NOTUS trials.
bThe level of certainty was rated down 1 level for serious imprecision. Based on the MID identified in the literature (4 points based on within-group data), the point estimates suggested little to no difference, and the 95% CIs for the between-group difference crossed the MID threshold in the BOREAS and NOTUS trials.
cAn AE of special interest is an AE (serious or nonserious) of scientific and medical concern specific to the sponsor’s product or program for which ongoing monitoring and immediate notification of the sponsor by the investigator are required. Specifically, AEs of special interest in the BOREAS and NOTUS studies included the following: clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms); anaphylactic reactions; systemic allergic reactions that are related to the investigational medicinal product and require treatment; severe injection site reactions that last longer than 24 hours; and any serious infection (serious AE), infection requiring parenteral (IV, intramuscular, subcutaneous) antimicrobial therapy, infection requiring oral antimicrobial therapy for longer than 2 weeks, parasitic infection, or opportunistic infection.
dThe level of evidence was rated down 2 levels for very serious imprecision. The review team was unable to identify the MID to assess a between-group difference from the literature or the clinical experts consulted for this review; therefore, the null was used to assess certainty. The 95% CIs of the absolute effects included the null threshold of 0 in the BOREAS and NOTUS trials.
Sources: Clinical Study Reports for the BOREAS and NOTUS trials and the sponsor’s submissions. Details included in Table 3 are from the sponsor’s Summary of Clinical Evidence.
Table 4: Summary of Economic Evaluation
Component | Description |
|---|---|
Type of economic evaluation | Cost-utility analysis Markov |
Target population | Patients with uncontrolled COPD associated with type 2 inflammation (characterized by elevated blood eosinophil counts) |
Treatment | Dupilumab as an add-on to background therapy |
Dose regimen | 300 mg given every other week |
Submitted price | Dupilumab: $978.70 per single-use syringe or pen |
Submitted treatment cost | $27,078 per patient annually |
Comparator | Background therapy (ICS + LABA + LAMA) |
Perspective | Canadian publicly funded health care payer |
Outcomes | QALYs, LYs |
Time horizon | Lifetime (35 years) |
Key data sources | The BOREAS and NOTUS clinical trials |
Key limitations |
|
CDA-AMC reanalysis results |
|
CDA-AMC = Canada’s Drug Agency; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in the first second; ICER = incremental cost-effectiveness ratio; ICS = inhaled corticosteroid; LABA = long-acting beta2-agonist; LAMA = long-acting muscarinic antagonist; LY = life-year; QALY = quality-adjusted life-year.
CDA-AMC identified the following key limitation from the sponsor’s submitted analysis: uncertainty in the market uptake of dupilumab as an add-on to background therapy. CDA-AMC conducted a scenario analysis to explore the impact of alternative market uptake estimates for dupilumab as an add-on to background therapy. In the sponsor’s submitted base case, the budget impact of reimbursing dupilumab as an add-on to background therapy for the treatment in adult patients with uncontrolled COPD associated with type 2 inflammation was $71,498,300 in year 1, $185,495,190 in year 2, and $319,316,259 in year 3. Therefore, the 3-year budget impact was $576,309,748. In the scenario analysis examining the impact of increased market uptake of dupilumab, the 3-year budget was estimated to increase to $1,153,939,794 if the market uptake of dupilumab doubled relative to the sponsor’s base-case estimate.
The sponsor filed a request for minor reconsideration of the draft recommendation for dupilumab for the treatment of COPD. In its request, the sponsor identified the following issues:
The sponsor noted that the implementation guidance for Reimbursement Condition 1.2 (under Initiation) does not allow physician judgment when interpreting spirometry results, which creates practical challenges and could limit access for patients with COPD who are severely ill. They requested that the guidance be revised to allow clinical judgment when identifying appropriate patients using postbronchodilator FEV1, particularly for patients with postbronchodilator FEV1 predicted to be less than 30%.
Condition 4 (under Renewal) may cause premature discontinuation because comparing exacerbations with the previous 12 months rather than with baseline levels could stop treatment in patients who have maintained a meaningful response, potentially leading to worse outcomes once therapy is stopped. The sponsor requested revising the wording to allow proper assessment of clinical benefit: renewal should occur if moderate or severe exacerbations in the past 12 months have not increased compared with baseline, unless explained by a medical comorbidity.
The public drug plans also filed a request for minor reconsideration of the draft recommendation for dupilumab for the treatment COPD. In their request, the public drug plans identified the following issues:
The drug plans proposed adding implementation guidance to define what constitutes a contraindication to ICS for Condition 1.3 (under Initiation).
The drug plans sought clarification on Condition 1.3 (under Initiation) because the timing of COPD exacerbations relative to optimized background therapy was unclear.
The drug plans sought clarification on how to calculate the annualized COPD exacerbation rate at baseline specified in Condition 2 (under Initiation). Based on the wording in the draft recommendation, it was unclear to the drug plans whether the baseline annualized exacerbation rate should be extrapolated based on the number of exacerbations while patients are receiving optimized background therapy.
The drug plans proposed revising Condition 6 (under Prescribing) to allow dupilumab to be prescribed by, or in consultation with, a respirologist to increase flexibility and align with prescribing conditions for biologic drugs for the treatment of asthma.
In the meeting to discuss the sponsor’s and public drug plan’s requests for reconsideration, CDEC considered the following information:
information from the initial submission related to the issues identified by the sponsor
feedback from 2 clinical specialists with expertise in diagnosing and treating patients with COPD
feedback on the draft recommendation from 1 patient group (the Lung Health Foundation, which also submitted patient input for the original submission)
feedback on the draft recommendation from 2 clinician groups (the Department of Medicine, Division of Respirology and Sleep Medicine at Queen’s University in Kingston, Ontario; and the Canadian Thoracic Society [which also submitted clinician input for the original submission]) and 1 independent clinician
feedback on the draft recommendation from the public drug plans that participate in the CDA-AMC review process
feedback on the draft recommendation from the sponsor.
All feedback received in response to the draft recommendation is available on the CDA-AMC website.
Dr. Peter Jamieson (Chair), Dr. Kerry Mansell (Vice Chair), Dr. Sally Bean, Daryl Bell, Dan Dunsky, Dr. Ran Goldman, Dr. Trudy Huyghebaert, Morris Joseph, Dr. Dennis Ko, Dr. Christine Leong, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Nicholas Myers, Dr. Krishnan Ramanathan, Dr. Marco Solmi, Dr. Edward Xie, and Dr. Peter Zed.
Meeting date: May 28, 2025
Regrets: Three expert committee members did not attend.
Conflict of interest: None
Minor reconsideration CDEC subpanel meeting date: February 25, 2026
ISSN: 2563-6596
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