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Indication: For the treatment of patients aged 6 months and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable
CADTH recommends that Dupixent be reimbursed by public drug plans for the treatment of patients aged 6 months to younger than 12 years with moderate to severe atopic dermatitis (AD) whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable, if certain conditions are met.
The CADTH Canadian Drug Expert Committee (CDEC) recommendation for Dupixent for the treatment of patients aged 12 years and older with moderate to severe AD dated February 2023 continues to apply to patients who are not included in the population evaluated in this recommendation.
Dupixent should only be covered to treat patients aged 6 months to younger than 12 years with moderate to severe AD who previously tried and did not experience improvement with, or are unable to use, topically applied drugs.
Dupixent should only be reimbursed if the patient is under the care of a dermatologist, allergist, clinical immunologist, or pediatrician who has expertise in the management of moderate to severe AD, and if the cost of Dupixent is reduced. When first prescribed, Dupixent should only be reimbursed for 6 months. Dupixent should not be used in combination with phototherapy, any immunomodulatory drugs (including biologics), or a Janus kinase (JAK) inhibitor treatment for moderate to severe AD.
AD is a condition that affects the skin, causing dry, red skin that is extremely itchy. Constant scratching causes the skin to split and bleed, which can lead to infections. Oozing and weeping sores occur in more severe forms. Severe AD can be physically incapacitating and cause anxiety or depression. Lifetime prevalence is estimated to be up to 17% in Canada.
There is no cure for AD, although treatment aims to provide symptom relief and control in the longer term. Although there are treatments for AD approved in Canada, some patients’ symptoms may not be controlled with existing drugs, and other treatment options are needed.
Treatment with Dupixent is expected to cost approximately $12,723 per year for patients aged 6 months to 5 years and $25,446 per year for patients aged 6 years to 12 years.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that dupilumab be reimbursed for the treatment of patients aged 6 months to younger than 12 years with moderate to severe atopic dermatitis (AD) whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable, only if the conditions listed in Table 1 are met.
The CDEC recommendation for dupilumab for the treatment of patients aged 12 years and older with moderate to severe AD dated February 2023 continues to apply to patients who are not included in the population evaluated in this recommendation.
Two double-blind randomized controlled trials (RCTs) (the LIBERTY AD PRESCHOOL trial, N = 162, and the LIBERTY AD PEDS trial, N = 367) evaluated the use of dupilumab in patients with AD whose disease was not adequately controlled with topical prescription therapies. The LIBERTY AD PRESCHOOL trial enrolled patients aged 6 months to younger than 6 years with moderate to severe AD, and the LIBERTY AD PEDS trial enrolled patients aged 6 years to younger than 12 years with severe AD. Both the LIBERTY AD PRESCHOOL and LIBERTY AD PEDS trials demonstrated that, compared with placebo in combination with topical corticosteroids (TCSs), 16 weeks of treatment with dupilumab in combination with TCSs was associated with statistically significant and clinically meaningful improvements in a range of outcomes that are important to patients, caregivers, and clinicians in the management of AD, including overall severity of AD (Eczema Area and Severity Index [EASI] and Investigator’s Global Assessment [IGA]) response), intensity of itching (itch numeric rating scale [NRS]), and health-related quality of life (HRQoL) (Dermatitis Family Index [DFI], Children’s Dermatology Life Quality Index [CDLQI], and Infants’ Dermatology Quality of Life Index [IDQoL], the last of which was only assessed in the LIBERTY AD PRESCHOOL trial).
Patients and caregivers identified a need for treatment options that effectively manage the disease, improve symptoms, improve HRQoL, and are simpler to administer. CDEC concluded that dupilumab appears to address some of these needs, such as improving all disease-related symptoms (including itching and disease severity), and also meaningful improvement in HRQoL.
Using the sponsor-submitted price for dupilumab and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for dupilumab plus best supportive care (BSC) was $130,945 per quality-adjusted life-year (QALY) gained, compared to BSC alone. At this ICER, dupilumab is not cost-effective at a $50,000 per QALY willingness-to-pay (WTP) threshold for patients aged 6 months to younger than 12 years with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. A price reduction is required for dupilumab to be considered cost-effective at a $50,000 per QALY threshold.
Reimbursement Conditions and Reasons.
AD is a chronic, relapsing, inflammatory skin condition characterized by intense itching, red and swollen skin, and rash. The condition is estimated to affect 15% to 20% of children globally, and in Canada, the lifetime prevalence of AD is up to 17% of the population. Pediatric patients with AD experience substantial symptom burden, poor sleep quality, reduced HRQoL, and frequent comorbidities. The care required for these pediatric patients can be time-consuming and interferes with day-to-day activities, leading to increased feelings of caregiver anxiety, depression, worry, and helplessness. According to the clinical experts consulted by CADTH, the goals of treatment for pediatric patients with moderate to severe AD are to reduce symptom severity and improve HRQoL with minimal adverse effects, as well as to reduce caregiver burden. Treatments include moisturizers and topical anti-inflammatory drugs; however, these are noted as being time-consuming and can have side effects, which can lead to low compliance and refractory disease. Phototherapy and systemic immunosuppressants (off-label use) are occasionally used in patients with severe disease who do not respond to topical treatments or in addition to topical treatments, although the use of systemic immunosuppressants is uncommon in patients younger than 5 years and rare in patients younger than 2 years, as these therapies have significant limitations and intolerable adverse effects.
Dupilumab has been approved by Health Canada for the treatment of patients aged 6 months and older with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable, and can be used with or without TCSs. Dupilumab is a recombinant human immunoglobulin G4 monoclonal antibody that inhibits interleukin (IL)-4 and IL-13. For patients aged 6 months to 11 years, the drug is available as prefilled syringes containing either 200 mg or 300 mg dupilumab for subcutaneous injection, with age-based and weight-based dosing. For pediatric patients aged 6 years to 17 years with AD, the recommended dose is 300 mg every 4 weeks (for patients weighing 15 kg to less than 30 kg), 200 mg every 2 weeks (for patients weighing 30 kg to less than 60 kg), or 300 mg every 2 weeks (for patients weighing at least 60 kg), following an initial dose of 600 mg, 400 mg, or 600 mg, respectively. For pediatric patients aged 6 months to 5 years with AD, the recommended dose is 200 mg every 4 weeks (for patients weighing 5 kg to less than 15 kg) or 300 mg every 4 weeks (for patients weighing 15 kg to less than 30 kg).
Dupilumab has been previously reviewed 3 times by CADTH for the treatment of patients with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable: as a new drug in 2018, as a resubmission for an expanded indication in 2020, and as a request for advice in 2022. The initial review for dupilumab was for the treatment of adult patients with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The original CADTH systematic review of dupilumab included 4 double-blind RCTs: the SOLO-1 (N = 671), SOLO-2 (N = 708), LIBERTY AD CAFÉ (N = 325), and LIBERTY AD CHRONOS (N = 740) trials. All trials included patients with moderate to severe AD, and patients were randomized to dupilumab every week or every other week, or placebo, for a treatment duration of 16 weeks (in the SOLO studies and the LIBERTY AD CAFÉ trial) or 52 weeks (in the LIBERTY AD CHRONOS trial). In July 2018, CDEC issued a recommendation that dupilumab should not be reimbursed for this indication. Reasons for the CDEC recommendation included the lack of evidence comparing dupilumab to other drugs commonly used for managing AD, the lack of long-term safety data, concerns over generalizability of the data to patients who would be expected to use the drug in clinical practice, and a lack of efficacy and safety data for dupilumab in patients for whom topical prescription therapies are not advisable. A resubmission was subsequently filed by the sponsor for a new indication, which expanded the initial patient population limited to adults to include adolescents. In April 2020, CDEC issued a recommendation that dupilumab should be reimbursed for the treatment of AD only if conditions are met. A request for advice was filed in July 2022 by the public drug programs that participate in the CADTH reimbursement review process to address discordant reimbursement conditions between dupilumab and Janus kinase (JAK) inhibitors (upadacitinib and abrocitinib), which were recommended to be reimbursed with conditions for the treatment of AD. In February 2023, CDEC issued a recommendation that dupilumab should be reimbursed for the treatment of 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, only if conditions were met.
Dupilumab received a Notice of Compliance from Health Canada for an expansion in indication from 12 years of age and older to 6 years of age and older in February 2021, and to 6 months of age and older in April 2023. Thus, dupilumab is currently approved for the treatment of patients aged 6 months 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 current review is for a submission filed by the sponsor and focuses on the expanded age group of patients. This submission is based on new evidence (2 RCTs and 1 long-term extension study) submitted by the sponsor evaluating the use of dupilumab in patients aged 6 months to younger than 12 years with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.
To make its recommendation, the committee considered the following information:
CADTH received input from 3 patient groups: the Eczema Society of Canada, and joint input from the Canadian Skin Patient Alliance and Eczéma Québec. The inputs were provided for a previous CADTH submission for dupilumab in 2021, where the indication was for patients aged 6 years to 11 years with moderate to severe AD. No new patient input was received for the current review of dupilumab.
According to the patient groups, the symptoms of AD negatively affect individuals and their families and interfere with sleep, contribute to missed school and activities, result in psychosocial issues, and result in an increased risk of mental health problems. The groups stated that disease symptoms, quality of life, access to care, and disease management are concerns that are associated with significant psychosocial, educational, financial, and occupational burden. The authors of the joint input stated that the complex, time-consuming skin treatment routines and other associated burdens make managing the disease very challenging and exhausting. Furthermore, comorbidities associated with pediatric AD require multidisciplinary management and screening to manage the disease. Patients seek a treatment that safely and effectively manages symptoms, reduces flares, and improves the quality of life of both patients and caregivers.
The clinical experts explained that current topical treatments for AD do not work for all patients, can be burdensome and have low adherence, and can have side effects, and some are expensive and not covered by insurance plans. Likewise, systemic immunosuppressants are associated with numerous adverse effects, are poorly tolerated, and require regular blood monitoring. Phototherapy can be inaccessible to patients and is often not feasible for young children.
According to the experts, dupilumab would be used as a second-line therapy after failure of an adequate trial with topical therapies (e.g., TCSs, topical calcineurin inhibitors [TCIs]) but before systemic immunosuppressants, due to their poor safety profile. Both experts believed that it would be inappropriate to require patients under the age of 12 years to show nonresponse to either phototherapy or systemic immunosuppressants before being eligible for dupilumab.
Both clinical experts indicated that patients who could receive dupilumab would be identified based on clinician examination and judgment, taking into account disease severity and inadequate response to topical therapies. They also stated that patients with severe disease that is refractory to topical treatments and has a major impact on their HRQoL are most in need of effective treatment.
The experts indicated that outcomes used in clinical trials can help to gauge treatment response but are not typically used in clinical practice, except when required by a health insurer. Instead, patient assessments are usually a combination of discussion with the patient and caregiver and examination of the skin. It was noted that patients receiving dupilumab can have a delayed response, and that it would be reasonable to assess patients for response to treatment approximately 3 months to 6 months after initiating treatment with dupilumab, and then every 6 months thereafter.
According to the experts, discontinuation of dupilumab should be considered if there is a lack of response to treatment (e.g., no improvement in rash, itch, or HRQoL) or there are intolerable adverse effects. One clinician added that patients often continue to use topical treatments alongside dupilumab, and that this would not be a reason for discontinuing treatment. Although it is possible to outgrow childhood AD, both experts explained that this is less likely for patients with severe disease, other atopic comorbidities, or persistent and generalized AD. It was suggested that a trial of increasing the time between injections once disease control is achieved, with a plan to stop dupilumab altogether, could be an option discussed and decided on between the treating physician, patient, and caregiver, although stopping the drug should not be forced.
The experts agreed that a specialist (i.e., dermatologist) would prescribe dupilumab, and it would be initiated in a hospital or community clinical setting. In situations where there is limited access to a dermatologist or pediatric dermatologist, the experts suggested that a general pediatrician, allergist, immunologist, or a physician with training in AD could prescribe the drug.
Clinician group input was provided by the Canadian Dermatology Association. The input provided was largely aligned with that of the clinical experts consulted by CADTH. According to the clinician group input, patients can experience long wait times before seeing a specialist while their AD remains poorly controlled. They also noted that most dermatologists in Canada are neither trained in nor comfortable with managing pediatric safety lab work in the context of systemic immunosuppression. It was highlighted in the input that dupilumab is the only systemic treatment for AD indicated for this age group and does not carry the same risk profile as traditional immunosuppressants. The clinician group stated that an ideal treatment would have a proven safety record in this age group and would also be able to reduce symptoms and improve sleep, concentration at school, and the overall quality of life for both patients and caregivers. It was also emphasized that a trial of systemic immunosuppression should not be a prerequisite for dupilumab coverage in patients aged 6 months to 5 years. The authors of the input highlighted remote Indigenous communities as being vulnerable groups in which individuals with poorly controlled AD tend to be at higher risk for chronic skin diseases and secondary infections, and that dupilumab can be a good option for patients in these communities.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for dupilumab:
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Summary of Drug Plan Input and Clinical Expert Response.
Two phase III, double-blind RCTs assessed whether dupilumab with TCSs reduced a patient’s IGA score to 0 or 1 compared to placebo with TCSs after 16 weeks of treatment in patients aged 6 months to younger than 6 years with moderate to severe AD (the LIBERTY AD PRESCHOOL trial, N = 162), or 6 years to younger than 12 years with severe AD (the LIBERTY AD PEDS trial, N = 367). Patients enrolled in these studies had disease that was not adequately controlled with topical prescription therapies. Key secondary outcomes included the proportion of patients with an EASI-75, percent change from baseline in EASI score, and percent change from baseline in weekly average of daily worst itch NRS score at week 16. In both studies, HRQoL outcomes were assessed as other secondary outcomes, and included the DFI, CDLQI, and IDQoL, the last of which was only assessed in the LIBERTY AD PRESCHOOL trial.
The IGA is a 5-point scale that provides a global clinical assessment of AD severity ranging from 0 (clear) to 4 (severe AD). A decrease in score relates to an improvement in signs and symptoms. The EASI is a tool used in clinical trials to assess the severity and extent of AD. For this scale, 4 disease characteristics of AD (erythema, thickness, scratching, and lichenification) are assessed for severity by the investigator on a scale of 0 (absent) to 3 (severe), and the scores are added up for each of the 4 body regions (head, arms, trunk, and legs). The area affected by AD is assessed as a percentage by each body region and is converted to a score of 0 to 6, where the area affected is expressed as 0 (none), 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). Each of the body area scores are multiplied by the area affected. Therefore, the total EASI score ranges from 0 to 72 points, with a higher score indicating worse disease severity. The itch NRS is a tool that patients use to report the intensity of their itch with a daily recall period. Patients rate their overall (average) and maximum intensity of itch experienced during the previous 24 hours, based on a scale of 0 (no itch) to 10 (worst itch imaginable). The DFI is an AD-specific, self-administered, 10-item questionnaire designed to assess the impact of disease on the quality of life of families of children affected by disease based on a 1-week recall. Responses are scored on a 4-point Likert scale (from 0 to 3) and the total score ranges from 0 to 30, with higher scores indicating greater impairment in family quality of life. The CDLQI is a questionnaire completed by the child (aged 3 years to 16 years) designed to measure the impact of any skin disease on their quality of life with a recall period of 7 days. It consists of 10 questions asking about the impact of a skin disease on the life of the affected child, including symptoms, embarrassment, friendships, clothes, playing, sports, bullying, sleep, and impact of treatment. Each response is rated on a 4-point Likert scale (from 0 to 3) and the total score ranges from 0 to 30, with higher scores indicating a greater degree of impairment in HRQoL. The IDQoL is a questionnaire designed to measure the impact of the skin disease on the quality of life of infants and preschool children younger than 4 years. It consists of 10 questions that examine the impact of the disease on the life of the affected child, and includes but is not limited to mood, sleep, and daily activities. Each question is rated on a 4-point Likert scale (from 0 to 3) and the total score ranges from 0 to 30, with higher scores indicating worse quality of life.
Overall, baseline patient characteristics were balanced among treatment groups in both trials. In the LIBERTY AD PRESCHOOL trial, the mean age of patients was 3.8 years, there were fewer females (38.9%) than males (61.1%), and the mean EASI score of patients was 34.1. In the LIBERTY AD PEDS trial, the mean age of patients was 8.5 years, males and females were evenly balanced, and the mean EASI score of patients was ||||.
For the primary efficacy end point, there was a larger proportion of patients in the dupilumab group who had an IGA 0 or 1 compared to the placebo group at week 16, with a between treatment group difference of 23.8% (95% confidence interval [CI], 13.27% to 34.37%; P < 0.0001) in the LIBERTY AD PRESCHOOL trial. Results were similar in the LIBERTY AD PEDS trial, with a larger proportion of patients in both the group receiving dupilumab every 4 weeks and the group receiving dupilumab every 2 weeks who had an IGA 0 or 1 compared to the placebo group at week 16, with between treatment group differences of 21.4% (95% CI, 11.36% to 31.45%; P < 0.0001) and 18.1% (95% CI, 8.28% to 27.97%; P < 0.0001), respectively.
In the LIBERTY AD PRESCHOOL trial, a larger proportion of patients in the dupilumab group had an EASI-75 score compared to the placebo group at week 16, with a between treatment group difference of 42.3% (95% CI, 29.47% to 55.16%; P < 0.0001). Similarly, there was a larger percent change from baseline to week 16 EASI score observed in the dupilumab group compared to the placebo group, with a between treatment group least squares mean (LSM) difference of –50.4% (95% CI, –62.38% to –38.40%; P < 0.0001). Results for the proportion of patients achieving a 90% or greater improvement in the EASI total score (EASI-90) at week 16 also favoured treatment with dupilumab. In the LIBERTY AD PEDS trial, a larger proportion of patients in both the group receiving dupilumab every 4 weeks and the group receiving dupilumab every 2 weeks had an EASI-75 score compared to the placebo group at week 16, with between treatment group differences of 42.8% (95% CI, 31.54% to 54.15%; P < 0.0001) and 40.4% (95% CI, 28.95% to 51.82%; P < 0.0001), respectively. Likewise, there was a larger percent change from baseline to week 16 EASI score observed in both the group receiving dupilumab every 4 weeks and the group receiving dupilumab every 2 weeks compared to the placebo group, with between group LSM differences of –33.4% (95% CI, –40.06% to –26.82%; P < 0.0001) and –29.8% (95% CI, –36.33% to –23.24%; P < 0.0001), respectively. Results for the proportion of patients with an EASI-90 at week 16 also favoured treatment with dupilumab.
In the LIBERTY AD PRESCHOOL trial, for the itch NRS score, a larger percent change from baseline to week 16 was observed in the dupilumab group compared to the placebo group, with a between group LSM difference of –47.1% (95% CI, –59.47% to –34.79%; P < 0.0001). Results for the proportion of patients with an improvement of at least 4 points in itch NRS score from baseline to week 16 also favoured treatment with dupilumab. In the LIBERTY AD PEDS trial, a larger percent change from baseline to week 16 was observed for the itch NRS score in both the group receiving dupilumab every 4 weeks and the group receiving dupilumab every 2 weeks compared to the placebo group, with between group LSM differences versus placebo of –28.6% (95% CI, –36.47% to –20.82%; P < 0.0001) and –31.0% (95% CI, –38.76% to –23.26%; P < 0.0001), respectively. Results for the proportion of patients achieving an improvement of at least 4 points in itch NRS score from baseline to week 16 also favoured treatment with dupilumab.
In the LIBERTY AD PRESCHOOL trial, a larger change from baseline to week 16 in the DFI score was observed in the dupilumab group compared to the placebo group, with a between group LSM difference of –7.80 (95% CI, –9.79 to –5.81; P < 0.0001). In the LIBERTY AD PEDS trial, a larger change from baseline to week 16 in the DFI score was observed in both the group receiving dupilumab every 4 weeks and the group receiving dupilumab every 2 weeks compared to the placebo group, with between group LSM differences versus placebo of ||||| |||| ||| ||||| || |||||| ||| ||||| |||| ||| ||||| || ||||||| respectively.
In the LIBERTY AD PRESCHOOL trial, a larger change from baseline to week 16 in the CDLQI score was observed in the dupilumab group compared to the placebo group, with a between group LSM difference of –7.5 (95% CI, –10.29 to –4.75; P < 0.0001). In the LIBERTY AD PEDS trial, a larger change from baseline to week 16 in the CDLQI score was observed in both the group receiving dupilumab every 4 weeks and the group receiving dupilumab every 2 weeks compared to the placebo group, with between group LSM differences versus placebo || |||| |||| ||| ||||| || |||||| || ||||||| ||| |||| |||| ||| ||||| || |||||| || |||||||| respectively.
In the LIBERTY AD PRESCHOOL trial, a larger change from baseline to week 16 in the IDQoL score was observed in the dupilumab group compared to the placebo group, with a between group LSM difference of –8.96 (95% CI, –11.71 to –6.20; P < 0.0001). This was not an outcome in the LIBERTY AD PEDS trial.
During the 16-week treatment period, more than half of patients in any treatment group for both trials experienced at least 1 treatment-emergent adverse event (TEAE). In the LIBERTY AD PRESCHOOL trial, 63.9% of patients in the dupilumab group and 74.4% of patients in the placebo group reported a TEAE, with the most frequently reported events being AD (13.3% with dupilumab and 32.1% with placebo), nasopharyngitis (8.4% with dupilumab and 9.0% with placebo), and upper respiratory tract infection (6.0% with dupilumab and 7.7% with placebo). In the LIBERTY AD PEDS trial, 65.0% of patients in the group receiving dupilumab every 4 weeks, 67.2% of patients in the group receiving dupilumab every 2 weeks, and 73.3% of patients in the placebo group reported a TEAE, with the most frequently reported events also being nasopharyngitis (12.5% with dupilumab every 4 weeks, 6.6% with dupilumab every 2 weeks, and 6.7% with placebo), upper respiratory tract infection (10.8% with dupilumab every 4 weeks, 8.2% with dupilumab every 2 weeks, and 10.0% with placebo), and AD (6.7% with dupilumab every 4 weeks, 8.2% with dupilumab every 2 weeks, and 14.2% with placebo).
In the LIBERTY AD PRESCHOOL trial, there were 4 patients who reported serious adverse events (SAEs) in the placebo group and 0 in the dupilumab group. In the LIBERTY AD PEDS trial, there were 2 patients who reported SAEs in the group receiving dupilumab every 4 weeks, 0 patients in the group receiving dupilumab every 2 weeks, and 2 patients in the placebo group. No SAE was reported by more than 1 patient per trial.
In the LIBERTY AD PRESCHOOL trial, 2 patients stopped treatment because of adverse events (AEs) due to AD (dupilumab group) and nightmares (placebo group). In the LIBERTY AD PEDS trial, 4 patients stopped treatment because of AEs: 2 due to food allergy and bacterial conjunctivitis (both patients were in the group receiving dupilumab every 2 weeks) and 2 due to AD and asthma (both patients were in the placebo group).
There were no patient deaths in either trial.
There were no reports of anaphylactic reaction in either trial.
There were no reports of hypersensitivity in the LIBERTY AD PRESCHOOL trial. In the LIBERTY AD PEDS trial, no treatment-related events of hypersensitivity or anaphylaxis occurred during the study.
There were no reports of helminthic infection in the LIBERTY AD PRESCHOOL trial. In the LIBERTY AD PEDS trial, | ||||||| || |||| in the group receiving dupilumab every 4 weeks and the placebo group reported a helminthic infection and || |||||||| in the group receiving dupilumab every 2 weeks.
In the LIBERTY AD PRESCHOOL trial, 3 patients in the dupilumab group and 0 patients in the placebo group reported conjunctivitis. In the LIBERTY AD PEDS trial, 5 patients, 7 patients, and 3 patients in the group receiving dupilumab every 4 weeks, the group receiving dupilumab every 2 weeks, and the placebo group, respectively, reported conjunctivitis.
In the LIBERTY AD PRESCHOOL trial, 2 patients in the dupilumab group and 0 patients in the placebo group reported blepharitis. In the LIBERTY AD PEDS trial, | ||||||| ||| ||||||||| in the group receiving dupilumab every 2 weeks and the placebo group, respectively, reported blepharitis, and | | patients in the group receiving dupilumab every 4 weeks.
In the LIBERTY AD PRESCHOOL trial, | ||||||| || ||| ||||||||| ||||| ||| ||||||||| in the placebo group reported keratitis. In the LIBERTY AD PEDS trial, 1 patient in the group receiving dupilumab every 2 weeks reported keratitis, while no patients in either the group receiving dupilumab every 4 weeks or the placebo group reported keratitis.
In the LIBERTY AD PRESCHOOL trial, 2 patients in the dupilumab group and 0 patients in the placebo group reported eosinophilia. In the LIBERTY AD PEDS trial, 1 patient in the group receiving dupilumab every 2 weeks reported eosinophilia and no patients in either the group receiving dupilumab every 4 weeks or the placebo group reported this.
Facial erythema was not captured in either trial.
Injection site pain was not captured in the LIBERTY AD PRESCHOOL trial. In the LIBERTY AD PEDS trial, | ||||||||| |||||||||| ||||||||||| in the group receiving dupilumab every 4 weeks, the group receiving dupilumab every 2 weeks, and the placebo group, respectively, reported injection site pain.
In both pivotal trials, the few differences in baseline patient characteristics were mostly small and could have been due to chance, and the clinical experts did not think they were likely to change treatment outcomes. In the LIBERTY AD PEDS trial, 68 patients may have been unblinded to their treatment assignment, but the trial enrolled additional patients and included a modified full analysis set (mFAS) for supportive analyses to mitigate the issue. In both trials, fewer patients in the dupilumab groups used rescue treatment compared to the placebo groups, and the difference could impact how some outcomes (e.g., harms, HRQoL) are interpreted, although the direction of bias is not clear. Additionally, there was a lack of validity and reliability evidence for the itch NRS, and there were no minimal important differences (MIDs) for the IGA, DFI, or IDQoL for the patient population identified from the literature.
Although the LIBERTY AD PEDS trial included only patients with severe AD, the clinical experts were of the opinion that the results would likely be generalizable to those with moderate disease, given the evidence for age groups both younger and older than those in the trial (i.e., 6 years to younger than 12 years). The experts suggested that, in practice, a patient with moderate AD and an EASI score lower than 16 may be eligible for dupilumab if, for example, they have severe lesions but low percent BSA affected, or have lesions localized to specific areas (e.g., hands, feet, scalp). This is supported by the literature showing that patients with moderate AD can have an EASI score as low as 6. In the trials, patients who used rescue treatment were considered nonresponders, which the clinical experts stated was inconsistent with clinical practice. As per the clinical experts, non-TCS topical therapies would be acceptable add-on treatments while receiving dupilumab, and a short course (fewer than 8 weeks) of systemic therapies could be permitted without having to discontinue dupilumab. Although the trial outcomes addressed most of the treatment goals and patients’ needs from the stakeholder input, it is unclear if dupilumab injections every 2 weeks or every 4 weeks meet the need for a simpler treatment, particularly if patients or their caregivers are uncomfortable with administering the injection and must receive the injections in a clinic, or if patients are especially afraid of needles.
Study 1434 is an ongoing, global, open-label, single-group, long-term extension study of patients aged 6 months to younger than 18 years with AD, with the aim to assess the long-term safety and efficacy of dupilumab. Patients who participated in the parent (pivotal) trials were eligible to enrol in Study 1434; 180 patients were from the LIBERTY AD PRESCHOOL trial and 368 were from the LIBERTY AD PEDS trial. The primary outcome was the incidence rate (events per patient-year) of TEAEs. Results presented were based on a prespecified second-step analysis conducted using data from patients aged 6 years to younger than 12 years (data cut-off date July 22, 2019) and from a third-step analysis conducted using data from patients aged 6 months to younger than 6 years (data cut-off date July 31, 2021).
At the time of this CADTH review, Study 1434 was still ongoing and no patients had completed the 260-week assessment. However, early findings from baseline, 4, 16, 28, 52, and 104 weeks of primary and secondary efficacy end points indicated that treatment effects were maintained with continued dupilumab use.
No new safety signals arose over the course of Study 1434 and early safety results indicated that the drug was generally well tolerated with an acceptable safety profile.
The limited availability of long-term data (i.e., mature data), open-label design, lack of control arm, and absence of formal statistical hypothesis testing were key constraints that limit the interpretation of the long-term efficacy and safety of study outcomes for treatment with dupilumab.
No indirect evidence was available.
The PEDISTAD study, which is an observational study, was submitted by the sponsor to address gaps in the RCT evidence comparing dupilumab to other systemic treatments, such as methotrexate or cyclosporine, for patients younger than 12 years with moderate to severe AD whose disease is not adequately controlled with topical therapies, or when those therapies are not medically advisable. The PEDISTAD study is an ongoing, international, longitudinal, 5-year, prospective study initiated on September 28, 2018, aiming to examine the impact of systemic treatments on disease severity, safety, and treatment discontinuation in this patient population. Patients were eligible to enrol if they were currently receiving systemic treatment for AD, UV therapy, or immunosuppressants, or were currently using topical treatment and would be candidates for systemic treatment. All analyses were descriptive, with no comparisons performed between different systemic treatment cohorts.
Based on findings from a 2-year interim analysis in the sponsor’s Summary of Clinical Evidence, there appeared to be greater numerical improvements in the EASI total score, percent BSA affected by AD, Patient Oriented Eczema Measure score, and combined CDLQI or IDQoL score among the patients receiving dupilumab compared to methotrexate or cyclosporine.
Patients receiving dupilumab had a lower discontinuation rate and reported fewer AEs than those treated with methotrexate or cyclosporine.
Based on the limited data available and how they were presented, it was not possible to determine if the treatment groups were similar enough to be compared to one another. Additionally, available data were limited to the 2-year interim results, which prevent long-term conclusions from being drawn for any outcome. There was a potential increased risk of uncontrolled confounding and selection bias in the study, no formal comparison between study groups was considered, and there was no information regarding how many patients had been lost to follow-up or how many patients were censored. The study included a small number of patients living in Canada, and it is unclear how representative the preliminary results are to the population of pediatric patients with AD living in Canada.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s analysis:
CADTH reanalysis included aligning the eligibility of dupilumab with the Health Canada indication and reimbursement request, incorporating the proportion of patients eligible for public drug plan coverage, and correcting the Non-Insured Health Benefits (NIHB) and Ontario Drug Benefit (ODB) population size. CADTH reanalyses suggest that the reimbursement of dupilumab for the requested reimbursement population (patients aged 6 months to < 12 years) would be associated with a budgetary increase of $1,523,349,925 over the first 3 years (year 1: $381,570,740; year 2: $504,258,676; year 3: $637,520,510).
The estimated budget impact is highly sensitive to the number of patients eligible to receive dupilumab and the price of dupilumab.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.
Meeting date: August 23, 2023
Regrets: None
Conflicts of interest: None
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Indication: For the treatment of patients aged 6 months and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.
Sponsor: Sanofi-Aventis Canada Inc.
Final recommendation: Reimburse with conditions
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