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Dupilumab (Dupixent): CADTH Reimbursement Review: Therapeutic area: Asthma [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2023 Apr.
Asthma Canada is the only national, patient-driven charity, solely devoted to enhancing the quality of life for people living with asthma and respiratory allergies. The Board of Directors has a strong patient and caregiver presence. For nearly 50 years, Asthma Canada has proudly served as the national voice for Canadians living with asthma. We empower patients with evidence-based information, education programs and support asthma research in Canada. For more information about our organization, visit our website at: www.asthma.ca
A survey was independently developed and launched to seek the perspectives of people living with asthma, including caregivers. The survey was open from February 28th and closed on March 10th, 2022. Over 100 people responded to the survey and participants were from British Columbia (25%), Alberta (11%), Saskatchewan (2%), Manitoba (5%), Ontario (51%), Quebec (3%) and the Atlantic provinces (2%). Most participants lived with asthma (92%) while the rest were caregivers (8%). Four survey participants had experience taking Dupixent (dupilumab).
One of the authors (LP) of this submission lives with asthma that was diagnosed in childhood and also has a family history of severe asthma. Various reports and resources were referenced in developing this submission, such as clinical practice guidelines, the Dupixent (dupilumab) product monograph, websites of not-for-profit organizations, research papers, etc.
Asthma is a chronic, inflammatory condition of the airways of the lungs that causes difficulty breathing, chest tightness, coughing and wheezing. Asthma affects people at any age, including children and can be intermittent to severe. When diagnosed in childhood, the condition can continue into adulthood and becomes a lifelong disease. The disease affects an estimated 850,000 children under the age of 14, making it the most common chronic disease among children in Canada, and is the leading cause of hospitalization and school absenteeism. More than 20,000 hospitalizations each year means that children with asthma spend more time in the hospital, and less time playing outside, socializing, or learning in school.
Parents and children aim to control asthma by identifying environmental triggers and finding the right combination of pharmacological treatment(s) to reduce or eliminate asthma exacerbations (known as “asthma attacks”) with the support of a respirologist, family physician and/or pediatrician. The pharmacological treatments used to treat asthma depend on the type of asthma, severity of the condition, and how the child responds to various treatment options. What works for one person with asthma changes over time and means that many treatment options are needed to manage their health successfully. One in 4 people who completed our survey indicated they have poor symptom control even with currently available treatments. Many people with asthma have challenges in accessing the needed health providers, like respirologists and specialized asthma clinics, to manage their health. There can be significant time and burden involved to manage care with health care providers made worse with poor asthma control. There can be travel involved for those living in rural areas to centres providing the health care need. This means children miss school and parents and caregivers may miss work. Some parents and caregivers may not have paid leave to attend these appointments or may need to use vacation leave, if available.
“Sometimes not being able to breathe is just too scary for a child to endure.”
Parents and children have significant daily responsibility to self-manage asthma symptoms with the goal of ensuring the child can fully participate in day-to-day activities, like school and play. Inhaler technique is important and can be particularly difficult to manage with children. When well-controlled, there can be periods of stability however exacerbations or asthma attacks can occur due to environmental triggers like pollution, smoking, and allergies. Asthma attacks can also be triggered by viral infection and uncontrolled disease. Often, children with asthma face several barriers as adults and other children don’t adequately understand the impact of asthma on their lives or how environmental triggers can trigger asthma attacks.
“(I wish) places like schools understood the seriousness of asthma. (The most frustrating thing is) the judgement from others who don’t understand what it’s like with a child with asthma”.
Parents and caregivers are often concerned with accessing adequate and necessary medical care within a short period of time, as exacerbations can lead to urgent trips to the Emergency Department (ED) to address and restore airway function. In severe asthma attacks, loss of consciousness or hypoxia can occur. Visits to the ED can be stressful as parents and caregivers navigate busy and overcrowded ED, particularly during the COVID-19 pandemic and still currently, as backlogs and staff shortages continue. Access to specialists with knowledge of asthma continues to be a challenge. People with asthma and caregivers that responded to our survey noted the worry and fear of an asthma attack was the most concerning (60%) followed by potential for hospital visits / admissions (47%) and missed work and school days (47%).
Asthma symptoms impact both the child and family’s quality of life. Children may experience fatigue and have less energy to play and exercise. Making and keeping friends can be made more difficult due to the symptoms of the disease, the presence of environmental triggers, or activity limitations. School is an important part of a child’s development however children may not be able to attend and concentrate at school due to disease symptoms, fatigue, and exacerbations. The sleep of children with asthma can be disturbed and parents and caregivers are often called on to support their child in the night (38% of survey participants noted sleep as a concern). Children and parents / caregivers are faced with barriers in understanding the seriousness of asthma. They spend a significant amount of time educating their children’s friends, daycares, schools, and others about the seriousness of asthma.
“Having an asthmatic child has changed a lot. I am nervous to let him sleep over at friends. Constantly reminding him when he walks out the door to make sure Ventolin is in his pocket.”
The impact of asthma on parents and caregivers means missing work to care for their child when they are suffering from an asthma attack or bringing them to medical appointments. Children, parents, and caregivers are affected due to stress and concerns of the current and future health of the child. Medications need to always be kept on hand in case of emergency. Managing an asthma attack can cause panic in the child and their parents due to the life-threatening nature asthma attacks. There can be added stress due to financial hardships with paying for current treatments which can be expensive and strain a family’s finances.
“I have had to decline full time employment as I couldn't guarantee my availability if she (my child) was sick or in hospital.”
The COVID-19 pandemic has impacted children with asthma and their families. Asthma attacks can be triggered by respiratory viruses, like COVID-19. Many parents and caregivers fear seeking needed health care at ED’s and other facilities due to the fear of contracting COVID-19. ED’s have been deeply affected by the pandemic and this has affected services provided to others needing emergency care, like the asthma community. Drug shortages have impacted children with asthma due to limited supply. During the COVID-19 pandemic, many pharmacies dispensed a limited 30-day supply of medications causing further stress and anxiety in the asthma community. Many families suffered financial stress during the pandemic, and these factors created additional strain for families dealing with asthma.
“The ER (Emergency Room) won't give oxygen treatments anymore because of covid.”
The treatment of asthma involves both pharmacological and non-pharmacological treatments. Asthma self-management education is important especially since it is important to manage symptoms on a regular basis. It is important to identify triggers like respiratory viruses, indoor allergens, secondhand smoke, and exercise. However, access to self-management and appropriate specialist care can be challenging for many children with asthma.
“We worry about what this does to his body as he grows. He has been on and off since age 1 and he is 10 now.”
“Even with the inhalers, (I) still get out of breath when walking or climbing stairs.”
There are a range of pharmacological treatment options for children with asthma depending on the severity of the illness. There are “rescue medications’ like short-acting beta antagonists (SABA’s) that provide quick relief for asthma symptoms, like shortness of breath. There are “controller medications’ like inhaled corticosteroids, leukotriene modifiers, long-acting beta agonists (LABAs), Theophylline and combination inhalers. Varying doses of these medications are tried before finding the ideal dosage. Side effects of SABA’s include increased heart rate, nervousness, trembling, and sore throat. “Controller medications” can cause side effects, such as thrush, sore throat, and hoarseness. Many of the people who responded to our survey noted they took a variety of medications, such as inhaled corticosteroids (26%), rescue inhalers (61%), combination medications (75%), Leukotriene Receptor Antagonists (19%), and biologics (12%).
“(Managing asthma is) like a yo-yo. We’ve tried most biological, but none are long lasting.”
These medications are taken through a metered-dose inhalers or dry-powder inhaler and can be taken at home. It can be challenging to take these medications regularly given the frequency of administration. Children and parents are taught inhaler technique as it is crucial to maximizing the effectiveness of the medications. Often spacers are used to make administration easier but come at an additional cost and subject to varying degrees of insurance coverage. Nebulizers can be used at home and in a hospital to provide for easier administration however the child needs to cooperate and remain still. Nebulizer equipment comes at an additional cost to families.
“(I would like to) reduce usage of inhalers and antihistamine pills.”
For severe cases of asthma, children may take oral corticosteroids. Although helpful in the short-term, these medications have a long list of side effects if taken for longer periods of time and at higher doses. Side effects include weight gain, acne, excess facial hair, mood swings, high blood pressure, hyperactivity, high blood sugar, increased infection. In the long term, oral corticosteroids can cause osteopenia, osteoporosis, glaucoma, cataracts, and heart disease. The growth of the child can be affected by inhaled and oral corticosteroids and impact long-term self-image and confidence.
“Yes (I worry about) taking prednisone especially since he is so young.”
Immunomodulator medications, or biologics, are also available to treat severe asthma. Some biologics are for eosinophilic asthma or for those that are dependant on oral corticosteroids. Some biologics are available however only Omalizumab (Xolair), Mepolizumab (Nucala) and now Dupixent (dupilumab) are approved for use in children from age six to twelve. Many biologics are available in a self-injectable form (e.g., autoinjector pen). Side effects include allergic reactions, injection site reactions, and infections. Self-injection provides flexibility and reduces the time involved in taking medicine. However, parents can feel additional stress in learning how to give injections as proper training is needed before initiating therapy. Children may also have needle phobia which is common in children of any age. These stressors may affect the willingness to take the medication. It can also be difficult to travel as the self-injectors need to be constantly refrigerated.
The expectations of the drug are to offer another treatment option for children with severe asthma and their families. New treatment options have the potential to ease the burden on patients’ families, caregivers, and the healthcare system. It also provides another option for children with severe asthma who have tried many other pharmacological and non-pharmacological treatments. The current risk-benefit profile of Dupixent (dupilumab) is similar to other biologics, e.g., allergic infection.
“I am always out of breath.”
Children and parents reported that current treatments can be difficult to take highlighting that the mode of administration and frequency of dosing is important. Medications taken less frequently can be especially useful in children as cooperation is important. About one in four survey participants indicated that they need too many daily doses.
“The family will have a better life when the child has a better health with this medicine.”
A variety of side effects of inhalers are difficult to manage such as elevated heart rate, anxiousness, and thrush. Minimizing these side effects are important outcomes that should be considered when evaluating new therapies. Survey participants noted that dry throat (50%), difficulty sleeping (42%), increased heart rate (38%), headaches (36%), hoarseness (35%) and weight gain (34%) were the most bothersome symptoms. Oral corticosteroids cause a long list of side effects and impact on a child’s growth and reducing or eliminating oral corticosteroids is also important to patients.
Survey participants indicated their expectations for a new medication and ranked these expectations in the following order:
“The medications are expensive and without an extended health plan it would be challenging for me.”
Broadly speaking, children and parents expect to see improvements in a range of day-to-day activities affecting qualify of life, for example:
“I can’t sleep very well and I often feel nauseated.”
“(The most difficult thing is) the exhaustion from actively working to breathe. It affects your whole life depending on your triggers.”
Over half of survey participants indicated that the benefits of the new treatment are worth tolerating the potential side effects to improve management of asthma.
Dupixent (dupilumab) is a new immunomodulator that can be prescribed as an add-on maintenance treatment in people living with severe type 2/eosinophilic phenotype or dependent on oral corticosteroids. We spoke with one person who is currently taking Dupixent (dupilumab) that was prescribed by a respirologist. They had tried several biologics, corticosteroids, rescue inhalers and controller inhalers before starting the medication. They indicated that managing severe asthma is “like a teeter totter” and they are regularly worried about viruses, like COVID-19, that could trigger an asthma attack that requires hospitalization. They also shared the following thoughts about living with asthma and taking Dupixent:
“For the first seven days after taking Dupixent, I feel pretty good. I feel in better control than without it.”
“I’ve noticed an improvement on this medication; however, I do need to go on dexamethasone about 10 days after taking Dupixent. I wish I could find a medication that addresses both my lower and upper airway. My respirologist feels I need medications that target both airways.”
“I feel agitated and depressed, but I can’t say if it comes from living with asthma, the medications, COVID-19, or what’s going on in the world. I am very unmotivated. I am tired...”
Many people with asthma will have tried and used many other treatments before using Dupixent. The addition of a new biologic for children with severe asthma provides another treatment option so they can tailor treatments to their needs. Patients and caregivers value a reduction in other medications, such as oral corticosteroids and inhalers and less medication side effects. The asthma community would also value improvements in quality of life, like participation in school. A variety of outcomes are also valued as described in Section 5 – Improved Outcomes.
Not applicable.
Live vaccines cannot be given with Dupixent and this could be a challenge since children using this medication may not be fully immunized (e.g. Hepatitis, Meningococcal, HPV).
Did you receive help from outside your patient group to complete this submission? If yes, please detail the help and who provided it.
|||||||||||||||||||, a patient who lives with asthma, diagnosed in childhood and also has a family history of severe asthma helped write and review the survey respondent’s data.
Did you receive help from outside your patient group to collect or analyze data used in this submission? If yes, please detai l the help and who provided it.
See above.
List any companies or organizations that have provided your group with financial payment over the past 2 years AND who may have direct or indirect interest in the drug under review.
Financial Disclosures for Asthma Canada.
The Ontario Lung Association (now named Lung Health Foundation) is registered with the CADTH and pCODR (www.lunghealth.ca). The Lung Health Foundation (Ontario Lung Association) is a registered charity that assists and empowers people living with or caring for others with lung disease. It is a recognized leader, voice and primary resource in the prevention and control of respiratory illness, tobacco cessation and prevention, and its effects on lung health. The Foundation provides programs and services to patients and health-care providers, invests in lung research and advocates for improved policies in lung health. It is run by a board of directors and has approximately 46 employees, supported by thousands of dedicated volunteers.
The information provided from the Lung Health Foundation in this submission was obtained From a survey completed by 27 people living with Asthma and 2 caregivers to people living with Asthma. Input was received from Jan 2021 to June 2022. All respondents live in Ontario. Information on age and gender was not collected within this survey.
The patient experience with asthma can be divided between symptoms and quality of life. The survey respondents describe symptoms such as fatigue (67.7%), cough (51.6%), shortness of breath (74.2%), excessive mucus (41.9%), wheezing (41.9%), and chest tightness (45.2%). Asthma affects their activities of daily living such as difficulty with housework (40.0%), difficulty with going to work (33.3%), difficulty climbing stairs (43.4%), difficulty with sports and physical activities (40.0%), and difficulty with leisure activities and hobbies (30.0%). The respondents’ comments regarding impacts of asthma on their quality of life included:
“I have challenges babysitting grandchildren”
“I can’t play soccer”
“When humid, I have to stay indoors”.
“It is horrible living with this. It is constantly on your mind and I feel like a burden to my family”
“I feel embarrassed from coughing and phlegm.”
Other negative impacts included waking at night or early morning because of breathing problems (34.5%), emotional well-being (37.9%), being short tempered or impatient with others (31.0%), managing symptoms (31%), being unable to do daily activities due to shortness of breath (55.2%), being unable to do daily activity due to fatigue (41.4%).
The patients indicated that they were treated with Alvesco, Symbicort, Ventolin, Onbrez, Spiriva, Advair, Trelegy, Pulmicort, Breo, Flovent, Arnuity, Bricanyl, Breo, Incruse, Respimat, Fasenra, Singulair, Combivent and Xolair.
Patients reported that medications have helped to reduce cough (40.7%), reduce shortness of breath (74.1%), increase energy (29.6%), increase ability to exercise (44.4%), increase participation in daily activities (37.0%).
The side effects reported from the medications were heart palpitations, poor sleep, voice hoarseness and inability to fight infection.
Key treatment outcomes for the patients interviewed include improving symptom management, improving energy, reducing cost, and improving quality of life. A survey respondent stated, “this condition affects negatively my emotional and social life. I have anxiety about nights, because quite often at night, I cannot breathe properly”. Another respondent stated, “each time meds are changed there is a fear that I will not be able to get the new drug. All have been via compassionate care program. Cost is prohibitive in most cases. Provincial and or federal coverage is a must.”
No patients within this evidence group submission had experience with the medication under review. Patients with uncontrolled asthma have a reduced quality of life due to exacerbations. There continues to be an unmet need in treatment options that reduce exacerbations.
Not applicable.
Not applicable.
To maintain the objectivity and credibility of the CADTH reimbursement review process, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This Patient Group Conflict of Interest Declaration is required for participation. Declarations made do not negate or preclude the use of the patient group input. CADTH may contact your group with further questions, as needed.
Did you receive help from outside your patient group to complete this submission? If yes, please detail the help and who provided it.
No.
Did you receive help from outside your patient group to collect or analyze data used in this submission? If yes, please detail the help and who provided it.
No.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review.
Financial Disclosures for the Lung Health Foundation/The Ontario Lung Association.
The Canadian Thoracic Society (CTS) is a national specialty society and membership-based professional association for health care providers (HCPs) working in respiratory care and research. Our mission is to promote lung health by enhancing the ability of HCPs through leadership, collaboration, research, learning and advocacy, and providing the best respiratory practices in Canada. CTS is recognized as an accrediting body of the Royal College of Physicians and Surgeons for specialist education and continuing professional development.
Website: https://cts-sct.ca/wp-content/uploads/2022/07/CTS-Sev-Asthma-Continuum.pdf
The following document has been prepared as a submission to CADTH in response to its request for clinician input into the application by Sanofi Canada regarding its add-on maintenance treatment, DUPIXENT™. The submission represents the viewpoint of the Canadian Thoracic Society with respect to severe asthma therapy in individuals aged 6 to 11 years of age with severe asthma with a type 2/eosinophilic phenotype or oral corticosteroid-dependent asthma. The draft document was prepared by the Asthma Assembly Steering Committee Co-Chairs and Pediatric Respirologists. The final draft document was then submitted to the CTS Executive Committee for review, revision and approval prior to its submission.
Children with severe asthma are those who require treatment with daily high dose inhaled corticosteroids and a second controller medication, or who remain uncontrolled despite that treatment. Unfortunately, non-pharmacologic treatments such as environmental modification are not effective enough in controlling asthma, and particularly severe asthma.
In Canada, children with severe asthma have limited treatment options in comparison to adults given that tiotropium is not approved for those under 18 years of age and is not regularly used off-label in children 6-11 years of age as there is no evidence for improvement in outcomes other than small benefits in lung function. The only other options include injectable biologic medications: omalizumab, mepolizumab and dupilumab. To date, omalizumab is the typical treatment recommended for children 6-11 years of age with severe asthma, evidence of aeroallergen sensitization and an IgE ranging from 30 IU/ml to 1300 IU/ml. Mepolizumab is approved for use in Canada for children 6-11 years of age with severe asthma, eosinophils >=150cells/uL at initiation of treatment or >=300cells/uL in the last 12 months. However, there has not been a large use of this medication in children 6-11 years of age given the limited longer term safety data (n=30 patients in 52 week open-label trial) and the paucity of efficacy data in this age group with no randomized-control data. Dupilumab was recently approved for use in children with severe asthma and there is safety data from trials of children 6-11 years of age with atopic dermatitis (>600 patients). It is currently being used in those 6 years of age and older with severe asthma (funded through extended health plans or compassionate release from the pharmaceutical company) and would be the first choice medication in those with severe asthma and concomitant eczema.
Clinical practice guidelines for severe asthma (CTS, ATS/ERS) only included clinical trials published up to 2018. For children 6-11 years of age, the guidelines recommend omalizumab (CTS, ATS/ERS) and the ATS/ERS but not the CTS recommends tiotropium.
An ideal asthma medication for children with severe asthma would allow them to have: well controlled asthma (less frequent and severe symptoms) including good activity tolerance, no to minimal severe exacerbations, normal lung function, improved quality of life, no to minimal side-effects from asthma medication, and be easy to administer. Compared to adults, it is particularly important for children to meet these asthma goals as their lungs are still growing and the consequences of poorly controlled asthma (e.g., decreased activity levels and missed school) have lifelong, irreversible detrimental effects. Children are also more susceptible to side effects from high dose inhaled corticosteroids compared to adults and can have irreversible growth suppression and life-threatening adrenal suppression. Chronic oral steroids are not considered a viable treatment option in children with severe asthma given the side-effect profile.
For those with severe asthma, asthma medications that have been shown to improve asthma control, decrease frequency of exacerbations and improve lung function in those with mild to moderate asthma are not as effective. In this age group, tiotropium can improve lung function and omalizumab improves lung function, asthma control and decreases exacerbations in those that meet the initiation criteria. There is no randomized control efficacy data for mepolizumab in this age group. To date, none of the asthma medication has been shown to cure asthma such that when medication is discontinued symptoms recur. Thus, we are in great need of additional asthma medications for this age group that can improve lung function and reduce exacerbations such as dupilumab.
Considering the treatment goals in Section 3, please describe goals (needs) that are not being met by currently available treatments.
In general, the key goals in asthma management include preventing asthma exacerbations (which are potentially life-threatening), maximizing quality of life, preventing symptoms, and maximizing exercise tolerance. Secondary goals include normalizing lung function, reducing airway inflammation, and avoiding permanent airway remodeling. In children, it is essential to achieve these goals while avoiding chronic use of oral corticosteroids and using the lowest effective dose of inhaled corticosteroids (ICS), to avoid growth suppression, adrenal suppression, and other important adverse events. In the majority of children, these goals can be achieved with low or moderate doses of ICS, with or without the addition of other controllers (long-acting beta-2 agonists or a leukotriene receptor antagonist). In the relatively small subgroup of children with severe asthma, achieving acceptable control typically requires high doses of ICS and/or oral steroids and add-on therapies, with a very high risk of important adverse events. In some children, acceptable control cannot be achieved even with these therapies. Children with severe asthma often have frequent severe exacerbations which are treated with oral steroids, so even if they’re not on chronic oral steroids, they can have recurrent exposures to oral steroids, with a high risk of side effects. Studies in adult Severe Asthma Clinics have demonstrated that many people with “severe asthma” have poor adherence, and evaluating adherence to existing therapies is challenging.
Biologic agents provide a means of improving asthma control in children with severe asthma with type II (eosinophilic or atopic) inflammation at significant risk of adverse events. In addition, if these agents are administered at a health care facility, adherence can be monitored. The first such agent, omalizumab, is limited to children with a serum IgE of 72 to 1680 mcg/L. Children with an IgE < 72 are generally not atopic and don’t require this type of product. However, many children with severe asthma and eczema have an IgE of 5,000 mcg/L or more, where omalizumab is not indicated. Biologics that target eosinophil survival and function require an elevated eosinophil count for efficacy but have no upper limit of eosinophil concentration, and don’t suffer from this limitation.
At present, mepolizumab is available for children with severe asthma ages 6-11 years with eosinophilic (type II inflammation). The indications for mepolizumab and dupilumab for the treatment of asthma overlap, and efficacy, while it has not directly compared, is probably fairly similar. According to their product monographs, mepolizumab is indicated for children with a blood eosinophil count of at least 150 cells/microliter at treatment initiation (or 300 in the past year) and dupilumab, in children with type 2/eosinophilic inflammation, although the pivotal trial (referenced in the monograph) also generally required an eosinophil count of 150 cells/microliter. Importantly, other indications vary between the products, and as children with severe asthma often have other, and often severe, atopic conditions, this is important. Mepolizumab is also indicated for individuals with chronic rhinosinusitis with nasal polyps and eosinophilic granulomatosis with polyangiitis, though both these conditions are uncommon in children. Dupilumab is also indicated for chronic rhinosinusitis with nasal polyps, but also for moderate to severe eczema, which is very common in children with asthma. Thus, for children with severe asthma and atopic dermatitis, dupilumab becomes an important therapeutic option. Other arguments for including dupilumab as a therapeutic option for this age group include children allergic to, or who have had severe adverse events with mepolizumab (although these circumstances are likely uncommon), and having an alternative therapy should supply issues render mepolizumab unavailable.
In terms of remaining unmet needs, younger children with severe asthma may have non-type 1 inflammation and recurrent severe exacerbations driven by viral acute respiratory tract infections. This involves neutrophilic inflammation, and effective add-on therapies for children with this phenotype who are incompletely controlled with inhaled corticosteroids have not been identified. Similarly, a subgroup of older children with severe asthma also have neutrophil-triggered inflammation, and effective add-on therapies are also needed in this population.
How would the drug under review fit into the current treatment paradigm?
Dupilumab targets type II inflammation by blocking the alpha subunit of the interleukin (IL)-4 receptor and inhibits signaling by IL-4 and IL-13. This mechanism of action differs from current available therapies for children with severe asthma, which commonly include inhaled or oral corticosteroids (ICS, OCS), long-acting beta-agonists (LABA), leukotriene receptor antagonists (LTRA). Other biologics available for children 6-11 include omalizumab (anti-IgE) and mepolizumab (anti-IL5), although they target different pathways than the IL-4/IL-13 pathway. Thus, the mechanism of action of dupilumab is complementary to other available treatments Additionally, while dupilumab is not the first treatment approved to address eosinophilic type II inflammation in pediatric severe asthma. However, it is the first to specifically inhibit the IL-4/IL-13 pathway.
The use of dupilumab would follow the Canadian Thoracic Society Severe Asthma Management Continuum. Following the current treatment paradigm, dupilumab would be recommended as an add-on therapy in severe asthma and would be considered when other biologics are indicated. This occurs when a child is not well controlled on a combination of high-dose ICS, LABA, and LTRA, or when a child experiences significant side effects from these medications or when these medications are contraindicated. Furthermore, injectable medications such as biologics are generally associated with a higher burden for families (thus less acceptability) and incur higher costs for the health system. Thus, it is appropriate to recommend biologics based on the child’s inflammatory profile and only after standard therapy has been adequately tried with good adherence.
Which patients would be best suited for treatment with the drug under review? Which patients would be least suitable for treatment with the drug under review?
The patients most likely to respond to treatment are those aged 6-11 years old with type II inflammation, moderate to severe asthma not adequately controlled on medium dose ICS plus LABA or high dose ICS and with a severe exacerbation in the past year. Those with type 2 inflammation are defined as having a serum eosinophil count >=150 and FeNO >=20 ppm) or with a serum eosinophil count >= 300. Those patients with an eosinophil count > 300 and with a baseline FeNO of 25 ppb have been shown to have the best response to dupilumab.
The patients in most need of this intervention are those with frequent severe exacerbations with evidence of type 2 inflammation as defined above despite medium dose inhaled corticosteroids plus a second controller or those on a high dose ICS. Patients with frequent exacerbations and frequent doses of corticosteroids will benefit the most.
The only disease characteristics that would differ in patients most likely to respond are markers of type 2 inflammation (FeNO elevation and eosinophil count > 150). They must also have moderate to severe asthma and be on at least moderate to high dose ICS, oral steroids and/or a second controller medication and still have ongoing symptoms and exacerbations.
The patients best suited for treatment would be identified by their treating respirologist or allergist. They should have confirmation of asthma diagnosis based on symptoms and spirometry showing reversibility (>10% change in FEV1). If not under the care of a respirologist or allergist they should be referred before considering this treatment to ensure their disease management is otherwise optimized. They would have spirometry pre and post bronchodilator, a clinical assessment and CBC with differential count done and a FeNO if available.
If the appropriate pulmonary function testing is done along with a clinical assessment by a respirologist or allergist there should be little issues related to diagnosis of asthma.
The only diagnostics tests required are spirometry to confirm diagnosis and measures of type two inflammation of which serum eosinophil count is readily available. FeNO was also used in the studies but eosinophil count alone also predicted response and nothing beyond usual care is required. The only tool that would likely be helpful is broader access to exhaled nitric oxide (FeNO).
Misdiagnosis of asthma does occur, but it is our recommendation that use of this drug be restricted to respirologists and allergists who look after severe asthma and thus the appropriate diagnostic test will be conducted and the chance of any misdiagnoses and thus any misuse of the drug would be very small.
It is possible to identify those patients who are likely to exhibit a response to the drug as they are that patients described in detail in the studies. Those with both high eosinophil counts and high FeNO will respond best but there is also a good response with lower levels of eosinophil count as long as it is above 150. The patient should also have an exacerbations history as reduction in exacerbations was the main outcome in the clinical trials.
What outcomes are used to determine whether a patient is responding to treatment in clinical practice? How often should treatment response be assessed?
The addition of biologic therapy such as dupilumab in severe asthma is done with specific treatment goals in mind. Clinically meaningful outcomes for patients would include lessening the frequency and severity of symptoms, improving quality of life (e.g. exercise tolerance, school/work attendance), reducing exacerbations and minimizing side effects from existing maximal therapy (e.g. steroid side effects). There is also the potential of reducing the burden of daily medication and improving compliance to treatment with injection therapy. Reduction of inflammatory markers, improvement of lung function and prevention of long-term airway remodeling, particularly relevant for the younger pediatric population aged 6-11, are also key outcomes.
In clinical trials, dupilumab was shown to significantly reduce the annualized rate of severe exacerbations in the pediatric population aged 6-11 years. It also resulted in higher asthma control scores (e.g. Asthma Control Questionnaire 7 -IA at week 24 where a 0.5 increase in score was considered clinically significant) and improved baseline FEV1 compared to existing therapy. Additional markers of airway (e.g. FeNO at week 12 from baseline) and circulatory (serum total IgE and serum thymus and activation-regulated chemokine or TARC) inflammation were also reduced with the drug under review compared to placebo. Dupilumab was shown to achieve these outcomes with a low incidence of severe adverse events in the pediatric group, similar to adolescents and adults, and importantly, a rate which did not differ from those on standard background therapy.
Clinical measures such as Asthma Control Questionnaires and assessment of FEV1 and exacerbation rates are routinely used in clinical practice and utilization would not differ amongst specialist physicians. However, secondary endpoints such as inflammatory markers may not be routinely used or accessible in practice and there may be variation in their application.
What factors should be considered when deciding to discontinue treatment with the drug under review?
Factors to consider for discontinuation of treatment with dupilumab would include lack of clinically meaningful positive outcomes over an expected timeframe, such as annualized rates of exacerbation similar to pre-treatment levels, similar or worse pre-bronchodilator FEV1 or patient symptom scores. Additionally, safety concerns around significant adverse local or systemic events, and patient choice e.g., regimen fatigue may play roles in the decision to discontinue this treatment.
Conversely, a positive response to treatment in these parameters may be relevant when considering renewal of treatment with dupilumab.
What settings are appropriate for treatment with [drug under review]? Is a specialist required to diagnose, treat, and monitor patients who might receive [drug under review]?
It is recommended that the first one or more doses of dupilumab should be administered by a healthcare professional in a hospital/medical setting to ensure correct technique for administration (e.g., identifying appropriate injection site, depth of injection) and tolerance by the patient, given their young age. Following this, injection by the caregiver can be undertaken in the community setting, at home, after the healthcare professional determines it is appropriate and the caregiver has received proper training on correct administration.
An asthma specialist is required to diagnose, treat and monitor patients who might receive the drug under review. This recommendation is made based on recommendations in the Canadian Thoracic Society Position Statement for the Recognition and Management of Severe Asthma (https://cts-sct.ca/wp-content/uploads/2018/01/Recognition-and-Management-of-Severe-Asthma.pdf) because this medication is indicated for children with moderate to severe asthma who are not responding to conventional therapies. Typically, the assessment of whether a child would qualify for a biologic asthma therapy (including determining adherence to typical therapies, correct administration technique and absence of an alternative diagnosis to explain suboptimal asthma control despite typical therapy) is best done by an asthma specialist. Asthma specialists can include (but may not be limited to): respirologists, allergists, pediatricians with a focus in childhood asthma. Per the Canadian Thoracic Society Position Statement for the Recognition and Management of Severe Asthma, “an operational definition of ‘asthma specialist’ would include specialists in asthma, general respirology, pediatrics, and/or allergy/immunology who have access to lung function, certified asthma/respiratory educators/nurse practitioners and FeNO C/¡ induced sputum analysis.”
To maintain the objectivity and credibility of the CADTH drug review programs, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This conflict of interest declaration is required for participation. Declarations made do not negate or preclude the use of the clinician group input. CADTH may contact your group with further questions, as needed.
Did you receive help from outside your clinician group to complete this submission? If yes, please detail the help and who provided it.
No outside help was sought or received.
Did you receive help from outside your clinician group to collect or analyze any information used in this submission? If yes, please detail the help and who provided it.
No outside analysis was sought or received.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review. Please note that this is required for each clinician who contributed to the input — please add more tables as needed (copy and paste). It is preferred for all declarations to be included in a single document.
Name: Dhenuka Radhakrishnan
Position: Co-Chair CTS Asthma Assembly - Pediatric Respirologist, Children’s Hospital of Eastern Ontario and Associate Professor, Department of Pediatrics, University of Ottawa
Date: 11-07-2022
COI Declaration for Canadian Thoracic Society — Clinician 1.
Name: Clare Ramsey
Position: Co-Chair CTS Asthma Assembly – Adult Respirologist, Health Sciences Centre Winnipeg, Associate Professor, Department of Respiratory Medicine, University of Manitoba
Date: 11-07-2022
COI Declaration for Canadian Thoracic Society — Clinician 2.
Name: Tom Kovesi
Position: Pediatric Respirologist, Children’s Hospital of Eastern Ontario, Professor, Department of Pediatrics, University of Ottawa
Date: 11-07-2022
COI Declaration for Canadian Thoracic Society — Clinician 3.
Name: Sze Man Tse
Position: Pneumologue pédiatrique, CHU Sainte-Justine, Professeure adjointe de clinique, Département de pédiatrie, Université de Montréal
Date: 11-07-2022
COI Declaration for Canadian Thoracic Society — Clinician 4.
Name: Tania Samanta
Position: Pediatric Respirologist at North York General Hospital
Date: 11-07-2022
COI Declaration for Canadian Thoracic Society — Clinician 5.
Name: Connie Yang
Position: Past Co-Chair, CTS Asthma Assembly - Pediatric Respirologist, British Columbia Children's Hospital, Clinical Associate Professor, Division of Respiratory Medicine, Department of Pediatrics, University of BC
Date: 11-07-2022
COI Declaration for Canadian Thoracic Society — Clinician 6.
Copyright © 2023 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
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