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Interleukin-4 (IL-4) Inhibitor Prior Authorization with Quantity Limit Program Summary
Policy Number: PH-91119
This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx, SourceRx-Performance, and Health Insurance Marketplace formularies.
POLICY REVIEW CYCLE
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Effective Date |
Date of Origin |
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10-01-2025 |
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FDA LABELED INDICATIONS AND DOSAGE
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Agent(s) |
FDA Indication(s) |
Notes |
Ref# |
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Dupixent® (dupilumab) Subcutaneous injection |
Treatment of adult and pediatric patients aged 6 months and older with moderate-to-severe atopic dermatitis (AD) whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Dupixent can be used with or without topical corticosteroids Add-on maintenance treatment of adult and pediatric patients aged 6 years and older with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma
Add-on maintenance treatment in adult and pediatric patients aged 12 years and older with inadequately controlled chronic rhinosinusitis with nasal polyps (CRSwNP) Treatment of adult and pediatric patients aged 1 year and older, weighing at least 15 kg, with eosinophilic esophagitis (EoE) Treatment of adult patients with prurigo nodularis (PN) Add-on maintenance treatment of adult patients with inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype
Treatment of adult and pediatric patients aged 12 years and older with chronic spontaneous urticaria (CSU) who remain symptomatic despite H1 antihistamine treatment
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1 |
See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm
CLINICAL RATIONALE
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Asthma |
Asthma is a chronic inflammatory disorder of the airways. It is characterized by a history of respiratory symptoms along with variable expiratory airflow limitation, and is typically associated with bronchial hyperresponsiveness and underlying inflammation. Symptoms are variable and recurrent and include wheezing, coughing, shortness of breath, and chest tightness. Exercise, exposure to allergens and irritants, infections, and changes in the weather can be contributing factors to the variability in symptoms and airflow limitation.(11) Guidelines recommend evaluating respiratory symptoms, medical history, physical examination, and spirometry to determine a diagnosis of asthma.(9,11) Long-term goals for asthma management are to achieve control of symptoms, maintain normal activity level, and to minimize the future risk of exacerbations, decline in lung function, and medication side effects.(11) Different types of asthma and levels of severity exist. Moderate asthma is asthma that requires a low- or medium-dose inhaled corticosteroid (ICS) used in combination with a long-acting beta agonist (LABA) to be well controlled. Severe asthma is asthma that remains uncontrolled despite optimized treatment with high-dose ICS-LABA, or that requires high-dose ICS-LABA or biologic therapy to prevent it from becoming uncontrolled (e.g., asthma worsens when high-dose treatment is decreased). Severe asthma needs to be distinguished from difficult-to-treat asthma that remains symptomatic due to poor adherence, poor inhaler technique, comorbidities, and/or continued exposure to environmental agents since treatment and management differs between the two.(11) The European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines (2014; updated 2020) define uncontrolled asthma for adults and pediatric patients 6 years of age and older as a patient having at least one of the following:(10)
The Type 2 inflammatory asthma phenotype is found in the majority of people with severe asthma. Type 2 inflammation involves a systemic allergic response and elevated levels of Type 2 inflammatory cytokines such as interleukin (IL)-4, IL-5, and IL-13. Elevated eosinophils or an increased fractional exhaled nitric oxide (FeNO) are characteristics of the eosinophilic subtype of Type 2 inflammatory asthma, while the allergic asthma subtype is additionally characterized by elevated immunoglobulin E (IgE) levels and positive skin prick testing with common environmental allergens. Type 2 inflammation typically responds well to ICS treatment and rapidly improves, however, in severe asthma Type 2 inflammation may be relatively refractory to high-dose ICS. Maintenance oral corticosteroids (OCS) may elicit a response, but the risk of serious adverse effects with daily OCS use deters their usefulness and an alternative treatment should be sought.(11) Type 2 inflammation is considered refractory if any of the following are found while the patient is taking high dose ICS or daily OCS:(11)
The Global Initiative for Asthma (GINA) guidelines recommend a stepwise approach for managing asthma. The 2024 GINA guidelines recommend all patients 6 years of age and older with asthma should receive ICS-containing controller medication to reduce the risk of serious exacerbation, even in patients with infrequent symptoms. It is recommended that patients with asthma symptoms most days should be started on low dose maintenance ICS-formoterol or an alternative ICS-LABA product. Patients' response to treatment should be reviewed after 2 to 3 months. If symptoms remain uncontrolled despite good adherence and correct inhaler technique, the next step up (Step 4) involves increasing controller therapy to medium or high dose ICS-formoterol (ICS-LABA). Other controller options that may be added on to ICS treatment at Step 4 include a long-acting muscarinic antagonist (LAMA), leukotriene receptor antagonist (LTRA), or theophylline. Both LTRA and theophylline are considered less efficacious than adding on a LABA or LAMA, and also come with safety concerns. Patients with uncontrolled symptoms and/or exacerbations despite being on Step 4 treatment for 3 to 6 months should be assessed for contributory factors, have their treatment optimized, and be referred for expert assessment, phenotyping, and potential add on biologic therapy. Maintenance oral corticosteroids (OCS) should be used only as last resort because short-term and long-term systemic side-effects are common and serious.(11) Biologic agents should be considered as add-on therapy for patients with refractory Type 2 inflammation with exacerbations and/or poor symptom control despite taking at least high dose ICS-LABA, and who have allergic or eosinophilic biomarkers or need maintenance OCS, and only after treatment has been optimized.(11) Tezepelumab is considered a broad-acting biologic and may be considered in patients without a Type 2 inflammatory phenotype due to it binding to circulating thymic stromal lymphopoietin (TSLP), which is upstream on the inflammatory cascade.(11,25) Based on efficacy results from clinical trials, the indication of use for tezepelumab is not restricted to a biomarker-defined phenotype.(25) 2024 GINA guidelines recommend the use of biologics based on the following patient eligibility factors:(11)
Patient response to biologic therapy should be evaluated 4 months after initiating therapy, and the patient should be re-evaluated every 3 to 6 months. If response is unclear after 4 months, the trial should be extended to 6-12 months.(11) 2024 GINA guidelines recommend the following step-down therapy process in patients responding well to targeted biologic therapy:(11)
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Atopic Dermatitis (AD) |
Atopic dermatitis (AD), also known as atopic eczema, is a chronic, pruritic inflammatory dermatosis affecting up to 25% of children and approximately 7% of adults.(2,7) AD follows a relapsing course and is associated with elevated serum immunoglobulin (IgE) levels and a personal or family history of type I allergies, allergic rhinitis, and/or asthma. Onset is most common between 3 and 6 months of age, with approximately 60% of patients developing the eruption in the first year of life and 90% by age 5. While the majority of affected individuals have resolution of disease by adulthood, 10-30% do not, and a smaller percentage first develop symptoms as adults. AD has a complex pathogenesis involving genetic, immunologic, and environmental factors, which lead to a dysfunctional skin barrier and dysregulation of the immune system. Clinical findings include erythema, edema, xerosis, erosions/excoriations, oozing and crusting, and lichenification. These clinical findings vary by patient age and chronicity of lesions. Pruritus is a hallmark of the condition that is responsible for much of the disease burden borne by patients and their families. Typical patterns include facial, neck and extensor involvement in infants and children; flexure involvement in any age group, with sparing of groin and axillary regions.(2) Goals of treatment are to reduce symptoms (pruritus and dermatitis), prevent exacerbations, and minimize therapeutics risks.(13) Despite its relapsing and remitting nature, the majority of patients with AD can achieve clinical improvement and disease control with topical emollient/moisturizer use and conventional topical therapies (including corticosteroids and calcineurin inhibitors).(5,13) Moisturizers reduce signs, symptoms, and inflammation in AD, and can improve severity while also increasing time between flares. Moisturizers are considered generally safe and are strongly recommended to be used as part of a treatment regimen for AD, either as monotherapy or as concurrent use with pharmacologic treatments.(4) Topical therapies remain the mainstay of treatment due to their proven track record and generally favorable safety profile. They can be utilized individually or in combination with other topical, physical, and/or systemic treatments; as different classes of treatment have different mechanisms of action, combining therapies allows for the targeting of AD via multiple disease pathways. The American Academy of Dermatology (AAD) strongly recommends the following topical agents:(4)
TCS are the most commonly utilized FDA-approved therapies in AD and are typically used as first-line treatment for mild-to-severe dermatitis in all skin regions. TCS target a variety of immune cells and suppress the release of proinflammatory cytokines. High to very high (super) potency TCS can be used to control flares and treat severe disease, while medium potency TCS are utilized for longer courses and as maintenance therapy. Lower potency TCS may be used, and it is important to consider the anatomical site (i.e., using lower potency agents on the face, neck, genitals, and body folds) and severity of the disease when choosing a steroid potency.(4) Clinical trials assessing efficacy generally had a duration of 2 to 6 weeks, and response to TCS therapy should be evaluated by week 4 in clinical practice.(7) Most studies of TCS in AD management involve twice daily application, but some studies (particularly for potent TCS) suggest once daily use may be sufficient. Traditionally, TCS were stopped once AD signs and symptoms of an AD flare were controlled. Maintenance in between AD flares with once to twice weekly use of TCS is another approach.(4) TCIs are a safe anti-inflammatory option for mild-to-severe AD, particularly when there is concern for adverse events secondary to corticosteroid use. Both tacrolimus and pimecrolimus have been shown to be effective in treating AD, but pimecrolimus may be more appropriate for patients who have milder disease or are sensitive to local reactions.(4) Prescribing information for pimecrolimus cream and tacrolimus ointment indicate evaluation after 6 weeks if symptoms of AD do not improve for adults and pediatrics.(6,12) When AD is more severe or refractory to topical treatment, advanced treatment with phototherapy or systemic medications can be considered. Phototherapy is conditionally recommended by the AAD as a treatment for AD based on low certainty evidence. The AAD strongly recommends the following systemic therapies:(5)
In a change from the 2014 AAD AD guidelines, the use of systemic antimetabolites such as methotrexate, immunosuppressants such as systemic corticosteroids, mycophenolate mofetil, azathioprine, and cyclosporine are now conditionally recommended for AD only in a small number of select patients due to low or very low certainty of evidence and need for monitoring. The most favored first-line systemic agent is dupilumab.(5) There is no clear consensus on how to operationalize a definition of the FDA indication for treatment of patients with "moderate to severe" AD. The severity of AD can vary substantially over time and, from a patient's perspective, can include a complex combination of intensity of itch, location, body surface area (BSA) involvement, and degree of skin impairment. Given the variability of patient phenotype and lack of familiarity among clinicians with scoring systems used in clinical trials, it is advisable to create a broad clinically relevant definition inclusive of multiple specific measures of disease intensity; for example:(26) One of the following:
OR One of the following:
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Chronic Obstructive Pulmonary Disease (COPD) |
Chronic obstructive pulmonary disease (COPD) is a common lung disease characterized by chronic respiratory symptoms caused by abnormalities of the airways and/or alveoli that cause persistent, and often progressive, airway obstruction. Symptoms include dyspnea, cough, wheezing, fatigue, sputum production, and/or exacerbations. The global prevalence of COPD is estimated to be 10.3% and comes with substantial economic and social burden. COPD is one of the top causes of death in the United States and is a leading cause of morbidity and mortality worldwide, with around three million deaths globally annually.(31) COPD develops due to a combination of environmental exposures and patient characteristics. Smoking and air pollution are the two leading environmental exposures leading to the development of COPD. Prolonged exposure to these toxins leads to chronic inflammation which causes structural changes, narrowing of the small airways (bronchiolitis), and destruction of the lung parenchyma (emphysema).(31) Chronic bronchitis is a common condition in patients with COPD, and it is defined as chronic cough and sputum production (e.g., chronic productive cough) for at least 3 months per year for two consecutive years in the absence of other conditions that may be causative. Long-term inflammation and excess mucus production can lead to the formation of mucus plugs and greater airflow obstruction. Large observational studies have shown that the prevalence of chronic bronchitis ranges from 27-35% in patients with COPD, with the primary risk factor being smoking. Chronic bronchitis contributes to a worse quality of life and increased mortality.(31) A diagnosis of COPD is dependent on the presence of pulmonary symptoms (i.e., dyspnea, chronic cough, sputum production), patient’s exposure history (e.g., current/previous smoker, history of recurrent lower respiratory tract infections), and evidence of airflow limitation. The diagnosis is confirmed by spirometry. A post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) less than 0.7 is indicative of the diagnosis.(31) Once a diagnosis of COPD is confirmed, it is important to determine the severity of airflow obstruction for assessment of prognosis and risk of exacerbations. Airflow obstruction severity is based on the post-bronchodilator value of FEV1. The cutoff points for each Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade of severity are as follows:(31)
Exacerbations of COPD are episodes of acute worsening of respiratory symptoms. They lead to increased dyspnea and/or cough and sputum that worsens over a less than 14 day period. They are often associated with increased airway inflammation, increased mucus production, and marked gas trapping. Symptoms of a COPD exacerbation are usually present for 7 to 10 days. They can be caused by infection, pollution, or other insult to the lungs. Moderate exacerbations are those that require treatment with a short acting bronchodilator (SABD) and oral corticosteroids, with or without an antibiotic. Severe exacerbations are associated with hospitalization or a visit to the emergency room, and may also be associated with acute respiratory failure requiring mechanical ventilation. Frequent exacerbations are defined as having two or more exacerbations per year and typically lead to a worse health status and morbidity for patients. A previous history of exacerbations is the best predictor of having frequent exacerbations, but worsening airflow obstruction is also associated with an increased prevalence of exacerbations, hospitalization, and risk of death.(31) The treatment goals of COPD are to reduce symptoms and prevent disease progression and exacerbations. The GOLD "ABE" assessment tool is recommended for determining initial pharmacotherapy for the management of COPD. The tool takes into account patient symptoms and history/risk of exacerbations to assign a GOLD group (A, B, or E). Exacerbation history is broken into two sections based on the number of exacerbations per year. For patients with 0 to 1 moderate exacerbations within the past year, a formal assessment of symptoms using validated questionnaires is required to further establish the patient's GOLD grade and initial therapy. The modified Medical Research Council (mMRC) dyspnea scale assesses breathlessness, which is a key symptom for many patients with COPD. A more comprehensive questionnaire is the COPD Assessment Test (CAT), which assesses the impact of COPD on a person's health status. For group E individuals, a blood eosinophil count can guide the use of an inhaled corticosteroid (ICS) as part of pharmacological management. Studies have shown that an ICS added to regular maintenance bronchodilator treatment in patients with higher blood eosinophil counts can prevent future exacerbations.(31)
Treatment recommendations based on GOLD "ABE" grouping are as follows:(31)
The GOLD guideline has a separate algorithm for follow up therapy, based on persistence of dyspnea and occurrence of exacerbations. Patients not responding to initial therapy should have inhaler technique, adherence, and possible interfering comorbidities addressed prior to adding or changing therapies. Follow-up recommendations are as follows:(31)
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Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) |
Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory condition affecting the paranasal sinuses.(16) The exact cause of CRSwNP is unknown, but biopsies of nasal polyps have shown elevated levels of eosinophils. Sinus computed tomography (CT) and/or nasal endoscopy are needed to determine the presence of sinonasal inflammation and nasal polyps.(15) The International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) indicates that the diagnostic criteria for CRSwNP consist of ALL the following:(24)
Topical saline irrigation and intranasal corticosteroids (INCS) are recommended in the guidelines as initial treatment for CRSwNP.(16,18,24) Nasal saline irrigation used as adjunct treatment with other therapies improves symptoms and quality of life (QoL) outcomes and is considered an important aspect of management of CRSwNP. Saline irrigation can improve nasal mucosa function through the mechanical clearance of thick mucus and inflammatory mediators, including eosinophilic mucin.(18,24) INCS can have a positive impact on the disease and improve symptoms, reduce nasal polyp size, and improve sense of smell.(18,24) The ICAR-RS strongly recommends INCS before or after sinus surgery.(24) INCS are well tolerated and long term treatment is effective and safe. Many different INCS have been used in the treatment of CRSwNP, including triamcinolone, mometasone, fluticasone, and budesonide, but no differences were shown to recommend a specific formulation.(18) For patients using INCS for at least 4 weeks and who continue to have high disease burden, biologics may be considered and preferred over other medical treatment choices.(16) Oral systemic corticosteroids (OCS), used as a short course, can result in a significant reduction in symptoms and nasal polyps for up to three months after the start of treatment. Up to 2 courses per year, taken in addition to INCS, can be useful for patients with partially or uncontrolled disease.(18) The ICAR-RS strongly recommends the use of OCS in the short term management of CRSwNP, but does not recommend longer term use due to the increased risk of adverse effects.(24) Endoscopic sinus surgery (ESS) is aimed at improving symptoms and creating better conditions for local treatment. Sinus surgery should be considered when disease is refractory and remains symptomatic despite trial of primary medical therapy (e.g., nasal sinus irrigation, INCS, oral corticosteroids). Based on current evidence, delaying surgical intervention can be detrimental to symptom improvement and outcomes.(18,24) After surgery, patients need to continue other treatments due to the chronic nature of the disease and nasal polyps potentially reoccurring despite surgery.(15,18) INCS can help to prevent nasal polyp recurrence.(18,24) Biologics can be considered in patients where their disease remains uncontrolled despite appropriate medical treatment and sinus surgery.(16,27) Biologics vary in their magnitude of benefits and harms and certainty of evidence across outcomes. Dupilumab and omalizumab are the most beneficial for most patient important outcomes when comparing with other biologics, followed by mepolizumab.(16) Response to biologic treatment should initially be evaluated 6 months after initiation of therapy. Response can be defined as reduced nasal polyp size, reduced need for systemic oral corticosteroids, improved QoL, improved sense of smell, and/or reduced impact of comorbidities. Patients with no response should have the current biologic drug discontinued and/or switched, or a revision surgery can be considered. Patients with partial response may continue the current biologic therapy and be re-evaluated at 12 months since some biologics need more than 6 months to reach their full potential. Patients with partial response may also switch to a different biologic, consider salvage surgery, or complete an additional short course of OCS.(27) |
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Eosinophilic Esophagitis (EoE) |
Eosinophilic esophagitis (EoE) is a chronic allergen/immune-mediated disease characterized by esophageal dysfunction and marked eosinophilic inflammation of the esophageal mucosa in the absence of secondary causes. EoE is characterized histologically with eosinophil-predominant inflammation confined to the esophagus. EoE is a progressive disease if left untreated, and the chronic inflammation can lead to tissue fibrosis and strictures in the esophagus. Atopic and allergic inflammatory conditions (e.g., asthma, atopic dermatitis, food/seasonal allergy) commonly occur concomitantly with EoE.(3) The symptoms of EoE are age dependent. Young children and infants may refuse to eat or have abdominal pain, trouble swallowing, or vomiting. In addition, persistent feeding difficulties may lead to weight loss or a failure to thrive. Older children and adults most commonly present with dysphagia to solid food, but may also have symptoms of chest pain or heartburn. Food impaction is a common cause for emergency room visits in these patients.(3,19) The diagnosis of EoE is suspected on the basis of chronic symptoms such as dysphagia, food impaction, food refusal, failure to progress with food introduction, heartburn, regurgitation, vomiting, chest pain, odynophagia, abdominal pain, and malnutrition. Due to the wide range of chronic symptoms, the diagnosis should be highly considered in the presence of concomitant atopic conditions and if there are endoscopic findings. Endoscopic findings associated with EoE include esophageal rings, longitudinal furrows, exudates, edema, strictures, or narrow caliber esophagus. When a patient's clinical presentation is suggestive of EoE, an esophageal biopsy should be performed. Patients with esophageal eosinophilia of greater than or equal to 15 eosinophils (eos) per high-power field (hpf) would be considered to have clinically suspected EoE. The eosinophilic infiltration should be isolated to the esophagus.(21) It should be brought into consideration that diet and medications, including those used to treat EoE, may lead to a falsely negative result on esophageal biopsy, and an endoscopy would ideally be performed while on no treatment to maximize diagnostic sensitivity.(20) The diagnosis is then finalized after evaluation shows that there are no significant other causes of symptoms and/or esophageal eosinophilia.(21) A summary of the EoE diagnostic criteria is as follows:(21)
Nonpharmacological treatment of EoE includes esophageal dilation and diet. Esophageal dilation is used to treat strictures and luminal narrowing and is conditionally recommended only for patients with dysphagia associated with strictures, noting that the dilation does not address the underlying inflammation or pathogenesis.(20,22) Both elemental and elimination diets have been shown to be effective, however, barriers of adherence and cost make this treatment modality feasible only for select patients.(22) Proton pump inhibitors (PPIs) are a first line treatment option for patients with EoE, and PPI monotherapy is widely used in practice. PPIs have a longstanding safety profile and have shown to be effective based on symptom response and histological remission.(20,22) In EoE, PPIs can provide benefit beyond acid suppression by decreasing expression of eotaxin-3 (the main cytokine that recruits eosinophils to the esophagus), improving esophageal barrier function, and helping to maintain esophageal epithelial transcriptional homeostasis.(20) Swallowed topical corticosteroids (STCs) are also a first line treatment option for patients with EoE. Both the American Gastroenterological Association (AGA) and the American College of Gastroenterology (ACG) strongly recommend their use.(20,22) STCs have demonstrated histologic efficacy, a reduction in symptoms (including dysphagia), and improvement in endoscopic disease activity.(20) In short term use of 3 months or less, STCs have a favorable safety profile, and studies have shown no increased risk of adverse events compared to placebo outside of candidal infection.(20,22) Options for STCs include fluticasone propionate or budesonide. Fluticasone propionate is swallowed using commercially available metered dose inhalers (MDIs) and budesonide is consumed via an oral slurry using aqueous budesonide respules mixed with sucralose, honey, or maple syrup. An oral budesonide suspension is also commercially available for the treatment of EoE. Off-label use of asthma preparations of corticosteroids adapted for esophageal delivery have comparable histologic efficacy with preparations designed for esophageal delivery. A trial comparing fluticasone to budesonide showed similar efficacy between the two drugs, and either one is a reasonable choice for initial treatment based on patient/provider preference.(20) Diet, PPIs, and STCs work by treating the inflammatory component of the disease and can also lead to benefit in esophageal caliber. A single anti-inflammatory therapy should be used for initial treatment of EoE and should be selected based on disease characteristics and patient preference. Combination therapy with multiple anti-inflammatory drug therapies is not recommended due to a current lack of data.(20) Treatment response should be assessed by clinical, endoscopic, and histologic disease activity 8 to 12 weeks after starting the new therapy.(19,20) Assessing clinical symptom improvement alone is not sufficient since there is only a modest correlation between symptomatic improvement and histologic remission or endoscopic response. If adequate response is achieved, the current medication can be continued, noting that a decrease in dose may be warranted and desired for maintenance therapy. If a patient has non-response with initial treatment, a change in medication, dose, or formulation may be considered prior to stepping up to therapy with a biologic agent.(20) Maintenance therapy is needed for the treatment of EoE due to the chronic relapsing nature of the disease and the current understanding that it is a lifelong condition. When EoE treatment is stopped, regardless of the treatment used, disease activity and flares almost always recur. Fibrostenotic progression also occurs in most patients. Data supports the long-term efficacy of PPIs and dietary elimination for maintenance therapy, but STCs may also be used. Using STCs for maintenance therapy comes with the risk of long-term adverse effects (such as candidal infection or adrenal insufficiency), and they may also have a loss of response over time. If using STCs long-term, the lowest effective dose should be used. Studies involving the discontinuation of STCs following initial therapy have shown that the median time to symptom relapse after stopping treatment is about 3 months.(20) Patients with rapid symptomatic/histologic relapse following STC initial therapy should consider reinitiating STC therapy based on shared decision-making. Patients with severe dysphagia, food impaction, or high-grade esophageal stricture may also consider reinitiation or maintenance therapy with a STC.(32) A biologic agent may be considered as a step-up therapy option in patients who do not respond to initial pharmacologic treatment, especially PPI non-responders. Dupilumab, an interleukin (IL)-4 receptor alpha antagonist, has been shown to decrease dysphagia symptoms and improve endoscopic and histologic severity in patients with EoE. Response should be assessed between 12 and 24 weeks after therapy is initiated. Data supports maintenance therapy with a biologic agent, and dupilumab demonstrated continued histologic, endoscopic, and symptom efficacy in patients treated for 52 weeks, with some patients having a higher response rate after 52 weeks than at 24 weeks.(20) The treatment algorithm for pediatric patients aligns with how the disease is managed in adults. This includes the use of biologic agents (e.g., dupilumab) for difficult-to-treat patients that do not respond to, or are intolerant of, alternative treatments.(19,20) |
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Chronic Spontaneous Urticaria (CSU) |
Chronic spontaneous urticaria (CSU) can be a debilitating condition that can significantly affect a patient's quality of life. Routine diagnostic work-up for CSU is limited to blood tests for complete blood count and inflammatory markers, such as C-reactive protein and/or erythrocyte sedimentation rate, mostly to rule out other potential diseases. Skin prick testing, typically used to identify specific allergens, is not useful for CSU as the condition is rarely caused by type 1 allergy. CSU is also referred to as chronic urticaria (CU) or chronic idiopathic urticaria (CIU).(33) Urticaria is characterized by the development of wheals (hives), angioedema, or both. Chronic urticaria is defined by the presence of urticaria that has been continuously or intermittently present for more than 6 weeks.(34,35) Treatment goals for CSU involves symptom control and improvement in quality of life that is acceptable to the patient.(35) The 2021 EAACI/GA LEN/EDF/WAO guidelines, endorsed by the American Academy of Allergy, Asthma, and Immunology, American Academy of Dermatology, American College of Asthma, and Allergy, and Immunology, recommend the following for the treatment of CIU:(35)
Omalizumab was approved for the treatment of CSU in 2014 and has since received placement in treatment guidelines. However, for some patients omalizumab provides partial or no improvement in their signs and symptoms.(36) Current guidelines support using cyclosporine as add-on therapy for patients with severe disease and an incomplete response to omalizumab and an antihistamine used in combination, but it is not recommended as standard treatment due to the risk and incidence of adverse effects.(35) Dupilumab has been shown to be an effective treatment for CSU per the LIBERTY CUPID CSU studies, but its place in treatment guidelines has yet to be established. The LIBERTY CSU CUPID-B trial was designed to determine if dupilumab is an effective alternative in patients with a lack of response to omalizumab, incomplete control of their CSU while taking omalizumab, or an inability to tolerate the use of omalizumab. The dupilumab group in this study did not meet statistical significance for reduction in the primary endpoint of change from baseline in itch severity score over 7 days (ISS7) at Week 24.(36) |
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Prurigo Nodularis (PN) |
Prurigo nodularis (PN) is a skin disorder that is defined by the presence of chronic pruritus and multiple elevated, firm, and nodular lesions. PN is more common in older adults but can occur in children. The underlying cause of PN is unknown, but it appears neural and immunologic processes both play a role in its development. The nodules form in a subset of patients that have chronic pruritus, with the nodules forming in areas with continuous scratching over prolonged periods of time. There is significant disease burden associated with PN including sleep disruption, anxiety, and depression. The nodules are typically firm, dome-shaped, and itchy and range in size from millimeters to several centimeters. The nodules can range in color from flesh tones to brown/black and can range in number from a few to hundreds. The pruritus associated with PN can range from sporadic to continuous, and generally the underlying cause is unknown. There are a number of conditions, both dermatologic and other diseases, that are associated with PN, such as atopic dermatitis, kidney disease, diabetes, and HIV.(23) The diagnosis of PN is generally one of exclusion. The diagnostic workup should include a clinical examination with a complete review of systems and an assessment of PN severity, comprising of both disease burden (e.g., quality of life, sleep disturbances) and pruritus intensity. The three core features associated with PN are:(23)
Management requires a multifaceted approach with a focus on reducing pruritus, interrupting the itch-scratch cycle, and healing lesions.(23) General measures that should be used at baseline include gentle skin care, moisturizers, and antipruritic emollients.(17,23) Treatment may need to address both the neural and immunologic components of pruritus based on patient signs and symptoms, and often involves the use of topical and systemic therapies.(30) Most therapies for PN have not been adequately studied, and their evidence for use is based on small clinical trials, observational studies, and case reports.(23) Topical therapies are the initial treatment for limited disease. Topical corticosteroids (TCS) target the immunologic component of PN.(23) The International Forum for the Study of Itch (IFSI) 2020 guideline on chronic prurigo including prurigo nodularis strongly recommends moderate to very potent topical corticosteroids on lesional skin.(17) Intralesional corticosteroids may be directly injected into thicker lesions where required, but use should be limited to patients with less than 10 lesions. Topical calcineurin inhibitors and topical calcipotriol have also been used in patients who failed TCS therapy and a prolonged course of a topical immunomodulator is desired. Topical capsaicin, which targets the neural component of PN, has limited clinical evidence and tends to have short term efficacy.(23) Systemic therapies are used for widespread disease or disease refractory to topical therapy.(23,30) Phototherapy is reasonably tolerated and addresses both the immunologic and neural components of PN.(23) However, phototherapy combined with topical therapy will not be adequate for most patients, and the majority will require supplemental systemic therapy.(30) Oral immunosuppressants, such as methotrexate and cyclosporine, have shown to reduce pruritus and heal lesions per limited data available. Methotrexate is generally preferred due to its more favorable side effect profile in comparison to cyclosporine, and cyclosporine should only be considered in more severe cases.(23,30) Other systemic therapies that have shown to be less efficacious and treat the neural component of PN include thalidomide, gabapentin, pregabalin, antidepressants, aprepitant, and naltrexone.(23) Since PN is a nonhistaminergic condition, antihistamines are unlikely to be effective and are not recommended.(23,30) Biologic agents are the first therapies to gain approval from the US Food and Drug Administration (FDA) for the treatment of PN. These immunomodulating drugs are believed to target molecules expressed by specific cell types that release a variety of itching mediators that directly or indirectly stimulate receptors on nerve endings in the skin. Biologic agents disrupt this cycle and have been proven to alleviate both pruritus and PN lesions.(30) |
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Efficacy |
Asthma Adults and Pediatric Subjects 12 Years of Age and Older DRI12544 was a 24-week dose-ranging study which included 776 adult subjects (18 years of age and older). Dupixent compared with placebo was evaluated in adult subjects with moderate-to-severe asthma on a medium or high-dose inhaled corticosteroid (ICS) and a long acting beta agonist. The primary endpoint was mean change from baseline to Week 12 in FEV1 (L) in subjects with baseline blood eosinophils greater than or equal to 300 cells/mcL. Other endpoints included percent change from baseline in FEV1 and annualized rate of severe asthma exacerbation events during the 24-week placebo-controlled treatment period. Results were evaluated in the overall population and subgroups based on baseline blood eosinophil count (greater than or equal to 300 cells/mcL and less than 300 cells/mcL).(1) QUEST was a 52-week study which included 1902 adult and pediatric subjects (12 years of age and older). Dupixent compared with placebo was evaluated in 107 pediatric subjects 12 to 17 years of age and 1795 adult subjects with moderate-to-severe asthma on a medium or high-dose ICS and a minimum of one and up to two additional controller medications. The primary endpoints were the annualized rate of severe exacerbation events during the 52-week placebo-controlled period and change from baseline in pre-bronchodilator FEV1 at Week 12 in the overall population (unrestricted by minimum baseline blood eosinophils count). Additional secondary endpoint included annualized severe exacerbation rates and FEV1 in subjects with different baseline levels of blood eosinophils.(1) DRI12544 and QUEST evaluated the frequency of severe asthma exacerbations defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or hospitalization or emergency room visit due to asthma that required systemic corticosteroids. In the primary analysis population (subjects with baseline blood eosinophil count of greater than or equal to 300 cells/mcL in DRI12544 and the overall population in QUEST), subjects receiving either Dupixent 200 mg or 300 mg Q2W had significant reductions in the rate of asthma exacerbations compared to placebo. Pre-specified subgroup analyses of DRI12544 and QUEST demonstrated that there were greater reductions in severe exacerbations in subjects with higher baseline blood eosinophil levels (greater than or equal to 150 cells/mcL) or FeNO (greater than or equal to 25 ppb). In QUEST, reductions in exacerbations were significant in the subgroup of subjects with baseline blood eosinophils greater than or equal to 150 cells/mcL. In subjects with baseline blood eosinophil count <150 cells/mcL and FeNO <25 ppb, similar severe exacerbation rates were observed between Dupixent and placebo. The time to first exacerbation was longer for the subjects receiving Dupixent compared to placebo in QUEST.(1) Significant increases in pre-bronchodilator FEV1 were observed at Week 12 for DRI12544 and QUEST in the primary analysis populations (subjects with baseline blood eosinophil count of greater than or equal to 300 cells/mcL in DRI12544 and the overall population in QUEST). Subgroup analysis of DRI12544 and QUEST demonstrated greater improvement in FEV1 in subjects with higher baseline blood eosinophils (greater than or equal to 150 cells/mcL) or FeNO (greater than or equal to 25 ppb). In subjects with baseline blood eosinophil count <150 cells/mcL and FeNO <25 ppb, similar differences in FEV1 were observed between Dupixent and placebo.(1) VENTURE was a 24-week oral corticosteroid-reduction study in 210 adult and pediatric subjects 15 years of age and older with asthma who required daily OCS in addition to regular use of high dose ICS plus an additional controller. The baseline mean OCS dose was 12 mg in the placebo group and 11 mg in the group receiving Dupixent. Subjects continued to receive their existing asthma medicine during the study; however, their OCS dose was reduced every 4 weeks during the OCS reduction phase (Week 4-20), as long as asthma control was maintained. The primary endpoint was the percent reduction of OCS dose at Weeks 20 to 24 compared with the baseline dose, while maintaining asthma control in the overall population (unrestricted by minimum baseline blood eosinophils count). An additional secondary endpoint included the annualized rate of severe exacerbation events during treatment period.(1) Compared with placebo, subjects receiving Dupixent achieved greater reductions in daily maintenance oral corticosteroid dose, while maintaining asthma control. The mean percent reduction in daily OCS dose from baseline was 70% (median 100%) in subjects receiving Dupixent (95% CI: 60%, 80%) compared to 42% (median 50%) in subjects receiving placebo (95% CI: 33%, 51%). In this 24-week trial, asthma exacerbations (defined as a temporary increase in OCS dose for at least 3 days) were lower in subjects receiving Dupixent compared with those receiving placebo (annualized rate 0.65 and 1.60 for the Dupixent and placebo group, respectively; rate ratio 0.41 [95% CI 0.26, 0.63]) and improvement in pre-bronchodilator FEV1 from baseline to Week 24 was greater in subjects receiving Dupixent compared with those receiving placebo (LS mean difference for Dupixent versus placebo of 0.22 L [95% CI: 0.09 to 0.34 L]). Effects on lung function and on oral steroid and exacerbation reduction were similar irrespective of baseline blood eosinophil levels.(1) Pediatric Subjects 6 to 11 Years of Age The primary endpoint was the annualized rate of severe asthma exacerbation events during the 52-week placebo-controlled period. Severe asthma exacerbations were defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or hospitalization or emergency room visit due to asthma that required systemic corticosteroids. The key secondary endpoint was the change from baseline in pre-bronchodilator FEV1 percent predicted at Week 12.(1) Dupixent significantly reduced the annualized rate of severe asthma exacerbation events during the 52-week treatment period compared to placebo in populations with an eosinophilic phenotype as indicated by elevated blood eosinophils and/or the population with elevated FeNO. Subgroup analyses for results of Dupixent treatment based upon either baseline eosinophil level or baseline FeNO level were similar to the pediatric (12 to 17 years of age) and adult trials. In subjects with baseline blood eosinophil count <150 cells/mcL and FeNO <20 ppb, similar severe asthma exacerbation rates were observed between Dupixent and placebo. Significant improvements in percent predicted pre-bronchodilator FEV1 were observed at Week 12. Significant improvements in percent predicted FEV1 were observed as early as Week 2 and were maintained through Week 52 in VOYAGE.(1) Atopic Dermatitis (AD) Adults In all three trials, subjects in the Dupixent group received subcutaneous injections of Dupixent 600 mg at Week 0, followed by 300 mg every other week (Q2W). In the monotherapy trials (SOLO 1 and SOLO 2), subjects received Dupixent or placebo for 16 weeks. In the concomitant therapy trial (CHRONOS), subjects received Dupixent or placebo with concomitant topical corticosteroids (TCS) and as needed topical calcineurin inhibitors for problem areas only, such as the face, neck, intertriginous and genital areas for 52 weeks.(1) All three trials assessed the primary endpoint, the change from baseline to Week 16 in the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) and at least a 2-point improvement. A secondary endpoint included the proportion of subjects with EASI-75 (improvement of at least 75% in EASI score from baseline) from baseline to Week 16.(1) In all three trials, significantly more subjects who received Dupixent met the primary outcome, as well as EASI-75, compared to those who received placebo. In CHRONOS, responders at Week 52 were a mixture of subjects who maintained their efficacy from Week 16 (e.g., 53% of Dupixent IGA 0 or 1 responders at Week 16 remained responders at Week 52) and subjects who were non-responders at Week 16 who later responded to treatment (e.g., 24% of Dupixent IGA 0 or 1 non-responders at Week 16 became responders at Week 52), and efficacy results at Week 52 were similar to those seen at Week 16. In SOLO 1, SOLO 2, and CHRONOS, a third randomized treatment arm of Dupixent 300 mg QW did not demonstrate additional treatment benefit over Dupixent 300 mg Q2W.(1) Subjects in SOLO 1 and SOLO 2 who had an IGA 0 or 1 with a reduction of greater than or equal to 2 points were re-randomized into SOLO CONTINUE (NCT02395133). SOLO CONTINUE evaluated multiple Dupixent monotherapy dose regimens for maintaining treatment response. The study included subjects randomized to continue with Dupixent 300 mg Q2W (62 subjects) or switch to placebo (31 subjects) for 36 weeks. IGA 0 or 1 responses at Week 36 were as follows: 33 (53%) in the Q2W group and 3 (10%) in the placebo group.(1) Pediatric Subjects 12 to 17 Years of Age The primary endpoint was the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) and at least a 2-point improvement from baseline to Week 16. An additional evaluated outcome was the proportion of subjects with EASI-75 (improvement of at least 75% from baseline) at Week 16. A significantly higher proportion of subjects treated with Dupixent reached the primary outcome compared to placebo. The proportion of subjects who reached EASI-75 at Week 16 was also significantly higher in the Dupixent treatment group compared to placebo.(1) Pediatric Subjects 6 to 11 Years of Age The primary endpoint was the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) at Week 16. An additional evaluated outcome was the proportion of subjects with EASI-75 (improvement of at least 75% from baseline) at Week 16. At Week 16, significantly more subjects receiving Dupixent plus TCS versus placebo plus TCS achieved the primary endpoint, and significantly more achieved EASI-75.(1) Pediatric Subjects 6 Months to 5 Years of Age The primary endpoint was the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) at Week 16. An additional evaluated outcome was the proportion of subjects with EASI-75 at Week 16. At Week 16, significantly more subjects receiving Dupixent plus TCS versus placebo plus TCS achieved the primary endpoint, and significantly more achieved EASI-75.(1) Chronic Obstructive Pulmonary Disease (COPD) The efficacy of Dupixent as add-on maintenance treatment of adult patients with inadequately controlled COPD and an eosinophilic phenotype was evaluated in two randomized, double-blind, multicenter, parallel-group, placebo-controlled trials (BOREAS [NCT03930732] and NOTUS [NCT04456673]) of 52 weeks duration. The two trials enrolled a total of 1874 adult subjects with COPD.(1) Both trials enrolled subjects with a diagnosis of COPD with moderate to severe airflow limitation (post-bronchodilator FEV1/FVC ratio less than 0.7 and post-bronchodilator FEV1 of 30% to 70% predicted) and a minimum blood eosinophil count of 300 cells/mcL at screening. Subjects had to have been receiving maintenance triple therapy consisting of a long-acting muscarinic antagonist (LAMA), long-acting beta agonist (LABA), and inhaled corticosteroid (ICS) for at least 3 months before randomization; LAMA/LABA dual therapy was allowed if ICS use was contraindicated. Trial enrollment required an exacerbation history of at least 2 moderate or 1 severe exacerbation(s) in the previous year despite receiving maintenance therapy, and symptoms of chronic productive cough for at least 3 months in the past year. Exacerbations of COPD were defined as clinically significant worsening of COPD symptoms including increases in dyspnea, wheezing, cough, sputum volume, and/or increase in sputum purulence. Exacerbation severity was further defined as moderate if treatment with systemic corticosteroids and/or antibiotics was required, or severe if they resulted in hospitalization or observation for over 24 hours in an emergency department or urgent care facility. One of the two required moderate exacerbations had to require the use of systemic corticosteroids. Greater than or equal to 95% of subjects in each trial had chronic bronchitis. Subjects also had a Medical Research Council (MRC) dyspnea score greater than or equal to 2 (range 0-4).(1,28,29) In both trials, subjects were randomized to receive Dupixent 300 mg subcutaneously every two weeks (Q2W) or placebo in addition to their background maintenance therapy for 52 weeks.(1) The primary endpoint for BOREAS and NOTUS trials was the annualized rate of moderate or severe COPD exacerbations during the 52-week treatment period. In both trials, Dupixent demonstrated a significant reduction in the annualized rate of moderate or severe COPD exacerbations compared to placebo when added to background maintenance therapy. In the BOREAS trial, the annualized rate of moderate or severe exacerbations of COPD was 0.78 (95% confidence interval [CI], 0.64 to 0.93) in the Dupixent group and 1.10 (95% CI, 0.93 to 1.30) in the placebo group (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P < 0.001). In the NOTUS trial, the annualized rate of moderate or severe exacerbations of COPD was lower in the Dupixent group (0.86; 95% CI, 0.70 to 1.06) than in the placebo group (1.30; 95% CI, 1.05 to 1.60), resulting in a rate ratio of 0.66 (95% CI, 0.54 to 0.82; P < 0.001). Treatment with Dupixent decreased the risk of a moderate to severe COPD exacerbation as measured by time to first exacerbation when compared with placebo in BOREAS (HR: 0.80; 95% CI: 0.66, 0.98) and NOTUS (HR: 0.71; 95% CI: 0.57, 0.89).(1,28,29) In both trials (BOREAS and NOTUS), Dupixent demonstrated numerical improvement in post-bronchodilator FEV1 at Weeks 12 and 52 compared to placebo when added to background maintenance therapy. Significant improvements of similar magnitude were observed in change from baseline in pre-bronchodilator FEV1 at Weeks 12 and 52 in subjects treated with Dupixent compared to placebo across both trials. In both trials (BOREAS and NOTUS), the St. George’s Respiratory Questionnaire (SGRQ) total score responder rate (defined as the proportion of subjects with SGRQ improvement from baseline of at least 4 points) at Week 52 was evaluated. SGRQ is a 50-item questionnaire designed to measure and quantify health status in adult patients with chronic airflow limitation and scores range from 0 to 100, with lower scores indicating a better quality of life. In BOREAS, the responder rate was 51% for subjects treated with Dupixent versus 43% for placebo (N=939, odds ratio: 1.44; 95% CI: 1.10, 1.89). In NOTUS, the responder rate was 51% for subjects treated with Dupixent versus 47% for placebo (N=721, odds ratio: 1.16; 95% CI: 0.86, 1.58).(1,28,29) Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) Two randomized, double-blind, parallel-group, multicenter, placebo-controlled studies (CSNP Trial 1 and CSNP Trial 2) evaluated Dupixent in CRSwNP. There were 724 subjects aged 18 years and older on background intranasal corticosteroids (INCS) included in the trials. These studies included subjects with CRSwNP despite prior sinonasal surgery or treatment with, or who were ineligible to receive or were intolerant to, systemic corticosteroids in the past 2 years. Subjects with chronic rhinosinusitis without nasal polyposis were not included in these trials. Rescue treatment with systemic corticosteroids or surgery was allowed during the studies at the investigator’s discretion. In CSNP Trial 1, a total of 276 subjects were randomized to receive either 300 mg Dupixent (N=143) or placebo (N=133) every other week for 24 weeks. In CSNP Trial 2, 448 subjects were randomized to receive either 300 mg Dupixent (N=150) every other week for 52 weeks, 300 mg Dupixent (N=145) every other week until week 24 followed by 300 mg Dupixent every 4 weeks until week 52, or placebo (N=153). All subjects had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan and 73% to 90% of subjects had opacification of all sinuses. Subjects were stratified based on their histories of prior surgery and co-morbid asthma/nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NSAID-ERD). A total of 63% of subjects reported previous sinus surgery, with a mean number of 2.0 prior surgeries, 74% used systemic corticosteroids in the previous 2 years with a mean number of 1.6 systemic corticosteroid courses in the previous 2 years, 59% had co-morbid asthma, and 28% had NSAID-ERD.(1) The co-primary efficacy endpoints were change from baseline to Week 24 in bilateral endoscopic nasal polyps score (NPS; 0-8 scale) as graded by central blinded readers and change from baseline to Week 24 in nasal congestion/obstruction score averaged over 28 days (NC; 0-3 scale), as determined by subjects using a daily diary. In both studies, key secondary endpoints at Week 24 included change from baseline in: LMK sinus CT scan score, daily loss of smell, and 22-item sinonasal outcome test (SNOT-22). In the pooled efficacy results, the reduction in the proportion of subjects rescued with systemic corticosteroids and/or sinonasal surgery (up to Week 52) were evaluated.(1) Statistically significant efficacy was observed in CSNP Trial 2 with regard to improvement in bilateral endoscopic NPS score at Week 24 and Week 52. Similar results were seen in CSNP Trial 1 at Week 24. In the post-treatment period when subjects were off Dupixent, the treatment effect diminished over time. In both studies, significant improvements in nasal congestion were observed as early as the first assessment at Week 4. A significant decrease in the LMK sinus CT scan score was observed. Dupixent significantly improved the loss of smell compared to placebo. In both studies, significant improvements in daily loss of smell severity were observed as early as the first assessment at Week 4. Dupixent significantly decreased sinonasal symptoms as measured by SNOT-22 compared to placebo.(1) In the pre-specified multiplicity-adjusted pooled analysis of two studies, treatment with Dupixent resulted in significant reduction of systemic corticosteroid use and need for sinonasal surgery versus placebo (HR of 0.24; 95% CI: 0.17, 0.35). The proportion of subjects who required systemic corticosteroids was reduced by 74% (HR of 0.26; 95% CI: 0.18, 0.38). The total number of systemic corticosteroid courses per year was reduced by 75% (RR of 0.25; 95% CI: 0.17, 0.37). The proportion of subjects who required surgery was reduced by 83% (HR of 0.17; 95% CI: 0.07, 0.46). The effects of Dupixent on the primary endpoints of NPS and nasal congestion and the key secondary endpoint of LMK sinus CT scan score were consistent in subjects with prior surgery and without prior surgery.(1) Chronic Spontaneous Urticaria (CSU) The efficacy of Dupixent for the treatment of adult and pediatric patients aged 12 years and older with chronic spontaneous urticaria who remain symptomatic despite H1 antihistamine treatment was evaluated in a master protocol clinical trial (CUPID [NCT04180488]) that included three 24-week, randomized, double-blind, parallel-group, multicenter, placebo-controlled trials (CUPID Study A, Study B, and Study C), followed by 12-week blinded safety follow-up periods. CUPID Study A and Study C included subjects who remained symptomatic despite H1 antihistamine treatment and were anti-IgE treatment naïve, while CUPID Study B included patients who remained symptomatic despite H1 antihistamine and anti-IgE treatments. The efficacy of Dupixent was based only on CUPID Study A and Study C; Study B did not meet the primary endpoint.(1) CUPID Study A and Study C enrolled a total of 284 adult and pediatric patients 12 years of age and older with CSU (Itch Severity Score over 7 days [ISS7] greater than or equal to 8 on a scale of 0 to 21 and Urticaria Activity Score over 7 days [UAS7] greater than or equal to 16 on a scale of 0 to 42) who were symptomatic despite the use of H1 antihistamines, but who were anti-IgE treatment naïve. In the Dupixent group, adults and pediatric subjects (12 years of age and older) weighing greater than or equal to 60 kg received a subcutaneous dose of Dupixent 600 mg on Day 1, followed by 300 mg every 2 weeks (Q2W), while pediatric subjects (12 years of age and older) weighing 30 kg to less than 60 kg received a subcutaneous dose of Dupixent 400 mg on Day 1, followed by 200 mg Q2W.(1) The primary endpoint was change from baseline in itch severity score over 7 days (ISS7) at Week 24. The ISS7 score was defined as the sum of the daily itch severity scores (ISS), from 0 to 3, recorded at the same time of the day for a 7-day period, ranging from 0 to 21. The key secondary endpoint was change from baseline in urticaria activity score over 7 days (UAS7) at Week 24. The UAS7 (range 0 to 42) was a composite of the weekly itch severity score (ISS7, range 0 to 21) and the weekly hive count score (HSS7, range 0 to 21). The results for primary and secondary endpoints in CUPID Study A and Study C are presented in the table below.(1)
*Values presented are LS mean change from baseline (SE) for continuous variables and number and percent of responders for binary variables In CUPID Study A and Study C, improvements in ISS7 and UAS7 at Week 24 were consistent regardless of the patients’ baseline IgE level.(1) Eosinophilic Esophagitis (EoE) Adults and Pediatric Subjects 12 Years of Age and Older The coprimary efficacy endpoints in Parts A and B were the proportion of subjects achieving histological remission defined as peak esophageal intraepithelial eosinophil count of less than or equal to 6 eos/hpf at week 24, and the absolute change in the subject reported DSQ score from baseline to Week 24.(1) In Parts A and B, a greater proportion of subjects randomized to Dupixent achieved histological remission (peak esophageal intraepithelial eosinophil count less than or equal to 6 eos/hpf) compared to placebo (Part A: 25% vs 2%; Part B: 47% vs 5%). Treatment with Dupixent also resulted in a significant improvement in LS mean change in DSQ score compared to placebo at Week 24 (Part A: -21.9 vs -9.6; Part B -23.8 vs -13.9). The results of the anchor-based analyses that incorporated the subjects’ perspectives indicated that the observed improvement in dysphagia from Parts A and B is representative of a clinically meaningful within-subject improvement.(1) Pediatric Subjects 1 to 11 Years of Age, Weighing at Least 15 kg The primary efficacy endpoint in Part A was the proportion of subjects achieving histological remission defined as peak esophageal intraepithelial eosinophil count of less than or equal to 6 eos/hpf at Week 16. A greater proportion of subjects randomized to Dupixent achieved histological remission compared to placebo (65.6% vs 3.1%).(1) Forty-seven subjects who completed Part A were evaluated in the 36-week extended active treatment period (Study EoE-2 Part B). All subjects in Part B were treated with the weight-based dosing regimens of Dupixent described for Part A. In Part B, histological remission was achieved at Week 52 in 17/32 subjects treated with Dupixent in Parts A and B and 8/15 subjects treated with placebo in Part A and Dupixent in Part B.(1) Prurigo Nodularis (PN) The PN development program included two 24-week randomized, double-blind, placebo-controlled, multicenter, parallel-group trials (PRIME [NCT04183335] and PRIME 2 [NCT04202679]) in 311 adult subjects 18 years of age and older with pruritus (WI-NRS greater than or equal to 7 on a scale of 0 to 10) and greater than or equal to 20 nodular lesions.(1) Subjects were required to have failed at least a 2-week trial of a medium to super potent topical corticosteroid, or topical corticosteroids were not medically advised. All subjects in both studies had used topical therapies in the past, with 98.7% and 98.1% reporting past use of TCS in PRIME and PRIME 2, respectively.(14) At baseline, the mean Worst Itch-Numeric Rating Scale (WI-NRS) was 8.5, 66% had 20 to 100 nodules (moderate), and 34% had greater than 100 nodules (severe). The WI-NRS is comprised of a single item, rated on a scale from 0 (no itch) to 10 (worst imaginable itch). Subjects were asked to rate the intensity of their worst pruritus (itch) over the past 24 hours using this scale. The Investigator’s Global Assessment for Prurigo Nodularis-Stage (IGA PN-S) is a scale that measures the approximate number of nodules using a 5-point scale from 0 (clear) to 4 (severe).(1) PRIME and PRIME 2 assessed the effect of Dupixent on pruritus improvement as well as its effect on PN lesions. In these two trials, subjects received either subcutaneous Dupixent 600 mg (two 300 mg injections) on day 1, followed by 300 mg once every other week (Q2W) for 24 weeks, or matching placebo.(1) Efficacy was assessed with the proportion of subjects with improvement (reduction) in WI-NRS by greater than or equal to 4 points, the proportion of subjects with IGA PN-S 0 or 1 (the equivalent of 0-5 nodules), and the proportion of subjects who achieved a response in both WI-NRS and IGA PN-S at Week 24. Overall, greater proportions of subjects treated with Dupixent saw improvement across each endpoint over placebo, and Dupixent demonstrated clinically meaningful and statistically significant improvements in itch and skin lesions.(1,14) |
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Safety |
Dupixent (dupilumab) is contraindicated in patients who have a known hypersensitivity to dupilumab or any excipients of the product.(1) |
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REFERENCES
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Number |
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1 |
Dupixent prescribing information. Regeneron Pharmaceuticals, Inc. April 2025. |
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2 |
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20 |
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27 |
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29 |
Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation. New England Journal of Medicine. 2024;390(24):2274-2283. doi:10.1056/nejmoa2401304 |
|
30 |
Yook HJ, Lee JH. Prurigo nodularis: Pathogenesis and the horizon of potential therapeutics. International Journal of Molecular Sciences. 2024;25(10):1-26. doi:10.3390/ijms25105164 |
|
31 |
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (2025 Report). 2025. https://goldcopd.org/2025-gold-report/ |
|
32 |
Dellon ES, Gonsalves N, Hirano I, Furuta GT, Liacouras CA, Katzka DA. ACG Clinical Guideline: Evidenced Based Approach to the Diagnosis and Management of Esophageal Eosinophilia and Eosinophilic Esophagitis (EOE). The American Journal of Gastroenterology. 2013;108(5):679-692. doi:10.1038/ajg.2013.71 |
|
33 |
Guideline for Diagnosis and Management of Chronic Spontaneous Urticaria. Physician's Weekly. Published April 13, 2021. https://www.physiciansweekly.com/guideline-for-diagnosis-and-management-of-chronic-spontaneous-urticaria/ |
|
34 |
Bernstein J, Lang D, Khan D, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133(5):1270-1277. doi:10.1016/j.jaci.2014.02.036 |
|
35 |
Zuberbier, T, Abdul Latiff, AH, Abuzakouk, M, et al. The international EAACI/GA^2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy. 2022;77(3):734-766. doi:10.1111/all.15090 |
|
36 |
Mathur SK, Rosenberg DL, Viswanathan RK. Dupilumab for chronic spontaneous urticaria-marvelous or meek? Journal of Allergy and Clinical Immunology. 2024;154(1):91-93. doi:10.1016/j.jaci.2024.05.004 |
POLICY AGENT SUMMARY PRIOR AUTHORIZATION
|
Target Brand Agent(s) |
Target Generic Agent(s) |
Strength |
Targeted MSC |
Available MSC |
Final Age Limit |
Preferred Status |
|
|
||||||
|
Dupixent |
dupilumab subcutaneous soln auto-injector |
200 MG/1.14ML ; 300 MG/2ML |
M ; N ; O ; Y |
N |
|
|
|
Dupixent |
dupilumab subcutaneous soln prefilled syringe |
100 MG/0.67ML ; 200 MG/1.14ML ; 300 MG/2ML |
M ; N ; O ; Y |
N |
|
|
POLICY AGENT SUMMARY QUANTITY LIMIT
|
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
QL Amount |
Dose Form |
Day Supply |
Duration |
Addtl QL Info |
Allowed Exceptions |
Targeted NDCs When Exclusions Exist |
|
|
|||||||||
|
Dupixent |
Dupilumab Subcutaneous Soln Pen-injector 200 MG/1.14ML |
200 MG/1.14ML |
2 |
Pens |
28 |
DAYS |
|
|
|
|
Dupixent |
Dupilumab Subcutaneous Soln Pen-injector 300 MG/2ML |
300 MG/2ML |
4 |
Pens |
28 |
DAYS |
|
|
|
|
Dupixent |
Dupilumab Subcutaneous Soln Prefilled Syringe |
100 MG/0.67ML |
2 |
Syringes |
28 |
DAYS |
|
|
|
|
Dupixent |
Dupilumab Subcutaneous Soln Prefilled Syringe 200 MG/1.14ML |
200 MG/1.14ML |
2 |
Syringes |
28 |
DAYS |
|
|
|
|
Dupixent |
Dupilumab Subcutaneous Soln Prefilled Syringe 300 MG/2ML |
300 MG/2ML |
4 |
Syringes |
28 |
DAYS |
|
|
|
CLIENT SUMMARY – PRIOR AUTHORIZATION
|
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
Client Formulary |
|
Dupixent |
dupilumab subcutaneous soln auto-injector |
200 MG/1.14ML ; 300 MG/2ML |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance |
|
Dupixent |
dupilumab subcutaneous soln prefilled syringe |
100 MG/0.67ML ; 200 MG/1.14ML ; 300 MG/2ML |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance |
CLIENT SUMMARY – QUANTITY LIMITS
|
Target Brand Agent Name(s) |
Target Generic Agent Name(s) |
Strength |
Client Formulary |
|
Dupixent |
Dupilumab Subcutaneous Soln Pen-injector 200 MG/1.14ML |
200 MG/1.14ML |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance |
|
Dupixent |
Dupilumab Subcutaneous Soln Pen-injector 300 MG/2ML |
300 MG/2ML |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance |
|
Dupixent |
Dupilumab Subcutaneous Soln Prefilled Syringe |
100 MG/0.67ML |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance |
|
Dupixent |
Dupilumab Subcutaneous Soln Prefilled Syringe 200 MG/1.14ML |
200 MG/1.14ML |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance |
|
Dupixent |
Dupilumab Subcutaneous Soln Prefilled Syringe 300 MG/2ML |
300 MG/2ML |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance |
PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL
|
Module |
Clinical Criteria for Approval |
||
|
PA |
Initial Evaluation Target Agent(s) will be approved when ALL of the following are met:
Compendia Allowed: AHFS, DrugDex 1 or 2a level of evidence, or NCCN 1 or 2a recommended use Length of Approval: 6 months for moderate-to-severe AD, moderate-to-severe asthma, CRSwNP, CSU, EoE, and PN; 12 months for COPD and all other indications NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.
Renewal Evaluation Target Agent(s) will be approved when ALL of the following are met:
Length of Approval: 12 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. |
QUANTITY LIMIT CLINICAL CRITERIA FOR APPROVAL
|
Module |
Clinical Criteria for Approval |
|
QL |
Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:
Length of Approval: up to 12 months Note: If approving initial loading dose, please approve initial loading dose for asthma, atopic dermatitis, or prurigo nodularis only. The loading dose plus maintenance dose may be approved for 1 month per FDA labeling, followed by maintenance dosing for the remainder of the length of approval. |
CONTRAINDICATION AGENTS
|
Contraindicated as Concomitant Therapy |
|
Agents NOT to be used Concomitantly Abrilada (adalimumab-afzb) |
This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.
Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.
Commercial _ PS _ IL-4_Inhibitors_PAQL _ProgSum_ 10-01-2025