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Interleukin-4 (IL-4) Inhibitor Prior Authorization with Quantity Limit Program Summary
Policy Number: PH-1119
This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx and Health Insurance Marketplace formularies.
POLICY REVIEW CYCLE
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Effective Date |
Date of Origin |
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10-01-2024 |
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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) Injection for subcutaneous use |
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 patients with inadequately controlled chronic rhinosinusitis with nasal polyposis (CRSwNP) Treatment of adult and pediatric patients aged 1 years and older, weighing at least 15 kg, with eosinophilic esophagitis (EoE) Treatment of adult patients with prurigo nodularis (PN) |
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See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm
CLINICAL RATIONALE
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Atopic Dermatitis |
Atopic dermatitis (AD), also known as atopic eczema, is a chronic, pruritic inflammatory dermatosis affecting up to 25% of children and 1-5% of adults. 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 to 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 commonly 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. 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 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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Asthma |
Asthma is a chronic inflammatory disorder of the airways.(9,11) It is characterized by variable and recurring clinical symptoms, airflow obstruction, bronchial hyperresponsiveness, and underlying inflammation.(9) Symptoms of asthma include wheezing, coughing, recurrent difficulty breathing, shortness of breath, and chest tightness. Generally, these symptoms will occur or worsen with exposure to allergens and irritants, infections, exercise, changes in weather, stress, or menstrual cycles. Guidelines recommend the use of detailed medical history, physical examination, and spirometry to make a diagnosis of asthma.(9,11) The Global Initiative for Asthma (GINA) guidelines recommend a stepwise approach for managing asthma. Long-term goals for asthma management are to achieve good control of symptoms, maintain normal activity level, and to minimize the future risk of exacerbations, fixed airflow limitation, and side-effects. IgE is the antibody responsible for activation of allergic reactions and is important to the pathogenesis of allergic asthma and the development and persistence of inflammation. GINA guidelines define moderate asthma as that which is well controlled with Step 3 or Step 4 treatment (e.g., low- or medium-dose inhaled corticosteroids [ICS] in combination with a long-acting beta agonist [LABA] in either treatment track). Severe asthma is defined as asthma that remains uncontrolled despite optimized treatment with high-dose ICS-LABA, or that requires high-dose ICS-LABA to prevent it from becoming uncontrolled. Severe asthma must be distinguished from asthma that is difficult to treat due to inadequate or inappropriate treatment, or persistent problems with adherence or comorbidities such as chronic rhinosinusitis or obesity, as they need very different treatment compared with if asthma is relatively refractory to high-dose ICS-LABA or even oral corticosteroids (OCS). Early initiation of low dose ICS in patients with asthma has led to greater improvement in lung function than initiation of ICS after symptoms have been present for more than 2 to 4 years. The 2023 GINA guidelines recommend every adult and adolescent with asthma should receive ICS-containing controller medication to reduce the risk of serious exacerbation, even in patients with infrequent symptoms.(11) 2023 GINA STEP recommendations for adults and adolescents (12 years of age and over) are intended to reduce the risk of serious exacerbations and are broken into two tracks based on reliever therapy. Track 1 is the preferred approach recommended by GINA, because using low dose ICS-formoterol as the reliever reduces the risk of exacerbations compared with regimens with short-acting β2-agonist (SABA) as the reliever, and is a simpler regimen:(11)
Track 2 is an alternative approach if Track 1 is not possible or is not preferred by a patient with no exacerbations on their current therapy. Before considering a regimen with SABA reliever, the clinician should consider whether the patient is likely to be adherent with their controller therapy; if not, they will be exposed to the higher risk of exacerbations with SABA-only treatment:(11)
2023 GINA STEP recommendations for children (6 to 11 years of age) are intended to reduce the risk of serious exacerbations:(11)
Severe Asthma Phenotype and Eosinophilic Asthma Subphenotype Roughly 3% to 10% of adults with asthma have severe asthma as defined by the GINA 2023 guidelines.(11) The European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines (2014; updated 2020) and the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group mirror the GINA definition of severe asthma.(9,25) The ERS/ATS definition uncontrolled asthma for adult and pediatric patients 6 years of age and over:(10)
A specialist, preferably in a multidisciplinary severe asthma clinic (if available) performs further assessment, which includes the patient’s inflammatory phenotype (i.e., Type 2 or non-Type 2).(11) Type 2 inflammation is characterized by the presence of cytokines such as interleukin (IL)-4, IL-5, and IL-13, which are often produced by the adaptive immune system on recognition of allergens. It is also characterized by eosinophilia or increased fraction of exhaled nitric oxide (FeNO) and may be accompanied by atopy. In many patients with asthma, Type 2 inflammation rapidly improves when ICS are taken regularly and correctly; this is classified as mild or moderate asthma. In severe asthma, Type 2 inflammation may be relatively refractory to high dose ICS. 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)
Biologic agents should be considered as add-on therapy for patients with refractory Type 2 inflammation with exacerbations or poor symptom control despite taking at least high dose ICS/LABA, and who have allergic or eosinophilic biomarkers or need maintenance OCS. 2023 GINA recommends the biologics below based on patient eligibility factors:(11)
Patient response should be evaluated 4 months after initiating therapy and follow up should occur every 3 to 6 months thereafter. 2023 GINA recommends the following step-down therapy process in patients responding well to targeted biologic therapy:(11)
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Chronic Rhinosinusitis with Nasal Polyps |
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) |
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Eosinophilic Esophagitis |
Eosinophilic Esophagitis (EoE) is an allergen/immune-mediated disease characterized by symptoms of esophageal dysfunction and marked eosinophilic inflammation of the esophageal mucosa in the absence of secondary causes. EoE has dramatically increased in prevalence over the years. EoE is characterized by symptoms related to esophageal dysfunction and histologically with eosinophil-predominant inflammation (a peak count of greater than or equal to 15 eosinophils per high-power field on esophageal biopsy). Atopic and allergic inflammatory conditions commonly occur concomitantly with EoE.(19) The symptoms of EoE are age dependent. Young children may refuse to eat, have decreased appetite, recurring abdominal pain, trouble swallowing, and vomiting. Young adults and adults have the same symptoms, but often struggle to swallow dry or dense, solid foods due to inflammation. Food impaction is a common cause for emergency room visits in patients with EoE. Patients may also have concurrent gastroesophageal reflux disease (GERD). EoE is a progressive disease if left untreated. The chronic inflammation can lead to tissue fibrosis and strictures in the esophagus that require esophageal dilation.(20) 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. Assessment of non-EoE disorders and esophageal biopsy are required to confirm the diagnosis of EoE, with at least 15 eosinophils (eos)/ high-power field (hpf) present on esophageal biopsy.(21) Nonpharmacological treatment of EoE includes dilation and diet. Dilation is only conditionally recommended for patients with dysphagia associated with strictures due to EoE, noting that the dilation does not address the underlying inflammation.(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.(3,22) 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. The 2020 American Gastroenterological Association (AGA) and the Joint Task Force on Allergy-Immunology Practice Parameters (JTF) guidelines conditionally recommend their use while the 2022 British Society of Gastroenterology (BSG) and British Society of Pediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) guidelines strongly recommend their use.(3,22) The AGA/JTF and BSG/BSPGHAN both strongly recommend the use of topical glucocorticoids for the treatment of EoE. Studies showed that topical (swallowed) budesonide or topical fluticasone induced histological remission significantly better than placebo and had similar adverse events to placebo. Due to the chronic nature of the disease and the risk of progression, topical corticosteroids may be continued as maintenance therapy after remission with short term use. A clinical review of the patient should guide this decision based on preference to avoid long term adverse effects of topical steroids, or to prevent undesirable outcomes of the disease itself.(3,22) |
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Prurigo Nodularis |
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 pruritis 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 American Academy of Dermatology (AAD) indicates that the diagnostic workup should include a clinical examination with a complete review of systems and assessment of PN severity, which should include both disease burden (e.g., quality of life, sleep disturbances) and pruritis intensity. The AAD notes three core features associated with PN:(23)
Management requires a multifaceted approach with a focus on controlling the underlying pruritis. Topical therapies are initial therapy for limited disease. Topical therapies include topical and intralesional corticosteroids.(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) Topical calcineurin inhibitors and topical calcipotriol have been used but have not been adequately studied. Phototherapy is used in patients with more widespread and refractory PN. Systemic oral therapies include cyclosporine and methotrexate and are generally used in patients with widespread, refractory disease that does not respond to phototherapy.(23) |
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Efficacy |
Atopic Dermatitis(1,7,8) Dupilumab was FDA approved through two randomized, double-blind, placebo-controlled phase 3 trials (SOLO 1 and SOLO 2). All patients in both trials were at least 18 years old, had chronic AD (according to American Academy of Dermatology Consensus Criteria Eichenfield 2014) that had been present for at least 3 years, and had greater than or equal to 10% body surface area (BSA) involvement at the screening and baseline visits. Additionally, all patients had a documented recent history (within 6 months before the screening visit) of inadequate response to treatment with topical medications (defined as failure to achieve and maintain remission or a low disease activity state despite treatment with a daily regimen of topical corticosteroids of medium to higher potency applied for greater than or equal to 28 days or for the maximum duration recommended by the product prescribing information [e.g., 14 days for super-potent topical corticosteroids], whichever is shorter), or whom topical treatments are otherwise medically inadvisable. The primary outcome measure in both trials was proportion of patients with both IGA (Investigator Global Assessment) 0 to 1 (on a 5-point scale) and a reduction from baseline of greater than or equal to 2 points at week 16. There were several secondary endpoints included. Some examples include: proportion of patients with Eczema Area and Severity Index (EASI) -75 (greater than or equal to 75% improvement from baseline) at week 16, percent change from baseline to week 16 in pruritus numerical rating scale (NRS), change from baseline to week 16 in % BSA, and changes in quality of life, anxiety, and depression. The manufacturer reports the following results from SOLO 1 and SOLO 2. In SOLO 1, the primary outcome (an IGA of 0-1 and a reduction of greater than or equal to 2 points from baseline at week 16) occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P less than 0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P less than 0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P less than 0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. The efficacy and safety of Dupixent monotherapy in adolescent subjects was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial in 251 adolescent subjects 12 to 17 years of age, with moderate-to-severe AD and a minimum BSA involvement of greater than or equal to 10%. Eligible subjects enrolled into this trial had previous inadequate response to topical medication. Subjects in the Dupixent group with baseline weight of less than 60 kg received an initial dose of 400 mg at Week 0, followed by 200 mg every 2 weeks for 16 weeks. Subjects with baseline weight of greater than or equal to 60 kg received an initial dose of 600 mg at Week 0, followed by 300 mg every 2 weeks for 16 weeks. Subjects were permitted to receive rescue treatment at the discretion of the investigator. Subjects who received rescue treatment were considered non-responders. 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. Other evaluated outcomes included the proportion of subjects with EASI-75 or EASI-90 (improvement of at least 75% or 90% in EASI from baseline, respectively), and reduction in itch as measured by the Peak Pruritus NRS (greater than or equal to 4-point improvement). The efficacy results at Week 16 were as follows:
Asthma(1) The asthma development program included three randomized, double-blind, placebo controlled, parallel-group, multi-center trials (AS Trials 1, 2, and 3) of 24 to 52 weeks in treatment duration which enrolled a total of 2888 subjects (12 years of age and older). Subjects enrolled in AS Trials 1 and 2 were required to have a history of 1 or more asthma exacerbations that required treatment with systemic corticosteroids or emergency department visit or hospitalization for the treatment of asthma in the year prior to trial entry. Subjects enrolled in AS Trial 3 required dependence on daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s). In all 3 trials, subjects were enrolled without requiring a minimum baseline blood eosinophil count. In AS Trials 2 and 3 subjects with screening blood eosinophil level of greater than 1500 cells/mcL (less than 1.3%) were excluded. Dupixent was administered as add-on to background asthma treatment. Subjects continued background asthma therapy throughout the duration of the studies, except in AS Trial 3 in which OCS dose was tapered as described below. AS Trial 1 was a 24-week dose-ranging study which included 776 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 and a long acting beta agonist. Subjects were randomized to receive either 200 mg (N equal to 150) or 300 mg (N equal to 157) Dupixent every other week (Q2W) or 200 mg (N equal to 154) or 300 mg (N equal to 157) Dupixent every 4 weeks following an initial dose of 400 mg, 600 mg or placebo (N equal to 158), respectively. 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. Additional secondary endpoints included responder rates in the patient reported Asthma Control Questionnaire (ACQ-5) and Asthma Quality of Life Questionnaire, Standardized Version (AQLQ(S)) scores. AS Trial 2 was a 52-week study which included 1902 subjects (12 years of age and older). Dupixent compared with placebo was evaluated in 107 adolescents and 1795 adult subjects with moderate-to-severe asthma on a medium or high-dose inhaled corticosteroid (ICS) and a minimum of one and up to two additional controller medications. Subjects were randomized to receive either 200 mg (N=631) or 300 mg (N=633) Dupixent Q2W (or matching placebo for either 200 mg [N equal to 317] or 300 mg [N equal to 321] Q2W) following an initial dose of 400 mg, 600 mg or placebo respectively. 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 endpoints included annualized severe exacerbation rates and FEV1 in patients with different baseline levels of blood eosinophils as well as responder rates in the ACQ-5 and AQLQ(S) scores. AS Trial 3 was a 24-week oral corticosteroid-reduction study in 210 subjects with asthma who required daily oral corticosteroids in addition to regular use of high dose inhaled corticosteroids plus an additional controller. After optimizing the OCS dose during the screening period, subjects received 300 mg Dupixent (N=103) or placebo (N=107) once Q2W for 24 weeks following an initial dose of 600 mg or placebo. 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 oral corticosteroid 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). Additional secondary endpoints included the annualized rate of severe exacerbation events during treatment period and responder rate in the ACQ-5 and AQLQ(S) scores. AS Trials 1 and 2 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 AS Trial 1 and the overall population in AS Trial 2), subjects receiving either Dupixent 200 mg or 300 mg Q2W had significant reductions in the rate of asthma exacerbations compared to placebo. In the overall population in AS Trial 2, the rate of severe exacerbations was 0.46 and 0.52 for Dupixent 200 mg Q2W and 300 mg Q2W, respectively, compared to matched placebo rates of 0.87 and 0.97. The rate ratio of severe exacerbations compared to placebo was 0.52 (95% CI: 0.41, 0.66) and 0.54 (95% CI: 0.43, 0.68) for Dupixent 200 mg Q2W and 300 mg Q2W, respectively. Prespecified subgroup analyses of AS Trials 1 and 2 demonstrated that there were greater reductions in severe exacerbations in subjects with higher baseline blood eosinophil levels. In AS Trial 2, 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 less than 150 cells/mcL, similar severe exacerbation rates were observed between Dupixent and placebo. Significant increases in pre-bronchodilator FEV1 were observed at Week 12 for AS Trials 1 and 2 in the primary analysis populations (subjects with baseline blood eosinophil count of greater than or equal to 300 cells/mcL in AS Trial 1 and the overall population in AS Trial 2). In the overall population in AS Trial 2, the FEV1 LS mean change from baseline was 0.32 L (21%) and 0.34 L (23%) for Dupixent 200 mg Q2W and 300 mg Q2W, respectively, compared to matched placebo means of 0.18 L (12%) and 0.21 L (14%). The mean treatment difference versus placebo was 0.14 L (95% CI: 0.08, 0.19) and 0.13 L (95% CI: 0.08, 0.18) for Dupixent 200 mg Q2W and 300 mg Q2W, respectively. Subgroup analysis of AS Trials 1 and 2 demonstrated greater improvement in subjects with higher baseline blood eosinophils. CRSwNP(1) 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. Patients with chronic rhinosinusitis without nasal polyposis were not included in these trials. Rescue 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. 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 end-points 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. 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. Dupilumab 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. Dupilumab significantly decreased sinonasal symptoms as measured by SNOT-22 compared to placebo. 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 patients with prior surgery and without prior surgery. EoE(1) A single randomized, double-blind, parallel-group, multicenter, placebo-controlled trial, including two 24-week treatment periods (Parts A and B), was conducted in adult and pediatric subjects 12 to 17 years of age, weighing at least 40 kg, with EoE (NCT03633617). In both parts, subjects were randomized to receive 300 mg Dupixent every week or placebo. Eligible subjects had greater than or equal to 15 intraepithelial eosinophils per high-power field (eos/hpf) following a treatment course of a proton pump inhibitor (PPI) either prior to or during the screening period and symptoms of dysphagia as measured by the Dysphagia Symptom Questionnaire (DSQ). At baseline, 43% of subjects in Part A and 37% of subjects in Part B had a history of prior esophageal dilations. The coprimary efficacy endpoints in Parts A and B were the (1) 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 (2) the absolute change in the subject reported DSQ score from baseline to week 24. 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. PN(1,14) The prurigo nodularis (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 (WINRS greater than or equal to 7 on a scale of 0 to 10) and greater than or equal to 20 nodular lesions. 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. 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). Patients 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. 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). 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 per the criteria described above. Overall, patients treated with Dupixent saw improvement in all endpoints over placebo. |
|
Safety |
Dupilumab is contraindicated in patients who have a known hypersensitivity to dupilumab or any excipients of Dupixent.(1) |
REFERENCES
|
Number |
Reference |
|
1 |
Dupixent prescribing information. Regeneron Pharmaceuticals, Inc. February 2024. |
|
2 |
Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of Care for the Management of Atopic Dermatitis: Section 1. Diagnosis and Assessment of Atopic Dermatitis. J Am Acad Dermatol. 2014 Feb;70(2):338-51. |
|
3 |
Dhar A, Haboubi H, Attwood S, et al. British Society of Gastroenterology (BSG) and British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) joint consensus guidelines on the diagnosis and management of eosinophilic oesophagitis in children and adults. Gut. May 2022:gutjnl-327326. doi:10.1136/gutjnl-2022-327326 |
|
4 |
Sidbury R, Alikhan A, Bercovitch L, et al. Guidelines of care for the management of atopic dermatitis in adults with topical therapies. J Am Acad Dermatol. 2023;89(1):e1-e20. |
|
5 |
Davis DM, Drucker AM, Alikhan A, et al. Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies. Journal of the American Academy of Dermatology. 2024;90(2):e43-e56. doi:10.1016/j.jaad.2023.08.102 |
|
6 |
Pimecrolimus cream prescribing information. Oceanside Pharmaceuticals. September 2020. |
|
7 |
Simpson, Eric, et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med 2016; 375: Supplementary Appendix 19-20. December 15, 2016. DOI: 10.1056/NEJMoa1610020. |
|
8 |
Simpson, Eric, et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med 2016; 375:2335-2348. December 15, 2016. DOI: 10.1056/NEJMoa1610020. |
|
9 |
Holguín F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. The European Respiratory Journal. 2020;55(1):1900588. doi:10.1183/13993003.00588-2019 |
|
10 |
Chung KF, Wenzel SE, Brożek J, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. The European Respiratory Journal. 2014;43(2):343-373. doi:10.1183/09031936.00202013 |
|
11 |
Global Initiative for Asthma (GINA). Global Strategy For Asthma Management and Prevention. 2023. Available at www.ginasthma.org. |
|
12 |
Tacrolimus ointment prescribing information. Glenmark Pharmaceuticals Inc., USA. August 2023. |
|
13 |
Sidbury R, Tom WL, Bergman JN, et al. Guidelines of care for the management of atopic dermatitis: Section 4. Prevention of disease flares and use of adjunctive therapies and approaches. J Am Acad Dermatol. 2014 Dec;71(6):1218-33. |
|
14 |
Yosipovitch G, Mollanazar N, Stander S, et al. Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials. Nature Medicine. 2023;29(5):1180-1190. doi:10.1038/s41591-023-02320-9 |
|
15 |
Stevens WW, Schleimer RP, Kern RC. Chronic Rhinosinusitis with Nasal Polyps. J Allergy Clin Immunol Pract. 2016;4(4):565-572. doi:10.1016/j.jaip.2016.04.012 |
|
16 |
Rank MA, Chu DK, Bognanni A, et al. The Joint Task Force on Practice Parameters GRADE guidelines for the medical management of chronic rhinosinusitis with nasal polyposis. J Allergy Clin Immunol. 2023;151(2):386-398. doi:10.1016/j.jaci.2022.10.026 |
|
17 |
Ständer S, Pereira MP, Berger TG, et al. IFSI-guideline on chronic prurigo including prurigo nodularis. Itch. 2020;5(4):e42. doi:10.1097/itx.0000000000000042 |
|
18 |
Fokkens W, Lund VJ, Mullol J, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology. 2020;0(0):1-464. doi:10.4193/rhin20.600 |
|
19 |
O'Shea KM, Aceves SS, Dellon ES, Gupta SK, Spergel JM, Furuta GT, Rothenberg ME. Pathophysiology of Eosinophilic Esophagitis. Gastroenterology. 2018 Jan;154(2):333-345. doi: 10.1053/j.gastro.2017.06.065. Epub 2017 Jul 27. PMID: 28757265; PMCID: PMC5787048. |
|
20 |
Eosinophilic esophagitis. American Academy of Allergy Asthma & Immunology. (n.d.). https://www.aaaai.org/Conditions-Treatments/related-conditions/eosinophilic-esophagitis |
|
21 |
Dellon ES, Liacouras CA, Molina-Infante J, et al. Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference. Gastroenterology 2018; 155:1022. |
|
22 |
Hirano I, Chan ES, Rank MA, et al. AGA institute and the joint task force on allergy-immunology practice parameters clinical guidelines for the management of eosinophilic esophagitis. Ann Allergy Asthma Immunol 2020; 124:416. |
|
23 |
Elmariah S, Kim B, Berger T, et al. Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus. J Am Acad Dermatol. 2021; 84:747-760. |
|
24 |
Orlandi RR, Kingdom TT, Smith TL, et al. International consensus statement on allergy and rhinology: rhinosinusitis 2021. International Forum of Allergy & Rhinology. 2021;11(3):213-739. doi:10.1002/alr.22741 |
|
25 |
National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. 2020 Focused updates to the asthma management guidelines. National Heart, Lung, and Blood Institute, 2007. Available at: https://www.nhlbi.nih.gov/health-topics/all-publications-and-resources/2020-focused-updates-asthma-management-guidelines |
|
26 |
Institute For Clinical and Economic Review (ICER). JAK Inhibitors and Monoclonal Antibodies for the Treatment of Atopic Dermatitis: Effectiveness and Value. Final Evidence Report. August 2021. Updated February 2023. |
|
27 |
Fokkens WJ, Viskens A, Backer V, et al. EPOS/EUFOREA update on indication and evaluation of Biologics in Chronic Rhinosinusitis with Nasal Polyps 2023. Rhinology. 2023;0(0):194-202. doi:10.4193/rhin22.489 |
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 pen-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 pen-injector |
200 MG/1.14ML ; 300 MG/2ML |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
|
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 |
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 |
|
Dupixent |
Dupilumab Subcutaneous Soln Pen-injector 300 MG/2ML |
300 MG/2ML |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
|
Dupixent |
Dupilumab Subcutaneous Soln Prefilled Syringe |
100 MG/0.67ML |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
|
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 |
|
Dupixent |
Dupilumab Subcutaneous Soln Prefilled Syringe 300 MG/2ML |
300 MG/2ML |
Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx |
PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL
|
Module |
Clinical Criteria for Approval |
||
|
|
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 Note: Initial loading dose is allowed for asthma, atopic dermatitis, or prurigo nodularis only and may require a Quantity Limit review. The loading dose plus maintenance dose may be approved for 1 month, followed by maintenance dosing for the remainder of the length of approval. 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:
Compendia Allowed: AHFS, DrugDex 1 or 2a level of evidence, or NCCN 1 or 2a recommended use 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 |
|
|
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, 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 _ Interleukin-4_(IL-4)_Inhibitor_PAQL _ProgSum_ 10-01-2024 _ _v2