Coverage Policy Manual
Policy #: 2017031
Category: Pharmacy
Initiated: September 2017
Last Review: June 2022
  Dupilumab (e.g., Dupixent)

Description:
Dupilumab is a human monoclonal antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by binding to the IL-4R alpha subunit shared by IL-4 and IL-13 receptors whereby IL-4 and IL-13 production and cytokine-induced inflammatory response is reduced.  
 
Atopic dermatitis is a type of inflammation of the skin. It is characterized by pruritis and eczema, presents with one of the characteristic patterns typical of this disease, and is chronic or relapsing in nature.  Typical presentation will also include dry skin and IgE reactivity. Usually it presents in childhood and many patients have a family history of the disease.
 
Regulatory Status
 
Dupilumab (e.g., Dupixent™) was approved in March 2017 by the US Food and Drug Administration (FDA) for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.
 
Dupilumab was FDA approved on 10/19/2018 as an add-on maintenance treatment in patients with moderate to severe asthma aged 12 years and older with an eosinophilic phenotype or with oral corticosteroid dependent asthma.
 
Dupilumab was FDA approved on 3/11/2019 in a new patient population: patients 12 to less than 18 years of age with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.
 
Dupilumab was FDA approved on 6/26/2019 as an add-on maintenance treatment in adult patients with inadequately controlled chronic rhinosinusitis with nasal polyposis.
 
On May 20, 2022, the U.S. Food and Drug Administration approved Dupilumab for the treatment of adult and pediatric patients ages 12 years and older, weighing at least 40 kg, with eosinophilic esophagitis.
 
Coding
 
The use of dupilumab is not covered under the medical benefit.  
 
The use of dupilumab is addressed under the pharmacy benefit.  
 

Policy/
Coverage:
Effective January 1, 2022, Dupilumab is not covered under the medical benefit. Please check the member’s pharmacy benefit for coverage. This policy applies to members whose plan utilizes AR BCBS pharmacy and has Dupilumab as a formulary option.
 
Effective December 7, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Dupilumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
ASTHMA, MODERATE TO SEVERE
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
 
    1. Individual is 6 years or older (FDA, Dupixent, 2019); AND
    2. *Evidence of moderate to severe asthma is demonstrated by ALL of the following (NHLBI, 2007):
a.  A pretreatment forced expiratory volume in 1 second (FEV1) less than or equal to 80% predicted; AND
b.  FEV1 reversibility of at least 12% and 200 milliliters (ml) after albuterol (salbutamol) administration; AND
3.  Individual has documented evidence of 2 or more asthma exacerbations in the previous 12 months which required one or more of the following (Castrim 2018; Rabe, 2018):
a.  Use of a systemic corticosteroid; OR
b.  Temporary increase in the usual maintenance oral corticosteroid dosage; AND
4.   One of the following (FDA, 2021):
a.  A blood eosinophil count (in the absence of other potential causes of eosinophilia, such as hypereosinophilic syndromes, neoplastic disease, and known or suspected parasitic infection) of 150 cells/microliter or greater at initiation of therapy (FDA, Dupixent, 2019); AND an inadequate response or intolerance to a three-month trial of combination controller therapy (medium-to-high dose inhaled corticosteroids plus long acting beta2 –agonists, leukotriene modifiers, theophylline or oral corticosteroids) (ERS/ATS, 2013; GINA, 2019); OR
b.  Oral corticosteroid dependent asthma with an inadequate response to or intolerance to a three-month trial of a high dose inhaled corticosteroid with daily oral glucocorticoids given in combination with a controller medication (either a long-acting beta2-agonist, or leukotriene receptor antagonist, or theophylline) (ERS/ATS, 2013; GINA, 2019).
5.  Dupilumab will NOT be used in combination with an additional biologic agent of asthma or atopic condition; AND
6.  Must be dosed in accordance with the FDA label.
 
* FeNO testing is non-covered and is not considered adequate for establishing the diagnosis of asthma.  Please see AR policy 2005020
 
CONTINUED APPROVAL for 1 year:
    1. Continuation of therapy with dupilumab after 6 months is considered medically necessary for an individual when treatment has resulted in clinical improvement as documented by one or more of the following:
a.  Decreased utilization of rescue medications, OR
b.  Decreased frequency of exacerbations (defined as worsening of asthma that requires an increase in inhaled corticosteroid dose or treatment with systemic corticosteroids or ER visit or hospitalization); OR
c.  Increase in predicted FEV1 from pretreatment baseline; AND
2.  Must be dosed in accordance with the FDA label.
 
Dosing and Administration
Dupilumab is administered by subcutaneous injection.
 
The recommended dose of Dupilumab for adults and adolescents (12 years of ag and older) is:
    • an initial dose of 400 mg (two 200 mg injections) followed by 200 mg given every other week OR
    • an initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every other week OR
    • for patients requiring concomitant oral corticosteroids or with co-morbid moderate-to-severe atopic dermatitis for which dupilumab is indicated, start with an initial dose of 600 mg followed by 300 mg given every other week
 
The recommended dose of Dupilumab for pediatric patients 6 to 11 years of age is:
    • 15 to less than 30 kg, initial and subsequent doses of 100 mg every other week or 300 mg every 4 weeks
    • Greater than or equal to 30 kg, initial and subsequent doses of 200 mg every week
    • For pediatric patients 6 to 11 years old with asthma and co-morbid moderate-to-severe atopic dermatitis, follow the recommended dosage above which includes an initial loading dose.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
CHRONIC RHINOSINUSITIS WITH NASAL POLYPOSIS (CRSwNP)
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
    1. Individual is 18 years of age or older; AND
    2. Dupilumab is prescribed by a physician with expertise in the treatment of CRSwNP, e.g., an otolaryngologist [ear, nose, and throat (ENT) specialist] OR an allergist/immunologist; AND
    3. Individual has BOTH moderate to severe symptoms of nasal obstruction AND either rhinorrhea or decreased sense of smell for at least 12 weeks; AND
    4. Bilateral sinonasal polyposis reaching the lower border of the middle turbinate or beyond, which has been confirmed by nasal endoscopy, anterior rhinoscopy, or sinus CT scan (AAO-HNSF, 2015); AND
    5. Individual has had an inadequate response (e.g., Significant reduction in size or resolution of nasal polyps) to at least 8 weeks of continuous treatment with an intranasal corticosteroid in the past 6 months (AAO-HNS, 2015); AND
    6. Individual is not a candidate for sinus surgery to remove polyps – reason(s) for non-candidacy must be provided (AAO-HNS, 2015); AND
    7. CRSwNP despite one of the following (FDA, 2021):
a.  Prior sinonasal surgery; OR
b.  Prior treatment with systemic corticosteroids, unless contraindicated or not tolerated, in the past 2 years; AND
8.  Individual will be using a daily intranasal corticosteroid during treatment with dupilumab, unless contraindicated or not tolerated; AND
9.  Dupilumab will NOT be used in combination with an additional biologic agent for the treatment of chronic rhinosinusitis with nasal polyposis [e.g., omalizumab (e.g., Xolair)] or another atopic condition; AND
10.  Must be dosed in accordance with the FDA label.    
 
CONTINUED APPROVAL for 1 year:
    1. Individual has had documented clinical improvement or stabilization in clinical signs and symptoms of the disease (including but not limited to improvement in nasal polyp score or nasal congestion score); AND
    2. Individual meets all of the following initial approval criteria:
a.  Dupilumab is prescribed by a physician with expertise in the treatment of CRSwNP, e.g., an otolaryngologist [ear, nose, and throat (ENT) specialist] OR an allergist/immunologist; AND
b.  The member will be using a daily intranasal corticosteroid during treatment with dupilumab, unless contraindicated or not tolerated; AND
c.  Dupilumab will NOT be used in combination with an additional biologic agent for the treatment of chronic rhinosinusitis with nasal polyposis [e.g., omalizumab (e.g., Xolair)] or another atopic condition; AND
3.  Must be dosed in accordance with the FDA label.
 
Dosing and Administration
Dupilumab is administered by subcutaneous injection.
 
The recommended dose of Dupilumab for adults (18 years of age and older) is 300 mg given every other week.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
ATOPIC DERMATITIS
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
    1. Individual has a confirmed diagnosis of atopic dermatitis supported by the submitted medical records; AND
    2. Individual is > 1 year of age; AND
    3. Individual has chronic or relapsing history that has been present for at least one year (Boguniewicz, 2018; Paller, 2020); AND
    4. Individual has a history of pruritus associated with atopic dermatitis (Boguniewicz, 2018); AND
    5. Individual has at least one of the following (Boguniewicz, 2018):
a.  Early age of onset (<5 years of age) (Lyons, 2015); OR
b.  Atopy; OR
c.  Family history; OR
d.  Xerosis; AND
6.  Individual has involvement of >10% of body surface area OR involvement of critical areas (e.g., palms, face, etc) (FDA, 2021) AND  
7.  Individual must have documentation of one of the following (Boguniewicz, 2018):
a.  For infants and children: facial, neck or extensor involvement; OR
b.  For any age group: current or previous flexural lesions; sparing of groin and axillary regions; AND
8.  All of the following skin conditions have been excluded or adequately treated (Boguniewicz, 2018):
a.  Scabies; AND  
b.  Seborrheic dermatitis; AND
c.  Contact dermatitis (irritant or allergic); AND
d.  Ichthyoses; AND
e.  Cutaneous T-cell lymphoma; AND
f.  Psoriasis; AND
g.  Photosensitivity dermatoses; AND
h.  Immune deficiency disease; AND
i.  Erythroderma of other causes; AND
9.  The drug is authorized and managed by a physician with expertise in the treatment of atopic dermatitis (e.g., allergist/immunologist or dermatologist) AND
10.  Topical therapy failure (FDA, 2021).  The patient has either failed a trial, proved intolerant of a medication, or has contraindications to both below topical treatments (in accordance with AAD Guidelines (Eichenfield, 2014) (Howe, 2022):
a.  A topical calcineurin inhibitor (excluding patients < 2 years of age) [i.e., pimecrolimus (Elidel) or tacrolimus (Protopic)] (For pediatric patients > 2 to <12 years old - use of appropriate pediatric formulation) with an inadequate response to maintenance therapy that includes intermittent use (at least 2 days per week) for at least 12 weeks; AND  
b.  A topical corticosteroid (For pediatric patients >6 months to <12 years old - use of appropriate pediatric formulation with precautions for adrenal suppression) with an inadequate response to maintenance therapy that includes intermittent use (at least 2 days per week) for at least 12 weeks of a moderate-to-high-potency topical corticosteroid, unless involvement is limited to the face and intertriginous areas in which a lower-potency corticosteroid may be used; AND
11.  The drug will NOT be used in combination with a janus kinase (JAK) inhibitor or another biologic agent for the treatment of atopic dermatitis [e.g., omalizumab (e.g., Xolair), mepolizumab (e.g., Nucala), reslizumab (e.g., Cinqair), tralokinumab (e.g., Adbry) and rituximab (e.g., Rituxan)] or another atopic condition; AND  
12.  Individual has an Investigator’s Global Assessment (IGA) score > 3 (FDA, 2021); AND
13.  Individual has at least one of the following:
a.  Eczema Area and Severity Index (EASI) score >21 (Simpson, 2016; Simpson 2020); OR
b.  Weekly-average baseline worst itch score (Peak, Pruritus Numerical Rating Scale [NRS]) >4 (Efficacy, 2022); AND
14.  Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for 1 year:
Requirement of documentation in the medical records that the member has achieved and maintains a clinically meaningful benefit as defined below:
    1. Reduction in disease severity (e.g., erythema, dryness, edema/papulation, excoriations, lichenification, oozing/crusting); AND
    2. Reduction in the frequency or intensity of pruritus associated with atopic dermatitis; AND
    3. Reduction in the frequency of disease exacerbations/flairs; AND
    4. Reduction in the amount of Body Surface Area involvement relative to pretreatment baseline; AND
    5. Improvement in overall patient quality of life (e.g., improved sleep, less depression or anxiety, etc.); AND
    6. Reduction in the use of other topical therapies; AND
    7. Must be dosed in accordance with the FDA label.
 
Dosing and Administration
Dupilumab is administered by subcutaneous injection.
 
The recommended dose of Dupilumab for adult patients (18 years of age or older) is an initial dose of 600 mg (two 300 mg injections in different injection sites), followed by 300 mg given every other week.
 
The recommended dose of Dupilumab for pediatric patients (6 to 17 years of age):
 
  Body Weight                 Initial Dose                                   Subsequent Doses  
 15 to less than 30 kg      600 mg (two 300 mg injections)      300 mg every 4 weeks
30 to less than 60 kg      400 mg (two 200 mg injections)       200 mg every 2 weeks                                                                                        
60 kg or more                600 mg (two 300 mg injections)        300 mg every 2 weeks
 
The recommended dose of dupilumab for pediatric patients 6 months to 5 years of age:  
 
Body Weight                          Maintenance Dose (no loading dose)   
5 to less than 15 kg                200 mg every 4 weeks  
15 to less than 30 kg              300 mg every 4 weeks  
 
EOSINOPHILIC ESOPHAGITIS
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
    1. Individual has a confirmed diagnosis of eosinophilic esophagitis supported by the submitted medical records; AND
    2. Individual is > 12 years of age (Study, 2022); AND  
    3. Individual weighs > 40 kg (Study, 2022); AND  
    4. Individual has documentation of an average of two or more episodes of dysphagia per week (Study, 2022) and/or documentation of food impaction and/or evidence of esophageal stricture (Bonis – Treatment, 2022); AND  
    5. Individual has had one or more esophageal biopsies that have shown eosinophil predominant inflammation consisting of a peak value of > 15 eosinophils per high power field (or 60 eosinophils per mm2) (FDA, 2022); AND  
    6. Individual has documentation of referral to an allergist with expertise in the evaluation and management of food allergies. Must include documentation of diagnosis, dietary counseling (registered dietician) and compliance with appropriate dietary changes and adequate treatment interval to allow assessment of response (Wechsler, 2021); AND
    7. Individual has a documented inadequate response (8-week trial) to both of the following:
a.  High-dose PPI therapy (defined as 1-2 mg/kg total daily dose for children or a daily dose equivalent to omeprazole 40 mg twice daily for adults*) (FDA, 2022; Lucendo, 2015); AND  
b.  Topical glucocorticoid therapy (budesonide oral viscous slurry) (Muir, 2021) AND
8.  Medication is prescribed by a gastroenterologist or prescribed by an allergist in consultation with a gastroenterologist; AND
9. Must be dosed in accordance with the FDA label.
 
*PPI dose conversion chart (Clinical resource, 2022; Dusky, 2006)
 
Drug                                            Approximate Oral Daily Dose Providing Similar Effects on Gastric pH
Dexlansoprazole (e.g., Dexilant      60 mg
Esomeprazole (e.g., Nexium)         40 mg
Lansoprazole (e.g., Prevacid)         30 mg
Omeprazole (e.g., Prilosec)           40 mg
Pantoprazole (e.g., Protonix)         40 mg
Rabeprazole (e.g., Aciphex)          20 mg
 
CONTINUED APPROVAL for 1 year:
    1. Requirement of documentation in the medical records that the member has achieved and maintains a clinically meaningful benefit as defined by any of the following (Bonis-Diagnosis, 2022; Study, 2022):
a.  Reduction in symptoms and associated complications, such as – symptom frequency, food impaction or hospitalization  
b.  Endoscopic features, such as – edema, furrows, exudates, rings, strictures.
c.  Reduction in eosinophil burden per high power field relative to pretreatment baseline AND
2.  Medication is prescribed by a gastroenterologist or prescribed by an allergist in consultation with a gastroenterologist; AND
3.  Must be dosed in accordance with the FDA label.
 
Dosing and Administration
Dupilumab is administered by subcutaneous injection.
 
The recommended dose of dupilumab for patients 12 years of age or older weighing more than 40 kg for the treatment of EoE is 300 mg given once weekly.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
PRURIGO NODULARIS (PN)
 
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
    1. Individual must have documentation of confirmed diagnosis of PN by a dermatologist (PRIME2, 2022); AND
    2. Individual has been diagnosed with PN a least 3 months prior to initiation of dupilumab (PRIME2, 2022); AND
    3. Individual is > 18 years of age (PRIME2, 2022); AND
    4. Individual has presence of chronic pruritus lasting longer than 6 weeks as documented by both of the following (Stander, 2020):
a.  An average worst itch numeric rating scale (WI-NRS) score > 7, (PRIME2, 2022); AND
b.  History and/or signs of repeated scratching (e.g. excoriations and scars) (Stander, 2020); AND
5.  Individual has at least 20 PN lesions in total located on at least two of the following (PRIME2, 2022):
a.  Both legs (bilaterally symmetric lesions); OR
b.  Both arms (bilaterally symmetric lesions); OR  
c.  Trunk; AND
6.  Individual has failed at least a 2-week course (or for the maximum duration recommended by the product prescribing information, whichever is shorter) or has a contraindication to a medium- to super high-potency topical corticosteroid (PRIME2, 2022); AND
7.  Individual has failed at least one systemic therapy (e.g. UV phototherapy, gabapentin, cyclosporine, methotrexate, etc); AND
8.  Medication is ordered by or in consultation with a dermatologist; AND
9.  Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for 1 year:
    1. Individual has confirmed diagnosis of PN by a dermatologist; AND
    2. Individual is > 18 years of age; AND
    3. Individual has documented clinical improvement as demonstrated by a decrease from baseline in the number of lesions and their WI-NRS score; AND
    4. Medication is ordered by or in consultation with a dermatologist; AND
    5. Must be dosed in accordance with the FDA label.  
 
Dosage and Administration
 
The recommended dose of dupilumab for PN is an initial dose of 600 mg followed by 300 mg given every other week.  
 
Dupilumab is available as a single-dose pre-filled syringe with 300 mg/2 mL.
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of dupilumab for treatment outside of these parameters or for any other condition does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and are not covered.
 
For members with contracts without primary coverage criteria the use of dupilumab for treatment outside of these parameters or for any other condition is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective September 14, 2022 to Decmber 6, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
ASTHMA, MODERATE TO SEVERE
Dupilumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for moderate to severe asthma or when all the following criteria are met (FDA, 2021):
 
Initial approval will be for 6 months
    1. Individual is 6 years or older (FDA, Dupixent, 2019); AND
    2. *Evidence of moderate to severe asthma is demonstrated by ALL of the following (NHLBI, 2007):
a.   A pretreatment forced expiratory volume in 1 second (FEV1) less than or equal to 80% predicted; AND
b.   FEV1 reversibility of at least 12% and 200 milliliters (ml) after albuterol (salbutamol) administration; AND
3.   Individual has documented evidence of 2 or more asthma exacerbations in the previous 12 months which required one or more of the following (Castrim 2018; Rabe, 2018):
a.   Use of a systemic corticosteroid; OR
b.   Temporary increase in the usual maintenance oral corticosteroid dosage; AND
4.    One of the following (FDA, 2021):
a.   A blood eosinophil count (in the absence of other potential causes of eosinophilia, such as hypereosinophilic syndromes, neoplastic disease, and known or suspected parasitic infection) of 150 cells/microliter or greater at initiation of therapy (FDA, Dupixent, 2019) ; AND an inadequate response or intolerance to a three-month trial of combination controller therapy (medium-to-high dose inhaled corticosteroids plus long acting beta2 –agonists, leukotriene modifiers, theophylline or oral corticosteroids) (ERS/ATS, 2013; GINA, 2019); OR
b.   Oral corticosteroid dependent asthma with an inadequate response to or intolerance to a three-month trial of a high dose inhaled corticosteroid with daily oral glucocorticoids given in combination with a controller medication (either a long-acting beta2-agonist, or leukotriene receptor antagonist, or theophylline) (ERS/ATS, 2013; GINA, 2019).
5.  Dupilumab will NOT be used in combination with an additional biologic agent of asthma or atopic condition
 
* FeNO testing is non-covered and is not considered adequate for establishing the diagnosis of asthma.  Please see AR policy 2005020
 
Continued approval will be for 12 months
Continuation of therapy with dupilumab after 6 months is considered medically necessary for an individual when treatment has resulted in clinical improvement as documented by one or more of the following:
    1.  Decreased utilization of rescue medications; OR
    2.  Decreased frequency of exacerbations (defined as worsening of asthma that requires an increase in inhaled corticosteroid dose or treatment with systemic corticosteroids or ER visit or hospitalization); OR
    3. Increase in predicted FEV1 from pretreatment baseline;
 
Dosing and administration
Dupilumab is administered by subcutaneous injection.
 
The recommended dose of Dupilumab for adults and adolescents (12 years of ag and older) is:
    • an initial dose of 400 mg (two 200 mg injections) followed by 200 mg given every other week OR
    • an initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every other week OR
    • for patients requiring concomitant oral corticosteroids or with co-morbid moderate-to-severe atopic dermatitis for which dupilumab is indicated, start with an initial dose of 600 mg followed by 300 mg given every other week
 
The recommended dose of Dupilumab for pediatric patients 6 to 11 years of age is:
    • 15 to less than 30 kg, initial and subsequent doses of 100 mg every other week or 300 mg every 4 weeks
    • Greater than or equal to 30 kg, initial and subsequent doses of 200 mg every week
    • For pediatric patients 6 to 11 years old with asthma and co-morbid moderate-to-severe atopic dermatitis, follow the recommended dosage above which includes an initial loading dose.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
CHRONIC RHINOSINUSITIS WITH NASAL POLYPOSIS (CRSwNP)
Dupilumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for chronic rhinosinusitis with nasal polyposis in members 18 years of age or older. When ALL of the following criteria are met authorization of 6 months may be granted for treatment of CRSwNP:
1. Dupilumab is prescribed by a physician with expertise in the treatment of CRSwNP, e.g. an otolaryngologist [ear, nose, and throat (ENT) specialist] OR an allergist/immunologist.
2. The member has BOTH moderate to severe symptoms of nasal obstruction AND either rhinorrhea or decreased sense of smell for at least 12 weeks.
3. Bilateral sinonasal polyposis reaching the lower border of the middle turbinate or beyond, which has been confirmed by nasal endoscopy, anterior rhinoscopy, or sinus CT scan (AAO-HNSF, 2015).
4. The member has had an inadequate response (e.g. Significant reduction in size or resolution of nasal polyps) to at least 8 weeks of continuous treatment with an intranasal corticosteroid in the past 6 months (AAO-HNS, 2015).
5. Member is not a candidate for sinus surgery to remove polyps – reason(s) for non-candidacy must be provided (AAO-HNS, 2015).
6. CRSwNP despite one of the following (FDA, 2021):
a. Prior sinonasal surgery; OR
b. Prior treatment with systemic corticosteroids, unless contraindicated or not tolerated, in the past 2 years
7. The member will be using a daily intranasal corticosteroid during treatment with dupilumab, unless contraindicated or not tolerated
8. Dupilumab will NOT be used in combination with an additional biologic agent for the treatment of chronic rhinosinusitis with nasal polyposis [e.g. omalizumab (Xolair)] or another atopic condition.    
 
Dosing and Administration
Dupilumab is administered by subcutaneous injection.
 
The recommended dose of Dupilumab for adults (18 years of age and older) is 300 mg given every other week.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
ATOPIC DERMATITIS
The use of dupilumab meets primary coverage criteria for effectiveness and is covered for the treatment of atopic dermatitis when ALL of the following criteria are met:
 
Initial 6 month Approval
There is a confirmed diagnosis of atopic dermatitis supported by the submitted medical records and ALL of the below:
    1. Reserved for those with severe atopic dermatitis with the condition present for >3 years AND
    2. There is involvement of >10% of body surface area for members >12 years old or there is involvement of >15% body surface area for members >6 to <12 years old OR involvement of critical areas (e.g. palms, face, etc) (FDA, 2021) AND  
    3. Other skin conditions have been excluded or adequately treated AND
    4. The drug is authorized and managed by a physician with expertise in the treatment of atopic dermatitis (e.g. allergist/immunologist or dermatologist) AND
    5. Topical therapy failure (FDA, 2021).  The patient has either failed a trial, proved intolerant of a medication, or has contraindications to both below topical treatments (in accordance with AAD Guidelines (Eichenfield, 2014):
      1. A topical calcineurin inhibitor [i.e., pimecrolimus (Elidel) or tacrolimus (Protopic)] (For pediatric patients >6 to <12 years old - use of appropriate pediatric formulation with precautions for adrenal suppression) with an inadequate response to maintenance therapy, AND  
      2. A topical corticosteroid (For pediatric patients >6 to <12 years old - use of appropriate pediatric formulation with precautions for adrenal suppression) with an inadequate response to maintenance therapy that includes intermittent use (at least 2 days per week) of a moderate-to-high-potency topical corticosteroid, unless involvement is limited to the face and intertriginous areas in which a lower-potency corticosteroid may be used AND
6. The drug will NOT be used in combination with another biologic agent for the treatment of atopic dermatitis [e.g., omalizumab (Xolair), mepolizumab (Nucala), reslizumab (Cinqair), and rituximab (Rituxan)] or another atopic condition, AND  
7. At least one of the following:
      1. Investigator’s Global Assessment (IGA) score = 4, OR
      2. Eczema Area and Severity Index (EASI) score >21, OR
      3. Weekly-average baseline worst itch score (Peak, Pruritus Numerical Rating Scale [NRS]) >4.
 
Continued approval will be for 12 months
Requirement of documentation in the medical records that the member has achieved and maintains a clinically meaningful benefit as defined below:
    1. Reduction in disease severity (e.g., erythema, dryness, edema/papulation, excoriations, lichenification, oozing/crusting)  
    2. Reduction in the frequency or intensity of pruritus associated with atopic dermatitis
    3. Reduction in the frequency of disease exacerbations/flairs  
    4. Reduction in the amount of Body Surface Area involvement relative to pretreatment baseline.  
    5. Improvement in overall patient quality of life (e.g., improved sleep, less depression or anxiety, etc.)
    6. Reduction in the use of other topical therapies.
 
Dosing and Administration
Dupilumab is administered by subcutaneous injection.
 
The recommended dose of Dupilumab for adult patients (18 years of age or older) is an initial dose of 600 mg (two 300 mg injections in different injection sites), followed by 300 mg given every other week.
 
The recommended dose of Dupilumab for pediatric patients:
 
   Body Weight                 Initial Dose                                   Subsequent Doses  
  15 to less than 30 kg      600 mg (two 300 mg injections)      300 mg every 4 weeks
  30 to less than 60 mg    400 mg (two 200 mg injections)       200 mg every 2 weeks                                                                                        
  60 kg or more                600 mg (two 300 mg injections)       300 mg every 2 weeks
 
EOSINOPHILIC ESOPHAGITIS
The use of dupilumab meets primary coverage criteria for effectiveness and is covered for the treatment of eosinophilic esophagitis (EoE) when ALL of the following criteria are met:
 
Initial 6 month Approval
There is a confirmed diagnosis of eosinophilic esophagitis supported by the submitted medical records and ALL of the below:
    1. Individual is > 12 years of age  (Study, 2022); AND  
    2. Individual weighs > 40 kg (Study, 2022); AND  
    3. Individual has documentation of an average of two or more episodes of dysphagia per week (Study, 2022) and/or documentation of food impaction and/or evidence of esophageal stricture (Bonis – Treatment, 2022); AND  
    4. Individual has had one or more esophageal biopsies that have shown eosinophil predominant inflammation consisting of a peak value of > 15 eosinophils per high power field (or 60 eosinophils per mm2)(FDA, 2022); AND  
    5. Individual has documentation of referral to an allergist with expertise in the evaluation and management of food allergies. Must include documentation of diagnosis, dietary counseling (registered dietician) and compliance with appropriate dietary changes and adequate treatment interval to allow assessment of response (Wechsler, 2021); AND
    6. Individual has a documented inadequate response (8-week trial) to both of the following:
        1. High-dose PPI therapy (defined as 1-2 mg/kg total daily dose for children or a daily dose equivalent to omeprazole 40 mg twice daily for adults*) (FDA, 2022; Lucendo, 2015); AND  
        2. Topical glucocorticoid therapy (budesonide oral viscous slurry) (Muir, 2021) AND
7. Medication is prescribed by a gastroenterologist or prescribed by an allergist in consultation with a gastroenterologist.
 
*PPI dose conversion chart (Clinical resource, 2022; Dusky, 2006)
 
Drug                                                          Approximate Oral Daily Dose Providing Similar Effects on Gastric pH
Dexlansoprazole (e.g., Desilant                     60 mg
Esomeprazole (e.g., Nexium)                        40 mg
Lansoprazole (e.g., Prevacid)                        30 mg
Omeprazole (e.g., Prilosec)                          40 mg
Pantoprazole (e.g., Prontonix)                       40 mg
Rabeprazole (e.g., Aciphex)                          20 mg
 
Continued approval will be for 12 months
    1. Requirement of documentation in the medical records that the member has achieved and maintains a clinically meaningful benefit as defined by any of the following (Bonis-Diagnosis, 2022; Study, 2022):
        1. Reduction in symptoms and associated complications, such as – symptom frequency, food impaction or hospitalization  
        2. Endoscopic features, such as – edema, furrows, exudates, rings, strictures.
        3. Reduction in eosinophil burden per high power field relative to pretreatment baseline AND
2. Medication is prescribed by a gastroenterologist or prescribed by an allergist in consultation with a gastroenterologist.
 
Dosing and Administration
Dupilumab is administered by subcutaneous injection.
 
The recommended dose of dupilumab for patients 12 years of age or older weighing more than 40 kg for the treatment of EoE is 300 mg given once weekly.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of dupilumab for treatment outside of these parameters or for any other condition does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and are not covered.
 
For members with contracts without primary coverage criteria the use of dupilumab for treatment outside of these parameters or for any other condition is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to September 14, 2022 are not online. If you would like a hardcopy print, please email:    codespecificinquiry@arkbluecross.com
   

Rationale:
Atopic Dermititis
The American Academy of Dermatology’s Guidelines for Atopic Dermatitis recommends corticosteroids and calcineurin inhibitors as options for patients in whom nonpharmacological therapies (such as moisturizers, bathing practices, wet-wraps, etc.) have provided inadequate relief. (Eichenfield, 2014)  These guidelines note that “the majority of patients with AD can achieve clinical improvement and disease control with nonpharmacologic interventions (eg, emollient use), conventional topical therapies (including corticosteroids and calcineurin inhibitors), and environmental and occupational modifications, when necessary.”  Phototherapy is considered a second-line options when these measures have failed and systemic oral therapies (including cyclosporine, azathioprine, methotrexate, mycophenolate mofetil) are listed as options if phototherapy does not provide adequate results. (Sidbury, 2014)
 
Dupilumab was evaluated in two randomized, placebo-controlled, phase 3 clinical trials of identical design to investigate the primary outcome of the proportion of patients who had both a score of 0-1 on the Investigator’s Global Assessment (IGA) at week 16 and a reduction of 2 or more points from baseline at week 16.  The two phase 3 trials were referred to as SOLO 1 and SOLO 2.  SOLO 1 enrolled 671 patients and SOLO 2 enrolled 708 patients.  Patients were randomly assigned to one of the three arms of the study in a 1:1:1 ratio.  The arms were (1) dupilumab 300mg SQ weekly, (2) dupilumab 300mg SQ every 2 weeks (alternating with placebo to be given a SQ injection weekly), and (3) placebo SQ weekly.  Patients involved in the study had moderate-to-severe atopic dermatitis, whose disease was uncontrolled by topical treatment.  SOLO 1 results of the primary outcome for dupilumab weekly was 37% (83 patients), dupilumab every 2 weeks was 38% (85 patients), and placebo was 10% (23 patients) (P<0.001 for both comparisons with placebo).  SOLO 2 results of the primary outcome for dupilumab weekly was 36% (87 patients), dupilumab every 2 weeks was 36% (84 patients), and placebo was 8% (20 patients) (P<0.001 for both comparisons).  In both SOLO 1 and SOLO 2, the improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported significantly higher in either group receiving dupilumab compared to placebo (P<0.001 for all comparisons).  Dupilumab was also associated with improvement in other endpoints such as reduction in pruritus, symptoms of anxiety or depression, and improvement in quality of life.  Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo group. (Simpson, 2016)
 
Dupilumab was evaluated in a randomized, double-blind, placebo-controlled trials in adults with moderate-to-severe atopic dermatitis who failed treatment on topical glucocorticoids and calcineurin inhibitors.  Two 4-week trials and one 12-week trial evaluated dupilumab as monotherapy and one 4-week trial evaluated dupilumab in combination with topical glucocorticoids.  The endpoints of these trials were the Eczema Area and Severity Index (EASI) score, the Investigator’s Global Assessment (IGA) score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome.    The results of the 4-week monotherapy trials showed dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptosome.  In the 12-week trial, the results of the 4-week trials were found and extended beyond the 4 weeks.  The results were 85% of patients in the dupilumab group compared to 35% had a 50% reduction in the EASI score (P<0.001); pruritus scores decreased by 55.7% in the dupilumab group vs. 15.1% in the placebo group (P<0.001).  In the 4-week combination trial of dupilumab and topical glucocorticoids, 100% of the patients in the dupilumab + topical glucocorticoid group met the criterion for EASI (P=0.002), compared to 50% of the placebo + topical glucocorticoids group.  Patients who received dupilumab + glucocorticoids used less than half the amount of topical glucocorticoids used by those in the placebo group (P=0.16).  In the placebo group, adverse events such as skin injections occurred more frequently.  Nasopharyngitis and headache were the most frequent side effects with dupilumab. (Beck, 2014).
 
Moderate to Severe Asthma
  
 
Dupilumab, a fully human anti-IL-4Rα monoclonal antibody, inhibits signaling of both interleukin (IL)-4 and IL-13, which are key drivers of type 2-mediated inflammation. Dupilumab is approved in the EU, USA, and other countries for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. Following positive phase 2 results in asthma, the phase 3 Liberty Asthma QUEST trial was initiated to provide further evidence for dupilumab efficacy and safety in patients with uncontrolled, moderate-to-severe asthma.
 
Liberty Asthma QUEST is a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (NCT02414854) in patients with persistent asthma who are receiving continuous treatment with inhaled corticosteroids (ICS) plus one or two other asthma controller medicines. A total of 1902 patients (aged ≥ 12 years) were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on therapy with subcutaneously administered dupilumab 200 or 300 mg every 2 weeks or matched placebo. The study consisted of a 4 ± 1-week screening period, 52-week randomized treatment period, and 12-week post-treatment follow-up period. All patients continued to receive their prescribed ICS plus up to two additional controller medications. The primary efficacy endpoints were annualized rate of severe exacerbation events during the 52-week treatment period and absolute change from baseline in pre-bronchodilator FEV1 at week 12 (Busse WW, Maspero JF, Rabe KF, et al May 2018).
 
The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV1 had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo(Castro M, Corren J, Pavord ID, et al. June 2018).
 
In conclusion, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients.
 
In another arm of this study, (Rabe KF, Nair P, Brusselle G, et al. May 2018) 210 patients with oral glucocorticoid-treated asthma were randomly assigned to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose-adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV1) before bronchodilator use were also assessed.
 
The percentage change in the glucocorticoid dose was -70.1% in the dupilumab group, as compared with -41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower than that in the placebo group and resulted in an FEV1 that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection-site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%).  
 
In conclusion, patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients.
 
December 2019 Update
Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) generally have a high symptom burden and poor health-related quality of life, often requiring recurring systemic corticosteroid use and repeated sinus surgery. Dupilumab is a fully human monoclonal antibody that inhibits signalling of interleukin (IL)-4 and IL-13, key drivers of type 2 inflammation, and has been approved for use in atopic dermatitis and asthma. In these two studies, we aimed to assess efficacy and safety of dupilumab in patients with CRSwNP despite previous treatment with systemic corticosteroids, surgery, or both.
LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 were two multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies assessing dupilumab added to standard of care in adults with severe CRSwNP. SINUS-24 was done in 67 centres in 13 countries, and SINUS-52 was done in 117 centres in 14 countries. Eligible patients were 18 years or older with bilateral CRSwNP and symptoms despite intranasal corticosteroid use, receiving systemic corticosteroids in the preceding 2 years, or having had sinonasal surgery. Patients in SINUS-24 were randomly assigned (1:1) to subcutaneous dupilumab 300 mg or placebo every 2 weeks for 24 weeks. Patients in SINUS-52 were randomly assigned (1:1:1) to dupilumab 300 mg every 2 weeks for 52 weeks, dupilumab every 2 weeks for 24 weeks and then every 4 weeks for the remaining 28 weeks, or placebo every 2 weeks for 52 weeks. All patients were randomly assigned centrally with a permuted block randomisation schedule. Randomisation was stratified by asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease status at screening, previous surgery at screening, and country. Patients with or without comorbid asthma were included. Coprimary endpoints were changes from baseline to week 24 in nasal polyp score (NPS), nasal congestion or obstruction, and sinus Lund-Mackay CT scores (a coprimary endpoint in Japan), done in an intention-to-treat population. Safety was assessed in a pooled population of both dupilumab groups in SINUS-52 up to week 24 and the dupilumab group in SINUS-24 and the placebo groups in both studies until week 24. The trials are complete and registered at ClinicalTrials.gov, NCT02912468 and NCT02898454.
Between Dec 5, 2016, and Aug 3, 2017, 276 patients were enrolled in SINUS-24, with 143 in the dupilumab group and 133 in the placebo group receiving at least one study drug dose. Between Nov 28, 2016, and Aug 28, 2017, 448 patients were enrolled in SINUS-52, with 150 receiving at least one dose of dupilumab every 2 weeks, 145 receiving at least one dose of dupilumab every 2 weeks for 24 weeks and every 4 weeks until week 52, and 153 receiving at least one dose of placebo. Dupilumab significantly improved the coprimary endpoints in both studies. At 24 weeks, least squares mean difference in NPS of dupilumab treatment versus placebo was -2·06 (95% CI -2·43 to -1·69; p<0·0001) in SINUS-24 and -1·80 (-2·10 to -1·51; p<0·0001) in SINUS-52; difference in nasal congestion or obstruction score was -0·89 (-1·07 to -0·71; p<0·0001) in SINUS-24 and -0·87 (-1·03 to -0·71; p<0·0001) in SINUS-52; and difference in Lund-Mackay CT scores was -7·44 (-8·35 to -6·53; p<0·0001) in SINUS-24 and -5·13 (-5·80 to -4·46; p<0·0001) in SINUS-52. The most common adverse events (nasopharyngitis, worsening of nasal polyps and asthma, headache, epistaxis, and injection-site erythema) were more frequent with placebo.
In adult patients with severe CRSwNP, dupilumab reduced polyp size, sinus opacification, and severity of symptoms and was well tolerated. These results support the benefits of adding dupilumab to daily standard of care for patients with severe CRSwNP who otherwise have few therapeutic options. (Bachert C, Han JK, Desrosiers M, Hellings PW, et. al., 2019)
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2020. No new literature was identified that would prompt a change in the coverage statement.
 
September 2020 Update
A randomized, double-blind, parallel-group, phase 3 clinical trial was conducted at 45 US and Canadian centers between March 21, 2017, and June 5, 2018 to assess the efficacy and safety of dupilumab monotherapy in adolescents with moderate to severe inadequately controlled AD. A total of 251 adolescents with moderate to severe AD inadequately controlled by topical medications or for whom topical therapy was inadvisable were included.
 
Patients were randomized (1:1:1; interactive-response system; stratified by severity and body weight) to 16-week treatment with dupilumab, 200 mg (n = 43; baseline weight <60 kg), or dupilumab, 300 mg (n = 39; baseline weight 60 kg), every 2 weeks; dupilumab, 300 mg, every 4 weeks (n = 84); or placebo (n = 85).
 
Proportion of patients with 75% or more improvement from baseline in Eczema Area and Severity Index (EASI-75) (scores range from 0 to 72, with higher scores indicating greater severity) and Investigator's Global Assessment (IGA) 0 or 1 on a 5-point scale (scores range from 0 to 4, with higher scores indicating greater severity) at week 16.
 
A total of 251 patients were randomized (mean [SD] age, 14.5 [1.7] years; 148 [59.0%] male). Of 250 patients with data available on concurrent allergic conditions, most had comorbid type 2 diseases (asthma, 134 [53.6%]; food allergies, 60.8%; allergic rhinitis, 65.6%). A total of 240 patients (95.6%) completed the study. Dupilumab achieved both coprimary end points at week 16. The proportion of patients with EASI-75 improvement from baseline increased (every 2 weeks, 41.5%; every 4 weeks, 38.1%; placebo, 8.2%) with differences vs placebo of 33.2% (95% CI, 21.1%-45.4%) for every 2 weeks and 29.9% (95% CI, 17.9%-41.8%) for every 4 weeks (P < .001). Efficacy of the every-2-week regimen was generally superior to the every-4-week regimen. Patients in the dupilumab arms had higher percentage values of conjunctivitis (every 2 weeks, 9.8%; every 4 weeks, 10.8%; placebo, 4.7%) and injection-site reactions (every 2 weeks, 8.5%; every 4 weeks, 6.0%; placebo, 3.5%), and lower non herpetic skin infections (every 2 weeks, 9.8%; every 4 weeks, 9.6%; placebo, 18.8%).
 
In this study, dupilumab significantly improved AD signs, symptoms, and quality of life in adolescents with moderate to severe AD, with an acceptable safety profile. Placebo-corrected efficacy and safety of dupilumab were similar in adolescents and adults. (Simpson EL, Paller AS, Siegfried EC, et al., 2019)
 
The efficacy and safety of DUPIXENT use concomitantly with TCS in pediatric subjects was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial (Trial 8; NCT03345914) in 367 subjects 6 to 11 years of age, with AD defined by an IGA score of 4 (scale of 0 to 4), an EASI score 21 (scale of 0 to 72), and a minimum BSA involvement of 15%. Eligible subjects enrolled into this trial had previous inadequate response to topical medication. Enrollment was stratified by baseline weight (<30 kg; 30 kg).
 
Subjects in the DUPIXENT Q4W + TCS group received an initial dose of 600 mg on Day 1, followed by 300 mg Q4W from Week 4 to Week 12, regardless of weight. Subjects in the DUPIXENT Q2W + TCS group with baseline weight of <30 kg received an initial dose of 200 mg on Day 1, followed by 100 mg Q2W from Week 2 to Week 14, and subjects with baseline weight of 30 kg received an initial dose of 400 mg on Day 1, followed by 200 mg Q2W from Week 2 to Week 14. Subjects were permitted to receive rescue treatment at the discretion of the investigator. Subjects who received rescue treatment were considered non-responders.
 
The mean age was 8.5 years, the median weight was 29.8 kg, 50% of subjects were female, 69% were white, 17% were black, and 8% were Asian. At baseline, the mean BSA involvement was 58%, and 17% had received prior systemic non-steroidal immunosuppressants. Also, at baseline the mean EASI score was 37.9, and the weekly average of daily worst itch score was 7.8 on a scale of 0-10. Overall, 92% of subjects had at least one co-morbid allergic condition; 64% had food allergies, 63% had other allergies, 60% had allergic rhinitis, and 47% had asthma.
 
The primary endpoint was the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) at Week 16. Other evaluated outcomes included the proportion of subjects with EASI-75 or EASI90 (improvement of at least 75% or 90% in EASI from baseline, respectively), and reduction in itch as measured by the Peak Pruritus NRS (4-point improvement).
A greater proportion of subjects randomized to DUPIXENT + TCS achieved an improvement in the Peak Pruritus NRS compared to placebo + TCS (defined as 4-point improvement at Week 16). Proportion of Pediatric Subjects with 4-point Improvement on the Peak Pruritus NRS at Week 16 <30 kg was 54.1% Dupilumab 300 mg Q4W plus TCS (N=61) versus 11.7% placebo and >30 kg was 61.4% Dupilumab 200 mg Q2W plus TCS (N=59) versus 12.9% placebo. FDA, 2020)
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement.
 
January 2022 Update
In a 52-week phase 3, randomized, double-blind, placebo-controlled trial, we assigned 408 children between the ages of 6 and 11 years who had uncontrolled moderate-to-severe asthma to receive a subcutaneous injection of dupilumab (at a dose of 100 mg for those weighing 30 kg and 200 mg for those weighing >30 kg) or matched placebo every 2 weeks. All the children continued to receive a stable dose of standard background therapy. The primary end point was the annualized rate of severe asthma exacerbations. Secondary end points included the change from baseline in the percentage of predicted prebronchodilator forced expiratory volume in 1 second (ppFEV1) at week 12 and in the score on the Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) at week 24. End points were evaluated in the two primary efficacy populations who had either a type 2 inflammatory asthma phenotype (150 blood eosinophils per cubic millimeter or a fraction of exhaled nitric oxide of 20 ppb at baseline) or a blood eosinophil count of at least 300 cells per cubic millimeter at baseline.
 
In patients with the type 2 inflammatory phenotype, the annualized rate of severe asthma exacerbations was 0.31 (95% confidence interval [CI], 0.22 to 0.42) with dupilumab and 0.75 (95% CI, 0.54 to 1.03) with placebo (relative risk reduction in the dupilumab group, 59.3%; 95% CI, 39.5 to 72.6; P<0.001). The mean (±SE) change from baseline in the ppFEV1 was 10.5±1.0 percentage points with dupilumab and 5.3±1.4 percentage points with placebo (mean difference, 5.2 percentage points; 95% CI, 2.1 to 8.3; P<0.001). Dupilumab also resulted in significantly better asthma control than placebo (P<0.001). Similar results were observed in the patients with an eosinophil count of at least 300 cells per cubic millimeter at baseline. The incidence of serious adverse events was similar in the two groups.
 
Among children with uncontrolled moderate-to-severe asthma, those who received add-on dupilumab had fewer asthma exacerbations and better lung function and asthma control than those who received placebo. (Bacharier LB, Maspero JF, Katelaris CH, et.al., 2021)
 
2022 Update
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease treated with sinus surgery when refractory to medical intervention. However, recurrence postsurgery is common. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor for interleukin 4 (IL-4) and IL-13, key and central drivers of type 2 inflammation. The efficacy of dupilumab is reported in patients with CRSwNP from the SINUS-24/SINUS-52 trials (NCT02912468/NCT02898454), by number of prior surgeries and time since last surgery.
 
Patients were randomized to placebo or dupilumab 300 mg every 2 weeks. Post hoc subgroup analyses were performed for patients with 0, 1, 1/2, or 3 prior surgeries, and for patients who had surgery within <3, 3 to <5, 5 to <10, or 10 years. Efficacy outcomes at 24 weeks included co-primary endpoints nasal polyp score (NPS) and nasal congestion (NC), and Lund-Mackay (LMK), 22-item Sino-Nasal Outcome Test (SNOT-22), and smell scores.
 
Of 724 patients randomized, 459 (63.4%) had 1 prior surgery. Baseline sinus disease (NPS, NC, LMK) and olfactory dysfunction (University of Pennsylvania Smell Identification Test [UPSIT] and loss of smell) scores were worse for patients with 3 prior surgeries vs no surgery. Baseline NPS and LMK were worse in patients with <3 years since last surgery than in patients with 5 years since last surgery. Dupilumab significantly improved all outcome measures vs placebo in all subgroups by number of surgeries and by time since last surgery. Improvements in NPS and LMK were greater in patients with <3 years since last surgery than patients with 5 years. Safety results were consistent with the known dupilumab safety profile.
 
Dupilumab improved CRSwNP outcomes irrespective of surgery history, with greater improvements in endoscopic outcomes in patients with shorter duration since last surgery. (Hopkins C, Wagenmann M, Bachert C, et.al., 2021)
 
September 2022 Update
EoE
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 dupilumab every week or placebo. Eligible subjects had 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).
 
A total of 81 subjects (61 adults and 20 pediatric subjects) were enrolled in Part A and 159 subjects (107 adults and 52 pediatric subjects) were enrolled in Part B. The mean age in years was 32 years (range 13 to 62 years) in Part A and 28 years (range 12 to 66 years) in Part B.
 
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 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 dupilumab achieved histological remission (peak esophageal intraepithelial eosinophil count 6 eos/hpf) compared to placebo. Treatment with dupilumab also resulted in a significant improvement in LS mean change in DSQ score compared to placebo at Week 24. 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 (FDA, 2022).
 
“[The role of dupilumab] in the management of EoE remains to be fully defined compared with other options such as dietary therapy and topical glucocorticoids. While no US Food and Drug Administration (FDA)-approved formulation of the latter is available in the United States or in some other regions, many studies have demonstrated a clinical benefit and clarified its safety profile. That, combined with the high expense of dupilumab, suggests that dupilumab may be best reserved for patients who are refractory to or decline other options. In addition, patients with EoE plus one or more atopic conditions (eg, severe asthma, eczema, sinus disease) may be candidates for dupilumab because it may consolidate their medical therapies.  
 
Long-term safety of dupilumab is still being established. The most common side effects occurring more often than placebo in trials of EoE included injection site reactions, upper respiratory tract infections, arthralgia, and herpes viral infections, but additional side effects have been described in trials using dupilumab for other indications. Preliminary data suggest that dupilumab use may be linked to an increased risk for developing other cytokine-mediated conditions including seronegative inflammatory arthritis, enthesitis, iridocyclitis (iritis with adjacent ciliary body inflammation), and psoriasis, possibly by shifting immune responses toward alternative cytokine pathways. Additional studies may help to describe the underlying mechanism and confirm these findings” (Bonis-treatment, 2022).
 
December 2022 Update
Atopic Dermatitis 6 months to <6 years
The efficacy and safety of DUPIXENT use concomitantly with TCS in pediatric subjects was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial (AD-1539; NCT03346434) in 162 subjects 6 months to 5 years of age, with moderate-to-severe AD defined by an IGA score ≥3 (scale of 0 to 4), an EASI score ≥16 (scale of 0 to 72), and a minimum BSA involvement of ≥10%. Eligible subjects enrolled into this trial had previous inadequate response to topical medication. Enrollment was stratified by baseline weight (≥5 to <15 kg and ≥15 to <30 kg).
 
Subjects in the DUPIXENT Q4W + TCS group with baseline weight of ≥5 to <15 kg received an initial dose of 200 mg on Day 1, followed by 200 mg Q4W from Week 4 to Week 12, and subjects with baseline weight of ≥15 to <30 kg received an initial dose of 300 mg on Day 1, followed by 300 mg Q4W from Week 4 to Week 12. Subjects were permitted to receive rescue treatment at the discretion of the investigator. Subjects who received rescue treatment were considered non-responders.
 
At baseline, the mean BSA involvement was 58%, and 29% of subjects had received prior systemic immunosuppressants. Also, at baseline the mean EASI score was 34.1, and the weekly average of daily worst scratch/itch score was 7.6 on a scale of 0-10.
 
The primary endpoint was the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) at Week 16. Other evaluated outcomes included the proportion of subjects with EASI-75 or EASI-90, and reduction in itch as measured by the Worst Scratch/Itch NRS (≥4-point improvement).
 
Among children treated with Dupixent, 28% and 53% achieved an IGA score of 0 or 1 and EASI-75, respectively, compared with 4% and 11% of children in the control group. A clinically meaningful itch reduction was also achieved in 48% of children treated with Dupixent compared with 9% in the control group. The safety profile of Dupixent was consistent with the profile established in older patients with AD.
 
Prurigo Nodularis
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 (WI-NRS ≥ 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 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).   
 
Efficacy was assessed with the proportion of subjects with improvement (reduction) in WI-NRS by ≥4 points, the proportion of subjects with Investigator's Global Assessment for Prurigo Nodularis-Stage (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.
 
In PRIME and PRIME2, 60% and 58% of patients receiving Dupixent, respectively, experienced a ≥4-point reduction in WI-NRS from baseline at 24 weeks, compared with 18% and 20% of patients receiving placebo. In addition, 48% and 45% of patients receiving Dupixent in the PRIME and PRIME2 trials, respectively, achieved clear or almost clear skin at 24 weeks on the IGA PN-S scale, compared with 18% and 16% of patients receiving placebo.  
 
The safety results from the PRIME and PRIME2 trials were consistent with the known safety profile of Dupixent in atopic dermatitis.

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