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Dupilumab (e.g., Dupixent) | |
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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 individuals have a family history of the disease.
Regulatory Status
Dupilumab (e.g., Dupixent) was approved by the US Food and Drug Administration (FDA) on March 28, 2017, for the treatment of adult individuals with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. On March 11, 2019, treatment for this indication was expanded to individuals 12 to less than 18 years of age. On May 26, 2020, treatment for this indication was expanded to individuals 6 to 11 years of age. On June 7, 2022, treatment for this indication was expanded to patients 6 months to 5 years of age.
On October 19, 2018, the FDA approved dupilumab (e.g., Dupixent) 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. On October 20, 2021, treatment for this indication was expanded to individuals 6 to 11 years of age.
On June 26, 2019, the FDA approved dupilumab (e.g., Dupixent) as an add-on maintenance treatment in adult individuals with inadequately controlled chronic rhinosinusitis with nasal polyposis.
On May 20, 2022, the FDA approved dupilumab (e.g., Dupixent) for the treatment of adult and pediatric individuals ages 12 years and older, weighing at least 40 kg, with eosinophilic esophagitis.
On September 29, 2022, the FDA approved dupilumab (e.g., Dupixent) for the treatment of adult individuals with prurigo nodularis.
Coding
See CPT/HCPCS code section below.
The use of dupilumab is not covered under the medical benefit.
The use of dupilumab is addressed under the pharmacy benefit.
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Policy/ Coverage: |
PRIOR APPROVAL IS REQUIRED FOR DUPILUMAB (e.g., DUPIXENT)
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.
The initial use of this drug requires documentation of direct physician involvement (MD/DO) in the ordering and evaluation, as well as signature, in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.
The Step Therapy Medication Act is applicable to fully-insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, Tyson or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard request is up to 1 year.
Effective July 1, 2023
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:
* FeNO testing is non-covered and is not considered adequate for establishing the diagnosis of asthma. Please see AR policy 2005020.
CONTINUED APPROVAL for up to 1 year:
CHRONIC RHINOSINUSITIS WITH NASAL POLYPOSIS (CRSwNP)
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
CONTINUED APPROVAL for up to 1 year:
ATOPIC DERMATITIS
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
CONTINUED APPROVAL for up to 1 year:
Requirement of documentation in the medical records that the member has achieved and maintains a clinically meaningful benefit as defined below:
EOSINOPHILIC ESOPHAGITIS
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
CONTINUED APPROVAL for up to 1 year:
PRURIGO NODULARIS (PN)
INITIAL APPROVAL STANDARD REVIEW for up to 6 months:
CONTINUED APPROVAL for up to 1 year:
Dosage and Administration
Dosing per FDA Guidelines
Dupilumab is administered by subcutaneous injection.
Policy Guidelines
The ERS/ATS definition of high doses of various inhaled glucocorticoids in relation to patient age (in mcg/day):
Age 6 to 12 years
Beclomethasone > 320 (HFA MDI)
Budesonide > 800 (MDI or DPI); (>720 mcg/day of US labeled budesonide DPI)
Ciclesonide > 160 (HFA MDI)
Fluticasone propionate > 500 (HFA MDI or DPI); (>440 mcg/day of US labeled fluticasone HFA MDI)
Mometasone >500 (DPI); (>550 mcg/day of US labeled mometasone DPI)
Age >12 years
Beclomethasone > 1000 (HFA MDI)
Budesonide > 1600 (MDI or DPI) ;(> 1440 mcg/day of US labeled budesonide DPI)
Ciclesonide > (HFA MDI)
Fluticasone propionate > 1000 (HFA MDI or DPI); (> 880 mcg/day of US labeled fluticasone HFA MDI)
Mometasone > 800 (DPI); (> 880 mcg/day of US labeled mometasone DPI)
Note: Designation of high doses is provided from manufacturers' recommendations where possible. Equivalent high doses may be expressed differently between countries and some products (e.g., beclomethasone) are available in multiple formulations with different dosing recommendations. Medication inserts should be carefully reviewed by the clinician for the equivalent high daily dosage.
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
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
Dupilumab, for any indication or circumstance not described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, dupilumab, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective December 7, 2022 to June 30, 2023
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:
CONTINUED APPROVAL for 1 year:
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:
The recommended dose of Dupilumab for pediatric patients 6 to 11 years of age is:
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:
CONTINUED APPROVAL for 1 year:
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:
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:
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:
CONTINUED APPROVAL for 1 year:
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:
CONTINUED APPROVAL for 1 year:
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
* 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:
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:
The recommended dose of Dupilumab for pediatric patients 6 to 11 years of age is:
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:
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:
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:
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:
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:
*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
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
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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.
2023 Update
The LIBERTY ASTHMA TRAVERSE study was a multinational, multicenter, single-arm, open-label extension study in patients ≥ 12 years of age with asthma who participated in previous dupilumab studies. Treatment consisted of dupilumab 300 mg every 2 weeks for up to 96 weeks. In this analysis, data from patients who initially enrolled in the LIBERTY ASTHMA VENTURE study, a 24-week placebo-controlled study of dupilumab in patients with OCS-dependent severe asthma and continued in the TRAVERSE study was presented. The subgroups analyzed were: those who received dupilumab in both (dupilumab/dupilumab group) and those who received placebo in the VENTURE study and dupilumab in the TRAVERSE study (placebo/dupilumab group). Outcomes included OCS use, exacerbation rates, and measures of lung function and asthma control.
Ninety patients treated with dupilumab/dupilumab, and 97 patients treated with placebo/dupilumab in the VENTURE study were enrolled and treated in the TRAVERSE study, with a mean OCS dosage of 11.0 mg/d (dupilumab) and 11.6 mg/d (placebo) at VENTURE study baseline. At TRAVERSE week 0, the mean daily OCS dosage was 3.1 mg/d and 6.4 mg/d (percentage decrease from the VENTURE study baseline, 68.8% and 41.3%) for the dupilumab/dupilumab group and placebo/dupilumab group, respectively, and decreased to 2.2 mg/d and 4.9 mg/d (78.3% and 53.4%) at week 48 and to 1.2 mg/d and 3.0 mg/d (89.3% and 74.4%) at week 96, respectively. Exacerbation rates were low during the TRAVERSE study. Further improvements from the VENTURE to TRAVERSE studies also were seen in FEV1 and 5-item Asthma Control Questionnaire scores. Safety findings were consistent with the known dupilumab safety profile.
In the open-label TRAVERSE study, dupilumab demonstrated the ability to sustain the OCS dosage reduction from the parent OCS-sparing study, while maintaining a low exacerbation rate and improved lung function. (Sher LD, Wechsler ME, Rabe KF, 2022)
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Al-Ahmad, M. et al.(2022) Expert Opinion on Biological Treatment of Chronic Rhinosinusitis with Nasal Polyps in the Gulf Region. J Asthma Allergy. 2022 Jan 4;15:1-12. doi: 10.2147/JAA.S321017. PMID: 35018101; PMCID: PMC8742580. Chung KF, Wenzel SE, Brozek JL, et.al.(2014) International European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines on definition, evaluation and treatment of severe asthma. . Eur Respir J. 2014; 43(2):343-373. Global Initiative for Asthma (GINA).(2022) Global Strategy for Asthma Management and Prevention 2022. Available from: www.ginasthma.org. Sher LD, Wechsler ME, Rabe KF, Maspero JF, Daizadeh N, Mao X, Ortiz B, Mannent LP, Laws E, Ruddy M, Pandit-Abid N, Jacob-Nara JA, Gall R, Rowe PJ, Deniz Y, Lederer DJ, Hardin M.(2022) Dupilumab Reduces Oral Corticosteroid Use in Patients With Corticosteroid-Dependent Severe Asthma: An Analysis of the Phase 3, Open-Label Extension TRAVERSE Trial. Chest. 2022 Jul;162(1):46-55. doi: 10.1016/j.chest.2022.01.071. Epub 2022 Feb 22. PMID: 35217003. |
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