Coverage Policy Manual
Policy #: 2017031
Category: Pharmacy
Initiated: September 2017
Last Review: March 2019
  Dupilumab

Description:
Dupilumab (Dupixent™) 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.
 
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.
 
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 March 2019
 
This is a Pharmacy Benefit – It is Not Covered under Medical Benefit
 
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:
Initial approval will be for 6 months:
    1. Individual is 12 years or older; and  
    2. *Evidence of moderate to severe asthma is demonstrated by all of the following:
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:
a.   Use of a systemic corticosteroid; or
b.   Temporary increase in the usual maintenance oral corticosteroid dosage; and
4.    One of the following:
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; 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); 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).
 
* 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 12 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:
 
Dosing for Adolescent patients:
Body Wt                                Initial Dose                        Subsequent Doses (every other week)
<60 kg                             400mg (two 200mg inj)                    200 mg
> 60 kg or more               600 mg (two 300mg inj)                   300mg  
 
Dosing for adults:  
The dose for adults is an initial dose of 600 mg (two 300 mg inj), followed by 300 mg every other week.
 
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.
 
This is a Pharmacy Benefit – It is Not Covered under Medical Benefit
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
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:
    1.   There is a confirmed diagnosis of atopic dermatitis supported by the submitted medical records and ALL of the below:
a.   The member is > 18 years old, AND
b.   The condition has been present for  > 3 years, AND
c.   There is involvement of >10% of body surface area or involvement of critical areas (e.g. palms, face, etc), AND
d.   Other skin conditions have been excluded or adequately treated.
2.   The drug is authorized and managed by a physician with expertise in the treatment of atopic dermatitis (e.g allergist/immunologist or dermatologist)
3.   Topical therapy trials failure.  The patient has either failed a trial, proved intolerant of a medication, or has contraindications to one of the therapies to both of the below topical treatments:
a.   A topical calcineurin inhibitor [i.e., pimecrolimus (Elidel) or tacrolimus (Protopic)] with an inadequate response to maintenance therapy that includes intermittent use (at least 2 days per week) for at least 16 weeks,  AND
b.   A topical corticosteroid with an Inadequate response to maintenance therapy that includes intermittent use (at least 2 days per week) for at least 16 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
4.   Systemic therapy or Phototherapy Failure.   The member has had an inadequate response to a 3-month or longer trial of EITHER of following treatments in the past 12 months, OR treatment or continued treatment is not advisable due to an FDA-labeled contraindication or intolerable adverse effect(s):
a.    Phototherapy (e.g., PUVA, UVB) , OR
b.    Systemic immunosuppressant therapy (e.g., cyclosporine, azathioprine, methotrexate, mycophenolate mofetil)
5.    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), rituximab (Rituxan), etanercept (Enbrel), and infliximab products].
 
Dosing and Administration
Dosing does not exceed the following:
      1. Loading dose: 600 mg as a single dose  
      2. Subsequent doses: 300 mg every two weeks
 
Concurrent review and approval will require 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 due to atopic dermatitis  
Improvement in overall patient quality of life (e.g., improved sleep, less depression or anxiety, etc.)
 
Effective prior to March 2019
 
This is a Pharmacy Benefit – It is Not Covered under Medical Benefit
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
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:
    1. There is a confirmed diagnosis of atopic dermatitis supported by the submitted medical records and ALL of the below:
      1.  The condition has been present for  > 3 years, AND
      2. There is involvement of >10% of body surface area or involvement of critical areas (e.g. palms, face, etc), AND
      3. The member is > 18 years old, AND
      4. Other skin conditions have been excluded or adequately treated.
b) The drug is authorized and managed by a physician with expertise in the treatment of atopic dermatitis (e.g allergist/immunologist or dermatologist)
c) Topical therapy trials failure.  The patient has either failed a trial, proved intolerant of a medication, or has contraindications to one of the therapies to both of the below topical treatments:
      1. A topical calcineurin inhibitor [i.e., pimecrolimus (Elidel) or tacrolimus (Protopic)] with an inadequate response to maintenance therapy that includes intermittent use (at least 2 days per week) for at least 16 weeks,  AND
      2. A topical corticosteroid with an Inadequate response to maintenance therapy that includes intermittent use (at least 2 days per week) for at least 16 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
d) Systemic therapy or Phototherapy Failure.   The member has had an inadequate response to a 3-month or longer trial of EITHER of following treatments in the past 12 months, OR treatment or continued treatment is not advisable due to an FDA-labeled contraindication or intolerable adverse effect(s):
      1.  Phototherapy (e.g., PUVA, UVB) , OR
      2.  Systemic immunosuppressant therapy (e.g., cyclosporine, azathioprine, methotrexate, mycophenolate mofetil)
 
e)  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), rituximab (Rituxan), etanercept (Enbrel), infliximab products].
f) Dosing does not exceed the following:
      1. Loading dose: 600 mg as a single dose
      2. Subsequent doses: 300 mg every two weeks
 
Concurrent review and approval will require 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 due to atopic dermatitis
5) Improvement in overall patient quality of life (e.g., improved sleep, less depression or anxiety, etc.)
 
 
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.      

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.

References: 1. Dupilumab.(2017) Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. c2017- [cited 2017 August 2]. http://www.clinicalpharmacology.com

3. Simpson, Eric L.(2017) “Dupilumab Improves General Health-Related Quality-of-Life in Patients with Moderate-to-Severe Atopic Dermatitis: Pooled Results from Two Randomized, Controlled Phase 3 Clinical Trials.” Dermatology and Therapy 7.2 (2017): 243–248. PMC. Web. 3 Aug. 2017.

4. Beck LA, Thaçi D, Hamilton JD, et al.(2014) Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371(2):130-9.

5. Eichenfield LF, Tom WL, Berger TG, et al.(2014) Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014 Jul;71(1):116-32.

6. Sidbury R, Davis DM, Cohen DE, et al.(2014) Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014 Aug;71(2):327-49

Busse WW, Maspero JF, Rabe KF, et al.(2018) Liberty Asthma QUEST: Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Dupilumab Efficacy/Safety in Patients with Uncontrolled, Moderate-to-Severe Asthma. Adv Ther. 2018 May;35(5):737-748. doi: 10.1007/s12325-018-0702-4. Epub 2018 May 3.

Castro M, Corren J, Pavord ID, et al.(2018) upilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. 2018 Jun 28;378(26):2486-2496. doi: 10.1056/NEJMoa1804092 Epub 2018 May 21.

Rabe KF, Nair P, Brusselle G, Maspero JF, et al.(2018) Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018 Jun 28;378(26):2475-2485. doi: 10.1056/NEJMoa1804093. Epub 2018 May 21.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.