Clinical UM Guideline

 

Subject: Dupilumab (Dupixent®)
Guideline #: CG-DRUG-88 Publish Date:    11/15/2018
Status: Revised Last Review Date:    11/08/2018

Description

This document addresses the use of dupilumab (Dupixent) (Regeneron, Tarrytown, NY and Sanofi Genzyme, Cambridge, MA), a fully human monoclonal antibody for the treatment of moderate to severe atopic dermatitis (AD) or as an add on therapy for individuals with moderate to severe eosinophilic phenotype or oral corticosteroid dependent asthma. Dupilumab inhibits the signaling of the type 2 inflammatory cytokine, interleukin-4 (IL-4) and interleukin-13 (IL-13), which are thought to be the major drivers in AD. Dupilumab is also being studied for other uses including nasal polyps.

Note: Please see the following related documents for additional information regarding the treatment of atopic dermatitis or asthma:

Clinical Indications

Medically Necessary:

The use of dupilumab is considered medically necessary for the following indications:

I.  Moderate to severe atopic dermatitis when all the following criteria have been met:

  1. Individual is age 18 years or older; and
  2. Chronic atopic dermatitis has been present for 3 years or more; and
  3. Failure of topical pharmacological therapy as indicated by one or more of the following:
    1. Daily treatment of topical corticosteroids of medium to higher potency for the maximum treatment period indicated in the product prescribing information has failed to achieve and maintain remission of low or mild disease activity state; or
    2. Topical calcineurin inhibitors if topical corticosteroids are not indicated*, for the maximum treatment period indicated in the product prescribing information has failed to achieve and maintain remission of low or mild disease activity state; or
    3. Topical treatment is medically inadvisable as defined by treatments which have side effects or safety concerns which outweigh potential treatment benefits as evidenced by any of the following:
      1. Intolerance to treatment
      2. Hypersensitivity reactions
      3. Significant skin atrophy
      4. Systemic effects; and
  4. One of the following:
    1. Phototherapy (UVB or PUVA) has failed to achieve and maintain remission of low or mild disease activity state or is contraindicated; or
    2. Systemic treatment (for example, immunosuppressants) has failed to achieve and maintain remission of low or mild disease activity state or is contraindicated.

*Topical corticosteroids may not be indicated in the following concomitant clinical situations:

  1. Individual has lesions located in sensitive areas (such as face, anogenital area or skin folds)
  2. Individual has steroid-induced atrophy
  3. History of long-term or uninterrupted topical steroid use

II.  Moderate to severe asthma or when all the following criteria are met:

  1. Individual is 12 years or older; and
  2. Evidence of moderate to severe asthma is demonstrated by all of the following:
    1. A pretreatment forced expiratory volume in 1 second (FEV1) less than or equal to 80% predicted; and
    2. FEV1 reversibility of at least 12% and 200 milliliters (ml) after albuterol (salbutamol) administration; and
  3. Documented evidence of two or more asthma exacerbations in the previous 12 months which required one or more of the following:
    1. Use of a systemic corticosteroid; or
    2. Temporary increase in the usual maintenance oral corticosteroid dosage; and
  4. One of the following:
    1. 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
    2. 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).

**1 microliter (µL) is equal to 1 cubic millimeter (mm3)

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
  3. Increase in predicted FEV1 from pretreatment baseline; or
  4. Reduction in reported asthma-related symptoms, such as, asthmatic symptoms upon awakening, coughing, fatigue, shortness of breath, sleep disturbance, or wheezing.

Not Medically Necessary:

Dupilumab is considered not medically necessary when the above criteria are not met and for all other indications.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J3490

Unclassified drugs [when specified as dupilumab (Dupixent)]

 

 

J3590

Unclassified biologics [when specified as dupilumab (Dupixent)]

 

 

 

ICD-10 Diagnosis

 

 

J44.0-J44.9

Other chronic obstructive pulmonary disease

 

J45.40-J45.52

Moderate/severe persistent asthma

 

J45.901-J45.998

Other and unspecified asthma

 

J82

Pulmonary eosinophilia, not elsewhere classified

 

L20.0-L20.9

Atopic dermatitis

 

Discussion/General Information

On March 28, 2017, the U.S. Food and Drug Administration (FDA) approved dupilumab (Dupixent) for the treatment of moderate to severe atopic dermatitis which is not adequately controlled with topical prescription therapies or when topical prescription therapies are not advised. Dupilumab may be used with or without topical corticosteroids. The most common adverse reactions related to atopic dermatitis include injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infections and dry eye.

Atopic Dermatitis (AD)

AD, the most common form of eczema, affects approximately 2% to 3% of adults and 25% of children (Eichenfield, 2014). AD is frequently associated with a personal or family history of allergies, allergic rhinitis and asthma. AD typically follows a relapsing/chronic course but often resolves by adulthood. Symptoms can include erythema, edema, xerosis, excoriations, pruritus, oozing and crusting, or lichenification (Eichenfield, 2014). While there is no accepted standardized method of classifying disease severity, categorization is usually based upon objective disease features, extent of skin involvement and possibly subjective disease features. Due to the impaired skin integrity, affected individuals are more susceptible to skin infections. Management of AD includes a variety of treatments, such as pharmacological, topical, phototherapy, and systemic interventions.

There are multiple scales which are used to assess the severity of AD in individuals. Some scales include multi-item scores (for example, Eczema Area and Severity Index) which are suited for clinical trials and not widely used in the clinical setting. Global assessments score an individual on an ordinal scale which tends to be easier to use and understand for clinicians and affected individuals (Futamura, 2016). An Investigator Global Assessment (IGA) is often used as a standard benchmark comparator tool for other scales. The following is an example of an IGA tool (Futamura, 2016):

0 Clear (no inflammatory signs of AD)
1 Almost clear (just perceptible erythema, and just perceptible papulation/infiltration)
2 Mild disease (mild erythema, and mild papulation/infiltration)
3 Moderate disease (moderate erythema, and moderate papulation/infiltration)
4 Severe disease (severe erythema, and severe papulation/infiltration)
5 Very severe disease (severe erythema, and severe papulation/infiltration with oozing/crusting)

Blauvelt and colleagues (2017) conducted a 1 year, randomized, double-blinded, placebo-controlled, phase III study over evaluating the long-term efficacy and safety of dupilumab when used with medium-potency topical corticosteroids. A total of 740 adults with at least a 3 year history of atopic dermatitis with an IGA of 3 or higher and an inadequate response to medium to high-potency topical corticosteroids or systemic treatment were randomized to receive dupilumab weekly, biweekly or a placebo over a 52 week treatment period. All participants received concomitant topical corticosteroids. There were two co-primary endpoints at week 16, the proportion of participants with an IGA of 0/1 and a two point or higher reduction from baseline and the proportion of participants achieving a 75% improvement in Eczema Area and Severity Index (EASI)-75 from baseline. At week 16, more individuals met the co-primary endpoints in the weekly or biweekly dupilumab groups than in the placebo group (IGA: 39% versus 39% versus 12%; p<0.0001 and EASI-75: 64% versus 69% versus 23%; p<0.0001). These differences were maintained at week 52 (IGA: 40% versus 36% versus 13%; p<0.0001 and EASI-75: 64% versus 65% versus 22%; p<0.0001). Adverse event (AE) rates were similar across all groups; the placebo group did report a higher rate of overall serious AEs and discontinuations due to AEs. The groups treated with dupilumab reported higher rates of injection-site reactions and conjunctivitis. The safety profile was consistent with previous studies and the use of topical conjunctivitis along with dupilumab was not associated with an increased risk of injections.

Simpson and colleagues (2016) reported on the SOLO-1 and SOLO-2 trials, two randomized, placebo-controlled, phase III identically designed studies which evaluated the use of dupilumab in moderate to severe atopic dermatitis and provided a replication of the results. The SOLO-1 (n=671) and SOLO-2 (n=708) trials randomized individuals to one of three trial arms: (1) weekly subcutaneous (SQ) dupilumab injections, (2) weekly placebo SQ injections or (3) weekly SQ injections alternating between dupilumab and placebo, with each arm receiving treatment for 16 weeks. The primary endpoint was proportion of participants with an Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear) and a reduction of at least 2 points from baseline to week 16. In SOLO-1, individuals who received dupilumab weekly or biweekly reported significantly improved primary outcomes compared to placebo (38% [85/223], 37% [83/224] and 10% [23/224]; p<0.001 respectively). The authors reported similar outcomes for SOLO-2 (36% [84/239], 36% [87/233] and 8% [20/236]; p<0.001 respectively). Both trials reported significantly better outcomes in the dupilumab arms versus the placebo arm in the secondary endpoints including improvements in clinical severity as defined by the EASI, patient-reported symptoms, quality of life and use of rescue medications. Exacerbation of atopic dermatitis injection site reactions (8%-19% in dupilumab arms versus 6% in the placebo arms) and nasopharyngitis (8%-11% in dupilumab arms versus 8%-9% in the placebo arms) were the most common adverse events. Overall, infections in the dupilumab arms ranged from 28% to 35% compared to 28% to 33% in the placebo arms. Serious adverse events involving more than 2 individuals in any treatment group (serious exacerbation of atopic dermatitis) occurred in 3 individuals in a dupilumab arm and 8 individuals in the placebo arm. The authors noted that larger studies of longer duration are needed to assess the safety and effectiveness of long-term dupilumab treatment.

In 2014, Thaci and associates presented the results of a phase IIb randomized, double-masked, placebo-controlled study. A total of 380 individuals with AD rated as moderate to severe with an inadequate response to standard treatment were randomized to differing dose regimen groups or a control group: subcutaneous dupilumab 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks; or placebo once a week for 16 weeks. The percentage change in EASI score from baseline to week 16 was set as the primary efficacy endpoint. At week 16, the percentage of individuals in the 200 mg or 300 mg groups reporting an EASI-50 response (50% reduction in baseline EASI) was significantly greater compared to the percentage of individuals in the placebo group reporting an EASI-50 response (300 mg once a week - 83%, p<0.0001; 300 mg every 2 weeks - 78%, p<0.0001; 200 mg every 2 weeks - 62%, p=0.0003; 300 mg every 4 weeks - 71%, p<0.0001 versus placebo 30%). The group receiving suboptimal dosing of 100 mg every 4 weeks reported a greater percentage of individuals reporting an EASI-50 response compared to the placebo group, however, this response was not significant (45%, p=0.0797). While dupilumab was the only drug used as a comparator, this study showed dose-dependent efficacy amongst those who had an inadequate response to the current treatments.

Beck and colleagues (2014) reported on earlier studies involving dupilumab therapy to treat moderate to severe atopic dermatitis. The authors performed a series of randomized, double-blind, placebo-controlled trials which included three trials evaluating dupilumab as a monotherapy (two 4-week and one 12-week trials) and one trial evaluating dupilumab in combination with topical glucocorticoids (4-week trial). The 4-week monotherapy trials were phase I trials and individuals were randomly assigned to receive either placebo or dupilumab of varying dosages. In those groups receiving dupilumab, there was a dose-dependent increase in the proportion of participants who had a 50% improvement in the EASI score (EASI-50) at day 29 and a mean percentage decrease in the score on the pruritus numerical rating scale. The 12-week monotherapy trial assessed clinical efficacy as the primary endpoint and safety as the secondary endpoint, and individuals were randomly assigned to receive either dupilumab or placebo. At 4 weeks, the results were similar to the 4-week phase I results and continued treatment resulted in further improvements; at 12 weeks, the proportion of participants reporting an improved EASI-50 score was 85%, and the mean score on the pruritus numerical rating scale decreased by 55.7%. In the phase IIa study, in addition to receiving a standardized regimen of topical glucocorticoids, individuals were randomly assigned to receive either dupilumab or placebo. At 4 weeks, all of the participants in the dupilumab plus topical glucocorticoids group achieved the criteria for EASI-50 compared to only 50% of the individuals in the topical glucocorticoids plus placebo group (p=0.002). There was also a significant improvement in the pruritus numerical rating scale in the dupilumab group compared to the placebo group. The most common adverse events occurring more frequently in dupilumab groups compared to the placebo groups were nasopharyngitis and headache. Across all studies, there were 13 serious AEs in 9 of the 80 individuals in the placebo groups compared with 2 AEs in 2 of the 127 individuals in the dupilumab groups. The authors noted that the imbalance in the AEs was related to the greater number of skin infections and AD exacerbations in the placebo groups.

While AD disproportionately affects children and adolescents, at this time, the published studies include only the adult population. A clinical trial evaluating the use of dupilumab in children between the ages of 6 and 18 years old was recently completed, and results are pending (NCT02407756). The current evidence does not support that the use of dupilumab provides additional benefit over the standard treatments in this group.

Asthma

Asthma is a chronic heterogeneous disease which affects more than 25 million individuals in the United States. Approximately 20-25% of these individuals have moderate-to-severe uncontrolled disease. Type 2 cytokines (interleukin 4, interleukin 5, and interleukin 13) have been identified as a substantial pathobiological factor, contributing to a “type-2/T-helper-2-cell (Th2)-high molecular asthma phenotype” in approximately half of all cases (Wenzel, 2016).

On October 19, 2018 the FDA expanded the indications for dupilumab to include use as an add-on maintenance treatment in individuals with moderate-to-severe asthma aged 12 years and older with an eosinophilic phenotype or oral corticosteroid dependent asthmas. Dupilumab is not meant to be used to relieve acute bronchospasms or status asthmaticus attacks. The FDA considered evidence developed in three randomized, double-blind, placebo-controlled, parallel-group, multi-center trials which included 2888 participants.

In the first study (Wentzel, 2016), 776 adults with asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist therapy were randomized into 5 groups: 200 mg or 300 mg dupilumab every 2 weeks or every 4 weeks, or placebo in addition to their background therapy. Individuals were subject to a 24 week treatment period and a 16 week post treatment follow-up period. The primary endpoint was change in forced expiratory volume in 1 s (FEV1 in L) from baseline to week 12 in individuals with baseline blood eosinophil counts of at least 300 eosinophils/μL, approximately 42.0% of study participants (325/776). At week 12, all dupilumab groups reported a significant increase in FEV1 from baseline compared to baseline and were sustained through week 24. At week 24, FEV1 percentage change from baseline at week 24 varied from 22.9% to 24.9% in the subgroups with 300 eosinophils/μL or greater and in the subgroups with fewer than 300 eosinophils/μL from 12.6% to 13.4 %. Treatment emergent AEs were reported as 75-83% within the dupilumab groups and 75% in the placebo groups. Serious treatment-emergent AEs were similar across the groups (45 individuals (7%) within the dupilumab groups and 9 individuals (6%) within the placebo group).

In the Liberty Asthma Quest study (Castro, 2018), 1902 participants age 12 and older with uncontrolled asthma were randomized to receive either dupilumab or a placebo in addition to their regular therapy for 52 weeks. Individuals who received dupilumab were randomized to receive either a 200mg or 300mg dose biweekly which was matched in the placebo groups. The primary efficacy endpoint include the annualized rate of severe exacerbation events during the 52 week period and the absolute change from baseline in the FEV1 before bronchodilator use at week 12. The adjusted annualized rate of severe asthma exacerbations in the 200 mg dupilumab group compared to the matched placebo group was significantly lower by 47.7% (0.46 (95% confidence interval [CI], 0.39 to 0.53) versus 0.87 (95% CI, 0.72 to 1.05) respectively. The adjusted annualized rate of severe asthma exacerbations in the 300 mg dupilumab group compared to the matched placebo group was significantly lower by 46.0% (0.52 (95% CI, 0.45 to 0.61) versus 0.87 (95% CI, 0.72 to 1.05) respectively. At week 12, the change from baseline in FEV1 in the 200mb dupilumab group was 0.32 liters compared to 0.18 liters in the matched placebo group (p<0.001). The change from baseline in the FEV1 in the 300mb dupilumab group compared to the matching placebo group was also significant (0.21 versus 0.13, p<0.001 respectively). The dupilumab groups and the placebo groups were combined to report the incidence of adverse events (AEs), they were similar across the groups; 81.0% in the dupilumab groups and 83.1% in the placebo groups. The most frequent AE was injection-site reaction.

An accompanying study, Liberty Asthma Venture (Rabe, 2018) included 210 individuals age 12 and older with glucocorticoid-dependent severe asthma for one year or more were randomized to receive dupilumab (300 mg every 2 weeks) or placebo for 24 weeks. There were 3 components to the 24 week trial: a 4 week induction period, a 16 week period in which oral glucocorticoid use was adjusted down every 4 weeks, and a 4 week maintenance period. A 12 week evaluation period immediately followed the 24 week intervention period. The primary efficacy end point deemed to be the percentage reduction in the oral glucocorticoid dose from baseline to week 24 while asthma control was maintained. In those individuals who had an exacerbation, the final oral dose was reported as one step higher than the dose received at the time of exacerbation. The intention-to-treat group percentage change in oral glucocorticoid dose from baseline to week 24 in the dupilumab group compared to placebo was -70.1 ± 4.9% versus -41.9 ± 4.6% respectively (p<0.001). In the dupilumab group, 80% of the participants tolerated at least a 50% dose reduction compared to 50% in the placebo group.

Warnings and Precautions

Definitions

Eczema: A chronic inflammatory, pruritic skin disease.

Eczema area and severity index (EASI): A disease severity scale primarily used in clinical trials which utilizes objective physician estimates of disease extent and severity.

Maintain remission: Comparable rating on a disease severity scale which corresponds to “clear” or “mild.”

Pruritus: Itching sensation.

References

Peer Reviewed Publications:

  1. Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014; 371(2):130-139.
  2. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017; 389(10086):2287-2303.
  3. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018; 378(26):2486-2496.
  4. Futamura M, Leshem YA, Thomas KS, et al. A systematic review of Investigator Global Assessment (IGA) in atopic dermatitis (AD) trials: many options, no standards. J Am Acad Dermatol. 2016; 74(2):288-294.
  5. Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of Dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med. 2018; 378(26):2475-2485.
  6. Simpson EL, Bieber T, Guttman-Yassky E, et al.; SOLO 1 and SOLO 2 Investigators. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016; 375(24):2335-2348.
  7. Thaci D, Simpson EL, Beck LA, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2016; 387(10013):40-52.
  8. Tsianakas A, Ständer S. Dupilumab: a milestone in the treatment of atopic dermatitis. Lancet. 2016; 387(10013):4-5.
  9. Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016; 388(10039):31-44.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Akdis CA, Akdis M, Bieber T, et al.; European Academy of Allergology; Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Group. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. Allergy. 2006; 61(8):969-987.
  2. American Academy of Dermatology (AAD). Atopic dermatitis clinical guideline. 2014. Available at: https://www.aad.org/practice-tools/quality-care/clinical-guidelines/atopic-dermatitis. Accessed on October 20, 2018.
  3. Arkwright PD, Motala C, Subramanian H, et al.; Atopic Dermatitis Working Group of the Allergic Skin Diseases Committee of the AAAAI. Management of difficult-to-treat atopic dermatitis. J Allergy Clin Immunol Pract. 2013; 1(2):142-151. Available at: https://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20and%20Parameters/Management-of-difficult-to-treat-AD-2013.pdf. Accessed on October 20, 2018.
  4. Dupixent® (dupilumab) [Product Information], Tarrytown, NY. Regeneron and Sanofi Genzyme. October 2018. Available at: https://www.regeneron.com/sites/default/files/Dupixent_FPI.pdf. Accessed on October 20, 2018.
  5. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014; 70(2):338-351.
  6. U.S. National Institutes of Health. Clinical Trials.gov. A Study to Determine the Safety and Tolerability of Dupilumab (REGN668/SAR231893) in Patients Aged ≥6 to <18 Years with Atopic Dermatitis (Eczema). Available at: https://clinicaltrials.gov/ct2/show/NCT02407756. Accessed on October 20, 2018.
Websites for Additional Information
  1. National Heart, Lung, and Blood Institute. Asthma. Available at: https://www.nhlbi.nih.gov/health-topics/asthma. Accessed on October 20, 2018.
  2. National Institute of Allergy and Infectious Diseases. Eczema (Atopic Dermatitis). April 19, 2017. Available at: https://www.niaid.nih.gov/diseases-conditions/eczema-atopic-dermatitis. Accessed on October 20, 2018.
  3. U.S. National Library of Medicine. MedlinePlus. Eczema. Updated on April 23, 2018. Available at: https://medlineplus.gov/eczema.html. Accessed on October 20, 2018.
Index

Atopic eczema
Eczema

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Revised

11/08/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. Revised document to add medically necessary indications for asthma. Revised format for medically necessary indications for atopic dermatitis without change in intent. Updated Discussion, Coding and References sections.

New

01/25/2018

MPTAC review. Initial document development. Moved contents of DRUG.00094 Dupilumab (Dupixent) to clinical utilization management guideline document with the same title.