Medical Policy

 

Subject: Dupilumab (Dupixent®)
Document #: DRUG.00094 Publish Date:    04/11/2017
Status: New Last Review Date:    04/07/2017

Description/Scope

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). 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, asthma and nasal polyps.

Note: Please see the following related documents for additional information:

Position Statement

Medically Necessary:

The use of dupilumab is considered medically necessary when all of the following criteria have been met:

  1. Individual is age 18 years or older; and
  2. Individual has a diagnosis of moderate to severe atopic dermatitis; and
  3. Chronic atopic dermatitis has been present for 3 years or more; and
  4. 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
  5. 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

Investigational and Not Medically Necessary:

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

Rationale

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 recations include injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infections and dry eye. In addition, the current prescribing information for dupilumab (Dupixent) notes that individuals with asthma should not adjust or stop their asthma treatment without consultation with their physicians.

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 Eczema Area and Severity Index (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 randomised, 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 adverse events (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, but has not yet been published (NCT02407756).

Background/Overview

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)

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.

Coding

The following codes for treatments and procedures applicable to this document 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.

When services may be Medically Necessary when criteria are met:

HCPCS  
J3490 Unclassified drugs [when specified as dupilumab (Dupixent)]
J3590 Unclassified biologics [when specified as dupilumab (Dupixent)]
     
ICD-10 Diagnosis    
L20.0-L20.9 Atopic dermatitis  

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

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. 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.
  3. 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.
  4. 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.
  5. Tsianakas A, Ständer S. Dupilumab: a milestone in the treatment of atopic dermatitis. Lancet. 2016; 387(10013):4-5.
  6. 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 March 28, 2017.
  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 March 28, 2017.
  4. Dupixent® (dupilumab) [Product Information], Tarrytown, NY. Regeneron and Sanofi Genzyme. March 2017. Available at: https://www.regeneron.com/sites/default/files/Dupixent_FPI.pdf . Accessed on March 28, 2017.
  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 March 28, 2017.
Websites for Additional Information
  1. National Institute of Allergy and Infectious Diseases. Eczema (Atopic Dermatitis). Available at: https://www.niaid.nih.gov/diseases-conditions/eczema-atopic-dermatitis . Accessed on March 28, 2017.
  2. U.S. National Library of Medicine. MedlinePlus. Eczema. Updated on March 15, 2017. Available at: https://medlineplus.gov/eczema.html . Accessed on March 28, 2017.
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.

Document History
Status Date Action
New 04/07/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Initial document development.
Preliminary Discussion 11/03/2016 MPTAC review. Pre-FDA approval review.