Dupixent (Dupilumab) First Biologic Drug Approved for Patients with Moderate-to-Severe Atopic Dermatitis

March 2018, Vol 11, Ninth Annual Payers' Guide - FDA Approvals, News & Updates
Lisa A. Raedler, PhD, RPh
Medical Writer
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Atopic dermatitis, the most common form of eczema, is a chronic inflammatory disease that is characterized by skin rash and itching. Patients with moderate-to-severe atopic dermatitis often have extensive rashes that are accompanied by intense, persistent itching and skin dryness, cracking, and redness.1 Itching is one of the most burdensome symptoms for patients with atopic dermatitis and can become debilitating.2

The treatment of patients with atopic dermatitis is multifaceted and includes topical over-the-counter moisturizers; oral antihistamines; topical corticosteroids (eg, creams or ointments); topical immunomodulators, such as calcineurin inhibitors; and topical coal tar or anthralin.1,2 Oral steroids, oral antibiotics, oral immunomodulators, and phototherapy are considered for patients with more severe atopic dermatitis.1

A recent addition to the treatment armamentarium for atopic dermatitis is the topical phosphodiesterase-4 inhibitor crisaborole (Eucrisa). In December 2016, the US Food and Drug Administration (FDA) approved crisaborole for the treatment of mild-to-moderate atopic dermatitis in patients aged ≥2 years.3

Dupixent Approved for Moderate-to-Severe Atopic Dermatitis

On March 28, 2017, the FDA approved dupilumab (Dupixent; Regeneron), a parenterally administered interleukin (IL)-4 receptor alpha antagonist, for the treatment of adults with moderate-to-severe atopic derma­titis that is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Dupilumab can be used with or without topical corticosteroids.4,5

“FDA’s approval of Dupixent demonstrates our commitment to approving new and innovative therapies for patients with skin disease,” said Julie Beitz, MD, Director of the FDA’s Office of Drug Evaluation and Research.4 “Eczema can cause significant skin irritation and discomfort for patients, so it is important to have a variety of treatment options available to patients, including those patients whose disease is not controlled by topical therapies,” she added.4

Mechanism of Action

Dupilumab is a human monoclonal antibody that binds to the shared alpha chain subunit of the IL-4 and IL-13 receptors.5 Dupilumab blocks IL-4 signaling via type 1 receptor and blocks IL-4 and IL-13 signaling through type 2 receptor. By blocking IL-4 and IL-13 signaling, dupilumab inhibits IL-4 and IL-13 cytokine-induced responses, which include the release of proinflammatory cytokines, chemokines, and immunoglobulin E.5

Dosing and Administration

Dupilumab is administered by subcutaneous injection and should be dosed initially at 600 mg (two 300-mg subcutaneous injections), followed by 300 mg every other week.5

Dupilumab can be used with or without topical corticosteroids. Topical calcineurin inhibitors should be reserved for the face, neck, intertriginous skin, and genital areas.5

Pivotal Clinical Trials

The efficacy and safety of dupilumab were evaluated in 3 randomized clinical trials, which enrolled more than 2000 adults with moderate-to-severe atopic dermatitis.4-7 In the 3 studies, patients in the dupilumab arm received dupilumab 600 mg at week 0, followed by 300 mg every other week.5-7

In the monotherapy SOLO 1 and SOLO 2 studies, patients received dupilumab or placebo for 16 weeks.5,6 Concomitant topical glucocorticoids and calcineurin inhibitors were allowed only as rescue therapy.6 In the LIBERTY AD CHRONOS study, concomitant topical corticosteroids were used with or without topical calcineurin inhibitors. Topical corticosteroids were tapered, stopped, or restarted based on disease activity.7

The primary end point in the 3 studies was the change from baseline to week 16 in the proportion of patients with an Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) and at least a 2-point improvement.5-7 Other end points included the proportion of patients with Eczema Area and Severity Index (EASI)-75 (improvement of ≥75% in the EASI score from baseline), and reduction in itch (at least a 4-point improvement in Peak Pruritus Numerical Rating Scale from baseline to week 16).5-7

SOLO 1 and SOLO 2

Overall, 1379 patients were enrolled in SOLO 1 (N = 671) and in SOLO 2 (N = 708).6 At baseline, 33% of patients in both studies had received systemic glucocorticoids, and 26% and 31%, respectively, had received systemic immunosuppressant drugs.6

After 16 weeks, 38% of those who received dupil­umab in SOLO 1 had an IGA score of 0 or 1 versus 10% in the placebo arm. Similarly, 36% in the dupil­umab arm in SOLO 2 had an IGA score of 0 or 1 versus 9% in the placebo arm.5 The change in EASI-75 score was significantly higher with dupilumab than with placebo (Table).5,6

Table

SOLO 1 and SOLO 2 were designed to provide replication of results, which were determined to be consistent across the 2 studies.6

LIBERTY AD CHRONOS

Overall, 740 patients participated in the LIBERTY AD CHRONOS clinical trial: 319 patients received dupilumab weekly plus topical corticosteroids, 106 patients received dupilumab every other week plus topical corticosteroids, and 315 patients received placebo plus topical corticosteroids.7

The addition of dupilumab to topical corticosteroids with or without topical calcineurin inhibitors showed significant benefit versus placebo in many efficacy measures, including patient-reported symptoms and quality of life (Table).5,7

Because topical corticosteroids are a mainstay of treatment for moderate-to-severe atopic dermatitis based on the current treatment guidelines, their concomitant, as-needed use in the LIBERTY AD CHRONOS study mimics real-world treatment protocols. As such, study findings provide relevant guidance regarding the adjunctive use of dupilumab in adults with moderate-to-severe atopic dermatitis.7

Adverse Reactions

Adverse events for dupilumab reflect experience in 1472 patients with moderate-to-severe atopic dermatitis in 4 clinical trials, including a dose-ranging study.5 Approximately 50% of these patients received dupilumab for at least 1 year.5

The most common (≥1%) adverse reactions included injection-site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, and dry eye. Dupilumab was discontinued because of adverse events in 2% of patients in the monotherapy clinical trials.5

Antibodies to dupilumab were detected in 7% of patients with atopic dermatitis. Overall, 2 patients had serum sickness or serum sickness–like reactions and high titers of antibodies to dupilumab.5

Contraindications

Dupilumab is contraindicated in patients with known hypersensitivity to dupilumab or to any of its excipients.5

Drug Interactions

Patients who receive dupilumab should avoid the use of live vaccines.5

Antibody responses to tetanus vaccine and meningococcal polysaccharide vaccine were similar between patients who received dupilumab and patients who received placebo.5

Dupilumab could modulate the formation of cytochrome (CY) P450 enzymes. Dosage modification of the CYP450 substrate should be considered when starting or discontinuing dupilumab in patients who are receiving concomitant drugs that are CYP450 substrates, particularly those with a narrow therapeutic index.5

Use in Specific Populations

There are no data on the use of dupilumab in pregnant women, the presence of dupilumab in human milk, the effects of dupilumab on the breastfed infant, or on milk production. The benefits of breastfeeding should be considered in light of the mother’s clinical need for dupilumab and any potential adverse effects on a breastfed child.5

The safety and efficacy of dupilumab in pediatric patients have not been established, and no differences were observed between older and younger patients in clinical trials.5

Warnings and Precautions

Hypersensitivity reactions, including serum sickness and generalized urticaria, were reported with dupilumab therapy. Dupilumab should be discontinued if a clinically significant hypersensitivity reaction occurs.5

Conjunctivitis and keratitis can occur with dupilu­mab therapy. The majority of patients with these reactions recovered or were recovering during the treatment period. Patients should report new onset or worsening eye symptoms to healthcare providers.5

Patients with comorbid asthma should not adjust or stop asthma treatments without consulting a physician. Dupilumab has not demonstrated safety or efficacy in the treatment of asthma.5

Patients with known helminth infections were excluded from participating in clinical studies of dupilu­mab. Whether dupilumab influences the body’s immune response against helminth infections is unknown.5

Conclusion

Dupilumab, a parenterally administered inhibitor of IL-4 and IL-13, is the first biologic drug approved for use in adults with moderate-to-severe atopic dermatitis, a chronic skin disorder that is characterized by itching and rash. The safety and efficacy of dupilumab in these patients were demonstrated in 3 large randomized clinical trials.

References
1. Icahn School of Medicine at Mount Sinai. Atopic dermatitis. www.mountsinai.org/patient-care/health-library/diseases-and-conditions/atopic-dermatitis#risk. Accessed September 18, 2017.
2. Zuberbier T, Orlow SJ, Paller AS, et al. Patient perspectives on the management of atopic dermatitis. J Allergy Clin Immunol. 2006;118:226-232.
3. US Food and Drug Administration. FDA approves Eucrisa for eczema. December 14, 2016. www.fda.gov/newsevents/newsroom/pressannouncements/ucm533371.htm. Accessed September 18, 2017.
4. US Food and Drug Administration. FDA approves new eczema drug Dupixent. March 28, 2017. www.fda.gov/newsevents/newsroom/pressannouncements/ucm549078.htm. Accessed September 18, 2017.
5. Dupixent (dupilumab) injection [prescribing information]. Tarrytown, NY: Regeneron Pharmaceuticals; Bridgewater, NJ: sanofi-aventis US; March 2017.
6. Simpson EL, Bieber T, Guttman-Yassky E, et al; for the SOLO 1 and SOLO 2 investigators. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335-2348.
7. 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;389:2287-2303.

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