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About DUPIXENT

DUPIXENT is indicated 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.


DUPIXENT can be used with or without topical corticosteroids.

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Self-Injectable,
Inhibitor of
IL-4 and 1L-13
Signaling
For Adult Patients with Moderate-to-Severe Atopic Dermatitis

Description

Dupilumab, an interleukin-4 receptor alpha antagonist, is a human monoclonal antibody of the IgG4 subclass that binds to the IL-4Rα subunit and inhibits IL-4 and IL-13 signaling. Dupilumab has an approximate molecular weight of 147 kDa.

 

Clinical Pharmacology

Mechanism of Action

Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor.

Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine-induced responses, including the release of proinflammatory cytokines, chemokines and IgE.

 

Dosage and Administration

Dosage

DUPIXENT is administered by subcutaneous injection.

The recommended dose of DUPIXENT for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week.

DUPIXENT can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas.

If a dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.

Important Administration Instructions

DUPIXENT is intended for use under the guidance of a healthcare provider. A patient may self-inject DUPIXENT after training in subcutaneous injection technique using the pre-filled syringe. Provide proper training to patients and/or caregivers on the preparation and administration of DUPIXENT prior to use according to the Instructions for Use.

For the initial 600 mg dose, administer each of the two DUPIXENT 300 mg injections at different injection sites.

Administer subcutaneous injection into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. The upper arm can also be used if a caregiver administers the injection.

Rotate the injection site with each injection. DO NOT inject DUPIXENT into skin that is tender, damaged, bruised, or scarred.

Preparation for Use of DUPIXENT Pre-Filled Syringe With Needle Shield

Before injection, remove DUPIXENT pre-filled syringe from the refrigerator and allow DUPIXENT to reach room temperature (45 minutes) without removing the needle cap.

Inspect DUPIXENT visually for particulate matter and discoloration prior to administration. DUPIXENT is a clear to slightly opalescent, colorless to pale yellow solution. Do not use if the liquid contains visible particulate matter, is discolored or cloudy (other than clear to slightly opalescent, colorless to pale yellow). DUPIXENT does not contain preservatives; therefore, discard any unused product remaining in the pre-filled syringe.

Please see Instructions for Use and full Prescribing Information above for additional details.
 

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Three randomized, double-blind, placebo-controlled, multicenter trials (Trials 1, 2, and 3) and one dose-ranging trial (Trial 4) evaluated the safety of DUPIXENT in subjects with moderate-to-severe atopic dermatitis. The safety population had a mean age of 38 years; 41% of subjects were female, 67% were white, 24% were Asian, and 6% were black; in terms of comorbid conditions, 48% of the subjects had asthma, 49% had allergic rhinitis, 37% had food allergy, and 27% had allergic conjunctivitis. In these 4 trials, 1472 subjects were treated with subcutaneous injections of DUPIXENT, with or without concomitant topical corticosteroids (TCS).

A total of 739 subjects were treated with DUPIXENT for at least 1 year in the development program for moderate-to-severe atopic dermatitis.

Trials 1, 2, and 4 compared the safety of DUPIXENT monotherapy to placebo through Week 16. Trial 3 compared the safety of DUPIXENT + TCS to placebo + TCS through Week 52.

Weeks 0 to 16 (Trials 1 to 4):

In DUPIXENT monotherapy trials (Trials 1, 2, and 4) through Week 16, the proportion of subjects who discontinued treatment because of adverse events was 1.9% in both the DUPIXENT 300 mg Q2W and placebo groups.

Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% in the DUPIXENT 300 mg Q2W monotherapy groups, and in the DUPIXENT + TCS group, all at a higher rate than in their respective comparator groups during the first 16 weeks of treatment.

Table 1:

Adverse Reactions Occurring in ≥1% of the DUPIXENT Monotherapy Group of the DUPIXENT +TCS Group in the Atopic Dermatitis Trials through Week 16

Adverse Reactions Occurring in ≥1% of Patients with Atopic Dermatitis Treated with DUPIXENT Through Week 16 in Placebo-Controlled Trials

a pooled analysis of Trials 1, 2, and 4

b analysis of Trial 3 where subjects were on background TCS therapy

c DUPIXENT 600 mg at Week 0, followed by 300 mg every two weeks

d Conjunctivitis cluster includes conjunctivitis, allergic conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, giant papillary conjunctivitis, eye irritation, and eye inflammation.

e Keratitis cluster includes keratitis, ulcerative keratitis, allergic keratitis, atopic keratoconjunctivitis, and ophthalmic herpes simplex.

f Other herpes simplex virus infection cluster includes herpes simplex, genital herpes, herpes simplex otitis externa, and herpes virus infection, but excludes eczema herpeticum.

Safety through Week 52 (Trial 3):

In the DUPIXENT with concomitant TCS trial (Trial 3) through Week 52, the proportion of subjects who discontinued treatment because of adverse events was 1.8% in DUPIXENT 300 mg Q2W + TCS group and 7.6% in the placebo + TCS group. Two subjects discontinued DUPIXENT because of adverse reactions: atopic dermatitis (1 subject) and exfoliative dermatitis (1 subject).

The safety profile of DUPIXENT + TCS through week 52 was generally consistent with the safety profile observed at week 16.

Specific Adverse Reactions:

Conjunctivitis

During the 52-week treatment period of concomitant therapy trial (Trial 3), conjunctivitis was reported in 16% of the DUPIXENT 300 mg Q2W + TCS group (20 per 100 subject-years) and in 9% of the placebo + TCS group (10 per 100 subject-years).

Eczema Herpeticum and Herpes Zoster

The rate of eczema herpeticum was similar in the placebo and DUPIXENT groups.

Herpes zoster was reported in <0.1% of the DUPIXENT groups (<1 per 100 subject-years) andin <1% of the placebo group (1 per 100 subject-years) in the 16-week monotherapy trials. In the 52-week DUPIXENT + TCS trial, herpes zoster was reported in 1% of the DUPIXENT + TCS group (1 per 100 subject-years) and 2% of the placebo + TCS group (2 per 100 subject-years).

Hypersensitivity Reactions

Hypersensitivity reactions were reported in <1% of DUPIXENT-treated subjects. These included serum sickness reaction, serum sickness-like reaction, and generalized urticaria.

Eosinophils

DUPIXENT-treated subjects had a greater mean initial increase from baseline in eosinophil count compared to subjects treated with placebo in the monotherapy trials. Eosinophil counts declined to near baseline levels by Week 16. The initial increase in eosinophils was not observed in the 52-week DUPIXENT + TCS trial.

In Trials 1, 2, and 3, the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was similar in DUPIXENT and placebo groups. In Trials 1, 2, and 3, treatment-emergent eosinophilia (≥5,000 cells/mcL) was reported in <1% of DUPIXENT-treated patients and none in placebo-treated patients. In most cases, eosinophil counts declined to near baseline during study treatment.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to dupilumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Approximately 7% of subjects with atopic dermatitis who received DUPIXENT 300 mg Q2W for 16 weeks developed antibodies to dupilumab. Of the subjects who developed antibodies to dupilumab, approximately 30% (2% of all subjects receiving DUPIXENT) had antibodies that were classified as neutralizing.

Of the subjects with atopic dermatitis who received DUPIXENT 300 mg Q2W + TCS for 52 weeks, approximately 7% developed antibodies to dupilumab and approximately 2% had persistent antibody responses, defined as having at least 2 consecutive positive post-baseline samples. Of the subjects who developed antibodies to dupilumab, approximately 14% (1% of all subjects receiving DUPIXENT + TCS) had antibodies that were classified as neutralizing.

In subjects who received DUPIXENT, development of antibodies to dupilumab was associated with lower serum dupilumab concentrations.

Antibodies to dupilumab were detected in approximately 2% and 8% of subjects with atopic dermatitis in the placebo or the placebo + TCS groups, respectively.

The antibody titers detected in both DUPIXENT and placebo subjects were generally low. Two subjects developed serum sickness or serum sickness-like reactions and high titers of antibodies to dupilumab during DUPIXENT therapy.

 

Clinical Studies

Three randomized, double-blind, placebo-controlled trials (Trials 1, 2, and 3) enrolled a total of 2119 subjects 18 years of age and older with moderate-to-severe atopic dermatitis (AD) not adequately controlled by topical medication(s). Disease severity was defined by an Investigator’s Global Assessment (IGA) score ≥3 in the overall assessment of AD lesions on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥16 on a scale of 0 to 72, and a minimum body surface area involvement of ≥10%. At baseline, 59% of subjects were male, 67% were white, 52% of subjects had a baseline IGA score of 3 (moderate AD), and 48% of subjects had a baseline IGA of 4 (severe AD). The baseline mean EASI score was 33 and the baseline weekly averaged peak pruritus Numeric Rating Scale (NRS) was 7 on a scale of 0-10.

In all three trials, subjects in the DUPIXENT group received subcutaneous injections of DUPIXENT 600 mg at Week 0, followed by 300 mg every other week (Q2W). In the monotherapy trials (Trials 1 and 2), subjects received DUPIXENT or placebo for 16 weeks.

In the concomitant therapy trial (Trial 3), subjects received DUPIXENT or placebo with concomitant topical corticosteroids (TCS) and as needed topical calcineurin inhibitors for problem areas only, such as the face, neck, intertriginous and genital areas for 52 weeks.

All three trials assessed the primary endpoint, the change from baseline to Week 16 in the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) and at least a 2-point improvement. Other endpoints included the proportion of subjects with EASI-75 (improvement of at least 75% in EASI score from baseline), and reduction in itch as defined by at least a 4-point improvement in the peak pruritus NRS from baseline to Week 16.

Clinical Response at Week 16 (Trials 1, 2, and 3)

The results of the DUPIXENT monotherapy trials (Trials 1 and 2) and the DUPIXENT with concomitant TCS trial (Trial 3) are presented in Table 2.

Table 2:

Efficacy Results of DUPIXENT With or Without Concomitant TCS at Week 16 (FAS)

a Full Analysis Set (FAS) includes all subjects randomized.

b Responder was defined as a subject with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥2 points on a 0-4 IGA scale.

c Subjects who received rescue treatment or with missing data were considered as non-responders.

Figure 1:

Proportion of Subjects with ≥4-point Improvement on the Pruritus NRS in Trial 1a and Trial 2a Studies (FAS)b

Figure 1: Proportion of Patients who achieved an IGA 0 or 1 response up to Week 16

a In the primary analyses of the efficacy endpoints, subjects who received rescue treatment or with the missing data were considered non-responders

b Full Analysis Set (FAS) includes all subjects randomized.

In Trial 3, of the 421 subjects, 353 had been on study for 52 weeks at the time of data analysis. Of these 353 subjects, responders at Week 52 represent a mixture of subjects who maintained their efficacy from Week 16 (e.g., 53% of DUPIXENT IGA 0 or 1 responders at Week 16 remained responders at Week 52) and subjects who were non-responders at Week 16 who later responded to treatment (e.g., 24% of DUPIXENT IGA 0 or 1 non-responders at Week 16 became responders at Week 52). Results of supportive analyses of the 353 subjects in the DUPIXENT with concomitant TCS trial (Trial 3) are presented in Table 3.

Table 3:

Efficacy Results (IGA 0 or 1) of DUPIXENT with Concomitant TCS at Weeks 16 and 52

a In Trial 3, of the 421 randomized and treated subjects, 68 subjects (16%) had not been on study for 52 weeks at the time of the data analysis.

b Responder was defined as a subject with IGA 0 or 1 (“clear” or “almost clear”) with a reduction of ≥2 points on a 0-4 IGA scale.

c Subjects who received rescue treatment or with missing data were considered as non-responders.

Treatment effects in subgroups (weight, age, gender, race, and prior treatment, including immunosuppressants) in Trials 1, 2, and 3 were generally consistent with the results in the overall study population.

In Trials 1, 2, and 3, a third randomized treatment arm of DUPIXENT 300 mg QW did not demonstrate additional treatment benefit over DUPIXENT 300 mg Q2W.

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