Get your patient on Dupixent (Dupilumab)

Three randomized, double-blind, placebo-controlled trials (SOLO 1 (NCT02277743), SOLO 2 (NCT02277769), and CHRONOS (NCT02260986)) enrolled a total of 2119 adult subjects with moderate-to-severe 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, the mean age of subjects was 38 years; 59% of subjects were male, 67% were White, 24% were Asian, and 6% were Black; 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 2 weeks (Q2W). In the monotherapy trials (SOLO 1 and SOLO 2), subjects received DUPIXENT or placebo for 16 weeks.

In the concomitant therapy trial (CHRONOS), 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.

The results of the DUPIXENT monotherapy trials (SOLO 1 and SOLO 2) and the DUPIXENT with concomitant TCS trial (CHRONOS) are presented in Table 16.

Figure 1: Proportion of Adult Subjects with Moderate-to-Severe AD with ≥4-point Improvement on the Peak Pruritus NRS in SOLO 1In the primary analyses of the efficacy endpoints, subjects who received rescue treatment or with missing data were considered non-responders.and SOLO 2 Studies (FAS)Full Analysis Set (FAS) includes all subjects randomized.
SOLO 1	SOLO 2

In CHRONOS, 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 (CHRONOS) are presented in Table 17.

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

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

Subjects in SOLO 1 and SOLO 2 who had an IGA 0 or 1 with a reduction of ≥2 points were re-randomized into SOLO CONTINUE (NCT02395133). SOLO CONTINUE evaluated multiple DUPIXENT monotherapy dose regimens for maintaining treatment response. The study included subjects randomized to continue with DUPIXENT 300 mg Q2W (62 subjects) or switch to placebo (31 subjects) for 36 weeks. IGA 0 or 1 responses at Week 36 were as follows: 33 (53%) in the Q2W group and 3 (10%) in the placebo group.

The efficacy of DUPIXENT monotherapy in pediatric subjects 12 years of age and older was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial (AD-1526; NCT03054428) in 251 pediatric subjects 12 to 17 years of age, with moderate-to-severe AD defined by an IGA score ≥3 (scale of 0 to 4), an EASI score ≥16 (scale of 0 to 72), and a minimum BSA involvement of ≥10%. Eligible subjects enrolled into this trial had previous inadequate response to topical medication.

Subjects in the DUPIXENT group with baseline weight of <60 kg received an initial dose of 400 mg at Week 0, followed by 200 mg Q2W for 16 weeks. Subjects with baseline weight of ≥60 kg received an initial dose of 600 mg at Week 0, followed by 300 mg Q2W for 16 weeks. Subjects were permitted to receive rescue treatment at the discretion of the investigator. Subjects who received rescue treatment were considered non-responders.

In AD-1526, the mean age was 14.5 years, the median weight was 59.4 kg, 41% of subjects were female, 63% were White, 15% were Asian, and 12% were Black. At baseline, 46% of subjects had an IGA score of 3 (moderate AD), 54% had an IGA score of 4 (severe AD), the mean BSA involvement was 57%, and 42% had received prior systemic immunosuppressants. Also, at baseline, the mean EASI score was 36, and the weekly averaged Peak Pruritus NRS was 8 on a scale of 0-10. Overall, 92% of subjects had at least one co-morbid allergic condition; 66% had allergic rhinitis, 54% had asthma, and 61% had food allergies.

The primary endpoint was the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) and at least a 2-point improvement from baseline to Week 16. Other evaluated outcomes included the proportion of subjects with EASI-75 or EASI-90 (improvement of at least 75% or 90% in EASI from baseline, respectively), and reduction in itch as measured by the Peak Pruritus NRS (≥4-point improvement).

The efficacy results at Week 16 for AD-1526 are presented in Table 18.

A greater proportion of subjects randomized to DUPIXENT achieved an improvement in the Peak Pruritus NRS compared to placebo (defined as ≥4-point improvement at Week 4). See

Figure 2: Proportion of Pediatric Subjects 12 Years of Age and Older with Moderate-to-Severe AD with ≥4-point Improvement on the Peak Pruritus NRS in AD-1526In the primary analyses of the efficacy endpoints, subjects who received rescue treatment or with missing data were considered non-responders.(FAS)Full Analysis Set (FAS) includes all subjects randomized.

The efficacy and safety of DUPIXENT use concomitantly with TCS in pediatric subjects was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial (AD-1652; NCT03345914) in 367 subjects 6 to 11 years of age, with AD defined by an IGA score of 4 (scale of 0 to 4), an EASI score ≥21 (scale of 0 to 72), and a minimum BSA involvement of ≥15%. Eligible subjects enrolled into this trial had previous inadequate response to topical medication. Enrollment was stratified by baseline weight (<30 kg; ≥30 kg).

Subjects in the DUPIXENT Q4W + TCS group received an initial dose of 600 mg on Day 1, followed by 300 mg Q4W from Week 4 to Week 12, regardless of weight. Subjects in the DUPIXENT Q2W + TCS group with baseline weight of <30 kg received an initial dose of 200 mg on Day 1, followed by 100 mg Q2W from Week 2 to Week 14, and subjects with baseline weight of ≥30 kg received an initial dose of 400 mg on Day 1, followed by 200 mg Q2W from Week 2 to Week 14. Subjects were permitted to receive rescue treatment at the discretion of the investigator. Subjects who received rescue treatment were considered non-responders.

In AD-1652, the mean age was 8.5 years, the median weight was 29.8 kg, 50% of subjects were female, 69% were White, 17% were Black, and 8% were Asian. At baseline, the mean BSA involvement was 58%, and 17% had received prior systemic non-steroidal immunosuppressants. Also, at baseline the mean EASI score was 37.9, and the weekly average of daily worst itch score was 7.8 on a scale of 0-10. Overall, 92% of subjects had at least one co-morbid allergic condition; 64% had food allergies, 63% had other allergies, 60% had allergic rhinitis, and 47% had asthma.

The primary endpoint was the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) at Week 16. Other evaluated outcomes included the proportion of subjects with EASI-75 or EASI-90 (improvement of at least 75% or 90% in EASI from baseline, respectively), and reduction in itch as measured by the Peak Pruritus NRS (≥4-point improvement).

Table 19 presents the results by baseline weight strata for the approved dose regimens.

A greater proportion of subjects randomized to DUPIXENT + TCS achieved an improvement in the Peak Pruritus NRS compared to placebo + TCS (defined as ≥4-point improvement at Week 16). See

Figure 3: Proportion of Pediatric Subjects 6 to 11 Years of Age with AD with ≥4-point Improvement on the Peak Pruritus NRS at Week 16 in AD-1652In the primary analyses of the efficacy endpoints, subjects who received rescue treatment or with missing data were considered non-responders.(FAS)Full Analysis Set (FAS) includes all subjects randomized.

The efficacy and safety of DUPIXENT use concomitantly with TCS in pediatric subjects was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial (AD-1539; NCT03346434) in 162 subjects 6 months to 5 years of age, with moderate-to-severe AD defined by an IGA score ≥3 (scale of 0 to 4), an EASI score ≥16 (scale of 0 to 72), and a minimum BSA involvement of ≥10%. Eligible subjects enrolled into this trial had previous inadequate response to topical medication. Enrollment was stratified by baseline weight (≥5 to <15 kg and ≥15 to <30 kg).

Subjects in the DUPIXENT Q4W + TCS group with baseline weight of ≥5 to <15 kg received an initial dose of 200 mg on Day 1, followed by 200 mg Q4W from Week 4 to Week 12, and subjects with baseline weight of ≥15 to <30 kg received an initial dose of 300 mg on Day 1, followed by 300 mg Q4W from Week 4 to Week 12. Subjects were permitted to receive rescue treatment at the discretion of the investigator. Subjects who received rescue treatment were considered non-responders.

In AD-1539, the mean age was 3.8 years, the median weight was 16.5 kg, 39% of subjects were female, 69% were White, 19% were Black, and 6% were Asian. At baseline, the mean BSA involvement was 58%, and 29% of subjects had received prior systemic immunosuppressants. Also, at baseline the mean EASI score was 34.1, and the weekly average of daily worst scratch/itch score was 7.6 on a scale of 0-10. Overall, 81.4% of subjects had at least one co-morbid allergic condition; 68.3% had food allergies, 52.8% had other allergies, 44.1% had allergic rhinitis, and 25.5% had asthma.

The primary endpoint was the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) at Week 16. Other evaluated outcomes included the proportion of subjects with EASI-75 or EASI-90 (improvement of at least 75% or 90% in EASI from baseline, respectively), and reduction in itch as measured by the Worst Scratch/Itch NRS (≥4-point improvement).

The efficacy results at Week 16 for AD-1539 are presented in Table 20.

The efficacy and safety of DUPIXENT was evaluated in a 16-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial (Liberty-AD-HAFT; NCT04417894) in 133 adult and pediatric subjects 12 to 17 years of age with atopic dermatitis with moderate-to-severe hand and/or foot involvement, defined by an established diagnosis of atopic dermatitis and screening to rule out irritant and allergic contact dermatitis through history and appropriate patch testing, and by an IGA (hand and foot) score ≥3 (scale of 0 to 4) and a hand and foot Peak Pruritus Numeric Rating Scale (NRS) score for maximum itch intensity ≥4 (scale of 0 to 10). Fifty-three (53) percent (N=70/133) of the subjects also had moderate-to-severe AD outside of the hands or feet (IGA global ≥3). Eligible subjects had previous inadequate response or intolerance to treatment of hand and/or foot dermatitis with topical AD medications. In this trial 67 subjects received DUPIXENT, and 66 subjects received placebo. DUPIXENT-treated subjects received the recommended dosage based on their age and body weight

In Liberty-AD-HAFT, 38% of subjects were male, 80% were White, 13% were Asian, and 5% were Black or African American. For ethnicity, 4% were identified as Hispanic or Latino and 96% were identified as not Hispanic or Latino. Seventy-two (72) percent (N=96/133) of subjects had a baseline IGA (hand and foot) score of 3 (atopic dermatitis with moderate hand and/or foot involvement), and 28% (N=37/133) of subjects had a baseline IGA (hand and foot) score of 4 (atopic dermatitis with severe hand and/or foot involvement). The baseline weekly averaged hand and foot Peak Pruritus NRS score was 7.1.

The primary endpoint was the proportion of subjects with an IGA hand and foot score of 0 (clear) or 1 (almost clear) at Week 16. The key secondary endpoint was reduction of itch as measured by the hand and foot Peak Pruritus NRS (≥4-point improvement).

The efficacy results at Week 16 for Liberty-AD-HAFT are presented in Table 21.

DRI12544 was a 24-week dose-ranging study which included 776 adult subjects (18 years of age and older). DUPIXENT compared with placebo was evaluated in adult subjects with moderate-to-severe asthma on a medium or high-dose inhaled corticosteroid and a long acting beta agonist. Subjects were randomized to receive either 200 mg (N=150) or 300 mg (N=157) DUPIXENT every 2 weeks (Q2W) or 200 mg (N=154) or 300 mg (N=157) DUPIXENT every 4 weeks following an initial dose of 400 mg, 600 mg or placebo (N=158), respectively. The primary endpoint was mean change from baseline to Week 12 in FEV₁(L) in subjects with baseline blood eosinophils ≥300 cells/mcL. Other endpoints included percent change from baseline in FEV₁and annualized rate of severe asthma exacerbation events during the 24-week placebo-controlled treatment period. Results were evaluated in the overall population and subgroups based on baseline blood eosinophil count (≥300 cells/mcL and <300 cells/mcL). Additional secondary endpoints included responder rates in the patient reported Asthma Control Questionnaire (ACQ-5) and Asthma Quality of Life Questionnaire, Standardized Version (AQLQ(S)) scores.

QUEST was a 52-week study which included 1902 adult and pediatric subjects (12 years of age and older). DUPIXENT compared with placebo was evaluated in 107 pediatric subjects 12 to 17 years of age and 1795 adult subjects with moderate-to-severe asthma on a medium or high-dose inhaled corticosteroid (ICS) and a minimum of one and up to two additional controller medications. Subjects were randomized to receive either 200 mg (N=631) or 300 mg (N=633) DUPIXENT Q2W (or matching placebo for either 200 mg [N=317] or 300 mg [N=321] Q2W) following an initial dose of 400 mg, 600 mg or placebo, respectively. The primary endpoints were the annualized rate of severe exacerbation events during the 52-week placebo-controlled period and change from baseline in pre-bronchodilator FEV₁at Week 12 in the overall population (unrestricted by minimum baseline blood eosinophils count). Additional secondary endpoints included annualized severe exacerbation rates and FEV₁in subjects with different baseline levels of blood eosinophils as well as responder rates in the ACQ-5 and AQLQ(S) scores.

VENTURE was a 24-week oral corticosteroid-reduction study in 210 adult and pediatric subjects 15 years of age and older with asthma who required daily oral corticosteroids in addition to regular use of high dose inhaled corticosteroids plus an additional controller. After optimizing the OCS dose during the screening period, subjects received 300 mg DUPIXENT (N=103) or placebo (N=107) once Q2W for 24 weeks following an initial dose of 600 mg or placebo. Subjects continued to receive their existing asthma medicine during the study; however, their OCS dose was reduced every 4 weeks during the OCS reduction phase (Week 4-20), as long as asthma control was maintained. The primary endpoint was the percent reduction of oral corticosteroid dose at Weeks 20 to 24 compared with the baseline dose, while maintaining asthma control in the overall population (unrestricted by minimum baseline blood eosinophils count). Additional secondary endpoints included the annualized rate of severe exacerbation events during treatment period and responder rate in the ACQ-5 and AQLQ(S) scores.

The demographics and baseline characteristics of these 3 trials are provided in Table 22 below.

DRI12544 and QUEST evaluated the frequency of severe asthma exacerbations defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or hospitalization or emergency room visit due to asthma that required systemic corticosteroids. In the primary analysis population (subjects with baseline blood eosinophil count of ≥300 cells/mcL in DRI12544 and the overall population in QUEST), subjects receiving either DUPIXENT 200 mg or 300 mg Q2W had significant reductions in the rate of asthma exacerbations compared to placebo. In the overall population in QUEST, the rate of severe exacerbations was 0.46 and 0.52 for DUPIXENT 200 mg Q2W and 300 mg Q2W, respectively, compared to matched placebo rates of 0.87 and 0.97. The rate ratio of severe exacerbations compared to placebo was 0.52 (95% CI: 0.41, 0.66) and 0.54 (95% CI: 0.43, 0.68) for DUPIXENT 200 mg Q2W and 300 mg Q2W, respectively. Results in subjects with baseline blood eosinophil counts ≥300 cells/mcL in DRI12544 and QUEST are shown in Table 23.

Response rates by baseline blood eosinophils and baseline FeNO for QUEST are shown for the overall population in Figure 4 and Figure 5, respectively. Elevation of FeNO can be a marker of the eosinophilic asthma phenotype when supported by clinical data. Pre-specified subgroup analyses of DRI12544 and QUEST demonstrated that there were greater reductions in severe exacerbations in subjects with higher baseline blood eosinophil levels (≥150 cells/mcL) or FeNO (≥25 ppb). In QUEST, reductions in exacerbations were significant in the subgroup of subjects with baseline blood eosinophils ≥150 cells/mcL. In subjects with baseline blood eosinophil count <150 cells/mcL and FeNO <25 ppb, similar severe exacerbation rates were observed between DUPIXENT and placebo.

In QUEST, the estimated rate ratio of exacerbations leading to hospitalizations and/or emergency room visits versus placebo was 0.53 (95% CI: 0.28, 1.03) and 0.74 (95% CI: 0.32, 1.70) with DUPIXENT 200 mg or 300 mg Q2W, respectively.

The time to first exacerbation was longer for the subjects receiving DUPIXENT compared to placebo in QUEST (Figure 6).

Figure 6: Kaplan Meier Incidence Curve for Time to First Severe Exacerbation in Subjects with Moderate-to-Severe Asthma with Baseline Blood Eosinophils ≥300 cells/mcL (QUEST)At the time of the database lock, not all subjects had completed Week 52

Significant increases in pre-bronchodilator FEV₁were observed at Week 12 for DRI12544 and QUEST in the primary analysis populations (subjects with baseline blood eosinophil count of ≥300 cells/mcL in DRI12544 and the overall population in QUEST). In the overall population in QUEST, the FEV₁LS mean change from baseline was 0.32 L (21%) and 0.34 L (23%) for DUPIXENT 200 mg Q2W and 300 mg Q2W, respectively, compared to matched placebo means of 0.18 L (12%) and 0.21 L (14%). The mean treatment difference versus placebo was 0.14 L (95% CI: 0.08, 0.19) and 0.13 L (95% CI: 0.08, 0.18) for DUPIXENT 200 mg Q2W and 300 mg Q2W, respectively. Results in subjects with baseline blood eosinophil counts ≥300 cells/mcL in DRI12544 and QUEST are shown in Table 24.

Improvements in FEV₁by baseline blood eosinophils and baseline FeNO for QUEST are shown in Figure 7 and 8, respectively. Subgroup analysis of DRI12544 and QUEST demonstrated greater improvement in subjects with higher baseline blood eosinophils (≥150 cells/mcL) or FeNO (≥25 ppb). In subjects with baseline blood eosinophil count <150 cells/mcL and FeNO <25 ppb, similar differences in FEV₁were observed between DUPIXENT and placebo.

Mean changes in FEV₁over time in QUEST are shown in Figure 9.

VENTURE evaluated the effect of DUPIXENT on reducing the use of maintenance oral corticosteroids. The baseline mean oral corticosteroid dose was 12 mg in the placebo group and 11 mg in the group receiving DUPIXENT. The primary endpoint was the percent reduction from baseline of the final oral corticosteroid dose at Week 24 while maintaining asthma control.

Compared with placebo, subjects receiving DUPIXENT achieved greater reductions in daily maintenance oral corticosteroid dose, while maintaining asthma control. The mean percent reduction in daily OCS dose from baseline was 70% (median 100%) in subjects receiving DUPIXENT (95% CI: 60%, 80%) compared to 42% (median 50%) in subjects receiving placebo (95% CI: 33%, 51%). Reductions of 50% or higher in the OCS dose were observed in 82 (80%) subjects receiving DUPIXENT compared to 57 (53%) in those receiving placebo. The proportion of subjects with a mean final dose less than 5 mg at Week 24 was 72% for DUPIXENT and 37% for placebo (odds ratio 4.48 95% CI: 2.39, 8.39). A total of 54 (52%) subjects receiving DUPIXENT versus 31 (29%) subjects in the placebo group had a 100% reduction in their OCS dose.

In this 24-week trial, asthma exacerbations (defined as a temporary increase in oral corticosteroid dose for at least 3 days) were lower in subjects receiving DUPIXENT compared with those receiving placebo (annualized rate 0.65 and 1.60 for the DUPIXENT and placebo group, respectively; rate ratio 0.41 [95% CI 0.26, 0.63]) and improvement in pre-bronchodilator FEV₁from baseline to Week 24 was greater in subjects receiving DUPIXENT compared with those receiving placebo (LS mean difference for DUPIXENT versus placebo of 0.22 L [95% CI: 0.09 to 0.34 L]). Effects on lung function and on oral steroid and exacerbation reduction were similar irrespective of baseline blood eosinophil levels. The ACQ-5 and AQLQ(S) were also assessed in VENTURE and showed improvements similar to those in QUEST.

The efficacy and safety of DUPIXENT in pediatric subjects was evaluated in a 52-week multicenter, randomized, double-blind, placebo-controlled study (VOYAGE; NCT02948959) in 408 subjects 6 to 11 years of age, with moderate-to-severe asthma on a medium or high-dose ICS and a second controller medication or high-dose ICS alone. Subjects were required to have a history of 1 or more asthma exacerbation(s) that required treatment with systemic corticosteroids or emergency department visit or hospitalization for the treatment of asthma in the year prior to trial entry. Subjects were randomized to DUPIXENT (N=273) or matching placebo (N=135) every 2 weeks based on body weight <30 kg (100 mg Q2W) or ≥30 kg (200 mg Q2W). The effectiveness of DUPIXENT 300 mg Q4W was extrapolated from efficacy of 100 mg Q2W in VOYAGE with support from population pharmacokinetic analyses showing higher drug exposure levels with 300 mg Q4W

[see Pediatric Use (8.4)]

8.4 Pediatric Use

Atopic Dermatitis

The safety and effectiveness of DUPIXENT have been established in pediatric patients 6 months of age and older with moderate-to-severe AD, whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Use of DUPIXENT in this age group is supported by data from the following clinical trials:

• AD-1526 which included 251 pediatric subjects 12 years of age and older with moderate-to-severe AD. Of the 251 subjects, 82 were treated with DUPIXENT 200 mg Q2W (<60 kg) or 300 mg Q2W (≥60 kg) and 85 were treated with matching placebo
• AD-1652 which included 367 pediatric subjects 6 to 11 years of age with severe AD. Of the 367 subjects, 120 were treated with DUPIXENT 300 mg Q4W + TCS (15 to <30 kg) or 200 mg Q2W + TCS (≥30 kg) and 123 were treated with matching placebo + TCS
• AD-1539 which included 162 pediatric subjects 6 months to 5 years of age with moderate-to-severe AD. Of the 162 subjects, 83 were treated with DUPIXENT 200 mg Q4W + TCS (5 to <15 kg) or 300 mg Q4W + TCS (15 to <30 kg) and 79 subjects were assigned to be treated with matching placebo + TCS
• AD-1434, an open-label extension study that enrolled 275 pediatric subjects 12 years of age and older treated with DUPIXENT ± TCS, 368 pediatric subjects 6 to 11 years of age treated with DUPIXENT ± TCS, and 180 pediatric subjects 6 months to 5 years of age treated with DUPIXENT ± TCS
• Liberty-AD-HAFT which included 27 pediatric subjects 12 years of age and older with atopic dermatitis with moderate-to-severe hand and/or foot involvement treated with DUPIXENT (N=14) or matching placebo (N=13)

The safety and effectiveness were generally consistent between pediatric and adult patients. In addition, hand-foot-and-mouth disease was reported in 9 (5%) pediatric subjects and skin papilloma was reported in 4 (2%) pediatric subjects 6 months to 5 years of age treated with DUPIXENT ± TCS in AD-1434. These cases did not lead to study drug discontinuation

[see Adverse Reactions (6.1)] andClinical Studies (14.1)]

Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 6 months of age with AD.

Asthma

The safety and effectiveness of DUPIXENT for an add-on maintenance treatment in patients with moderate-to-severe asthma characterized by an eosinophilic phenotype or with oral corticosteroid dependent asthma have been established in pediatric patients 6 years of age and older. Use of DUPIXENT for this indication is supported by evidence from adequate and well-controlled studies in adult and pediatric patients 6 years and older

[see Clinical Studies (14.2)]]

14.2 Asthma

The asthma development program for patients aged 12 years and older included three randomized, double-blind, placebo-controlled, parallel-group, multicenter trials (DRI12544 (NCT01854047), QUEST (NCT02414854), and VENTURE (NCT02528214)) of 24 to 52 weeks in treatment duration which enrolled a total of 2888 subjects. Subjects enrolled in DRI12544 and QUEST were required to have a history of 1 or more asthma exacerbations that required treatment with systemic corticosteroids or emergency department visit or hospitalization for the treatment of asthma in the year prior to trial entry. Subjects enrolled in VENTURE required dependence on daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s). In all 3 trials, subjects were enrolled without requiring a minimum baseline blood eosinophil count. In QUEST and VENTURE, subjects with screening blood eosinophil level of >1500 cells/mcL (<1.3%) were excluded. DUPIXENT was administered as add-on to background asthma treatment. Subjects continued background asthma therapy throughout the duration of the studies, except in VENTURE in which OCS dose was tapered as described below.

DRI12544

DRI12544 was a 24-week dose-ranging study which included 776 adult subjects (18 years of age and older). DUPIXENT compared with placebo was evaluated in adult subjects with moderate-to-severe asthma on a medium or high-dose inhaled corticosteroid and a long acting beta agonist. Subjects were randomized to receive either 200 mg (N=150) or 300 mg (N=157) DUPIXENT every 2 weeks (Q2W) or 200 mg (N=154) or 300 mg (N=157) DUPIXENT every 4 weeks following an initial dose of 400 mg, 600 mg or placebo (N=158), respectively. The primary endpoint was mean change from baseline to Week 12 in FEV₁(L) in subjects with baseline blood eosinophils ≥300 cells/mcL. Other endpoints included percent change from baseline in FEV₁and annualized rate of severe asthma exacerbation events during the 24-week placebo-controlled treatment period. Results were evaluated in the overall population and subgroups based on baseline blood eosinophil count (≥300 cells/mcL and <300 cells/mcL). Additional secondary endpoints included responder rates in the patient reported Asthma Control Questionnaire (ACQ-5) and Asthma Quality of Life Questionnaire, Standardized Version (AQLQ(S)) scores.

QUEST

QUEST was a 52-week study which included 1902 adult and pediatric subjects (12 years of age and older). DUPIXENT compared with placebo was evaluated in 107 pediatric subjects 12 to 17 years of age and 1795 adult subjects with moderate-to-severe asthma on a medium or high-dose inhaled corticosteroid (ICS) and a minimum of one and up to two additional controller medications. Subjects were randomized to receive either 200 mg (N=631) or 300 mg (N=633) DUPIXENT Q2W (or matching placebo for either 200 mg [N=317] or 300 mg [N=321] Q2W) following an initial dose of 400 mg, 600 mg or placebo, respectively. The primary endpoints were the annualized rate of severe exacerbation events during the 52-week placebo-controlled period and change from baseline in pre-bronchodilator FEV₁at Week 12 in the overall population (unrestricted by minimum baseline blood eosinophils count). Additional secondary endpoints included annualized severe exacerbation rates and FEV₁in subjects with different baseline levels of blood eosinophils as well as responder rates in the ACQ-5 and AQLQ(S) scores.

VENTURE

VENTURE was a 24-week oral corticosteroid-reduction study in 210 adult and pediatric subjects 15 years of age and older with asthma who required daily oral corticosteroids in addition to regular use of high dose inhaled corticosteroids plus an additional controller. After optimizing the OCS dose during the screening period, subjects received 300 mg DUPIXENT (N=103) or placebo (N=107) once Q2W for 24 weeks following an initial dose of 600 mg or placebo. Subjects continued to receive their existing asthma medicine during the study; however, their OCS dose was reduced every 4 weeks during the OCS reduction phase (Week 4-20), as long as asthma control was maintained. The primary endpoint was the percent reduction of oral corticosteroid dose at Weeks 20 to 24 compared with the baseline dose, while maintaining asthma control in the overall population (unrestricted by minimum baseline blood eosinophils count). Additional secondary endpoints included the annualized rate of severe exacerbation events during treatment period and responder rate in the ACQ-5 and AQLQ(S) scores.

The demographics and baseline characteristics of these 3 trials are provided in Table 22 below.

Table 22: Demographics and Baseline Characteristics of Asthma Trials

Parameter	DRI12544 (N=776)	QUEST (N=1902)	VENTURE (N=210)
ICS = inhaled corticosteroid; FEV1= Forced expiratory volume in 1 second; AD = atopic dermatitis; NP = nasal polyps; AR = allergic rhinitis; FeNO = fraction of exhaled nitric oxide
Mean age (years) (SD)	49 (13)	48 (15)	51 (13)
% Female	63	63	61
% White	78	83	94
Duration of Asthma (years), mean (± SD)	22 (15)	21 (15)	20 (14)
Never smoked (%)	77	81	81
Mean exacerbations in previous year (± SD)	2.2 (2.1)	2.1 (2.2)	2.1 (2.2)
High dose ICS use (%)	50	52	89
Pre-dose FEV1(L) at baseline (± SD)	1.84 (0.54)	1.78 (0.60)	1.58 (0.57)
Mean percent predicted FEV1at baseline (%) (± SD)	61 (11)	58 (14)	52 (15)
% Reversibility (± SD)	27 (15)	26 (22)	19 (23)
Atopic Medical History % Overall (AD %, NP %, AR %)	73 (8, 11, 62)	78 (10, 13, 69)	72 (8, 21, 56)
Mean FeNO ppb (± SD)	39 (35)	35 (33)	38 (31)
Mean total IgE IU/mL ( ± SD)	435 (754)	432 (747)	431 (776)
Mean baseline blood Eosinophil count (± SD) cells/mcL	350 (430)	360 (370)	350 (310)

Exacerbations in Subjects with Asthma

DRI12544 and QUEST evaluated the frequency of severe asthma exacerbations defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or hospitalization or emergency room visit due to asthma that required systemic corticosteroids. In the primary analysis population (subjects with baseline blood eosinophil count of ≥300 cells/mcL in DRI12544 and the overall population in QUEST), subjects receiving either DUPIXENT 200 mg or 300 mg Q2W had significant reductions in the rate of asthma exacerbations compared to placebo. In the overall population in QUEST, the rate of severe exacerbations was 0.46 and 0.52 for DUPIXENT 200 mg Q2W and 300 mg Q2W, respectively, compared to matched placebo rates of 0.87 and 0.97. The rate ratio of severe exacerbations compared to placebo was 0.52 (95% CI: 0.41, 0.66) and 0.54 (95% CI: 0.43, 0.68) for DUPIXENT 200 mg Q2W and 300 mg Q2W, respectively. Results in subjects with baseline blood eosinophil counts ≥300 cells/mcL in DRI12544 and QUEST are shown in Table 23.

Response rates by baseline blood eosinophils and baseline FeNO for QUEST are shown for the overall population in Figure 4 and Figure 5, respectively. Elevation of FeNO can be a marker of the eosinophilic asthma phenotype when supported by clinical data. Pre-specified subgroup analyses of DRI12544 and QUEST demonstrated that there were greater reductions in severe exacerbations in subjects with higher baseline blood eosinophil levels (≥150 cells/mcL) or FeNO (≥25 ppb). In QUEST, reductions in exacerbations were significant in the subgroup of subjects with baseline blood eosinophils ≥150 cells/mcL. In subjects with baseline blood eosinophil count <150 cells/mcL and FeNO <25 ppb, similar severe exacerbation rates were observed between DUPIXENT and placebo.

In QUEST, the estimated rate ratio of exacerbations leading to hospitalizations and/or emergency room visits versus placebo was 0.53 (95% CI: 0.28, 1.03) and 0.74 (95% CI: 0.32, 1.70) with DUPIXENT 200 mg or 300 mg Q2W, respectively.

Table 23: Rate of Severe Exacerbations in Asthma Trials (DRI12544 and QUEST)

Trial	Treatment	Baseline Blood EOS ≥300 cells/mcL (primary analysis population, DRI12544)
		N	Rate (95% CI)	Rate Ratio (95% CI)
DRI12544	DUPIXENT 200 mg Q2W	65	0.30 (0.13, 0.68)	0.29 (0.11, 0.76)
	DUPIXENT 300 mg Q2W	64	0.20 (0.08, 0.52)	0.19 (0.07, 0.56)
	Placebo	68	1.04 (0.57, 1.90)
QUEST	DUPIXENT 200 mg Q2W	264	0.37 (0.29, 0.48)	0.34 (0.24, 0.48)
	Placebo	148	1.08 (0.85, 1.38)
	DUPIXENT 300 mg Q2W	277	0.40 (0.32, 0.51)	0.33 (0.23, 0.45)
	Placebo	142	1.24 (0.97, 1.57)

Figure 4: Relative Risk in Annualized Event Rate of Severe Exacerbations across Baseline Blood Eosinophil Count (cells/mcL) in Subjects with Moderate-to-Severe Asthma (QUEST)

Figure 5: Relative Risk in Annualized Event Rate of Severe Exacerbations across Baseline FeNO Group (ppb) in Subjects with Moderate-to-Severe Asthma (QUEST)

The time to first exacerbation was longer for the subjects receiving DUPIXENT compared to placebo in QUEST (Figure 6).

Figure 6: Kaplan Meier Incidence Curve for Time to First Severe Exacerbation in Subjects with Moderate-to-Severe Asthma with Baseline Blood Eosinophils ≥300 cells/mcL (QUEST)At the time of the database lock, not all subjects had completed Week 52

Lung Function in Subjects with Asthma

Significant increases in pre-bronchodilator FEV₁were observed at Week 12 for DRI12544 and QUEST in the primary analysis populations (subjects with baseline blood eosinophil count of ≥300 cells/mcL in DRI12544 and the overall population in QUEST). In the overall population in QUEST, the FEV₁LS mean change from baseline was 0.32 L (21%) and 0.34 L (23%) for DUPIXENT 200 mg Q2W and 300 mg Q2W, respectively, compared to matched placebo means of 0.18 L (12%) and 0.21 L (14%). The mean treatment difference versus placebo was 0.14 L (95% CI: 0.08, 0.19) and 0.13 L (95% CI: 0.08, 0.18) for DUPIXENT 200 mg Q2W and 300 mg Q2W, respectively. Results in subjects with baseline blood eosinophil counts ≥300 cells/mcL in DRI12544 and QUEST are shown in Table 24.

Improvements in FEV₁by baseline blood eosinophils and baseline FeNO for QUEST are shown in Figure 7 and 8, respectively. Subgroup analysis of DRI12544 and QUEST demonstrated greater improvement in subjects with higher baseline blood eosinophils (≥150 cells/mcL) or FeNO (≥25 ppb). In subjects with baseline blood eosinophil count <150 cells/mcL and FeNO <25 ppb, similar differences in FEV₁were observed between DUPIXENT and placebo.

Mean changes in FEV₁over time in QUEST are shown in Figure 9.

Table 24: Mean Change from Baseline and Difference vs Placebo in Pre-Bronchodilator FEV₁at Week 12 in Subjects with Moderate-to-Severe Asthma (DRI12544 and QUEST)

Trial	Treatment	Baseline Blood EOS ≥300 cells/mcL (primary analysis population, DRI12544)
		N	LS Mean Change from baseline L (%)	LS Mean Difference vs. placebo (95% CI)
DRI12544	DUPIXENT 200 mg Q2W	65	0.43 (25.9)	0.26 (0.11, 0.40)
	DUPIXENT 300 mg Q2W	64	0.39 (25.8)	0.21 (0.06, 0.36)
	Placebo	68	0.18 (10.2)
QUEST	DUPIXENT 200 mg Q2W	264	0.43 (29.0)	0.21 (0.13, 0.29)
	Placebo	148	0.21 (15.6)
	DUPIXENT 300 mg Q2W	277	0.47 (32.5)	0.24 (0.16, 0.32)
	Placebo	142	0.22 (14.4)

Figure 7: LS Mean Difference in Change from Baseline vs Placebo to Week 12 in Pre-Bronchodilator FEV₁across Baseline Blood Eosinophil Counts (cells/mcL) in Subjects with Moderate-to-Severe Asthma (QUEST)

Figure 8: LS Mean Difference in Change from Baseline vs Placebo to Week 12 in Pre-bronchodilator FEV₁across Baseline FeNO (ppb) in Subjects with Moderate-to-Severe Asthma (QUEST)

Figure 9: Mean Change from Baseline in Pre-Bronchodilator FEV₁(L) Over Time in Subjects with Moderate-to-Severe Asthma with Baseline Blood Eosinophils ≥300 cells/mcL (QUEST)

Additional Secondary Endpoints in Asthma Trial (QUEST)

ACQ-5 and AQLQ(S) were assessed in QUEST at 52 weeks. The responder rate was defined as an improvement in score of 0.5 or more (scale range 0-6 for ACQ-5 and 1-7 for AQLQ(S)).

• The ACQ-5 responder rate for DUPIXENT 200 mg and 300 mg Q2W in the overall population was 69% vs 62% placebo (odds ratio 1.37; 95% CI: 1.01, 1.86) and 69% vs 63% placebo (odds ratio 1.28; 95% CI: 0.94, 1.73), respectively; and the AQLQ(S) responder rates were 62% vs 54% placebo (odds ratio 1.61; 95% CI: 1.17, 2.21) and 62% vs 57% placebo (odds ratio 1.33; 95% CI: 0.98, 1.81), respectively.
• The ACQ-5 responder rate for DUPIXENT 200 mg and 300 mg Q2W in subjects with baseline blood eosinophils ≥300 cells/mcL was 75% vs 67% placebo (odds ratio: 1.46; 95% CI: 0.90, 2.35) and 71% vs 64% placebo (odds ratio: 1.39; 95% CI: 0.88, 2.19), respectively; and the AQLQ(S) responder rates were 71% vs 55% placebo (odds ratio: 2.02; 95% CI: 1.24, 3.32) and 65% vs 55% placebo (odds ratio: 1.79; 95% CI: 1.13, 2.85), respectively.

Oral Corticosteroid Reduction in Asthma Trial (VENTURE)

VENTURE evaluated the effect of DUPIXENT on reducing the use of maintenance oral corticosteroids. The baseline mean oral corticosteroid dose was 12 mg in the placebo group and 11 mg in the group receiving DUPIXENT. The primary endpoint was the percent reduction from baseline of the final oral corticosteroid dose at Week 24 while maintaining asthma control.

Compared with placebo, subjects receiving DUPIXENT achieved greater reductions in daily maintenance oral corticosteroid dose, while maintaining asthma control. The mean percent reduction in daily OCS dose from baseline was 70% (median 100%) in subjects receiving DUPIXENT (95% CI: 60%, 80%) compared to 42% (median 50%) in subjects receiving placebo (95% CI: 33%, 51%). Reductions of 50% or higher in the OCS dose were observed in 82 (80%) subjects receiving DUPIXENT compared to 57 (53%) in those receiving placebo. The proportion of subjects with a mean final dose less than 5 mg at Week 24 was 72% for DUPIXENT and 37% for placebo (odds ratio 4.48 95% CI: 2.39, 8.39). A total of 54 (52%) subjects receiving DUPIXENT versus 31 (29%) subjects in the placebo group had a 100% reduction in their OCS dose.

In this 24-week trial, asthma exacerbations (defined as a temporary increase in oral corticosteroid dose for at least 3 days) were lower in subjects receiving DUPIXENT compared with those receiving placebo (annualized rate 0.65 and 1.60 for the DUPIXENT and placebo group, respectively; rate ratio 0.41 [95% CI 0.26, 0.63]) and improvement in pre-bronchodilator FEV₁from baseline to Week 24 was greater in subjects receiving DUPIXENT compared with those receiving placebo (LS mean difference for DUPIXENT versus placebo of 0.22 L [95% CI: 0.09 to 0.34 L]). Effects on lung function and on oral steroid and exacerbation reduction were similar irrespective of baseline blood eosinophil levels. The ACQ-5 and AQLQ(S) were also assessed in VENTURE and showed improvements similar to those in QUEST.

Pediatric Subjects 6 to 11 Years of Age with Asthma

The efficacy and safety of DUPIXENT in pediatric subjects was evaluated in a 52-week multicenter, randomized, double-blind, placebo-controlled study (VOYAGE; NCT02948959) in 408 subjects 6 to 11 years of age, with moderate-to-severe asthma on a medium or high-dose ICS and a second controller medication or high-dose ICS alone. Subjects were required to have a history of 1 or more asthma exacerbation(s) that required treatment with systemic corticosteroids or emergency department visit or hospitalization for the treatment of asthma in the year prior to trial entry. Subjects were randomized to DUPIXENT (N=273) or matching placebo (N=135) every 2 weeks based on body weight <30 kg (100 mg Q2W) or ≥30 kg (200 mg Q2W). The effectiveness of DUPIXENT 300 mg Q4W was extrapolated from efficacy of 100 mg Q2W in VOYAGE with support from population pharmacokinetic analyses showing higher drug exposure levels with 300 mg Q4W

[see Pediatric Use (8.4)] andPharmacokinetics (12.3)]

The primary endpoint was the annualized rate of severe asthma exacerbation events during the 52-week placebo-controlled period. Severe asthma exacerbations were defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or hospitalization or emergency room visit due to asthma that required systemic corticosteroids. The key secondary endpoint was the change from baseline in pre-bronchodilator FEV₁percent predicted at Week 12. Additional secondary endpoints included mean change from baseline and responder rates in the ACQ-7-IA (Asthma Control Questionnaire-7-Interviewer Administered) and PAQLQ(S)-IA (Pediatric Asthma Quality of Life Questionnaire with Standardized Activities Interviewer Administered) scores.

The demographics and baseline characteristics for VOYAGE are provided in Table 25 below.

Table 25: Demographics and Baseline Characteristics of Pediatric Subjects 6 to 11 Years of Age with Asthma (VOYAGE)

Parameter	VOYAGE (N=408)
ICS = inhaled corticosteroid; FEV1= Forced expiratory volume in 1 second; AD = atopic dermatitis; AR = allergic rhinitis; FeNO = fraction of exhaled nitric oxide
Mean age (years) (SD)	9 (2)
% Female	36
% White	88
Mean body weight (kg)	36
Mean exacerbations in previous year (± SD)	2.4 (2.2)
High dose ICS use (%)	44
Pre-dose FEV1(L) at baseline (± SD)	1.48 (0.41)
Mean percent predicted FEV1(%) (±SD)	78 (15)
Mean % Reversibility (± SD)	20 (21)
Atopic Medical History % Overall (AD %, AR %)	92 (36, 82)
Mean FeNO ppb (± SD)	28 (24)
% subjects with FeNO ppb ≥20	50
Median total IgE IU/mL (±SD)	792 (1093)
Mean baseline Eosinophil count (± SD) cells/mcL	502 (395)

DUPIXENT significantly reduced the annualized rate of severe asthma exacerbation events during the 52-week treatment period compared to placebo in populations with an eosinophilic phenotype as indicated by elevated blood eosinophils and/or the population with elevated FeNO. Subgroup analyses for results of DUPIXENT treatment based upon either baseline eosinophil level or baseline FeNO level were similar to the pediatric (12 to 17 years of age) and adult trials and are described for the adult and pediatric (12 to 17 years of age) asthma population above. In subjects with baseline blood eosinophil count <150 cells/mcL and FeNO <20 ppb, similar severe asthma exacerbation rates were observed between DUPIXENT and placebo.

Significant improvements in percent predicted pre-bronchodilator FEV₁were observed at Week 12. Significant improvements in percent predicted FEV₁were observed as early as Week 2 and were maintained through Week 52 in VOYAGE (Figure 10).

The efficacy results for VOYAGE are presented in Table 26.

Table 26: Efficacy Results of DUPIXENT in Pediatric Subjects 6 to 11 Years of Age with Asthma (VOYAGE)

Treatment	EOS ≥300 cells/mcLThis reflects the prespecified primary analysis population for VOYAGE in the United States.
Annualized Severe Exacerbations Rate over 52 Weeks
	N	Rate (95% CI)	Rate Ratio (95% CI)
DUPIXENT 100 mg Q2WThe effectiveness of DUPIXENT 300 mg Q4W was extrapolated from efficacy of 100 mg Q2W.(<30 kg)/ 200 mg Q2W (≥30 kg)	175	0.24 (0.16, 0.35)	0.35 (0.22, 0.56)
Placebo	84	0.67 (0.47, 0.95)
Mean Change from Baseline in Percent Predicted FEV1at Week 12
	N	LS mean Δ from Baseline	LS mean difference vs. Placebo (95% CI)
DUPIXENT 100 mg Q2W (<30 kg)/ 200 mg Q2W (≥30 kg)	168	10.15	5.32 (1.76, 8.88)
Placebo	80	4.83

Figure 10: Mean Change from Baseline in Percent Predicted Pre-bronchodilator FEV₁(L) Over Time in Pediatric Subjects 6 to 11 Years of Age in VOYAGE (Baseline Blood Eosinophils ≥300 cells/mcL)

Improvements were also observed for ACQ-7-IA and PAQLQ(S)-IA at Week 24 and were sustained at Week 52. Greater responder rates were observed for ACQ-7-IA and PAQLQ(S)-IA compared to placebo at Week 24. The responder rate was defined as an improvement in score of 0.5 or more (scale range 0-6 for ACQ-7-IA and 1-7 for PAQLQ(S)-IA). In the subgroup of subjects with baseline blood eosinophil count ≥300 cells/mcL, DUPIXENT led to a higher proportion of subjects with a response in ACQ-7-IA (80.6% versus 64.3% for placebo) with an OR of 2.79 (95% CI: 1.43, 5.44), and in PAQLQ(S)-IA (72.8% versus 63.0% for placebo) with an OR of 1.84 (95% CI: 0.92, 3.65) at Week 24.

Pediatric Subjects 12 to 17 Years of Age

:

A total of 107 pediatric subjects 12 to 17 years of age with moderate-to-severe asthma were enrolled in QUEST and received either 200 mg (N=21) or 300 mg (N=18) DUPIXENT (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) Q2W. Asthma exacerbations and lung function were assessed in both pediatric subjects 12 to 17 years of age and adults. For both the 200 mg and 300 mg Q2W doses, improvements in FEV₁(LS mean change from baseline at Week 12) were observed (0.36 L and 0.27 L, respectively). For the 200 mg Q2W dose, subjects had a reduction in the rate of severe exacerbations that was consistent with adults. Dupilumab exposure was higher in pediatric subjects 12 to 17 years of age than that in adults at the respective dose level which was mainly accounted for by difference in body weight

[see Clinical Pharmacology (12.3)]

The adverse event profile in pediatric subjects 12 to 17 years of age was generally similar to the adults

[see Adverse Reactions (6.1)]

Pediatric Subjects 6 to 11 Years of Age

:

A total of 408 pediatric subjects 6 to 11 years of age with moderate-to-severe asthma were enrolled in VOYAGE, which evaluated doses of 100 mg Q2W or 200 mg Q2W. Improvement in asthma exacerbations and lung function were demonstrated

[see Clinical Studies (14.2)]

The effectiveness of DUPIXENT 300 mg Q4W in subjects 6 to 11 years of age with body weight 15 to <30 kg was extrapolated from efficacy of 100 mg Q2W in VOYAGE with support from population pharmacokinetic analyses showing higher drug exposure levels with 300 mg Q4W

[see Clinical Pharmacology (12.3)]

Subjects who completed the treatment period of the VOYAGE study could participate in the open-label extension study (LTS14424). Eighteen subjects (≥15 to <30 kg) out of 365 subjects were exposed to 300 mg Q4W in this study, and the safety profile in these eighteen subjects was consistent with that seen in VOYAGE. Additional safety for DUPIXENT 300 mg Q4W is based upon available safety information from the pediatric AD indication

[see Adverse Reactions (6.1)] and[Clinical Pharmacology (12.3)]

Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 6 years of age with asthma.

CRSwNP

The safety and effectiveness of DUPIXENT for add-on maintenance treatment in patients with inadequately controlled chronic rhinosinusitis with nasal polyps (CRSwNP) have been established in pediatric patients aged 12 years and older. Use of DUPIXENT for this indication is supported by evidence from adequate and well-controlled studies of DUPIXENT as add-on maintenance treatment in adults with inadequately controlled CRSwNP (SINUS-24 and SINUS-52) with the following additional data:

• Pharmacokinetic (PK) data from adult and pediatric patients aged 12 years and older with moderate-to-severe asthma and adult patients with inadequately controlled CRSwNP
• Safety data in pediatric patients aged 12 years and older with moderate-to-severe asthma
  [see Adverse Reactions (6.1)] ,[Clinical Pharmacology (12.3)] , andClinical Studies (14.3)]

Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 12 years of age with CRSwNP.

EoE

The safety and effectiveness of DUPIXENT for the treatment of EoE have been established in pediatric subjects 1 year of age and older, weighing at least 15 kg. Use of DUPIXENT in this population is supported by an adequate well-controlled study in adults and 72 pediatric subjects 12 to 17 years of age (Study EoE-1), a clinical study in 61 pediatric subjects 1 to 11 years of age (Study EoE-2), and pharmacokinetic data in adult and pediatric subjects 1 to 17 years of age. The safety of DUPIXENT in pediatric subjects 1 to 17 years of age was similar to adults

[see Adverse Reactions (6.1)] ,[Clinical Pharmacology (12.3)] , andClinical Studies (14.4)]

Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 1 year of age, or weighing less than 15 kg, with EoE.

Prurigo Nodularis

Safety and effectiveness of DUPIXENT have not been established in pediatric patients with PN.

Chronic Obstructive Pulmonary Disease

The safety and effectiveness of DUPIXENT have not been established in pediatric patients with COPD. COPD is largely a disease of adult patients.

Chronic Spontaneous Urticaria

The safety and effectiveness of DUPIXENT for the treatment of CSU in patients who remain symptomatic despite H1 antihistamine treatment have been established in pediatric patients 12 years of age and older. The use of DUPIXENT in this indication is supported by evidence from two adequate and well-controlled studies in adults with additional pharmacokinetic data in 6 pediatric patients 12 years of age and older, and safety data in pediatric patients in other indications

[

see

[Dosage and Administration (2.9)]

,

[Clinical Pharmacology (12.3)]

, and

Clinical Studies (14.7)]

Safety and effectiveness of DUPIXENT have not been established in pediatric patients younger than 12 years of age, and/or weighing less than 30 kg, with CSU.

Bullous Pemphigoid

The safety and effectiveness of DUPIXENT have not been established in pediatric patients with BP. BP is largely a disease of adult patients.

and[Pharmacokinetics (12.3)]

The primary endpoint was the annualized rate of severe asthma exacerbation events during the 52-week placebo-controlled period. Severe asthma exacerbations were defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or hospitalization or emergency room visit due to asthma that required systemic corticosteroids. The key secondary endpoint was the change from baseline in pre-bronchodilator FEV₁percent predicted at Week 12. Additional secondary endpoints included mean change from baseline and responder rates in the ACQ-7-IA (Asthma Control Questionnaire-7-Interviewer Administered) and PAQLQ(S)-IA (Pediatric Asthma Quality of Life Questionnaire with Standardized Activities Interviewer Administered) scores.

The demographics and baseline characteristics for VOYAGE are provided in Table 25 below.

DUPIXENT significantly reduced the annualized rate of severe asthma exacerbation events during the 52-week treatment period compared to placebo in populations with an eosinophilic phenotype as indicated by elevated blood eosinophils and/or the population with elevated FeNO. Subgroup analyses for results of DUPIXENT treatment based upon either baseline eosinophil level or baseline FeNO level were similar to the pediatric (12 to 17 years of age) and adult trials and are described for the adult and pediatric (12 to 17 years of age) asthma population above. In subjects with baseline blood eosinophil count <150 cells/mcL and FeNO <20 ppb, similar severe asthma exacerbation rates were observed between DUPIXENT and placebo.

Significant improvements in percent predicted pre-bronchodilator FEV₁were observed at Week 12. Significant improvements in percent predicted FEV₁were observed as early as Week 2 and were maintained through Week 52 in VOYAGE (Figure 10).

The efficacy results for VOYAGE are presented in Table 26.

Improvements were also observed for ACQ-7-IA and PAQLQ(S)-IA at Week 24 and were sustained at Week 52. Greater responder rates were observed for ACQ-7-IA and PAQLQ(S)-IA compared to placebo at Week 24. The responder rate was defined as an improvement in score of 0.5 or more (scale range 0-6 for ACQ-7-IA and 1-7 for PAQLQ(S)-IA). In the subgroup of subjects with baseline blood eosinophil count ≥300 cells/mcL, DUPIXENT led to a higher proportion of subjects with a response in ACQ-7-IA (80.6% versus 64.3% for placebo) with an OR of 2.79 (95% CI: 1.43, 5.44), and in PAQLQ(S)-IA (72.8% versus 63.0% for placebo) with an OR of 1.84 (95% CI: 0.92, 3.65) at Week 24.

A single randomized, double-blind, parallel-group, multicenter, placebo-controlled trial, including two 24-week treatment periods (Study EoE-1 Parts A and B) was conducted in adult and pediatric subjects 12 years of age and older, weighing at least 40 kg, with EoE (NCT03633617). In both parts, subjects were randomized to receive 300 mg DUPIXENT every week or placebo. Eligible subjects had ≥15 intraepithelial eosinophils per high-power field (eos/hpf) following a treatment course of a proton pump inhibitor (PPI) either prior to or during the screening period and symptoms of dysphagia as measured by the Dysphagia Symptom Questionnaire (DSQ). At baseline, 43% of subjects in Part A and 37% of subjects in Part B had a history of prior esophageal dilations.

Demographics and baseline characteristics were similar in Parts A and B. A total of 81 subjects (61 adults and 20 pediatric subjects) were enrolled in Part A and 159 subjects (107 adults and 52 pediatric subjects) were enrolled in Part B. The mean age in years was 32 years (range 13 to 62 years) in Part A and 28 years (range 12 to 66 years) in Part B. The majority of subjects were male (60% in Part A and 68% in Part B) and White (96% in Part A and 90% in Part B). The mean baseline DSQ score (SD) was 33.6 (12.4) in Part A and 37.2 (10.7) in Part B.

The coprimary efficacy endpoints in Parts A and B were the (1) proportion of subjects achieving histological remission defined as peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at Week 24; and (2) the absolute change in the subject-reported DSQ score from baseline to Week 24.

Efficacy results for Parts A and B are presented in Table 29.

In Parts A and B, a greater proportion of subjects randomized to DUPIXENT achieved histological remission (peak esophageal intraepithelial eosinophil count ≤6 eos/hpf) compared to placebo. Treatment with DUPIXENT also resulted in a significant improvement in LS mean change in DSQ score compared to placebo at Week 24. The results of the anchor-based analyses that incorporated the subjects' perspectives indicated that the observed improvement in dysphagia from Parts A and B is representative of a clinically meaningful within-subject improvement.

The efficacy and safety of DUPIXENT was evaluated in pediatric subjects 1 to 11 years of age, weighing at least 15 kg, with EoE in a randomized, blinded, parallel-group, multicenter trial (Study EoE-2 Parts A and B; NCT04394351). Eligible subjects had ≥15 intraepithelial eosinophils per high-power field (eos/hpf) despite a treatment course of a proton pump inhibitor (PPI) either prior to or during the screening period and a history of EoE signs and symptoms. Part A evaluated weight-based dosing regimens of DUPIXENT, 200 mg Q2W (≥15 to <30 kg) and 300 mg Q2W (≥30 to <60 kg), or placebo in 61 subjects during the 16-week treatment period.

The recommended dosage of 300 mg QW for pediatric subjects 1 to 11 years of age weighing ≥40 kg is based on modeled pharmacokinetic data to provide comparable exposures to the 300 mg QW dosage in adult and pediatric subjects 12 years of age and older weighing ≥40 kg with EoE

Forty-seven subjects who completed Part A were evaluated in the 36-week extended active treatment period (Study EoE-2 Part B). All subjects in Part B were treated with the weight-based dosing regimens of DUPIXENT described for Part A.

Of the total subjects evaluated in Part A, the mean age was 8 years, the median weight was 28 kg, and 75% were male. Seven percent identified as Hispanic or Latino; 85% identified as White, 12% as Black, 2% as Asian, and 2% identified as another racial subgroup.

The primary efficacy endpoint in Part A was the proportion of subjects achieving histological remission defined as peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at Week 16.

Efficacy results for Part A are presented in Table 30.

In Part B, histological remission was achieved at Week 52 in 17/32 subjects treated with DUPIXENT in Parts A and B and 8/15 subjects treated with placebo in Part A and DUPIXENT in Part B.

In Study EoE-2 Part A, an observer-reported outcome, the Pediatric EoE Sign/Symptom Questionnaire-Caregiver (PESQ-C), was used to measure signs of EoE. A greater decrease in the proportion of days with 1 or more signs of EoE (based on the PESQ-C) was observed for subjects treated with DUPIXENT compared to placebo after 16 weeks of treatment.

The primary endpoint for BOREAS and NOTUS trials was the annualized rate of moderate or severe COPD exacerbations during the 52-week treatment period. In both trials, DUPIXENT demonstrated a significant reduction in the annualized rate of moderate or severe COPD exacerbations compared to placebo when added to background maintenance therapy (see

Treatment with DUPIXENT decreased the risk of a moderate to severe COPD exacerbation as measured by time to first exacerbation when compared with placebo in BOREAS (HR: 0.80; 95% CI: 0.66, 0.98) and NOTUS (HR: 0.71; 95% CI: 0.57, 0.89).

In both trials (BOREAS and NOTUS), DUPIXENT demonstrated numerical improvement in post-bronchodilator FEV₁at Weeks 12 and 52 compared to placebo when added to background maintenance therapy (see

Figure 17: LS Mean Change from Baseline in Post-Bronchodilator FEV1(mL) Over Time in BOREAS and NOTUSEfficacy results for mean change from baseline in post-bronchodilator FEV1over time are presented for 721 out of 935 subjects who completed the 52-week treatment period or had discontinued the trial at the time of data analysis.Trials for COPD
BOREAS	NOTUS

In both trials (BOREAS and NOTUS), the St. George's Respiratory Questionnaire (SGRQ) total score responder rate (defined as the proportion of subjects with SGRQ improvement from baseline of at least 4 points) at Week 52 was evaluated. In BOREAS, the responder rate was 51% for subjects treated with DUPIXENT versus 43% for placebo (N=939, odds ratio: 1.44; 95% CI: 1.10, 1.89). In NOTUS, the responder rate was 51% for subjects treated with DUPIXENT versus 47% for placebo (N=721, odds ratio: 1.16; 95% CI: 0.86, 1.58).

A total of 284 adult and pediatric patients 12 years of age and older with CSU (Itch Severity Score over 7 days (ISS7) ≥8 on a scale of 0 to 21 and Urticaria Activity Score over 7 days (UAS7) ≥16 on a scale of 0 to 42) who were symptomatic despite the use of H1 antihistamines, but who were anti-IgE treatment naïve, were enrolled in CUPID Study A and Study C. In the DUPIXENT group, adults and pediatric subjects (12 years of age and older) weighing ≥60 kg received a subcutaneous dose of DUPIXENT 600 mg on Day 1, followed by 300 mg every 2 weeks (Q2W), while pediatric subjects (12 years of age and older) weighing 30 kg to less than 60 kg received a subcutaneous dose of DUPIXENT 400 mg on Day 1, followed by 200 mg Q2W. The demographics and baseline characteristics of the efficacy population in CUPID Study A and Study C are provided in Table 35.

The primary endpoint was change from baseline in itch severity score over 7 days (ISS7) at Week 24. The ISS7 score was defined as the sum of the daily itch severity scores (ISS), from 0 to 3, recorded at the same time of the day for a 7-day period, ranging from 0 to 21.

The key secondary endpoint was change from baseline in urticaria activity score over 7 days (UAS7) at Week 24. The UAS7 (range 0 to 42) was a composite of the weekly itch severity score (ISS7, range 0 to 21) and the weekly hive count score (HSS7, range 0 to 21).

The results for primary and secondary endpoints in CUPID Study A and Study C are presented in Table 36.

CUPID Study A showed significant improvement in ISS7 and UAS7 from baseline at Week 12 in the DUPIXENT group (LS mean difference DUPIXENT versus placebo of -2.53 [95% CI: (-4.79, -0.27)] for ISS7 and -5.44 [95% CI: (-9.77, -1.11)] for UAS7). The proportion of patients with UAS7 ≤6 at Week 12 in CUPID Study A was 35.3% in the DUPIXENT group and 17.6% in the placebo group (Odds Ratio: 2.79 [95% CI: (1.22, 6.40)]).

Mean changes in ISS7 over time in CUPID Study A and Study C are shown in Figure 18.

Figure 18: LS Mean Change from Baseline in ISS7 Over 24 Weeks in CUPID Study A and Study C
Study A	Study C

Similar changes in UAS7 and HSS7 were observed over 24 weeks.

Improvements in ISS7 and UAS7 at Week 24 were consistent regardless of the patients' baseline IgE level.

CUPID Study B enrolled 108 adult and pediatric patients 12 years of age and older with CSU who were inadequate responders (N=104) to H1 antihistamines and anti-IgE treatments or intolerant (N=4) to anti-IgE therapy. At baseline, the mean ISS7 was 16, mean UAS7 score was 31.5 and the mean HSS7 was 15.4. The majority of participants (69.4%) had a UAS7 score of ≥28 at baseline. The median (Q1, Q3) total IgE (IU/mL) at baseline was 77 (20, 204.5). CUPID Study B evaluated efficacy using the same primary and secondary endpoints as CUPID Study A and Study C. The DUPIXENT group in CUPID Study B did not meet statistical significance for reduction in the primary endpoint ISS7 at Week 24.