14 CLINICAL STUDIES

14.1 Atopic Dermatitis

Adults with Atopic Dermatitis

Three randomized, double-blind, placebo-controlled trials (SOLO 1 (NCT02277743), SOLO 2 (NCT02277769), and CHRONOS (NCT02260986)) enrolled a total of 2119 adult subjects 18 years of age and older 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, 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 (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.

Clinical Response at Week 16 (SOLO 1, SOLO 2, and CHRONOS)

The results of the DUPIXENT monotherapy trials (SOLO 1 and SOLO 2) and the DUPIXENT with concomitant TCS trial (CHRONOS) are presented in Table 12.

Table 12: Efficacy Results of DUPIXENT with or without Concomitant TCS at Week 16 (FAS) in Adult Subjects 18 Years of Age and Older with Moderate-to-Severe AD
	SOLO 1		SOLO 2		CHRONOS
	DUPIXENT 300 mg Q2W	Placebo	DUPIXENT 300 mg Q2W	Placebo	DUPIXENT 300 mg Q2W + TCS	Placebo + TCS
* Full Analysis Set (FAS) includes all subjects randomized. † Responder was defined as a subject with an IGA 0 or 1 ("clear" or "almost clear") and a reduction of ≥2 points on a 0-4 IGA scale. ‡ Subjects who received rescue treatment or with missing data were considered as non-responders.
Number of subjects randomized (FAS)*	224	224	233	236	106	315
IGA 0 or 1†,‡	38%	10%	36%	9%	39%	12%
EASI-75‡	51%	15%	44%	12%	69%	23%
EASI-90‡	36%	8%	30%	7%	40%	11%
Number of subjects with baseline Peak Pruritus NRS score ≥4	213	212	225	221	102	299
Peak Pruritus NRS (≥4-point improvement)‡	41%	12%	36%	10%	59%	20%

Figure 1: Proportion of Adult Subjects 18 Years of Age and Older with Moderate-to-Severe AD with ≥4-point Improvement on the Peak Pruritus NRS in SOLO 1* and SOLO 2* Studies (FAS)†
SOLO 1	SOLO 2
* In the primary analyses of the efficacy endpoints, subjects who received rescue treatment or with missing data were considered non-responders. † Full Analysis Set (FAS) includes all subjects randomized.

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 13.

Table 13: Efficacy Results (IGA 0 or 1) of DUPIXENT with Concomitant TCS at Week 16 and 52 in Adult Subjects 18 Years of Age and Older with Moderate-to-Severe AD
	DUPIXENT 300 mg Q2W + TCS	Placebo + TCS
* In CHRONOS, of the 421 randomized and treated subjects, 68 subjects (16%) had not been on study for 52 weeks at the time of data analysis. † Responder was defined as a subject with an IGA 0 or 1 ("clear" or "almost clear") and a reduction of ≥2 points on a 0-4 IGA scale. ‡ Subjects who received rescue treatment or with missing data were considered as non-responders.
Number of Subjects*	89	264
Responder†,‡ at Week 16 and 52	22%	7%
Responder at Week 16 but Non-responder at Week 52	20%	7%
Non-responder at Week 16 and Responder at Week 52	13%	6%
Non-responder at Week 16 and 52	44%	80%
Overall Responder†,‡ Rate at Week 52	36%	13%

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.

Pediatric Subjects 12 to 17 Years of Age with Atopic Dermatitis

The efficacy of DUPIXENT monotherapy in pediatric subjects 12 to 17 years of age 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 14.

Table 14: Efficacy Results of DUPIXENT in AD-1526 at Week 16 (FAS)* in Pediatric Subjects 12 to 17 Years of Age with Moderate-to-Severe AD
	DUPIXENT† 200 mg (<60 kg) or 300 mg (≥60 kg) Q2W N=82*	Placebo N=85*
* Full Analysis Set (FAS) includes all subjects randomized. † At Week 0, subjects received 400 mg (baseline weight <60 kg) or 600 mg (baseline weight ≥60 kg) of DUPIXENT. ‡ Responder was defined as a subject with an IGA 0 or 1 ("clear" or "almost clear") and a reduction of ≥2 points on a 0-4 IGA scale. § Subjects who received rescue treatment or with missing data were considered as non-responders (59% and 21% in the placebo and DUPIXENT arms, respectively).
IGA 0 or 1‡,§	24%	2%
EASI-75§	42%	8%
EASI-90§	23%	2%
Peak Pruritus NRS (≥4-point improvement)§	37%	5%

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.

Figure 2: Proportion of Pediatric Subjects 12 to 17 Years of Age with Moderate-to-Severe AD with ≥4-point Improvement on the Peak Pruritus NRS in AD-1526* (FAS)†
* In the primary analyses of the efficacy endpoints, subjects who received rescue treatment or with missing data were considered non-responders. † Full Analysis Set (FAS) includes all subjects randomized.

Pediatric Subjects 6 to 11 Years of Age with Atopic Dermatitis

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

Table 15: Efficacy Results of DUPIXENT with Concomitant TCS in AD-1652 at Week 16 (FAS)* in Pediatric Subjects 6 to 11 Years of Age with AD
	DUPIXENT 300 mg Q4W† + TCS	Placebo + TCS	DUPIXENT 200 mg Q2W‡ + TCS	Placebo + TCS
	(N=61)	(N=61)	(N=59)	(N=62)
	<30 kg	<30 kg	≥30 kg	≥30 kg
* Full Analysis Set (FAS) includes all subjects randomized. † At Day 1, subjects received 600 mg of DUPIXENT. ‡ At Day 1, subjects received 200 mg (baseline weight <30 kg) or 400 mg (baseline weight ≥30 kg) of DUPIXENT. § Responder was defined as a subject with an IGA 0 or 1 ("clear" or "almost clear"). ¶ Subjects who received rescue treatment or with missing data were considered as non-responders.
IGA 0 or 1§,¶	30%	13%	39%	10%
EASI-75¶	75%	28%	75%	26%
EASI-90¶	46%	7%	36%	8%
Peak Pruritus NRS (≥4-point improvement)¶	54%	12%	61%	13%

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.

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-1652* (FAS)†
* In the primary analyses of the efficacy endpoints, subjects who received rescue treatment or with missing data were considered non-responders. † Full Analysis Set (FAS) includes all subjects randomized.

Pediatric Subjects 6 Months to 5 Years of Age with Atopic Dermatitis

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 16.

Table 16: Efficacy Results of DUPIXENT with Concomitant TCS in AD-1539 at Week 16 (FAS)* in Pediatric Subjects 6 Months to 5 Years of Age with Moderate-to-Severe AD
	DUPIXENT + TCS 200 mg (5 to <15 kg) or 300 mg (15 to <30 kg) Q4W†	Placebo + TCS	Difference vs. Placebo (95 % CI)
	(N=83)*	(N=79)*
CI = confidence interval
* Full Analysis Set (FAS) includes all subjects randomized. † At Day 1, subjects received 200 mg (5 to <15 kg) or 300 mg (15 to <30 kg) of DUPIXENT. ‡ Responder was defined as a subject with an IGA 0 or 1 ("clear" or "almost clear"). § Subjects who received rescue treatment (63% and 19% in the placebo and DUPIXENT arms, respectively) or with missing data were considered as non-responders.
IGA 0 or 1‡,§	28%	4%	24% (13%, 34%)
EASI-75§	53%	11%	42% (29%, 55%)
EASI-90§	25%	3%	23% (12%, 33%)
Worst Scratch/Itch NRS (≥4-point improvement)§	48%	9%	39% (26%, 52%)

Atopic Dermatitis with Hand and/or Foot Involvement

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 [see Dosage and Administration (2.3)]. Subjects were not allowed concomitant use of topical treatments for AD on the hands and feet during the trial, but were allowed the use of topical treatments for AD on other parts of the body with certain restrictions.

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 17.

Table 17: Efficacy Results of DUPIXENT in Liberty-AD-HAFT at Week 16 (FAS)* in Adult and Pediatric Subjects 12 to 17 Years of Age with AD with Moderate-to-Severe Hand and/or Foot Involvement
	DUPIXENT 200/300 mg Q2W†	Placebo	Difference vs. Placebo (95 % CI)
	(N=67)*	(N=66)*
CI = confidence interval
* Full Analysis Set (FAS) includes all subjects randomized. † Adults received a loading dose of DUPIXENT 600 mg SC followed by 300 mg SC Q2W. Pediatric subjects 12 to 17 years of age received a loading dose of DUPIXENT 600 mg SC followed by 300 mg SC Q2W (for body weight ≥60 kg) or a loading dose of DUPIXENT 400 mg SC followed by 200 mg SC Q2W (for body weight <60 kg). ‡ Responder was defined as a subject with an IGA 0 or 1 ("clear" or "almost clear"). § Subjects who received rescue treatment (21% and 3% in the placebo and DUPIXENT arms, respectively) or with missing data were considered as non-responders.
IGA (hand and foot) 0 or 1‡,§	40%	17%	24% (9%, 38%)
Improvement (reduction) of weekly averaged hand and foot Peak Pruritus NRS ≥4§	52%	14%	39% (24%, 53%)

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 other week (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 FEV1 and 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 FEV1 at Week 12 in the overall population (unrestricted by minimum baseline blood eosinophils count). Additional secondary endpoints included annualized severe exacerbation rates and FEV1 in 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 18 below.

Table 18: 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 FEV1 at 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 19.

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 19: Rate of Severe Exacerbations in Asthma Trials (DRI12544 and QUEST)
Trial	Treatment	Baseline Blood EOS ≥300 cells/mcL (primary analysis population, DRI12544)
Trial	Treatment	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 FEV1 were 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 FEV1 LS 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 20.

Improvements in FEV1 by 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 FEV1 were observed between DUPIXENT and placebo.

Mean changes in FEV1 over time in QUEST are shown in Figure 9.

Table 20: Mean Change from Baseline and Difference vs Placebo in Pre-Bronchodilator FEV1 at Week 12 in Subjects with Moderate-to-Severe Asthma (DRI12544 and QUEST)
Trial	Treatment	Baseline Blood EOS ≥300 cells/mcL (primary analysis population, DRI12544)
Trial	Treatment	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 FEV1 across 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 FEV1 across 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 FEV1 from 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 other week 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) 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 FEV1 percent 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 21 below.

Table 21: 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 FEV1 were observed at Week 12. Significant improvements in percent predicted FEV1 were 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 22.

Table 22: Efficacy Results of DUPIXENT in Pediatric Subjects 6 to 11 Years of Age with Asthma (VOYAGE)
Treatment	EOS ≥300 cells/mcL*
* This reflects the prespecified primary analysis population for VOYAGE in the United States. † The effectiveness of DUPIXENT 300 mg Q4W was extrapolated from efficacy of 100 mg Q2W.
Annualized Severe Exacerbations Rate over 52 Weeks
	N	Rate (95% CI)	Rate Ratio (95% CI)
DUPIXENT 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 FEV1 at 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.

14.3 Chronic Rhinosinusitis with Nasal Polyps

The efficacy of DUPIXENT as an add-on maintenance treatment in adults with inadequately controlled chronic rhinosinusitis with nasal polyps (CRSwNP) was evaluated in two randomized, double-blind, parallel-group, multicenter, placebo-controlled studies (SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454)) in 724 adult subjects 18 years of age and older on background intranasal corticosteroids (INCS). These studies included subjects with CRSwNP despite prior sino-nasal surgery or treatment with, or who were ineligible to receive or were intolerant to, systemic corticosteroids in the past 2 years. Subjects with chronic rhinosinusitis without nasal polyps were not included in these trials. Rescue with systemic corticosteroids or surgery was allowed during the studies at the investigator's discretion. In SINUS-24, a total of 276 subjects were randomized to receive either 300 mg DUPIXENT (N=143) or placebo (N=133) every other week for 24 weeks. In SINUS-52, 448 subjects were randomized to receive either 300 mg DUPIXENT (N=150) every other week for 52 weeks, 300 mg DUPIXENT (N=145) every other week until Week 24 followed by 300 mg DUPIXENT every 4 weeks until Week 52, or placebo (N=153). All subjects had evidence of sinus opacification on the Lund Mackay (LMK) sinus CT scan and 73% to 90% of subjects had opacification of all sinuses. Subjects were stratified based on their histories of prior surgery and co-morbid asthma/nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NSAID-ERD). A total of 63% of subjects reported previous sinus surgery, with a mean number of 2.0 prior surgeries, 74% used systemic corticosteroids in the previous 2 years with a mean number of 1.6 systemic corticosteroid courses in the previous 2 years, 59% had co-morbid asthma, and 28% had NSAID-ERD.

The co-primary efficacy endpoints were change from baseline to Week 24 in bilateral endoscopic nasal polyps score (NPS; 0-8 scale) as graded by central blinded readers, and change from baseline to Week 24 in nasal congestion/obstruction score averaged over 28 days (NC; 0-3 scale), as determined by subjects using a daily diary. For NPS, polyps on each side of the nose were graded on a categorical scale (0=no polyps; 1=small polyps in the middle meatus not reaching below the inferior border of the middle turbinate; 2=polyps reaching below the lower border of the middle turbinate; 3=large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate; 4=large polyps causing complete obstruction of the inferior nasal cavity). The total score was the sum of the right and left scores. Nasal congestion was rated daily by the subjects on a 0 to 3 categorical severity scale (0=no symptoms; 1=mild symptoms; 2=moderate symptoms; 3=severe symptoms).

In both studies, key secondary end-points at Week 24 included change from baseline in: LMK sinus CT scan score, daily loss of smell, and 22-item sino-nasal outcome test (SNOT-22). The LMK sinus CT scan score evaluated the opacification of each sinus using a 0 to 2 scale (0=normal; 1=partial opacification; 2=total opacification) deriving a maximum score of 12 per side and a total maximum score of 24 (higher scores indicate more opacification). Loss of smell was scored reflectively by the subject every morning on a 0-3 scale (0=no symptoms, 1=mild symptoms, 2=moderate symptoms, 3=severe symptoms). SNOT-22 includes 22 items assessing symptoms and symptom impact associated with CRSwNP with each item scored from 0 (no problem) to 5 (problem as bad as it can be) with a global score ranging from 0 to 110. SNOT-22 had a 2 week recall period. In the pooled efficacy results, the reduction in the proportion of subjects rescued with systemic corticosteroids and/or sino-nasal surgery (up to Week 52) were evaluated.

The demographics and baseline characteristics of these 2 trials are provided in Table 23 below.

Table 23: Demographics and Baseline Characteristics of Adult Subjects in CRSwNP Trials
Parameter	SINUS-24 (N=276)	SINUS-52 (N=448)
SD = standard deviation; AM = morning; NPS = nasal polyps score; SNOT-22 = 22-item sino-nasal outcome test; NSAID-ERD = asthma/nonsteroidal anti-inflammatory drug exacerbated respiratory disease
* Higher scores indicate greater disease severity
Mean age (years) (SD)	50 (13)	52 (12)
% Male	57	62
Mean CRSwNP duration (years) (SD)	11 (9)	11 (10)
Subjects with ≥1 prior surgery (%)	72	58
Subjects with systemic corticosteroid use in the previous 2 years (%)	65	80
Mean Bilateral endoscopic NPS* (SD), range 0-8	5.8 (1.3)	6.1 (1.2)
Mean Nasal congestion (NC) score* (SD), range 0-3	2.4 (0.6)	2.4 (0.6)
Mean LMK sinus CT total score* (SD), range 0-24	19 (4.4)	18 (3.8)
Mean loss of smell score *(AM), (SD) range 0-3	2.7 (0.5)	2.8 (0.5)
Mean SNOT-22 total score* (SD), range 0-110	49.4 (20.2)	51.9 (20.9)
Mean blood eosinophils (cells/mcL) (SD)	440 (330)	430 (350)
Mean total IgE IU/mL (SD)	212 (276)	240 (342)
Atopic Medical History % Overall	75	82
Asthma (%)	58	60
NSAID-ERD (%)	30	27

Clinical Response (SINUS-24 and SINUS-52)

The results for primary endpoints in CRSwNP studies are presented in Table 24.

Table 24: Results of the Primary Endpoints in CRSwNP Trials
	SINUS-24					SINUS-52
	Placebo (n=133)		DUPIXENT 300 mg Q2W (n=143)		LS mean difference vs. Placebo (95% CI)	Placebo (n=153)		DUPIXENT 300 mg Q2W (n=295)		LS mean difference vs. Placebo (95% CI)
Primary Endpoints at Week 24
Scores	Baseline mean	LS mean change	Baseline mean	LS mean change		Baseline mean	LS mean change	Baseline mean	LS mean change
A reduction in score indicates improvement. NPS = nasal polyps score; NC = nasal congestion/obstruction
NPS	5.86	0.17	5.64	-1.89	-2.06 (-2.43, -1.69)	5.96	0.10	6.18	-1.71	-1.80 (-2.10, -1.51)
NC	2.45	-0.45	2.26	-1.34	-0.89 (-1.07, -0.71)	2.38	-0.38	2.46	-1.25	-0.87 (-1.03, -0.71)

Statistically significant efficacy was observed in SINUS-52 with regard to improvement in bilateral endoscopic NPS score at week 24 and week 52 (see Figure 11).

Figure 11: LS Mean Change from Baseline in Bilateral Nasal Polyps Score (NPS) up to Week 52 in Subjects 18 Years of Age and Older with CRSwNP (SINUS-52 - ITT Population)

Similar results were seen in SINUS-24 at Week 24. In the post-treatment period when subjects were off DUPIXENT, the treatment effect diminished over time (see Figure 12).

Figure 12: LS Mean Change from Baseline in Bilateral Nasal Polyps Score (NPS) up to Week 48 in Subjects 18 Years of Age and Older with CRSwNP (SINUS-24 - ITT Population)

At Week 52, the LS mean difference for nasal congestion in the DUPIXENT group versus placebo was -0.98 (95% CI -1.17, -0.79). In both studies, significant improvements in nasal congestion were observed as early as the first assessment at Week 4. The LS mean difference for nasal congestion at Week 4 in the DUPIXENT group versus placebo was -0.41 (95% CI: -0.52, -0.30) in SINUS-24 and -0.37 (95% CI: -0.46, -0.27) in SINUS-52.

A significant decrease in the LMK sinus CT scan score was observed. The LS mean difference for LMK sinus CT scan score at Week 24 in the DUPIXENT group versus placebo was -7.44 (95% CI: -8.35, -6.53) in SINUS-24 and -5.13 (95% CI: -5.80, -4.46) in SINUS-52. At Week 52, in SINUS-52 the LS mean difference for LMK sinus CT scan score in the DUPIXENT group versus placebo was -6.94 (95% CI: -7.87, -6.01).

Dupilumab significantly improved the loss of smell compared to placebo. The LS mean difference for loss of smell at Week 24 in the DUPIXENT group versus placebo was -1.12 (95% CI: -1.31, -0.93) in SINUS-24 and -0.98 (95% CI: -1.15, -0.81) in SINUS-52. At Week 52, the LS mean difference for loss of smell in the DUPIXENT group versus placebo was -1.10 (95% CI -1.31, -0.89). In both studies, significant improvements in daily loss of smell severity were observed as early as the first assessment at Week 4.

Dupilumab significantly decreased sino-nasal symptoms as measured by SNOT-22 compared to placebo. The LS mean difference for SNOT-22 at Week 24 in the DUPIXENT group versus placebo was -21.12 (95% CI: -25.17, -17.06) in SINUS-24 and -17.36 (95% CI: -20.87, -13.85) in SINUS-52. At Week 52, the LS mean difference in the DUPIXENT group versus placebo was -20.96 (95% CI -25.03, -16.89).

In the pre-specified multiplicity-adjusted pooled analysis of two studies, treatment with DUPIXENT resulted in significant reduction of systemic corticosteroid use and need for sino-nasal surgery versus placebo (HR of 0.24; 95% CI: 0.17, 0.35) (see Figure 13). The proportion of subjects who required systemic corticosteroids was reduced by 74% (HR of 0.26; 95% CI: 0.18, 0.38). The total number of systemic corticosteroid courses per year was reduced by 75% (RR of 0.25; 95% CI: 0.17, 0.37). The proportion of subjects who required surgery was reduced by 83% (HR of 0.17; 95% CI: 0.07, 0.46).

Figure 13: Kaplan Meier Curve for Time to First Systemic Corticosteroid Use and/or Sino-Nasal Surgery During Treatment Period in Subjects 18 Years of Age and Older with CRSwNP (SINUS-24 and SINUS-52 Pooled - ITT Population)

The effects of DUPIXENT on the primary endpoints of NPS and nasal congestion and the key secondary endpoint of LMK sinus CT scan score were consistent in subjects with prior surgery and without prior surgery.

In subjects with co-morbid asthma, improvements in pre-bronchodilator FEV1 were similar to subjects in the asthma program.

14.4 Eosinophilic Esophagitis

Adult and Pediatric Subjects 12 Years of Age and Older with EoE

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 25.

Table 25: Efficacy Results of DUPIXENT at Week 24 in Adult and Pediatric Subjects 12 Years of Age and Older with EoE (Study EoE-1 Parts A and B)
	Study EoE-1 Part A			Study EoE-1 Part B
	DUPIXENT 300 mg QW*	Placebo*	Difference vs. Placebo (95% CI)*	DUPIXENT 300 mg QW*	Placebo*	Difference vs. Placebo (95% CI)*
	N = 42	N = 39		N = 80	N = 79
* For histological remission, the difference in percentages is estimated using the Cochran Mantel Haenszel method, adjusting for randomization stratification factors. For absolute change in DSQ score, the LS mean changes, standard errors, and differences are estimated using an ANCOVA model with treatment group, randomization stratification factors, and baseline measurement as covariates. † Total biweekly DSQ scores range from 0 to 84; higher scores indicate greater frequency and severity of dysphagia
Co-primary Endpoints
Proportion of subjects achieving histological remission (peak esophageal intraepithelial eosinophil count ≤6 eos/hpf), n (%)	25 (59.5)	2 (5.1)	57.0 (40.9, 73.1)	47 (58.8)	5 (6.3)	53.5 (41.2, 65.8)
Absolute change from baseline in DSQ score (0-84†), LS mean (SE)	-21.9 (2.5)	-9.6 (2.8)	-12.3 (-19.1, -5.5)	-23.8 (1.9)	-13.9 (1.9)	-9.9 (-14.8, -5.0)

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.

Pediatric Subjects 1 to 11 Years of Age, Weighing at Least 15 kg, with EoE

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 [see Dosage and Administration (2.6) and Pharmacokinetics (12.3)].

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 26.

Table 26: Efficacy Results of DUPIXENT at Week 16 in Subjects 1 to 11 Years of Age with EoE, Weighing at Least 15 kg (Study EoE-2 Part A)
	DUPIXENT* N=32	Placebo N=29	Difference vs Placebo (95% CI)
* DUPIXENT was evaluated at tiered dosing regimens based on body weight: ≥15 to <30 kg (200 mg Q2W) and ≥30 to <60 kg (300 mg Q2W). The 300 mg Q2W dosing regimen is lower than the recommended dosage of DUPIXENT in subjects ≥40 kg [see Dosage and Administration (2.6)]. † The difference in percentages is estimated using the Mantel-Haenszel method, adjusting for baseline weight group (≥15 to <30 kg and ≥30 to <60 kg).
Proportion of subjects achieving histological remission (peak esophageal intraepithelial eosinophil count ≤6 eos/hpf), n (%)†	21 (65.6)	1 (3.4)	62.0 (44.00, 79.95)

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.

14.5 Prurigo Nodularis

The prurigo nodularis (PN) development program included two 24-week randomized, double-blind, placebo-controlled, multicenter, parallel-group trials (PRIME (NCT04183335) and PRIME 2 (NCT04202679)) in 311 adult subjects 18 years of age and older with pruritus (WI-NRS ≥ 7 on a scale of 0 to 10) and greater than or equal to 20 nodular lesions. PRIME and PRIME 2 assessed the effect of DUPIXENT on pruritus improvement as well as its effect on PN lesions.

In these two trials, subjects received either subcutaneous DUPIXENT 600 mg (two 300 mg injections) on day 1, followed by 300 mg once every other week (Q2W) for 24 weeks, or matching placebo.

In these trials, the mean age was 49.5 years, the median weight was 71 kg, 65% of subjects were female, 57% were White, 6% were Black, and 34% were Asian. At baseline, the mean Worst Itch-Numeric Rating Scale (WI-NRS) was 8.5, 66% had 20 to 100 nodules (moderate), and 34% had greater than 100 nodules (severe). Eleven percent (11%) of subjects were taking stable doses of antidepressants at baseline and were instructed to continue taking these medications during the trial. Forty-three percent (43%) had a history of atopy (defined as having a medical history of AD, allergic rhinitis/rhinoconjunctivitis, asthma, or food allergy).

The WI-NRS is comprised of a single item, rated on a scale from 0 ("no itch") to 10 ("worst imaginable itch"). Subjects were asked to rate the intensity of their worst pruritus (itch) over the past 24 hours using this scale. The Investigator's Global Assessment for Prurigo Nodularis-Stage (IGA PN-S) is a scale that measures the approximate number of nodules using a 5-point scale from 0 (clear) to 4 (severe).

Efficacy was assessed with the proportion of subjects with improvement (reduction) in WI-NRS by ≥4 points, the proportion of subjects with IGA PN-S 0 or 1 (the equivalent of 0-5 nodules), and the proportion of subjects who achieved a response in both WI-NRS and IGA PN-S per the criteria described above.

The efficacy results for PRIME and PRIME2 are presented in Table 27 and Figures 14, 15, and 16.

Table 27: Efficacy Results of DUPIXENT in Adult Subjects with PN in PRIME and PRIME2
	PRIME			PRIME2
	Placebo (N=76)	DUPIXENT 300 mg Q2W (N=75)	Difference (95% CI) for DUPIXENT vs. Placebo	Placebo (N=82)	DUPIXENT 300 mg Q2W (N=78)	Difference (95% CI) for DUPIXENT vs. Placebo
* Subjects who received rescue treatment earlier or had missing data were considered as non-responders. † Not adjusted for multiplicity in PRIME.
Proportion of subjects with both an improvement (reduction) in WI-NRS by ≥4 points from baseline to Week 24 and an IGA PN-S 0 or 1 at Week 24*	9.2%	38.7%	29.6% (16.4, 42.8)	8.5%	32.1%	25.5% (13.1, 37.9)
Proportion of subjects with improvement (reduction) in WI-NRS by ≥4 points from baseline at Week 24*	18.4%	60.0%	42.7% (27.8, 57.7)	19.5%	57.7%	42.6% (29.1, 56.1)
Proportion of subjects with IGA PN-S 0 or 1 at Week 24*	18.4%	48.0%	28.3% (13.4, 43.2)	15.9%	44.9%	30.8% (16.4, 45.2)
Proportion of subjects with improvement (reduction) in WI-NRS by ≥4 points from baseline at Week 12*	15.8%†	44.0%†	29.2% (14.5, 43.8)†	22.0%	37.2%	16.8% (2.3, 31.2)

Figure 14: Proportion of Adult Subjects with PN with Both WI-NRS ≥4-point Improvement and IGA PN-S 0 or 1 Over Time in PRIME and PRIME2

Figure 15: Proportion of Adult Subjects with PN with WI-NRS ≥4-point Improvement Over Time in PRIME and PRIME2

Figure 16: Proportion of Adult Subjects with IGA PN-S 0 or 1 Over Time in PRIME and PRIME 2

The efficacy data did not show differential treatment effect across demographic subgroups.

14.6 Chronic Obstructive Pulmonary Disease

The efficacy of DUPIXENT as add-on maintenance treatment of adult patients with inadequately controlled COPD and an eosinophilic phenotype was evaluated in two randomized, double-blind, multicenter, parallel-group, placebo-controlled trials (BOREAS [NCT03930732] and NOTUS [NCT04456673]) of 52 weeks duration. The two trials enrolled a total of 1874 adult subjects with COPD.

Both trials enrolled subjects with a diagnosis of COPD with moderate to severe airflow limitation (post-bronchodilator FEV1/FVC ratio <0.7 and post-bronchodilator FEV1 of 30% to 70% predicted) and a minimum blood eosinophil count of 300 cells/mcL at screening. Trial enrollment required an exacerbation history of at least 2 moderate or 1 severe exacerbation(s) in the previous year despite receiving maintenance triple therapy consisting of a long-acting muscarinic antagonist (LAMA), long-acting beta agonist (LABA), and inhaled corticosteroid (ICS), and symptoms of chronic productive cough for at least 3 months in the past year. Greater than or equal to 95% of subjects in each trial had chronic bronchitis. Subjects also had a Medical Research Council (MRC) dyspnea score ≥2 (range 0-4). Exacerbations of COPD were defined as clinically significant worsening of COPD symptoms including increases in dyspnea, wheezing, cough, sputum volume, and/or increase in sputum purulence. Exacerbation severity was further defined as moderate if treatment with systemic corticosteroids and/or antibiotics was required, or severe if they resulted in hospitalization or observation for over 24 hours in an emergency department or urgent care facility.

In both trials, subjects were randomized to receive DUPIXENT 300 mg subcutaneously every two weeks (Q2W) or placebo in addition to their background maintenance therapy for 52 weeks.

The demographics and baseline characteristics of BOREAS and NOTUS trial populations are provided in Table 28 below.

Table 28: Demographics and Baseline Characteristics of Adult Subjects with COPD for BOREAS and NOTUS Trial Populations
Parameter	BOREAS (N = 939)	NOTUS (N = 935)
ICS = inhaled corticosteroid; LAMA = long-acting muscarinic antagonist; LABA = long-acting beta agonist; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity
* Exacerbations treated with either systemic corticosteroids and/or antibiotics. † Exacerbations requiring hospitalization or observation for over 24 hours in an emergency department or urgent care facility. ‡ Reported screening eosinophil value is the highest values from up to three retests § Reported baseline eosinophil value was obtained within 4 weeks of screening value
Mean age (years) (± SD)	65.1 (8.1)	65.0 (8.3)
Male (%)	66.0	67.6
White, N (%)	790 (84.1)	838 (89.6)
Asian, N (%)	134 (14.3)	10 (1.1)
Black, N (%)	5 (0.5)	12 (1.3)
American Indian or Alaska Native, N (%)	7 (0.7)	48 (5.1)
Other/Multiple, N (%)	3 (0.3)	27 (2.9)
Ethnicity Hispanic/Latino, N (%)	261 (27.8)	300 (32.1)
Mean smoking history (pack-years) (± SD)	40.5 (23.4)	40.3 (27.2)
Current smokers (%)	30.0	29.5
Chronic Bronchitis (%)	95.0	99.9
Emphysema (%)	32.6	30.4
Mean number of moderate* or severe† exacerbations in previous year (± SD)	2.3 (1.0)	2.1 (0.9)
Background COPD medications at randomization: ICS/LAMA/LABA (%)	97.6	98.8
Mean post-bronchodilator FEV1/FVC ratio (± SD)	0.49 (0.12)	0.50 (0.12)
Mean post-bronchodilator FEV1 (L) (± SD)	1.40 (0.47)	1.45 (0.49)
Mean percent predicted post-bronchodilator FEV1 (%) (± SD)	50.6 (13.1)	50.1 (12.6)
Mean SGRQ total score (± SD)	48.4 (17.4)	51.5 (17.0)
Mean screening blood eosinophil count‡ (cells/mcL) (± SD)	521 (307)	538 (333)
Mean baseline blood eosinophil count§ (cells/mcL) (± SD)	401 (298)	407 (336)

Exacerbations in Adult Subjects with COPD

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 Table 29).

Table 29: Annualized Rate of Moderate* or Severe† COPD Exacerbations in BOREAS and NOTUS Trials
Trial	Treatment (N)	Rate (exacerbations/year)	Rate Ratio vs. Placebo (95% CI)
* Exacerbations treated with either systemic corticosteroids and/or antibiotics. † Exacerbations requiring hospitalization or observation for over 24 hours in an emergency department or urgent care facility or resulting in death.
BOREAS	DUPIXENT 300 mg Q2W (N=468)	0.78	0.71 (0.58, 0.86)
	Placebo (N=471)	1.10
NOTUS	DUPIXENT 300 mg Q2W (N=470)	0.86	0.66 (0.54, 0.82)
	Placebo (N=465)	1.30

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).

Lung Function in Adult Subjects with COPD

In both trials (BOREAS and NOTUS), DUPIXENT demonstrated numerical improvement in post-bronchodilator FEV1 at Weeks 12 and 52 compared to placebo when added to background maintenance therapy (see Table 30 and Figure 17). Significant improvements of similar magnitude were observed in change from baseline in pre-bronchodilator FEV1 at Weeks 12 and 52 in subjects treated with DUPIXENT compared to placebo across both trials.

Table 30: Mean Change from Baseline and Difference in Post-Bronchodilator FEV1 at Weeks 12 and 52 in BOREAS and NOTUS Trials for COPD
Trial	Treatment (N)	LS Mean Change from baseline mL	LS Mean Difference vs. placebo mL (95% CI)
* Efficacy results for mean change from baseline in post-bronchodilator FEV1 at Week 52 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.
Post-bronchodilator FEV1 at Week 12
BOREAS	DUPIXENT 300 mg Q2W (N=468)	158	74 (31, 117)
BOREAS	Placebo (N=471)	84
NOTUS	DUPIXENT 300 mg Q2W (N=470)	134	68 (26, 110)
NOTUS	Placebo (N=465)	67
Post-bronchodilator FEV1 at Week 52
BOREAS	DUPIXENT 300 mg Q2W (N=468)	138	79 (34, 124)
BOREAS	Placebo (N=471)	58
NOTUS*	DUPIXENT 300 mg Q2W (N=362)	127	67 (16, 119)
NOTUS*	Placebo (N=359)	59

Figure 17: LS Mean Change from Baseline in Post-Bronchodilator FEV1 (mL) Over Time in BOREAS and NOTUS* Trials for COPD
BOREAS	NOTUS
* Efficacy results for mean change from baseline in post-bronchodilator FEV1 over 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.

Health-Related Quality of Life

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).

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