14 CLINICAL STUDIES

The efficacy of CIBINQO as monotherapy and in combination with background topical corticosteroids was evaluated in 4 randomized, double-blind, placebo-controlled trials [Trial-AD-1 (NCT03349060), Trial-AD-2 (NCT03575871), Trial-AD-3 (NCT03720470), and Trial-AD-4 (NCT03796676)] in 1900 subjects (see Table 8). Trial-AD-1 and Trial-AD-2 enrolled adult and pediatric subjects 12 years of age and older. Trial-AD-3 enrolled only adults (≥18 years of age) and Trial-AD-4 enrolled only pediatric subjects 12 to less than 18 years of age. The trials enrolled subjects with moderate-to-severe atopic dermatitis as defined by Investigator’s Global Assessment (IGA) score ≥3, Eczema Area and Severity Index (EASI) score ≥16, body surface area (BSA) involvement ≥10%, and Peak Pruritus Numerical Rating Scale (PP-NRS) ≥4 at the baseline visit prior to randomization.

Baseline Characteristics

In Trial-AD-1, Trial-AD-2, and Trial-AD-3, 53% of subjects were male, 69% of subjects were white, 64% of subjects had a baseline IGA score of 3 (moderate AD), and 36% of subjects had a baseline IGA score of 4 (severe AD). The baseline mean EASI score was 30. The baseline mean age was 36 years old with 8% of subjects 12 to less than 18 years old and 92% of subjects 18 years of age or older. Subjects in these trials were those who had inadequate response to previous topical therapy or were subjects for whom topical treatments were medically inadvisable or who had received systemic therapies including dupilumab. In each of the trials, over 40% of subjects had prior exposure to systemic therapy. In Trial-AD-1 and Trial-AD-2, 6% of the subjects had received dupilumab, whereas prior use of dupilumab was not allowed in Trial-AD-3.

In Trial-AD-4, 49% of subjects were female, 56% of subjects were White, 33% of subjects were Asian and 6% of subjects were Black. The median age was 15 years and the proportion of subjects with severe atopic dermatitis (IGA of 4) was 38%.

Trial Designs and Endpoints

Trial-AD-1, Trial-AD-2, Trial-AD-3, and Trial-AD-4 assessed the co-primary endpoints of IGA and EASI-75 responses at Week 12. The designs of the trials are summarized in Table 8.

Table 8. Summary of Clinical Trial Designs
Abbreviations: EASI=Eczema Area and Severity Index; IGA=Investigator’s Global Assessment; QD=once daily; Q2W=once every 2 weeks.
* IGA response was based on IGA score of clear (0) or almost clear (1) (on a 5-point scale) and a reduction from baseline of ≥2 points. † EASI-75 was based on ≥75% improvement in EASI from baseline. ‡ Dupilumab treatment in Trial-AD-3: An initial dose of 600 mg on day 1, followed by 300 mg Q2W.
Study Name (regimen type) Treatment Duration	Population (number of randomized and dosed subjects)	Treatment Arms	Co-Primary Endpoints
Trial-AD-1 (monotherapy) 12 weeks	Subjects 12 years of age or older (387)	Oral administration of: • CIBINQO 200 mg QD • CIBINQO 100 mg QD • Placebo	• IGA response* at Week 12 • EASI-75† at Week 12
Trial-AD-2 (monotherapy) 12 weeks	Subjects 12 years of age or older (391)	Oral administration of: • CIBINQO 200 mg QD • CIBINQO 100 mg QD • Placebo
Trial-AD-3 (combination therapy) 16 weeks	Subjects 18 years of age or older (837)	Oral administration of: • CIBINQO 200 mg QD • CIBINQO 100 mg QD • Placebo Subcutaneous administration of: • Dupilumab 300 mg Q2W SC‡ All subjects received background topical corticosteroids
Trial-AD-4 (combination therapy) 12 weeks	Subjects 12 to less than 18 years of age (285)	Oral administration of: • CIBINQO 200 mg QD • CIBINQO 100 mg QD • Placebo All subjects received background topical corticosteroids

Clinical Response

Monotherapy Trials

The results of the CIBINQO monotherapy trials (Trial-AD-1 and Trial-AD-2) are presented in Table 9.

Table 9. Efficacy Results of CIBINQO Monotherapy at Week 12 in Subjects 12 Years of Age and Older with Moderate-to-Severe AD (Trial-AD-1 and Trial-AD-2)
Abbreviations: CI=confidence interval; EASI=Eczema Area and Severity Index; IGA=Investigator Global Assessment; QD=once daily.
* IGA responders were subjects with IGA score of clear (0) or almost clear (1) (on a 5-point scale) and a reduction from baseline of ≥2 points. † EASI -75 responders were patients with ≥75% improvement in EASI from baseline.
	Trial-AD-1			Trial-AD-2
	CIBINQO		Placebo N=77	CIBINQO		Placebo N=78
	200 mg QD N=154	100 mg QD N=156	Placebo N=77	200 mg QD N=155	100 mg QD N=158	Placebo N=78
IGA 0 or 1*	44%	24%	8%	38%	28%	9%
Difference from Placebo (95% CI)	36% (26%, 46%)	16% (7%, 25%)	-	29% (19%, 39%)	19% (9%, 29%)	-
EASI-75†	62%	40%	12%	61%	44%	10%
Difference from Placebo (95% CI)	51% (40%, 61%)	28% (18%, 39%)	-	50% (40%, 61%)	33% (23%, 44%)	-

The proportion of subjects achieving PP-NRS4 at Week 2 (defined as an improvement of ≥4 points from baseline in PP-NRS) was higher in subjects treated with CIBINQO monotherapy 200 mg once daily (28% in Trial-AD-1 and 24% in Trial-AD-2) and 100 mg once daily (11% in both trials) compared to placebo (2% in both trials).

A higher proportion of subjects in the CIBINQO monotherapy 100 mg or 200 mg once daily arms compared to placebo achieved improvement in itching at Week 12.

Combination Therapy Trials

The results of CIBINQO in combination with background topical corticosteroids in subjects 18 years of age and older (Trial-AD-3) are presented in Table 10.

Table 10. Efficacy Results of CIBINQO with Concomitant Topical Corticosteroids at Week 12 in Subjects 18 Years of Age and Older with Moderate-to-Severe AD (Trial-AD-3)
Abbreviations: CI=confidence interval; EASI=Eczema Area and Severity Index; IGA=Investigator Global Assessment; QD=once daily.
* IGA responders were subjects with IGA score of clear (0) or almost clear (1) (on a 5-point scale) and a reduction from baseline of ≥2 points. † EASI-75 responders were subjects with ≥75% improvement in EASI, from baseline.
% Responders	CIBINQO		Placebo N=131
% Responders	200 mg QD N=226	100 mg QD N=238	Placebo N=131
IGA 0 or 1* at Week 12	47%	36%	14%
Difference from Placebo (95% CI)	34% (25%, 42%)	23% (15%, 31%)	-
EASI-75† at Week 12	68%	58%	27%
Difference from Placebo (95% CI)	41% (32%, 51%)	32% (22%, 41%)	-

The proportions of subjects achieving PP-NRS4 at Week 2 was higher in subjects treated with CIBINQO 200 mg once daily (30%) and 100 mg once daily (14%) in combination with background medicated topical therapies compared to placebo (8%).

The results of CIBINQO in combination with background topical corticosteroids for pediatric subjects 12 to less than 18 years of age (Trial-AD-4) are presented in Table 11.

Table 11. Efficacy Results of CIBINQO with Concomitant Topical Corticosteroids at Week 12 in Pediatric Subjects 12 to less than 18 Years of Age with Moderate-to-Severe AD (Trial-AD-4)
Abbreviations: CI=confidence interval; EASI=Eczema Area and Severity Index; IGA=Investigator Global Assessment; N=number of patients treated; QD=once daily.
* IGA responders were patients with IGA score of clear (0) or almost clear (1) (on a 5-point scale) and a reduction from baseline of ≥2 points. † EASI-75 responders were patients with ≥75% improvement in EASI from baseline.
% Responders	CIBINQO		Placebo N=95
% Responders	200 mg QD N=94	100 mg QD N=95	Placebo N=95
IGA 0 or 1*	46%	39%	24%
Difference from Placebo (95% CI)	21% (8%, 34%)	15% (2%, 28%)	-
EASI-75†	71%	64%	41%
Difference from Placebo (95% CI)	29% (16%, 43%)	23% (10%, 36%)	-

The proportion of pediatric subjects 12 to less than 18 years of age achieving PP-NRS4 at Week 2 in Trial-AD-4 was higher with CIBINQO 200 mg once daily (25%) and 100 mg once daily (13%) compared to placebo (8%).

A higher proportion of subjects in the CIBINQO 200 mg once daily arm compared to placebo achieved improvement in itching at Week 12.

Subgroup Analysis (Monotherapy Trials and the Combination Therapy Trial in Subjects 18 Years of Age and Older)

Examination of age, gender, race, weight, and previous systemic AD therapy treatment did not identify differences in response to CIBINQO 100 mg or 200 mg once daily among these subgroups in Trial-AD-1, Trial-AD-2, and Trial-AD-3.