14 CLINICAL STUDIES

14.1 Plaque Psoriasis

Four multicenter, randomized, double-blind trials [PsO-1 (NCT02684370), PsO-2 (NCT02684357), PsO-3 (NCT02672852), and PsO-4 (NCT02694523)] enrolled 2,109 subjects 18 years of age and older with moderate to severe plaque psoriasis who had a body surface area (BSA) involvement of ≥10%, a static Physician’s Global Assessment (sPGA) score of ≥3 (“moderate”) in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 4, and a Psoriasis Area and Severity Index (PASI) score ≥12.

Overall, subjects had a median baseline PASI score of 17.8 and a median BSA of 20%. Baseline sPGA score was 4 (“severe”) in 19% of subjects. A total of 10% of trial subjects had a history of diagnosed psoriatic arthritis.

Across all trials, 38% of subjects had received prior phototherapy, 48% had received prior non-biologic systemic therapy, and 42% had received prior biologic therapy for the treatment of psoriasis.

Trials PsO-1 and PsO-2

In trials PsO-1 and PsO-2, 997 subjects were enrolled (including 598 subjects randomized to the SKYRIZI 150 mg group, 200 subjects randomized to the placebo group, and 199 to the biologic active control group). Subjects received treatment at Weeks 0, 4, and every 12 weeks thereafter.

Both trials assessed the responses at Week 16 compared with placebo for the two co-primary endpoints:

the proportion of subjects who achieved an sPGA score of 0 (“clear”) or 1 (“almost clear”)
the proportion of subjects who achieved at least a 90% reduction from baseline PASI (PASI 90)

Secondary endpoints included the proportion of subjects who achieved PASI 100, sPGA 0, and Psoriasis Symptom Scale (PSS) 0 at Week 16.

The results are presented in Table 6.

Table 6. Efficacy Results at Week 16 in Adults with Plaque Psoriasis in PsO-1 and PsO-2
PsO-1		PsO-2
SKYRIZI (N=304) n (%)	Placebo (N=102) n (%)	SKYRIZI (N=294) n (%)	Placebo (N=98) n (%)
sPGA 0 or 1 (“clear or almost clear”) ^a	267 (88)	8 (8)	246 (84)	5 (5)
PASI 90 ^a	229 (75)	5 (5)	220 (75)	2 (2)
sPGA 0 (“clear”)	112 (37)	2 (2)	150 (51)	3 (3)
PASI 100	109 (36)	0 (0)	149 (51)	2 (2)
^aCo-primary endpoints

Examination of age, gender, race, body weight, baseline PASI score and previous treatment with systemic or biologic agents did not identify differences in response to SKYRIZI among these subgroups at Week 16.

In PsO-1 and PsO-2 at Week 52, subjects receiving SKYRIZI achieved sPGA 0 (58% and 60%, respectively), PASI 90 (82% and 81%, respectively), and PASI 100 (56% and 60%, respectively).

Patient Reported Outcomes

Improvements in signs and symptoms related to pain, redness, itching and burning at Week 16 compared to placebo were observed in both trials as assessed by the PSS. In PsO-1 and PsO-2, about 30% of the subjects who received SKYRIZI achieved PSS 0 (“none”) at Week 16 compared to 1% of the subjects who received placebo.

Trial PsO-3

Trial PsO-3 enrolled 507 subjects (407 randomized to SKYRIZI 150 mg and 100 to placebo). Subjects received treatment at Weeks 0, 4, and every 12 weeks thereafter.

At Week 16, SKYRIZI was superior to placebo on the co-primary endpoints of sPGA 0 or 1 (84% SKYRIZI and 7% placebo) and PASI 90 (73% SKYRIZI and 2% placebo). The respective response rates for SKYRIZI and placebo at Week 16 were: sPGA 0 (46% SKYRIZI and 1% placebo); PASI 100 (47% SKYRIZI and 1% placebo); and PASI 75 (89% SKYRIZI and 8% placebo).

Maintenance and Durability of Response

In PsO-1 and PsO-2, among the subjects who received SKYRIZI and had PASI 100 at Week 16, 80% (206/258) of the subjects who continued on SKYRIZI had PASI 100 at Week 52. For PASI 90 responders at Week 16, 88% (398/450) of the subjects had PASI 90 at Week 52.

In PsO-3, subjects who were originally on SKYRIZI and had sPGA 0 or 1 at Week 28 were re-randomized to continue SKYRIZI every 12 weeks or withdrawal of therapy. At Week 52, 87% (97/111) of the subjects re-randomized to continue treatment with SKYRIZI had sPGA 0 or 1 compared to 61% (138/225) who were re-randomized to withdrawal of SKYRIZI.

Plaque Psoriasis of the Scalp or Genital Area (Trial PsO-5)

The efficacy of SKYRIZI was assessed in a multicenter, randomized, double-blind, placebo-controlled trial [PsO-5 (NCT05969223)] that enrolled subjects 18 years of age and older with moderate to severe plaque psoriasis of the scalp (Trial S), defined as Psoriasis Scalp Severity Index (PSSI) ≥12, scalp Investigator Global Assessment (scalp IGA) ≥3 (“moderate”), and ≥30% of the scalp affected, or moderate to severe plaque psoriasis of the genital area (Trial G), defined as static Physician’s Global Assessment of Genitalia (sPGA-G) ≥3 (“moderate”) at baseline. All subjects had BSA ≥1% and sPGA ≥3 (“moderate”) at baseline.

In trial PsO-5, subjects were randomized to receive either SKYRIZI 150 mg or placebo subcutaneously at Weeks 0 and 4. Starting at Week 16, all subjects received SKYRIZI 150 mg every 12 weeks until the last dose at Week 40.

Plaque Psoriasis of the Scalp

PsO-5 Trial S enrolled 105 subjects with moderate to severe plaque psoriasis of the scalp. The median age of enrolled subjects at baseline was 44 years (range 20 to 83 years) and 10% of the subjects were 65 years of age and older. Fifty-six (56)% of the subjects were male, 83% were White, 8% were Black or African American, and 5% were Asian; for ethnicity, 36% of the subjects identified as Hispanic or Latino. At baseline, 74% of the subjects had moderate plaque psoriasis of the scalp (scalp IGA of 3) and 26% had severe plaque psoriasis of the scalp (scalp IGA of 4). Median baseline PSSI was 32. Baseline BSA involvement was ≥10% for 62% of the subjects and <10% for the remaining subjects. Median baseline BSA involvement was 11%. Baseline sPGA score was 4 (“severe”) in 24% of the subjects.

At baseline, 54% of subjects were naïve to both non-biologic systemic and biologic therapy, 0% of subjects had received prior phototherapy, 15% had received prior non-biologic systemic therapy, and 37% had received prior biologic therapy.

The results are presented in Table 7.

Table 7. Efficacy Results at Week 16 in Adults with Psoriasis of the Scalp in PsO-5 Trial S
Endpoint	SKYRIZI (N=51) n (%)	Placebo (N=54) n (%)	Treatment Difference (95% CI)
scalp IGA of 0 or 1 (“clear or almost clear”) ^a	31 (61)	7 (13)	47 (31, 63)
PSSI 90 ^b	27 (53)	7 (13)	40 (24, 55)
PSSI 100 ^c	23 (45)	7 (13)	31 (15, 47)
^aPrimary endpoint ^bAchievement of ≥90% improvement from baseline in PSSI ^cAchievement of 100% improvement from baseline in PSSI

Plaque Psoriasis of the Genital Area

PsO-5 Trial G enrolled 109 subjects with moderate to severe plaque psoriasis of the genital area. The median age of enrolled subjects at baseline was 45 years (range 19 to 77 years) and 15% of the subjects were 65 years of age and older. Sixty-five (65)% of the subjects were male, 90% were White, 4% were Asian, and 2% were Black or African American; for ethnicity, 29% of the subjects identified as Hispanic or Latino. At baseline, 62% of the subjects had moderate plaque psoriasis of the genital area (sPGA-G of 3) and 38% had severe or very severe plaque psoriasis of the genital area (sPGA-G of 4 or 5). Baseline BSA involvement was ≥10% for 63% of the subjects and <10% for the remaining subjects. Median baseline BSA involvement was 11%. Baseline sPGA score was 4 (“severe”) in 19% of the subjects.

At baseline, 61% of subjects were naïve to both non-biologic systemic and biologic therapy, 3% of subjects had received prior phototherapy, 17% had received prior non-biologic systemic therapy, and 26% had received prior biologic therapy.

The results are presented in Table 8.

Table 8. Efficacy Results at Week 16 in Adults with Psoriasis of the Genital Area in PsO-5 Trial G
Endpoint	SKYRIZI (N=55) n (%)	Placebo (N=54) n (%)	Treatment Difference (95% CI)
sPGA-G of 0 or 1 (“clear or minimal ”) ^a	38 (69)	7 (13)	57 (42, 72)
sPGA-G of 0 (“clear”)	28 (51)	3 (6)	47 (33, 61)
GPI- NRS reduction of ≥4-point from baseline ^b	N=41 20 (49)	N=45 3 (7)	43 (27, 59)
GenPs-SFQ item 2 score of 0 (never) or 1 (rarely) ^c,d	N=31 22 (71)	N=32 7 (22)	46 (27, 66)
^aPrimary endpoint ^bImprovement of genital itch severity as measured by a reduction of at least 4 points in the 11-point Genital Psoriasis Itch (GPI) Numeric Rating Scale (NRS) from the Genital Psoriasis Symptom Scale (GPSS) among subjects with baseline score ≥4 ^cGenital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ) Item 2 (In the past week, how often did your genital psoriasis limit the frequency of your sexual activity?) score ranges from 0 to 4 (0 = never, 1 = rarely, 2 = sometimes, 3 = often, 4 = always); where higher scores indicate greater limitations on the frequency of sexual activity in the past week ^dAmong subjects with baseline score ≥2

14.2 Psoriatic Arthritis

The safety and efficacy of SKYRIZI were assessed in 1407 subjects in 2 randomized, double-blind, placebo-controlled trials (964 in PsA-1 [NCT03675308] and 443 in PsA-2 [NCT03671148]) in subjects 18 years and older with active psoriatic arthritis (PsA).

Subjects in these trials had a diagnosis of PsA for at least 6 months based on the Classification Criteria for Psoriatic Arthritis (CASPAR), a median duration of PsA of 4.9 years at baseline, ≥ 5 tender joints and ≥ 5 swollen joints, and active plaque psoriasis or psoriatic nail disease at baseline. Regarding baseline clinical presentation, 55.9% of subjects had ≥3% BSA with active plaque psoriasis; 63.4% and 27.9% of subjects had enthesitis and dactylitis, respectively. In PsA-1 where psoriatic nail disease was further assessed, 67.3% had psoriatic nail disease.

In PsA-1, all subjects had a previous inadequate response or intolerance to non-biologic DMARD therapy and were biologic naïve. In PsA-2, 53.5% of subjects had a previous inadequate response or intolerance to non-biologic DMARD therapy, and 46.5% of subjects had a previous inadequate response or intolerance to biologic therapy.

In both trials, subjects were randomized to receive SKYRIZI 150 mg or placebo at Weeks 0, 4, and 16. Starting from Week 28, all subjects received SKYRIZI every 12 weeks. Both trials included a long-term extension for up to an additional 204 weeks. Regarding use of concomitant medications, 59.6% of subjects were receiving concomitant methotrexate (MTX), 11.6% were receiving concomitant non-biologic DMARDs other than MTX, and 28.9% were receiving SKYRIZI monotherapy.

For both trials, the primary endpoint was the proportion of subjects who achieved an American College of Rheumatology (ACR) 20 response at Week 24.

Clinical Response

In both trials, treatment with SKYRIZI resulted in significant improvement in measures of disease activity compared with placebo at Week 24. See Tables 9 and 10 for key efficacy results.

In both trials, similar responses were seen regardless of concomitant non-biologic DMARD use, number of prior non-biologic DMARDs, age, gender, race, and BMI. In PsA-2, responses were seen regardless of prior biologic therapy.

Table 9. Efficacy Results in Trial PsA-1
Endpoint	Placebo N=481 Response Rate	SKYRIZI N=483 Response Rate	Difference from Placebo (95% CI)
ACR20 Response•
Week 16	33.4%	56.3% ^a	23.1% (16.8, 29.4)
Week 24	33.5%	57.3% ^a	24.0% (18.0, 30.0)
ACR50 Response•
Week 16	11.1%	26.4%	15.4% (10.6, 20.2)
Week 24	11.3%	33.4 %	22.2% (17.3, 27.2)
ACR70 Response•
Week 16	2.7%	11.8%	9.2% (6.1, 12.4)
Week 24	4.7%	15.3%	10.5% (6.9, 14.2)
a. multiplicity-controlled p≤0.001, SKYRIZI vs. placebo comparison. •A Subject was considered as a non-responder after initiation of rescue medication or concomitant medications for PsA that could meaningfully impact efficacy assessment.

Table 10. Efficacy Results in Trial PsA-2
Endpoint	Placebo N=219 Response Rate	SKYRIZI N=224 Response Rate	Difference from Placebo (95% CI)
ACR20 Response•
Week 16	25.3%	48.3% ^a	22.6% (13.9, 31.2)
Week 24	26.5%	51.3% ^a	24.5% (15.9, 33.0)
ACR50 Response•
Week 16	6.8%	20.3%	13.5% (7.3, 19.7)
Week 24	9.3%	26.3%	16.6% (9.7, 23.6)
ACR70 Response•
Week 16	3.4%	11.2%	7.8% (3.0, 12.6)
Week 24	5.9%	12.0%	6.0% (0.8, 11.3)
a. multiplicity-controlled p≤0.001, SKYRIZI vs. placebo comparison. •A Subject was considered as a non-responder after initiation of rescue medication or concomitant medications for PsA that could meaningfully impact efficacy assessment.

The percent of subjects achieving ACR20 responses in trial PsA-1 through Week 24 is shown in Figure 1.

Figure 1. Percent of Subjects Achieving ACR20 Responses in Trial PsA-1 through Week 24

Referenced Image

The results of the components of the ACR response criteria for both trials are shown in Table 11.

Table 11. Mean Change from Baseline in ACR Components
PsA-1		PsA-2
Placebo (N=481) Mean (SD)	SKYRIZI (N=483) Mean (SD)	Placebo (N=219) Mean (SD)	SKYRIZI (N=224) Mean (SD)
Number of Swollen Joints (0-66)
Baseline	12.2 (8.0)	12.1 (7.8)	13.6 (9.0)	13.0 (8.7)
Mean change at Week 16	-5.5 (7.0)	-7.7 (7.2)	-5.4 (8.5)	-8.0 (7.4)
Mean change at Week 24	-6.7 (7.2)	-8.7 (7.2)	-6.5 (7.8)	-9.1 (7.6)
Number of Tender Joints (0-68)
Baseline	20.5 (12.8)	20.8 (14.0)	22.3 (13.8)	22.8 (14.9)
Mean change at Week 16	-6.3 (11.1)	-10.7 (11.4)	-6.0 (13.1)	-11.3 (13.0)
Mean change at Week 24	-7.9 (10.7)	-12.0 (12.3)	-8.3 (11.3)	-13.0 (12.5)
Patient’s Assessment of Pain ^a
Baseline	57.1 (22.6)	57.1 (22.6)	57.0 (23.1)	55.0 (23.5)
Mean change at Week 16	-8.6 (23.7)	-18.4 (26.3)	-5.7 (22.7)	-14.4 (26.4)
Mean change at Week 24	-10.9 (25.4)	-21.4 (26.5)	-8.7 (25.3)	-15.3 (26.5)
Patient’s Global Assessment ^a
Baseline	57.4 (22.1)	57.9 (21.7)	56.2 (23.0)	56.2 (21.8)
Mean change at Week 16	-10.2 (23.9)	-19.4 (25.7)	-4.9 (23.6)	-17.0 (27.1)
Mean change at Week 24	-11.1 (25.1)	-22.6 (26.9)	-8.7 (25.4)	-17.7 (27.7)
Physician Global Assessment ^a
Baseline	62.4 (17.0)	61.3 (17.6)	60.7 (16.4)	63.0 (17.0)
Mean change at Week 16	-18.3 (22.5)	-31.1 (23.4)	-19.0 (23.3)	-32.7 (24.7)
Mean change at Week 24	-22.2 (22.8)	-34.8 (23.2)	-21.3 (25.2)	-35.5 (25.6)
Health Assessment Questionnaire - Disability Index (HAQ-DI) ^b
Baseline	1.2 (0.7)	1.2 (0.7)	1.1 (0.6)	1.1 (0.6)
Mean change at Week 16	-0.1 (0.5)	-0.3 (0.5)	-0.1 (0.5)	-0.2 (0.5)
Mean change at Week 24	-0.1 (0.5)	-0.3 (0.5)	-0.1 (0.4)	-0.2 (0.5)
High sensitivity C-reactive protein (hs-CRP) mg/L
Baseline	11.3 (14.1)	11.9 (15.9)	8.2 (17.1)	7.4 (10.9)
Mean change at Week 16	-0.3 (14.7)	-4.8 (14.2)	-0.1 (6.8)	-2.1 (7.5)
Mean change at Week 24	-0.2 (11.7)	-4.3 (12.8)	-0.5 (14.5)	-1.8 (13.4)
SD= Standard Deviation. a. Assessment based on Visual Analog Scale (100 mm) with the left end indicating “no pain” (for patient’s assessment of pain), “very well” (for patient global assessment), or “no arthritis activity” (for physician global assessment) and the right end indicating “the worst possible pain” (for patient assessment of pain), “poor” (for patient global assessment), or “extremely active arthritis” (for physician global assessment). b. Disability Index of the Health Assessment Questionnaire; 0 = no difficulty to 3 = inability to perform, measures the patient’s ability to perform the following: dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living.

Treatment with SKYRIZI resulted in improvement in dactylitis and enthesitis in subjects with pre-existing dactylitis or enthesitis.

In patients with coexistent plaque psoriasis receiving SKYRIZI, the skin lesions of psoriasis improved with treatment, relative to placebo, as measured by the Psoriasis Area Severity Index (PASI 90) at Week 24.

Physical Function

In both trials, patients treated with SKYRIZI showed statistically significant improvement from baseline in physical function compared with placebo as assessed by HAQ-DI at Week 24 (Table 9 ). The mean difference (95% CI) from placebo in HAQ-DI change from baseline at Week 24 was -0.20 (-0.26, -0.14) in trial PsA-1 and -0.16 (-0.26, -0.07) in trial PsA-2.

In both trials, a greater proportion of subjects achieved a reduction of at least 0.35 in HAQ-DI score from baseline in the SKYRIZI group compared with placebo at Week 24.

Other Health Related Outcomes

In both trials, general health status was assessed by the 36-Item Short Form Health Survey (SF-36 V2). Fatigue was assessed by Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue).

In both trials at Week 24, subjects treated with SKYRIZI showed improvements in the SF-36 physical component summary scores compared with subjects who received placebo. There were also numerical improvements in subjects treated with SKYRIZI in physical functioning, role physical, bodily pain, general health, vitality, social functioning, mental health, role emotional domain scores and mental component summary scores in both trials at week 24 compared to placebo. In both trials at Week 24, subjects treated with SKYRIZI showed improvements in FACIT-Fatigue scores compared with subjects who received placebo.

14.3 Crohn’s Disease

Induction Trials ( Trials CD-1 and CD-2)

In two 12-week induction trials (CD-1; NCT03105128 and CD-2; NCT03104413), subjects with moderately to severely active Crohn’s disease were randomized to receive SKYRIZI 600 mg, SKYRIZI 1,200 mg, or placebo as an intravenous infusion at Week 0, Week 4, and Week 8. Moderately to severely active CD was defined as a Crohn’s Disease Activity Index (CDAI) of 220 to 450 and Simple Endoscopic Score for Crohn’s disease (SES-CD) ≥6 (or ≥4 for isolated ileal disease). Subjects with inadequate response, loss of response, or intolerance to oral aminosalicylates, corticosteroids, immunosuppressants, and/or biologic therapy were enrolled.

At baseline, the median CDAI was 307 (range: 76 – 634) and 307 (range: 72 – 651), and the median SES-CD was 12 (range: 4 – 45) and 13 (range 4 – 40), in CD-1 and CD-2, respectively. In CD-1, 58% (491/850) of subjects had failed or were intolerant to treatment with one or more biologic therapies (prior biologic failure). All subjects in CD-2 had prior biologic failure. At baseline, 30% and 34% of patients were receiving corticosteroids, 24% and 23% of patients were receiving immunomodulators (azathioprine, 6-mercaptopurine, methotrexate), and 31% and 19% of patients were receiving aminosalicylates in CD-1 and CD-2, respectively. In CD-1 and CD-2 combined, the median age was 36 years (ranging from 16 to 80 years), 81% (1145/1419) of subjects were white, and 53% (753/1419) were male.

In CD-1 and CD-2, the co-primary endpoints were clinical remission and endoscopic response at Week 12. Secondary endpoints included clinical response and endoscopic remission (see Table 12 and Table 13 ). The SKYRIZI 1,200 mg dosage did not demonstrate additional treatment benefit over the 600 mg dosage and is not a recommended regimen [see Dosage and Administration (2.6 )] .

Table 12. Proportion of Subjects Meeting Efficacy Endpoints at Week 12 – Trial CD-1
Endpoint	Placebo	SKYRIZI 600 mg Intravenous Infusion ^a	Treatment Difference ^b (95% CI)
Clinical Remission ^c,d
Total Population	N=175 25%	N=336 45%	21% ^e (12%, 29%)
Prior biologic failure ^f	N=97 26%	N=195 42%
Without prior biologic failure	N=78 23%	N=141 49%
Endoscopic Response ^c,^g
Total Population	N=175 12%	N=336 40%	28% ^e (21%, 35%)
Prior biologic failure ^f	N=97 11%	N=195 33%
Without prior biologic failure	N=78 13%	N=141 50%
Clinical Response ^h
Total Population	N=175 37%	N=336 60%	23% ^e (14%, 32%)
Prior biologic failure ^f	N=97 34%	N=195 58%
Without prior biologic failure	N=78 40%	N=141 62%
Endoscopic Remission ⁱ
Total Population	N=175 9%	N=336 24%	15% ^e (9%, 21%)
Prior biologic failure ^f	N=97 5%	N=195 18%
Without prior biologic failure	N=78 14%	N=141 32%
a. SKYRIZI 600 mg as an intravenous infusion at Week 0, Week 4, and Week 8 b. Adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomization stratification factors c. Co-primary endpoints d. CDAI <150 e. p <0.001 f. Prior biologic failure includes inadequate response, loss of response, or intolerance to one or more biologic treatments for CD g. A decrease in SES-CD > 50% from baseline, or a decrease of at least 2 points for subjects with a baseline score of 4 and isolated ileal disease, based on central reading h. A reduction of CDAI ≥ 100 points from baseline i. SES-CD ≤ 4 and at least a 2-point reduction from baseline, with no individual subscore greater than 1, based on central reading

Table 13. Proportion of Subjects Meeting Efficacy Endpoints at Week 12 – Trial CD-2 ^a
Endpoint	Placebo N=187	SKYRIZI 600 mg Intravenous Infusion ^b N=191	Treatment Difference ^c (95% CI)
Clinical Remission ^d,^e	20%	42%	22% ^f (13%, 31%)
Endoscopic Response ^d,g	11%	29%	18% ^f (10%, 25%)
Clinical Response ^h	30%	60%	29% ^f (20%, 39%)
Endoscopic Remission ⁱ	4%	19%	15% ^f (9%, 21%)
a. All subjects enrolled in CD-2 had prior biologic failure. Prior biologic failure includes inadequate response, loss of response, or intolerance to one or more biologic treatments for CD b. SKYRIZI 600 mg as an intravenous infusion at Week 0, Week 4, and Week 8 c. Adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomization stratification factors d. Co-primary endpoints e. CDAI score <150 f. p < 0.001 g. A decrease in SES-CD > 50% from baseline, or a decrease of at least 2 points for subjects with a baseline score of 4 and isolated ileal disease, based on central reading h. A reduction of CDAI ≥ 100 points from baseline i. SES-CD ≤ 4 and at least a 2-point reduction versus from baseline, with and no individual subscore greater than 1, based on central reading

Onset of clinical response and clinical remission based on CDAI occurred as early as Week 4 in a greater proportion of subjects treated with the SKYRIZI 600 mg induction regimen compared to placebo.

Reductions in stool frequency and abdominal pain were observed in a greater proportion of subjects treated with the SKYRIZI 600 mg induction regimen compared to placebo at Week 12.

Trial CD-3

The maintenance trial CD-3 evaluated 382 subjects who achieved clinical response defined as a reduction in CDAI of at least 100 points from baseline after 12 weeks of induction treatment with intravenous SKYRIZI in trials CD-1 and CD-2. Subjects were randomized to receive a maintenance regimen of SKYRIZI 180 mg or SKYRIZI 360 mg or placebo at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks.

The co-primary endpoints in CD-3 were clinical remission and endoscopic response at Week 52 (see Table 14 ).

Table 14. Proportion of Subjects Meeting Efficacy Endpoints at Week 52 - Trial CD-3
Endpoint	Placebo ^a	SKYRIZI 180 mg Subcutaneous Injection ^b	SKYRIZI 360 mg Subcutaneous Injection ^c	Treatment Difference vs Placebo ^d (95% CI )
SKYRIZI 180 mg	SKYRIZI 360 mg
Clinical Remission ^e,f
Total Population	N=130 46%	N=135 61%	N=117 57%	17% ^g (6%, 28%)		14% ^g (3%, 26%)
Prior biologic failure ^h	N=99 40%	N=95 56%	N=83 51%
Without prior biologic failure	N=31 65%	N=40 75%	N=34 71%
Endoscopic Response ^e,i
Total Population	N=130 22%	N=135 50%	N=117 48%	30% ^g (20%, 39%)	31% ^g (21%, 41%)
Prior biologic failure ^h	N=99 21%	N=95 44%	N=83 44%
Without prior biologic failure	N=31 23%	N=40 65%	N=34 59%
a. The placebo group consisted of patients who were in response to SKYRIZI and were randomized to receive placebo at the start of maintenance therapy. b. SKYRIZI 180 mg at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks c. SKYRIZI 360 mg at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks d. Adjusted treatment difference and 95% CI computed using Cochran-Mantel-Haenszel method adjusted for randomization stratification factors e. Co-primary endpoints f. CDAI <150 g. p <0.05 h. Prior biologic failure includes inadequate response, loss of response, or intolerance to one or more biologic treatments for CD i. A decrease in SES-CD > 50% from baseline, or a decrease of at least 2 points for subjects with a baseline score of 4 and isolated ileal disease, based on central reading

Endoscopic remission was observed at Week 52 in 33% (44/135) of subjects treated with the SKYRIZI 180 mg maintenance regimen and 41% (48/117) of subjects treated with the SKYRIZI 360 mg maintenance regimen, compared to 13% (17/130) of subjects treated with placebo. This endpoint was not statistically significant under the prespecified multiple testing procedure.

14.4 Ulcerative Colitis

Induction Trial ( Trial UC-1)

In the 12-week induction trial (UC-1; NCT03398148), 966 subjects with moderately to severely active ulcerative colitis were randomized and received SKYRIZI 1,200 mg or placebo as an intravenous infusion at Week 0, Week 4, and Week 8. Disease activity was assessed by the modified Mayo score (mMS), a 3-component Mayo score (0-9) which consists of the following subscores (0 to 3 for each subscore): stool frequency (SFS), rectal bleeding (RBS), and findings on centrally read endoscopy score (ES). An ES of 2 was defined by marked erythema, lack of vascular pattern, any friability, and/or erosions; an ES of 3 was defined by spontaneous bleeding and ulceration. Enrolled subjects had a mMS between 5 and 9, with an ES of 2 or 3. Subjects with inadequate response, or intolerance to oral aminosalicylates, corticosteroids, immunomodulators, biologics, Janus Kinase inhibitors (JAKi), and/or sphingosine-1-phosphate receptor modulators (S1PRM) were enrolled.

At baseline in UC-1, the median mMS was 7; 37% had severely active disease (mMS >7); 69% had an ES of 3. In UC-1, 52% (499/966) of subjects had failed (inadequate response or intolerance) treatment with one or more biologics, JAKi or S1PRM. Of these 499 subjects, 484 (97%) failed biologics and 90 (18%) failed JAK inhibitors. Enrolled subjects were permitted to use a stable dose of oral corticosteroids (up to 20 mg/day prednisone or equivalent), immunomodulators, and aminosalicylates. At baseline, 36% of subjects were receiving corticosteroids, 16% of subjects were receiving immunomodulators (including azathioprine, 6-mercaptopurine, methotrexate), and 73% of subjects were receiving aminosalicylates in UC-1.

In UC-1, the primary endpoint was clinical remission defined using the mMS at Week 12 (see Table 15 ). Key secondary endpoints included clinical response, endoscopic improvement, and histologic endoscopic mucosal improvement (see Table 15 ).

Table 15. Proportion of Subjects Meeting Efficacy Endpoints at Week 12 – Trial UC-1
Endpoint	Placebo	SKYRIZI 1,200 mg Intravenous Infusion ^a	Treatment Difference (95% CI) ^b
Clinical Remission ^c
Total Population	N=320 8%	N=646 24%	16% ^h (12%, 20%)
Prior biologic, JAKi, or S1PRM failure ^d	N=168 6%	N=331 14%
Without prior biologic, JAKi, or S1PRM failure	N=152 9%	N=315 33%
Clinical Response ^e
Total Population	N=320 36%	N=646 65%	29% ^h (23%, 35%)
Prior biologic, JAKi, or S1PRM failure ^d	N=168 32%	N=331 56%
Without prior biologic, JAKi, or S1PRM failure	N=152 41%	N=315 75%
Endoscopic Improvement ^f
Total Population	N=320 12%	N=646 36%	25% ^h (20%, 30%)
Prior biologic, JAKi, or S1PRM failure ^d	N=168 10%	N=331 26%
Without prior biologic, JAKi, or S1PRM failure	N=152 14%	N=315 47%
Histologic Endoscopic Mucosal Improvement (HEMI) ^g
Total Population	N=320 7%	N=646 24%	17% ^h (13%, 21%)
Prior biologic, JAKi, or S1PRM failure ^d	N=168 7%	N=331 16%
Without prior biologic, JAKi, or S1PRM failure	N=152 8%	N=315 33%
^aSKYRIZI 1,200 mg as an intravenous infusion at Week 0, Week 4, and Week 8 ^bAdjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for stratification factors ^cPer mMS: SFS ≤ 1 and not greater than baseline, RBS = 0, and ES ≤ 1 without friability ^dPrior failure includes inadequate response or intolerance to treatment with one or more of the following: biologic therapies, Janus Kinase inhibitors (JAKi), and/or sphingosine-1-phosphate receptor modulators (S1PRM) ^ePer mMS: decrease ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 from baseline or an absolute RBS ≤ 1 ^fES ≤ 1 without the evidence of friability ^gES ≤ 1 without the evidence of friability and Geboes score ≤ 3.1 (indicating neutrophil infiltration in <5% of crypts, no crypt destruction and no erosions, ulcerations or granulation tissue) ^hp < 0.001

UC-1 was not designed to evaluate the relationship of histologic endoscopic mucosal improvement at week 12 to disease progression and long-term outcomes.

Rectal Bleeding and Stool Frequency Subscores

Decreases in rectal bleeding and stool frequency subscores in subjects treated with SKYRIZI compared to placebo were observed as early as 4 weeks.

Endoscopic Assessment

Endoscopic remission was defined as ES of 0. At Week 12, a greater proportion of subjects treated with SKYRIZI compared to placebo achieved endoscopic remission (11% vs 3%).

Bowel Urgency

A greater proportion of subjects treated with the SKYRIZI 1,200 mg induction regimen compared to placebo had no bowel urgency (44% vs 27%) at Week 12.

Fatigue

In UC-1, subjects treated with SKYRIZI experienced a clinically meaningful improvement in fatigue, assessed by change from baseline in FACIT-F score, at Week 12, compared to placebo-treated subjects. The effect of SKYRIZI to improve fatigue after 12 weeks of induction has not been established.

Other UC Symptoms

The proportion of subjects who had no nocturnal bowel movements was greater in subjects treated with SKYRIZI compared to placebo at Week 12 (67% vs 43%).

Maintenance Trial UC-2

The maintenance trial (UC-2; NCT03398135) evaluated 547 subjects who received one of three SKYRIZI induction regimens, including the 1,200 mg regimen, for 12 weeks in Trials UC-1 or UC-3 and demonstrated clinical response per mMS after 12 weeks. Subjects were randomized to receive a maintenance regimen of subcutaneous (SC) SKYRIZI 180 mg or SKYRIZI 360 mg or placebo at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks.

In UC-2, 75% (411/547) of subjects had failed (inadequate response or intolerance) treatment with one or more biologics, JAKi, or S1PRM. Of these 411 subjects, 407 (99%) failed biologics and 78 (19%) failed JAK inhibitors.

The primary endpoint in UC-2 was clinical remission using mMS at Week 52 (see Table 16 ). Key secondary endpoints included corticosteroid-free clinical remission, endoscopic improvement, and histologic endoscopic mucosal improvement (see Table 16 ).

Table 16. Proportion of Subjects Meeting Efficacy Endpoints at Week 52 - Trial UC-2
Endpoint	Placebo ^a	SKYRIZI 180 mg SC Injection ^b	SKYRIZI 360 mg SC Injection ^c
Clinical remission ^d
Total Population	N=182 26%	N=179 45%	N=186 41%
Treatment Difference vs Placebo ^e(95% CI)	20% ^j [11%, 29%]	16% ^j [7%, 25%]
Prior biologic, JAKi, or S1PRM failure ^f	N=138 24%	N=134 41%	N=139 32%
Without prior biologic, JAKi, or S1PRM failure	N=44 32%	N=45 58%	N=47 67%
Corticosteroid-free clinical remission ^g
Total Population	N=182 26%	N=179 45%	N=186 40%
Treatment Difference vs Placebo ^e(95% CI)	20% ^j [11%, 29%]	16% ^j [7%, 25%]
Prior biologic, JAKi, or S1PRM failure ^f	N=138 24%	N=134 40%	N=139 32%
Without prior biologic, JAKi, or S1PRM failure	N=44 32%	N=45 58%	N=47 64%
Endoscopic improvement ^h
Total Population	N=182 31%	N=179 51%	N=186 48%
Treatment Difference vs Placebo ^e(95% CI)	20% ^j [11%, 30%]	18% ^j [8%, 27%]
Prior biologic, JAKi, or S1PRM failure ^f	N=138 30%	N=134 48%	N=139 39%
Without prior biologic, JAKi, or S1PRM failure	N=44 34%	N=45 60%	N=47 76%
Histologic Endoscopic Mucosal Improvement ⁱ
Total Population	N=182 24%	N=179 43%	N=186 42%
Treatment Difference vs Placebo ^e(95% CI)	20% ^j [11%, 29%]	20% ^j [11%, 29%]
Prior biologic, JAKi, or S1PRM failure ^f	N=138 22%	N=134 39%	N=139 33%
Without prior biologic, JAKi, or S1PRM failure	N=44 30%	N=45 55%	N=47 69%
^aThe placebo group consisted of subjects who were in response to 12 weeks of SKYRIZI induction and were randomized to receive placebo at the start of maintenance therapy. ^bSKYRIZI 180 mg at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks ^cSKYRIZI 360 mg at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks ^dPer mMS: SFS ≤ 1 and not greater than baseline, RBS = 0, and ES ≤ 1 without friability ^eAdjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for stratification factors ^fPrior failure includes inadequate response or intolerance to treatment with one or more of the following: biologic therapies, Janus Kinase inhibitors (JAKi), and/or sphingosine-1-phosphate receptor modulators (S1PRM) ^gClinical remission per mMS at Week 52 and corticosteroid-free for ≥90 days ^hES ≤ 1 without the evidence of friability ⁱES ≤ 1without the evidence of friability and Geboes score ≤ 3.1 (indicating neutrophil infiltration in <5% of crypts, no crypt destruction and no erosions, ulcerations or granulation tissue) ^jp < 0.001

Endoscopic Assessment

Endoscopic remission was defined as ES of 0. In UC-2, a greater proportion of subjects treated with SKYRIZI 180 mg and SKYRIZI 360 mg compared to placebo achieved endoscopic remission at Week 52 (23% and 24% vs 15%).

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