Leaflet SKYRIZI 600mg 60mg / ml concentrate for solution for infusion

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC18

Risankizumab is a humanised immunoglobulin G1 (IgG1) monoclonal antibody that selectively bindswith high affinity to the p19 subunit of human interleukin 23 (IL-23) cytokine without binding to IL-12 and inhibits its interaction with the IL-23 receptor complex. IL-23 is a cytokine that is involved ininflammatory and immune responses. By blocking IL-23 from binding to its receptor, risankizumabinhibits IL-23-dependent cell signalling and release of proinflammatory cytokines.

In a study of subjects with psoriasis, expression of genes associated with the IL-23/IL-17 axis wasdecreased in the skin after single doses of risankizumab. Reductions in epidermal thickness,infiltration of inflammatory cells, and expression of psoriatic disease markers were also observed inpsoriatic lesions.

In a Phase 2 study of subjects with Crohn’s disease, expression of genes associated with the IL-23/Th17 axis were decreased in gut tissue after multiple doses of risankizumab. Reductions in faecalcalprotectin (FCP), serum C reactive protein (CRP) and IL-22 were also observed after multiple dosesin Phase 3 induction studies in Crohn’s patients. Decreases in FCP, CRP and serum IL-22 weremaintained out to week 52 of the maintenance study.

In a Phase 2b/3 study of subjects with ulcerative colitis, statistically significant and clinicallymeaningful reduction from baseline was observed in the inflammatory biomarkers, FCP and CRP, andin the IL-23 pathway-associated biomarker, serum IL-22, at week 12 of the induction study. Decreasesin FCP, CRP and serum IL-22 were maintained out to week 52 of the maintenance study.

The efficacy and safety of risankizumab were assessed in 1 419 subjects with moderately to severelyactive Crohn’s disease in three multicentre, randomised, double-blind, placebo-controlled clinicalstudies. Enrolled subjects were 16 years of age or older with a Crohn’s Disease Activity Index (CDAI)of 220 to 450, an average daily stool frequency (SF) ≥4 and/or average daily abdominal pain score(APS) ≥2, and a Simple Endoscopic Score for CD (SES-CD) of ≥6, or ≥4 for isolated ileal disease,excluding the narrowing component and confirmed by a central reviewer.

There were two 12-week intravenous induction studies (ADVANCE and MOTIVATE), whichincluded a 12-week extension period for subjects who did not achieve SF/APS clinical response (≥30% decrease in SF and/or ≥ 30% decrease in APS and both not worse than baseline) at week 12.

ADVANCE and MOTIVATE were followed by a 52-week randomised withdrawal study ofsubcutaneous maintenance treatment (FORTIFY) that enrolled subjects with SF/APS clinical responseto intravenous induction treatment, representing at least 64 weeks of therapy.

ADVANCE and MOTIVATE

In studies ADVANCE and MOTIVATE, subjects were randomised to receive risankizumab at either600 mg (recommended dose), 1 200 mg, or placebo, at week 0, week 4, and week 8.

In ADVANCE, 58% (491/850) subjects had failed or were intolerant to treatment with one or morebiologic therapies (prior biologic failure), and 42% (359/850) had failed or were intolerant to therapywith conventional therapies but not biologic therapies (without prior biologic failure). In ADVANCE,among the subjects without prior biologic failure, (87%) 314/359 were naïve to biologic therapy andthe remaining 13% had received a biologic but never failed or demonstrated intolerance. All patientsin MOTIVATE had prior biologic failure.

In both studies, a greater proportion of subjects treated with risankizumab achieved the co-primaryendpoints of clinical remission at week 12 and endoscopic response at week 12 compared to placebo.

Enhanced SF/APS clinical response and clinical remission were significant as early as week 4 insubjects treated with risankizumab and continued to improve through week 12 (Table 2).

Table 2. Efficacy results in ADVANCE and MOTIVATE

ADVANCE MOTIVATE

Placebo Risankizumab Treatment Placebo Risankizumab Treatmentintravenous 600 mg differenced intravenous 600 mg differencedly intravenously (95% CI) ly intravenously (95% CI)(N=175) (N=336) (N=187) (N=191)% % % %

Co-primary endpoints

Clinical22% 15%remission at 22% 43% 19% 35%[14%, 30%]a [6%, 24%]bweek 12e

Endoscopic28% 18%response at 12% 40% 11% 29%[21%, 35%]a [10%, 25%]aweek 12f

Additional endpoints

Enhanced

SF/APS clinical 15% 14%31% 46% 32% 45%response at [6%, 23%]b [4%, 23%]cweek 4g

Enhanced

SF/APS clinical 21% 23%42% 63% 39% 62%response at [12%, 30%]a [13%, 33%]aweek 12g

CDAI <150 at 8% 10%10% 18% 11% 21%week 4 [1%, 14%]c [2%, 17%]c

CDAI <150 at 21% 22%25% 45% 20% 42%week 12 [12%, 29%]a [13%, 31%]a

Mucosal healing (N=173) (N=336) 14% (N=186) (N=190) 9%at week 12h 8% 21% [8%, 19%]a 4% 14% [4%, 15%]b

Endoscopic15% 15%remission at 9% 24% 4% 19%[9%, 21%]a [9%, 21%]aweek 12ia Statistically significant under multiplicity-control for risankizumab vs placebo comparison (p<0.001).b Statistically significant under multiplicity-control for risankizumab vs placebo comparison (p≤0.01).c Nominal p ≤ 0.05 risankizumab vs placebo comparison.d Adjusted treatment difference.e Clinical remission based on SF/APS: average daily SF ≤2.8 and not worse than baseline and average daily

AP score ≤1 and not worse than baseline.f Endoscopic response: greater than 50% decrease in SES-CD from baseline, or a decrease of at least 2 pointsfor subjects with a baseline score of 4 and isolated ileal disease.g Enhanced SF/APS clinical response: ≥60% decrease in average daily SF and/or ≥35% decrease in averagedaily AP score and both not worse than Baseline, and/or clinical remission.h Mucosal healing: SES-CD ulcerated surface subscore of 0 in subjects with a subscore of ≥1 at Baseline.i Endoscopic remission: SES-CD ≤4 and at least a 2 point reduction versus Baseline and no subscore greaterthan 1 in any individual variable.

At week 12, a higher proportion of subjects treated with risankizumab achieved a decrease of at least100 points in baseline CDAI compared to placebo (ADVANCE, risankizumab =60%, placebo=37%,p<0.001; MOTIVATE, risankizumab =60%, placebo=30%, p<0.001).

At week 12, a higher proportion of subjects treated with risankizumab achieved both enhanced

SF/APS clinical response and endoscopic response at week 12 compared to placebo (ADVANCE,risankizumab =31%, placebo=8%, p<0.001; MOTIVATE, risankizumab =21%, placebo=7%,p<0.001).

The results for the co-primary endpoints for the subgroups (without allowing for multiplicity) ofsubjects with and without prior biologic failure are presented in Table 3.

Table 3. Efficacy results at week 12 in subgroups of subjects with prior biologic treatmentfailure and subjects without prior biologic failure in ADVANCE

ADVANCE

Risankizumab 600 mg Treatment difference

Placebo intravenously(95% CI)

Clinical remission per SF/AP Score

Prior biologic failure 23% (N=97) 41% (N=195) 18% [7%, 29%]

Without prior biologic 27% [15%, 39%]21% (N=78) 48% (N=141)failure

Endoscopic response

Prior biologic failure 11% (N=97) 33% (N=195) 21% [12%, 31%]

Without prior biologic 38% [27%, 49%]13% (N=78) 50% (N=141)failure

In ADVANCE, a higher proportion of subjects treated with risankizumab with and without priorbiologic failure achieved CDAI<150 compared to placebo (With prior biologic failure, risankizumab=42%, placebo=26%; Without prior biologic failure, risankizumab =49%, placebo=23%).

CD-related hospitalisations

Rates of CD-related hospitalisations through week 12 were lower in subjects treated withrisankizumab compared to placebo (ADVANCE, risankizumab =3%, placebo=12%, p<0.001;

MOTIVATE, risankizumab =3%, placebo=11%, p≤0.01).

FORTIFY

The maintenance study FORTIFY evaluated 462 subjects with SF/APS clinical response to 12 weeksof risankizumab intravenous induction treatment in studies ADVANCE and MOTIVATE. Subjectswere randomised to continue to receive a maintenance regimen of risankizumab 360 mgsubcutaneously (recommended dose), or risankizumab 180 mg subcutaneously every 8 weeks, or towithdraw from risankizumab induction and receive placebo subcutaneously every 8 weeks for up to 52weeks.

The co-primary endpoints were clinical remission at week 52 and, endoscopic response at week 52.

Co-primary endpoints were also measured in subjects with and without prior biologic failure (see

Table 4).

Table 4. Efficacy results in FORTIFY at week 52 (64 weeks from initiation of induction dose)

FORTIFY

Risankizumab Risankizumab Treatment differenceintravenous induction/ intravenous induction/ (95% CI)

Placebo subcutaneously f Risankizumab(N=164) % 360 mgsubcutaneously(N=141) %

Co-primary endpoints

Clinical remission 40% 52% 15% [5%, 25%]a,g

Prior biologic failure 34% (N=123) 48% (N=102) 14% [1%, 27%]

Without prior biologic failure 56% (N=41) 62% (N=39) 5% [-16%, 27%]

Endoscopic response 22% 47% 28% [19%, 37%]b,g

Prior biologic failure 20% (N=123) 44% (N=102) 23% [11%, 35%]

Without prior biologic failure 27% (N=41) 54% (N=39) 27% [6%, 48%]

Additional endpoints

Enhanced SF/APS clinical49% 59% 13% [2%, 23%]e,gresponse

Maintenance of clinical (N = 91) (N = 72)21% [6%, 35%]d,gremissionh 51% 69%

Endoscopic remission 13% 39% 28% [20%, 37%]c,g(N = 162) (N = 141)

Mucosal healing 22% [14%, 30%]c,g10% 31%a Statistically significant under multiplicity-control for risankizumab vs placebo comparison (p≤0.01).b Statistically significant under multiplicity-control for risankizumab vs placebo comparison (p<0.001).c Nominal p<0.001 risankizumab vs placebo comparison without overall type I error control.d Nominal p≤0.01 risankizumab vs placebo comparison without overall type I error control.

e Nominal p≤0.05 risankizumab vs placebo comparison without overall type I error control.f The induction-only group consisted of subjects who achieved clinical response to risankizumab inductiontherapy and were randomised to receive placebo in the maintenance study (FORTIFY).g Adjusted treatment difference.h Maintenance of clinical remission: clinical remission at week 52 in subjects with clinical remission at week0.

Deep remission (clinical remission and endoscopic remission) at week 52 was observed at higher ratesin subjects treated with risankizumab intravenously/risankizumab subcutaneously compared tosubjects who received risankizumab intravenously/placebo subcutaneously (28% vs. 10%,respectively, nominal p<0.001).

At week 52, a higher proportion of subjects treated with risankizumab intravenously/risankizumabsubcutaneously achieved CDAI < 150 compared to risankizumab intravenously /placebosubcutaneously (52% vs. 41%, respectively, nominal p≤0.01). A higher proportion of subjects treatedwith risankizumab intravenously/risankizumab subcutaneously achieved a decrease of at least100 points in baseline CDAI score compared to subjects treated with risankizumab intravenously/placebo subcutaneously (62% vs. 48%, respectively, nominal p≤ 0.01).

91 subjects who did not demonstrate SF/APS clinical response 12 weeks after risankizumab inductionin studies ADVANCE and MOTIVATE received subcutaneous 360 mg dose of risankizumab atweek 12 and week 20. Of these subjects, 64% (58/91) achieved SF/APS clinical response at week 24;33 of the subjects achieving SF/APS clinical response enrolled in FORTIFY and continued receivingrisankizumab 360 mg subcutaneously every 8 weeks for up to 52 weeks. Among these subjects, 55%(18/33) achieved clinical remission and 45% (15/33) achieved endoscopic response at week 52.

During FORTIFY, 30 subjects had loss of response to risankizumab 360 mg subcutaneously treatmentand received rescue treatment with risankizumab (1 200 mg intravenous single dose, followed by360 mg subcutaneously every 8 weeks). Of these subjects, 57% (17/30) achieved SF/APS clinicalresponse at week 52. In addition, 20% (6/30) and 34% (10/29) of subjects achieved clinical remissionand endoscopic response at week 52, respectively.

Health-related and quality of life outcomes

Health-related quality of life was assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)and 36-Item Short Form Health Survey (SF-36). Improvement in fatigue was evaluated by the

Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale. Work productivitywas assessed by the Work Productivity and Activity Impairment CD (WPAI-CD) Questionnaire.

At week 12 of ADVANCE and MOTIVATE, subjects treated with risankizumab achieved clinicallymeaningful improvements from baseline in IBDQ total score, all IBDQ domain scores (bowelsymptoms, systemic function, emotional function, and social function), SF-36 Physical and Mental

Component Summary Score, FACIT-Fatigue and WPAI-CD compared to placebo. For WPAI-CDgreater reductions in impairment while working, overall work impairment, and activity impairmentwere demonstrated in ADVANCE; and greater reduction in activity impairment was demonstrated in

MOTIVATE. These improvements were maintained in subjects treated with risankizumabintravenously/ risankizumab subcutaneously in FORTIFY through week 52.

The efficacy and safety of risankizumab was assessed in subjects with moderately to severely activeulcerative colitis in two multicentre, randomised, double-blind, placebo-controlled clinical studies.

Enrolled subjects were ≥ 18 and ≤ 80 years of age with adapted Mayo Score (aMS) of 5 to 9 (using the

Mayo scoring system, excluding Physician’s Global Assessment) with an endoscopic subscore (ES) of2 or 3 on screening endoscopy, confirmed by central review.

The 12-week intravenous induction study (INSPIRE) included a 12-week extension period for subjectswho did not achieve clinical response [defined as a decrease from baseline in the aMS ≥ 2 points and≥ 30% from baseline, and a decrease in rectal bleeding subscore (RBS) ≥ 1 or an absolute RBS ≤ 1] at

Week 12. INSPIRE was followed by a 52-week randomised withdrawal study of subcutaneousmaintenance treatment (COMMAND) that enrolled subjects with clinical response to 12 weeks ofrisankizumab intravenous induction treatment, representing at least 64 weeks of therapy.

INSPIRE

In study INSPIRE, 975 subjects were randomised and received either risankizumab 1 200 mg orplacebo, at week 0, week 4, and week 8.

In INSPIRE, 52% (503/975) of subjects had failed (inadequate response or intolerance) one or morebiologics therapies, JAK inhibitors, and/or S1P receptor modulators. Of these 503 subjects, 488 (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/dayprednisone or equivalent), immunomodulators, and aminosalicylates. At baseline in INSPIRE, 36% ofsubjects received corticosteroids, 17% of subjects received immunomodulators and 73% of subjectsreceived aminosalicylates. Patient disease activity was moderate (aMS ≤7) in 58% of subjects andsevere (aMS >7) in 42% of subjects.

In INSPIRE, a significantly greater proportion of subjects treated with risankizumab achieved theprimary endpoint of clinical remission per aMS [defined as stool frequency subscore (SFS) ≤ 1, andnot greater than baseline, RBS = 0, and ES ≤ 1 without evidence of friability] at week 12 compared toplacebo (Table 5). Results of the primary endpoint and key secondary endpoints are listed in Table 5.

Table 5. Efficacy results in INSPIRE at week 12

Placebo Risankizumab Treatmentintravenously 1 200 mg difference

Endpoint (N=325) intravenously (95% CI)% (N=650)%

Disease activity and UC symptoms14%f

Clinical remissionab 6% 20%[10%, 18%]7%

With biologic and/or JAK inhibitor failure 4% (N=170) 11% (N=333)[3%, 12%]21%

Without biologic and/or JAK inhibitor failure 8% (N=155) 30% (N=317)[15%, 28%]29%f

Clinical responsec 36% 64%[22%, 35%]24%

With biologic and/or JAK inhibitor failure 31% (N=170) 55% (N=333)[15%, 33%]33%

Without biologic and/or JAK inhibitor failure 41% (N=155) 74% (N=317)[24%, 42%]

Endoscopic and histologic assessment24%f

Mucosal healingd 12% 37%[19%, 29%]16%

With biologic and/or JAK inhibitor failure 10% (N=170) 26% (N=333)[9%, 22%]33%

Without biologic and/or JAK inhibitor failure 14% (N=155) 48% (N=317)[26%, 41%]17%f

Histologic-endoscopic mucosal healinge 8% 24%[12%, 21%]9%

With biologic and/or JAK inhibitor failure 7% (N=170) 16% (N=333)[3%, 14%]

Without biologic and/or JAK inhibitor failure 8% (N=155) 33% (N=317) 25%[18%, 32%]a Primary endpointb Clinical remission per aMS: SFS ≤ 1, and not greater than baseline, RBS = 0, and ES ≤ 1 without evidence offriabilityc Clinical response per aMS: decrease from Baseline ≥ 2 points and ≥ 30%, and a decrease in RBS ≥ 1 or anabsolute RBS ≤ 1d ES ≤ 1 without the evidence of friabilitye ES ≤ 1 without the evidence of friability and Geboes score ≤ 3.1 (indicating neutrophil infiltration in <5% ofcrypts, no crypt destruction and no erosions, ulcerations or granulation tissue)f p < 0.00001, adjusted treatment difference (95% CI)

Clinical disease activity and symptoms

The partial adapted Mayo score (paMS) is composed of SFS and RBS. Clinical response per paMS isdefined as a decrease of ≥1 point and ≥30% from Baseline and a decrease in RBS ≥1 or an absolute

RBS ≤1. The results of clinical response per paMS over time in INSPIRE are shown in Figure 1. Onsetof efficacy was rapid with a greater proportion of subjects treated with risankizumab achieving clinicalresponse as early as week 4 compared to placebo (52% vs 31%, respectively, p < 0.00001).

Figure 1. Proportion of subjects achieving clinical response per paMS over time in inductionstudy INSPIRE

Weeks

Placebo intravenously (N=325)

Risankizumab 1 200 mg intravenously (N=650)

A significantly greater proportion of subjects treated with risankizumab compared to placebo had noabdominal pain (36% vs 26%, respectively, p < 0.01) and no bowel urgency (44% vs 28%,respectively, p < 0.00001) at week 12.

Other UC Symptoms

Number of faecal incontinence episodes per week was reduced in a significantly greater amount insubjects treated with risankizumab compared to placebo at week 12 (change from baseline inrisankizumab = -3.8, placebo = -2.2, p = 0.00003).

The proportion of subjects who had no nocturnal bowel movements was significantly greater insubjects treated with risankizumab compared to placebo at week 12 (67% vs 43%, respectively,p < 0.00001).

The proportion of subjects who had no tenesmus was significantly greater in subjects treated withrisankizumab compared to placebo at week 12 (49% vs 30%, respectively, p < 0.00001).

Response Rate (%) and 95% CI

Number of days with sleep interruption due to UC symptoms per week were reduced in a significantlygreater amount in subjects treated with risankizumab compared to placebo at week 12 (change frombaseline in risankizumab = -2.5, placebo = -1.5, p < 0.00001).

UC-related hospitalisations

Rates of UC-related hospitalisations through week 12 were significantly lower in subjects treated withrisankizumab compared to placebo (1% vs 6%, respectively, p < 0.00001).

Extended treatment in week 12 non-responders

A total of 141 subjects who did not demonstrate clinical response at week 12 of risankizumabinduction in INSPIRE received either subcutaneous 180 mg or 360 mg dose of risankizumab at week12 and week 20. Of the 71 subjects who received risankizumab 180 mg subcutaneously and 70subjects who received risankizumab 360 mg subcutaneously, 56% and 57% achieved clinical responseat week 24, respectively.

COMMAND

The maintenance study COMMAND evaluated 548 subjects with clinical response after 12 weeks ofrisankizumab intravenous induction treatment in study INSPIRE. Subjects were randomised to receivea maintenance regimen of risankizumab 180 mg subcutaneously or 360 mg subcutaneously every 8weeks, or to withdraw from risankizumab induction and receive placebo subcutaneously every 8weeks for up to 52 weeks.

In COMMAND, 75% (411/548) of subjects had failed (inadequate response or intolerance) one ormore biologics therapies, JAK inhibitors, and/or S1P receptor modulators prior to induction baseline.

Of these 411 subjects, 407 (99%) failed biologics and 78 (19%) failed JAK inhibitors.

In COMMAND, a significantly greater proportion of the above 548 subjects treated with risankizumab180 mg subcutaneously or risankizumab 360 mg subcutaneously achieved the primary endpoint ofclinical remission per aMS at week 52 compared to placebo (see Table 6). Results of the primaryendpoint and key secondary endpoints are listed in Table 6.

Table 6. Efficacy results in COMMAND at week 52 (64 weeks from initiation of induction dose)

Risankizumab Risankizumab Risankizumab Treatment differenceintravenous intravenous intravenous (97.5% CI)++induction/ induction/ induction/

Risankizumab Risankizumab

Placebo Risankizumab Risankizumabintravenous intravenous

Endpoint subcutaneousl 180 mg 360 mginduction/ induction/y+ subcutaneously subcutaneousl

Risankizumab Risankizumab(N=183) % (N=179) % y180 mg 360 mg(N=186) %subcutaneousl subcutaneouslyy

Disease activity and UC symptoms16%h 14%h

Clinical remissionab 25% 40% 38%[6%, 27%] [4%, 24%]

With biologic and/or 13% 6%23% (N=138) 37% (N=134) 29% (N=139)

JAK inhibitor failure [1%, 26%] [-6%, 18%]

Without biologic and/or 20% 31%31% (N=45) 51% (N=45) 62% (N=47)

JAK inhibitor failure [-3%, 43%] [8%, 53%]

Maintenance of clinical 29%h 13%k40% (N=53) 70% (N=44) 50% (N=40)remissionc [7%, 51%] [-11%, 36%]

With biologic and/or 28% 7%37% (N=35) 65% (N=26) 44% (N=25)

JAK inhibitor failure [0%, 56%] [-22%, 36%]

Without biologic and/or 33% 16%44% (N=18) 77% (N=18) 60% (N=15)

JAK inhibitor failure [-2%, 67%] [-23%, 54%]

Corticosteroid-free 16% h 14% hd 25% 40% 37%clinical remission [6%, 26%] [3%, 24%]

With biologic and/or 13% 6%23% (N=138) 36% (N=134) 29% (N=139)

JAK inhibitor failure [0%, 25%] [-6%, 18%]

Without biologic and/or 20% 28%31% (N=45) 51% (N=45) 60% (N=47)

JAK inhibitor failure [-3%, 43%] [6%, 51%]17%i 11%j

Clinical responsee 52% 68% 62%[6%, 28%] [0%, 23%]

With biologic and/or 18% 11%46% (N=138) 63% (N=134) 57% (N=139)

JAK inhibitor failure [4%, 31%] [-2%, 25%]

Without biologic and/or 11% 8%71% (N=45) 82% (N=45) 79% (N=47)

JAK inhibitor failure [-9%, 31%] [-13%, 28%]

Endoscopic and histologic assessment20% h 17% h

Mucosal healingf 32% 51% 48%[9%, 31%] [7%, 28%]

With biologic and/or 17% 8%30% (N=138) 48% (N=134) 39% (N=139)

JAK inhibitor failure [4%, 30%] [-4%, 21%]

Without biologic and/or 24% 41%36% (N=45) 60% (N=45) 76% (N=47)

JAK inhibitor failure [1%, 47%] [19%, 62]

Histologic-endoscopic 20%h 20% hg 23% 43% 42%mucosal healing [10%, 31%] [10%, 30%]

With biologic and/or 17% 11%22% (N=138) 39% (N=134) 33% (N=139)

JAK inhibitor failure [5%, 29%] [-1%, 23%]

Without biologic and/or 26% 40%29% (N=45) 55% (N=45) 69% (N=47)

JAK inhibitor failure [3%, 49%] [19%, 62%]+ The induction-only group consisted of subjects who achieved clinical response to risankizumabinduction therapy and were randomised to receive placebo in the maintenance study (COMMAND).++ Adjusted difference for the overall treatment difference.a Primary endpointb Clinical remission per aMS: SFS ≤ 1, and not greater than baseline, RBS = 0, and ES ≤ 1 withoutevidence of friabilityc Clinical remission per aMS at week 52 among subjects who achieved clinical remission at the end ofinduction treatmentd Clinical remission per aMS at week 52 and corticosteroid-free for ≥90 dayse Clinical response per aMS: decrease from Baseline ≥ 2 points and ≥ 30%, and a decrease in RBS ≥ 1or an absolute RBS ≤ 1f ES of ≤ 1 without the evidence of friabilityg ES ≤ 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)h Statistically significant under multiplicity-control for risankizumab vs placebo comparison (p ≤ 0.01).i Nominal p ≤ 0.01 risankizumab vs placebo comparisonj Nominal p ≤ 0.05 risankizumab vs placebo comparisonk p = 0.2234

Clinical disease activity and symptoms

A significantly greater proportion of subjects treated with risankizumab intravenously/risankizumab180 mg subcutaneously compared to risankizumab intravenously/placebo had no abdominal pain (47%vs 30%, respectively, p < 0.001) and no bowel urgency (54% vs 31%, respectively, p < 0.00001) atweek 52. A greater proportion of subjects treated with risankizumab intravenously /risankizumab360 mg subcutaneously compared to risankizumab intravenously/placebo had no bowel urgency (49%vs 31%, respectively, p < 0.001) at week 52, and a numerically higher proportion of subjects had noabdominal pain compared to risankizumab intravenously/placebo (38% vs 30%, respectively,p = 0.0895) at week 52.

Other UC symptoms

The proportion of subjects who had no nocturnal bowel movements was greater in subjects treatedwith risankizumab intravenously/risankizumab 180 mg subcutaneously and risankizumabintravenously/risankizumab 360 mg subcutaneously compared to risankizumab intravenously/placeboat week 52 (42% and 43% vs 30%, p < 0.01 and p < 0.001, respectively).

The proportion of subjects who had no tenesmus was greater in subjects treated with risankizumabintravenously/risankizumab 180 mg subcutaneously and risankizumab intravenously/risankizumab360 mg subcutaneously compared to risankizumab intravenously/placebo at week 52 (37% and 37%vs 23%, respectively, p < 0.01).

UC-related hospitalisations

Occurrence of UC-related hospitalisations through week 52 were numerically lower in subjects treatedwith risankizumab intravenously/risankizumab 180 mg subcutaneously and risankizumabintravenously/risankizumab 360 mg subcutaneously compared to risankizumab intravenously/placebo(0.6 per 100 subject-years and 1.2 per 100 subject-years vs 3.1 per 100 subject-years, p = 0.0949 andp = 0.2531, respectively).

Endoscopic and histologic assessment

Endoscopic remission (normalisation of the endoscopic appearance of the mucosa) was defined as ESof 0. At week 12 of INSPIRE, a significantly greater proportion of subjects treated with risankizumabcompared to placebo achieved endoscopic remission (11% vs 3%, respectively, p < 0.00001). Atweek 52 of COMMAND, a significantly greater proportion of subjects treated with risankizumabintravenously/risankizumab 180 mg subcutaneously and risankizumab intravenously/risankizumab360 mg subcutaneously compared to risankizumab intravenously/placebo achieved endoscopicremission (23% and 24% vs 15%, respectively, p < 0.05).

Deep mucosal healing was defined as ES of 0 and Geboes score < 2.0 (indicating no neutrophil incrypts or lamina propria and no increase in eosinophil, no crypt destruction, and no erosions,ulcerations or granulation tissue). At week 12 of INSPIRE, a significantly greater proportion ofsubjects treated with risankizumab compared to placebo achieved deep mucosal healing (6% vs 1%,respectively, p < 0.00001). At week 52 of COMMAND, a numerically higher proportion of subjectstreated with risankizumab intravenously/risankizumab 180 mg subcutaneously and risankizumabintravenously/risankizumab 360 mg subcutaneously compared to risankizumab intravenously/placeboachieved deep mucosal healing (13% and 16% vs 10%, p = 0.2062 and p = 0.0618, respectively).

In COMMAND, maintenance of mucosal healing at week 52 (ES ≤1 without friability) was seen in agreater proportion of subjects treated with risankizumab intravenously/risankizumab 180 mgsubcutaneously and risankizumab intravenously/risankizumab 360 mg subcutaneously compared torisankizumab intravenously/placebo among subjects who achieved mucosal healing at the end ofinduction (74% and 54% vs 47%, p < 0.01 and p = 0.5629, respectively).

Rescue treatment

During COMMAND, subjects who had loss of response to risankizumab subcutaneously treatmentreceived rescue treatment with risankizumab (a single intravenous induction dose, followed by 360 mgsubcutaneously every 8 weeks). Among these subjects, in the risankizumab 180 mg subcutaneous andrisankizumab 360 mg subcutaneous treatment group, 85% (17/20) and 74% (26/35) achieved clinicalresponse at week 52, respectively. In addition, 24% (6/25) and 35% (13/37) of subjects achievedclinical remission per aMS, and 38% (10/26) and 45% (17/38) of subjects achieved endoscopicimprovement at week 52 in the risankizumab 180 mg subcutaneous and risankizumab 360 mgsubcutaneous treatment group, respectively.

Week 24 responders

A total of 100 subjects did not demonstrate clinical response after 12 weeks of induction treatment,received either subcutaneous 180 mg (N=56) or 360 mg (N=44) dose of risankizumab at week 12 andweek 20, demonstrated clinical response at week 24, and continued receiving risankizumab 180 mg or360 mg subcutaneously every 8 weeks for up to 52 weeks in COMMAND. Among these subjects,46% and 45% achieved clinical response per aMS at week 52, and 18% and 23% achieved clinicalremission per aMS at week 52, for risankizumab 180 mg and 360 mg subcutaneously respectively.

Health-related and quality of life outcomes

Subjects treated with risankizumab achieved clinically meaningful improvements from baseline in the

Inflammatory Bowel Disease Questionnaire (IBDQ) (bowel symptoms, systemic function, emotionalfunction, and social function) compared to placebo. Changes from baseline in IBDQ total score atweek 12 with risankizumab compared to placebo were 42.6 and 24.3, respectively. Changes frombaseline in IBDQ total score at week 52 were 52.6, 50.3 and 35.0 in subjects treated withrisankizumab intravenously/risankizumab 180 mg subcutaneously, risankizumabintravenously/risankizumab 360 mg subcutaneously and risankizumab intravenously/placebo,respectively.

Subjects receiving risankizumab experienced significantly greater improvement from baseline infatigue, as measured by FACIT-F score at week 12 compared to placebo. Changes from baseline in

FACIT-F score at Week 12 with risankizumab compared to placebo were 7.9 and 3.3, respectively.

Changes from baseline in FACIT-F score at week 52 were 10.9, 10.3 and 7.0 in subjects treated withrisankizumab intravenously/risankizumab 180 mg subcutaneously, risankizumabintravenously/risankizumab 360 mg subcutaneously and risankizumab intravenously/placebo,respectively.

The European Medicines Agency has deferred the obligation to submit the results of studies with Skyriziin one or more subsets of the paediatric population in the treatment of Crohn’s disease and ulcerativecolitis (see section 4.2 for information on paediatric use).