SKYRIZI 150mg 150mg / 1ml injection for pre-filled pen medication leaflet

Skyrizi 150 mg solution for injection in pre-filled pen

Skyrizi 150 mg solution for injection in pre-filled syringe

Skyrizi 75 mg solution for injection in pre-filled syringe

Skyrizi 150 mg solution for injection in pre-filled pen

Each pre-filled pen contains 150 mg risankizumab in 1 mL solution.

Skyrizi 150 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 150 mg risankizumab in 1 mL solution.

Skyrizi 75 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 75 mg risankizumab in 0.83 mL solution.

Risankizumab is a humanised immunoglobulin G1 (IgG1) monoclonal antibody produced in Chinese

Hamster Ovary cells using recombinant DNA technology.

Excipients with known effect (75 mg solution for injection only)

This medicinal product contains 68.0 mg sorbitol per 150 mg dose.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Skyrizi 150 mg solution for injection in pre-filled pen and in pre-filled syringe

The solution is colourless to yellow and clear to slightly opalescent.

Skyrizi 75 mg solution for injection in pre-filled syringe

The solution is colourless to slightly yellow and clear to slightly opalescent.

Plaque psoriasis

Skyrizi is indicated for the treatment of moderate to severe plaque psoriasis in adults who arecandidates for systemic therapy.

Skyrizi, alone or in combination with methotrexate (MTX), is indicated for the treatment of activepsoriatic arthritis in adults who have had an inadequate response or who have been intolerant to one ormore disease-modifying antirheumatic drugs (DMARDs).

This medicinal product is intended for use under the guidance and supervision of a physicianexperienced in the diagnosis and treatment of conditions for which Skyrizi is indicated.

The recommended dose is 150 mg administered as a subcutaneous injection at week 0, week 4, andevery 12 weeks thereafter (either as two 75 mg pre-filled syringe injections or one 150 mg pre-filledpen or pre-filled syringe injection).

Consideration should be given to discontinuing treatment in patients who have shown no responseafter 16 weeks of treatment. Some plaque psoriasis patients with initial partial response maysubsequently improve with continued treatment beyond 16 weeks.

If a dose is missed, the dose should be administered as soon as possible. Thereafter, dosing should beresumed at the regular scheduled time.

No dose adjustment is required (see section 5.2).

There is limited information in subjects aged ≥ 65 years.

No specific studies were conducted to assess the effect of hepatic or renal impairment on thepharmacokinetics of risankizumab. These conditions are generally not expected to have any significantimpact on the pharmacokinetics of monoclonal antibodies and no dose adjustments are considerednecessary (see section 5.2).

The safety and efficacy of risankizumab in children and adolescents aged 5 to less than 18 years havenot been established. No data are available.

There is no relevant use of risankizumab in children aged below 6 years for the indication of moderateto severe plaque psoriasis or in children aged below 5 years for the indication of psoriatic arthritis.

Overweight patients

No dose adjustment is required (see section 5.2).

Skyrizi is administered by subcutaneous injection.

The injection should be administered in the thigh or abdomen. Patients should not inject into areaswhere the skin is tender, bruised, erythematous, indurated, or affected by psoriasis.

Patients may self-inject Skyrizi after training in subcutaneous injection technique. Patients should beinstructed to read the ‘Instructions for use’ provided in the package leaflet before administration.

Administration of Skyrizi in the upper, outer arm may only be performed by a healthcare professionalor caregiver.

Skyrizi 75 mg solution for injection in pre-filled syringe

Two pre-filled syringes should be injected for the full 150 mg dose. The two injections should beadministered at different anatomic locations.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Clinically important active infections (e.g. active tuberculosis, see section 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Risankizumab may increase the risk of infection.

In patients with a chronic infection, a history of recurrent infection, or known risk factors for infection,risankizumab should be used with caution. Treatment with risankizumab should not be initiated inpatients with any clinically important active infection until the infection resolves or is adequatelytreated.

Patients treated with risankizumab should be instructed to seek medical advice if signs or symptoms ofclinically important chronic or acute infection occur. If a patient develops such an infection or is notresponding to standard therapy for the infection, the patient should be closely monitored andrisankizumab should not be administered until the infection resolves.

Prior to initiating treatment with risankizumab, patients should be evaluated for tuberculosis (TB)infection. Patients receiving risankizumab should be monitored for signs and symptoms of active TB.

Anti-TB therapy should be considered prior to initiating risankizumab in patients with a past history oflatent or active TB in whom an adequate course of treatment cannot be confirmed.

Prior to initiating therapy with risankizumab, completion of all appropriate immunisations should beconsidered according to current immunisation guidelines. If a patient has received live vaccination(viral or bacterial), it is recommended to wait at least 4 weeks prior to starting treatment withrisankizumab. Patients treated with risankizumab should not receive live vaccines during treatmentand for at least 21 weeks after treatment (see section 5.2).

Serious hypersensitivity reactions, including anaphylaxis, have been reported with use ofrisankizumab (see section 4.8). If a serious hypersensitivity reaction occurs, administration ofrisankizumab should be discontinued immediately and appropriate therapy initiated.

Skyrizi 150 mg solution for injection in pre-filled pen or pre-filled syringe

This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled pen or pre-filledsyringe, that is to say, essentially ‘sodium free’.

Skyrizi 75 mg solution for injection in pre-filled syringe

This medicinal product contains 68.0 mg sorbitol per 150 mg dose.

The additive effect of concomitantly administered products containing sorbitol (or fructose) anddietary intake of sorbitol (or fructose) should be taken into account.

This medicinal product contains less than 1 mmol sodium (23 mg) per 150 mg dose, that is to say,essentially ‘sodium free’.

Risankizumab is not expected to undergo metabolism by hepatic enzymes or renal elimination.

Interactions between risankizumab and inhibitors, inducers, or substrates of medicinal productmetabolising enzymes are not expected, and no dose adjustment is needed (see section 5.2).

Concomitant immunosuppressive therapy or phototherapy

The safety and efficacy of risankizumab in combination with immunosuppressants, including biologicsor phototherapy, have not been evaluated.

Women of childbearing potential should use an effective method of contraception during treatmentand for at least 21 weeks after treatment.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use ofrisankizumab in pregnant women. Animal studies do not indicate direct or indirect harmful effectswith respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use ofrisankizumab during pregnancy.

It is unknown whether risankizumab is excreted in human milk. Human IgGs are known to be excretedin breast milk during the first few days after birth, which decreases to low concentrations soonafterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. Adecision should be made whether to discontinue/abstain from risankizumab therapy, taking intoaccount the benefit of breast-feeding to the child and the benefit of risankizumab therapy to thewoman.

The effect of risankizumab on human fertility has not been evaluated. Animal studies do not indicatedirect or indirect harmful effects with respect to fertility.

Risankizumab has no or negligible influence on the ability to drive and use machines.

The most frequently reported adverse reactions were upper respiratory infections (13.0% in psoriasis).

Adverse reactions for risankizumab from clinical studies (Table 1) are listed by MedDRA systemorgan class and are based on the following convention: very common (≥ 1/10); common (≥ 1/100 to< 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000) andnot known (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

Table 1: List of adverse reactions

System Organ Class Frequency Adverse reactions

Infections and Very common Upper respiratoryinfestations infectionsa

Common Tinea infectionsb

Uncommon Folliculitis

Immune system Rare Anaphylactic reactionsdisorders

Nervous system Common Headachecdisorders

Skin and subcutaneous Common Pruritustissue disorders Rash

Eczema

Uncommon Urticaria

General disorders and Common Fatiguedadministration site Injection site reactionseconditionsa Includes: respiratory tract infection (viral, bacterial or unspecified), sinusitis(including acute), rhinitis, nasopharyngitis, pharyngitis (including viral), tonsillitis,laryngitis, tracheitisb Includes: tinea pedis, tinea cruris, body tinea, tinea versicolor, tinea manuum,onychomycosis, fungal skin infectionc Includes: headache, tension headache, sinus headached Includes: fatigue, astheniae Includes: injection site bruising, erythema, haematoma, haemorrhage, irritation, pain,pruritus, reaction, swelling, induration, rash

The rate of infections was 75.5 events per 100 subject-years from the psoriasis clinical studies and43.0 events per 100 subject-years from the psoriatic arthritis clinical studies, including long-termexposure to risankizumab. The majority of cases were non-serious and mild to moderate in severityand did not lead to discontinuation of risankizumab. The rate of serious infections was 1.7 events per100 subject-years from the psoriasis studies and 2.6 events per 100 subject-years from the psoriaticarthritis studies (see section 4.4).

For subjects treated with risankizumab at the recommended clinical dose for up to 52 weeks inpsoriasis clinical trials, treatment-emergent anti-drug antibodies and neutralising antibodies weredetected in 24% (263/1 079) and 14% (150/1 079) of evaluated subjects, respectively. For subjectsexposed to long term treatment of risankizumab in the extension study, the immunogenicity profileobserved up to 204 weeks of treatment was consistent compared to the first 52 weeks of treatment.

For most subjects with psoriasis, antibodies to risankizumab including neutralising antibodies were notassociated with changes in clinical response or safety. Among the few subjects (approximately 1%;7/1 000 at week 16 and 6/598 at week 52) with high antibody titres (>128), clinical response appearedto be reduced. The incidence of injection site reactions is numerically higher in the anti-drug antibody-positive groups compared with anti-drug antibody-negative groups over short-term (16 weeks: 2.7%vs 1.3%) and longer-term treatment (52 weeks: 5.0% vs 3.3%). The injection site reactions were allmild to moderate in severity, none were serious, and none led to discontinuation of risankizumab.

For subjects treated with risankizumab at the recommended clinical dose for up to 28 weeks inpsoriatic arthritis clinical trials, treatment-emergent anti-drug antibodies and neutralizing antibodieswere detected in 12.1% (79/652) and 0% (0/652) of evaluated subjects, respectively. Antibodies torisankizumab were not associated with changes in clinical response or safety for psoriatic arthritis.

Overall, the safety profile observed in patients with psoriatic arthritis treated with risankizumab wasconsistent with the safety profile observed in patients with plaque psoriasis.

There is limited safety information in subjects aged ≥65 years.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of overdose, it is recommended that the patient be monitored for any signs or symptomsof adverse reactions and appropriate symptomatic treatment be instituted immediately.

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 study of subjects with psoriatic arthritis, statistically significant and clinically meaningfulreduction from baseline was observed at week 24 in IL-23 and IL-17-associated biomarkers, includingserum IL-17A, IL-17F, and IL-22 following treatment with risankizumab 150 mg subcutaneously atweek 0, week 4, and every 12 weeks thereafter.

Plaque Psoriasis

The efficacy and safety of risankizumab was assessed in 2 109 subjects with moderate to severeplaque psoriasis in four multicentre, randomised, double-blind studies (ULTIMMA-1, ULTIMMA-2,

IMMHANCE, and IMMVENT). Enrolled subjects were 18 years of age and older with plaquepsoriasis who had a body surface area (BSA) involvement of ≥10%, a static Physician Global

Assessment (sPGA) score of ≥3 in the overall assessment (plaque thickness/induration, erythema, andscaling) of psoriasis on a severity scale of 0 to 4, a Psoriasis Area and Severity Index (PASI) score≥12, and who were candidates for systemic therapy or phototherapy.

Overall, subjects had a median baseline PASI score of 17.8, a median BSA of 20.0%, and a medianbaseline DLQI score of 13.0. Baseline sPGA score was severe in 19.3% of subjects and moderate in80.7% of subjects. A total of 9.8% of study subjects had a history of diagnosed psoriatic arthritis.

Across all studies, 30.9% of subjects were naïve to any systemic therapy (including non-biologic andbiologic), 38.1% had received prior phototherapy or photochemotherapy, 48.3% had received priornon-biologic systemic therapy, 42.1% had received prior biologic therapy, and 23.7% had received atleast one anti-TNF alpha agent for the treatment of psoriasis. Patients who completed these studies andother Phase 2/3 studies had the opportunity to enrol in an open-label extension study, LIMMITLESS.

ULTIMMA-1 and ULTIMMA-2

ULTIMMA-1 and ULTIMMA-2 enrolled 997 subjects (598 randomised to risankizumab 150 mg, 199to ustekinumab 45 mg or 90 mg [according to baseline weight], and 200 to placebo). Subjects receivedtreatment at week 0, week 4, and every 12 weeks thereafter. The two co-primary endpoints in

ULTIMMA-1 and ULTIMMA-2 were the proportion of subjects who achieved 1) PASI 90 responseand 2) sPGA score of clear or almost clear (sPGA 0 or 1) at week 16 versus placebo. The results forthe co-primary and other endpoints are presented in Table 2 and Figure 1.

Table 2: Efficacy and quality of life results in adults with plaque psoriasis in ULTIMMA-1 and

ULTIMMA-2

ULTIMMA-1 ULTIMMA-2

Risankizumab Ustekinumab Placebo Risankizumab Ustekinumab Placebo(N=304) (N=100) (N=102) (N=294) (N=99) (N=98)n (%) n (%) n (%) n (%) n (%) n (%)sPGA of clear or almost clear (0 or 1)

Week 16a 267 (87.8) 63 (63.0) 8 (7.8) 246 (83.7) 61 (61.6) 5 (5.1)

Week 52 262 (86.2) 54 (54.0) -- 245 (83.3) 54 (54.5) --sPGA of clear (0)

Week 16 112 (36.8) 14 (14.0) 2 (2.0) 150 (51.0) 25 (25.3) 3 (3.1)

Week 52 175 (57.6) 21 (21.0) -- 175 (59.5) 30 (30.3) --

PASI 75

Week 12 264 (86.8) 70 (70.0) 10 (9.8) 261 (88.8) 69 (69.7) 8 (8.2)

Week 52 279 (91.8) 70 (70.0) -- 269 (91.5) 76 (76.8) --

PASI 90

Week 16a 229 (75.3) 42 (42.0) 5 (4.9) 220 (74.8) 47 (47.5) 2 (2.0)

Week 52 249 (81.9) 44 (44.0) -- 237 (80.6) 50 (50.5) --

PASI 100

Week 16 109 (35.9) 12 (12.0) 0 (0.0) 149 (50.7) 24 (24.2) 2 (2.0)

Week 52 171 (56.3) 21 (21.0) -- 175 (59.5) 30 (30.3) --

DLQI 0 or 1b

Week 16 200 (65.8) 43 (43.0) 8 (7.8) 196 (66.7) 46 (46.5) 4 (4.1)

Week 52 229 (75.3) 47 (47.0) -- 208 (70.7) 44 (44.4) --

PSS 0 (symptom-free)c

Week 16 89 (29.3) 15 (15.0) 2 (2.0) 92 (31.3) 15 (15.2) 0 (0.0)

Week 52 173 (56.9) 30 (30.0) -- 160 (54.4) 30 (30.3) --

All comparisons of risankizumab versus ustekinumab and placebo achieved p<0.001 except for PASI 75 at week 52 in

ULTIMMA-2 where p=0.001a Co-primary endpoints versus placebob No impact on health-related quality of lifec Psoriasis Symptom Scale (PSS) of 0 means no symptoms of pain, itching, redness, and burning during the last 24hours

Figure 1: Time course of mean percent change from baseline of PASI in ULTIMMA-1 and

ULTIMMA-20 4 8 12 16 22 28 34 40 46 52

Weeks

RZB = risankizumab

UST = ustekinumab

PBO = placebop<0.001 at each time point

Examination of age, gender, race, body weight ≤130 kg, baseline PASI score, concurrent psoriaticarthritis, previous non-biologic systemic treatment, previous biologic treatment, and previous failureof a biologic did not identify differences in response to risankizumab among these subgroups.

Improvements were observed in psoriasis involving the scalp, the nails, and the palms and soles atweek 16 and week 52 in subjects treated with risankizumab.

PASI Percent Change from Baseline

Table 3: Mean changes from baseline in NAPSI, PPASI, and PSSI

ULTIMMA-1 ULTIMMA-2 IMMHANCE

Risankizumab Placebo Risankizumab Placebo Risankizumab Placebo

NAPSI: N=58;

N=56; N=49;

Change N=178; N=177; N=235; 2.52.1 (1.86) 3.0 (1.76)at Week -9.0 (1.17) -7.5 (1.03) -7.5 (0.89) (1.70)

*** ***16 (SE) ***

PPASI: N=34; N=23; N=26;

N=95; N=113;

Change -3.17 N=86; -3.74 -0.27

- 5.93 (0.324) -7.39 (0.654)at Week (0.445) -7.24 (0.558) (1.025) (1.339)16 (SE) *** ** ***

PSSI: N=92; N=83; N=88;

Change N=267; -2.9 N=252; -4.6 N=357; -5.5at Week -17.6 (0.47) (0.69) -18.4 (0.52) (0.82) -20.1 (0.40) (0.77)16 (SE) *** *** ***

NAPSI:

Change N=178; N=183;

- - - -at Week -15.7 (0.94) -16.7 (0.85)52 (SE)

PPASI:

N=95;

Change N=89;

- 6.16 (0.296) - - - -at Week -8.35 (0.274)52 (SE)

PSSI:

Change N=269; N=259;

- - - -at Week -17.9 (0.34) -18.8 (0.24)52 (SE)

Nail Psoriasis Severity Index (NAPSI), Palmoplantar Psoriasis Severity Index (PPASI), Psoriasis Scalp

Severity Index (PSSI), and Standard Error (SE)

** P < 0.01 comparing to risankizumab

*** P < 0.001 comparing to risankizumab

Anxiety and depression, as measured by the Hospital Anxiety and Depression Scale (HADS),improved in the risankizumab group at week 16 compared with the placebo group.

In an integrated analysis of subjects receiving risankizumab in ULTIMMA-1 and ULTIMMA-2 for

PASI 100 responders at week 16, 79.8% (206/258) of the subjects who continued on risankizumabmaintained the response at week 52. For PASI 90 responders at week 16, 88.4% (398/450) of subjectsmaintained the response at week 52.

Of the patients who received risankizumab in ULTIMMA-1 and ULTIMMA-2, 525 continued toreceive risankizumab every 12 weeks in LIMMITLESS. Of these, 376 (71.6%) completed anadditional 252 weeks of open-label treatment. Among subjects remaining in the study, improvementsachieved with risankizumab in rates of PASI 90 and sPGA of clear or almost clear at week 52 weremaintained through week 304.

Of the patients who received ustekinumab in ULTIMMA-1 and ULTIMMA-2, 172 receivedrisankizumab every 12 weeks in LIMMITLESS. Of these, 116 (67.4%) completed the study, including252 weeks of open-label risankizumab treatment and end of study follow-up. Among subjectsremaining in the study, rates of PASI 90 and sPGA response of clear or almost clear increased fromweek 52 through week 76 and were then maintained through week 304.

Figures 2 and 3 show the response rates for PASI 90 and sPGA of clear or almost clear, respectively,in subjects who completed 252 weeks of open-label treatment in LIMMITLESS.

Figure 2: Percent of subjects who achieved a PASI 90 response (OC) in LIMMITLESS

Risankizumab (N) 524 517 511 509 506 500 489 486 473 468 459 462 418 424 430 410 398 374

Ustekinumab to risankizumab (N) 172 171 168 165 162 156 152 147 146 145 143 140 130 129 128 127 120 119

Week 52 64 76 88 100 112 124 136 148 160 172 184 196 208 232 256 280 304

- M-

Treatment Risankizumab Ustekinumab to

Risankizumab

Figure 3: Percent of subjects who achieved an sPGA clear or almost clear response by visit (OC) in

LIMMITLESS

Risankizumab (N) 524 517 511 509 506 500 489 486 473 468 459 462 418 424 429 410 398 375

Ustekinumab to risankizumab (N) 172 171 168 165 162 156 152 147 146 145 143 140 130 129 128 127 120 119

Week 52 64 76 88 100 112 124 136 148 160 172 184 196 208 232 256 280 304

Treatment Risankizumab Ustekinumab to

Risankizumab

Response Rate (%) Response Rate (%)

Improvements in Dermatology Life Quality Index (DLQI 0 or 1) were maintained in patients receivingcontinuous risankizumab treatment through week 304 in the open label extension study

LIMMITLESS.

The safety profile of risankizumab with more than 5 years of exposure was consistent with the profileobserved up to 16 weeks.

IMMHANCE

IMMHANCE enrolled 507 subjects (407 randomised to risankizumab 150 mg and 100 to placebo).

Subjects received treatment at week 0, week 4, and every 12 weeks thereafter. Subjects who wereoriginally on risankizumab and had a sPGA of clear or almost clear at week 28 were re-randomised tocontinue risankizumab every 12 weeks through week 88 (with follow-up 16 weeks after lastrisankizumab dose) or have treatment withdrawn.

At week 16, risankizumab was superior to placebo on the co-primary endpoints of sPGA of clear oralmost clear (83.5% risankizumab vs 7.0% placebo) and PASI 90 (73.2% risankizumab vs 2.0%placebo).

Of the 31 subjects from the IMMHANCE study with latent tuberculosis (TB) who did not receiveprophylaxis during the study, none developed active TB during the mean follow-up of 55 weeks onrisankizumab.

Among subjects with sPGA of clear or almost clear at week 28 in IMMHANCE, 81.1% (90/111) ofsubjects re-randomised to continued treatment with risankizumab maintained this response at week104 compared with 7.1% (16/225) who were re-randomised to withdrawal from risankizumab. Ofthese subjects, 63.1% (70/111) of subjects re-randomised to continued treatment with risankizumabachieved a sPGA clear response at week 104 compared with 2.2% (5/225) who were re-randomised towithdrawal from risankizumab.

Among subjects who achieved sPGA of clear or almost clear at week 28 and relapsed to sPGA ofmoderate or severe following withdrawal from risankizumab, 83.7% (128/153) regained sPGA of clearor almost clear after 16 weeks of retreatment. Loss of sPGA of clear or almost clear was observed asearly as 12 weeks after a missed dose. Of those subjects who were re-randomised to withdraw fromtreatment, 80.9% (182/225) relapsed, and the median time to relapse was 295 days. No characteristicswere identified to predict the time to loss of response or likelihood of regaining response at theindividual patient level.

IMMVENT

IMMVENT enrolled 605 subjects (301 randomised to risankizumab and 304 to adalimumab). Subjectsrandomised to risankizumab received 150 mg of treatment at week 0, week 4, and every 12 weeksthereafter. Subjects randomised to adalimumab received 80 mg at week 0, 40 mg at week 1, and 40 mgevery other week through week 15. Starting at week 16, subjects who were receiving adalimumabcontinued or switched treatment based on response:

* <PASI 50 were switched to risankizumab

* PASI 50 to <PASI 90 were re-randomised to either continue adalimumab or switch torisankizumab

* PASI 90 continued to receive adalimumab

Results are presented in Table 4.

Table 4: Efficacy and quality of life results at week 16 in adults with plaque psoriasis in

IMMVENT

Risankizumab Adalimumab(N=301) (N=304)n (%) n (%)asPGA of clear or almost clear 252 (83.7) 183 (60.2)

PASI 75 273 (90.7) 218 (71.7)a

PASI 90 218 (72.4) 144 (47.4)

PASI 100 120 (39.9) 70 (23.0)b

DLQI 0 or 1 198 (65.8) 148 (48.7)

All comparisons achieved p<0.001a Co-primary endpointsb No impact on health-related quality of life

For subjects who had PASI 50 to <PASI 90 with adalimumab at week 16 and were re-randomised,differences in PASI 90 response rates between switching to risankizumab and continuing adalimumabwere noted 4 weeks after re-randomisation (49.1% vs 26.8%, respectively).

Results 28 weeks after re-randomisation are presented in Table 5 and Figure 4.

Table 5: Efficacy results 28 weeks after re-randomisation in IMMVENT

Switched to Continued on

Risankizumab Adalimumab(N=53) (N=56)n (%) n (%)

PASI 90 35 (66.0) 12 (21.4)

PASI 100 21 (39.6) 4 (7.1)

All comparisons achieved p<0.001

Figure 4: Time course of PASI 90 after re-randomisation in IMMVENT100%.t. ADA/RZB (N=53)90%

- O* * ADA/ADA (N=56)80%70%60%50%40%30% O .... -- -- O - - -O.* ''' '' .'(>'' % % .... -004. -20% * **40,' '11. '' 'O/10% /0%0 4 8 12 16 20 24 28

Weeks After Re-Randomisation

ADA/ADA: Subjects randomised to adalimumab and continued on adalimumab

ADA/RZB: Subjects randomised to adalimumab and switched to risankizumabp<0.05 at week 4 and p<0.001 at each time point beginning at week 8

Percent of Subjects

In 270 subjects who switched from adalimumab to risankizumab without a washout period, the safetyprofile of risankizumab was similar to that in subjects who initiated risankizumab after washout of anyprior systemic therapies.

Risankizumab has been shown to improve signs and symptoms, physical function, health-relatedquality of life, and the proportion of subjects with no radiographic progression in adults with activepsoriatic arthritis (PsA).

The safety and efficacy of risankizumab were assessed in 1 407 subjects with active PsA in 2randomised, double-blind, placebo-controlled studies (964 in KEEPSAKE1 and 443 in KEEPSAKE2).

Subjects in these studies 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, ≥ 5tender joints and ≥ 5 swollen joints, and active plaque psoriasis or nail psoriasis at baseline. 55.9% ofsubjects had ≥ 3% BSA with active plaque psoriasis. 63.4% and 27.9% of subjects had enthesitis anddactylitis, respectively. In KEEPSAKE1, where nail psoriasis was further assessed, 67.3% had nailpsoriasis.

In both studies, subjects were randomised to receive risankizumab 150 mg or placebo at weeks 0, 4,and 16. Starting from week 28, all subjects received risankizumab every 12 weeks.

In KEEPSAKE1, all subjects had a previous inadequate response or intolerance to non-biologic

DMARD therapy and were biologic naïve. In KEEPSAKE2, 53.5% of subjects had a previousinadequate response or intolerance to non-biologic DMARD therapy and 46.5% of subjects had aprevious inadequate response or intolerance to biologic therapy.

In both studies, 59.6% of subjects were receiving concomitant methotrexate (MTX), 11.6% werereceiving concomitant non-biologic DMARDs other than MTX, and 28.9% were receivingrisankizumab monotherapy.

Treatment with risankizumab resulted in significant improvement in measures of disease activitycompared with placebo at week 24. For both studies, the primary endpoint was the proportion ofsubjects who achieved an American College of Rheumatology (ACR) 20 response at week 24. Thekey efficacy results are shown in Table 6.

Table 6. Efficacy results in studies KEEPSAKE1 and KEEPSAKE2

KEEPSAKE1 KEEPSAKE2

Placebo Risankizumab Placebo Risankizumab

Endpoint N=481 N=483 N=219 N=224n (%) n (%) n (%) n (%)

ACR20 Response

Week 16 161 (33.4) 272 (56.3) a 55 (25.3) 108 (48.3) a

Week 24 161 (33.5) 277 (57.3) a 58 (26.5) 115 (51.3) a

Week 52* - 338/433 (78.1) - 131/191 (68.6)

ACR50 Response

Week 24 54 (11.3) 162 (33.4) b 20 (9.3) 59 (26.3) b

Week 52* - 209/435 (48.0) - 72/192 (37.5)

ACR70 Response

Week 24 23 (4.7) 74 (15.3) b 13 (5.9) 27 (12.0) c

Week 52* - 125/437 (28.6) - 37/192 (19.3)

Resolution of Enthesitis (LEI=0)

Week 24* 156/448 (34.8) d 215/444 (48.4) a, d - -

Week 52* - 244/393 (62.1) d - -

Resolution of Dactylitis (LDI=0)

Week 24* 104/204 (51.0) e 128/188 (68.1) a, e - -

Week 52* - 143/171 (83.6) e - -

Minimal Disease Activity (MDA) Response

Week 24 49 (10.2) 121 (25.0) a 25 (11.4) 57 (25.6) a

Week 52* - 183/444 (41.2) - 61/197 (31.0)

*data are shown for available subjects in the format of n/N observed (%)a) multiplicity-controlled p≤0.001 risankizumab vs placebo comparison.b) nominal p≤0.001 risankizumab vs placebo comparison.c) nominal p≤0.05 risankizumab vs placebo comparison.d) Summarized from pooled data from KEEPSAKE1 and KEEPSAKE2 for subjects with baseline LEI>0.e) Summarized from pooled data from KEEPSAKE1 and KEEPSAKE2 for subjects with baseline LDI>0.

Response over time

In KEEPSAKE1, a greater ACR20 response was observed in the risankizumab group compared toplacebo as early as week 4 (25.7%) and the treatment difference continued over time to week 24(Figure 5).

Figure 5. Percent of subjects achieving ACR20 responses in study KEEPSAKE1 through week

Baseline Week 4 Week 8 Week 12 Week 16 Week 24

Visit○ Placebo (N=481) ──■── Risankizumab (N=483)

A greater ACR20 response for risankizumab versus placebo was seen as early as week 4 in 19.6% ofsubjects in KEEPSAKE2.

ACR20 response rate (%)

Responses observed in risankizumab groups were similar regardless of concomitant non-biologic

DMARD use, number of prior non-biologic DMARDs, age, gender, race, and BMI. In KEEPSAKE2,responses were seen regardless of prior biologic therapy.

The safety profile of risankizumab with up to 52 weeks of exposure was consistent with the profileobserved up to 24 weeks.

In both studies, the proportion of subjects achieving modified PsA Response Criteria (PsARC) at week24 was higher in subjects receiving risankizumab compared with placebo. In addition, subjectsreceiving risankizumab achieved greater improvement in Disease Activity Score (28 joints) using CRP(DAS28-CRP) compared with placebo at week 24. Improvements were maintained through week 52for PsARC and DAS28-CRP.

Treatment with risankizumab resulted in improvements in individual ACR components, Health

Assessment Questionnaire-Disability Index (HAQ-DI), pain assessment, and high-sensitivity C-reactive protein (hsCRP) compared with placebo.

Treatment with risankizumab resulted in statistically significant improvement in the skinmanifestations of psoriasis in subjects with PsA.

Treatment with risankizumab resulted in statistically significant improvement in the modified Nail

Psoriasis Severity Index (mNAPSI) and the 5-point Physician’s Global Assessment of Fingernail

Psoriasis (PGA-F) scores in subjects with nail psoriasis at baseline (67.3%) in KEEPSAKE1. Thisimprovement was maintained through week 52 (see Table 7).

Table 7. Nail psoriasis efficacy results in KEEPSAKE1

Placebo Risankizumab

N=338 N=309mNAPSI change from baseline a

Week 24 -5.57 -9.76 b

Week 52 - -13.64

PGA-F change from baseline a

Week 24 -0.4 -0.8 b

Week 52 - -1.2

PGA-F clear/minimal and ≥2-grade improvement c

Week 24 n (%) 30 (15.9) 71(37.8) d

Week 52 n (%) - 105 (58.0)a) Summarized for subjects with baseline nail psoriasis (Placebo N=338; risankizumab N=309;at week 52, for mNAPSI, observed risankizumab N=290, for PGA-F, observed risankizumab

N=291).b) Multiplicity-controlled p≤0.001 risankizumab vs placebo comparison.c) Summarized for subjects with nail psoriasis and a PGA-F overall global assessment score of‘Mild’, ‘Moderate’ or ‘Severe’ at Baseline (Placebo N=190; risankizumab N=188, at week 52observed risankizumab N=181).d) Nominal p≤0.001 risankizumab vs placebo comparison.

In KEEPSAKE1, inhibition of progression of structural damage was assessed radiographically andexpressed as the change in modified Total Sharp Score (mTSS) at week 24, compared with baseline.

The mTSS score was modified for PsA by addition of hand distal interphalangeal (DIP) joints. Atweek 24, the mean progression of structural damage with risankizumab (mean mTSS 0.23) comparedwith placebo (mean mTSS 0.32) was not statistically significant. At week 24, the proportion ofsubjects with no radiographic progression (defined as a change from baseline in mTSS ≤ 0) was higherwith risankizumab (92.4%) compared with placebo (87.7%). This response was maintained throughweek 52.

Physical function and health related quality of life

In both studies, subjects treated with risankizumab showed statistically significant improvement frombaseline in physical function as assessed by HAQ-DI at week 24 (KEEPSAKE1 (-0.31) comparedwith placebo (-0.11) (p ≤0.001)), (KEEPSAKE2 (-0.22) compared with placebo (-0.05) (p ≤0.001)).

At week 24, a greater proportion of subjects achieved a clinically meaningful reduction of at least 0.35in HAQ-DI score from baseline in the risankizumab group compared with placebo. Improvements inphysical function were maintained through week 52.

In both studies, subjects treated with risankizumab demonstrated significant improvements in the

SF-36 V2 physical component summary scores and in FACIT-Fatigue scores at week 24, comparedwith placebo, with improvements maintained through week 52.

At baseline, psoriatic spondylitis was reported in 19.6% (7.9% diagnosed by radiograph or MRI) ofsubjects in KEEPSAKE1 and 19.6% (5% diagnosed by radiograph or MRI) of subjects in

KEEPSAKE2. Subjects with clinically assessed psoriatic spondylitis who were treated withrisankizumab showed improvements from baseline in Bath Ankylosing Spondylitis Disease Activity

Index (BASDAI) scores compared with placebo at week 24. Improvements were maintained throughweek 52. There is insufficient evidence of the efficacy of risankizumab in subjects with radiograph- or

MRI-confirmed ankylosing spondylitis-like psoriatic arthropathy due to the small number of subjectsstudied.

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 plaque psoriasis and psoriaticarthritis (see section 4.2 for information on paediatric use).

The pharmacokinetics of risankizumab was similar between subjects with plaque psoriasis andsubjects with psoriatic arthritis.

Risankizumab exhibited linear pharmacokinetics with dose-proportional increase in exposure acrossdose ranges of 18 to 300 mg and 0.25 to 1 mg/kg administered subcutaneously, and 200 to 1 200 mgand 0.01 to 5 mg/kg administered intravenously.

Following subcutaneous dosing of risankizumab, peak plasma concentrations were achieved between3-14 days after dosing with an estimated absolute bioavailability of 89%. With dosing of 150 mg atweek 0, week 4, and every 12 weeks thereafter, estimated steady-state peak and trough plasmaconcentrations are 12 and 2 µg/mL, respectively.

Bioequivalence was demonstrated between a single risankizumab 150 mg injection and tworisankizumab 75 mg injections in pre-filled syringe. Bioequivalence was also demonstrated betweenrisankizumab 150 mg pre-filled syringe and pre-filled pen.

The mean (±standard deviation) steady-state volume of distribution (Vss) of risankizumab was11.4 (±2.7) L in Phase 3 studies in subjects with psoriasis, indicating that the distribution ofrisankizumab is primarily confined to the vascular and interstitial spaces.

Therapeutic IgG monoclonal antibodies are typically degraded into small peptides and amino acids viacatabolic pathways in the same manner as endogenous IgGs. Risankizumab is not expected to bemetabolised by cytochrome P450 enzymes.

The mean (±standard deviation) systemic clearance (CL) of risankizumab was 0.3 (±0.1) L/day in

Phase 3 studies in subjects with psoriasis. The mean terminal elimination half-life of risankizumabranged from 28 to 29 days in Phase 3 studies in subjects with psoriasis.

As an IgG1 monoclonal antibody, risankizumab is not expected to be filtered by glomerular filtrationin the kidneys or to be excreted as an intact molecule in the urine.

Risankizumab exhibited linear pharmacokinetics with approximately dose-proportional increases insystemic exposure (Cmax and AUC) in the evaluated dose ranges of 18 to 300 mg or 0.25 to 1 mg/kgsubcutaneous administration in healthy subjects or subjects with psoriasis.

An interaction study was conducted in subjects with plaque psoriasis to assess the effect of repeatedadministration of risankizumab on the pharmacokinetics of cytochrome P450 (CYP) sensitive probesubstrates. The exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole(CYP2C19 substrate), metoprolol (CYP2D6 substrate) and midazolam (CYP3A substrate) followingrisankizumab treatment were comparable to their exposures prior to risankizumab treatment,indicating no clinically meaningful interactions through these enzymes.

Population pharmacokinetic analyses indicated that risankizumab exposure was not impacted byconcomitant treatment used by some subjects with plaque psoriasis or psoriatic arthritis during theclinical studies.

The pharmacokinetics of risankizumab in paediatric subjects has not been established.

Of the 2 234 subjects with plaque psoriasis exposed to risankizumab, 243 were 65 years or older and24 subjects were 75 years or older. Of the 1 542 subjects with psoriatic arthritis exposed torisankizumab, 246 were 65 years or older and 34 subjects were 75 years or older. No overalldifferences in risankizumab exposure were observed between older and younger subjects who receivedrisankizumab.

No specific studies have been conducted to determine the effect of renal or hepatic impairment on thepharmacokinetics of risankizumab. Based on population pharmacokinetic analyses, serum creatininelevels, creatinine clearance, or hepatic function markers (ALT/AST/bilirubin) did not have ameaningful impact on risankizumab clearance in subjects with plaque psoriasis or psoriatic arthritis.

As an IgG1 monoclonal antibody, risankizumab is mainly eliminated via intracellular catabolism andis not expected to undergo metabolism via hepatic cytochrome P450 enzymes or renal elimination.

Risankizumab clearance and volume of distribution increase as body weight increases which mayresult in reduced efficacy in subjects with high body weight (>130 kg). However, this observation isbased on a limited number of subjects. No dose adjustment based on body weight is currentlyrecommended.

Gender or race

The clearance of risankizumab was not significantly influenced by gender or race in adult subjectswith plaque psoriasis or psoriatic arthritis. No clinically meaningful differences in risankizumabexposure were observed in Chinese or Japanese subjects compared to Caucasian subjects in a clinicalpharmacokinetic study in healthy volunteers.

Nonclinical data revealed no special hazard for humans based on repeat-dose toxicity studies includingsafety pharmacology evaluations, and an enhanced pre- and post-natal developmental toxicity study incynomolgus monkeys at doses of up to 50 mg/kg/week (producing exposures of about 70 times theclinical exposure at maximum recommended human dose [MRHD]).

Mutagenicity and carcinogenicity studies have not been conducted with risankizumab. In a 26-weekchronic toxicology study in cynomolgus monkeys at doses of up to 50 mg/kg/week (about 70 times theclinical exposure at the MRHD), there were no pre-neoplastic or neoplastic lesions observed and noadverse immunotoxicity or cardiovascular effects were noted.

Skyrizi 150 mg solution for injection in pre-filled pen and pre-filled syringe

Sodium acetate trihydrate

Acetic acid

Trehalose dihydrate

Polysorbate 20

Water for injections

Skyrizi 75 mg solution for injection in pre-filled syringe

Disodium succinate hexahydrate

Succinic acid

Sorbitol

Polysorbate 20

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

2 years

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep the pre-filled pen or the pre-filled syringe(s) in the outer carton in order to protect from light.

Skyrizi 150 mg pre-filled pen or pre-filled syringe may be stored out of the refrigerator (up to amaximum of 25°C) for up to 24 hours in the original carton to protect from light.

Skyrizi 150 mg solution for injection in pre-filled pen

Pre-filled glass syringe assembled in a pre-filled pen with an automatic needle sleeve.

Skyrizi 150 mg solution for injection in pre-filled syringe

Pre-filled glass syringe with a fixed needle and needle cover, assembled in an automatic needle guard.

Skyrizi 150 mg is available in packs containing 1 pre-filled pen or 1 pre-filled syringe.

Skyrizi 75 mg solution for injection in pre-filled syringe

Pre-filled glass syringe with a fixed needle and needle cover, assembled in an automatic needle guard.

Skyrizi 75 mg is available in packs containing 2 pre-filled syringes and 2 alcohol pads.

Not all presentations may be marketed.

Skyrizi 150 mg solution for injection in pre-filled pen

Before injecting, patients should remove the carton from the refrigerator and allow to reach roomtemperature out of direct sunlight (30 to 90 minutes) without removing the pre-filled pen from thecarton.

The solution should be colourless to yellow and clear to slightly opalescent.

Skyrizi 150 mg solution for injection in pre-filled syringe

Before injecting, patients may remove the carton from the refrigerator and allow to reach roomtemperature out of direct sunlight (15 to 30 minutes) without removing the pre-filled syringe from thecarton.

The solution should be colourless to yellow and clear to slightly opalescent.

Skyrizi 75 mg solution for injection in pre-filled syringe

Before injecting, patients may remove the carton from the refrigerator and allow to reach roomtemperature out of direct sunlight (15 to 30 minutes) without removing the pre-filled syringes from thecarton.

The solution should be colourless to slightly yellow and clear to slightly opalescent.

Two pre-filled syringes should be injected for the full 150 mg dose.

General special precautions

Prior to use, a visual inspection of each pre-filled pen or pre-filled syringe is recommended. Thesolution may contain a few translucent to white product-related particles. Skyrizi should not be used ifthe solution is cloudy or discoloured, or contains large particles. Do not shake the pre-filled pen orpre-filled syringe.

Comprehensive instructions for use are provided in the package leaflet.

Each pre-filled pen or pre-filled syringe is for single use only.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

Skyrizi 150 mg solution for injection in pre-filled pen

EU/1/19/1361/002

Skyrizi 150 mg solution for injection in pre-filled syringe

EU/1/19/1361/003

Skyrizi 75 mg solution for injection in pre-filled syringe

EU/1/19/1361/001

Date of first authorisation: 26 April 2019

Date of latest renewal: 5 January 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.