Skyrizi 55 mg solution for injection in pre-filled syringe

Paediatric plaque psoriasis

Skyrizi is indicated for the treatment of moderate to severe plaque psoriasis in children and adolescents from the age of 6 years who are candidates for systemic therapy.

Skyrizi is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of conditions for which Skyrizi is indicated.

Posology

Paediatric plaque psoriasis (from 6 to less than 18 years of age)

The recommended dose for paediatric patients is based on body weight (Table 1) and administered as a subcutaneous injection at week 0, week 4, and every 12 weeks thereafter.

Table 1. Recommended dose for paediatric plaque psoriasis

*For children and adolescents weighing at least 40 kg, refer to the Skyrizi 150 mg pre-filled pen or 150 mg pre-filled syringe Summary of Product Characteristics.

For the above indication, consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment. Some plaque psoriasis patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks.

Missed dose

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

Special populations

Renal or hepatic impairment

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

Paediatric population

There is no relevant use of risankizumab in children aged below 6 years for the indication of moderate to severe plaque psoriasis.

Overweight patients

No dose adjustment is required (see section 5.2).

Method of administration

Skyrizi is administered by subcutaneous injection.

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

Patients may self-inject Skyrizi after training in subcutaneous injection technique. In children and adolescents 10 to less than 18 years of age, it is recommended that Skyrizi is administered by or under the supervision of an adult. In children 6 to less than 10 years of age, Skyrizi should be administered by an adult. Patients should be instructed 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 professional or caregiver.

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).

Traceability

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

Infections

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 in patients with any clinically important active infection until the infection resolves or is adequately treated.

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

Tuberculosis

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 of latent or active TB in whom an adequate course of treatment cannot be confirmed.

Immunisations

Prior to initiating therapy with risankizumab, completion of all appropriate immunisations should be considered 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 with risankizumab. Patients treated with risankizumab should not receive live vaccines during treatment and for at least 21 weeks after treatment (see section 5.2).

Hypersensitivity

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

Excipients with known effect

Polysorbate

This medicinal product contains 0.07 mg of polysorbate 20 in each 55 mg dose. Polysorbates may cause allergic reactions.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, 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 product metabolising 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 biologics or phototherapy, have not been evaluated.

Women of childbearing potential

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

Pregnancy

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

Breast-feeding

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

Fertility

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

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

Summary of the safety profile

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

Tabulated list of adverse reactions

Adverse reactions for risankizumab from clinical studies (Table 2) are listed by MedDRA system organ 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: List of adverse reactions

Description of selected adverse reactions

Infections

The rate of infections was 75.5 events per 100 subject-years from the psoriasis clinical studies and 43.0 events per 100 subject-years from the psoriatic arthritis clinical studies, including long-term exposure to risankizumab. The majority of cases were non-serious and mild to moderate in severity and did not lead to discontinuation of risankizumab. The rate of serious infections was 1.7 events per 100 subject-years from the psoriasis studies and 2.6 events per 100 subject-years from the psoriatic arthritis studies (see section 4.4).

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity with risankizumab. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

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

For most adult subjects with psoriasis, antibodies to risankizumab including neutralising antibodies were not associated 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 appeared to 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 all mild to moderate in severity, none were serious, and none led to discontinuation of risankizumab.

For paediatric subjects 6 to less than 18 years of age treated with risankizumab at the recommended clinical dose for up to 52 weeks in the psoriasis clinical trial, treatment-emergent anti-drug antibodies and neutralising antibodies were detected in 14.8% (13/88) and 2.3% (2/88) of evaluated subjects, respectively. Antibodies to risankizumab were not associated with changes in clinical response or safety; however, the number of patients who were positive for antibodies to risankizumab is too small for definitive conclusions about the impact on efficacy and safety of risankizumab.

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

Psoriatic arthritis

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

Paediatric population

The safety of risankizumab was assessed in a four-part trial of paediatric subjects with moderate to severe plaque psoriasis that evaluated safety for up to 52 weeks in 137 paediatric subjects 6 to less than 18 years of age. Overall, the safety profile observed in paediatric subjects with plaque psoriasis treated with risankizumab was consistent with the safety profile observed in adult subjects with plaque psoriasis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme:

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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

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

Mechanism of action

Risankizumab is a humanised immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds with 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 in inflammatory and immune responses. By blocking IL-23 from binding to its receptor, risankizumab inhibits IL-23-dependent cell signalling and release of proinflammatory cytokines.

Pharmacodynamic effects

In a study of subjects with psoriasis, expression of genes associated with the IL-23/IL-17 axis was decreased 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 in psoriatic lesions.

Clinical efficacy and safety

Adult plaque psoriasis

The efficacy and safety of risankizumab was assessed in 2 109 subjects with moderate to severe plaque 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 plaque psoriasis 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, and scaling) 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 median baseline DLQI score of 13.0. Baseline sPGA score was severe in 19.3% of subjects and moderate in 80.7% 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 and biologic), 38.1% had received prior phototherapy or photochemotherapy, 48.3% had received prior non-biologic systemic therapy, 42.1% had received prior biologic therapy, and 23.7% had received at least one anti‑TNF alpha agent for the treatment of psoriasis. Patients who completed these studies and other 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, 199 to ustekinumab 45 mg or 90 mg [according to baseline weight], and 200 to placebo). Subjects received treatment 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 response and 2) sPGA score of clear or almost clear (sPGA 0 or 1) at week 16 versus placebo. The results for the co-primary and other endpoints are presented in Table 3 and Figure 1.

Table 3: Efficacy and quality of life results in adults with plaque psoriasis in ULTIMMA‑1 and ULTIMMA‑2

Figure 1: Time course of mean percent change from baseline of PASI in ULTIMMA-1 and ULTIMMA-2

RZB = risankizumab

UST = ustekinumab

PBO = placebo

p<0.001 at each time point

Examination of age, gender, race, body weight ≤130 kg, baseline PASI score, concurrent psoriatic arthritis, previous non-biologic systemic treatment, previous biologic treatment, and previous failure of 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 at week 16 and week 52 in subjects treated with risankizumab.

Table 4: Mean changes from baseline in NAPSI, PPASI, and PSSI

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.

Maintenance of response

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 risankizumab maintained the response at week 52. For PASI 90 responders at week 16, 88.4% (398/450) of subjects maintained the response at week 52.

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

Of the patients who received ustekinumab in ULTIMMA-1 and ULTIMMA-2, 172 received risankizumab every 12 weeks in LIMMITLESS. Of these, 116 (67.4%) completed the study, including 252 weeks of open-label risankizumab treatment and end of study follow-up. Among subjects remaining in the study, rates of PASI 90 and sPGA response of clear or almost clear increased from week 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

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

Improvements in Dermatology Life Quality Index (DLQI 0 or 1) were maintained in patients receiving continuous 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 profile observed 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 were originally on risankizumab and had a sPGA of clear or almost clear at week 28 were re-randomised to continue risankizumab every 12 weeks through week 88 (with follow-up 16 weeks after last risankizumab dose) or have treatment withdrawn.

At week 16, risankizumab was superior to placebo on the co-primary endpoints of sPGA of clear or almost 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 receive prophylaxis during the study, none developed active TB during the mean follow-up of 55 weeks on risankizumab.

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

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

IMMVENT

IMMVENT enrolled 605 subjects (301 randomised to risankizumab and 304 to adalimumab). Subjects randomised to risankizumab received 150 mg of treatment at week 0, week 4, and every 12 weeks thereafter. Subjects randomised to adalimumab received 80 mg at week 0, 40 mg at week 1, and 40 mg every other week through week 15. Starting at week 16, subjects who were receiving adalimumab continued 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 to risankizumab

• PASI 90 continued to receive adalimumab

Results are presented in Table 5.

Table 5: Efficacy and quality of life results at week 16 in adults with plaque psoriasis in IMMVENT

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 adalimumab were noted 4 weeks after re-randomisation (49.1% vs 26.8%, respectively).

Results 28 weeks after re-randomisation are presented in Table 6 and Figure 4.

Table 6: Efficacy results 28 weeks after re-randomisation in IMMVENT

Figure 4: Time course of PASI 90 after re-randomisation in IMMVENT

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

ADA/RZB: Subjects randomised to adalimumab and switched to risankizumab

p<0.05 at week 4 and p<0.001 at each time point beginning at week 8

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

Plaque psoriasis involving the scalp or genital area

The efficacy and safety of risankizumab was assessed in a multicenter, randomised, double-blind, placebo-controlled study (UNLIMMITED) that enrolled subjects 18 years of age and older with moderate to severe scalp psoriasis (UNLIMMITED-S), defined as Psoriasis Scalp Severity Index (PSSI) ≥12, scalp Investigator Global Assessment (scalp IGA) ≥3, and ≥30% of the scalp affected, or moderate to severe genital psoriasis (UNLIMMITED-G), defined as static Physician's Global Assessment of Genitalia (sPGA-G) ≥3 at baseline. All subjects had BSA ≥1% and sPGA ≥3 at baseline.

In UNLIMMITED, subjects were randomised to receive either risankizumab 150 mg or placebo subcutaneously at weeks 0 and 4. Starting at week 16, all subjects received risankizumab 150 mg every 12 weeks until the last dose at week 40.

Scalp area (UNLIMMITED-S)

UNLIMMITED-S enrolled 105 subjects. Baseline BSA involvement was ≥10% for 61.9% of the subjects and <10% for 38.1% of the subjects. Mean baseline BSA involvement was 16.8%. At baseline, 76.2% of subjects had sPGA = 3 and 23.8% had sPGA = 4.

At baseline, 54.3% of subjects were naïve to any systemic therapy (including non-biologic and biologic), 0% of subjects had received prior phototherapy, 15.2% had received prior non-biologic systemic therapy, and 37.1% had received prior biologic therapy.

The results for the primary and key secondary endpoints are presented in Table 7.

Table 7. Efficacy results in adults with scalp psoriasis in UNLIMMITED-S at week 16

A greater proportion of subjects treated with risankizumab achieved a scalp IGA score of 0 at week 16 compared with placebo (41.2% vs 11.1%, respectively).

Scalp Itch Numeric rating scale (NRS) response, defined as achievement of ≥4-point improvement (reduction) from baseline on the Scalp Itch NRS among subjects with baseline scores ≥4, was achieved in a greater proportion of subjects treated with risankizumab at week 16 compared to placebo (50.0% vs 11.1%, respectively).

A greater proportion of subjects treated with risankizumab achieved a DLQI score of 0 or 1 (no impact on health-related quality of life) at week 16 compared with placebo (47.1% vs 11.1%, respectively).

Genital area (UNLIMMITED-G)

UNLIMMITED-G enrolled 109 subjects. Baseline BSA involvement was ≥10% for 63.3% of the subjects and <10% for 36.7% of the subjects. Mean baseline BSA involvement was 17.2%. At baseline, 80.7% of subjects had sPGA = 3 and 19.3% had sPGA = 4.

At baseline, 61.5% of subjects were naïve to any systemic therapy (including non-biologic and biologic), 2.8% of subjects had received prior phototherapy, 16.5% had received prior non-biologic systemic therapy, and 25.7% had received prior biologic therapy.

The results for the primary and all secondary endpoints are presented in Table 8.

Table 8. Efficacy results in adults with genital psoriasis in UNLIMMITED-G at week 16

Subjects treated with risankizumab achieved greater reduction in psoriasis symptoms severity in the genital area (itch, pain, discomfort, stinging, burning, redness, scaling, and cracking) from baseline as measured by GPSS at week 16 compared to placebo. The change from baseline in GPSS total score at week 16 was -26.5 for risankizumab and -1.0 for placebo.

A greater proportion of subjects treated with risankizumab compared to placebo achieved at least 2‑point reduction on Patient's Global Assessment of Genital Psoriasis (PatGA-Genital), among subjects with baseline score ≥2 (71.7% vs 22.9%, respectively).

The safety profile of risankizumab in studies UNLIMMITED-S and UNLIMMITED-G was consistent with the safety profile observed in previous studies of patients with plaque psoriasis.

Paediatric population

Paediatric plaque psoriasis

The efficacy, safety, and pharmacokinetics of risankizumab were assessed in a total of 137 paediatric subjects 6 to less than 18 years of age in a four-part study (OptIMMize-1) which enrolled 12, 82, 13 and 30 subjects to Parts 1, 2, 3 and 4, respectively. Subjects who completed this study had the opportunity to enrol in the open-label extension study, OptIMMize-2.

OptIMMize-1

Part 2 was a randomised, efficacy assessor-blinded, active treatment-controlled cohort that enrolled paediatric subjects 12 to less than 18 years of age. Part 4 was a single-arm, open-label cohort that enrolled paediatric subjects 6 to less than 12 years of age. Enrolled subjects had moderate to severe plaque psoriasis defined as BSA involvement of ≥10% with sPGA score of ≥3 or a PASI score ≥12.

In Part 2 and Part 4, subjects weighing ≥40 kg received risankizumab 150 mg and subjects weighing <40 kg received risankizumab 55 mg at week 0, week 4, and every 12 weeks thereafter. The co-primary endpoints were sPGA of clear or almost clear (0 or 1) and PASI 75 at week 16.

In Part 2, subjects had a median baseline PASI score of 15.7 and a median BSA of 18.0%. A total of 3.7% had received prior biologic therapy. Subjects were randomised 2:1 to receive risankizumab (N=54) or ustekinumab (N=28). Subjects randomised to ustekinumab received 0.75 mg/kg for subjects <60 kg; 45 mg for subjects 60 to <100 kg; 90 mg for subjects ≥100 kg, at week 0 and week 4. At week 16, ustekinumab subjects were switched to receive risankizumab every 12 weeks thereafter. The duration of treatment was up to 68 weeks.

In Part 4, subjects had a median baseline PASI score of 14.7, and a median BSA of 14.5%. A total of 3.3% received prior biologic therapy. The duration of treatment was 52 weeks.

The efficacy results using descriptive statistics in OptIMMize-1 at week 16 of initial treatment are presented below (see Table 9).

Table 9. Efficacy Results in OptIMMize-1 at Week 16

Efficacy was maintained through week 52 as assessed by the endpoints presented in Table 9.

In Part 2, subjects originally on risankizumab who achieved sPGA of clear or almost clear at week 16 were re-randomised to continue risankizumab every 12 weeks through week 52 (N=22) or were withdrawn from therapy (N=21). At week 52, 95.5% (21/22) of the subjects continuing risankizumab maintained sPGA of clear or almost clear compared with 42.9% (9/21) for those withdrawn from risankizumab.

In Part 2, improvements from baseline were reported in health-related quality of life in subjects treated with risankizumab and ustekinumab as measured by the Children's Dermatology Life Quality Index score (CDLQI: -7.4 and -6.8, respectively) at week 16 of initial treatment.

In Part 2, among subjects with a baseline itch score of at least 4 points, 64.9% (24/37) of subjects treated with risankizumab and 57.1% (8/14) treated with ustekinumab had an improvement in itch at week 16 of initial treatment as measured by a reduction of at least 4 points from baseline on an 11-point itch Numeric Rating Scale.

OptIMMize-2

In OptIMMize-2, the long-term efficacy, safety and tolerability of 150 mg or 55 mg (weight-based) risankizumab every 12 weeks were assessed in 129 paediatric subjects 6 to less than 18 years of age with moderate to severe plaque psoriasis who had completed participation in OptIMMize-1. In OptiIMMize-2, response rates for PASI 75/90/100 and sPGA of clear or almost clear were maintained among the 36 subjects who continued risankizumab treatment up to week 108.

Absorption

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

Following subcutaneous dosing of risankizumab, peak plasma concentrations were achieved between 3‑14 days after dosing with an estimated absolute bioavailability of 89%. With dosing of 150 mg at week 0, week 4, and every 12 weeks thereafter, estimated steady-state peak and trough plasma concentrations are 12 and 2 µg/mL, respectively.

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

Distribution

The mean (±standard deviation) steady-state volume of distribution (V_ss) of risankizumab was 11.4 (±2.7) L in Phase 3 studies in subjects with psoriasis, indicating that the distribution of risankizumab is primarily confined to the vascular and interstitial spaces.

Biotransformation

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

Elimination

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 risankizumab ranged 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 filtration in the kidneys or to be excreted as an intact molecule in the urine.

Linearity/non-linearity

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

Interactions

An interaction study was conducted in subjects with plaque psoriasis to assess the effect of repeated administration of risankizumab on the pharmacokinetics of cytochrome P450 (CYP) sensitive probe substrates. The exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), metoprolol (CYP2D6 substrate) and midazolam (CYP3A substrate) following risankizumab 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 by concomitant treatment used by some subjects with plaque psoriasis during the clinical studies.

Special populations

Paediatric population

Risankizumab exposures in subjects 6 to less than 18 years of age with plaque psoriasis were similar to those in adults. At the recommended dosing regimens evaluated in these subjects, estimated median steady-state peak and trough plasma concentrations were 15.7 and 2.3 µg/mL, respectively, in subjects weighing ≥40 kg, and 11.1 and 1.6 µg/mL, respectively, in subjects weighing <40 kg.

Patients with renal or hepatic impairment

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

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

Body weight

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

Gender or race

The clearance of risankizumab was not significantly influenced by gender or race in adult subjects with plaque psoriasis. No clinically meaningful differences in risankizumab exposure were observed in Chinese or Japanese subjects compared to Caucasian subjects in a clinical pharmacokinetic study in healthy volunteers.

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

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

Sodium acetate trihydrate

Acetic acid

Trehalose dihydrate

Polysorbate 20

Water for injections

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

2 years

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

Keep the pre-filled syringe in the outer carton in order to protect from light.

The pre-filled syringe may be stored out of the refrigerator (up to a maximum of 25°C) for up to 24 hours in the original carton to protect from light.

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

Skyrizi 55 mg is available in packs containing 1 pre-filled syringe.

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

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

General special precautions

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

Comprehensive instructions for use are provided in the package leaflet.

Each pre-filled syringe is for single use only.

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