risankizumab: prescribing information – dosing, contraindications, interactions, side effects

Adult plaque psoriasis

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

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.

Psoriatic arthritis

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

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.

Crohn’s disease

Skyrizi is indicated for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response to, lost response to, or were intolerant to conventional therapy or a biologic therapy.

Ulcerative colitis

Skyrizi is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to, lost response to, or were intolerant to conventional therapy or a biologic therapy.

Skyrizi is indicated for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response to, lost response to, or were intolerant to conventional therapy or a biologic therapy.

This medicinal product 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

Adult plaque psoriasis

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

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

Body weight at time of dosing
Recommended dose
<40 kg
55 mg (given as one 55 mg pre-filled syringe injection)*
≥40 kg
150 mg (given as two 75 mg pre-filled syringe injections or one 150 mg pre-filled pen or pre-filled syringe injection) *For children and adolescents weighing less than 40 kg, refer to the Skyrizi 55 mg pre-filled syringe Summary of Product Characteristics.

Psoriatic arthritis

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

For the above indications, 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

Elderly

No dose adjustment is required (see section 5.2).

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

The safety and efficacy of risankizumab in children and adolescents below the age of 18 years with psoriatic arthritis have not yet been established. No data are available.

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

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.

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 be administered at different anatomic locations.

This medicinal product 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

Body weight at time of dosing
Recommended dose
<40 kg
55 mg (given as one 55 mg pre-filled syringe injection)
≥40 kg
150 mg (given as two 75 mg pre-filled syringe injections or one 150 mg pre-filled pen or pre-filled syringe injection)* *For children and adolescents weighing at least 40 kg, refer to the Skyrizi 150 mg pre-filled pen, 150 mg pre-filled syringe and 75 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.

This medicinal product 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

Crohn’s disease

The recommended dose is 600 mg administered by intravenous infusion at week 0, week 4, and week 8, followed by 360 mg administered by subcutaneous injection at week 12, and every 8 weeks thereafter. Consideration should be given to discontinuing treatment in patients who have shown no evidence of therapeutic benefit by week 24.

For the posology of the subsequent subcutaneous dosing regimen, see section 4.2 of the Skyrizi 360 mg solution for injection in cartridge, Skyrizi 180 mg pre-filled syringe and Skyrizi 90 mg pre- filled syringe Summary of Product Characteristics.

Ulcerative colitis

The recommended induction dose is 1 200 mg administered by intravenous infusion at week 0, week 4, and week 8. Starting at week 12 and every 8 weeks thereafter, the recommended maintenance dose is based on individual patient presentation:
- A dose of 180 mg administered by subcutaneous injection is recommended for patients with adequate improvement in disease activity after induction
- A dose of 360 mg administered by subcutaneous injection is recommended for patients with inadequate improvement in disease activity after induction

Consideration should be given to discontinuing treatment in patients who have shown no evidence of therapeutic benefit by week 24.

For the posology of the subsequent subcutaneous dosing regimen, see section 4.2 of the Skyrizi 180 mg and 360 mg solution for injection in cartridge and Skyrizi 180 mg pre-filled syringe Summary of Product Characteristics.

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

Elderly

No dose adjustment is required (see section 5.2).
There is limited information in subjects aged ≥65 years.

Renal or hepatic impairment

No specific studies were conducted to assess the effect of hepatic or renal impairment on the pharmacokinetics of Skyrizi. 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

The safety and efficacy of Skyrizi in children aged 0-17 years for the treatment of Crohn’s disease and ulcerative colitis have not yet been established. Currently available data are described in section 5.1 and 5.2 but no recommendation on posology can be made.

Overweight patients

No dose adjustment is required (see section 5.2).

Method of administration

For intravenous infusion.

Skyrizi concentrate for solution for infusion is for intravenous use only. The 600 mg dose should be administered over at least one hour, and the 1 200 mg dose should be administered over at least two hours. For instructions on dilution of the medicinal product before administration, see section 6.6.

This medicinal product 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

Crohn’s disease

The recommended dose is 600 mg administered by intravenous infusion at week 0, week 4, and week 8, followed by 360 mg administered by subcutaneous injection at week 12, and every 8 weeks thereafter. Consideration should be given to discontinuing treatment in patients who have shown no evidence of therapeutic benefit by week 24.

For the posology of the initial intravenous dosing regimen, see section 4.2 of the Skyrizi 600 mg concentrate for solution for infusion Summary of Product Characteristics.

Ulcerative colitis

The recommended induction dose is 1 200 mg administered by intravenous infusion at week 0, week 4, and week 8. Starting at week 12 and every 8 weeks thereafter, the recommended maintenance dose is based on individual patient presentation:
- A dose of 180 mg administered by subcutaneous injection is recommended for patients with adequate improvement in disease activity after induction
- A dose of 360 mg administered by subcutaneous injection is recommended for patients with inadequate improvement in disease activity after induction

Consideration should be given to discontinuing treatment in patients who have shown no evidence of therapeutic benefit by week 24.

For the posology of the initial intravenous dosing regimen, see section 4.2 of the Skyrizi 600 mg concentrate for solution for infusion Summary of Product Characteristics.

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

Elderly

No dose adjustment is required (see section 5.2).
There is limited information in subjects aged ≥65 years.

Renal or hepatic impairment

No specific studies were conducted to assess the effect of hepatic or renal impairment on the pharmacokinetics of Skyrizi. 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

The safety and efficacy of Skyrizi in children aged 0-17 years for the treatment of Crohn’s disease and ulcerative colitis have not yet been established. Currently available data are described in section 5.1 and 5.2 but no recommendation on posology can be made.

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. Skyrizi should not be injected into areas where the skin is tender, bruised, erythematous, indurated or damaged.

Patients may self-inject Skyrizi after training in subcutaneous injection technique. Patients should be instructed to read section 7 ‘Instructions for use’ provided in the package leaflet before administration.

Skyrizi 180 mg solution for injection in pre-filled syringe

One pre-filled syringe should be injected to administer the 180 mg maintenance dose.

Two pre-filled syringes should be injected to administer the 360 mg maintenance dose. The two injections should be administered at different anatomic locations.

This medicinal product 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

The recommended dose is 600 mg administered by intravenous infusion at week 0, week 4, and week 8, followed by 360 mg administered by subcutaneous injection at week 12, and every 8 weeks thereafter. Consideration should be given to discontinuing treatment in patients who have shown no evidence of therapeutic benefit by week 24.

For the posology of the initial intravenous dosing regimen, see section 4.2 of the Skyrizi 600 mg concentrate for solution for infusion Summary of Product Characteristics.

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

Elderly

No dose adjustment is required (see section 5.2).
There is limited information in subjects aged ≥65 years.

Renal or hepatic impairment

No specific studies were conducted to assess the effect of hepatic or renal impairment on the pharmacokinetics of Skyrizi. 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

The safety and efficacy of Skyrizi in children aged 0-17 years for the treatment of Crohn’s disease have not yet been established. Currently available data are described in section 5.1 and 5.2 but no recommendation on posology can be made.

Overweight patients

No dose adjustment is required (see section 5.2).

Method of administration

This medicinal product should be administered by a healthcare professional.

Skyrizi is administered by subcutaneous injection.

The injection should be administered in the thigh or abdomen. Skyrizi should not be injected into areas where the skin is tender, bruised, erythematous, indurated or damaged.

Four pre-filled syringes should be injected to administer the full 360 mg dose. The four injections should be administered at different anatomic locations (see administration instructions provided with the package leaflet).

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).

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

System Organ Class
Frequency
Adverse reactions
Infections and infestations

Very common
Upper respiratory infectionsa
Common
Tinea infectionsb
Uncommon
Folliculitis
Immune system disorders
Rare
Anaphylactic reactions
Nervous system disorders
Common
Headachec
Skin and subcutaneous tissue disorders
Common
Pruritus
Rash
Eczema
Uncommon
Urticaria
General disorders and administration site conditions
Common
Fatigued
Injection site reactionse a Includes: respiratory tract infection (viral, bacterial or unspecified), sinusitis (including acute), rhinitis, nasopharyngitis, pharyngitis (including viral), tonsillitis, laryngitis, tracheitis b Includes: tinea pedis, tinea cruris, body tinea, tinea versicolor, tinea manuum, onychomycosis, fungal skin infection c Includes: headache, tension headache, sinus headache d Includes: fatigue, asthenia e Includes: injection site bruising, erythema, haematoma, haemorrhage, irritation, pain, pruritus, reaction, swelling, induration, rash

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

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 the national reporting system listed in Appendix V.

Summary of the safety profile

The most frequently reported adverse reactions were upper respiratory infections (15.6% in Crohn’s disease and 26.2% in ulcerative colitis).

Tabulated list of adverse reactions

Adverse reactions for risankizumab from clinical studies (Table 1) 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 1: List of adverse reactions

System Organ Class
Frequency
Adverse reactions
Infections and infestations

Very common
Upper respiratory infectionsa
Common
Tinea infectionsb
Uncommon
Folliculitis
Immune system disorders
Rare
Anaphylactic reactions
Nervous system disorders
Common
Headachec
Skin and subcutaneous tissue disorders
Common
Pruritus
Rash
Eczema
Uncommon
Urticaria
General disorders and administration site conditions
Common
Fatigued
Injection site reactionse a Includes: respiratory tract infection (viral, bacterial or unspecified), sinusitis (including acute), rhinitis, nasopharyngitis, pharyngitis (including viral), tonsillitis, laryngitis, tracheitis b Includes: tinea pedis, tinea cruris, body tinea, tinea versicolor, tinea manuum, onychomycosis, tinea infection c Includes: headache, tension headache, sinus headache d Includes: fatigue, asthenia, malaise e Includes: injection site bruising, erythema, haematoma, haemorrhage, irritation, pain, pruritus, reaction, swelling, induration, hypersensitivity, nodule, rash, urticaria, vesicles, warmth; infusion site erythema, extravasation, reaction, swelling

Description of selected adverse reactions

Psoriasis

Infections

Over the entire psoriasis programme including long-term exposure to risankizumab, the rate of infections was 75.5 events per 100 subject-years. 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 (see section 4.4).

Crohn’s disease

Overall, the safety profile observed in patients with Crohn’s disease treated with risankizumab was consistent with the safety profile observed in patients across indications.

Infections

The rate of infections in the pooled data from the 12-week induction studies was 83.3 events per 100 subject-years in subjects treated with risankizumab 600 mg intravenously compared to 117.7 events per 100 subject-years in placebo. The rate of serious infections was 3.4 events per 100 subject-years in subjects treated with risankizumab 600 mg intravenously compared to 16.7 events per 100 subject-years in placebo (see section 4.4).

The rate of infections in the 52-week maintenance study was 57.7 events per 100 subject-years in subjects treated with risankizumab 360 mg subcutaneously after risankizumab induction compared to 76.0 events per 100 subject-years in subjects who received placebo after risankizumab induction. The rate of serious infections was 6.0 events per 100 subject-years in subjects treated with risankizumab 360 mg subcutaneously after risankizumab induction compared to 5.0 events per 100 subject-years in subjects who received placebo after risankizumab induction (see section 4.4).

Ulcerative colitis

Overall, the safety profile observed in patients with ulcerative colitis treated with risankizumab was consistent with the safety profile observed in patients across indications.

Infections

The rate of infections in the pooled data from the 12-week induction study was 78.3 events per 100 subject-years in subjects treated with risankizumab 1 200 mg intravenously compared to 74.2 events per 100 subject-years in placebo. The rate of serious infections was 3.0 events per 100 subject-years in subjects treated with risankizumab 1 200 mg intravenously compared to 5.4 events per 100 subject-years in placebo (see section 4.4).

The rate of infections in the 52-week maintenance study was 67.4 events per 100 subject-years in subjects treated with risankizumab 180 mg subcutaneously and 56.5 events per 100 subject-years in subjects treated with risankizumab 360 mg subcutaneously after risankizumab induction compared to 64.6 events per 100 subject-years in subjects who received placebo after risankizumab induction. The rate of serious infections was 1.1 events per 100 subject-years in subjects treated with risankizumab 180 mg subcutaneously and 0.6 events per 100 subject-years in subjects treated with risankizumab 360 mg subcutaneously after risankizumab induction compared to 2.3 events per 100 subject-years in subjects who received placebo after risankizumab induction (see section 4.4).

Immunogenicity

For subjects with Crohn’s disease treated with risankizumab at the recommended intravenous induction and subcutaneous maintenance doses for up to 64 weeks in CD clinical trials, treatment- emergent anti-drug antibodies and neutralizing antibodies were detected in 3.4% (2/58) and 0% (0/58) of evaluated subjects, respectively.

For subjects with ulcerative colitis treated with risankizumab at the recommended intravenous induction and subcutaneous maintenance doses (180 mg or 360 mg) for up to 64 weeks in ulcerative colitis clinical trials, treatment-emergent anti-drug antibodies and neutralising antibodies were detected in 8.9% (8/90) and 6.7% (6/90) for the 180 mg subcutaneous dose, or 4.4% (4/91) and 2.2% (2/91) for the 360 mg subcutaneous dose, of evaluated subjects, respectively.

Antibodies to risankizumab including neutralizing antibodies were not associated with changes in clinical response or safety.

Elderly

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

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 the national reporting system listed in Appendix V.

Summary of the safety profile

The most frequently reported adverse reactions were upper respiratory infections (15.6% in Crohn’s disease and 26.2% in ulcerative colitis).

Tabulated list of adverse reactions

Adverse reactions for risankizumab from clinical studies (Table 1) 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 1: List of adverse reactions

System Organ Class
Frequency
Adverse reactions
Infections and infestations

Very common
Upper respiratory infectionsa
Common
Tinea infectionsb
Uncommon
Folliculitis
Immune system disorders
Rare
Anaphylactic reactions
Nervous system disorders
Common
Headachec
Skin and subcutaneous tissue disorders
Common
Pruritus
Rash
Eczema
Uncommon
Urticaria
General disorders and administration site conditions
Common
Fatigued
Injection site reactionse a Includes: respiratory tract infection (viral, bacterial or unspecified), sinusitis (including acute), rhinitis, nasopharyngitis, pharyngitis (including viral), tonsillitis, laryngitis, tracheitis b Includes: tinea pedis, tinea cruris, body tinea, tinea versicolor, tinea manuum, onychomycosis, tinea infection c Includes: headache, tension headache, sinus headache d Includes: fatigue, asthenia, malaise e Includes: injection site bruising, erythema, haematoma, haemorrhage, irritation, pain, pruritus, reaction, swelling, induration, hypersensitivity, nodule, rash, urticaria, vesicles, warmth; infusion site erythema, extravasation, reaction, swelling

Description of selected adverse reactions

Psoriasis

Infections

Over the entire psoriasis programme including long-term exposure to risankizumab, the rate of infections was 75.5 events per 100 subject-years. 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 (see section 4.4).

Crohn’s disease

Overall, the safety profile observed in patients with Crohn’s disease treated with risankizumab was consistent with the safety profile observed in patients across indications.

Infections

The rate of infections in the pooled data from the 12-week induction studies was 83.3 events per 100 subject-years in subjects treated with risankizumab 600 mg intravenously compared to 117.7 events per 100 subject-years in placebo. The rate of serious infections was 3.4 events per 100 subject-years in subjects treated with risankizumab 600 mg intravenously compared to 16.7 events per 100 subject- years in placebo (see section 4.4).

The rate of infections in the 52-week maintenance study was 57.7 events per 100 subject-years in subjects treated with risankizumab 360 mg subcutaneously after risankizumab induction compared to

76.0 events per 100 subject-years in subjects who received placebo after risankizumab induction. The rate of serious infections was 6.0 events per 100 subject-years in subjects treated with risankizumab 360 mg subcutaneously after risankizumab induction compared to 5.0 events per 100 subject-years in subjects who received placebo after risankizumab induction (see section 4.4).

Ulcerative colitis

Overall, the safety profile observed in patients with ulcerative colitis treated with risankizumab was consistent with the safety profile observed in patients across indications.

Infections

The rate of infections in the pooled data from the 12-week induction study was 78.3 events per 100 subject-years in subjects treated with risankizumab 1 200 mg intravenously compared to 74.2 events per 100 subject-years in placebo. The rate of serious infections was 3.0 events per 100 subject- years in subjects treated with risankizumab 1 200 mg intravenously compared to 5.4 events per 100 subject-years in placebo (see section 4.4).

The rate of infections in the 52-week maintenance study was 67.4 events per 100 subject-years in subjects treated with risankizumab 180 mg subcutaneously and 56.5 events per 100 subject-years in subjects treated with risankizumab 360 mg subcutaneously after risankizumab induction compared to 64.6 events per 100 subject-years in subjects who received placebo after risankizumab induction. The rate of serious infections was 1.1 events per 100 subject-years in subjects treated with risankizumab 180 mg subcutaneously and 0.6 events per 100 subject-years in subjects treated with risankizumab 360 mg subcutaneously after risankizumab induction compared to 2.3 events per 100 subject-years in subjects who received placebo after risankizumab induction (see section 4.4).

Immunogenicity

For subjects with Crohn’s disease treated with risankizumab at the recommended intravenous induction and subcutaneous maintenance doses for up to 64 weeks in CD clinical trials, treatment- emergent anti-drug antibodies and neutralizing antibodies were detected in 3.4% (2/58) and 0% (0/58) of evaluated subjects, respectively.

For subjects with ulcerative colitis treated with risankizumab at the recommended intravenous induction and subcutaneous maintenance doses (180 mg or 360 mg) for up to 64 weeks in ulcerative colitis clinical trials, treatment-emergent anti-drug antibodies and neutralising antibodies were detected in 8.9% (8/90) and 6.7% (6/90) for the 180 mg subcutaneous dose, or 4.4% (4/91) and 2.2% (2/91) for the 360 mg subcutaneous dose, of evaluated subjects, respectively.

Antibodies to risankizumab including neutralizing antibodies were not associated with changes in clinical response or safety.

Elderly

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

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 the national reporting system listed in Appendix V.

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 0.2 mg of polysorbate 20 in each 150 mg dose. Polysorbates may cause allergic reactions.

Sodium

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

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’.

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 2 mg of polysorbate 20 in each 600 mg dose and 4 mg of polysorbate 20 in each 1 200 mg dose. Polysorbates may cause allergic reactions.

Sodium

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

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 0.24 mg of polysorbate 20 in each 180 mg dose and 0.48 mg of polysorbate 20 in each 360 mg dose. Polysorbates may cause allergic reactions.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 180 mg dose and 360 mg dose, that is to say essentially ‘sodium-free’.

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 0.8 mg of polysorbate 20 in each 360 mg dose. Polysorbates may cause allergic reactions.

Sorbitol

This medicinal product contains 164 mg sorbitol per 360 mg dose.
The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 360 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 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.

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

The safety and efficacy of risankizumab in combination with immunosuppressants, including biologics, 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.

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.

5.
PHARMACOLOGICAL PROPERTIES

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.

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

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

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.

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.

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 faecal calprotectin (FCP), serum C reactive protein (CRP) and IL-22 were also observed after multiple doses in Phase 3 induction studies in Crohn’s patients. Decreases in FCP, CRP and serum IL-22 were maintained out to week 52 of the maintenance study.

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

Clinical efficacy and safety

Crohn’s disease

The efficacy and safety of risankizumab were assessed in 1 419 subjects with moderately to severely active Crohn’s disease in three multicentre, randomised, double-blind, placebo-controlled clinical studies. 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), which included 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 of subcutaneous maintenance treatment (FORTIFY) that enrolled subjects with SF/APS clinical response to intravenous induction treatment, representing at least 64 weeks of therapy.

ADVANCE and MOTIVATE

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.

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 faecal calprotectin (FCP), serum C reactive protein (CRP) and IL-22 were also observed after multiple doses in Phase 3 induction studies in Crohn’s patients. Decreases in FCP, CRP and serum IL-22 were maintained out to week 52 of the maintenance study.

Clinical efficacy and safety

Crohn’s disease

The efficacy and safety of risankizumab were assessed in 1 419 subjects with moderately to severely active Crohn’s disease in three multicentre, randomised, double-blind, placebo-controlled clinical studies. 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), which included 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 of subcutaneous maintenance treatment (FORTIFY) that enrolled subjects with SF/APS clinical response to 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 either 600 mg (recommended dose), 1 200 mg, or placebo, at week 0, week 4, and week 8.

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

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 (Vss) 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

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 (Vss) 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

The pharmacokinetics of risankizumab was similar between plaque psoriasis and psoriatic arthritis, and between Crohn’s disease and ulcerative colitis.

Absorption

Risankizumab exhibited linear pharmacokinetics with dose-proportional increase in exposure across dose ranges of 18 to 360 mg and 0.25 to 1 mg/kg administered subcutaneously, and 200 to 1 800 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 74-89%. 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.

In subjects with Crohn’s disease treated with 600 mg intravenous induction dose at weeks 0, 4, and 8 followed by 360 mg subcutaneous maintenance dose at week 12 and every 8 weeks thereafter, maximum median peak and trough concentrations are estimated to be 156 and 38.8 µg/mL respectively during the induction period (weeks 8-12) and steady-state median peak and trough concentrations are estimated to be 28.0 and 8.13 µg/mL respectively during the maintenance period (weeks 40-48).

In subjects with ulcerative colitis treated with 1 200 mg intravenous induction dose at weeks 0, 4, and 8 followed by 180 mg or 360 mg subcutaneous maintenance dose at week 12 and every 8 weeks thereafter, maximum median peak and trough concentrations are estimated to be 350 and 87.7 µg/mL respectively during the induction period (weeks 8-12) and steady-state median peak and trough concentrations are estimated to be 19.6 and 4.64 µg/mL for the 180 mg subcutaneous dose and 39.2 and 9.29 µg/mL for the 360 mg subcutaneous dose, respectively, during the maintenance period (weeks 40-48).

Distribution

The pharmacokinetics of risankizumab was similar between plaque psoriasis and psoriatic arthritis, and between Crohn’s disease and ulcerative colitis.

Absorption

Risankizumab exhibited linear pharmacokinetics with dose-proportional increase in exposure across dose ranges of 18 to 360 mg and 0.25 to 1 mg/kg administered subcutaneously, and 200 to 1 800 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 74-89%. 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.

In subjects with Crohn’s disease treated with 600 mg intravenous induction dose at weeks 0, 4, and 8 followed by 360 mg subcutaneous maintenance dose at week 12 and every 8 weeks thereafter, maximum median peak and trough concentrations are estimated to be 156 and 38.8 µg/mL respectively during the induction period (weeks 8-12) and steady-state median peak and trough concentrations are estimated to be 28.0 and 8.13 µg/mL respectively during the maintenance period (weeks 40-48).

Distribution

The mean (±standard deviation) steady-state volume of distribution (Vss) 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. In a typical 70 kg subject with Crohn’s disease, Vss was 7.68 L.

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