Summary of medicine characteristics - Skyrizi
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Skyrizi 150 mg solution for injection in pre-filled pen
Each pre-filled pen contains 150 mg risankizumab in 1 mL solution.
Skyrizi 150 mg solution for injection in pre-filled syringe
Each pre-filled syringe contains 150 mg risankizumab in 1 mL solution.
Skyrizi 75 mg solution for injection in pre-filled syringe
Each pre-filled syringe contains 75 mg risankizumab in 0.83 mL solution.
Risankizumab is a humanised immunoglobulin G1 (IgG1) monoclonal antibody selective to the interleukin (IL)-23 protein produced in Chinese Hamster Ovary cells using recombinant DNA technology.
Excipients with known effect (75 mg solution for injection only)
This medicinal product contains 68.0 mg sorbitol per 150 mg dose.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection (injection)
Skyrizi 150 mg solution for injection in pre-filled pen and in pre-filled syringe
The solution is colourless to yellow and clear to slightly opalescent.
Skyrizi 75 mg solution for injection in pre-filled syringe
The solution is colourless to slightly yellow and clear to slightly opalescent.
4. CLINICAL PARTICULARS4.1 Therapeutic indications
Plaque Psoriasis
Skyrizi is indicated for the treatment of moderate to severe plaque psoriasis in adults 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).
4.2 Posology and method of administration
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
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).
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 (aged 65 years and over)
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 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 aged 5 to 18 years have not 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. 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.
4.3 Contraindications
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).
4.4 Special warnings and precautions for use
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 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
If a serious hypersensitivity reaction occurs, administration of risankizumab should be discontinued immediately and appropriate therapy initiated.
Excipients with known effect
Skyrizi 150 mg solution for injection in pre-filled pen or pre-filled syringe
This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled pen or pre-filled syringe, that is to say, essentially ‘sodium free’.
Skyrizi 75 mg solution for injection in pre-filled syringe
This medicinal product contains 68.0 mg sorbitol per 150 mg dose.
The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.
This medicinal product contains less than 1 mmol sodium (23 mg) per 150 mg dose, that is to say, essentially ‘sodium free’.
4.5 Interaction with other medicinal products and other forms of interaction
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.
4.6 Fertility, pregnancy and lactation
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.
4.7 Effects on ability to drive and use machines
Risankizumab has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions were upper respiratory infections.
Tabulated list of adverse reactions
Adverse reactions for risankizumab from clinical studies (Table 1) for psoriasis and psoriatic arthritis 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); and very rare (< 1/10 000).
Table 1: List of adverse reactions
| System Organ Class | Frequency | Adverse reactions |
| Infections and infestations | Very common | Upper respiratory infections3 |
| Common | Tinea infectionsb | |
| Uncommon | Folliculitis | |
| Nervous system disorders | Common | Headache6 |
| Skin and subcutaneous tissue disorders | Common | Pruritus |
| General disorders and administration site conditions | Common | Fatigued Injection site reactions6 |
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: inj ection 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).
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.
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 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 most 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 antibodypositive 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 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.
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
4.9 Overdose
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 PROPERTIES5.1 Pharmacodynamic 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
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.
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 2 and Figure 1.
Table 2: Efficacy and quality of life results in adults with plaque psoriasis in ULTIMMA-1 and ULTIMMA-2
| ULTIMMA-1 | ULTIMMA-2 | |||||
| Risankizumab (N=304) n (%) | Ustekinumab (N=100) n (%) | Placebo (N=102) n (%) | Risankizumab (N=294) n (%) | Ustekinumab (N=99) n (%) | Placebo (N=98) n (%) | |
| sPGA of clear or almost clear (0 or 1) | ||||||
| Week 16a | 267 (87.8) | 63 (63.0) | 8(7.8) | 246 (83.7) | 61 (61.6) | 5 (5.1) |
| Week 52 | 262 (86.2) | 54 (54.0) | -- | 245 (83.3) | 54 (54.5) | -- |
| sPGA of clear (0) | ||||||
| Week 16 | 112 (36.8) | 14 (14.0) | 2(2.0) | 150 (51.0) | 25 (25.3) | 3 (3.1) |
| Week 52 | 175 (57.6) | 21 (21.0) | -- | 175 (59.5) | 30 (30.3) | -- |
| PASI 75 | ||||||
| Week 12 | 264 (86.8) | 70 (70.0) | 10 (9.8) | 261 (88.8) | 69 (69.7) | 8 (8.2) |
| Week 52 | 279 (91.8) | 70 (70.0) | -- | 269 (91.5) | 76 (76.8) | -- |
| PASI 90 | ||||||
| Week 16a | 229 (75.3) | 42 (42.0) | 5 (4.9) | 220 (74.8) | 47 (47.5) | 2(2.0) |
| Week 52 | 249 (81.9) | 44 (44.0) | -- | 237 (80.6) | 50 (50.5) | -- |
| PASI 100 | ||||||
| Week 16 | 109 (35.9) | 12 (12.0) | 0(0.0) | 149 (50.7) | 24 (24.2) | 2(2.0) |
| Week 52 | 171 (56.3) | 21 (21.0) | -- | 175 (59.5) | 30 (30.3) | -- |
| DLQI 0 or 1b | ||||||
| Week 16 | 200 (65.8) | 43 (43.0) | 8(7.8) | 196 (66.7) | 46 (46.5) | 4(4.1) |
| Week 52 | 229 (75.3) | 47 (47.0) | -- | 208 (70.7) | 44 (44.4) | -- |
| PSS 0 (symptom-free)c | ||||||
| Week 16 | 89 (29.3) | 15 (15.0) | 2(2.0) | 92 (31.3) | 15 (15.2) | 0(0.0) |
| Week 52 | 173 (56.9) | 30 (30.0) | -- | 160 (54.4) | 30 (30.3) | -- |
| All comparisons of risankizumab versus ustekinumab and pl week 52 in ULTIMMA-2 where p=0.001 a Co-primary endpoints versus placebo b No impact on health-related quality of life c Psoriasis Symptom Scale (PSS) of 0 means no symptoms last 24 hours | acebo achieved p<0.001 except for PASI 75 at f pain, itching, redness, and burning during the | |||||
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 3: Mean changes from baseline in NAPSI, PPASI, and PSSI
| ULTIMMA-1 | ULTIMMA-2 | IMMHANCE | ||||
| Risankizumab | Placebo | Risankizumab | Placebo | Risankizumab | Placebo | |
| NAPSI: Change at Week 16 (SE) | N=178; –9.0 (1.17) | N=56; 2.1 (1.86)
| N=177; –7.5 (1.03) | N=49; 3.0 (1.76)
| N=235; –7.5 (0.89) | N=58; 2.5 (1.70)
|
| PPASI: Change at Week 16 (SE) | N=95; –5.93 (0.324) | N=34; –3.17 (0.445) | N=86; –7.24 (0.558) | N=23; –3.74 (1.025) ** | N=113; –7.39 (0.654) | N=26; –0.27 (1.339) |
| PSSI: Change at Week 16 (SE) | N=267; –17.6 (0.47) | N=92; –2.9 (0.69) | N=252; –18.4 (0.52) | N=83; –4.6 (0.82) *** | N=357; –20.1 (0.40) | N=88; –5.5 (0.77) *** |
| NAPSI: Change at Week 52 (SE) | N=178; –15.7 (0.94) | – | N=183; –16.7 (0.85) | – | – | – |
| PPASI: Change at Week 52 (SE) | N=95; –6.16 (0.296) | – | N=89; –8.35 (0.274) | – | – | – |
| PSSI: Change at Week 52 (SE) | N=269; –17.9 (0.34) | – | N=259; –18.8 (0.24) | – | – | – |
| Nail Psoriasis Severity Index (NAPSI), Palmoplantar Psoriasis Severity Index (PPASI), Scalp Severity Index (PSSI), and Standard Error (SE)
| Psoriasis | |||||
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.
The safety profile of risankizumab with up to 77 weeks 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 response of clear or almost clear at week 28 were rerandomised 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 4.
Table 4: Efficacy and quality of life results at week 16 in adults with plaque psoriasis in IMMVENT
| Risankizumab (N=301) n (%) | Adalimumab (N=304) n (%) | |
| sPGA of clear or almost clear a | 252 (83.7) | 183 (60.2) |
| PASI 75 | 273 (90.7) | 218 (71.7) |
| PASI 90a | 218 (72.4) | 144 (47.4) |
| PASI 100 | 120 (39.9) | 70 (23.0) |
| DLQI 0 or 1b | 198 (65.8) | 148 (48.7) |
| All comparisons achieved p<0.001 a Co-primary endpoints b No impact on health-related quality of life | ||
For subjects who had PASI 50 to <PASI 90 with adalimumab at week 16 and were re-randomised, differences in PASI 90 response rates between switching to risankizumab and continuing adalimumab were noted 4 weeks after re-randomisation (49.1% vs 26.8%, respectively).
Results 28 weeks after re-randomisation are presented in Table 5 and Figure 2.
Table 5: Efficacy results 28 weeks after re-randomisation in IMMVENT
| Switched to Risankizumab (N=53) n (%) | Continued on Adalimumab (N=56) n (%) | |
| PASI 90 | 35 (66.0) | 12 (21.4) |
| PASI 100 | 21 (39.6) | 4 (7.1) |
| All comparisons achieved p<0.001 | ||
Figure 2: Time course of PASI 90 after re-randomisation in IMMVENT
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
■ ADA/RZB (N=53)
– O – ADA/ADA (N=56)
Weeks After Re-Randomisation
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.
Psoriatic arthritis
Risankizumab has been shown to improve signs and symptoms, physical function, health-related quality of life, and the proportion of subjects with no radiographic progression in adults with active psoriatic arthritis (PsA).
The safety and efficacy of risankizumab were assessed in 1 407 subjects with active PsA in 2 randomised, double-blind, placebo-controlled studies (964 in KEEPSAKE1 and 443 in KEEPSAKE2).
Subjects in these studies had a diagnosis of PsA for at least 6 months based on the Classification Criteria for Psoriatic Arthritis (CASPAR), a median duration of PsA of 4.9 years at baseline, > 5 tender joints and > 5 swollen joints, and active plaque psoriasis or nail psoriasis at baseline. 55.9% of subjects had > 3% BSA with active plaque psoriasis. 63.4% and 27.9% of subjects had enthesitis and dactylitis, respectively. In KEEPSAKE1, where nail psoriasis was further assessed, 67.3% had nail psoriasis.
In both studies, subjects were randomised to receive risankizumab 150 mg or placebo at weeks 0, 4, and 16. Starting from week 28, all subjects received risankizumab every 12 weeks.
In KEEPSAKE1, all subjects had a previous inadequate response or intolerance to non-biologic DMARD therapy and were biologic naïve. In KEEPSAKE2, 53.5% of subjects had a previous inadequate response or intolerance to non-biologic DMARD therapy and 46.5% of subjects had a previous inadequate response or intolerance to biologic therapy.
In both studies, 59.6% of subjects were receiving concomitant methotrexate (MTX), 11.6% were receiving concomitant non-biologic DMARDs other than MTX, and 28.9% were receiving risankizumab monotherapy.
Clinical Response
Treatment with risankizumab resulted in significant improvement in measures of disease activity compared with placebo at week 24. For both studies, the primary endpoint was the proportion of subjects who achieved an American College of Rheumatology (ACR) 20 response at week 24. The key efficacy results are shown in Table 6.
Table 6. Efficacy resuts in studies KEEPSAKE1 and KEEPSAKE2 ____________________
| keepsakei | KEEPSAKE2 | |||
| Endpoint | Placebo N=481 n (%) | Risankizumab N=483 n (%) | Placebo N=219 n (%) | Risankizumab N=224 n (%) |
| ACR20 Response | ||||
| Week 16 | 161 (33.4) | 272 (56.3) a | 55 (25.3) | 108 (48.3) a |
| Week 24 | 161 (33.5) | 277 (57.3) a | 58 (26.5) | 115(51.3) a |
| Week 52* | – | 338/433 (78.1) | – | 131/191 (68.6) |
| ACR50 Response | ||||
| Week 24 | 54 (11.3) | 162 (33.4) b | 20 (9.3) | 59 (26.3) b |
| Week 52* | – | 209/435 (48.0) | – | 72/192 (37.5) |
| ACR70 Response | ||||
| Week 24 | 23 (4.7) | 74 (15.3) b | 13 (5.9) | 27(12.0) c |
| Week 52* | – | 125/437 (28.6) | – | 37/192 (19.3) |
| Resolution of Enthesitis (LEI=0) | ||||
| Week 24* | 156/448 (34.8) d | 215/444 (48.4) a, d | – | – |
| Week 52* | – | 244/393 (62.1) d | – | – |
| Resolution of Dactylitis (LDI=0) | ||||
| Week 24* | 104/204 (51.0) e | 128/188 (68.1) a, e | – | – |
| Week 52* | – | 143/171 (83.6) e | – | – |
| Minimal Disease Activity (MDA) Response | ||||
| Week 24 | 49 (10.2) | 121 (25.0) a | 25 (11.4) | 57 (25.6) a |
| Week 52* | – | 183/444 (41.2) | – | 61/197 (31.0) |
| *data are shown for available subjects in the format of n/N observed (%)
| ||||
Response over time
In KEEPSAKE1, a greater ACR20 response was observed in the risankizumab group compared to placebo as early as week 4 (25.7%) and the treatment difference continued over time to week 24 (Figure 3).
Figure 3. Percent of subjects achieving ACR20 responses in study KEEPSAKE1 through week 24
A greater ACR20 response for risankizumab versus placebo was seen as early as week 4 in 19.6% of subjects in KEEPSAKE2.
Responses observed in risankizumab groups were similar regardless of concomitant non-biologic DMARD use, number of prior non-biologic DMARDs, age, gender, race, and BMI. In KEEPSAKE2, responses were seen regardless of prior biologic therapy.
The safety profile of risankizumab with up to 52 weeks of exposure was consistent with the profile observed up to 24 weeks.
In both studies, the proportion of subjects achieving modified PsA Response Criteria (PsARC) at week 24 was higher in subjects receiving risankizumab compared with placebo. In addition, subjects receiving risankizumab achieved greater improvement in Disease Activity Score (28 joints) using CRP (DAS28-CRP) compared with placebo at week 24. Improvements were maintained through week 52 for PsARC and DAS28-CRP.
Treatment with risankizumab resulted in improvements in individual ACR components, Health Assessment Questionnaire-Disability Index (HAQ-DI), pain assessment, and high-sensitivity C-reactive protein (hsCRP) compared with placebo.
Treatment with risankizumab resulted in statistically significant improvement in the skin manifestations of psoriasis in subjects with PsA.
Treatment with risankizumab resulted in statistically significant improvement in the modified Nail Psoriasis Severity Index (mNAPSI) and the 5-point Physician’s Global Assessment of Fingernail Psoriasis (PGA-F) scores in subjects with nail psoriasis at baseline (67.3%) in KEEPSAKE1. This improvement was maintained through week 52 (see Table 7).
Table 7. Nail psoriasis efficacy results in KEEPSAKE1
| Placebo N=338 | Risankizumab N=309 | |
| mNAPSI change from baseline a | ||
| Week 24 | –5.57 | –9.76 b |
| Week 52 | – | –13.64 |
| PGA-F change from baseline a | ||
| Week 24 | –0.4 | –0.8 b |
| Week 52 | – | –1.2 |
| PGA-F clear/minima | and >2-grade improvement c | |
| Week 24 n (%) | 30 (15.9) | 71 (37.8) d |
| Week 52 n (%) | – | 105 (58.0) |
| ||
Radiographic Response
In KEEPSAKE1, inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified Total Sharp Score (mTSS) at week 24, compared with baseline. The mTSS score was modified for PsA by addition of hand distal interphalangeal (DIP) joints. At week 24, the mean progression of structural damage with risankizumab (mean mTSS 0.23) compared with placebo (mean mTSS 0.32) was not statistically significant. At week 24, the proportion of subjects with no radiographic progression (defined as a change from baseline in mTSS < 0) was higher with risankizumab (92.4%) compared with placebo (87.7%). This response was maintained through week 52.
Physical Function and Health Related Quality of Life
In both studies, subjects treated with risankizumab showed statistically significant improvement from baseline in physical function as assessed by HAQ-DI at week 24 (KEEPSAKE1 (-0.31) compared with placebo (-0.11) (p <0.001)), (KEEPSAKE2 (-0.22) compared with placebo (-0.05) (p <0.001)). At week 24, a greater proportion of subjects achieved a clinically meaningful reduction of at least 0.35 in HAQ-DI score from baseline in the risankizumab group compared with placebo. Improvements in physical function were maintained through week 52.
In both studies, subjects treated with risankizumab demonstrated significant improvements in the SF-36 V2 physical component summary scores and in FACIT-Fatigue scores at week 24, compared with placebo, with improvements maintained through week 52.
At baseline, psoriatic spondylitis was reported in 19.6% (7.9% diagnosed by radiograph or MRI) of subjects in KEEPSAKE1 and 19.6% (5% diagnosed by radiograph or MRI) of subjects in
KEEPSAKE2. Subjects with clinically assessed psoriatic spondylitis who were treated with risankizumab showed improvements from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores compared with placebo at week 24. Improvements were maintained through week 52. There is insufficient evidence of the efficacy of risankizumab in subjects with radiograph- or MRI-confirmed ankylosing spondylitis-like psoriatic arthropathy due to the small number of subjects studied.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with risankizumab in one or more subsets of the paediatric population in the treatment of plaque psoriasis and psoriatic arthritis (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
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 tig. 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
Risankizumab exhibited linear pharmacokinetics with approximately dose-proportional increases in systemic exposure (Cmax 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 or psoriatic arthritis during the clinical studies.
Special populations
Paediatric population
The pharmacokinetics of risankizumab in paediatric subjects has not been established.
Elderly
Of the 2 234 subjects with plaque psoriasis exposed to risankizumab, 243 were 65 years or older and 24 subjects were 75 years or older. Of the 1 542 subjects with psoriatic arthritis exposed to risankizumab, 246 were 65 years or older and 34 subjects were 75 years or older. No overall differences in risankizumab exposure were observed between older and younger subjects who received risankizumab.
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 or psoriatic arthritis.
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.
Gender or race
The clearance of risankizumab was not significantly influenced by gender or race in adult subjects with plaque psoriasis or psoriatic arthritis. No clinically meaningful differences in risankizumab exposure were observed in Chinese or Japanese subjects compared with Caucasian subjects in a clinical pharmacokinetic study.
5.3 Preclinical safety data
Nonclinical data revealed no special hazard for humans based on repeat-dose toxicity studies including safety pharmacology evaluations, and a reproductive and 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.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Skyrizi 150 mg solution for injection in pre-filled pen and pre-filled syringe
Sodium acetate trihydrate
Acetic acid
Trehalose dihydrate
Polysorbate 20
Water for injections
Skyrizi 75 mg solution for injection in pre-filled syringe
Disodium succinate hexahydrate
Succinic acid
Sorbitol
Polysorbate 20
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze.
Keep the pre-filled pen or the pre-filled syringe(s) in the outer carton in order to protect from light.
Skyrizi 150 mg pre-filled pen or pre-filled syringe may be stored out of the refrigerator (up to a maximum of 25°C) for up to 24 hours in the original carton to protect from light.
6.5 Nature and contents of container
Skyrizi 150 mg solution for injection in pre-filled pen
Pre-filled glass syringe assembled in a pre-filled pen with an automatic needle sleeve.
Skyrizi 150 mg solution for injection in pre-filled syringe
Pre-filled glass syringe with a fixed needle and needle cover, assembled in an automatic needle guard.
Skyrizi 150 mg is available in packs containing 1 pre-filled pen or 1 pre-filled syringe.
Skyrizi 75 mg solution for injection in pre-filled syringe
Pre-filled glass syringe with a fixed needle and needle cover, assembled in an automatic needle guard.
Skyrizi 75 mg is available in packs containing 2 pre-filled syringes and 2 alcohol pads.
Not all presentations may be marketed.
6.6 Special precautions for disposal and other handling
Skyrizi 150 mg solution for injection in pre-filled pen
Before injecting, patients should remove the carton from the refrigerator and allow to reach room temperature out of direct sunlight (30 to 90 minutes) without removing the pre-filled pen from the carton.
The solution should be colourless to yellow and clear to slightly opalescent.
Skyrizi 150 mg solution for injection in pre-filled syringe
Before injecting, patients may remove the carton from the refrigerator and allow to reach 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.
Skyrizi 75 mg solution for injection in 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 syringes from the carton.
The solution should be colourless to slightly yellow and clear to slightly opalescent.
Two pre-filled syringes should be injected for the full 150 mg dose.
General special precautions
Prior to use, a visual inspection of each pre-filled pen or pre-filled syringe is recommended. 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 pen or pre-filled syringe.
Comprehensive instructions for use are provided in the package leaflet.
Each pre-filled pen or pre-filled syringe is for single use only.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
AbbVie Deutschland GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
8. MARKETING AUTHORISATION NUMBER(S)
Skyrizi 150 mg solution for injection in pre-filled pen
EU/1/19/1361/002
Skyrizi 150 mg solution for injection in pre-filled syringe
EU/1/19/1361/003
Skyrizi 75 mg solution for injection in pre-filled syringe
EU/1/19/1361/001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 26 April 2019