SKYRIZI Solution for injection Ref.[8750] Active ingredients: Risankizumab

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

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:

All comparisons of risankizumab versus ustekinumab and placebo achieved p<0.001 except for PASI 75 at week 52 in ULTIMMA-2 where p=0.001
^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 of pain, itching, redness, and burning during the last 24 hours

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

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:

Nail Psoriasis Severity Index (NAPSI), Palmoplantar Psoriasis Severity Index (PPASI), Psoriasis Scalp Severity Index (PSSI), and Standard Error (SE)
** P<0.01 comparing to risankizumab
*** P<0.001 comparing to risankizumab

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

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 re-randomised to continue risankizumab every 12 weeks 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 to 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 to 2.2% (5/225) who were re-randomised to withdrawal from risankizumab.

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:

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:

All comparisons achieved p<0.001

Figure 2. Time course of PASI 90 after re-randomisation in IMMVENT:

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

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 (see section 4.2 for information on paediatric use).