Skyrizi (Page 4 of 13)

11 DESCRIPTION

Risankizumab-rzaa, an interleukin-23 (IL-23) antagonist, is a humanized immunoglobulin G1 (IgG1) monoclonal antibody. Risankizumab-rzaa is produced by recombinant DNA technology in Chinese hamster ovary cells and has an approximate molecular weight of 149 kDa.

SKYRIZI (risankizumab-rzaa) injection 150 mg/mL prefilled syringe or prefilled pen for subcutaneous use

Each SKYRIZI prefilled pen or prefilled syringe contains a sterile, preservative-free, colorless to yellow, and clear to slightly opalescent solution. Each syringe and pen delivers 150 mg of risankizumab-rzaa and the inactive ingredients glacial acetic acid (0.054 mg), polysorbate 20 (0.2 mg), sodium acetate (0.75 mg), trehalose (63.33 mg), and Water for Injection, USP. The pH is 5.7.

SKYRIZI (risankizumab-rzaa) injection 75 mg/0.83 mL prefilled syringe for subcutaneous use

Each SKYRIZI prefilled syringe contains a sterile, preservative-free, colorless to slightly yellow, and clear to slightly opalescent solution. Each syringe delivers 75 mg of risankizumab-rzaa, and the inactive ingredients sodium succinate (0.53 mg), polysorbate 20 (0.17 mg), sorbitol (34 mg), succinic acid (0.049 mg), and Water for Injection, USP. The pH is 6.2.

SKYRIZI (risankizumab-rzaa) injection 360 mg/2.4 mL (150 mg/mL) prefilled cartridge for use with the supplied o n- b ody i njector for subcutaneous use

Each SKYRIZI prefilled cartridge contains a sterile, preservative-free, colorless to yellow, and clear to slightly opalescent solution. Each cartridge delivers 360 mg of risankizumab-rzaa, and the inactive ingredients glacial acetic acid (0.13 mg), polysorbate 20 (0.48 mg), sodium acetate (1.8 mg), trehalose (152 mg), and Water for Injection, USP. The pH is 5.7.

SKYRIZI 600 mg/10 mL (60 mg/mL) in a vial for intravenous infusion

SKYRIZI (risankizumab-rzaa) injection 600 mg/10 mL (60 mg/mL) is a sterile, preservative-free, colorless to slightly yellow, and clear to slightly opalescent solution in a 10 mL single-dose vial.

Each 10 mL single-dose vial contains 600 mg of risankizumab-rzaa, and the inactive ingredients glacial acetic acid (0.54 mg), polysorbate 20 (2 mg), sodium acetate (7.5 mg), trehalose (633.3 mg), and Water for Injection, USP. The pH is 5.7.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Risankizumab-rzaa is a humanized IgG1 monoclonal antibody that selectively binds to the p19 subunit of human IL-23 cytokine and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses.

Risankizumab-rzaa inhibits the release of pro-inflammatory cytokines and chemokines.

12.2 Pharmacodynamics

No formal pharmacodynamics studies have been conducted with risankizumab-rzaa.

12.3 Pharmacokinetics

Risankizumab-rzaa plasma concentrations, after single dose administration increased dose proportionally from 18 mg to 360 mg when administered subcutaneously (0.05-2.4 times the lowest recommended dose to the highest recommended dose) and from 200 mg to 1800 mg when administered as an up to 3-hour intravenous infusion (0.3 to 3 times the recommended dose) in healthy subjects.

In subjects with plaque psoriasis treated with 150 mg subcutaneously at Weeks 0, 4, and every 12 weeks thereafter, steady-state peak concentration (Cmax ) and trough concentration (Ctrough ) are estimated to be 12 mcg/mL and 2 mcg/mL, respectively.

With the same dosing regimen, the pharmacokinetics of risankizumab-rzaa in subjects with psoriatic arthritis was similar to that in subjects with plaque psoriasis.

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, the median Cmax and Ctrough are estimated to be 156 mcg/mL and 38.8 mcg/mL, respectively, during Weeks 8-12; and the steady state median Cmax and Ctrough are estimated to be 28.0 mcg/mL and 8.13 mcg/mL, respectively, during Weeks 40-48.

Absorption

The absolute bioavailability of risankizumab-rzaa was estimated to be 74 to 89% following subcutaneous injection. In healthy subjects, following administration of a single subcutaneous dose, Cmax was reached by 3 to 14 days.

Distribution

The estimated steady-state volume of distribution (inter-subject CV%) was 11.2 L (34%) in subjects with plaque psoriasis, and 7.68 L (64%) in subjects with Crohn’s disease.

Elimination

The estimated systemic clearance (inter-subject CV%) was 0.31 L/day (24%) and 0.30 L/day (34%) and terminal elimination half-life was approximately 28 days and 21 days in subjects with plaque psoriasis and Crohn’s disease, respectively.

Metabolism

The metabolic pathway of risankizumab-rzaa has not been characterized. As a humanized IgG1 monoclonal antibody, risankizumab-rzaa is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.

Specific Populations

No clinically significant differences in the pharmacokinetics of risankizumab-rzaa were observed based on age (≥18 years). Risankizumab-rzaa exposures (Ctrough ) in geriatric patients (≥65 years) are comparable to those in younger adult patients with Crohn’s disease. No studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of risankizumab-rzaa.

Body Weight

Risankizumab-rzaa clearance and volume of distribution increase and plasma concentrations decrease as body weight increases; however, no dose adjustment is recommended based on body weight.

Drug Interaction Studies

Cytochrome P450 Substrates

No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), metoprolol (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly with risankizumab-rzaa 150 mg administered subcutaneously at Weeks 0, 4, 8 and 12 (more frequent than the approved recommended dosing frequency) in subjects with plaque psoriasis.

Clinical drug interactions have not been evaluated in subjects with Crohn’s disease at the recommended dosage.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity and mutagenicity studies have not been conducted with SKYRIZI.

No effects on male fertility parameters were observed in sexually mature male cynomolgus monkeys dosed weekly for 26 weeks with 50 mg/kg risankizumab-rzaa at 10 times the exposure (AUC) in humans administered the 600 mg induction regimen for Crohn’s disease, and 3.9 times the exposure in humans administered the 360 mg maintenance regimen for Crohn’s disease, respectively.

14 CLINICAL STUDIES

Figure 1. Percent of Subjects Achieving ACR20 Responses in Study PsA-1 through Week 24

14.1 Plaque Psoriasis

Four multicenter, randomized, double-blind studies [PsO-1 (NCT02684370), PsO-2 (NCT02684357), PsO-3 (NCT02672852), and PsO-4 (NCT02694523)] enrolled 2109 subjects 18 years of age and older with moderate to severe plaque psoriasis who had a body surface area (BSA) involvement of ≥10%, a static Physician’s Global Assessment (sPGA) score of ≥3 (“moderate”) in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 4, and a Psoriasis Area and Severity Index (PASI) score ≥12.

Overall, subjects had a median baseline PASI score of 17.8 and a median BSA of 20%. Baseline sPGA score was 4 (“severe”) in 19% of subjects. A total of 10% of study subjects had a history of diagnosed psoriatic arthritis.

Across all studies, 38% of subjects had received prior phototherapy, 48% had received prior non-biologic systemic therapy, and 42% had received prior biologic therapy for the treatment of psoriasis.

Studies PsO-1 and PsO-2

In studies PsO-1 and PsO-2, 997 subjects were enrolled (including 598 subjects randomized to the SKYRIZI 150 mg group, 200 subjects randomized to the placebo group, and 199 to the biologic active control group). Subjects received treatment at Weeks 0, 4, and every 12 weeks thereafter.

Both studies assessed the responses at Week 16 compared with placebo for the two co-primary endpoints:

  • the proportion of subjects who achieved an sPGA score of 0 (“clear”) or 1 (“almost clear”)
  • the proportion of subjects who achieved at least a 90% reduction from baseline PASI (PASI 90)

Secondary endpoints included the proportion of subjects who achieved PASI 100, sPGA 0, and Psoriasis Symptom Scale (PSS) 0 at Week 16.

The results are presented in Table 4.

Table 4. Efficacy Results at Week 16 in Adults with Plaque Psoriasis in PsO-1 and PsO-2
PsO-1 PsO-2
SKYRIZI (N=304) n (%) Placebo (N=102) n (%) SKYRIZI (N=294) n (%) Placebo (N=98) n (%)
sPGA 0 or 1 (“clear or almost clear”) a 267 (88)8 (8)246 (84)5 (5)
PASI 90 a 229 (75)5 (5)220 (75)2 (2)
sPGA 0 (“clear”) 112 (37)2 (2)150 (51)3 (3)
PASI 100 109 (36)0 (0)149 (51)2 (2)
a Co-primary endpoints

Examination of age, gender, race, body weight, baseline PASI score and previous treatment with systemic or biologic agents did not identify differences in response to SKYRIZI among these subgroups at Week 16.

In PsO-1 and PsO-2 at Week 52, subjects receiving SKYRIZI achieved sPGA 0 (58% and 60%, respectively), PASI 90 (82% and 81%, respectively), and PASI 100 (56% and 60%, respectively).

Patient Reported Outcomes

Improvements in signs and symptoms related to pain, redness, itching and burning at Week 16 compared to placebo were observed in both studies as assessed by the PSS. In PsO-1 and PsO-2, about 30% of the subjects who received SKYRIZI achieved PSS 0 (“none”) at Week 16 compared to 1% of the subjects who received placebo.

Study PsO-3

Study PsO-3 enrolled 507 subjects (407 randomized to SKYRIZI 150 mg and 100 to placebo). Subjects received treatment at Weeks 0, 4, and every 12 weeks thereafter.

At Week 16, SKYRIZI was superior to placebo on the co-primary endpoints of sPGA 0 or 1 (84% SKYRIZI and 7% placebo) and PASI 90 (73% SKYRIZI and 2% placebo). The respective response rates for SKYRIZI and placebo at Week 16 were: sPGA 0 (46% SKYRIZI and 1% placebo); PASI 100 (47% SKYRIZI and 1% placebo); and PASI 75 (89% SKYRIZI and 8% placebo).

Maintenance and Durability of Response

In PsO-1 and PsO-2, among the subjects who received SKYRIZI and had PASI 100 at Week 16, 80% (206/258) of the subjects who continued on SKYRIZI had PASI 100 at Week 52. For PASI 90 responders at Week 16, 88% (398/450) of the subjects had PASI 90 at Week 52.

In PsO-3, subjects who were originally on SKYRIZI and had sPGA 0 or 1 at Week 28 were re-randomized to continue SKYRIZI every 12 weeks or withdrawal of therapy. At Week 52, 87% (97/111) of the subjects re-randomized to continue treatment with SKYRIZI had sPGA 0 or 1 compared to 61% (138/225) who were re-randomized to withdrawal of SKYRIZI.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2022. All Rights Reserved.