Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials

Gordon, Kenneth B.; Strober, Bruce; Lebwohl, Mark; Augustin, Matthias; Blauvelt, Andrew; Poulin, Yves; Papp, Kim; Sofen, Howard; Puig, Lluís; Foley, Peter; Ohtsuki, Mamitaro; Flack, Mary; Geng, Ziqian; Gu, Yihua; Valdes, Joaquin; Thompson, Elizabeth H.; Bachelez, H.

doi:10.1016/s0140-6736(18)31713-6

Cited by 512 publications

(601 citation statements)

References 28 publications

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“…39,40 These findings were confirmed by results of randomized, controlled phase 3 clinical trials ( safety concerns identified for any available IL-23p19 inhibitor. [41][42][43][44][45] Key exclusion criteria for these studies typically included any malignancy within the past 5 years (except nonmelanoma skin cancer), active or untreated latent tuberculosis and testing positive for human immunodeficiency, hepatitis B virus or hepatitis C virus infection. Women could not be pregnant, and those of child-bearing potential had to practice abstinence or use medically accepted contraception methods.…”

Section: Safety Data From Clinical Trialsmentioning

confidence: 99%

“…Two 52-week, phase 3 trials of risankizumab vs. ustekinumab have been reported, with no unexpected safety findings: UltIMMa-1 (NCT02684370) and UltIMMa-2 (NCT02684357). 45 In both studies, adult patients were randomized (3 : 1 : 1) to receive risankizumab 150 mg, ustekinumab 45 mg or 90 mg or placebo (506 in UltIMMa-1 and 491 in UltIMMa-2). Rates of AEs were similar across all groups during both the placebo-controlled period (Weeks 0-16) and long-term follow-up (Weeks 16-52) ( Table 2).…”

Section: Risankizumabmentioning

confidence: 99%

“…Risankizumab was compared with ustekinumab in a 48-week phase 2 trial (NCT02054481) 40 and in the phase 3 UltIMMAa-1 and UltIMMAa-2 studies, in which broadly similar safety profiles were reported for both treatments. 45 Ustekinumab was compared with guselkumab in the NAVIGATE trial (described above), 43 in which more AEs occurred in the guselkumab group (64%) than the ustekinumab group (56%). Further studies comparing treatments are ongoing or awaiting publication, including guselkumab vs. secukinumab (phase 2, NCT03553823; phase 3, NCT03090100) and vs. ixekizumab (phase 4, NCT03573323) and risankizumab vs. secukinumab (phase 3, NCT03478787).…”

Section: Other Safety Datamentioning

confidence: 99%

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Safety of selective IL‐23p19 inhibitors for the treatment of psoriasis

Crowley

Warren

Cather³

2019

Acad Dermatol Venereol

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Psoriasis is a chronic disease that requires long‐term treatment. Consequently, understanding the safety and tolerability of any potential treatment over time is critical to effective prescribing. The biologic agents currently available for the treatment of psoriasis target a number of different inflammatory cytokines involved in psoriasis disease pathogenesis. The monoclonal antibodies tildrakizumab, guselkumab and risankizumab target the p19 subunit that is specific to interleukin (IL)‐23. This article reviews published data on the safety of these IL‐23p19 inhibitors in patients with psoriasis compared with other currently available biologic therapies. Data from randomized, placebo‐ and active‐controlled phase 3 clinical trials show tildrakizumab, guselkumab and risankizumab to have a favourable risk–benefit profile in patients with moderate to severe psoriasis. No significant safety concerns have been observed for any of these IL‐23p19 inhibitors in the data published to date. The most commonly reported adverse events (AEs) associated with these agents in phase 3 studies were upper respiratory tract infections. No increase was seen in rates of serious infections, malignancies or major adverse cardiovascular events, with no signals suggestive of an elevated risk of opportunistic infections, active tuberculosis or reactivation of latent tuberculosis infection, mucocutaneous Candida infections, triggering or worsening of inflammatory bowel disease, demyelinating disorders or suicidal ideation. Selectively targeting IL‐23p19 may help avoid AEs that have been associated with biologic agents with other mechanisms of action. Data from long‐term extension studies and patient registries will further establish the safety profile of IL‐23p19 inhibitors for the treatment of moderate to severe psoriasis in routine practice.

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Section: Safety Data From Clinical Trialsmentioning

confidence: 99%

Section: Risankizumabmentioning

confidence: 99%

Section: Other Safety Datamentioning

confidence: 99%

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Safety of selective IL‐23p19 inhibitors for the treatment of psoriasis

Crowley

Warren

Cather³

2019

Acad Dermatol Venereol

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“…Risankizumab has recently completed three phase III studies in subjects with psoriasis and had the primary timepoint readout from a fourth phase III trial [20,21]. The recent phase III trials confirmed the efficacy of a risankizumab SC regimen of 150 mg administered at weeks 0 and 4 and every 12 weeks thereafter in subjects with psoriasis and demonstrated the superior efficacy of risankizumab relative to both adalimumab and ustekinumab in the treatment of psoriasis.…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics of the Interleukin-23 Inhibitor Risankizumab in Subjects with Psoriasis and Crohn’s Disease: Analyses of Phase I and II Trials

et al. 2018

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Background and Objectives Risankizumab is a humanized anti-interleukin-23 monoclonal antibody in development for the treatment of several inflammatory diseases. This work characterized the pharmacokinetics of risankizumab and evaluated covariates that may affect its exposures using phase I and II trial data in subjects with psoriasis and Crohn's disease. Methods Plasma concentration measurements from a phase I study and a phase II study in subjects with psoriasis (n = 157; single doses of 0.01-5 mg/kg intravenously, 0.25-1 mg/kg subcutaneously, and 18 mg subcutaneously, and multiple doses of 90 and 180 mg subcutaneously), and a phase II study in subjects with Crohn's disease (n = 115; doses of 200 or 600 mg intravenously every 4 weeks followed by 180 mg subcutaneously every 8 weeks) were analyzed using non-linear mixedeffects modeling. The model was qualified using bootstrap and simulation-based diagnostics. Results A two-compartment model with first-order absorption and elimination described the pharmacokinetics of risankizumab. Considering the body weight and baseline albumin central tendency differences between disease populations, risankizumab clearance, steady-state volume of distribution, and terminal-phase elimination half-life were estimated to be approximately 0.35 L/day, 11.7 L, and 27 days, respectively, for a typical 90-kg subject with psoriasis with an albumin level of 42 g/L, and 0.31 L/day, 8.45 L, and 22 days, respectively, for a typical 65-kg subject with Crohn's disease with an albumin level of 37 g/L. Risankizumab absolute subcutaneous bioavailability and absorption rate constant were 72% and 0.18 day −1 , respectively. Inter-individual variability for clearance was 37%. Conclusions Risankizumab displayed pharmacokinetic characteristics typical for an IgG1 monoclonal antibody with no apparent target-mediated disposition. Accounting for the effects of body weight and baseline albumin explained the small differences in the pharmacokinetics of risankizumab between psoriasis and Crohn's disease, with no further differences between the patient populations. Electronic supplementary materialThe online version of this article (https ://doi.org/10.1007/s4026 2-018-0704-z) contains supplementary material, which is available to authorized users. Key PointsA robust two-compartment model with dose-and timeindependent pharmacokinetic parameters was developed to characterize the disposition of risankizumab, an antiinterleukin-23 monoclonal antibody, in subjects with plaque psoriasis and Crohn's disease.Of the factors evaluated (demographics, disease population, laboratory values, and anti-drug antibody development), only body weight and baseline albumin level were statistically correlated with risankizumab clearance. Body weight had a modest effect on risankizumab exposure while albumin had no meaningful impact.After accounting for differences in body weight and baseline albumin levels between psoriasis and Crohn's disease patient populations, no significant differences in the pharmacokinetics of ri...

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“…More recently, biologics that target the p19 subunit (which is specific for IL‐23), such as guselkumab, have been shown to be highly effective . To date, there have been no phase III randomized controlled trials studying p19 vs. p40 inhibitors in comparable populations of patients with moderate‐to‐severe psoriasis …”

mentioning

confidence: 99%

Risankizumab vs. ustekinumab for plaque psoriasis: a critical appraisal

et al. 2019

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Summary Aim Gordon et al. investigated the efficacy and safety of risankizumab [an anti‐interleukin (IL)‐23p19 biologic] compared with ustekinumab (anti‐IL‐12/23p40) and placebo in patients with moderate‐to‐severe chronic plaque psoriasis. This was a parallel‐group controlled study up to 16 weeks with a planned switch of the placebo group to risankizumab at 16 weeks. Setting and design This study consisted of two replicate phase III, double‐blinded randomized controlled trials (UltIMMa‐1 and UltIMMa‐2) conducted across 139 centres in Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Japan, Mexico, Poland, Portugal, South Korea, Spain and the U.S.A. Study exposure Patients with a minimum 6‐month history of chronic plaque psoriasis were randomly assigned to receive either 150 mg risankizumab, 45 mg or 90 mg ustekinumab or placebo. Prior to this, each group was also stratified by weight (either more than or less than 100 kg) and previous exposure to tumour necrosis factor inhibitors. Those assigned to receive placebo were transitioned onto risankizumab at week 16. The study drugs were given at weeks 0, 4, 16, 28 and 40. Outcomes The severity of psoriasis was measured using the Psoriasis Area and Severity Index (PASI) and a static Physician's Global Assessment (sPGA). The authors additionally recorded the number of adverse events in each treatment arm, and a measure of quality of life. Primary outcome measures The coprimary outcomes were the proportions of patients achieving ≥ 90% reduction in their baseline PASI (PASI 90) and an sPGA score of 0 or 1 (clear or almost clear) at week 16. Results In total 506 patients were included in UltIMMa‐1 and 491 patients in UltIMMa‐2. In UltIMMa‐1, PASI 90 by week 16 was achieved by 75·3% of patients receiving risankizumab, compared with 42·0% receiving ustekinumab and 4·9% receiving placebo (P < 0·001 vs. placebo and ustekinumab). sPGA of 0 or 1 by week 16 was achieved by 87·6% of patients receiving risankizumab, compared with 63·0% receiving ustekinumab and 7·8% receiving placebo (P < 0·001 vs. placebo and ustekinumab). The results for UltIMMa‐2 are similar. The frequencies of adverse events in the risankizumab, ustekinumab and placebo groups were similar in both studies. Conclusions Gordon et al. conclude that risankizumab has a higher efficacy than placebo and ustekinumab in the treatment of moderate‐to‐severe chronic plaque psoriasis, and that the adverse‐event profiles were similar across all treatment groups.

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Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials

Cited by 512 publications

References 28 publications

Safety of selective IL‐23p19 inhibitors for the treatment of psoriasis

Safety of selective IL‐23p19 inhibitors for the treatment of psoriasis

Population Pharmacokinetics of the Interleukin-23 Inhibitor Risankizumab in Subjects with Psoriasis and Crohn’s Disease: Analyses of Phase I and II Trials

Risankizumab vs. ustekinumab for plaque psoriasis: a critical appraisal

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