1University of Edinburgh Medical School, Edinburgh, United Kingdom
2Faculty of Medicine, University of Toronto, Toronto, ON, Canada
3SKiN Centre for Dermatology, Peterborough, ON, Canada
4Queen’s University, Kingston, ON, Canada
5Probity Medical Research, Waterloo, ON, Canada
Conflict of interest:
Julian McDonald and Khalad Maliyar have no conflicts of interest. Melinda Gooderham has been an investigator, speaker, advisor or consultant for AbbVie, Amgen, Akros, Arcutis, BMS, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, GSK, Janssen, Kyowa Kirin, Medimmune, Merck, Novartis, Pfizer, Roche, Regeneron, Sanofi Genzyme, Sun Pharma, UCB, and Valeant/Bausch Health.
Psoriasis is a common, chronic, immune-mediated, inflammatory disorder with significant skin manifestations and substantial burden on quality of life. Interleukin-23 is a key regulator of different effector cytokines and plays a cardinal role in the pathogenesis of psoriasis. The monoclonal antibody, risankizumab, inhibits this key cytokine and thus prevents the downstream inflammatory cascade. This article aims to review our current understanding of risankizumab through the analysis of the various clinical trials.
Role of Immune Dysfunction in Psoriasis
Studies have linked the immunological basis for psoriasis susceptibility to variants in genes for the interleukin-23 (IL-23) receptor and p19 subunit of IL-23.1 IL-23 is produced primarily by antigen-presenting cells and induces T helper 17 (TH17) and TH22 cell differentiation,2,3 which are sources of proinflammatory cytokines, including IL-17 (from TH17 cells) and IL-22 (from TH22 cells) that mediate tissue inflammation and epidermal hyperplasia.4 Risankizumab (BI 655066/ABBV-066) is a human immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to the unique p19 subunit of IL-23 with high affinity, thus blocking the activity of IL-23 and its signalling cascade.5
Risankizumab Clinical Trials
First phase testing of risankizumab was through a randomized, placebo-controlled, double-blinded, single-rising-dose, multicenter, within-dose cohort trial.5 Its primary objective was to evaluate the safety and tolerability of risankizumab based on the results of clinical examination and the presence of adverse events (AEs). Secondary efficacy endpoints included changes from baseline Psoriasis Area and Severity Index (PASI) and Static Physician Global Assessment (sPGA) scores over time. Patients aged 18 to 75 years with moderate-to-severe plaque psoriasis for ≥6 months were included. Thirty-nine eligible patients received a single dose of intravenous (IV) risankizumab (n=18), subcutaneous (SC) risankizumab (n=13), or matched placebo (n=8), with follow-up over the subsequent 24 weeks.
Risankizumab was well tolerated. AEs were reported with similar frequency in risankizumab and placebo groups, with 65% (20/31) of patients receiving IV or SC risankizumab experiencing an AE compared with 88% (7/8) on placebo. Mild-to-moderate upper respiratory tract infections, mild nasopharyngitis and mild-tomoderate headache were the most frequently reported AEs.
Assessment of secondary endpoints were also positive with rapid, substantial, and enduring clinical improvement.5 At week 12, 75%, 90% and 100% decreases in PASI (PASI75, PASI90 and PASI100) were achieved by 87%, 58% and 16% of risankizumabtreated patients, respectively, vs. none receiving placebo. PASI100 responses were maintained in some patients for up to 66 weeks after treatment, as observed in patients who entered an optional follow-up extension study. These marked clinical improvements, represented by significant PASI score reductions, supported the idea of the IL-23 pathway playing a central role in the pathogenesis of psoriasis and further studies were completed.
The Phase II trial compared the efficacy of risankizumab to that of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with moderate-to-severe plaque psoriasis.6 Ustekinumab targets the p40 subunit, common to both IL-12 and IL-23, thus blocking the activity of both cytokines. While ustekinumab has demonstrated significant efficacy and safety in the treatment of psoriasis, it is now understood that inhibition of IL-23 to be primarily responsible for its efficacy. This Phase II trial was the first direct comparison between ustekinumab and a drug that specifically targets IL-23, risankizumab, via selective p19 inhibition.6 The primary endpoint was reaching PASI90 at week 12.
The 48-week, multicenter, randomized, dose-ranging trial enrolled patients aged 18 to 74 years with >6-month history of moderate-to-severe plaque psoriasis, ≥10% body surface area (BSA) involvement, a PASI score of ≥12, and a sPGA score of ≥3. A total of 166 patients were randomly assigned to receive either risankizumab or ustekinumab at weeks 0, 4, and 16. Those allocated to risankizumab received either a single 18 mg dose at week 0 only (n=43), 3 doses of 90 mg (n=41) or 3 doses of 180 mg (n=42), while ustekinumab was administered according to label in 3 doses of 45 mg or 90 mg, depending on body weight (if less than or greater than 100 kg) (n=40). The study was doubleblinded and 139 patients (84%) finished the trial, including 107 patients (77%) who completed follow-up through week 48.
Although small numbers and short duration limits drawing conclusions about safety, 81%, 80%, 69% and 72% of the 18 mg risankizumab, 90 mg risankizumab, 180 mg risankizumab and ustekinumab groups, respectively, experienced AEs with nasopharyngitis the most commonly reported. Additionally, 5 patients (12%), 6 patients (15%), 0 and 3 patients (8%) had serious AEs in the 18 mg, 90 mg and 180 mg risankizumab groups and ustekinumab group, respectively. Basal cell carcinoma was diagnosed in 2 patients and a major adverse cardiac event occurred in 1 patient who had received risankizumab treatment.
SustaIMM7 was a Phase II/III, double-blinded, placebo-controlled study of Japanese patients with moderate-to-severe plaque psoriasis (n=171) that was conducted to evaluate the efficacy and safety of two different dose regimens of risankizumab. Patients were randomized 2:2:1:1 to 75 mg risankizumab, 150 mg risankizumab, placebo with cross-over to 75 mg risankizumab and placebo with cross-over to 150 mg risankizumab. The primary endpoint was PASI90 at week 16 for risankizumab vs. placebo. At week 16, the PASI90 response was significantly higher in patients who received 75 mg (76%) or 150 mg (75%) risankizumab compared to placebo (2%). The study concluded that both doses of risankizumab were superior to placebo in the treatment of Japanese patients with moderate-to-severe plaque psoriasis. Moreover, the safety profile was similar to other previous risankizumab trials, with no new AEs reported.
These preliminary findings support the use of selective IL-23 blockade through p19 subunit inhibition to provide more complete suppression of IL-23 activity vs. that offered by p40 inhibition.
Risankizumab has been investigated in four Phase III clinical trials. Refer to Table 1 for a brief overview of each of the trials and Figure 1 for a summary of efficacy results. Two Phase III studies, UltIMMa-1 and UltIMMa-2, were the first of four Phase III studies to report findings on the efficacy and safety of risankizumab compared with placebo or ustekinumab in patients with moderate-to-severe chronic plaque psoriasis.8 UltIMMa-1 and UltIMMa-2 are replicate randomized, double-blinded, placebo-controlled and active compactor-controlled trials. Adult patients (aged ≥18 years) were included in the study if they had stable (≥6 months) moderate-to-severe chronic plaque psoriasis (with or without psoriatic arthritis), with a BSA involvement 10% or greater, PASI score of 12 or more and sPGA score of 3 or greater.
|Phase III Clinical Trial Program||Treatment Arms||Study Duration||Co-Primary Endpoints|
|UltIMMa-18 (NCT02684370)||52 weeks||PASI90 and sPGA 0/1 responders at week 16|
|UltIMMa-28 (NCT02684357)||52 weeks||PASI90 and sPGA 0/1 responders at week 16|
|IMMvent9 (NCT02694523)||44 weeks||PASI90 and sPGA 0/1 responders at week 16|
|IMMhance10 (NCT02672852)||104 weeks||PASI90 and sPGA 0/1 responders at week 16|
|LIMMitless12 (NCT03047395)||3 years||sPGA 0, PASI100, PASI75, PASI90, sPGA 0/1 every 12 weeks up to week 172|
|Table 1: Overview of the Phase III clinical trial program for risankizumab.8-10|
Part A of the study was a 16-week double-blinded treatment period. In Part A of UltIMMa-1, 506 patients were randomly assigned (3:1:1) to receive either risankizumab 150 mg (n=304), ustekinumab dosed per label (45 mg for body weight ≤100 kg or 90 mg for body weight >100 kg) (n=100), or placebo (n=102). In Part A of UltIMMa-2, 491 patients were assigned to receive either risankizumab 150 mg (n=294), ustekinumab dosed per label (45 mg or 90 mg) (n=99), or placebo (n=98). After the 16 week-period, in Part B (double-blinded, weeks 16- 52), patients who were initially assigned to placebo switched to 150 mg risankizumab at week 16; while other patients continued their originally randomized treatment. The study drug was administered subcutaneously at weeks 0 and 4 during Part A and at weeks 16, 28, and 40 during Part B. Safety was measured throughout the study. Co-primary endpoints were PASI90 and sPGA 0 or 1 at week 16. At week 16 of UltIMMa-1, PASI90 was achieved by 75.3% of patients on risankizumab compared to 4.9% on placebo and 42% on ustekinumab. At week 16 of UltIMMa-2, PASI90 was achieved by 74.8% patients on risankizumab compared to 2% on placebo and 47.5% on ustekinumab. At week 16 of UltMMa-1, sPGA 0 or 1 was achieved by 87.8%, 7.8% and 63.0% in patients receiving risankizumab, placebo and ustekinumab, respectively. At week 16 of UltMMa-2, sPGA 0 or 1 was achieved by 83.7%, 5.1% and 61.6% in patients receiving risankizumab, placebo and ustekinumab, respectively. The authors concluded that risankizumab demonstrates superior efficacy when compared with both placebo and ustekinumab in the treatment of moderate-to-severe plaque psoriasis.
IMMvent was the next Phase III study to investigate the efficacy and safety of risankizumab compared with adalimumab for moderate-to-severe chronic plaque psoriasis.9 IMMvent is a randomized, double-blinded, active-comparator-controlled trial in a patient population similar to the UltIMMa trials.
Part A of the study was a 16-week double-blinded treatment period in which 605 patients were randomly assigned (1:1) to receive either 150 mg risankizumab SC (n=301, 50%) at weeks 0 and 4, or 80 mg adalimumab SC (n=304, 50%) at week 0, then 40 mg at weeks 1, 3, 5, and every other week for the duration of the 16-week period. For weeks 16-44, Part B of the study, patients who achieved a PASI90 on adalimumab (n=144, 47%) remained on adalimumab; individuals who achieved a PASI50 or higher to less than PASI90 (adalimumab intermediate responders) (n=109 patients, 36%) were re-randomized to continue 40 mg adalimumab (n=51/56, 91%) or switch to 150 mg risankizumab (n=51/53, 96%); and individuals who achieved less than PASI50 (n=38, 13%) switched to 150 mg risankizumab. Participants who were initially randomized to risankizumab in Part A remained on risankizumab in Part B. Co-primary endpoints in Part A were PASI90 and sPGA score of 0 or 1 at week 16, and for Part B was PASI90 at week 44 (non-responder imputation). At week 16, PASI90 was achieved in 72% of patients receiving risankizumab and 47% receiving adalimumab, and sPGA scores of 0 or 1 were achieved in 84% and 60% of patients given risankizumab and adalimumab, respectively.
In Part B, among adalimumab intermediate responders, PASI90 at week 44 was achieved by 66% of patients who switched from adalimumab to risankizumab and 21% of patients that continued on adalimumab through to week 44.9 Risankizumab showed significantly greater efficacy than adalimumab in the treatment of moderate-to-severe plaque psoriasis.
The IMMhance trial was the fourth Phase III study conducted to assess safety and maintenance of efficacy for continuous risankizumab treatment compared to withdrawal of therapy (receiving placebo) in patients with moderate-to-severe plaque psoriasis.10 This was a multinational, multicenter, randomized, double-blinded, placebo-controlled study.
In Part A1 of the study, 507 participants were randomized at baseline, at a ratio of 4:1, to receive either 150 mg risankizumab (n=407) at weeks 0 and 4 or placebo (n=100). In Part A2 of the study, all patients who were randomized at baseline to placebo, received a 150 mg dose of risankizumab at week 16, week 28, and every 12 weeks thereafter up to 88 weeks. In Part B, patients who were originally on risankizumab and achieved a sPGA of 0/1 (n=336) were re-randomized at a ratio of 1:2 to receive risankizumab 150 mg (n=111) or placebo (n=225), and every 12 weeks thereafter up to 88 weeks. The participants who received risankizumab in Part A and were nonresponders (sPGA ≥2) at week 28 (n=63) received risankizumab 150 mg at week 28 and every 12 weeks up to 88 weeks. Starting at week 32, re-randomized participants who relapsed (defined as sPGA ≥3) (n=153) were switched to risankizumab 150 mg every 12 weeks. In Part A, the co-primary endpoints were the percentage of patients with an sPGA of 0/1 at week 16, and the percentage of patients achieving a PASI90 from baseline to week 16. At week 16, it was found that an sPGA 0/1 and PASI90 was achieved by 340 (83.5%) and 298 (73.2%) patients being treated with risankizumab, respectively, compared with 7 (7.0%) and 2 (2.0%) patients receiving placebo.11
In Part B, the primary endpoint was the percentage of patients with a sPGA of 0/1 at week 52. Of the patients who were rerandomized to continue risankizumab, 97 (87.4%) achieved a sPGA of 0/1, whereas those who were re-randomized to placebo 138 (61.3%) maintained a sPGA of 0/1. Among patients who were re-randomized to withdrawal and achieved a loss of response (defined as a sPGA ≥3 on or after Week 32), 83.7% (128/153) regained sPGA 0/1 after 16 weeks of re-treatment (i.e., 2 doses) with 150 mg of risankizumab. The IMMhance trial demonstrated risankizumab’s significant efficacy and durability vs. placebo.
In terms of safety, the most commonly reported AEs with risankizumab treatment include upper respiratory tract infections, nasopharyngitis, and headaches. No dose-dependent associations with AEs have been detected to date. In regard to major adverse cardiac events (MACE), there were few reports of cerebrovascular AEs in all phases of development, but these were unlikely treatment related and the rates would be expected in the population studied. There were also no reports of active tuberculosis or reactivation of latent tuberculosis, hepatitis or other opportunistic infections in risankizumab treated patients. The trials revealed that risankizumab is generally very well tolerated and can provide significant clinical improvements in patients with moderate-to-severe plaque psoriasis.
Moving forward, risankizumab is further being investigated in two studies for psoriasis. The LIMMitless study (NCT03047395), a Phase III, single-arm, multicenter open-label extension study is designed to evaluate the long-term safety and efficacy of 150 mg risankizumab in approximately 2200 patients who had previously been enrolled in risankizumab trials.12 Risankizumab is also currently being evaluated in a 52-week head-to-head comparator study against the IL-17A inhibitor, secukinumab (NCT03478787) for the treatment of adult subjects with moderate-to-severe plaque psoriasis.13
The addition of biologics that target IL-23p19 to our therapeutic armamentarium has succeeded in improving outcomes in patients with moderate-to-severe plaque psoriasis. The Phase I, II, and III clinical trials of risankizumab have clearly demonstrated that the use of risankizumab provides substantial and durable skin clearance with an excellent safety profile. The data presented from these trials further supports the therapeutic value of risankizumab in patients with moderate-to-severe plaque psoriasis.
- Gooderham MJ, Papp KA, Lynde CW. Shifting the focus – the primary role of IL-23 in psoriasis and other inflammatory disorders. J Eur Acad Dermatol Venereol. 2018 Jul;32(7):1111-9.
- Wohn C, Ober-Blobaum JL, Haak S, et al. Langerin(neg) conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice. Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10723-8.
- Yoshiki R, Kabashima K, Honda T, et al. IL-23 from Langerhans cells is required for the development of imiquimod-induced psoriasis-like dermatitis by induction of IL-17A-producing gammadelta T cells. J Invest Dermatol. 2014 Jul;134(7):1912-21.
- Rizzo HL, Kagami S, Phillips KG, et al. IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A. J Immunol. 2011 Feb 1;186(3):1495-502.
- Krueger JG, Ferris LK, Menter A, et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2015 Jul;136(1):116-24 e7.
- Papp KA, Blauvelt A, Bukhalo M, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med. 2017 Apr 20;376(16):1551-60.
- Ohtsuki M, Fujita H, Watanabe M, et al. Efficacy and safety of risankizumab in Japanese patients with moderate to severe plaque psoriasis: results from the SustaIMM phase 2/3 trial. J Dermatol. 2019 Aug;46(8):686-94.
- Gordon KB, Strober B, Lebwohl M, et al. 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. Lancet. 2018 Aug 25;392(10148):650-61.
- Reich K, Gooderham M, Thaci D, et al. Risankizumab compared with adalimumab in patients with moderate-to-severe plaque psoriasis (IMMvent): a randomised, double-blind, active-comparator-controlled phase 3 trial. Lancet. 2019 Aug 17; 394(10198):576-86.
- Blauvelt A, Leonardi C, Gooderham MJ, et al. Efficacy and safety of continuous Q12W risankizumab versus treatment withdrawal: 2-year double-blinded results from the phase 3 IMMhance trial. 24th World Congress of Dermatology; June 10, 2019; Milan, Italy.
- Blauvelt A, Leonardi CL, Gooderham M, et al. Efficacy and safety of continuous risankizumab therapy vs treatment withdrawal in patients with moderate to severe plaque psoriasis: a phase 3 randomized clinical trial. JAMA Dermatol. 2020 Apr 8. doi:10.1001/jamadermatol.2020.0723 [Epub ahead of print]
- Abbvie. A Study to Assess the Safety and Efficacy of Risankizumab for Maintenance in Moderate to Severe Plaque Type Psoriasis (LIMMITLESS). In: ClinicalTrials.gov [Internet], Identifier: NCT03047395. Last updated October 29, 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT03047395.
- Abbvie. Risankizumab Versus Secukinumab for Subjects With Moderate to Severe Plaque Psoriasis. In: ClinicalTrials.gov [Internet], Identifier: NCT03478787. Last updated September 20, 2019. Available from: https://clinicaltrials.gov/ct2/show/ record/NCT03478787.