Risankizumab: Mechanism of action, clinical and translational science

Abstract

Risankizumab is a high-affinity neutralizing anti-interleukin (IL)-23 monoclonal antibody marketed in over 40 countries across the globe to treat several inflammatory diseases, such as plaque psoriasis (PsO), psoriatic arthritis (PsA), and Crohn's disease (CD). This paper reviews the regulatory approval, mechanism of action, pharmacokinetics (PKs)/pharmacodynamics, immunogenicity, and clinical efficacy and safety data for risankizumab, focusing on the three main approved indications. Risankizumab binds to the p19 subunit of IL-23 and inhibits IL-23 from interacting with the IL-23 receptor and subsequent signaling. Biomarker data obtained following treatment with risankizumab in multiple indications provided supportive evidence for downstream blockade of IL-23 signaling associated with disease pathology. The PKs of risankizumab is linear and time-independent, consistent with typical IgG1 monoclonal antibodies, across all evaluated indications. Risankizumab exhibited positive exposure-response relationships for efficacy with no apparent exposure-dependent worsening in safety. Immunogenicity to risankizumab had no major clinical consequences for either efficacy or safety. Efficacy and safety of risankizumab have been established in PsO, PsA, and CD in the pivotal clinical trials where superior benefit/risk profiles were demonstrated compared to placebo and/or active comparators. Moreover, safety evaluations in open-label extension studies following long-term treatment with risankizumab showed stable and favorable safety profiles consistent with shorter-term studies. These data formed the foundation for risankizumab's marketing approvals to treat multiple inflammatory diseases across the globe.

FIGURE 1

Overview of risankizumab mechanism of action. Created with BioRender.com and adapted from Sanchez et al. In plaque psoriasis, IL‐23 is thought to be required for the maintenance and generation of pathogenic TH17 cells that produce the inflammatory cytokines, IL‐17 and IL‐22, which in turn stimulate keratinocyte responses including proliferation and secretion of psoriasis‐associated mediators. Blocking the activity of IL‐23 with a neutralizing antibody directly reduces the IL‐17–induced inflammation and therefore offers an attractive therapeutic intervention for psoriasis. IL‐23 signaling pathways in the gut involve not only TH17 cells, but also γδTcells and innate lymphoid cells 3 (ILC3s) which are involved in the pathogenesis of IBD. These cells produce IL‐17A, IL‐17F, and IL‐22, which can lead to chronic intestinal inflammation and epithelial damage associated with IBD. Of note, ILC3s also play a role in maintaining gut homeostasis and similarly, IL‐22 is a pleotropic cytokine that can be both inflammatory and protective in the gut depending on the cytokine milieu. IL, interleukin; ILC3, innate lymphoid cells 3; Th, T‐helper cells; Th/Tc, T‐helper and cytotoxic T cells producing IL‐17 or IL‐22.

FIGURE 2

Impact of covariates identified in the population pharmacokinetic analyses on risankizumab exposures. Covariate forest plot per indication (a) psoriasis, (b) psoriatic arthritis, and (c) Crohn's disease. Points represent medians, and error bars represent 95% confidence intervals of the normalized model‐predicted exposure ratios across 200 simulation replicates. The vertical black dashed line shows exposure ratio of 1 relative to the reference group, and the shaded area represents the 0.8–1.25 default equivalence boundaries. ADA, anti‐drug antibody; AUC, area under the concentration–time curve for weeks 40 to 52 (a), weeks 16 to 28 (b) and weeks 0 to 12 (c); C _max, maximum concentration between weeks 40 to 52 (a); Creatinine CL: Creatinine clearance; C _trough, trough concentration at week 28 (b), week 12 (c); hsCRP, high‐sensitivity C‐reactive protein.

FIGURE 3

ER analyses for efficacy across indications (a) psoriasis, (b) psoriatic arthritis, (c) Crohn's disease (applying non‐responder imputation). (a1, a2) Observed and model‐estimated exposure–efficacy relationships for PASI and sPGA at weeks 16 and 52 using data from phase II and III trials. Black solid symbols with error bars: observed PASI 90 ([a1] week 16 and [a2] week 52) response and corresponding 95% exact binomial confidence intervals within each C _avg decile. Blue solid line and shaded area: model estimated probability of response and 95% confidence interval. Black solid circle and line: median C _avg and 5th and 95th percentiles with 150 mg s.c. dose at weeks 0 and 4 and every 12 weeks thereafter, integrated across weeks 0 to 16 (a1) or 40 to 52 (a2). The model estimated probabilities for PASI end points at week 16 are shown at the median value of baseline high‐sensitivity C‐reactive protein for all end points. (b) Exposure‐response relationships for efficacy end point ACR20 at week 24 from phase III studies. Values on the x‐axis represent the range of the observed phase III risankizumab C _trough at week 28 for each quartile. Plots show %response and n/N, where n represents number of responders and N represents total number of patients in each exposure‐quartile bin. For ACR analyses at week 24, 52 patients from phase III studies were excluded from these analyses owing to missing C _trough values at week 28. Of these 52 patients for ACR, 28 (53.8%) were ACR20. ACR20, at least 20% improvement in American College of Rheumatology response criteria; C _trough, concentration at the end of a dosing interval. (c1–c4) ER relationships for efficacy end points CDAI (c1 and c2) and endoscopic remission (c3 and c4), logistic regression models at (c1 and c3) week 12 in the phase II and III induction studies and (c2 and c4) week 52 in the phase III maintenance study. Upper panels represent the model predictions overlaid with the observed response rates (grouped into placebo and exposure quartiles) at (c1 and c2) 12 weeks (left) and (c2 and c4) 52 weeks (right). Description of lines and shaded area in panels (a1) and (a2) applies to panels (c1–c4). ACR, American College of Rheumatology; C_avg, average drug concentration; CDAI, Crohn's disease activity index; C _trough, trough plasma concentration; ER, exposure‐response; IV, intravenous; PASI, Psoriasis Area and Severity Index; sPGA, Static Physician Global Assessment.