Mechanism of Action of Skyrizi (Risankizumab)
Risankizumab (Skyrizi) is a humanized IgG1 monoclonal antibody that selectively inhibits interleukin-23 (IL-23) by specifically binding to the p19 subunit of IL-23, thereby preventing its interaction with the IL-23 receptor and inhibiting downstream inflammatory signaling pathways.
Detailed Mechanism
Risankizumab works through a highly targeted mechanism:
- Target specificity: Selectively binds to the p19 subunit of IL-23 1
- Receptor blockade: Prevents IL-23 from interacting with its receptor on immune cells 1
- Downstream effects: Inhibits the release of pro-inflammatory cytokines and chemokines 1
This selective targeting represents an advancement over earlier biologics like ustekinumab, which targets both IL-12 and IL-23 by binding to their shared p40 subunit.
IL-23 in Psoriasis Pathophysiology
IL-23 plays a critical role in psoriasis pathogenesis:
- Acts as a key driver of inflammatory responses in psoriatic disease
- Promotes differentiation and maintenance of pathogenic T cells
- Stimulates production of additional inflammatory mediators
- Contributes to keratinocyte hyperproliferation and skin plaque formation
Pharmacokinetic Properties
- Administration: Subcutaneous injection
- Bioavailability: 74-89% following subcutaneous administration 1
- Peak concentration: Reached in 3-14 days after single dose 1
- Half-life: Approximately 28 days in plaque psoriasis patients 1
- Steady state: Achieved with 150 mg dosing at weeks 0,4, and every 12 weeks thereafter 1
Clinical Implications of Mechanism
The p19-specific targeting provides several clinical advantages:
- High efficacy: In clinical trials, risankizumab demonstrated superior efficacy compared to both placebo and ustekinumab, with 77% of patients achieving PASI 90 at week 12 versus 40% with ustekinumab 2
- Durable response: The specific IL-23 inhibition provides sustained disease control with 12-week dosing intervals
- Safety profile: By selectively targeting IL-23 rather than multiple cytokines, risankizumab may offer a favorable safety profile 3
Comparison to Other IL-23 Inhibitors
Risankizumab belongs to a class of IL-23p19 inhibitors that includes:
- Guselkumab: A fully human IgG1 lambda monoclonal antibody that also targets the p19 subunit of IL-23 2
- Tildrakizumab: A humanized IgG1 monoclonal antibody that selectively blocks IL-23 by binding to the p19 subunit 2
All these agents share the same molecular target but differ in their molecular structure, pharmacokinetics, and dosing schedules.
Important Clinical Considerations
- Onset of action: Definitive response assessment should be made after 12 weeks of continuous therapy 2
- Monitoring: Regular assessment of treatment response and vigilance for signs of infection is recommended
- Caution: Use with caution in patients with pre-existing immunosuppression-related conditions 2
The specific p19 targeting of risankizumab represents an important advancement in the treatment of psoriasis, offering high efficacy with a favorable safety profile through its selective inhibition of the IL-23 inflammatory pathway.