Ustekinumab is a human monoclonal antibody that binds with high affinity and specificity to the shared p40 protein subunit of human interleukins 12 and 23, thereby preventing interaction with IL12Rβ1 receptor proteins expressed on the surface of immune cells.1 Abnormal regulation of IL-12 and IL-23 has been associated with immune-mediated diseases such as psoriasis. It is believed that by preventing IL-12 and IL-23 contributions to immune cell activation, ustekinumab interrupts signalling and cytokine cascades that are relevant to psoriasis pathology.1
The safety and efficacy of ustekinumab in patients with moderate to severe plaque psoriasis was assessed in two double-blind placebo-controlled trials (PHOENIX 1 and 2).2,3
In PHOENIX 1 (n=766) patients were randomised to receive ustekinumab 45mg or 90mg at weeks 0 and 4, then every 12 weeks, or placebo at weeks 0 and 4 with crossover to ustekinumab (45mg or 90mg) at weeks 12 and 16, then every 12 weeks. At week 40, patients in the ustekinumab groups with at least 75 per cent improvement from baseline in psoriasis area and severity index score (PASI 75) at weeks 28 and 40 were re-randomised to continue maintenance treatment with ustekinumab or placebo.
In PHOENIX 2 (n=1230), patients were randomised to ustekinumab or placebo as in PHOENIX 1. At week 28, partial responders (≥PASI 50, < PASI 75 response) were re-randomised to ustekinumab every 12 weeks or to intensified dosing every eight weeks.*
In both trials significantly more patients receiving ustekinumab achieved a PASI 75 response at week 12 than did those receiving placebo. Onset of efficacy was rapid with significantly more patients in the ustekinumab groups achieving PASI 50 by week 2 and PASI 75 by week 4, compared with placebo.
In PHOENIX 1, maintenance of PASI 75 response was significantly better in patients re-randomised at week 40 to receive maintenance therapy than in those receiving placebo through at least one year.
In PHOENIX 2, dosing intensification in the ustekinumab 90mg group resulted in a higher PASI 75 response rate at week 52 than did continuing at 12-weekly dosing, an improvement not seen in the ustekinumab 45mg group.
Treatment was well tolerated in both trials and clinical improvements were paralleled by improvements in patient-reported outcomes, as measured by dermatology life quality index.
Ustekinumab was compared with etanercept in another trial involving 903 patients with moderate to severe plaque psoriasis where ciclosporin, methotrexate or PUVA were ineffective, not tolerated or contraindicated. Patients treated with two doses of 45mg or 90mg ustekinumab at weeks 0 and 4 demonstrated significantly superior response compared with those treated with etanercept 50mg twice weekly through week 12 (PASI 75 response at week 12 achieved by 68 per cent and 74 per cent of patients vs 57 per cent in the etanercept group).
* Stelara SPC recommends a 12-week dosing interval.
1. Stelara, Summary of Product Characteristics.
2. Leonardi CL, Kimball AB, Papp KA et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371: 1665-74.
3. Papp KA, Langley RG, Lebwohl M et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371: 1675-84.
4. Griffiths CEM, Strober B, van der Kerkhof PCM et al. A phase 3, multicentre, randomised study comparing ustekinumab and etanercept for the treatment of moderate to severe plaque psoriasis. Poster presented at the European Association of Dermatology and Venerology; 2008; September 1721: Paris, France.
Further information: Janssen-Cilag