Author: Anoma Ranaweera B.V. Sc; PhD (Clinical Biochemistry, University of Liverpool, UK), 2011.
Ustekinumab (STELARA™; Centocor Inc., Horsham, PA, USA) is a human interleukin-12 and -23 antagonist. It is indicated for the treatment of adult patients (18 years or older) with moderate to severe psoriasis that are candidates for phototherapy or systemic therapy. Ustekinumab was approved in the United States (September 2009) for the treatment of moderate-to-severe plaque psoriasis, and has already been marketed in Canada (December 2008) and Europe (January 2009). In April 2010, Medsafe’s Medicines Classification Committee recommended that ustekinumab should be added to the New Zealand Schedule as a prescription medicine for the treatment of plaque psoriasis in adult patients. To date (May 2011), it is not funded by PHARMAC.
Psoriasis imposes a heavy burden on the lifestyle of those affected. Recent research has focused on the genetic and immunologic features of psoriasis to create more targeted, effective, and safe treatment. In recent years, biologics have increased the options for the treatment of severe psoriasis. These drugs are potentially less toxic to the liver, kidneys, and bone marrow, and do not cause birth deformities unlike traditional systemic therapies for psoriasis (acitretin, methotrexate, and ciclosporin).
T-cell mediated inflammatory conditions are influenced by cytokines, the chemical messengers produced by cells. The cytokines interleukin (IL)-12 and IL-23 result in skin disease such as psoriasis due to dysregulation of the immune system. Ustekinumab is a monoclonal antibody belonging to a newly developed class of biological, anti-cytokine medications that notably targets the p40 subunit of both interleukin (IL)-12 and -23.
Psoriasis is caused by an increase in the production of T-cells (lymphocytes) in response to the attachment of a stimulant, such as IL, to the lymphocyte. Stimulated T-cells cause skin cells to grow rapidly, producing plaques of psoriasis. Ustekinumab reduces psoriasis by attaching to IL-12 and IL-23, and preventing them from binding and activating T-lymphocytes.
In psoriasis subjects, the median time to reach the maximum serum concentration (Tmax) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of 45 mg (N=22) and 90 mg (N=24) of ustekinumab. In healthy subjects (N=30), the median Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in psoriasis subjects. Following multiple subcutaneous doses of ustekinumab, the steady-state serum concentrations were achieved by week 28. The mean (±SD) steady-state trough serum concentration ranged from 0.31 ± 0.33 mcg/mL (45 mg) to 0.64 ± 0.64 mcg/mL (90 mg). There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks.
The mean (± SD) systemic clearance (CL) following a single intravenous administration of ustekinumab to psoriasis subjects ranged from 1.90 ± 0.28 to 2.22 ± 0.63 mL/day/kg. The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all psoriasis studies following intravenous and subcutaneous administration.
Ustekinumab's safety and efficacy has been evaluated for the treatment of moderate-to-severe plaque psoriasis in 3 phase III clinical trials, 2 placebo-controlled (PHOENIX 1 and 2), and 1 comparator-controlled (ACCEPT) study. Ustekinumab was effective in patients who had not received previous treatment, who had previously failed other immunosuppressive medications including ciclosporin or methotrexate, who were unresponsive to phototherapy, or who were unable to use or tolerate other therapies.
PHOENIX 1 enrolled 766 subjects and PHOENIX 2 enrolled 1230 subjects. The studies had the same design through Week 28. In both studies, subjects were randomised in equal proportion to placebo, 45 mg, or 90 mg of ustekinumab. Subjects randomised to ustekinumab received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomised to receive placebo at Weeks 0 and 4, crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16. The endpoints were the proportion of subjects who achieved at least a 75% reduction in Psoriasis Area Severity Index score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the Physician's Global Assessment (PGA). The PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician's overall assessment of psoriasis focusing on plaque thickness/induration, erythema (redness), and scaling.
Median baseline PASI scores in PHOENIX 1 and 2 ranged from approximately 17 to 18. Baseline PGA scores were marked or severe in 44% of subjects in PHOENIX 1 and 40% of subjects in PHOENIX 2. Approximately two-thirds of all subjects in PHOENIX 1 and 2 had received prior phototherapy and 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis. A total of 28% of study subjects had a history of psoriatic arthritis.
Results of PHOENIX 1 and 2 are summarised in the tables below.
|Week 12||Placebo||Ustekinumab 45mg||Ustekinumab 90mg|
|PASI 75% response||8 (3%)||171 (67%)||170 (61%)|
|PGA cleared or minimal||10 (4%)||151 (59%)||156 (66%)|
|Week 12||Placebo||Ustekinumab 45mg||Ustekinumab 90mg|
|PASI 75% response||15 (4%)||273 (67%)||311 (76%)|
|PGA cleared or minimal||18 (4%)||277 (68%)||300 (73%)|
Examination of age, sex, and race subgroups did not identify differences in response to ustekinumab among these subgroups. In subjects who weighed <100 kg, response rates were similar with both the 45 mg and 90 mg doses; however, in subjects who weighed >100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg dosing.
Subjects in PHOENIX 1 were evaluated through Week 52. At Week 40, those who were PASI 75 responders at both Weeks 28 and 40 were re-randomized to either continued dosing (ustekinumab at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re-randomised to ustekinumab were PASI 75 responders compared with 63% (100/159) of subjects re-randomised to placebo (treatment withdrawal after Week 28 dose).
Adverse events were similar for patients treated with placebo or either of the ustekinumab doses. Upper respiratory tract infection, nasopharyngitis headache, and arthralgias were the most common adverse events reported.
Ustekinumab was also studied in phase III multicenter, randomised, head-to-head study comparing ustekinumab and etanercept for the treatment of moderate-to-severe plaque psoriasis. Findings from this landmark study showed that ustekinumab was more effective than etanercept in both primary (PASI 75 at week 12) and secondary (PGscore of cleared (0) or minimal (1) at week 12 and PASI 90 at week 12) efficacy endpoints. The ACCEPT trial included 903 patients (3:5:5 ratio; etanercept = 347, ustekinumab 45 mg = 209, ustekinumab 90 mg = 347) with chronic plaque psoriasis. Patients were randomised to receive either ustekinumab 45 mg or 90 mg subcutaneously at weeks 0 and 4 or etanercept 50 mg subcutaneously two times per week for 12 weeks. The primary endpoint of the trial was the percentage of patients achieving a PASI 75 at week 12.
Ustekinumab was shown to result in modest clinical improvement in a phase II study in patients with psoriatic arthritis.This study was a double-blind, randomised, placebo-controlled, crossover study at 24 sites in North America and Europe. Patients with active psoriatic arthritis were randomly assigned to either: ustekinumab (90 mg or 63 mg) subcutaneous every week for 4 weeks (weeks 0–3) followed by placebo at weeks 12 and 16 (group 1); or placebo subcutaneous every week for 4 weeks (weeks 0–3) followed by ustekinumab (63 mg) at weeks 12 and 16 (group 2). The primary endpoint was a 20% improvement in the American College of Rheumatology core set of measures (ACR20) at week 12. ACR20, ACR50, and ACR70 were determined in both groups at week 12. Groups 1 and 2 demonstrated: 42% versus 14%, 25% versus 7%, and 11% versus 0% for the respective ACR scores. ACR20 was maintained by 36% of patients treated only with ustekinumab throughout the trial for up to 32 weeks. Ustekinumab significantly reduced signs and symptoms of psoriatic arthritis, diminished skin lesions compared with placebo, and was well tolerated. Larger and longer term phase III studies are needed to definitively establish safety and efficacy in this population of patients. Nonetheless, results from this study are promising and suggest that treatment with ustekinumab can remain safe and effective for a long duration as well as maintain improvements in physical function and quality of life.
To date adverse infections are consistent with that seen with other biologics.
No contraindications to ustekinumab have been reported.
There are no studies of ustekinumab in pregnant women. Ustekinumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No teratogenic effects were observed in the developmental and reproductive toxicology studies performed in cynomolgus monkeys at doses up to 45 mg/kg ustekinumab.
Caution should be exercised when ustekinumab is administered to a nursing woman. The unknown risks to the infant from gastrointestinal or systemic exposure to ustekinumab should be weighed against the known benefits of breast-feeding.
Safety and effectiveness of ustekinumab in children have not been evaluated.
No differences in safety or efficacy have been observed between older and younger subjects treated with ustekinumab; however, the number of subjects aged 65 and over participating in clinical trials is not sufficient to determine whether they respond differently from younger subjects. In a population pharmacokinetic analysis study there were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution) in subjects older than 65 years old.
No pharmacokinetic data are available in patients with liver or kidney disease treated with ustekinumab.
Single doses of ustekinumab up to 4.5 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately.
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