Pharmacology Update

Ustekinumab Injection (Stelara™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

A monoclonal antibody against interleukin-12 and interleukin-23 has been approved by the FDA for the treatment of plaque psoriasis. Ustekinumab is marketed as a subcutaneous injection by Centocor Ortho Biotech as Stelara™.

Indications

Ustekinumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for phototherapy or systemic therapy.1

Dosage

The recommended dose (given subcutaneously) is 45 mg (patients 100 kg or less) or 90 mg (over 100 kg) initially and 4 weeks later, and followed by 45 mg or 90 mg every 12 weeks. Injection should be given by a health care provider.

Ustekinumab is available as 45 mg or 90 mg single-use vials.

Potential Advantages

Ustekinumab was more effective than etanercept in achieving a 75% reduction on the Psoriasis Area and Severity Index (PASI) and clearing psoriatic lesions.2

Potential Disadvantages

Ustekinumab carries warnings and precautions similar to other biological agents that affect the immune system (i.e., infections including tuberculosis, malignancies, and reversible posterior leukoencephalopathy syndrome).1 Common adverse events (3%-8%) include nasopharyngitis, upper respiratory infection, headache, and fatigue. Monitoring is recommending for patients on concomitant therapy with narrow therapeutic index drugs that are substrates of the CYP450 isoenzymes (e.g., warfarin, cyclosporine).1

Comments

Ustekinumab is a human immunoglobulin G1k monoclonal antibody that binds the shared p40 subunit of human interleukin-12 and interleukin-23. These cytokines are believed to play an important role in the pathogenesis of psoriasis.3 The efficacy and safety of ustekinumab was based on two randomized, double-blind, placebo-controlled, phase III studies in 1996. Subjects included adults with moderate-to-severe plaque psoriasis with a minimum body surface involvement of 10% and a PASI score of 12 or higher, who were candidates for phototherapy or systemic therapy.1,4,5 In study 1 (Phoenix 1), subjects were randomized to ustekinumab 45 mg or 90 mg at weeks 0, 4, and every 12 weeks. The control group received placebo at week 0 and 4 and were crossed over to ustekinumab at week 12. Those initially randomized to ustekinumab and who achieved long-term response were subsequently randomized, at week 40, to maintenance therapy or withdrawal of treatment until loss of response. The primary endpoint was the proportion of subjects achieving 75% reduction in PASI (PASI 75) and treatment success on the 6-category scale on the Physician Global Assessment (PGA) at week 12.

Study 2 (Phoenix 2) was similar in design except that partial responders (> PASI 50 but < PASI 75) were randomized at week 28 to continue therapy every 12 weeks or increased to every 8 weeks. PASI 75 response rates were 67% in the two 45 mg groups, 66% and 76% in the 90 mg group, and 3% and 4% for placebo. PGA success rates were similar in magnitude. In Study 1, 89% of subjects that were responders at week 28 and week 40 were still responders at week 52 on maintenance therapy compared to 63% who were withdrawn from therapy.1 In Study 2, increased dosing frequency improved treatment success in partial responders for those initiated on 90 mg but not 45 mg.5

In a three-arm comparative trial (ustekinumab 45 mg, 90 mg, and etanercept 50 mg twice weekly) ustekinumab showed better efficacy at 12 weeks.2 Ustekinumab appears to be well tolerated; however, long-term safety resulting from blockade of IL-12/IL-23 has not been established.

Clinical Implications

Ustekinumab is a biological agent with a different mechanism of action from currently available drugs for psoriasis. Most drugs such as etanercept, infliximab, and adalimumab target tissue necrosis factor (TNF). Ustekinumab, in contrast, targets IL-12 and IL-23. One unpublished study showed that ustekinumab was more effective than etanercept. Comparative studies with other biological agents will better define the role of this agent in the management of moderate-to-severe psoriasis.

References

1. Stelara Product Labeling. Horsham, PA: Centocor Ortho Biotech Inc.; September 2009.

2. Griffiths C, et al. Presentation at: 17th meeting of the European Academy of Dermatology and Venereology. Paris, France; September 17-21, 2008.

3. O'Neill JL, Kalb RE. Ustekinumab in the therapy of chronic plaque psoriasis. Biologics 2009;3:159-168.

4. Leonardi CL, et al. Efficacy and safety of ustekinumab, a human interleuikin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008;371:1665-1674.

5. Papp KA, et al. Efficacy and safety of ustekinumab, a human interleuikin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008;371:1675-1684.