Compound Name:UstekinumabMolecular Target:p40 subunit of the cyokines IL-12 and IL-23Molecular Structure:human IgG1k monoclonal antibodyLicensed Indication:adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapyManufacturer and/or Distributor:Centocor Ortho Biotech Inc.Initial FDA Approval:2009Summary:Ustekinumab (Stelara®) is a human IgG1k monoclonal antibody that targets the p40 subunit of the cytokines IL-12 and IL-23. IL-12 and IL-23 are naturally occurring proteins that are important in regulating immune responses and are thought to be associated with some immune-mediated inflammatory disorders, including plaque psoriasis. Ustekinumab is administered by subcutaneous injection at week 0, week 4 and then every 12 weeks. It was first approved in 2009 for the treatment of adult patients (age 18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. In 2013, an indication was added for adults 18 years and older with active psoriatic arthritis (PsA), either used alone or with methotrexate. In two large pivotal Phase III, multi-center, randomized, double-blind, placebo controlled trials (PHOENIX 1 & 2) in nearly 2000 adult patients with moderate to severe plaque psoriasis, ustekinumab treatment demonstrated a significant improvement in patients' psoriasis as well as improvements in quality of life. The primary endpoint of both trials was a reduction in psoriasis severity (measured using the Psoriasis Area and Severity Index, PASI) of at least 75% (PASI 75) by week 12. Just over two-thirds of patients achieved this outcome in both studies (after two doses at weeks 0 and 4), compared to <4% in the placebo groups. Improvement in skin quality was seen after approximately two weeks in PHOENIX 1 and was maintained as long as five years. A third Phase III trial, ACCEPT, compared the efficacy and safety of ustekinumab with etanercept in the treatment of moderate to severe plaque psoriasis. This trial found a significantly higher clinical response with ustekinumab over the 12-week study period compared to high-dose etanercept. It also demonstrated the clinical benefit of ustekinumab among patients who failed to respond to etanercept. Approval for use in psoriatic arthritis was based on two randomized controlled trials involving over 900 patients treated with placebo, or one of two doses of ustekinumab (PSUMMIT 1 and PSUMMIT 2). At week 24, both drug-treated groups showed significant improvement, which was maintained in follow-up to week 100 and was accompanied by less radiographic damage. As a selective immunosuppressant, ustekinumab may have the potential to increase the risk of infections and reactivate latent infections. Patients should be evaluated for tuberculosis (TB) and appropriately treated prior to initiating treatment with ustekinumab. Caution should be exercised when considering the use of ustekinumab in patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy. A few patients have been reported who developed multiple cutaneous squamous cell carcinomas after starting ustekinumab therapy. One case of reversible posterior leukencephalopathy syndrome has been seen. Hypersensitivity reactions have also been observed. The drug is also currently being investigated for the treatment of Crohn’s disease, ankylosing spondylitis, sarcoidosis, and a number of other inflammatory/immunological conditions.References

Prescribing Information:

1. Griffiths CE, Strober BE, van de Kerkhof P, Ho V, Fidelus-Gort R, Yeilding N, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010 Jan 14;362(2):118-128.

2. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, 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 May 17; 371(9625):1665-1674.

3. Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, 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 May 17; 371(9625): 1675-1684.

4. Tsai TF, Ho V, Song M, Szapary P, Kato T, Wasfi Y, et al. The safety of ustekinumab treatment in patients with moderate-to-severe psoriasis and latent tuberculosis infection. Br J Dermatol. 2012 Nov;167 (5):1145-1152.

5. Young L, Czarnecki D. The rapid onset of multiple squamous cell carcinomas in two patients commenced on ustekinumab as treatment of psoriasis. Australas J Dermatol. 2012 Feb;53(1):57-60.

6. Papp KA, Griffiths CEM, Gordon K, et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from five years of follow-up. Br J Dermatol. 2013;168(4):844-854.

7. McKeage K. Ustekinumab: a review of its use in psoriatic arthritis. Drugs. 2014 Jun; 74(9):1029-39.

8. Kalb RE, Fiorentino DF, Lebwohl MG, Toole J, Poulin Y, Cohen AD, et al. Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis: Results From the Psoriasis Longitudinal Assessment and Registry (PSOLAR). JAMA dermatology. 2015;151(9):961-969.

9. McInnes IB, Kavanaugh A, Gottlieb AB, Puig L, Rahman P, Ritchlin C, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013;382(9894):780-789.

10. Ritchlin C, Rahman P, Kavanaugh A, McInnes IB, Puig L, Li S, et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Annals of the rheumatic diseases. 2014;73(6):990-999.

11. Teng MW, Bowman EP, McElwee JJ, Smyth MJ, Casanova J-LL, Cooper AM, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nature medicine. 2015;21(7):719-729.