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Ustekinumab

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Ustekinumab
Monoclonal antibody
Type?
SourceHuman
TargetIL-12 and IL-23
Clinical data
License data
Routes of
administration		Subcutaneous injection
ATC code
Legal status
Legal status
Identifiers
CAS Number
Chemical and physical data
FormulaC6482H10004N1712O2016S46
Molar mass145.64 kDa g·mol−1

Ustekinumab (INN, experimental name CNTO 1275, proprietary commercial name Stelara,[1] Centocor) is a human monoclonal antibody. It is directed against interleukin 12 and interleukin 23, naturally occurring proteins that regulate the immune system and immune-mediated inflammatory disorders.[2]

In two Phase III trials for moderate to severe psoriasis, the longest >76 weeks, ustekinumab was safe and effective.[3][4] Ustekinumab is approved in Canada and Europe to treat moderate to severe plaque psoriasis and is currently under review in the United States.[5]

As of November 2009, the drug is being investigated for the treatment of psoriatic arthritis.[6][7] It has also been tested in Phase II studies for multiple sclerosis[8] and sarcoidosis, the latter versus golimumab (Simponi)[9].

Development

As of January 2007, there were 5 NIH-listed research studies involving CNTO 1275 on a multinational basis, including 3 Phase II and 2 Phase III trials. Three studies were focused on patients with psoriasis, one on psoriatic arthritis, and one on multiple sclerosis.

On December 4, 2007, a Biologics License Application (BLA) with the U.S. Food and Drug Administration (FDA) was filed by Centocor and Janssen-Cilag International (collaborator) has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA).

On June 17, 2008, the Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC) of the U.S. Food and Drug Administration unanimously recommended the approval of ustekinumab (CNTO 1275) for the treatment of adult patients with moderate to severe plaque psoriasis. The decision by the committee is non-binding and final decisions on approval of the drug are made by the FDA. As yet, there is no schedule for when the FDA will make a decision on CNTO 1275.

On November 21, 2008, the European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for ustekinumab for the treatment of moderate to severe plaque psoriasis in adult patients who failed to respond to other systemic therapies.[10]

On December 12, 2008 the Canadian Health Authority approved the use of ustekinumab for the treatment of chronic moderate to severe plaque psoriasis in adult patients who are candidates for phototherapy or systemic therapy.[11]

In September 2008, Centocor released result of a study comparing etanercept and ustekinumab. The entanercept group received subcutaneous injections of the drug twice weekly for 12-weeks while the ustekinumab group received 2 injections, one-month apart, of either 90 or 45 milligrams. At twelve weeks, psoriatic plaques were reduced by at least three-quarters in 68% of the low-dose ustekinumab group and 74% of the high-dose group. Both groups fared better than the etanercept group, 57% of whom saw such improvement. Dr. Alan Menter, chairman of psoriasis research at Baylor Research Institute said of the results, "now we have a drug that will be used less frequently ... with a significant increase in effectiveness. These results are as good as we've seen in psoriasis."[12]

Delivery

Patients enrolled in clinical trials of CNTO 1275 are scheduled to receive the drug by subcutaneous injections at doses of either 45 or 90 mg. The dosage and frequency varies by study and application (type of disease targeted). Generally the initial dosing interval is once per week followed by a step-down to once per month or even once every three months.

Mechanism of action

CNTO 1275 is designed to interfere with the triggering of the body's inflammatory response through the suppression of certain cytokines. Specifically, CNTO 1275 blocks interleukin IL-12 and IL-23 which help activiate certain T-cells.

Efficacy

In two large, phase III trials in patients with moderate to severe plaque psoriasis, significantly more subcutaneous ustekinumab 45 or 90 mg recipients (administered as two injections 4 weeks apart) than placebo recipients achieved a 75% improvement on the Psoriasis Area and Severity Index (PASI 75) score at 12 weeks.[13] Health-related quality of life, assessed using the Dermatology Life Quality Index and the Health Assessment Questionnaire disability index, was improved to a significantly greater extent with ustekinumab than with placebo at week 12.[13]

Tolerability

Subcutaneous ustekinumab was generally well tolerated in clinical trials, with most treatment-emergent adverse events being of mild severity.[13]

References

  1. ^ European Medicines Agency, 20 November 2008, http://www.emea.europa.eu/pdfs/human/opinion/Stelara_58227008en.pdf
  2. ^ Reddy M, Davis C, Wong J, Marsters P, Pendley C, Prabhakar U (2007). "Modulation of CLA, IL-12R, CD40L, and IL-2Ralpha expression and inhibition of IL-12- and IL-23-induced cytokine secretion by CNTO 1275". Cell. Immunol. 247 (1): 1–11. doi:10.1016/j.cellimm.2007.06.006. PMID 17761156. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Leonardi CL, Kimball AB, Papp KA; et al. (2008). "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. 371 (9625): 1665–74. doi:10.1016/S0140-6736(08)60725-4. PMID 18486739. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Papp KA, Langley RG, Lebwohl M; et al. (2008). "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. 371 (9625): 1675–84. doi:10.1016/S0140-6736(08)60726-6. PMID 18486740. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Medarex to Receive Milestone Payment for Approval of STELARA(TM) (Ustekinumab) for the Treatment of Moderate to Severe Plaque Psoriasis
  6. ^ Clinical trial number NCT00267956 for "A Study of the Safety and Efficacy of CNTO 1275 in Patients With Active Psoriatic Arthritis" at ClinicalTrials.gov
  7. ^ Clinical trial number NCT01009086 for "A Study of the Safety and Efficacy of Ustekinumab in Patients With Psoriatic Arthritis" at ClinicalTrials.gov
  8. ^ Clinical trial number NCT00207727 for "A Safety and Efficacy Study of CNTO1275 in Patients With Multiple Sclerosis" at ClinicalTrials.gov
  9. ^ Clinical trial number NCT00955279 for "A Study to Evaluate the Safety and Effectiveness of Ustekinumab or Golimumab Administered Subcutaneously (SC) in Patients With Sarcoidosis" at ClinicalTrials.gov
  10. ^ Centocor 12/19/08 Press Release, http://www.centocor.com/centocor/i/press_releases/FDA_ISSUES_COMPLETE_RESPONSE_LETTER_TO_CENTOCOR_FOR_USTEKINUMAB_BIOLOGIC_LICENSE_APPLICATION_
  11. ^ Centocor 12/19/08 Press Release, http://www.centocor.com/centocor/i/press_releases/FDA_ISSUES_COMPLETE_RESPONSE_LETTER_TO_CENTOCOR_FOR_USTEKINUMAB_BIOLOGIC_LICENSE_APPLICATION_
  12. ^ Johnson LL. "Study: Drug for serious psoriasis tops competition" The Associated Press. 18 Sept 2008.
  13. ^ a b c Weber J, Keam S.[1]. BioDrugs 2009;23(1): 53-61.doi:10.2165/00063030-200923010-00006.

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