Ustekinumab

Drugbox
type = mab


source = Human
target = IL-12 and IL-23
CAS_number = 815610-63-0
ATC_prefix = L04
ATC_suffix = AC05
PubChem =
DrugBank =
C=6482|H=10004|N=1712|O=2016|S=46
molecular_weight = 145.64 kDa
bioavailability =
protein_bound =
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pregnancy_AU =
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legal_AU =
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legal_status = Investigational
routes_of_administration = Subcutaneous injection

Ustekinumab (INN, experimental name CNTO 1275, is a human immunosuppressive drug developed by the biotechnology company Centocor. It is a laboratory-manufactured monoclonal antibody directed against interleukins IL-12 and IL-23.cite journal |author=Reddy M, Davis C, Wong J, Marsters P, Pendley C, Prabhakar U |title=Modulation of CLA, IL-12R, CD40L, and IL-2Ralpha expression and inhibition of IL-12- and IL-23-induced cytokine secretion by CNTO 1275 |journal=Cell. Immunol. |volume=247 |issue=1 |pages=1–11 |year=2007 |month=May |pmid=17761156 |doi=10.1016/j.cellimm.2007.06.006 |url=http://linkinghub.elsevier.com/retrieve/pii/S0008-8749(07)00149-9] Ustekinumab is presently undergoing clinical trials to determine its safety and effectiveness against multiple sclerosis, psoriasis, and psoriatic arthritis. The results of Phase III trials for psoriasis have been encouraging; two large randomized controlled trials, one conducted over 76 weeks and the other over a year, showed ustekinumab to be safe and effective for moderate to severe psoriasis.cite journal |author=Leonardi CL, Kimball AB, Papp KA, "et al" |title=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) |journal=Lancet |volume=371 |issue=9625 |pages=1665–74 |year=2008 |month=May |pmid=18486739 |doi=10.1016/S0140-6736(08)60725-4 |url=] cite journal |author=Papp KA, Langley RG, Lebwohl M, "et al" |title=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) |journal=Lancet |volume=371 |issue=9625 |pages=1675–84 |year=2008 |month=May |pmid=18486740 |doi=10.1016/S0140-6736(08)60726-6 |url=]

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 are 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.

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 Menzer, 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." [Johnson LL. [http://ap.google.com/article/ALeqM5h_tdxEcXc1GVJ0JaD3-pP7hKEFRQD93947K00 "Study: Drug for serious psoriasis tops competition"] The Associated Press. 18 Sept 2008.]

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 inflamatory response through the suppression of certain cytokines. Specifically, CNTO 1275 blocks interleukin IL-12 and IL-23 which help activiate certain T-cells.

References

External links

* [http://www.centocor.com/ Centocor official site]

* CNTO 1275 research studies registered with U.S. National Institutes of Health:
** [http://www.clinicaltrials.gov/ct/show/NCT00207727 Phase II Study on Multiple Sclerosis (NCT00207727)]
** [http://www.clinicaltrials.gov/ct/show/NCT00320216 Phase II Study on Psoriasis (NCT00320216)]
** [http://www.clinicaltrials.gov/ct/show/NCT00267969 Phase III Study on Psoriasis (NCT00267969)]
** [http://www.clinicaltrials.gov/ct/show/NCT00307437 Phase III Study on Psoriasis (NCT00307437)]
** [http://www.clinicaltrials.gov/ct/show/NCT00267956 Phase II Study on Psoriatic Arthritis (NCT00267956)]

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