Ustekinumab

Ustekinumab
Monoclonal antibody
Type Whole antibody
Source Human
Target IL-12 and IL-23
Clinical data
Trade names Stelara
AHFS/Drugs.com Monograph
MedlinePlus a611013
License data
Pregnancy
category
  • contraindicated
Routes of
administration		 subcutaneous injection
ATC code L04AC05 (WHO)
Legal status
Legal status
Pharmacokinetic data
Metabolism unknown[1]
Biological half-life 15–32 days (average 3 weeks)[1]
Identifiers
CAS Number 815610-63-0 N
ChemSpider none
UNII FU77B4U5Z0 YesY
KEGG D09214 YesY
ChEMBL CHEMBL1201835 N
Chemical and physical data
Formula C6482H10004N1712O2016S46
Molar mass 145.64 kg/mol
 NYesY (what is this?)  (verify)

Ustekinumab[2] (INN, experimental name CNTO 1275, proprietary commercial name Stelara,[3] Centocor) is a human monoclonal antibody. It is manufactured in the Netherlands. It is directed against interleukin 12 and interleukin 23, naturally occurring proteins that regulate the immune system and immune-mediated inflammatory disorders.[4]

Since 2009, Ustekinumab is approved in Canada, Europe and the United States to treat moderate to severe plaque psoriasis.[5]

It has been tested in Phase II studies for sarcoidosis, (versus golimumab (Simponi)).[6]

It was found not effective for multiple sclerosis.[7]

On September 24, 2013, the FDA approved the use of ustekinumab for the treatment of psoriatic arthritis.

Clinical trials

Psoriasis

In two Phase III trials for moderate to severe psoriasis, the longest >76 weeks, ustekinumab was safe and effective.[8][9]

A third Phase III trial, ACCEPT, compared the efficacy and safety of ustekinumab with etanercept in the treatment of moderate to severe plaque psoriasis.[10] This trial found a significantly higher clinical response with ustekinumab over the 12-week study period compared to high-dose etanercept.[10][10]

Systemic Lupus Erythematosus

A Phase IIa trial sponsored by Janssen is a multicenter, randomized, double-blind, placebo-controlled, proof-of-concept study of Ustekinumab in subjects with active Systemic Lupus Erythematosus.

Ankylosing Spondylitis

A clinical trial conducted in 2013 of 90 mg Ustekinumab administered subcutaneously brought a remission of Ankylosing Spondylitis in about half of the patients.[11]

Crohn's Disease

UNITI trial which looked into the use of Ustekinumab in Crohn's diseasae results were published in November 2016. The trial compared use of the drug for both induction and maintenance of remission in patients with severe drug unresponsive Crohn's disease. It showed higher rates of response compared to placebo. [12]

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 Biologic 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).

In September 2008, Centocor released result of a study comparing etanercept and ustekinumab. The etanercept 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."[13]

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.[14]

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.[14]

The FDA approved the drug on September 25, 2009 for the treatment of adult patients with moderate to severe plaque psoriasis.[15]

In November 2011, a study conducted at the Mount Sinai Medical Center in New York City by Drs. Kornbluth and Sandborn showed Ustekinumab's potential for treating severe Crohn's disease.[16]

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 once every three months, after the first two doses are administered four weeks apart.

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 activate certain T-cells. It binds to the p-40 subunit of both IL-12 and IL-23 so that they subsequently cannot bind to their receptors.[17]

Efficacy

Plaque psoriasis

In 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.[18] Health-related quality of life (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.[18]

Multiple sclerosis

A double-blind placebo controlled randomised dose-ranging Phase II trial in patients with RRMS (relapsing-remitting multiple sclerosis) [19] found that Ustekinumab was not efficacious in reducing the cumulative number of gadolinium-enhancing T1-weighted lesions (the primary endpoint of the study) or the number of clinical or objective relapses (the secondary endpoint). The drug was relatively well tolerated compared to placebo.[7]

Adverse effects

According to information provided by Centocor, maker of one medication based on ustekinumab, their version of the drug is associated with several types of serious adverse effects. These include an increased risk of infection, such as by tuberculosis and an increased risk of certain types of cancer. As with some other immunosuppressant drugs like ciclosporin, the brain swelling of posterior reversible encephalopathy syndrome is a risk. The pharmaceutical company also reports serious allergic reaction as a possible side effect. More common side effects are upper respiratory infection, headache, and tiredness.[20]

Pregnancy

Consult your doctor if you are pregnant or plan on becoming pregnant as it is unknown if the medication has any effects on your unborn baby. This medication may be passed into your breast milk, consult your doctor before breast-feeding.[21]

Tolerability

Clinical trials have shown that subcutaneous ustekinumab was generally well tolerated. Most treatment-emergent adverse events were of mild severity.[18]

References

  1. 1 2 Summary of production characteristics Stelara, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000958/WC500058513.pdf
  2. ↑ Cingoz, Oya (2009). "Ustekinumab". MAbs. 1 (3): 216–221. doi:10.4161/mabs.1.3.8593. PMC 2726595Freely accessible. PMID 20069753.
  3. ↑ European Medicines Agency, 20 November 2008, http://www.emea.europa.eu/pdfs/human/opinion/Stelara_58227008en.pdf
  4. ↑ Reddy M, Davis C, Wong J, Marsters P, Pendley C, Prabhakar U (May 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.
  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 NCT00955279 for "A Study to Evaluate the Safety and Effectiveness of Ustekinumab or Golimumab Administered Subcutaneously (SC) in Patients With Sarcoidosis" at ClinicalTrials.gov
  7. 1 2 Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH (September 2008). "Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study". Lancet Neurol. 7 (9): 796–804. doi:10.1016/S1474-4422(08)70173-X. PMID 18703004.
  8. ↑ Leonardi CL, Kimball AB, Papp KA, et al. (May 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.
  9. ↑ Papp KA, Langley RG, Lebwohl M; et al. (May 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.
  10. 1 2 3 Griffiths C, Strober B, van de Kerkhof P, et al. (2010). "Comparison of Ustekinumab and Etanercept for Moderate-to-Severe Psoriasis". N Engl J Med. 362 (2): 118–28. doi:10.1056/NEJMoa0810652. PMID 20071701.
  11. ↑ http://ard.bmj.com/content/early/2014/01/03/annrheumdis-2013-204248.short
  12. ↑ "Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease". NEJM. Retrieved 20 November 2016.
  13. ↑ Johnson LL. "Study: Drug for serious psoriasis tops competition" The Associated Press. 18 Sept 2008. Archived September 27, 2008, at the Wayback Machine.
  14. 1 2 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_
  15. ↑ Stelara approved for moderate to severe psoriasis. Sept 2009
  16. ↑ Wild, David (November 2011), "Novel IL-12/23 Antagonist Shows Potential in Severe Crohn's", Gastroenterology & Endoscopy News, 62 (11), retrieved 2011-12-04
  17. ↑ Koutruba, N; Emer, J; Lebwohl, M (15 April 2010). "Review of ustekinumab, an interleukin-12 and interleukin-23 inhibitor used for the treatment of plaque psoriasis.". Therapeutics and clinical risk management. 6: 123–41. PMID 20421912.
  18. 1 2 3 Weber J, Keam SJ (2009). "Ustekinumab". BioDrugs. 23 (1): 53–61. doi:10.2165/00063030-200923010-00006. PMID 19344192.
  19. ↑ Clinical trial number NCT00207727 for "A Safety and Efficacy Study of CNTO1275 in Patients With Multiple Sclerosis" at ClinicalTrials.gov
  20. ↑ "Important Safety Information". STELARA® (ustekinumab). Janssen Biotech.
  21. ↑ "STELARA® (ustekinumab) for Plaque Psoriasis & Psoriatic Arthritis". www.stelarainfo.com. Retrieved 2015-12-13.
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