Home » Posts tagged 'Ustekinumab'
Tag Archives: Ustekinumab
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
.....FOR BLOG HOME CLICK HEREFlag and hits
ORGANIC SPECTROSCOPY
SUBSCRIBE
Subscribe in a reader
Enter your email address:
Delivered by FeedBurner
Subscribe to New Drug Approvals by Email
Recent Comments
 | shivkr2 on SPSR Excellence Award 2025 – S… |
 | Bonkasaurus on Infigratinib phosphate |
 | PALOVAROTENE | ORGAN… on Palovarotene |
| Pfizer just purchase… on Temanogrel | |
| Pfizer To Cash In On… on Temanogrel |
Stelara (ustekinumab) Receives FDA Approval to Treat Active Psoriatic Arthritis
Ustekinumab
| CAS No: | 815610-63-0 |
|---|---|
| Molecular Weight: | 145.64 g/mol |
| Chemical Formula: | C9H18N2O2 |
| IUPAC Name: | Immunoglobulin G1, anti-(human interleukin 12 p40 subunit) (human monoclonal CNTO 1275 gamma1-chain), disulfide with human monoclonal CNTO 1275 kappa-chain, dimer |
HORSHAM, Pa., Sept. 23, 2013 /PRNewswire/ — Janssen Biotech, Inc., announced today that the U.S. Food and Drug Administration (FDA) has approved Stelara (ustekinumab) alone or in combination with methotrexate for the treatment of adult patients (18 years or older) with active psoriatic arthritis. It is estimated that more than two million people in the U.S. are living with psoriatic arthritis, a chronic autoimmune disease characterized by both joint inflammation and psoriasis skin lesions
read all at
Ustekinumab (INN, experimental name CNTO 1275, proprietary commercial name Stelara, 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.
Ustekinumab is a fully human monoclonal antibody (mAb) targeting the interleukin (IL)-12/23p40 subunit.
Interleukins are small soluble proteins that communicate between white blood cells (leukocytes), such as T cells. Interleukins mediate the differentiation, proliferation and many other processes of these cells. IL-12 and IL-23 are involved in the differentiation of naive T cells into T helper (Th) 1 and Th17 cells respectively.
Th1 and Th17 cells have been implicated in several autoimmune disorders, such as psoriasis. Ustekinumab targets the common p40 subunit of IL-12 and IL-23 to stop these cytokines from binding to their receptors and consequently preventing the development of Th1 and Th17 cells in an immune response.
In two Phase III trials for moderate to severe psoriasis, the longest >76 weeks, ustekinumab was safe and effective.
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.
Ustekinumab is approved in Canada, Europe and the United States to treat moderate to severe plaque psoriasis.
As of November 2009, the drug is being investigated for the treatment of psoriatic arthritis. It has also been tested in Phase II studies for multiple sclerosis and sarcoidosis, the latter versus golimumab (Simponi).
The US Food and Drug Administration (FDA) and European Union (EU) have approved the interleukin (IL) 12/23 inhibitor ustekinumab (Stelara, Janssen Biotech) for adults with active psoriatic arthritis who have not responded adequately to previous nonbiological disease-modifying antirheumatic drug therapy, the company announced today.
Approval of ustekinumab for psoriatic arthritis is “significant for patients and physicians as it marks the first treatment approved for this devastating and complex disease since the introduction of anti-TNF biologic medicines more than a decade ago,” Jerome A. Boscia, MD, vice president and head of immunology development, Janssen Research & Development, LLC, said in a statement.
The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended approval of ustekinumab for active psoriatic arthritis in June, as reported by Medscape Medical News.
Ustekinumab is already approved in the US and EU for treatment of moderate to severe psoriatic plaques in adults. The drug, which can be used alone or in combination with methotrexate, is novel in that it targets both IL-12 and IL-23.
Image source: Crystal structure of human IL-12, Wikipedia, public domain
Ustekinumab binding to IL-12/23p40
Phase 2 Drug: Ustekinumab A monoclonal antibody against the p40 subunit of IL-12/23 Other Name: Stelara
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Human |
| Target | IL-12 and IL-23
|
Ustekinumab, CAS number 815610-63-0, is also known by it’s brand name Stelara, which is marketed by Janssen Biotech, Inc. Developed as a treatment for adults with moderate to severe plaque psoriasis
Rockefeller University, MAR 2013
http://clinicaltrials.gov/ct2/show/NCT01806662
Atopic dermatitis (AD) is a chronic disease associated with intense itching, which affects most aspects of everyday life in the majority of patients. Acute inflammation and extensor/facial involvement is common in infants, whereas chronic inflammation increases in prevalence with age, as do localization to flexures. AD has a complex background characterized by immune activation, increased epidermal thickness in chronic diseased skin, and defective barrier function. In normal, healthy skin, the outer layer of the epidermis, the stratum corneum is made up flattened dead cells called corneocytes held together by a mixture of lipids and proteins. The stratum corneum and, in particular, the lipid layer are vital in providing a natural barrier function that locks water inside the skin and keeps allergens and irritants out. In people with AD, the barrier function is defective, which leads to dry skin. As the skin dries out, it cracks allowing allergens and irritants to penetrate.
Mild AD can be controlled with emollients and topical medications. However, moderate to severe AD is extremely difficult to control and requires systemic treatment that is often unsatisfactory due to impracticality and lack of effectiveness. Only three therapeutic options exist for moderate to severe AD, including: 1) oral steroids 2) cyclosporine A (CsA), that is not widely used in the US as it is not FDA approved for AD and 3) ultraviolet phototherapy. Oral steroids and CsA treatments have major side effects and UV radiation therapy is highly inconvenient for patients. Several biologic medications, such as TNF-alpha inhibitors, are effective, convenient, and relatively safe therapies for psoriasis, but have thus far not shown efficacy in AD. Ustekinumab is a unique biologic medication that may specifically target AD.
The investigators study will determine whether there is a reversal of the skin thickness and the immune pathways involved in the disease during treatment with Ustekinimab and what specific immune cells are involved. The investigators are also interested to understand how the clinical reversal of the disease will correlate with tissue reversal of the disease.
Detailed Description:
In psoriasis, epidermal hyperplasia is driven by underlying immune activation, whether as a direct response to IL-20 family cytokines that induces hyperplasia and inhibits keratinocyte terminal differentiation or as an indirect response to immune-mediated injury to keratinocytes. The epidermal reaction in psoriasis is largely restored to normal with selective immune suppression. Hence, one might hypothesize that similar epidermal responses should occur in the presence of “generalized” cellular immune activation, in diseases with similar inflammatory infiltrate and epidermal hyperplasia, such as AD. In fact, psoriasis and AD share features of dense T-cells and dentritic cell infiltrates, as well as over-expression of IL-22 in skin lesions. These diseases also share similar epidermal hyperplasia in their chronic phases.
Work from the investigators group showed that IL-22 is a key cytokine in the pathogenesis of both AD and psoriasis. The investigators have demonstrated that in psoriasis, ustekinumab suppresses the production of IL-12, IL-23, and IL-22. Additionally, by RT-PCR the investigators demonstrated that the mRNA expression of p40 cytokine and the IL23R is up-regulated in AD as compared to both normal skin and psoriasis. The investigators therefore hypothesize that ustekinumab will suppress IL-22 and possibly also p40 production in AD lesions and reverse both the epidermal growth/differentiation defects and the underlying immune activation, and hence will suppress disease activity. Interestingly, p40 was also found to be significantly up-regulated in non-lesional AD skin as compared with normal skin.
Although AD is thought to be predominately a disease of Th2-type cells, in the chronic stage, there is large Th1 component. To date, the precise mechanism by which sequential activation of Th2 and Th1 cells in AD is achieved remains unknown. IL-12 induces the differentiation and maturation of human Th cells into Th1-type cells. Recent circumstantial evidence suggests that in AD patients IL-12 may facilitate a change from the Th2-type to a Th1 cytokine profile. IL-12 was recently shown to be highly elevated in pediatric AD and its levels were strongly associated with disease severity.
Expression of IL-12 p40 mRNA is significantly enhanced in lesional skin from AD, suggesting that the enhanced local production of IL-12 in dendritic cells and macrophages may be responsible for the increased production of IFN-γ in chronic lesions potentially suggesting that IL-12 may have a pivotal role in promoting inflammation in atopic dermatitis. Topical steroids which constitute a mainstay of therapy in AD are known to strongly down-regulate IL-12 expression, possibly also indicating that targeted anti IL-12 therapy might important role in treating AD.
Recently, the Th1/Th2 paradigm in autoimmunity and allergy has been revisited to include a role for a new population of IL-17-producing Th cells known as Th17. Th17 cells are characterized by the production of inflammatory cytokines such as IL-17A, IL-17F, IL-22, and IL-26. One of the key factors involved in naive Th-cell commitment to a Th17 phenotype is IL-23.
Patients with acute AD were found to have increased Th17 T-cells in peripheral blood by flow cytometry and intracellular cytokine staining 26 as well as by immunohistochemistry (IHC) in lesions. Since IL-23 is the major inducer of Th17 T-cells, as well as “T22” T-cells, neutralization of IL-23 could potentially result in both decreased Th17 signal in acute AD as well as decreased “T22/IL22″ signal. Therefore the investigators postulate that ustekinumab in AD will act both inhibiting the IL-12-dependent Th1 shift in chronic AD stage as well as the pathogenic IL-22/”T22” axis in this disease.
Ustekinumab [1] (INN, experimental name CNTO 1275, proprietary commercial name Stelara,[2] 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.[3]
In two Phase III trials for moderate to severe psoriasis, the longest >76 weeks, ustekinumab was safe and effective.[4][5]
A third Phase III trial, ACCEPT, compared the efficacy and safety of ustekinumab with etanercept in the treatment of moderate to severe plaque psoriasis.[6] This trial found a significantly higher clinical response with ustekinumab over the 12-week study period compared to high-dose etanercept.[6] It also demonstrated the clinical benefit of ustekinumab among patients who failed to respond to etanercept.[6]
Ustekinumab is approved in Canada, Europe and the United States to treat moderate to severe plaque psoriasis.[7]
As of November 2009, the drug is being investigated for the treatment of psoriatic arthritis.[8][9] It has also been tested in Phase II studies for multiple sclerosis[10] and sarcoidosis, the latter versus golimumab (Simponi).[11]
- Cingoz, Oya (2009). “Ustekinumab”. MAbs 1 (3): 216–221. doi:10.4161/mabs.1.3.8593. PMC 2726595. PMID 20069753.
- ^ European Medicines Agency, 20 November 2008, http://www.emea.europa.eu/pdfs/human/opinion/Stelara_58227008en.pdf
- ^ 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.
- ^ 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.
- ^ 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.
- ^ a b c 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.
- ^ Medarex to Receive Milestone Payment for Approval of STELARA(TM) (Ustekinumab) for the Treatment of Moderate to Severe Plaque Psoriasis
- ^ ClinicalTrials.gov NCT00267956 A Study of the Safety and Efficacy of CNTO 1275 in Patients With Active Psoriatic Arthritis
- ^ ClinicalTrials.gov NCT01009086 A Study of the Safety and Efficacy of Ustekinumab in Patients With Psoriatic Arthritis
- ^ ClinicalTrials.gov NCT00207727 A Safety and Efficacy Study of CNTO1275 in Patients With Multiple Sclerosis
- ^ ClinicalTrials.gov NCT00955279 A Study to Evaluate the Safety and Effectiveness of Ustekinumab or Golimumab Administered Subcutaneously (SC) in Patients With Sarcoidosis
- ^ http://www.empr.com/stelara-approved-for-moderate-to-severe-psoriasis/article/149760/
- ^ a b 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_
- ^ Johnson LL. “Study: Drug for serious psoriasis tops competition” The Associated Press. 18 Sept 2008.[dead link]
- ^ Wild, David (November 2011), “Novel IL-12/23 Antagonist Shows Potential in Severe Crohn’s”, Gastroenterology & Endoscopy News 62 (11), retrieved 2011-12-04
- ^ a b c Weber J, Keam SJ (2009). “Ustekinumab”. BioDrugs 23 (1): 53–61. doi:10.2165/00063030-200923010-00006. PMID 19344192.
- ^ 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.
- ^ “Important Safety Information”. STELARA® (ustekinumab). Janssen Biotech.
External links
- Centocor Ortho Biotech official site
- CNTO 1275 research studies registered with U.S. National Institutes of Health:
- ClinicalTrials.gov NCT00207727 Phase II Study on Multiple Sclerosis
- ClinicalTrials.gov NCT00320216 Phase II Study on Psoriasis
- ClinicalTrials.gov NCT00267969 Phase III Study on Psoriasis
- ClinicalTrials.gov NCT00307437 Phase III Study on Psoriasis
- ClinicalTrials.gov NCT00267956 Phase II Study on Psoriatic Arthritis
- Sylvester, Bruce (2006-03-06). “CNTO 1275 Shows Efficacy for Psoriasis: Presented at AAD”. Doctor’s Guide Publishing. Retrieved 2007-01-25.
New Drug Approvals 
