26 Sept 2016
The US Food and Drug Administration (FDA) has approved ustekinumab (Stelara, Janssen Biotech, Inc) for the treatment of moderately to severely active Crohn’s disease in patients aged 18 years or older.
Ustekinumab is already approved in the United States for treatment of patients with plaque psoriasis and psoriatic arthritis.
Ustekinumab is a human IgG1κ monoclonal antibody against the p40 subunit of the IL-12 and IL-23 cytokines.
Using DNA recombinant technology, ustekinumab is produced in a well characterized recombinant cell line and is purified using standard bio-processing technology.
The manufacturing process contains steps for the clearance of viruses. Ustekinumab is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons.
Mechanism of Action
Ustekinumab is a human IgG1қ monoclonal antibody that binds with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines.
IL-12 and IL-23 are naturally 17 occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation.
In in vitro models, ustekinumab was shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1.
The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn’s Disease.
In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab, was shown to be protective.
STELARA® was evaluated in three randomized, double-blind, placebo-controlled clinical studies in adult patients with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] score of 220 to 450). There were two 8-week intravenous induction studies (CD-1 and CD-2) followed by a 44-week subcutaneous randomized withdrawal maintenance study (CD-3) representing 52 weeks of therapy.
WARNINGS AND PRECAUTIONS
- Infections: Serious infections have occurred. Do not start STELARA during any clinically important active infection. If a serious infection or clinically significant infection develops, consider discontinuing STELARA® until the infection resolves.
- Theoretical Risk for Particular Infections: Serious infections from mycobacteria, salmonella and Bacillus Calmette-Guerin (BCG) vaccinations have been reported in patients genetically deficient in IL- 12/IL-23. Diagnostic tests for these infections should be considered as dictated by clinical circumstances.
- Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with STELARA®. Initiate treatment of latent TB before administering STELARA.
- Malignancies: STELARA may increase risk of malignancy. The safety of STELARA® in patients with a history of or a known malignancy has not been evaluated.
- Hypersensitivity Reactions: Anaphylaxis or other clinically significant hypersensitivity reactions may occur.
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS): One case was reported. If suspected, treat promptly and discontinue STELARA.
Most common adverse reactions are:
Crohn’s Disease, induction (≥3%): vomiting.
Crohn’s Disease, maintenance (≥3%): nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis.
- FDA PIL