Ustekinumab, a human IgG1κ monoclonal antibody, is a human interleukin-12 and -23 antagonist. Based on DNA recombinant technology, ustekinumab is produced in a murine cell line. 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.
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 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 and ulcerative colitis. 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.
In a small exploratory study, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in lesional skin biopsies measured at baseline and up to two weeks post-treatment in subjects with psoriasis.
In both study UC-1 (induction) and study UC-2 (maintenance), a positive relationship was observed between exposure and rates of clinical remission, clinical response, and endoscopic improvement. The response rate approached a plateau at the ustekinumab exposures associated with the recommended dosing regimen for maintenance treatment.
STELARA® (ustekinumab) injection Initial U.S. Approval: 2009
STELARA® (ustekinumab) injection is a sterile, preservative-free, colorless to light yellow solution and may contain a few small translucent or white particles with pH of 5.7- 6.3.
INDICATIONS
STELARA® is a human interleukin-12 and -23 antagonist indicated for the treatment of: Adult patients with:
• moderate to severe plaque psoriasis (Ps) who are candidates for phototherapy or systemic therapy.
• active psoriatic arthritis (PsA).
• moderately to severely active Crohn’s disease (CD).
• moderately to severely active ulcerative colitis.
Pediatric patients 6 years and older with:
• moderate to severe plaque psoriasis, who are candidates for phototherapy or systemic therapy.
• active psoriatic arthritis (PsA).
DOSAGE AND ADMINISTRATION
The psoriasis subcutaneous recommended dosage depends on body weight. For example, weight greater than 100 Kg: 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks; weight range (Kg) less than or equal to 100 kg: 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks. Even lower dosages are recommended for pediatric patients.
DOSAGE FORMS AND STRENGTHS
STELARA® (ustekinumab) is a colorless to light yellow solution and may contain a few small translucent or white particles.
Subcutaneous Injection
• Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe
• Injection: 45 mg/0.5 mL solution in a single-dose vial
Intravenous Infusion
• Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial
PK
• Tmax (healthy subjects): 8.5 days
• Steady-state serum concentrations of ustekinumab (subjects with psoriasis, multiple doses): Week 28
• Apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks: No
• half-life (mean): 14.9+/-4.6 to 45.6+/-89.2 days across all psoriasis studies following subcutaneous administration.
• The metabolic pathway of ustekinumab has not been characterized. As a human IgG1κ monoclonal antibody, ustekinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
ADVERSE REACTIONS
Most common adverse reactions are:
• Psoriasis (≥3%): nasopharyngitis, upper respiratory tract infection, headache, and fatigue.
• 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.
• Ulcerative colitis, induction (≥3%): nasopharyngitis
• Ulcerative colitis, maintenance (≥3%): nasopharyngitis, headache, abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea
MARKET
Authorization paves way for biosimilar competition in the approximately
€2.5 billion (US$2.7 billion) EU ustekinumab market as soon as possible
after expiry of intellectual-property rights in July 2024.
As of today, February 1st, 2024, one ustekinumab biosimilar is approved in the EU market. This biosimilar, named Uzpruvo, was developed by Alvotech and commercially licensed to STADA. It received marketing authorization in the EU in September 2023.
Technically, there are 0 ustekinumab biosimilars curretly approved and actively available in the US market. However, on October 26, 2023, the FDA approved the first ustekinumab biosimilar called Wezlana (ustekinumab-auub). It's important to note that due to a patent lawsuit, Wezlana's launch is delayed. The applicant for Wezlana (ustekinumab-auub) in the US is Pfizer Inc. The biosimilar was developed by Samsung Bioepis.
Samsung Bioepis reported that it has signed a settlement and license agreement with Johnson
& Johnson (“J&J”) in the United States relating to SB17, Samsung
Bioepis’s ustekinumab biosimilar to J&J’s STELARA®. If SB17 is
approved by the FDA, the license period in the United States will begin
on February 22, 2025. (Goodwin, Dec. 13, 2023)
On the other hand, Alvotech and Teva Pharmaceuticals Inc. announced that they reached a settlement and license agreement with
Johnson & Johnson regarding AVT04, Alvotech’s proposed biosimilar to
STELARA (ustekinumab) in the United States. “According to the
settlement agreement, AVT04 (ustekinumab) can be marketed in the US,
subject to regulatory approval, no later than February 21, 2025.” (Goodwin. June 13, 2023)
On May 23, 2023, Amgen settled patent lawsuit over biosimilar of J&J's big-selling Stelara. Amgen said that the settlement terms are
confidential, but it will allow the company to sell its biosimilar of
Stelara "no later than January 1st, 2025." (Reuters, May 23, 2023)
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