Ustekinumab (Stelara®): A Comprehensive Monograph on a First-in-Class IL-12/23 Inhibitor

Executive Summary

Ustekinumab is a first-in-class, fully human IgG1κ monoclonal antibody that represents a significant milestone in the treatment of immune-mediated inflammatory diseases. Marketed under the brand name Stelara® and now available as multiple biosimilars, it functions as a dual inhibitor, uniquely targeting the shared p40 protein subunit of two critical cytokines: Interleukin-12 (IL-12) and Interleukin-23 (IL-23).[1] This targeted mechanism of action allows Ustekinumab to potently downregulate the Th1 and Th17 inflammatory pathways, which are central to the pathophysiology of several autoimmune conditions.[1]

The therapeutic utility of Ustekinumab has been firmly established through a robust clinical development program, leading to regulatory approvals for a range of indications. These include the treatment of moderate-to-severe plaque psoriasis (PsO), active psoriatic arthritis (PsA), moderately to severely active Crohn's disease (CD), and moderately to severely active ulcerative colitis (UC).[1] Its approval extends to pediatric populations for both plaque psoriasis and psoriatic arthritis, underscoring its well-characterized efficacy and safety profile across different age groups.[7] Clinical trials have consistently demonstrated that Ustekinumab can achieve significant clinical endpoints, including skin clearance in psoriasis, joint symptom improvement in psoriatic arthritis, and clinical and endoscopic remission in inflammatory bowel diseases.[9]

The safety profile of Ustekinumab is well-defined and is a direct consequence of its immunomodulatory mechanism. While generally well-tolerated, its primary risks include an increased susceptibility to infections, necessitating pre-treatment screening for tuberculosis and vigilance for other serious infections during therapy.[1] Its long pharmacokinetic half-life of approximately three weeks supports convenient maintenance dosing regimens of every 8 or 12 weeks, a significant advantage for patient adherence.[1]

As a blockbuster therapeutic, Ustekinumab has had a profound impact on clinical practice and the pharmaceutical market. The recent market entry of multiple FDA- and EMA-approved biosimilars marks a pivotal moment, poised to dramatically alter the commercial landscape by increasing competition and expanding patient access through lower costs.[15] The evolution of Ustekinumab, from its initial approval for psoriasis to its current role as a multi-indication therapy and its ongoing investigation for new uses, highlights its enduring importance in the armamentarium against chronic inflammatory diseases.

Drug Profile and Molecular Characteristics

This section establishes the fundamental identity of Ustekinumab, providing a definitive reference for its biological classification, nomenclature, and key physicochemical properties.

Classification and Nomenclature

Ustekinumab is classified as a biotech drug, specifically a fully human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody.[1] Within the therapeutic landscape, it is categorized as an interleukin inhibitor, a biologic Disease-Modifying Anti-Rheumatic Drug (bDMARD), and a systemic antipsoriatic agent.[5] Its development represents a significant advancement in targeted immunotherapy. The antibody was generated through the immunization of human immunoglobulin (hu-Ig) transgenic mice with recombinant human IL-12, a process that yields a fully human antibody, thereby minimizing the potential for immunogenicity that can be associated with chimeric or humanized antibodies.[5] The development was pioneered by Centocor Ortho Biotech, which later became part of Janssen, a pharmaceutical company of Johnson & Johnson.[1]

Identifiers and Brand Names

To ensure unambiguous identification in clinical, research, and regulatory contexts, Ustekinumab is associated with a range of standard identifiers and commercial names. The reference product is globally recognized as Stelara®. Following the expiration of key patents, a number of biosimilar products have been approved and launched, particularly in the United States and European Union.

The U.S. Food and Drug Administration (FDA) has adopted a specific naming convention for biologics, appending a unique, meaningless four-letter suffix to the nonproprietary name of each biosimilar product. This system is designed to enhance pharmacovigilance by enabling precise tracking of adverse events to a specific manufacturer's product and to prevent the inadvertent substitution of products that have not been designated as "interchangeable".[15] In contrast, the European Medicines Agency (EMA) approves biosimilars with distinct brand names but does not utilize the suffix system for the nonproprietary name, a key difference in global regulatory practice.[17] The consolidation of these various names and identifiers is crucial for healthcare professionals, researchers, and industry analysts.

Table 1: Ustekinumab Identifiers and Commercial Names

Category	Identifier/Name	Source(s)
Generic Name	Ustekinumab	5
DrugBank ID	DB05679	1
CAS Number	815610-63-0	1
ATC Code	L04AC05	1
Other Identifiers	UNII: FU77B4U5Z0KEGG: D09214ChEMBL: ChEMBL1201835	1
Developmental Code	CNTO 1275, CNTO-1275	21
Reference Product	Stelara®	1
Approved Biosimilars	Wezlana (ustekinumab-auub)Selarsdi (ustekinumab-aekn)Pyzchiva (ustekinumab-ttwe)Otulfi (ustekinumab-aauz)Yesintek (ustekinumab-kfce)Imuldosa (ustekinumab-srlf)Steqeyma (ustekinumab-stba)Starjemza (ustekinumab-hmny)Uzpruvo (EU)	15

Physicochemical Properties

As a large protein therapeutic, Ustekinumab possesses physicochemical properties characteristic of a monoclonal antibody.

• Molecular Formula: The empirical chemical formula for Ustekinumab is C6482​H10004​N1712​O2016​S46​.[1]
• Molar Mass: The calculated molar mass is approximately 145,648.06 g·mol⁻¹, reflecting its large and complex protein structure.[1]
• Structure: Ustekinumab has the archetypal 'Y'-shaped structure of an IgG1 antibody, consisting of two identical heavy chains and two identical light chains (kappa type) linked by disulfide bonds. The variable regions at the tips of the 'Y' form the antigen-binding sites (Fab) that confer its high specificity for the p40 subunit of IL-12 and IL-23, while the constant region (Fc) at the base mediates effector functions and contributes to its long pharmacokinetic half-life.[1]

Mechanism of Action: Targeting the IL-12/IL-23 Axis

The therapeutic efficacy of Ustekinumab is derived from its precise and targeted interference with the Interleukin-12 (IL-12) and Interleukin-23 (IL-23) signaling pathways. This section provides a detailed scientific explanation of its mechanism, from the broader immunological context to the specific molecular interactions that define its function.

The Role of Interleukins 12 and 23 in Autoimmunity

IL-12 and IL-23 are naturally occurring, heterodimeric cytokines that serve as master regulators of adaptive immunity, but their dysregulation is a cornerstone of the pathophysiology of many autoimmune diseases.[5] Both cytokines are produced by antigen-presenting cells, such as dendritic cells and macrophages, and are found at elevated levels in the affected tissues—including the skin, joints, and gastrointestinal mucosa—of patients with psoriasis, psoriatic arthritis, and inflammatory bowel disease.[2]

The IL-12 pathway is central to the development of T-helper 1 (Th1) cell-mediated immunity. IL-12, which is composed of a p35 and a p40 subunit, promotes the differentiation of naive T-cells into Th1 cells. These Th1 cells are crucial for defending against intracellular pathogens but, when overactivated in autoimmune states, they produce high levels of pro-inflammatory cytokines, most notably interferon-gamma (IFNγ), which drives tissue inflammation and damage.[18]

The IL-23 pathway is essential for the maintenance and expansion of the T-helper 17 (Th17) cell lineage. IL-23 is composed of a p19 and a p40 subunit. Its primary role is to sustain Th17 cells, which are potent producers of inflammatory cytokines like IL-17A, IL-17F, and IL-22. The Th17 pathway is now understood to be a dominant driver of pathology in conditions like psoriasis and has a critical role in the chronic inflammation characteristic of psoriatic arthritis and inflammatory bowel disease.[1]

A fascinating aspect of Ustekinumab's development history is that its dual specificity was a serendipitous discovery rather than an initial design feature. The drug was developed to target the p40 subunit, which was known to be part of IL-12. The existence and pro-inflammatory role of IL-23, which also utilizes the p40 subunit, were described after the initial discovery and preclinical development of Ustekinumab.[18] This realization transformed the understanding of the drug's mechanism, elevating it from a specific IL-12 inhibitor to a broader immunomodulator that could simultaneously suppress both the Th1 and the highly pathogenic Th17 pathways. This "accidental" dual targeting is a key reason for its broad efficacy across multiple distinct autoimmune diseases.

Specific Binding to the p40 Subunit

The p40 protein is the common structural element shared by both IL-12 and IL-23, making it an ideal strategic target for simultaneously neutralizing both cytokines.[18] Ustekinumab is a high-affinity human IgG1κ monoclonal antibody engineered to bind with exceptional specificity to this p40 subunit.[1] This binding is a direct, physical interaction confirmed by co-crystal structure analysis, where the fragment antigen-binding (Fab) portion of the antibody engages the p40 protein.[18] This action effectively sequesters the p40 subunit, preventing its assembly into functional IL-12 or IL-23 heterodimers and blocking their ability to interact with their respective cell surface receptors.

Downstream Effects: Disruption of Inflammatory Cascades

The therapeutic effect of Ustekinumab is realized through the downstream consequences of its p40 blockade. By binding to p40, Ustekinumab prevents both IL-12 and IL-23 from docking with their shared receptor component, the IL-12 receptor beta 1 (IL-12Rβ1) chain, which is expressed on the surface of immune effector cells like natural killer (NK) cells and T-cells.[1]

This receptor blockade prevents the initiation of intracellular signaling cascades. For the IL-12 pathway, it inhibits the phosphorylation of the signal transducer and activator of transcription 4 (STAT4). For the IL-23 pathway, it blocks the phosphorylation of STAT3.[18] The interruption of these critical signaling events has profound functional consequences:

1. Inhibition of T-cell Differentiation and Activation: The drug prevents IL-12-mediated Th1 differentiation and IL-23-mediated Th17 cell expansion and survival.[1]
2. Suppression of Pro-inflammatory Cytokine Production: The ultimate result is a significant reduction in the production and release of key inflammatory mediators. This includes the downregulation of gene expression for cytokines like IFNγ (from Th1 cells) and IL-17A (from Th17 cells), as well as other inflammatory chemokines such as MCP-1, TNF-alpha, IP-10, and IL-8.[5]

By disrupting these cascades, Ustekinumab effectively dampens the overactive immune response that drives chronic inflammation in its target diseases. This mechanism, while highly effective, also provided the scientific rationale for the development of its successors. The success of Ustekinumab validated the IL-12/23 axis as a therapeutic target. This led to the development of second-generation biologics that are more selective, targeting only the p19 subunit of IL-23 (e.g., risankizumab, guselkumab).[9] The hypothesis behind this evolution is that specifically inhibiting the Th17 pathway via IL-23p19 blockade may offer comparable or superior efficacy, particularly in diseases like psoriasis, while potentially improving the safety profile by sparing the IL-12/Th1 pathway, which plays a role in host defense. Thus, Ustekinumab's mechanism is both its core strength and the foundation upon which its competition was built.

Clinical Pharmacology: Pharmacokinetics and Pharmacodynamics

The clinical use of Ustekinumab is guided by its distinct pharmacokinetic (PK) and pharmacodynamic (PD) properties. Its absorption, distribution, metabolism, and elimination profile dictates its dosing regimen, while its pharmacodynamic effects correlate directly with its therapeutic mechanism.

Pharmacokinetics (PK)

The pharmacokinetic profile of Ustekinumab is characterized by slow absorption after subcutaneous administration, limited distribution, a long elimination half-life, and low clearance, all typical features of a monoclonal antibody therapeutic.

• Absorption: Ustekinumab is administered via either subcutaneous (SC) or intravenous (IV) routes.[1] Following SC administration in adult patients with psoriasis, the median time to reach maximum serum concentration ( Tmax​) ranges from 7 to 13.5 days.[5] The absolute bioavailability ( F) after a single SC dose is estimated to be 57.2%, indicating that just over half of the administered dose reaches systemic circulation.[5] Following a single IV induction dose in patients with Crohn's disease or ulcerative colitis, maximum concentrations are achieved rapidly, with mean Cmax​ values around 125-129 mcg/mL.[5] Systemic exposure, as measured by Cmax​ and the area under the concentration-time curve (AUC), increases in a dose-proportional manner with SC doses, indicating predictable pharmacokinetics within the therapeutic range.[5]
• Distribution: The volume of distribution of Ustekinumab is relatively small, with a total volume at steady-state (Vd​) of approximately 4.4 to 4.6 liters in patients with inflammatory bowel disease.[5] This low volume suggests that the drug is primarily confined to the vascular and interstitial compartments and does not extensively penetrate into tissues, which is consistent with a large protein molecule.
• Metabolism: The precise metabolic pathway of Ustekinumab has not been fully characterized. However, as a fully human IgG1 monoclonal antibody, it is expected to be degraded into smaller peptides and individual amino acids through general, nonspecific protein catabolism, similar to the breakdown of endogenous immunoglobulins.[1] Crucially, it is not metabolized by the hepatic cytochrome P450 (CYP) enzyme system. This lack of CYP-mediated metabolism is a significant clinical advantage. While chronic inflammation itself can suppress the activity of certain CYP enzymes, and treatment with an anti-inflammatory agent like Ustekinumab could theoretically normalize this activity, dedicated clinical studies have demonstrated no clinically significant effects on the activity of human CYP enzymes.[5] This finding indicates a very low potential for metabolic drug-drug interactions with small-molecule drugs that are substrates of the CYP system (e.g., warfarin, cyclosporine), simplifying its use in patients who require polypharmacy.
• Elimination: The elimination of Ustekinumab is slow. The median elimination half-life (t1/2​) is long, ranging from 15 to 32 days, with an average of approximately 3 weeks (19-21 days) across different patient populations and studies.[1] Systemic clearance (CL) is low, measured at approximately 0.19 L/day in patients with IBD.[5] This combination of a long half-life and low clearance is the fundamental pharmacokinetic basis for its convenient maintenance dosing schedule of every 8 or 12 weeks. The drug remains at therapeutic concentrations in the body for an extended period, obviating the need for more frequent administration and thereby improving patient adherence and quality of life compared to many other biologics.

Table 2: Summary of Key Pharmacokinetic Parameters for Ustekinumab

Parameter	Value	Patient Population / Notes	Source(s)
Route of Administration	Subcutaneous (SC), Intravenous (IV)	SC for maintenance; IV for IBD induction	1
Bioavailability (F)	57.2%	After single SC dose	5
Time to Max Concentration (Tmax​)	7 - 13.5 days	After single SC dose in PsO patients	5
Volume of Distribution (Vd​)	4.4 - 4.6 L	Steady-state in IBD patients	5
Metabolism	Catabolic pathways (protein degradation)	Not metabolized by CYP450 enzymes	5
Elimination Half-Life (t1/2​)	~19 - 21 days (average 3 weeks)	Range: 15-32 days across studies	1
Clearance (CL)	~0.19 L/day	In IBD patients	5

Pharmacodynamics (PD)

The pharmacodynamic effects of Ustekinumab are a direct manifestation of its mechanism of action. By binding the p40 subunit and blocking IL-12 and IL-23 signaling, Ustekinumab produces measurable changes in the inflammatory milieu.[5] Treatment leads to a significant downregulation in the gene expression and serum levels of various pro-inflammatory cytokines and chemokines that are downstream of the IL-12/23 axis. These include reductions in mediators such as Monocyte Chemoattractant Protein-1 (MCP-1), Tumor Necrosis Factor-alpha (TNF-α), Interferon-inducible Protein-10 (IP-10), and IL-8.[5] The suppression of these biomarkers of inflammation provides a biological measure of the drug's activity and correlates with the clinical improvements observed in patients.

Approved Therapeutic Indications and Clinical Efficacy

Ustekinumab has undergone extensive clinical investigation, leading to its approval by major regulatory bodies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for several distinct immune-mediated inflammatory diseases. This section details the pivotal clinical trial evidence supporting its use for each approved indication. The chronological expansion of these indications—from plaque psoriasis in 2009, to psoriatic arthritis in 2013, Crohn's disease in 2016, and ulcerative colitis in 2019—illustrates a highly successful lifecycle management strategy.[20] This "pipeline in a product" approach strategically leveraged the understanding of a common underlying pathophysiology across different medical specialties, transforming a single drug into a multi-specialty cornerstone therapy.

Plaque Psoriasis (PsO)

• Indication: Ustekinumab is indicated for the treatment of moderate to severe plaque psoriasis in adult and pediatric patients aged 6 years and older who are candidates for phototherapy or systemic therapy.[1]
• Pivotal Trials and Efficacy: The efficacy of Ustekinumab in adults was established in two large, randomized, double-blind, placebo-controlled Phase 3 trials (PHOENIX 1 and PHOENIX 2; e.g., NCT00267969, NCT00307437), which enrolled nearly 2,000 patients.[9] The primary efficacy endpoint in these studies was the proportion of patients achieving at least a 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at week 12. The results were compelling: across both studies, approximately 69% of patients treated with Ustekinumab achieved a PASI 75 response, compared to only about 3% of patients receiving placebo.[12] Furthermore, a head-to-head trial (ACCEPT; NCT00454584) demonstrated the superiority of Ustekinumab over the TNF inhibitor etanercept, with a significantly higher proportion of patients achieving PASI 75 at week 12.[9] Long-term data from these trials showed that the clinical benefit was well-maintained with continuous treatment for up to five years.[12]
• Pediatric Efficacy: The indication was extended to pediatric populations based on dedicated studies. In a trial involving 110 adolescents (ages 12-17), 69% of those treated with Ustekinumab achieved a Physician's Global Assessment (PGA) score of "cleared or minimal" at week 12, versus 5% for placebo.[12] A subsequent study in 44 children (ages 6-11) showed that 77% achieved this endpoint, confirming its efficacy in a younger population.[12]

Table 3: Efficacy in Pivotal Adult Plaque Psoriasis Trials

Trial / Comparison	Treatment Arms	Primary Endpoint	Result at Week 12	Source(s)
PHOENIX 1 & 2	Ustekinumab 45 mg & 90 mgPlacebo	% of patients with PASI 75 response	~69% (Ustekinumab)~3% (Placebo)	12
ACCEPT	Ustekinumab 45 mg & 90 mgEtanercept 50 mg	% of patients with PASI 75 response	Ustekinumab was significantly more effective than Etanercept	9

Psoriatic Arthritis (PsA)

• Indication: Ustekinumab is indicated for the treatment of active psoriatic arthritis in adults, either as monotherapy or in combination with methotrexate (MTX). It is also approved for active PsA in pediatric patients aged 6 years and older.[1]
• Pivotal Trials and Efficacy: Approval for PsA was based on two pivotal Phase 3, randomized, double-blind, placebo-controlled studies (PSUMMIT I and PSUMMIT II; e.g., NCT00267956) that enrolled a total of 927 patients with active PsA despite treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or DMARDs.[11] The primary endpoint was the proportion of patients achieving an American College of Rheumatology (ACR) 20 response (a 20% improvement in disease activity criteria) at week 24.
• In PSUMMIT I, an ACR20 response was achieved by 42% of patients receiving Ustekinumab 45 mg and 50% of those receiving 90 mg, compared to 23% of patients on placebo.[12]
• In PSUMMIT II, which included patients with prior exposure to TNF inhibitors, 44% of patients in both Ustekinumab dose groups achieved an ACR20 response, compared to 20% for placebo.[12]
• Significant improvements were also demonstrated in key secondary endpoints, including higher-level responses (ACR50), skin clearance (PASI 75), resolution of enthesitis (inflammation where tendons/ligaments attach to bone) and dactylitis ("sausage digits"), and physical function as measured by the Health Assessment Questionnaire–Disability Index (HAQ-DI).[11]

Table 4: Efficacy in Pivotal Psoriatic Arthritis Trials (ACR20 Response at Week 24)

Trial	Treatment Arms	% of Patients with ACR20 Response	Source(s)
PSUMMIT I	Ustekinumab 45 mgUstekinumab 90 mgPlacebo	42%50%23%	11
PSUMMIT II	Ustekinumab 45 mgUstekinumab 90 mgPlacebo	44%44%20%	11

Crohn's Disease (CD)

• Indication: Ustekinumab is indicated for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNF-α antagonist.[1] The EMA has also extended this indication to pediatric patients.[27]
• Pivotal Trials and Efficacy: The efficacy in CD was established in a comprehensive program consisting of two induction studies (UNITI-1 and UNITI-2) and one maintenance study (IM-UNITI).[12] The endpoints used in these trials reflect an increasing regulatory and clinical demand for objective measures beyond symptom control, such as endoscopic healing, which is associated with better long-term outcomes.
• Induction: In the induction studies, patients received a single, weight-based intravenous dose of Ustekinumab or placebo. At week 6, a significantly greater proportion of patients treated with Ustekinumab achieved a clinical response (defined by a significant reduction in the Crohn's Disease Activity Index) compared to placebo. Response rates were 34% for Ustekinumab versus 21% for placebo in UNITI-1 (patients who had failed TNF therapy) and 56% versus 29% in UNITI-2 (patients who had failed conventional therapy).[12]
• Maintenance: Patients who responded to the IV induction dose were then re-randomized in the IM-UNITI study to receive subcutaneous maintenance injections of Ustekinumab (90 mg every 8 or 12 weeks) or placebo. At week 44, a significantly higher percentage of patients on Ustekinumab maintenance were in clinical remission compared to those who were switched to placebo. Remission rates were 53% for the every-8-week group and 49% for the every-12-week group, versus 36% for the placebo group.[12]

Ulcerative Colitis (UC)

• Indication: Ustekinumab is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic.[1]
• Pivotal Trials and Efficacy: The approval for UC was based on the UNIFI clinical trial program, which included one Phase 3 induction study and one maintenance study (e.g., NCT02407236).[10]
• Induction: In the induction study, 961 patients received a single weight-based IV dose of Ustekinumab or placebo. The primary endpoint was clinical remission at week 8, as defined by the Mayo score. 16% of patients in the Ustekinumab group achieved clinical remission, compared to just 5% of patients in the placebo group.[12]
• Maintenance: Patients who responded to induction therapy were enrolled in the maintenance study and received subcutaneous injections of Ustekinumab or placebo. At week 44, clinical remission was maintained in 44% of patients receiving Ustekinumab every 8 weeks and 38% of those receiving it every 12 weeks, compared to 24% of patients in the placebo group.[12] These results established Ustekinumab as the first and, at the time, only approved biologic therapy for UC that targets the IL-12 and IL-23 pathways.[5]

Dosage, Administration, and Formulations

The practical application of Ustekinumab in clinical practice requires a clear understanding of its available formulations and the specific, often complex, dosing regimens tailored to each indication and patient population.

Available Formulations

Ustekinumab is supplied in sterile, preservative-free liquid solutions for parenteral administration. The available formats are designed to accommodate both intravenous loading doses and subcutaneous maintenance therapy.[14]

• Solution for Intravenous (IV) Infusion: This formulation is intended for the initial induction dose in patients with Crohn's disease and ulcerative colitis. It is supplied in single-use vials containing 130 mg of Ustekinumab in 26 mL of solution (concentration of 5 mg/mL), which must be diluted by a healthcare professional prior to infusion.[14]
• Solution for Subcutaneous (SC) Injection: This formulation is used for all doses in psoriatic diseases and for maintenance therapy in inflammatory bowel diseases. It is available in several presentations to provide dosing flexibility:
• Single-dose pre-filled syringes: 45 mg in 0.5 mL and 90 mg in 1.0 mL.[14]
• Single-dose vials: 45 mg in 0.5 mL.[14]
• Pre-filled pen / Autoinjector: Some products, including the reference product and certain biosimilars, offer a patient-controlled injector for adult use, containing 45 mg/0.5 mL or 90 mg/1.0 mL.[14]

Dosing Regimens by Indication

The dosing strategy for Ustekinumab varies significantly depending on the disease being treated, the patient's body weight, and whether the treatment is for induction or maintenance. A particularly important distinction is the bimodal administration strategy for inflammatory bowel disease (IBD). This approach utilizes a one-time, weight-based IV induction dose to rapidly achieve therapeutic drug concentrations and induce a swift clinical response in acutely ill patients. This is followed by a transition to a simpler, fixed-dose SC maintenance regimen for long-term management. This strategy is tailored to the distinct clinical needs of IBD patients, where rapid control of severe inflammation is paramount, compared to the all-subcutaneous regimen used for psoriatic diseases.

Furthermore, the emergence of biosimilars has introduced a critical nuance for pediatric care. Not all biosimilar manufacturers have developed formulations that permit the precise weight-based dosing required for children weighing less than 60 kg. For instance, some biosimilars may not be suitable for this patient group, requiring clinicians to select the originator product or a biosimilar that specifically offers the appropriate dosage forms.[15] Conversely, some biosimilar developers are actively seeking approvals for new pediatric-friendly formulations to address this gap, creating a dynamic and fragmented market where product choice can be dictated by patient weight.[16]

Table 7: Dosing and Administration Regimens for Ustekinumab by Indication

Indication	Patient Population	Induction Dose	Maintenance Dose	Source(s)
Plaque Psoriasis (PsO)	Adults	≤100 kg: 45 mg SC at weeks 0 & 4>100 kg: 90 mg SC at weeks 0 & 4	≤100 kg: 45 mg SC every 12 weeks>100 kg: 90 mg SC every 12 weeks	7
	Pediatric (≥6 yrs)	<60 kg: 0.75 mg/kg SC at weeks 0 & 460-100 kg: 45 mg SC at weeks 0 & 4>100 kg: 90 mg SC at weeks 0 & 4	<60 kg: 0.75 mg/kg SC every 12 weeks60-100 kg: 45 mg SC every 12 weeks>100 kg: 90 mg SC every 12 weeks	7
Psoriatic Arthritis (PsA)	Adults	45 mg SC at weeks 0 & 4(90 mg if >100 kg with co-existent mod-sev PsO)	45 mg SC every 12 weeks(90 mg if >100 kg with co-existent mod-sev PsO)	7
	Pediatric (≥6 yrs)	<60 kg: 0.75 mg/kg SC at weeks 0 & 4≥60 kg: 45 mg SC at weeks 0 & 4(90 mg if >100 kg with co-existent mod-sev PsO)	<60 kg: 0.75 mg/kg SC every 12 weeks≥60 kg: 45 mg SC every 12 weeks(90 mg if >100 kg with co-existent mod-sev PsO)	7
Crohn's Disease (CD) & Ulcerative Colitis (UC)	Adults	Single IV infusion based on weight:≤55 kg: 260 mg>55 kg to ≤85 kg: 390 mg>85 kg: 520 mg	90 mg SC 8 weeks after IV dose, then 90 mg SC every 8 weeks	7

Comprehensive Safety and Tolerability Profile

The safety profile of Ustekinumab has been extensively characterized through a large body of clinical trial data and over a decade of post-marketing experience. While generally well-tolerated, its use is associated with specific risks that are a direct and predictable consequence of its immunomodulatory mechanism of action. Suppressing the Th1 and Th17 pathways, which are essential for host defense against certain types of pathogens, logically leads to an increased risk of infections.

Common and Serious Adverse Events

• Overall Profile: In pivotal clinical trials, Ustekinumab was generally well-tolerated, with the majority of reported treatment-emergent adverse events being of mild to moderate severity.[1]
• Common Adverse Events: The most frequently reported adverse events (typically with an incidence of ≥3%) across all indications include nasopharyngitis (common cold), upper respiratory tract infection, headache, and fatigue. Other common events include injection site erythema, nausea, vomiting, abdominal pain, diarrhea, sinusitis, pruritus, and fever.[1]
• Serious Adverse Events:
• Infections: This is the most significant safety concern. Treatment with Ustekinumab may increase the risk of serious bacterial, mycobacterial, fungal, and viral infections that may require hospitalization. Reported serious infections include cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, diverticulitis, gastroenteritis, anal abscess, Listeria meningitis, and ophthalmic herpes zoster.[6] The risk profile reflects the known vulnerability of individuals with genetic deficiencies in the IL-12/23 pathway to disseminated infections from mycobacteria and Salmonella, translating a basic science observation into a critical clinical consideration.[13]
• Malignancies: As an immunosuppressant, Ustekinumab may increase the risk of malignancy. Malignancies have been reported in patients during clinical trials. A particular focus is on non-melanoma skin cancer (NMSC), such as squamous cell carcinoma, especially in patients with pre-existing risk factors like age over 60, a history of phototherapy (PUVA), or prolonged prior immunosuppressant treatment.[2] The safety of Ustekinumab has not been evaluated in patients with a history of malignancy.[6]
• Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported. These reactions can occur and require immediate medical attention.[7]
• Neurological Events: Rare cases of Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a neurological disorder with symptoms such as headache, seizures, confusion, and visual disturbances, have been reported in patients receiving Ustekinumab.[2]
• Hepatotoxicity: The risk of direct, idiosyncratic drug-induced liver injury with Ustekinumab appears to be low. Mild-to-moderate, transient elevations in serum aminotransferases have been observed in a small percentage of patients (0.5% to 1.4%), but these were typically self-limited and resolved even with continued therapy.[2] A more specific hepatic risk is the potential for reactivation of Hepatitis B virus (HBV) in patients who are chronic carriers. This underscores the importance of viral hepatitis screening before initiating therapy rather than just routine liver function monitoring for direct toxicity.[2]

Warnings and Precautions

The prescribing information for Ustekinumab and its biosimilars includes several key warnings and precautions to guide safe use.

• Infections: Treatment should not be initiated in patients with a clinically important, active infection until it resolves or is adequately treated. Patients should be instructed to seek medical advice if they develop signs or symptoms of an infection during or after treatment. For serious or clinically significant infections, Ustekinumab should be discontinued.[6]
• Tuberculosis (TB): All patients must be evaluated for active or latent TB infection prior to starting Ustekinumab. If latent TB is diagnosed, treatment for TB must be initiated before administering the drug. Patients should be closely monitored for signs and symptoms of active TB during and after therapy.[6]
• Malignancies: All patients, particularly the elderly and those with a history of extensive immunosuppression, should be monitored for the appearance of NMSC.[6]
• Immunizations: Live vaccines should not be administered concurrently with Ustekinumab. It is recommended that patients be brought up to date with all age-appropriate immunizations prior to initiating therapy.[7]

Contraindications

The use of Ustekinumab is contraindicated in patients with a known history of clinically significant hypersensitivity to the active substance or to any of the excipients in the formulation.[6] It is also contraindicated in patients with a clinically important, active infection.[14]

Use in Specific Populations

• Pregnancy and Lactation: There is limited data on the use of Ustekinumab in pregnant women. As a human IgG antibody, it is expected to cross the placental barrier. Its use during pregnancy should only be considered if the potential benefit justifies the potential risk to the fetus. It is also present in human milk, and a decision on whether to continue breastfeeding or therapy should be made based on a risk-benefit assessment.[7]
• Geriatric Use: Clinical studies did not show overall differences in efficacy or safety between older (≥65 years) and younger patients. However, because elderly patients have a higher background incidence of infections and malignancies, caution should be exercised when treating this population.[8]

Drug Interactions and Concomitant Therapies

The potential for drug-drug interactions with Ustekinumab is relatively low, primarily due to its specific mechanism of action and metabolic pathway. However, certain combinations, particularly with other immunomodulating agents, require careful consideration.

Interactions with Other Biologics and Immunosuppressants

The concomitant use of Ustekinumab with other biologic therapies that suppress the immune system is not recommended. Combining Ustekinumab with TNF antagonists (e.g., adalimumab, infliximab, etanercept) or other biologics such as abatacept, anakinra, or rituximab has not been studied in depth but is expected to increase the risk of serious infections without providing additional clinical benefit.[30] Therefore, such combinations should be avoided.

Effect on CYP450 Substrates

As detailed in the Clinical Pharmacology section, Ustekinumab is a monoclonal antibody that is degraded via catabolic pathways and is not metabolized by the cytochrome P450 (CYP) enzyme system.[5] Clinical studies have confirmed that it does not have a clinically significant effect on the activity of major CYP enzymes.[5] This is a key advantage, as it means that Ustekinumab is not expected to alter the metabolism of co-administered drugs that are substrates for these enzymes. Consequently, no dose adjustments are required for concomitant medications such as warfarin, cyclosporine, or others that are metabolized through CYP pathways.[8] This low potential for metabolic interactions simplifies its use in patients with multiple comorbidities who are often on complex medication regimens.

Allergen Immunotherapy

The interaction between Ustekinumab and allergen immunotherapy (allergy shots) has not been formally studied. Ustekinumab works by modulating the immune system, and it is theoretically possible that it could interfere with the efficacy of allergen immunotherapy or, conversely, increase the risk of allergic reactions associated with it. Caution is advised if these treatments are used concurrently.[7]

Regulatory and Commercial Landscape

Ustekinumab's journey from a novel investigational compound to a multi-billion-dollar blockbuster therapeutic, and now to a market facing biosimilar competition, provides a compelling case study in modern pharmaceutical development, lifecycle management, and market dynamics.

Development and Approval History

Ustekinumab was developed by Centocor, a subsidiary of Johnson & Johnson, with foundational technology from Medarex, and is marketed globally by Janssen Pharmaceuticals.[1] Its regulatory path was marked by a strategic, indication-by-indication expansion that leveraged a growing understanding of the central role of the IL-12/23 axis in various autoimmune diseases. This methodical approach allowed the drug to penetrate multiple medical specialties, including dermatology, rheumatology, and gastroenterology. The timeline of its major regulatory milestones in the US and Europe highlights this successful strategy.

Table 9: Key FDA and EMA Approval Timeline for Stelara® (Ustekinumab)

Date	Regulatory Body	Action / Indication	Source(s)
Dec 2007	FDA / EMA	Marketing applications submitted for moderate to severe plaque psoriasis	20
Sep 25, 2009	FDA	Approval for moderate to severe Plaque Psoriasis (Adults)	20
Sep 23, 2013	FDA	Approval for active Psoriatic Arthritis (Adults)	11
Nov 11, 2016	EMA	Approval for moderately to severely active Crohn's Disease (Adults)	26
Sep 26, 2016	FDA	Approval for moderately to severely active Crohn's Disease (Adults)	20
Oct 13, 2017	FDA	Approval for moderate to severe Plaque Psoriasis (Adolescents)	20
Oct 21, 2019	FDA	Approval for moderately to severely active Ulcerative Colitis (Adults)	20
Jul 30, 2020	FDA	Approval for moderate to severe Plaque Psoriasis (Pediatric ≥6 yrs)	20
Aug 1, 2022	FDA	Approval for active Psoriatic Arthritis (Pediatric ≥6 yrs)	20
Apr 2025 (est.)	EMA	Approval for moderately to severely active Crohn's Disease (Pediatric)	27

The Advent of Biosimilars

For many years, Stelara® enjoyed market exclusivity, generating billions of dollars in annual revenue for Johnson & Johnson. The expiration of its primary patents and supplementary protection certificates in the mid-2020s has ushered in a new era of competition from biosimilar products.[16] A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product.[7]

The entry of Ustekinumab biosimilars has not been a single event but rather a "wave" of launches staggered throughout 2025. This pattern is the result of complex legal negotiations and settlement agreements—often referred to as the "patent dance"—between the innovator company (J&J) and each individual biosimilar manufacturer. These agreements dictate the precise date on which each competitor can enter the market, creating a dynamic and complex transition period.[16]

As of early 2025, several biosimilars have been approved by the FDA and/or EMA and have begun to launch, including:

• Wezlana (ustekinumab-auub)
• Pyzchiva (ustekinumab-ttwe)
• Selarsdi (ustekinumab-aekn)
• Yesintek (ustekinumab-kfce)
• Otulfi (ustekinumab-aauz)
• Imuldosa (ustekinumab-srlf)
• Steqeyma (ustekinumab-stba)
• Uzpruvo (approved in the EU)

[15]

A key regulatory distinction in the US market is the concept of interchangeability. An interchangeable biosimilar has met additional FDA requirements demonstrating that it can be expected to produce the same clinical result as the reference product in any given patient and that the risk of switching between the two is no greater than using the reference product alone. This designation allows for substitution by a pharmacist without the intervention of the prescribing physician, potentially accelerating uptake.[15]

The implications of this market shift are profound. The introduction of multiple biosimilars is expected to drive significant price competition, leading to substantial cost savings for healthcare systems and payers. This, in turn, is anticipated to improve patient access to this important class of therapy. For clinicians and health systems, this new landscape will require careful management of formularies and prescribing choices, balancing factors of cost, brand familiarity, and specific product attributes like interchangeability status or the availability of pediatric-friendly formulations.

The Future of Ustekinumab: Investigational Uses and Ongoing Research

While Ustekinumab is a mature product with a well-established role in several major inflammatory diseases, research continues to explore its potential utility in other conditions and specific patient populations. This ongoing investigation represents a strategy to further define the therapeutic boundaries of IL-12/23 inhibition and potentially expand the drug's label, a key consideration in the face of increasing biosimilar competition.

Off-Label Use

Based on the shared inflammatory pathways involving IL-12 and IL-23, Ustekinumab has been used off-label by clinicians to treat a variety of other autoimmune and inflammatory conditions where these cytokines are implicated. Documented off-label uses include hidradenitis suppurativa, Behçet disease, pyoderma gangrenosum, and certain forms of arteritis, although the evidence for these uses is less robust than for its approved indications.[23]

Ongoing Clinical Trials

The clinical trial landscape for Ustekinumab remains active, with studies focused on both expanding into new therapeutic areas and generating more data within currently approved indications. These trials serve as a roadmap for the drug's future, representing strategic efforts to either find new markets or solidify its position in existing ones.

Key investigational areas include:

• Inflammatory Myopathies: A significant ongoing Phase 3 study (NCT03981744) is evaluating the efficacy and safety of Ustekinumab in adult patients with active polymyositis and dermatomyositis who have not responded adequately to standard-of-care treatments. Success in this trial would represent a major breakthrough, potentially establishing Ustekinumab as a new therapeutic option for these rare and difficult-to-treat orphan rheumatologic diseases.[31]
• Expansion in Approved Indications: Research continues to refine the use of Ustekinumab in its core indications. This includes studies in specific patient populations that were underrepresented in initial trials, such as a Phase 4 study in Chinese patients with Crohn's disease (NCT05029921) to provide region-specific efficacy and safety data.[32] Another key area is the expansion into younger age groups, as exemplified by an ongoing Phase 3 trial evaluating Ustekinumab in pediatric patients with moderately to severely active ulcerative colitis (NCT04630028).[33]
• Other Autoimmune Diseases: While some early explorations did not prove successful (e.g., a trial in multiple sclerosis found it to be ineffective [1]), earlier phase trials have investigated its potential in conditions like systemic lupus erythematosus (SLE), sarcoidosis, and axial spondyloarthritis.[3] The results of these studies help to define the boundaries of where IL-12/23 inhibition is a viable therapeutic strategy.

Expert Analysis and Concluding Remarks

Ustekinumab holds a pivotal place in the history of immunology and therapeutic medicine. As the first agent to successfully target the IL-12/23 pathway, it not only provided a powerful new treatment option for millions of patients but also validated a novel biological target, paving the way for a subsequent generation of more selective therapies. This concluding analysis synthesizes its clinical positioning, key considerations for practice, and its likely future trajectory in an evolving healthcare landscape.

Clinical Positioning and Therapeutic Niche

Ustekinumab occupies a unique and important niche in the treatment algorithms for chronic inflammatory diseases. Its position relative to other biologic classes is nuanced and indication-specific.

• In plaque psoriasis and psoriatic arthritis, it is often considered a first-line biologic option, valued for its robust efficacy, convenient dosing schedule, and a safety profile that differs from that of the older TNF-alpha inhibitors.
• In inflammatory bowel disease (Crohn's disease and ulcerative colitis), it is typically positioned as a second-line biologic, often used after patients have failed or become intolerant to one or more TNF antagonists. Its distinct mechanism of action provides an effective alternative for this difficult-to-treat population.

Compared to its direct competitors, Ustekinumab sits in a unique mechanistic space. It offers a more targeted approach than the broad immunosuppression of TNF-alpha inhibitors. At the same time, it is less selective than the newer IL-23p19 inhibitors (e.g., risankizumab, guselkumab) and IL-17 inhibitors (e.g., secukinumab, ixekizumab). This dual IL-12/23 inhibition is both its defining feature and a point of clinical debate. While some argue that the added IL-12 blockade may contribute to certain infection risks without adding significant efficacy in some diseases, others value its long-established track record and efficacy across a broad spectrum of conditions, from skin to joints to gut.

Key Considerations for Clinicians

For practicing clinicians, the effective use of Ustekinumab requires several key considerations:

1. Patient Selection: The choice of Ustekinumab should be guided by the specific indication, prior treatment history (especially response to TNF inhibitors in IBD), and patient comorbidities.
2. Pre-treatment Screening: Mandatory screening for latent and active tuberculosis (TB) and screening for Hepatitis B virus (HBV) are critical risk mitigation steps that must be performed before initiating therapy.
3. Long-Term Monitoring: Vigilance for signs and symptoms of infection throughout the course of treatment is paramount. Regular skin examinations to monitor for non-melanoma skin cancer are also recommended, particularly in high-risk patients.
4. Navigating the Biosimilar Landscape: The availability of multiple biosimilars requires clinicians to be aware of local formulary preferences, payer coverage, and any differences in approved indications or available formulations (e.g., for pediatric weight-based dosing). Understanding the concept of interchangeability will be increasingly important for managing prescriptions and patient expectations.

Future Trajectory

The future of Ustekinumab will be shaped by two opposing forces: the erosion of its market share by lower-cost biosimilars and the enduring value of its decade-plus legacy of proven safety and efficacy. It will likely remain a cornerstone therapy for the foreseeable future, particularly as biosimilar competition drives down its cost and increases its accessibility. However, its role as a first-choice agent may be challenged in some areas, especially psoriasis, by the newer, more selective IL-23 and IL-17 inhibitors as they accumulate more long-term data.

Ultimately, Ustekinumab's value proposition will increasingly hinge on a compelling balance between cost-effectiveness (driven by the biosimilar market) and the clinical confidence that comes with a well-understood, reliable, and broadly effective therapy. Its story is a testament to the power of targeted immunology and a paradigm for successful drug development in the modern era.

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