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Review

Ustekinumab Biosimilars

by
Elena Carmona-Rocha
1,2,3 and
Lluís Puig
1,2,3,*
1
Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Carrer de Sant Quintí, 89, 08041 Barcelona, Spain
2
Institut de Recerca Sant Pau, Carrer de Sant Quintí, 77, 08041 Barcelona, Spain
3
Unitat Docent Hospital Universitari Sant Pau, Facultat de Medicina, Universitat Autònoma de Barcelona, Carrer de Sant Antoni Maria Claret, 167, 08041 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Biologics 2024, 4(4), 407-422; https://doi.org/10.3390/biologics4040025
Submission received: 22 September 2024 / Revised: 28 October 2024 / Accepted: 31 October 2024 / Published: 13 November 2024
(This article belongs to the Section Monoclonal Antibodies)
Browse Figure
Figure 1
<p>Ustekinumab mechanism of action. Ustekinumab binds to the p40 subunit of interleukin (IL)-12 and IL-23, blocking their interaction with the IL-12Rβ1 receptor on the cell surface of natural killer cells and T cells. This inhibits IL-12- and IL-23-driven cell signaling, activation, and cytokine production.</p> ">
Versions Notes

Abstract

:
Ustekinumab is a fully human IgG1k monoclonal antibody that binds with high affinity and specificity to the p40 subunit of interleukins (IL-) 12 and 23, inhibiting their activity by preventing binding to their receptors. The European extension of the patent (Supplementary Protection Certificate) of ustekinumab expired on 20 July 2024. Biosimilar alternatives to ustekinumab are now an additional option for treating patients. The efficacy data for this drug in moderate-to-severe psoriasis obtained both from clinical trials and indirect comparisons through meta-analyses, are superior to those of etanercept and adalimumab, and its safety profile is more favorable than that of tumor necrosis factor (TNF) inhibitors. Several ustekinumab biosimilars have already been approved by regulatory agencies: between October 2023 and October 2024, Wezlana® (Amgen ABP 654), Uzpruvo® (Alvotech AVT04) and Pyzchiva® (Samsung/Bioepis SB17) have been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). SteQeyma® (Celltrion Healthcare CT-P43) was approved by the EMA in August 2024. Otulfi® (Fresenius Kabi/Formycon) was approved by the FDA in October 2024. Several other potential biosimilar candidates are under development, including BAT2206 (Bio-Thera), DMB-3115 (Dong-A ST), QX001S (Qyuns Therapeutic), BFI-751 (BioFactura), NeuLara (Neuclone), ONS3040 (Oncobiologics), and BOW090 (Epirus Biopharmaceuticals). In most cases, these monoclonal antibodies are expressed in cell lines (e.g., Chinese Hamster Ovary, CHO) different from those used for the originator (Sp2/0 spleen cell murine myeloma); of note, the cell line of origin is not a requirement for biosimilarity in the totality-of-evidence comparison exercise and may facilitate the production and reduce the immunogenicity of biosimilars originated in CHO cultures. This narrative review summarizes the available data on characteristics of the full comparability exercises and comparative clinical trials of these drugs.

1. Introduction

Psoriasis is a chronic immune-mediated inflammatory skin condition affecting approximately 1–3% of the global population [1]. The importance of the interleukin (IL) 12/23 pathway in the pathogenesis of psoriasis has been widely documented [2,3,4]. This inflammatory pathway is known to be overexpressed in psoriasis, driving the activation of Th1/Th17 lymphocytes, and promoting inflammation and keratinocyte proliferation [5].
Biologics have revolutionized the management of chronic inflammatory disorders like psoriasis. However, their high costs of acquisition have significantly increased healthcare expenditures and limited broader accessibility to biologic treatment [6]. To enhance access, regulatory agencies such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and others worldwide have established streamlined development and approval pathways for biosimilars—biologic therapies that closely resemble an already approved reference product (RP) [7]. US and EU guidelines advocate for a stepwise totality-of-evidence (TOE) strategy, which involves compiling data from comparative analytical, non-clinical, and clinical studies [8]. The goal of this TOE approach is to demonstrate that the biosimilar candidate matches the RP in terms of safety and efficacy, with no clinically significant differences. The abbreviated regulatory pathway for biosimilars minimizes the need for unnecessary animal and human testing. Instead, biosimilar development primarily emphasizes preclinical analytical evaluation and focuses on pharmacokinetic (PK) and pharmacodynamic studies. To gain approval, biosimilars must undergo thorough physicochemical and biological assessments to verify molecular similarity, using both in vivo and in vitro tests. This process is followed by a phase I trial to confirm PK equivalence, and a phase III trial to validate clinical biosimilarity [9,10].
Most biosimilars developed for the treatment of psoriasis and other immune-mediated inflammatory diseases correspond to tumor necrosis factor (TNF) inhibitors [11,12,13]. While TNF inhibitors remain important therapies for psoriasis, other biologics with improved safety and efficacy profiles are currently available. Among the first of these newer treatments is the interleukin 12/23 inhibitor reference ustekinumab, which is approved for the treatment of psoriasis, psoriatic arthritis, and inflammatory bowel disease [14,15]. Ustekinumab offers several advantages over TNF inhibitors, including less frequent dosing and a more favorable safety profile [16].
The European extension of the Stelara® patent (Supplementary Protection Certificate) expired on 20 July 2024. As the exclusivity period for ustekinumab approached expiration, interest in ustekinumab biosimilars as safe and effective alternatives grew, and biosimilar alternatives to ustekinumab are now an additional option for treating patients.
This narrative review will provide an overview of ustekinumab biosimilars, specifically focusing on their clinical outcomes and the regulatory status in the EU and US, as well as those biosimilars currently in development.

2. Ustekinumab and Proposed Biosimilars

2.1. Ustekinumab

2.1.1. Generation

Ustekinumab is a human IgG1 kappa (κ) monoclonal antibody (mAb) originally developed by Centocor Research and Development, a branch of Johnson and Johnson Pharmaceutical Research and Development, LLC, based in Malvern, PA, USA. Its development involved the use of human immunoglobulin transgenic mice from GenPharm, originally based in Mountain View, CA, USA (later acquired by Medarex, headquartered in Princeton, NJ, USA, and now part of Bristol-Myers Squibb, headquartered in New York, NY, USA).
Four targeted genetic modifications replaced the murine immunoglobulin loci with human antibody transgenes, resulting in a mouse strain capable of producing human antibodies upon immunization with any antigen [17,18]. This human Ig transgenic mouse technology facilitated the generation of diverse, high-affinity, and specific monoclonal antibodies (mAbs). To develop human anti-human IL-12 therapeutic mAbs, the transgenic mice were immunized with human IL-12 antigen [19]. Mice with high serum levels of anti-IL-12 antibodies were selected to undergo hybridoma fusion, in which splenocytes containing B cells that produce antibodies were fused with cells from an immortalized cell line [19]. Then, the resulting cells were cultured, and IL-12-specific, growth-positive hybridomas were further subcloned [19]. Antibodies were evaluated via binding and functional assays with human T cells, focusing on those that specifically attached to IL-12 and blocked IL-12-induced responses [19]. A monoclonal hybridoma clone producing a human IgG1κ antibody with the ability to bind and neutralize human and non-human primate IL-12 was identified [19]. Initially called 12B75, then CNTO1275, and later ustekinumab, this antibody was selected for further development due to its exceptional IL-12 binding and neutralization properties, but its IL-23 inhibitory action was later identified as much more relevant from a therapeutic perspective.

2.1.2. Mechanism of Action

Ustekinumab selectively binds to the p40 subunit of IL-12 and IL-23, preventing these cytokines from interacting with the IL-12Rβ1 receptor chain in the receptor complexes IL-12 (IL-12Rβ1/β2) and IL-23 (IL-12Rβ1/23R) found on NK and T cells (Figure 1). By preventing the coupling of IL-12 and IL-23 to the IL-12Rβ1 receptor, ustekinumab effectively neutralizes IL-12- and IL-23-mediated cell signaling, activation, and cytokine production [19,20].
IL-12 is a heterodimeric cytokine composed of two different subunits, p40 and p35, which were named after their estimated molecular weights. IL-12 interacts with a heterodimeric receptor complex formed by the IL-12 receptor (IL-12R) β1 and IL-12Rβ2 chains, which are expressed on the surface of T cells and NK cells [21]. IL-12-mediated signaling involves intracellular phosphorylation of the signal transducers and activators of transcription (STAT)4 and STAT6 proteins, leading to functional responses such as the expression of cell surface molecules, enhancement of NK cell lytic activity, and IFNγ cytokine production [19].
The p40 protein subunit of IL-12 also combines with a p19 subunit to form IL-23 [22]. Since IL-23 shares the IL-12p40 subunit, ustekinumab is able to bind to and neutralize human IL-23. IL-23 also uses the IL-12Rβ1 chain to bind to the surface of effector cells. The association of the IL-23p19 subunit with the second component of the IL-23 receptor complex (IL-23R) triggers IL-23-specific intracellular signaling, including the phosphorylation of STAT3 and the activation of lymphocytes, leading to the expression of the RORγT transcription factor and stabilization of a T17 phenotype with the production of cytokines such as IL-17A [23].

2.1.3. Indications and Efficacy Data

Stelara® (ustekinumab RP) was first approved in 2009 for the treatment of moderate-to-severe plaque psoriasis in adults and subsequently gained approval for psoriatic arthritis (2013), Crohn’s disease (2016), ulcerative colitis (2019), and pediatric psoriasis (2020) (Table 1).
The efficacy data of ustekinumab have been gathered from both clinical trials and indirect comparisons. The PHOENIX 1 and PHOENIX 2 clinical trials evaluated the efficacy and safety of ustekinumab in patients with moderate-to-severe plaque psoriasis and demonstrated significant improvement in psoriasis symptoms, with 66–76% of patients showing a minimum of 75% reduction in Psoriasis Area and Severity Index (PASI 75) at week 12 [24,25]. Stable clinical response and safety profile were observed through 5 years of continuous treatment [26]. In real-world clinical practice, approximately 80% of patients maintain a PASI75 response at 2 years [27].
Compared to other biologics approved for psoriasis treatment, ustekinumab is less effective than newer anti-IL-17 and anti-IL-23 agents [28]. However, it has shown greater efficacy than etanercept in a phase III head-to-head study (ACCEPT trial) [29]. Indirect evidence from multiple meta-analyses suggests that ustekinumab demonstrates superior efficacy compared to etanercept and adalimumab with a more favorable safety profile than TNF inhibitors [30,31]. Ustekinumab is one of the biologic therapies with the lowest rate of adverse events, demonstrating a very low risk of serious infections and malignancies, with a safety profile similar to anti-IL-23 drugs [28].
Table 1. Approved indications of ustekinumab.
Table 1. Approved indications of ustekinumab.
Ustekinumab Approved IndicationsClinical TrialsApproval YearReferences
Adults with moderate to severe psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills)PHOENIX 1 (NCT00267969) and PHOENIX 2 (NCT00307437)2009Leonardi et al. [24]
Papp et al. [25]
Children 6 years and older with moderate to severe psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills)CADMUS (NCT01090427) and CADMUS Jr (NCT02698475)2017 (adolescents 12 years and older)
2020 (children 6 years and older)		Landells et al. [32]
Philipp et al. [33]
Adults with active psoriatic arthritisPSUMMIT I (NCT01009086) and PSUMMIT II (NCT01077362)2013McInnes et al. [34]
Ritchlin et al. [35]
Children 6 years and older with active psoriatic arthritisExtrapolation of the efficacy and safety data from multiple phase III studies in adult and pediatric patients with psoriasis (PSTELLAR, CADMUS, and CADMUS Jr) and adult patients with active psoriatic arthritis (PSUMMIT I and II).2022-
Adults 18 years and older with moderately to severely active Crohn’s diseaseUNITI-1 (NCT01369329), UNITI-2 (NCT01369342) and IM-UNITI (NCT01369355)2016Feagan et al. [36]
Adults 18 years and older with moderately to severely active ulcerative colitisUNIFI (NCT02407236)2019Sands et al. [37]
Additionally, since its mechanism of action inhibits pathways involved in various inflammatory dermatoses, ustekinumab has been extensively used off-label with favorable results, for instance in patients with hidradenitis suppurativa or pityriasis rubra pilaris, among others (Table 1). There are currently two phase III trials evaluating the efficacy and safety of ustekinumab for the treatment of systemic lupus erythematosus (NCT03517722, NCT04060888).

2.2. ABP 654 (Wezlana® or Wezenla®)

Amgen’s ustekinumab biosimilar is called Wezenla® in Europe and Wezlana® in Canada and the US.

2.2.1. Pharmacology

ABP 654 is an ustekinumab biosimilar developed by Amgen, Thousand Oaks, CA, USA. While ustekinumab RP is produced using an Sp2/0 cell line system, ABP 654 is manufactured in a glyco-engineered Chinese hamster ovary (CHO) cell line, specifically designed to increase its biosimilarity to ustekinumab RP [38]. ABP 654 has the same dosage forms and presentations as ustekinumab RP and shares an identical amino acid sequence, with demonstrated comparability in structure, function, purity, and potency [38,39].
A randomized study by Chow et al. examined the PKs, safety, and immunogenicity of ABP 654 compared to the United States (US) and European Union (EU)-sourced ustekinumab in 238 healthy subjects [39]. The PK results showed high similarity across all groups, with peak concentrations around 6–8 days post-treatment and a half-life between 21.9 and 23.9 days, consistent with ustekinumab’s known profile [40]. The 90% confidence intervals (CIs) for the geometric mean ratios of the primary PK endpoints (area under the concentration-time curve from time 0 extrapolated to infinity [AUCinf] and maximum observed serum concentration [Cmax]) were within the prespecified margin of 0.8–1.25 [39], indicating no meaningful differences between ABP 654 and RP. The immunogenicity results showed a lower incidence of anti-drug antibodies (ADAs) in the ABP 654 group (15.4%) compared to the EU (36.3%) and US (38.0%) ustekinumab groups, without affecting drug exposure. Adverse events, mostly mild to moderate (Common Terminology Criteria for Adverse Events, or CTCAE grade 1 or 2), occurred in 28.2% of ABP 654 subjects, 22.8% in the US RP group, and 36.3% in the EU RP group, aligning with ustekinumab’s safety profile [39].
A second randomized, double-blind study confirmed similar findings, with consistent PK, safety, tolerability, and immunogenicity results across ABP 654, US, and EU ustekinumab groups [39].

2.2.2. Clinical Efficacy and Safety

A multicenter, randomized, double-blinded, phase III trial (NCT04607980) evaluated the efficacy and safety of ABP 654 compared to ustekinumab RP in 563 adult patients with moderate-to-severe plaque psoriasis. The primary endpoint was the mean difference in PASI percent improvement from baseline to week 12. The results confirmed equivalence, with the mean percent change in PASI score being 89.1% for both the ABP 654 and ustekinumab groups, and with CI 95% (−3.16 to 3.43) falling within the predefined equivalence margins of (−15, +15). PASI75 response at week 12 was achieved by 69.8% and 70.2% of patients treated with ABP 654 and ustekinumab, respectively.
At week 28, patients in the ustekinumab group who achieved at least PASI75 response were re-randomized in a blinded fashion to either continue on ustekinumab or switch to ABP 654. The response was maintained to week 52, with PASI75 responses being held by 89.5%, 92.3%, and 92.2% of participants in the ABP 654/ABP 654 group, ustekinumab/ABP 654 group, and ustekinumab/ustekinumab group, respectively.
Treatment-emergent adverse events (TEAEs) were found equally in the three groups after week 28, including mostly infections. Only 2.6% of the patients in the ustekinumab/ustekinumab group presented with serious TEAEs, compared to less than 1% in the other groups.
In terms of immunogenicity, binding ADAs were identified in 18.6% of patients receiving ABP 654 and 37.1% of those receiving ustekinumab RP. Among ADA-positive individuals, neutralizing ADAs were found in 8.6% of the ABP 654 group and 17.9% of the ustekinumab group.

2.2.3. Switching from Ustekinumab RP

Another phase III, multicenter, randomized, double-blinded study evaluated the PKs, efficacy, and safety of multiple switches between ustekinumab and ABP 654 in 494 subjects with moderate-to-severe plaque psoriasis (NCT04761627). Initially, all participants received ustekinumab RP. At week 28, eligible participants with a PASI 50 response or better were randomized either to receive ustekinumab RP (continued-use group) or to receive ABP 654 at week 28, ustekinumab RP at week 40, and ABP 654 at week 52 (switching group). Primary outcome measures included area under the curve over the dosing interval (AUCtau) between week 52 and week 64, and Cmax between week 52 and week 64. PK similarity was confirmed based on the 90% CIs for the primary endpoints falling within the predefined margin of 0.8–1.25.
On 31 October 2023, Wezlana® (ustekinumab-auub) was approved by the FDA as a biosimilar to and interchangeable with Stelara®, with the same indications as ustekinumab RP; this was the first approval for a ustekinumab biosimilar. Subsequently, on April 2024, the Committee for Medicinal Products for Human Use of the EMA recommended marketing authorization for Wezenla®.

2.3. AVT04 (Uzpruvo® or Selarsdi®)

Alvotech’s ustekinumab biosimilar is called Uzpruvo® in Europe, Japan and Canada, and Selarsdi® (ustekinumab-aekn) in the US.

2.3.1. Pharmacology

AVT04 is produced in a murine myeloma Sp2/0 line. AVT04 exhibits comparable physicochemical and functional properties to reference ustekinumab [41]. PK equivalence between AVT04 and both EU and US-sourced ustekinumab was established in a randomized, multicenter, double-blind, phase I trial involving 298 healthy adults [42]. The 90% CIs for the geometric mean ratios of key PK parameters, including AUCinf and Cmax, as well as the secondary endpoint of AUC from time zero to the last quantifiable concentration (AUClast), fell within the predefined equivalence range of 0.8–1.25 after normalization for protein content. Other PK measures, such as median time to Cmax, clearance, volume of distribution, and terminal half-life, were also similar between AVT04 and the ustekinumab RP groups.
Moreover, in another phase III trial comparing AVT04 and ustekinumab RP in patients with moderate-to-severe chronic plaque psoriasis, no clinically significant differences in mean serum trough concentrations were observed between AVT04 and ustekinumab through week 52 [43].

2.3.2. Clinical Efficacy and Safety

A randomized, double-blind, multicenter phase III trial evaluated the efficacy, safety, tolerability, and immunogenicity between AVT04 and ustekinumab RP in adult patients with moderate-to-severe plaque psoriasis (NCT04930042) [43]. The study included 581 patients and was conducted in two distinct phases: the first phase (weeks 1–15) focused on evaluating primary efficacy, while the second phase (weeks 16–52) aimed to assess long-term efficacy and safety. The main objective was to assess the percentage change in PASI from baseline to week 12. Patients were randomly assigned to receive subcutaneous injections of either AVT04 or ustekinumab RP. By week 16, those who had been treated with AVT04 continued with the same treatment, while patients initially receiving ustekinumab were re-randomized to either switch to AVT04 or maintain treatment with ustekinumab RP.
AVT04 demonstrated comparable efficacy to ustekinumab RP in terms of percentage improvement in PASI at week 12. The percentage PASI improvement for AVT04 vs. ustekinumab RP was 87.3% vs. 86.8%, respectively, and the least squares mean (LSM) difference in PASI improvement between the two products was 0.4%, with both 90% and 95% CIs falling within the predefined equivalence margins, confirming therapeutic equivalence [43]. Secondary endpoints such as proportions of patients achieving PASI50, 75, 90, and 100 responses, the proportion of patients achieving a static Physician’s Global Assessment (sPGA) response of ‘clear’ or ‘almost clear’, the improvement in Dermatology Life Quality Index (DLQI) score, and the reduction in affected body surface area (BSA), were also similar in both groups. Efficacy in terms of PASI improvement rates and secondary endpoints were maintained throughout the switching period (weeks 16–52), irrespective of whether patients continued on AVT04, transitioned from ustekinumab RP to AVT04, or remained on ustekinumab RP [43].
AVT04 showed a similar safety and tolerability profile compared to ustekinumab RP, with TEAEs being reported in 34.5% and 33.6% of the participants, respectively. Most TEAEs were mild or moderate and the most frequently reported TEAEs were infections and infestations. Safety profiles were also comparable across all three treatment groups during the switching period (weeks 16–52).
In terms of immunogenicity, binding ADAs were identified in 25.4% of patients receiving AVT04 and 48.2% of those receiving ustekinumab RP. Among ADA-positive individuals, neutralizing ADAs were found in 26.5% of the AVT04 group and 31.0% of the ustekinumab group. The presence of ADAs did not seem to affect the therapeutic efficacy of AVT04.
Based on these results, Uzpruvo® became the first ustekinumab biosimilar approved in Europe after the European Medicines Agency (EMA) granted marketing authorization (to STADA) on January 2024, with the same indications as Stelara®. It has also been approved in Japan, Canada, and more recently in the US; FDA approval was received in April 2024 under the name of Selarsdi® (ustekinumab-aekn), marketed by Teva Pharmaceuticals, headquartered in Petah Tikva, Israel. The FDA has only approved Selarsdi® for the treatment of psoriasis and psoriatic arthriti and has not designated it as interchangeable because its approval only covers the subcutaneous formulation, not the intravenous vial formulation. At the time of writing the only presentations available in the American market are 45 mg/0.5 mL or 90 mg/mL solution in single-dose prefilled syringes.

2.4. SB17 (Pyzchiva®, Eksunbi®)

2.4.1. Pharmacology

SB17 is a fully human IgG1κ ustekinumab biosimilar developed by Samsung Bioepis (Incheon, Republic of Korea), produced in a recombinant CHO cell line, and physicochemically similar to ustekinumab RP.
A randomized, double-blind, phase I study (NCT04772274) compared PK, safety, tolerability, and immunogenicity of SB17 with US and EU ustekinumab RP in 201 healthy subjects [44]. The primary PK endpoints were AUCinf and Cmax. Equivalence for the primary PK endpoints was determined since the 90% CIs for the geometric mean ratios of the compared groups fell within the predefined equivalence margin of 0.80–1.25. Regarding immunogenicity, overall incidences of post-dose ADAs were comparable (26.9% in the SB17 group and 34.3% in both the EU-ustekinumab and US-ustekinumab groups). The proportions of subjects experiencing TEAEs were also similar across the groups, with rates of 68.7% for SB17, 58.2% for EU-ustekinumab, and 65.7% for US-ustekinumab. Importantly, no deaths, serious adverse events, severe TEAEs, or discontinuations due to TEAEs related to the study products occurred. The three ustekinumab products were overall well tolerated and demonstrated similar safety profiles.

2.4.2. Clinical Efficacy and Safety

A randomized, double-blind, multicenter phase III study was conducted to evaluate the efficacy, safety, PKs, and immunogenicity of SB17 compared to ustekinumab RP in adult subjects with moderate-to-severe plaque psoriasis (NCT04967508) [45]. Patients were randomized to receive subcutaneous SB17 or ustekinumab RP at weeks 0, 4, and every 12 weeks. The primary endpoint was the percentage change from baseline in PASI at week 12 with an equivalence margin of [−15%, 15%]. Other secondary endpoints were measured through week 28.
A total of 503 subjects were included (249 subjects under SB17 and 254 under ustekinumab). At week 12, the adjusted difference in PASI change from baseline was 0.6% (95% CI: −3.780 to 2.579), remaining within the predefined equivalence margin. Comparable outcomes were also observed for the PGA and DLQI. TEAEs occurred at similar rates across both groups (48.2% and 48.8% in the SB17 and ustekinumab RP groups, respectively). Most were mild to moderate and deemed not linked to the investigational products. The overall incidence of ADAs up to week 28 was 13.3% for SB17, lower than for ustekinumab (39.4%). Similarly, neutralizing antibodies up to week 28 were found in 13.7% of subjects in the SB17 group, a lower rate than in the ustekinumab group (35.4%).
These results indicate that SB17 shows comparable efficacy, safety, and PKs to ustekinumab RP, along with reduced immunogenicity, through week 28 in patients with moderate-to-severe psoriasis.
In April 2024, Samsung Bioepis announced that the European Commission had granted marketing authorization for Pyzchiva® (SB17, ustekinumab-ttwe) for the treatment of plaque psoriasis, psoriatic arthritis, ulcerative colitis, and Crohn’s disease, following a positive opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP) in February. Later, in July 2024, Pyzchiva®, marketed by Sandoz (Holzkirchen, Germany), received approval from the U.S. FDA as an interchangeable ustekinumab biosimilar. Additionally, in July 2024, Samsung Bioepis received a positive opinion from the CHMP for another biosimilar, Eksunbi®.

2.5. CT-P43 (SteQeyma®)

CT-P43 is a fully human IgG1κ ustekinumab biosimilar developed by Celltrion (Incheon, Republic of Korea). It is obtained from a recombinant CHO cell line cultured by continuous perfusion and is physicochemically similar to ustekinumab RP.
A phase I, randomized, double-blind, single-dose study evaluated the PK, safety, and immunogenicity of CT-P43 compared to US and EU ustekinumab in 271 male subjects (NCT04428814). Equivalent efficacy was subsequently demonstrated in a randomized, active-controlled, double-blind, phase III trial including 509 adult patients with moderate-to-severe psoriasis (NCT04673786) [46]. Subjects were initially randomized to receive either CT-P43 (n = 256) or ustekinumab RP (n = 254) at week 0 and week 4. At week 16, patients receiving ustekinumab RP were re-randomized to continue ustekinumab or switch to CT-P43. The primary endpoint was the average percentage improvement in PASI score from baseline at week 12. Equivalence was confirmed if the confidence intervals for the estimated treatment difference fell within the specified equivalence margins: ±10% [90% CI; modified intent-to-treat population; FDA method] or ±15% [95% CI; full analysis population; EMA method]. Further assessments of efficacy, safety, pharmacokinetics, and immunogenicity were conducted through week 52.
The mean percentage improvement in PASI score at week 12 was 77.93% for CT-P43 and 75.89% for ustekinumab RP under the FDA criteria. According to the EMA criteria, the respective values were 78.26% and 77.33%. Equivalence was established based on both sets of assumptions. Additionally, other efficacy measures, along with safety, PK, and immunogenicity results, were consistent across treatment groups, even after transitioning from ustekinumab to CT-P43.
After receiving a positive opinion from the EMA’s Committee for Medicinal Products for Human Use in June 2024, the European Commission has recently approved the use of SteQeyma® as an ustekinumab biosimilar in August 2024.
As a final note, Rani Therapeutics has recently announced a phase I clinical trial to evaluate the safety and tolerability of RT-111 (RaniPill®), an orally administered capsule containing CT-P43 (NCT05890118). RT-111 has already shown comparable bioavailability to subcutaneous injection in preclinical testing in animal models.

2.6. BAT2206

BAT2206 is a proposed ustekinumab biosimilar developed by Bio-Thera Solutions, Ltd. (Guangzhou, China). Biosimilarity of BAT2206 and ustekinumab RP in PK profiles, safety, and immunogenicity was evaluated in a double-blinded, randomized, single-dose, parallel-group, phase I trial (NCT04371185) [47]. In total, 270 healthy male subjects were included and received a single subcutaneous injection of either BAT2206 or ustekinumab RP (US or EU).
The results showed that the 90% CIs of the geometric mean ratios for primary PK parameters (AUCinf and Cmax) among BAT2206 and ustekinumab groups were all within the predefined equivalent interval of 0.8–1.25, supporting the bioequivalence between the groups. Incidence of TEAEs was similar across the groups, with most cases being mild or moderate in severity grading.
ADAs were detected in 26.7% of subjects in the BAT2206 group, a higher rate than in the EU and US ustekinumab groups (14.8% and 18.9%, respectively), although the incidence of neutralizing ADAs was similar among the three groups.
A multicenter, randomized, double-blind, parallel-arm, phase III trial was subsequently designed to compare the efficacy, safety, immunogenicity, and PK of BAT2206 with ustekinumab in 556 patients with moderate-to-severe plaque psoriasis (NCT04728360). Bio-Thera has already announced positive outcomes from this phase III trial, although results are not yet posted on ClinicalTrials.gov (accessed on 15 October 2024).
The FDA has accepted Bio-Thera’s biologics license application for BAT2206 as an interchangeable biosimilar to the reference product Stelara®, while the EMA has accepted the marketing authorization application for BAT2206 as a biosimilar to the reference product Stelara®, but the respective final approvals are still pending. Furthermore, in June 2024, BAT2206 received approval in Brazil as a monotherapy or in conjunction with methotrexate to treat active psoriatic arthritis in adults.

2.7. DMB-3115

DMB-3115 is a proposed ustekinumab biosimilar developed by Dong-A Socio Holdings (Seoul, Republic of Korea) and Meiji Seika Pharma (Tokyo, Japan). In May 2021, the company announced positive results of a randomized, double-blind, three-arm, single-dose phase I study comparing the PK, safety, and tolerability of DMB-3115 with ustekinumab RP (US and EU-sourced Stelara®) in 296 healthy volunteers. After that, a randomized, double-blind, multicentric, parallel-group phase III study was conducted to compare the efficacy, safety, and immunogenicity of DMB-3115 and ustekinumab RP in patients with moderate-to-severe plaque psoriasis (Opportuniti, NCT04785326). In total, 598 subjects were included. Patients were initially randomized to receive either DMB-3115 or ustekinumab RP. At week 28, patients who received ustekinumab RP at the beginning of the study were re-randomized in a 1:1 ratio to either continue on ustekinumab RP or transition to DMB-3115. The primary endpoint was the percentage improvement in PASI from baseline. The results showed comparable efficacy between DMB-3115 and ustekinumab RP. Specifically, the least squares mean percentage change in PASI from baseline to week 12 was 87.59% for the DMB-3115 group and 87.89% for the ustekinumab RP group. The difference in LSM percent change between the two treatments was within the predefined equivalence margin of ±10%. The overall incidence of TEAEs was similar between the two groups (24.41% and 30.10% in the DMB-3115 and ustekinumab RP groups, respectively). The most common TEAEs included nasopharyngitis, upper respiratory tract infection, and headache, occurring at comparable rates between the two treatments.
Overall, DMB-3115 demonstrated equivalent efficacy, safety, and immunogenicity to ustekinumab RP, supporting its potential as a biosimilar treatment for psoriasis. In January 2024, the FDA accepted the biologics license application for the proposed biosimilar DMB-3115; similarly, the EMA recently accepted the marketing authorization application in July 2024, with final approval pending at the time of writing.

2.8. FYB202 (Fymskina®, Otulfi®)

FYB202 is a proposed ustekinumab biosimilar developed by Formycon AG (Planegg-Martinsried, Germany). After the successful conclusion of the extended phase I clinical study comparing the PK of FYB202 and ustekinumab RP, a randomized, double-blind, multicenter phase III trial (VESPUCCI study; NCT04595409) achieved the primary endpoint of the percentage improvement in PASI with respect to baseline at 12 weeks, demonstrating the comparable efficacy, safety, and immunogenicity of FYB202 and the reference drug in patients with moderate-to-severe plaque psoriasis.
In February 2023, Formycon concluded a license agreement with Fresenius Kabi AG (Bad Homburg, Germany) for the global commercialization of FYB202. The EMA accepted the Marketing Authorization Application for FYB202 in September 2023 and a positive opinion from the EMA’s Committee for Medicinal Products for Human Use was announced in July 2024, while the FDA recently declared its approval as biosimilar to and interchangeable with Stelara® in October 2024.

2.9. QX001S

QX001S is a proposed ustekinumab biosimilar developed by Qyuns Therapeutics (Guangzhou, China). A randomized, double-blind, single-dose phase I trial was conducted to assess the PK, tolerance, and variability of QX001S in a cohort of healthy Chinese men [48]. In total, 178 participants were included and received either 45 mg of QX001S or ustekinumab RP.
The results demonstrated that QX001S exhibited a PK profile closely aligned with ustekinumab RP. The 90% CIs for the geometric mean ratios of key PK parameters (Cmax, AUClast, and AUCinf) fell within the predefined bioequivalence range of 0.8–1.25. Despite notable inter-subject variability (32.0% to 33.5%), the biosimilarity between the two drugs was affirmed. ADAs were detected in 19.1% of QX001S recipients and 40.9% of ustekinumab recipients, though these did not impact the bioequivalence outcomes. Adverse reactions were comparable between the groups, with upper respiratory infections and elevated alanine aminotransferase levels being the most frequently reported. Overall, this study confirmed that QX001S is pharmacokinetically equivalent to ustekinumab, despite the high variability observed among subjects.
Qyuns Therapeutics has reported positive outcomes of a phase III clinical trial evaluating the clinical equivalence of QX001S to ustekinumab in terms of efficacy, safety, immunogenicity, and PK profile in psoriasis patients, although results have not been published. Zhongmei Huadong (Hangzhou, China), a subsidiary of Huadong Medicine and commercialization partner for QX001S, submitted a biologics license application in China in July 2023, which was accepted by the National Medical Products Administration in August 2023 and is currently under review.

2.10. BFI-751

BFI-751 is a proposed biosimilar to ustekinumab developed by BioFactura (Frederick, MD, USA). A multicenter, randomized, double-blind, phase I study has assessed the PK, safety, and immunogenicity of BFI-751 compared to EU and US ustekinumab RP (NCT04843631) [49]. The primary PK endpoints were AUCinf, AUClast, and Cmax. The results showed that BFI-751 met bioequivalence criteria when compared to both reference products, with 90% CIs of the primary endpoints within the accepted range of 0.8–1.25. No significant safety or tolerability differences were noted, and treatment-emergent adverse events were mild to moderate across all groups. ADAs were detected in 16% of BFI-751 recipients, compared to 44% of EU ustekinumab recipients and 49% of US ustekinumab recipients.

2.11. Other Proposed Ustekinumab Biosimilars

Other molecules are currently under evaluation as potential ustekinumab biosimilars, including NeuLara (Neuclone/Serum Institute of India), which has already shown positive results in phase I trial (although results are not published), or ONS3040 (Oncobiologics (now Outlook Therapeutics, headquartered in Iselin, NJ, USA) and BOW090 (Epirus Biopharmaceuticals/Bioceros Holding, Utrecht, The Netherlands), which are in pre-clinical development stages (Table 2).

3. Discussion

Ustekinumab, an interleukin-12/23 inhibitor, has been a cornerstone in the management of chronic inflammatory conditions such as psoriasis, psoriatic arthritis, and inflammatory bowel disease. With the expiration of the patent exclusivity for ustekinumab, the development and approval of biosimilars have gained momentum. Ustekinumab biosimilars, designed to be highly similar in structure, efficacy, and safety to the reference product (Stelara®,; Janssen Biotech, Horsham, PA, USA), offer the potential for broader patient access and reduced healthcare costs.
At the moment of writing, five ustekinumab biosimilars have been approved by the FDA and/or the EMA: ABP 654 (Wezenla®/Wezlana®; Amgen Inc, Thousand Oaks, CA, USA); AVT04 (Uzpruvo®/Selarsdi®; Alvotech, Reykjavik, Iceland); SB17 (Pyzchiva®/EpyztekTM; Samsung Bioepis, Incheon, Republic of Korea); CT-P43 (SteQeyma®; Celltrion Healthcare, Incheon, Republic of Korea); and FYB202 (Otulfi®; Formycon, Planegg-Martinsried, Germany/Fresenius Kabi, Bad Homburg, Germany). At least two more candidates (BAT2206, DMB-3115) are expected to be approved in the upcoming months, after the acceptance of the FDA’s biologics license application and the EMA’s marketing authorization application. While the acceptance of these applications by the FDA and EMA does not guarantee approval, it is a significant step forward. The regulatory agencies will still need to conduct a thorough review before deciding whether to grant final approval for the biosimilars’ use in different clinical settings. Other molecules are being evaluated at pre-clinical and clinical level (Table 2).
The phase I and phase III studies required for the approval of ustekinumab biosimilars have consistently demonstrated PK equivalence, with key metrics such as Cmax and AUC falling within the predefined bioequivalence margins, as well as comparable clinical efficacy and safety. These findings align with the rigorous standards set by regulatory agencies such as the FDA and EMA for the approval of biosimilars.
Immunogenicity remains a relevant consideration, with ustekinumab biosimilars generally showing comparable or slightly lower rates of ADA formation compared to the RP (Table 3), which do not impinge on the TOE-determined biosimilarity.
The lower immunogenicity of ustekinumab biosimilars has been attributed to the differences in manufacturing processes compared to the RP. The most common mammalian cell lines used for biopharmaceutical manufacturing include CHO cells, baby hamster kidney cells (BHK21), and murine myeloma cells (NS0 and Sp2/0) [50]. Ustekinumab RP is produced using Sp2/0 cells, while most ustekinumab biosimilars are produced using CHO cell lines, which provide manufacturing advantages. Murine cell lines produce post-translational modifications that are not expressed in humans and are potentially immunogenic, such as galactose-a1,3-galactose (a-gal) and N-glycolylneuraminic acid (NGNA), but these modifications in recombinant CHO cells are apparently closer to those in humans [51]. Thus, different cell lines may lead to variations in glycosylation profiles, which could potentially influence the immunogenicity of biosimilars. Interestingly, lower immunogenicity has been observed even in biosimilars that utilize the same cell line as the RP, like AVT04 [43]. The underlying cause of the reduced immunogenicity of ustekinumab biosimilars remains unclear.
However, the presence of ADAs does not appear to compromise the clinical efficacy of these biosimilars. In the case of SB17, for instance, the primary efficacy endpoint—measured by the percentage change in PASI scores at week 12—was comparable between ADA-positive and ADA-negative patients. This suggests that ADAs may not significantly affect the therapeutic outcome in patients treated with these biosimilars. In psoriasis, the pooled ADA rate to ustekinumab RP is 4.1% across nine studies with 4044 patients [52], but the sensitivity of current tests for ADA has greatly increased. The presence of ADA decreases the serum concentrations of ustekinumab and slightly attenuates the clinical response, especially after switching in patients with prior ADAs to adalimumab [53,54,55]. Interestingly, in patients with psoriatic arthritis, ADA formation is not associated with impairments in ustekinumab RP safety, efficacy or trough levels, and concomitant methotrexate has no effect on ustekinumab RP immunogenicity [56]. On the other hand, the development of ustekinumab ADAs is associated with loss of response to ustekinumab RP in patients with inflammatory bowel disease [57]. Further investigation in real-world settings to fully understand the long-term impact of ustekinumab biosimilars with lower immunogenicity on clinical outcomes in different settings.
All approved and proposed ustekinumab biosimilars have undergone clinical trials in patients with psoriasis. Extrapolation allows regulatory authorities to extend the approved indications of the biosimilar to other conditions treated by the RP, such as psoriatic arthritis or Crohn’s disease, without the need for conducting separate clinical trials for each condition. This process is based on the principle that the ustekinumab mechanism of action is the same across all indications of the RP.
A recent systematic review of 14 randomized clinical trials and 3 cohort studies assessed the efficacy and safety of biosimilars of adalimumab, etanercept, infliximab, and ustekinumab compared to originator biologics in treating psoriasis [58]. The findings did not show clinically or statistically significant differences in efficacy (in terms of achieving PASI75 response) or in the risk of adverse events between biosimilars and originators at weeks 16 and 52. These results confirm the remarkable equivalence between biosimilars and originators and support the adoption of biosimilars in the treatment of psoriasis and other inflammatory diseases pathogenetically mediated by IL-23.
Despite their potential cost benefits, several barriers hinder the widespread adoption of biosimilars [59]. Public perception often favors brand-name biologics over biosimilars, viewing the latter as inferior “copies”. Additionally, the unique development process of biosimilars, which differs from traditional drug development, has contributed to the hesitancy of some prescribers. Long-term efficacy and safety assessments for biosimilars in different indications also remain partially uncertain. However, biosimilars offer significant societal benefits, including broader access to treatments and potential cost savings. As an important and expanding class of biologics, their widespread adoption should lead to improved patient outcomes and more sustainable healthcare systems.

4. Conclusions

Ustekinumab biosimilars provide cost-effective alternatives that have demonstrated equivalent efficacy and safety to the reference product. The accumulated experience and extensive published data support their role in clinical practice, aligning with the standards of the original biologic. While continued pharmacovigilance is essential to monitor long-term outcomes, the approval of biosimilars ensures that patients receive the same level of care as with the reference product, helping to broaden access to effective biologic therapies.

Author Contributions

All authors declare to have contributed to the conception and design of the article, the writing of the draft, the critical review of the intellectual content and the final approval of the version presented. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Data sharing is not applicable.

Conflicts of Interest

Elena Carmona-Rocha has perceived speaker’s honoraria from Boehringer-Ingelheim, Amgen and Astellas. Lluís Puig has received consultancy/speaker’s honoraria from and/or participated in clinical trials sponsored by Abbvie, Almirall, Amgen, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Fresenius-Kabi, Gebro, Janssen, JS BIOCAD, Leo-Pharma, Lilly, Novartis, Pfizer, Samsung-Bioepis, and UCB.

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Biologics 04 00025 g001
Figure 1. Ustekinumab mechanism of action. Ustekinumab binds to the p40 subunit of interleukin (IL)-12 and IL-23, blocking their interaction with the IL-12Rβ1 receptor on the cell surface of natural killer cells and T cells. This inhibits IL-12- and IL-23-driven cell signaling, activation, and cytokine production.
Figure 1. Ustekinumab mechanism of action. Ustekinumab binds to the p40 subunit of interleukin (IL)-12 and IL-23, blocking their interaction with the IL-12Rβ1 receptor on the cell surface of natural killer cells and T cells. This inhibits IL-12- and IL-23-driven cell signaling, activation, and cytokine production.
Biologics 04 00025 g001
Table 2. Ustekinumab and biosimilars of ustekinumab (approved, proposed, or under development).
Table 2. Ustekinumab and biosimilars of ustekinumab (approved, proposed, or under development).
Product NameCompany NameProduction SystemStage of Development
Ustekinumab (Stelara®)Janssen Biotech (Horsham, PA, USA) Sp2/0 cell line Reference product
ABP 654 (Wezlana® in US and Canada; Wezenla® in Europe)Amgen (Thousand Oaks, CA, USA) CHO cell line FDA-approved * in October 2023
Australian Therapeutic Goods Administration approval in January 2024
Health Canada approval in March 2024
EMA approved in April 2024
AVT04 (Uzpruvo® in Europe and Japan; Selarsdi® in US; Jamteki™ in Canada)Alvotech (Reykjavik, Iceland)/Stada (Bad Vilbel, Germany)/Teva (Petah Tikva, Israel) Sp2/0 cell line Japan approval in September 2023
Health Canada approval in November 2023
EMA approved in January 2024
FDA approved ** in April 2024
SB17 (Pyzchiva® in US and Europe; Eksunbi® in Europe; EpyztekTM in Korea)Samsung Bioepis (Incheon, Republic of Korea) CHO cell line EMA approved in April 2024
FDA approved * in July 2024
Korea approval in April 2024
CT-P43 (SteQeyma®)Celltrion Healthcare (Incheon, Republic of Korea) CHO cell line Approved In South Korea (South Korean Ministry of Food and Drug Safety) in June 2024
Approved In Canada in July 2024
EMA approved in August 2024
BLA submitted to FDA, pending acceptance
RT-111 (oral CT-P43; RaniPill®) Rani Therapeutics (San Jose, CA, USA) Unknown Phase I study ongoing (NCT05890118)
FYB202 (Fymskina®, Otulfi®)Formycon (Planegg-Martinsried, Germany)/Fresenius Kabi (Bad Homburg, Germany) CHO cell line Phase I and phase III trials completed with positive results
FDA approved * in July 2024
MAA accepted by EMA with positive opinion from the CHMP in July 2024
BAT2206Bio-Thera (Guangzhou, China)/Hikma (London, UK) CHO cell line Phase I and phase III trials completed with positive results
BLA accepted by FDA
MAA accepted by EMA
Approved in Brazil for psoriatic arthritis
DMB-3115 Dong-A ST (Seoul, Republic of Korea)/Accord BioPharma (Durham, NC, USA) Sp2/0 cells Phase I and phase III trials completed with positive results
BLA accepted by FDA
MAA accepted by EMA
QX001S Qyuns Therapeutics (Guangzhou, China) CHO cell line Phase I and phase III trials completed with positive results
BLA accepted by China National Medical Products Administration
BFI-751 BioFactura (Frederick, MD, USA)/CuraTeQ (Hyderabad, India) Murine myeloma, NS0 Phase I completed with positive results (NCT04843631)
NeuLara Neuclone (Sydney, Australia)/Serum Institute of India (Pune, India) Unknown Phase I completed in April 2020 with positive results
ONS3040 Oncobiologics (now Outlook Therapeutics, Iselin, NJ, USA) Unknown Pre-clinical development
BOW090 Epirus Biopharmaceuticals/Bioceros Holding (Utrecht, The Netherlands) Unknown Pre-clinical development
Abbreviations: CHO, Chinese hamster ovary; BLA, biologic license spplication; MAA, marketing authorization application; CHMP, Committee for Medicinal Products for Human Use. * Approved as interchangeable biosimilar, meaning it can be substituted for the reference product at the pharmacy level, without the intervention of the healthcare provider who prescribed the original product. ** Only for psoriasis and psoriatic arthritis.
Table 3. Immunogenicity of ustekinumab RP and approved biosimilars.
Table 3. Immunogenicity of ustekinumab RP and approved biosimilars.
ProductADA Incidence in Healthy IndividualsADA Incidence in Psoriasis Patients *NADA Incidence in Psoriasis Patients **
UST RP [15]5.6%4.1%67%
ABP 654 [38,39]ABP 654: 15.4%
EU UST: 36.3%
US UST: 38.0%		ABP 654: 18.6%
UST: 37.1%		ABP 654: 8.6%
UST: 17.9%
AVT04 [42,43]AVT04: 36.7%
EU UST: 59.6%
US UST: 53.6%		AVT04: 21.2%
UST: 26.2%%		AVT04: 33.3%
UST: 22.9%
SB17 [44,45]SB17: 26.9%
EU UST: 34.3%
US UST: 34.3%		SB17: 13.3%
UST: 39.4%		SB17: 13.7%
UST: 35.4%
CT-P43 [46]N/ACT-P43: 10.2%
UST: 17.0%		CT-P43: 5.9%
UST: 7.9%
FYB202N/AN/AN/A
* ADA incidences in psoriasis patients were obtained from phase II studies with UST RP (week 52) and from phase III studies with ABP 654 (week 28), AVT04 (week 52), SB17 (week 28), and CT-P43 (week 28). ** NADA were evaluated in patients with positive results for ADAs. Abbreviations: ADA, anti-drug antibody; NADA, neutralizing anti-drug antibody; EU, European Union; US, United States; N/A, not available; UST, ustekinumab; RP, reference product.
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Carmona-Rocha, E.; Puig, L. Ustekinumab Biosimilars. Biologics 2024, 4, 407-422. https://doi.org/10.3390/biologics4040025

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Carmona-Rocha E, Puig L. Ustekinumab Biosimilars. Biologics. 2024; 4(4):407-422. https://doi.org/10.3390/biologics4040025

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Carmona-Rocha, Elena, and Lluís Puig. 2024. "Ustekinumab Biosimilars" Biologics 4, no. 4: 407-422. https://doi.org/10.3390/biologics4040025

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Carmona-Rocha, E., & Puig, L. (2024). Ustekinumab Biosimilars. Biologics, 4(4), 407-422. https://doi.org/10.3390/biologics4040025

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