Randomized, double-blind, multicenter study to evaluate efficacy, safety, tolerability, and immunogenicity between AVT04 and the reference product ustekinumab in patients with moderate-to-severe chronic plaque psoriasis

ABSTRACT

Background

This study compared efficacy, safety, tolerability, pharmacokinetics (PK), and immunogenicity between AVT04 and reference product (RP) ustekinumab (Stelara®) in patients with moderate-to-severe chronic plaque psoriasis (PsO).

Patients and methods

This multicenter, double-blind, 52-week study randomized patients in 1:2 ratio to AVT04 or RP. At week 16, responsive patients (≥50% improvement in psoriasis area and severity index (PASI)) previously on AVT04 continued on AVT04, while those on RP were re-randomized 1:1 to switch to AVT04 or stay on RP. The primary endpoint was a percent improvement in PASI from baseline to week 12. Therapeutic equivalence was demonstrated if the confidence interval (CI) for the adjusted difference in means was contained within the equivalence margins; ±10% (90%CI).

Results

Of the 581 patients initially randomized (AVT04:RP, 194:387), 575 completed week 16 and 544 completed end of study visit. The percent PASI improvement for AVT04 vs RP was 87.3% vs 86.8% (CI: −2.14%, 3.01%); study met its primary endpoint. Efficacy, safety and PK profiles were comparable across treatment arms throughout the entire study duration, and the incidence of antibodies to ustekinumab had no clinically meaningful impact.

Conclusion

This study demonstrates the therapeutic equivalence between AVT04 and RP in patients with moderate-to-severe chronic PsO, with similar safety and tolerability. 

Trial registration

NCT04930042; EudraCT Number: 2020-004,493-22

KEYWORDS:

• AVT04
• ustekinumab
• biosimilar
• moderate-to-severe chronic plaque psoriasis
• therapeutic equivalence

1. Introduction

Reference product (RP) ustekinumab (Stelara®) is a fully human IgG1k monoclonal antibody that binds to interleukin (IL)-12 and IL-23 via their common p40 protein subunit. It inhibits IL-12 and IL-23 by preventing p40 from binding to the IL-12R1 receptor protein, expressed on the surface of immune cells, and modulating the T helper 1 (Th1) and T helper 17 (Th17) cytokine pathways. IL-12 and IL-23 dysregulation has been linked to psoriasis and other inflammatory diseases [1].

RP was approved by the European Medicines Agency (EMA) in January 2009, the US Food and Drug Administration (FDA) in September 2009, and the Pharmaceuticals and Medical Devices Agency of Japan (PMDA) in January 2011 [2]. Now it is currently approved for the treatment of a variety of inflammatory diseases [3–5].

To improve access to reference product biologics while increasing cost-effectiveness, biosimilars are being developed [5, 6, 7]. The development of biosimilars, however, is a difficult process due to the complex molecular structure of the reference biologics. Various regulations and guidelines have been put in place for the development and licensing of biosimilar products [8–12]. Currently, no biosimilar to RP has been approved.

AVT04 is being developed as a proposed biosimilar to RP for subcutaneous (SC) and intravenous (IV) use, and the totality of evidence is being generated to demonstrate biosimilarity. AVT04 is formulated in the same concentrations as the RP, with the same excipients. Direct comparison of ustekinumab quality attributes between AVT04 and RP, using sensitive, state-of-the-art physicochemical analytical methods and in-vitro functional assays (including binding to target antigen and potency in relevant cells), revealed structural, post-translational, and functional similarities. Where differences in post-translational properties were observed, further assessment in functional assays and clinical studies was conducted and supports the evaluation that these differences have no clinically meaningful impact on efficacy. A randomized, double-blind, 3-arm, parallel study in healthy adults demonstrated pharmacokinetic similarity between AVT04 and United States (US)-licensed- and European Union (EU)-approved RP with comparable safety profiles (NCT04744363) [13,14]. The current study assessed therapeutic equivalence between AVT04 and RP (EU approved) by comparing efficacy, safety, tolerability, pharmacokinetics (PK), and immunogenicity in participants with moderate-to-severe chronic plaque psoriasis (PsO).

2. Patients and methods

2.1. Study design and participant population

This multicenter, double-blind, randomized, active control study was conducted at 30 sites in Georgia, Ukraine, Poland, and Estonia in patients with moderate-to-severe chronic PsO between 3 June 2021 and 11 October 2022. (The trial was registered with ClinicalTrials.gov, NCT04930042 and EudraCT, 2020-004493-22.) The study was conducted in accordance with the Declaration of Helsinki, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and the requirements of all the applicable local regulatory authorities. Informed consent form (ICF) was appropriately signed and dated by the patient and the person obtaining the consent well before initiation of the study procedures. The study was modified during the Coronavirus Disease 2019 (COVID19) outbreak to minimize risks while maximizing potential benefits for the patients in accordance with the standard guidelines [15] In addition, urgent safety measures were introduced during emerging crisis situation for sites in Ukraine prioritizing patients’ safety.

The study comprised two stages: primary efficacy assessment (day 1 (week 1) to week 15) and long-term efficacy and safety assessment (week 16 to week 52). On day 1 post-screening, eligible patients were randomly assigned to one of two groups in a 1:2 ratio (AVT04:RP) to receive either AVT04 or RP at 45 mg (patients with ≤100 kg body weight) or 90 mg (>100 kg body weight) by SC. At week 16, patients who had been initially randomized to AVT04 continued to receive AVT04. Patients who were initially randomized to RP were re-randomized in a 1:1 ratio to switch to either AVT04 or continue on RP.

Patients were dosed on day 1 (week 1), week 4, and then every 12 weeks at weeks 16, 28, and 40 (unless withdrawn from the study). Patients who were nonresponsive (<50% improvement in Psoriasis Area and Severity Index (PASI)) at week 28 were not administered further study treatment at and after week 28; however, they were encouraged to complete the end of study (EoS) assessments at week 52. The treatment responders (≥50% improvement in PASI) were allowed to continue in the study to complete end of treatment (EoT) visit at week 40 and EoS visit at week 52. (Figure 1) At EoS, all responders who were still in the study underwent final study assessments, while all non-responders still in the study underwent only safety and immunogenicity assessments. Patients were allowed to discontinue the study any time for any reason. For these patients, the last study visit within 6 weeks after the last dose of the study drug was considered as an early EoS visit, during which safety and immunogenicity were assessed.

Figure 1. Study schema.

Note: BL: baseline; W: week; G; group; PASI: Psoriasis Area and Severity Index.

Key inclusion criteria of the study were as follows: 1) male or female patients aged 18–75 years old, inclusive, at time of screening; 2) moderate-to-severe chronic PsO for at least 6 months; 3) involved body surface area (BSA) ≥10%, PASI ≥ 12, and static Physician’s Global Assessment (sPGA) ≥3 (moderate) at screening and at baseline; 4) stable psoriatic disease for at least 2 months (i.e., without significant changes as defined by the investigator or designee) prior to screening; 5) had a previous failure, inadequate response, intolerance, or contraindication to at least 1 systemic antipsoriatic therapy including, but not limited to, methotrexate, cyclosporine, psoralen plus ultraviolet light A (PUVA), and ultraviolet light B (UVB).

The following were key exclusion criteria of the study: 1) Patient diagnosed with psoriatic arthritis, erythrodermic psoriasis, pustular psoriasis, guttate psoriasis, medication-induced psoriasis, other skin conditions (e.g., eczema), or other systemic autoimmune disorder inflammatory disease at the time of the Screening Visit that would have interfered with evaluations of the effect of the study drug on psoriasis.; 2) prior use of any of the protocol specified medications within stipulated time periods or would have been required to use during the study.

2.2. Randomization and masking

Eligible patients were randomized to receive study drug according to the randomization schedule generated by an independent statistician. The randomization was stratified by the presence or absence of previous biologic treatment for PsO, and body weight category (≤80 kg, >80 kg to ≤100 kg, >100 kg). Double blinding in the study was achieved by concealing the syringe content and plunger stoppers during storage, handling, and drug administration by masking prefilled syringes with a yellow semi-opaque blinding label. This ensured that the identity of the product could not be determined, while allowing a visual check of the contents before injection. Patients and investigators remained unaware of the treatment allocation until study completion. During the study, there was no emergency unblinding of any patient’s treatment assignment.

2.3. Outcomes

The primary efficacy endpoint was a percent improvement in PASI from baseline to week 12. Secondary efficacy endpoints included percent improvement in PASI from baseline to week 4, 8, 16, 28, 40 (EoT), and 52 (EoS); area under the effect curve for PASI from baseline through week 12; 50% improvement in PASI (PASI50), 75% improvement in PASI (PASI75), 90% improvement in PASI (PASI90), and 100% improvement in PASI (PASI100) response rates at weeks 4, 8, 12, 16, 28, 40 (EoT), and 52 (EoS); proportion of patients achieving sPGA responses of clear (0) or almost clear (1) at weeks 4, 8, 12, 16, 28, 40 (EoT), and 52 (EoS); change in dermatology life quality index (DLQI) scores from baseline to weeks 12, 28, 40 (EoT), and 52 (EoS); change in percent BSA (%BSA) affected by chronic PsO from baseline to weeks 4, 8, 12, 16, 28, 40 (EoT), and 52 (EoS). Additional secondary endpoints were serum trough concentrations at steady-state, safety, tolerability, and immunogenicity comparisons between AVT04 and RP.

2.4. Procedures

Patients received study drugs according to the approved dosing regimen by SC in the abdomen (preferred site) or in the thigh (secondary site) at weeks 1, 4, 16, 28, and 40 at the study center. Patients with body weight ≤100 kg received one SC injection (one prefilled syringe) of AVT04 or RP 45 mg at each dosing timepoint. While patients with a body weight >100 kg received two SC injections (two prefilled syringes) of AVT04 or RP 90 mg at each dosing timepoint on different body areas – abdomen and/or thigh(s).

Study drug compliance per protocol was assessed by the investigator and the study staff by recording the date and time of each dose administered. Any deviations from the planned dosing regimen were recorded as protocol deviations.

Measurements were performed over the entire study duration. The PASI was calculated by scoring of PsO lesions on a scale of 0 to 4 for three characteristics: erythema, infiltration, and desquamation, weighted by the area of involvement [16]. The lesions were scored within four anatomical regions: head, upper extremities, trunk, and lower extremities, including the buttocks. Within each of these regions, the area of involvement was scored on a scale of 0 to 6. The sPGA was scored on a scale of 0 to 5, with 0 indicating no psoriasis (clear of disease), 1 indicating almost clear of disease and 2 or higher scores indicating more severe disease. The DLQI is a validated questionnaire with 10 questions. The total score was calculated by adding the scores of each question, resulting in a maximum of 30 and a minimum of 0 score. The higher the score, the more impaired the quality of life [17]. The total % BSA was calculated as the number of hands needed to cover the entire affected area, assuming that the patient’s hand, including the palm, fingers, and thumb, represented roughly 1% of the body’s surface [18].

Anti-drug antibodies (ADAs) and neutralizing ADAs (Nabs) were assessed in pre-dose serum samples collected at baseline, and at weeks 4, 12, 16, 28, 40 (EoT), and 52 (EoS) using highly sensitive electrochemiluminescence (ECL) methods [19]. Serum trough concentrations in pre-dose serum samples collected at baseline, and at weeks 4, 16, 28, 40 (EoT), and 52 (EoS) were measured.

Frequency, type, and severity of treatment-emergent adverse events (TEAEs) including adverse drug reactions (ADRs) were recorded. TEAE was defined as any AE that had an onset on/or after the study drug administration, or any preexisting condition that worsened on/or after the first study drug administration. Adverse events (AEs) were coded and classified using the Medical Dictionary for Regulatory Activities (MedDRA) version 25.1 by System Organ Class (SOC) and Preferred Term (PT).

The frequency and severity of injection site reactions (ISR) were recorded in the diary as any ISRs by patients. The ISR characteristics include pain/tenderness, erythema/redness, swelling/induration, pruritus/itching, or hematoma/ecchymosis/bruising. The AE term ‘ISR’ was reported, with an AE grade consistent with the worst grade for any one of the findings.

Routine safety parameters were performed, including laboratory safety, vital signs, 12-lead electrocardiogram (ECG), chest X-ray, and physical examination. All AEs that occurred after the patient signed the ICF and up to week 52 (EoS) were recorded. Laboratory samples were analyzed by a central laboratory to ensure consistent interpretation of results except the urine pregnancy test, which was performed at the respective sites.

2.5. Statistical analysis

A sample size of 528 in a 1:2 randomization would give 89.9% power in a 5% level test (associated with a 90% confidence interval (CI)) with equivalence margins at ± 10% (requirement of FDA), and a sample size of 462 patients (body weight 100 kg) in a 1:2 randomization would provide 99.5% power in a 2.5% level test (associated with a 95% CI) with equivalence margins at ±15% (requirement of EMA).

An analysis of covariance (ANCOVA) model was used to analyze the primary endpoint. The model included percent improvement in PASI as the response variable, randomized treatment group, and baseline stratification variables of previous biologic treatment for PsO (yes/no) as factors. Baseline PASI score and body weight were included as continuous covariates. Estimates for the adjusted mean difference between treatment arms at week 12 and 2-sided 90% and 95% CIs for the adjusted mean difference were provided to address the equivalence. A similar model was used to evaluate secondary efficacy analyses.

A sub-group analysis using an ANCOVA model adjusted only for baseline PASI score for the defined subgroups (body weight [≤80 kg, >80 kg to ≤100 kg, >100 kg (as well as body weight ≤100 kg and overall)], and previous biologic treatment for PsO [yes/no]) was performed.

The primary efficacy analyses were performed on the per protocol (PP) analysis set. PP is a subset of the intention-to-treat (ITT) set, which includes patients who completed the study period up to week 12 without protocol deviations that impacted the efficacy assessment. For sensitivity analyses to test the robustness of the primary endpoint analysis, equivalence tests were performed on the ITT set using observed data and last observation carried forward to impute the missing data.

All secondary efficacy analyses were performed on the ITT set, while safety, pharmacokinetic, and immunogenicity analyses on the safety analysis set (SAS), defined as all randomized patients who received at least one dose of randomly allocated treatment (based on actual treatment received). All secondary endpoints and the supportive analyses were considered as descriptive evidence of efficacy upon which no inferential conclusions were made.

3. Results

3.1. Participant disposition

Overall, 786 patients were screened, and 581 of them (including 90 patients with body weight >100 kg) were randomly assigned to study treatments in stage 1 (AVT04 vs RP, 194 vs 387). A total of 575 patients (99.0%) completed stage 1 (week 16), and 544 patients (94%) completed stage 2 (EoS). The most common reasons for study discontinuation were withdrawal of consent, AEs, lost to follow-up, and the decision of the principal investigator (Figure 2).

Figure 2. Disposition of study participants (All patients).

Note: PI: principal investigator.

The demographic and baseline characteristics in the ITT set were well balanced across the treatment groups in both stages 1 and 2. The vast majority of the patients were males (62.7%), aged <65 years (94.3%), and not Hispanic or Latino (99.3%) (Table 1). Infections and infestations were the most commonly reported prior medical/surgical history by SOC (27.2%), while metabolism and nutrition disorders (18.8%) and vascular disorders (17.9%) were the most frequently reported ongoing medical/surgical history by SOC. The demographic and baseline characteristics in the PP set (Table S1) were also well balanced. For patients with body weight ≤100 kg similar demographic and baseline characteristics were observed across the treatment arms (Table Si).

Table 1. Demographics and baseline characteristics (Intention-to-Treat Set) (All patients).

-	AVT04 (N = 194) n (%)	RP (N = 387) n (%)	Overall (N = 581) n (%)
Age (years) at informed consent
Mean (SD)	42.3 (13.0)	41.9 (12.8)	42.0 (12.8)
Median	41.0	40.0	40.0
Min, max	18, 74	18, 73	18, 74
Age group, n (%)
<65 years	183 (94.3)	365 (94.3)	548 (94.3)
≥65 years	11 (5.7)	22 (5.7)	33 (5.7)
Gender, n (%)
Female	87 (44.8)	130 (33.6)	217 (37.3)
Male	107 (55.2)	257 (66.4)	364 (62.7)
Ethnicity, n (%)
Hispanic or Latino	1 (0.5)	3 (0.8)	4 (0.7)
Not Hispanic or Latino	193 (99.5)	384 (99.2)	577 (99.3)
Race, n (%)
White	194 (100.0)	387 (100.0)	581 (100.0)
Height (cm) at Screening
Mean (SD)	172.11 (9.5)	173.90 (9.0)	173.30 (9.2)
Median	172.0	175.0	174.0
Min, max	152.0, 196.0	149.0, 198.0	149.0, 198.0
Weight (kg) at Screening
Mean (SD)	83.48 (18.4)	84.19 (18.5)	83.96 (18.5)
Median	84.1	83.5	84.0
Min, max	45.0, 146.0	40.7, 150.2	40.7, 150.2
Body weight category
≤80 kg	84 (43.3)	167 (43.2)	251 (43.2)
>80 kg to ≤100 kg	80 (41.2)	160 (41.3)	240 (41.3)
>100 kg	30 (15.5)	60 (15.5)	90 (15.5)
BMI (kg/m^2) at Screening
Mean (SD)	28.1 (5.3)	27.8 (5.5)	27.9 (5.4)
Median	28.0	27.6	27.7
Min, max	16.9, 42.2	16.1, 46.2	16.1, 46.2
Prior biologic therapy for PsO
Yes	15 (7.7)	29 (7.5)	44 (7.6)
No	179 (92.3)	358 (92.5)	537 (92.4)
Psoriasis Area and Severity Index (PASI)
Mean (SD)	22.05 (8.1)	22.22 (7.5)	22.17 (7.7)
Median	20.2	20.0	20.0
Min, max	12.2, 55.2	12.2, 64.8	12.2, 64.8
Static Physician’s Global Assessment (sPGA), n (%)
Minimal	0	0	0
Mild	0	0	0
Moderate	132 (68.0)	241 (62.3)	373 (64.2)
Severe	49 (25.3)	117 (30.2)	166 (28.6)
Very severe	13 (6.7)	29 (7.5)	42 (7.2)
Percent of body surface area (%BSA) affected (%)
Mean (SD)	26.02 (13.2)	26.41 (12.3)	26.28 (12.6)
Median	23.0	23.0	23.0
Min, max	10.0, 75.0	10.0, 84.0	10.0, 84.0
Months from diagnosis of chronic plaque psoriasis to informed consent
Mean (SD)	193.4 (139.9)	201.0 (136.5)	198.5 (137.5)
Median	156.5	186.0	176.0
Min, max	7, 703	6, 691	6, 703
Country
Estonia	3 (1.5)	7 (1.8)	10 (1.7)
Georgia	25 (12.9)	37 (9.6)	62 (10.7)
Poland	107 (55.2)	214 (55.3)	321 (55.2)
Ukraine	59 (30.4)	129 (33.3)	188 (32.4)

Note: Percentages were based on the number of patients in the ITT Set by treatment group. %BSA: percentage of body surface area; BMI: body mass index; ITT: Intention-to-Treat; max: maximum; min: minimum; PASI: Psoriasis Area and Severity Index; PsO: plaque psoriasis; SD: standard deviation; sPGA: Static Physician’s Global Assessment.

Patients received the study treatments in accordance with the protocol. The extent of study drug exposure and treatment compliance were comparable; at week 16, treatment compliance was 100% in both AVT04 and RP arms, while at EOT, treatment compliance was 100% in AVT04/AVT04, 97.8% in RP/AVT04, and 98.4% in RP/RP arms, respectively.

3.2. Efficacy

The PASI improvement in AVT04-treated patients with moderate-to-severe chronic PsO was similar to that in RP-treated patients. The primary endpoint of percent PASI improvement from baseline to week 12, was 87.3% in the AVT04-treated patients and 86.8% in the RP-treated patients. The 90% CI for the least square (LS) means difference (0.4) in percent PASI improvement from baseline to week 12 in the PP set was −2.14%, 3.01%, within the pre-defined equivalence margin of ±10% in accordance with the FDA criteria (Table 2), and the study met its primary endpoint.

Table 2. Percent improvement in psoriasis area and severity index from Baseline to week 12 (Per protocol set).

Time Point	AVT04	RP
All patients	N = 194	N = 383
week 12	-	-
N	194	383
LS mean (SE) (%)	87.3 (1.73)	86.8 (1.49)
LS means difference (SE) (AVT04 vs EU-Stelara)	0.4 (1.56)	-
90% confidence interval	−2.14, 3.01	-
95% confidence interval	−2.63, 3.50	-
Patients with body weight ≤100 kg	N = 164	N = 324
week 12	-	-
N	164	324
LS mean (SE) (%)	86.9 (1.91)	86.8 (1.64)
LS means difference (SE) (AVT04 vs EU-Stelara)	0.1 (1.70)	-
90% confidence interval	−2.71, 2.89	-
95% confidence interval	−3.25, 3.43	-

Note: Baseline was defined as the last non-missing value (either scheduled, unscheduled, or repeat) before the patient received the first dose of study drug (day 1). Two-sided 90% and 95% CIs for the difference in LS means between AVT04 and RP were obtained from an ANCOVA model including percent PASI improvement as response variable, randomized treatment, and stratification factor (prior biologic therapy) as factors, and with baseline PASI score and baseline body weight as continuous covariates. Therapeutic equivalence between AVT04 and RP was established if the CI for adjusted difference in means was contained within the range [−10%, 10%] for the 90% CI and range [−15%, 15%] for the 95% CI. ANCOVA: analysis of covariance; CI: confidence interval; LS: least squares; PASI: Psoriasis Area and Severity Index; SE: standard error.

In patients with body weight ≤100 kg, similar PASI improvement was observed in both treatment arms (AVT04 vs RP; 86.9% vs 86.8%); the 95% CI for the LS means difference (0.1) in percent PASI improvement from baseline to week 12 was −3.25%, 3.43%, within the pre-defined EMA equivalence margin of ± 15%.

The robustness of the primary endpoint analysis was supported by sensitivity analyses performed in the ITT set using observed data (primary sensitivity analysis) and data from the last observation carried forward (secondary sensitivity analysis). The LS mean for percent PASI improvement from baseline to week 16 between AVT04 and RP was similar in both the primary and secondary analyses (Table S2).

From baseline to week 16, the percent PASI improvement increased steadily (Figure 3a). The primary endpoint analysis of therapeutic equivalence was confirmed by ANCOVA analysis of percent PASI improvement in the ITT set (Table S3). Furthermore, the area under the effect curve for PASI from baseline to week 12 revealed similarity between the treatment groups (Mean (standard deviation (SD)): 620.26 (202.956) in the AVT04 group vs 633.19 (199.910) in the RP group) (Table S4).

Figure 3. Percent improvement from baseline in psoriasis area and severity index by visit (a). Up to week 16 (b). over time (observed data, intention-to-treat set) (all patients).

Note: Missing percent improvement in PASI was not imputed. PASI: Psoriasis Area and Severity Index; SD: standard deviation.

In the long-term efficacy assessment (until EOS), the percent improvement in PASI was found to have been comparable between patients who switched from RP to AVT04 and those who continued on the previous treatments (AVT04/AVT04 and RP/RP) (Figure 3b). Similarly, the proportion of patients achieving PASI50, PASI75, PASI90, and PASI100 before and after switching was similar between the groups, with no clinically significant differences between treatment groups over the course of the study (Table S5). Prior to switching, the proportions of patients achieving sPGA responses of clear (0) or almost clear (1) and DLQI improvements were comparable without clinically meaningful differences between AVT04 and RP (up to week 16), with the responses lasting until EOS (Table S6, S7). The improvement in %BSA affected by chronic PsO was also similar between the treatment groups before switching (up to week 16) and after switching until EOS (Table S8). The findings corroborate the persistence of efficacy despite treatment switching at week 16. All secondary efficacy analyses showed similar results in a subset of patients with body weight ≤100 kg (Table Sii–Sviii).

The subgroup analysis of percent improvement in PASI from baseline to week 12 revealed no noteworthy differences by body weight, prior biologic therapy for psoriasis, age, gender, ADA status, or NAb status (Figure S1). (Figure Si shows subgroup analysis in patients with body weight ≤100 kg.)

3.3. Pharmacokinetics

From baseline to week 4, mean serum trough ustekinumab concentrations increased similarly in both the AVT04 and RP groups, then decreased at week 16 (Figure 4a). Following re-randomization and switching at week 16, mean serum trough levels of ustekinumab remained comparable between the AVT04/AVT04, RP/AVT04, and RP/RP groups at all timepoints up to EOS (Figure 4b). The results were similar in patients with body weight ≤100 kg (Table Sxi).

Figure 4. Serum trough pharmacokinetic concentrations (a). Up to week 16 (b). Over time (Safety analysis set) (All patients).

Note: SE: Standard error. Note: All baseline summary statistics are assigned a nominal value to enable plotting values of 0 on the log scale.

3.4. Immunogenicity

Overall, at week 16, 49 patients (25.4%) in the AVT04 group and 184 patients (48.2%) in the RP group had binding ADAs. Of these, 13 patients (26.5%) in the AVT04 group and 57 patients (31.0%) in the RP group had NAbs. At EoS, 39 patients (21.2%) in the AVT04/AVT04 group, 56 patients (31.5%) in the RP/AVT04 group, and 48 patients (26.7%) in the RP/RP group had binding ADAs. Of these, 13 patients (33.3%) in the AVT04/AVT04 group, 10 patients (17.9%) in the RP/AVT04 group, and 11 patients (22.9%) in the RP/RP group had NAbs.

The trend of higher binding ADA frequencies in the RP group compared to the AVT04 group prior to switching (until week 16) (Figure 5a) was found to be less pronounced in the second part of the study (Figure 5b). NAb frequencies have remained consistent over time. The numerical differences in the frequency of binding ADAs and NAbs had no clinically meaningful impact on the study treatments’ efficacy, safety, or PK profiles. Similar results were obtained in a subset of patients with body weight ≤100 kg (Table Sxii).

Figure 5. Positive antibody incidence (a). Up to week 16 (b). Over time (Safety analysis set) (All patients).

Note: Graph shows the total number of patients with ADA assessed at the specified time period.

3.5. Safety

Until week 16, a total of 67 patients (34.5%) reported 104 TEAEs in the AVT04 group and 130 patients (33.6%) reported 223 TEAEs in the RP group. The majority of the TEAEs were mild, with the exception of two patients (1.0%) in the AVT04 group who reported three severe TEAEs and six patients (1.6%) in the RP group who reported nine severe TEAEs. The TEAEs reported in at least 5% of patients by SOC were infections and infestations (17.0% in the AVT04 group, 14.5% in the RP group), and investigations (8.2% in the AVT04 group, 8.5% in the RP group).

The majority of TEAEs were unrelated to treatment assignment. Up to week 16, a total of 10 patients (5.2%) reported 13 treatment-related TEAEs in the AVT04 group and 37 patients (9.6%) reported 39 treatment-related TEAEs in the RP group. Until week 16, 10 serious TEAEs were reported by seven patients (1.8%) in the RP group that were not considered related to the treatment; no serious TEAEs were reported in the AVT04 group (Table 3).

Table 3. Summary of treatment-emergent adverse events (safety analysis set) (all patients).

	Up to Week 16				Week 16-Week 28						Week 28-Week52
	AVT04 (n = 194)		RP (n = 387)		AVT04/AVT04 (n = 193)		RP/AVT04 (n = 192)		RP/RP (n = 189)		AVT04/AVT04 (n = 191)		RP/AVT04 (n = 184)		RP/RP (n = 184)
	Patients n (%)	Events m	Patients n (%)	Events m	Patients n (%)	Events m	Patients n (%)	Events m	Patients n (%)	Events m	Patients n (%)	Events m	Patients n (%)	Events m	Patients n (%)	Events m
Any TEAE	67 (34.5)	104	130 (33.6)	223	21 (10.9)	26	30 (15.6)	35	29 (15.3)	36	32 (16.8)	49	42 (22.8)	66	39 (21.2)	49
Maximum severity of TEAEs	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Mild	40 (20.6)	64	66 (17.1)	115	10 (5.2)	14	18 (9.4)	21	20 (10.6)	26	15 (7.9)	26	21 (11.4)	41	19 (10.3)	23
Moderate	25 (12.9)	37	58 (15.0)	99	10 (5.2)	11	12 (6.3)	14	8 (4.2)	9	14 (7.3)	19	19 (10.3)	23	20 (10.9)	26
Severe	2 (1.0)	3	6 (1.6)	9	1 (0.5)	1	0	0	1 (0.5)	1	3 (1.6)	4	2 (1.1)	2	0	0
Treatment-related TEAEs	10 (5.2)	13	37 (9.6)	39	0	0	5 (2.6)	5	2 (1.1)	2	0	0	3 (1.6)	4	6 (3.3)	8
Serious TEAEs	0	0	7 (1.8)	10	0	0	0	0	1 (0.5)	1	1 (0.5)	1	1 (0.5)	1	1 (0.5)	1
Treatment-related serious TEAEs	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
TEAE leading to discontinuation from study treatment phase	0	0	3 (0.8)	3	1 (0.5)	1	3 (1.6)	3	4 (2.1)	4	0	0	0	0	1 (0.5)	2
Treatment-related TEAE leading to discontinuation from study treatment phase	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
TEAE leading to early termination from study	0	0	3 (0.8)	3	1 (0.5)	1	3 (1.6)	3	4 (2.1)	4	0	0	0	0	1 (0.5)	2
Treatment-related TEAE leading to early termination from study	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Serious TEAE leading to early termination from study	0	0	2 (0.5)	2	0	0	0	0	0	0	0	0	0	0	0	0
Treatment-related serious TEAE leading to early termination from study	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
TEAEs of special interest	3 (1.5)	4	16 (4.1)	17	0	0	2 (1.0)	2	1 (0.5)	1	0	0	3 (1.6)	4	2 (1.1)	2
Death	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Note: N represents number of patients treated in the relevant Safety Analysis Set and was used as the denominator for percentage calculations. n (%) represents the number and % of patients with events, and m represents the number of events within particular study period. Patients were counted only once at the maximum severity in the following order: severe, moderate, and mild. Events with unknown severity were counted as severe. A patient is presented only once in the respective patient count by highest relationship. Events with unknown relationship to study drug were counted as drug-related. TEAE: treatment-emergent adverse event.

Up to EOS, the safety profiles largely remained unchanged and similar between the treatment arms even after treatment switching at week 16. During week 16 to EOS, reported TEAEs were numerically higher in the RP/AVT04 and RP/RP groups than the AVT04/AVT04 group. From week 16 to week 28, 21 patients (10.9%) reported 26 TEAEs in the AVT04/AVT04 group, 30 patients (15.6%) reported 35 TEAEs in the RP/AVT04 group, and 29 patients (15.3%) reported 36 TEAEs in the RP/RP group. While from week 28 to EOS, a total of 32 patients (16.8%) reported 49 TEAEs in the AVT04/AVT04 group, 42 patients (22.8%) reported 66 TEAEs in the RP/AVT04 group, and 39 patients (21.2%) reported 49 TEAEs in the RP/RP group. Among them, most of the TEAEs were of mild to moderate in severity and were considered unrelated to the treatment assignment. Between week 16 and 28, five patients (2.6%) reported five treatment-related TEAEs in the RP/AVT04 group, while two patients (1.1%) reported two treatment-related TEAEs in the RP/RP group. One patient (0.5%) in the RP/RP group had one serious TEAE, which was not considered to be related to the study treatment; no serious TEAEs were reported in the other groups. While between week 28 to EOS, three patients (1.6%) reported four treatment-related TEAEs in the RP/AVT04 group and six patients (3.3%) reported eight treatment-related TEAEs in the RP/RP group. One patient (0.5%) in each group had one serious TEAE; none were considered to be related to study treatment (Table 3).

Until EOS, TEAEs in the ADA positive and negative patients were comparable across treatment groups (data not shown). Until EOS, overall, no significant differences in serious TEAEs, TEAEs that resulted in discontinuation from study treatment, or TEAEs of special interest, were observed between treatment groups until EOS. During the entire study, there were no serious TEAEs or TEAEs that caused discontinuation from study treatments. The only TEAE of special interest reported in at least 1% of patients in any treatment group among all patients was ISR (Table 4). Throughout the study, the incidence of ISR was similar across the treatment groups and ranged from mild to moderate in severity. No death was reported during the entire study period. During the study, no clinically significant differences in shifts from normal to low or high in any hematology, urinalysis, or vital sign values were observed across the treatment groups. Similar results were obtained in a subset of patients with body weight ≤100 kg (Tables 6, Sx).

Table 4. Summary of adverse events of special interest by primary system organ class and preferred term (safety analysis set) (all patients).

System Organ Class Preferred Term	Up to Week 16				Week 16-Week 28						Week 28-Week52
	AVT04 (n = 194)		RP (n = 387)		AVT04/AVT04 (n = 193)		RP/AVT04 (n = 192)		RP/RP (n = 189)		AVT04/AVT04 (n = 191)		RP/AVT04 (n = 184)		RP/RP (n = 184)
	Patients n (%)	Events m	Patients n (%)	Events m	Patients n (%)	Eventsm	Patients n (%)	Events m	Patients n (%)	Events m	Patients n (%)	Events m	Patients n (%)	Events m	Patients n (%)	Events m
Any TEAE of special interest	3 (1.5)	4	16 (4.1)	17	0	0	2 (1.0)	2	1 (0.5)	1	0	0	3 (1.6)	4	2 (1.1)	2
General disorders and administration site conditions	2 (1.0)	3	11 (2.8)	12	0	0	2 (1.0)	2	1 (0.5)	1	0	0	2 (1.1)	3	2 (1.1)	2
Injection site reaction	2 (1.0)	3	9 (2.3)	9	0	0	1 (0.5)	1	1 (0.5)	1	0	0	1 (0.5)	2	2 (1.1)	2
Injection site pain	0	0	1 (0.3)	2	0	0	0	0	0	0	0	0	1 (0.5)	1	0	0
Injection site hematoma	0	0	1 (0.3)	1	0	0	1 (0.5)	1	0	0	0	0	0	0	0	0
Vascular disorders	1 (0.5)	1	2 (0.5)	2	0	0	0	0	0	0	0	0	0	0	0	0
Haematoma	1 (0.5)	1	2 (0.5)	2	0	0	0	0	0	0	0	0	0	0	0	0
Skin and subcutaneous tissue disorders	0	0	2 (0.5)	2	0	0	0	0	0	0	0	0	0	0	0	0
Pruritus	0	0	2 (0.5)	2	0	0	0	0	0	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)	0	0	1 (0.3)	1	0	0	0	0	0	0	0	0	0	0	0	0
Pancreatic carcinoma metastatic	0	0	1 (0.3)	1	0	0	0	0	0	0	0	0	0	0	0	0
Infections and infestations	0	0	0	0	0	0	0	0	0	0	0	0	1 (0.5)	1	0	0
Lower respiratory tract infection	0	0	0	0	0	0	0	0	0	0	0	0	1 (0.5)	1	0	0

Note: N represents number of patients treated in the relevant Safety Analysis Set and was used as the denominator for percentage calculations. n (%) represents the number and % of patients with events, and m represents the number of events in the particular study period. Patients were counted once within a system organ class and once for each unique preferred term. Adverse events were coded using MedDRA version 25.1. MedDRA: Medical Dictionary for Regulatory Activities; TEAE: treatment-emergent adverse event.

4. Discussion

The current study was designed to demonstrate therapeutic equivalence of AVT04 and RP in patients with moderate-to-severe chronic PsO, as well as to confirm that there are no clinically meaningful differences in terms of safety and immunogenicity between AVT04 and RP, in order to support overall demonstration of biosimilarity between AVT04 and RP in accordance with the EMA, FDA, and other relevant global guidance on biosimilars [20–23].

The primary endpoint of the study supports the therapeutic equivalence of AVT04 and RP in patients with moderate-to-severe chronic PsO. Secondary efficacy analyses revealed comparable improvements in disease condition across the treatment arms in the proportion of patients achieving PASI 50–100, percent PASI improvement, quality of life (DLQI), sPGA responses, and %BSA affected by chronic PsO between the treatment arms until EOS, supporting the primary endpoint analysis. The data reinforce the sustained responses of both AVT04 and RP over time. Similarly, in previous studies, RP after SC administration at weeks 0 and 4 and then once every 12 weeks, resulted in a rapid and sustained clinical response as measured by PASI [24,25].

Biosimilars are anticipated to deliver the similar clinical response as the reference product, allowing patients to switch between the two without incurring additional risks [26]. This study simulates a real-world switching scenario between RP and AVT04, as accomplished through re-randomization and switching from RP to AVT04 at week 16. After re-randomization, the percent improvement in PASI and the proportion of patients achieving PASI50–100 remained similar between patients who switched from RP to AVT04 and those who remained on the same treatment (non-switching arms). Comparable improvements in DLQI scores, sPGA responses, and %BSA between the switching and non-switching arms also show a sustained and similar clinical effect throughout the study regardless of treatment switching.

Throughout the study, the safety and tolerability profiles remained comparable between the treatment arms. Since AVT04 is being developed as a biosimilar to RP, adverse events similar to those reported for RP should be expected for AVT04. Moreover, no new safety signals were reported for AVT04 in comparison to the RP. AVT04 was found to be safe and tolerable in patients with moderate-to-severe chronic PsO. Regardless of treatment switching, the PK profiles in this study also remained consistent across all treatment arms throughout the study.

Immunogenicity may result in a shift or loss of biologic efficacy and safety, which must be considered when developing biosimilars [23]. Prior to switching, RP had higher ADA frequencies than AVT04. However, post-switching, the difference between them was observed to be decreasing toward EOS. Furthermore, these numerical differences in ADA formation did not appear to have any clinically meaningful impact on efficacy, safety, or PK profiles, reinforcing the safety in the switch. Ustekinumab (the RP) has previously been shown in clinical studies to have a low incidence of antibody formation, which did not increase after re-exposure to the treatment. Moreover, the presence of antibodies to ustekinumab did not appear to affect its therapeutic effect [27]. However, comparing the ADA status in this study to previous studies may be misleading because ADA detection is highly dependent on assay techniques. In the current study, highly sensitive ECL methods were used for the assessment of ADAs and Nabs.

Patients with body weights ≤100 kg had similar efficacy, PK, immunogenicity, and safety profiles compared to ‘all patients’ in the study. The study included more women in AVT04 (44.8%) group than in RP (33.6%); nevertheless, the two treatment groups showed similar clinical response. It has been further substantiated by subgroup analysis which revealed no noteworthy differences by gender, body weight, prior biologic therapy for psoriasis, age, ADA status, or NAb status. The homogeneity of treatment effect across various subgroups, was one of the study’s strengths, as well as the high treatment compliance for both AVT04 and RP, and high response rate demonstrated by PASI improvement of 50% or more in all study patients at week 28.

Taken together, AVT04 had similar efficacy, safety, and tolerability to RP until week 16 and up to week 52, with immunogenicity profiles displaying no clinically meaningful impact on efficacy, safety, or PK profiles of both AVT04 and RP. The similarity between the switching and non-switching arms, as well as the long-term persistence of efficacy, safety, and tolerability, corroborates the demonstration of therapeutic equivalence between AVT04 and RP in the treatment of moderate-to-severe chronic PsO. The findings add to the totality of evidence supporting biosimilarity, which in turn reinforces the assertion that the risks and benefits for patients receiving AVT04 will be the same for this patient population as those established for RP. The evidence also supports the scientific rationale for potential extrapolation to other approved indications of ustekinumab.

5. Conclusions

The study demonstrates therapeutic equivalence between AVT04 and RP as well as similar safety and tolerability in the treatment of moderate-to-severe chronic PsO. Regardless of switching, AVT04 is expected to provide a comparable and persistent effect as established for RP.

Declaration of Interest

SR Feldman is an employee of Wake Forest University School of Medicine, Winston-Salem, U.S.A., and The University of Southern Denmark, Odense, Denmark, which received payment for carrying out the study. N Reznichenko is an employee of Military Hospital (Military Unit A3309) of Military-Medical Clinical Center of Eastern Region, Zaporizhzhia, Ukraine, which received payment for carrying out the study. H Stroissnig, P Duijzings, R Ruffieux, H Otto, HN Haliduola, S Leutz, and F Berti are employees at Alvotech. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Ethics statement

The study was conducted in accordance with the Declaration of Helsinki, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and the requirements of all the applicable local regulatory authorities. Informed consent form (ICF) was appropriately signed and dated by the patient and the person obtaining the consent well before initiation of the study procedures.

Acknowledgments

The authors thank the participants who volunteered in the study and all the investigators who contributed. The authors additionally thank Joseph McClellan of Alvotech for strategic guidance, and Lorna Rettig and Shital Desai of Alvotech for medical writing assistance.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14712598.2023.2235263

Data availability statement

The data that support the findings of this study are available from the corresponding author [Heimo Stroissnig; [email protected]] upon reasonable request.

Additional information

Funding

This study was funded by Alvotech Swiss AG, Zürich, Switzerland.