A multicenter, randomized, open-label, 2-arm parallel study to compare the pharmacokinetics, safety and tolerability of AVT02 administered subcutaneously via prefilled syringe or autoinjector in healthy adults

ABSTRACT

Background

AVT02 is an adalimumab biosimilar, with bioequivalence previously established along with clinical similarity. This study assessed the pharmacokinetic (PK) similarity of a single dose of 100 mg/mL AVT02 administered via prefilled syringe (PFS) or autoinjector (AI).

Research design and methods

In this open-label, 2-arm, parallel-group study, healthy adults were randomized 1:1 to receive one 40 mg (100 mg/mL) dose of AVT02 subcutaneously via PFS (N = 102) or AI (N = 105). Primary PK parameters (C_max, AUC_0-t and AUC_0-inf) were evaluated up to Day 64 of the study. Secondary PK parameters, safety, tolerability and immunogenicity were also assessed.

Results

The 90% CIs for the ratio of geometric least squares means were contained within the pre-specified 80–125% equivalence margins for the primary PK parameters, demonstrating bioequivalence of AVT02 when administered by PFS or AI. The incidence of treatment-emergent adverse events was comparable between the two groups, with a low frequency of injection site reactions observed. Immunogenicity profiles were also similar between the two groups.

Conclusion

Bioequivalence was demonstrated for a single dose of AVT02 administered via PFS or AI. These results will help to increase availability of devices for patients, enabling treatment choice and flexibility.

KEYWORDS:

• Adalimumab
• biosimilar
• pharmacokinetics
• autoinjector
• AVT02
• prefilled syringe

1. Introduction

Adalimumab is a recombinant, fully humanized monoclonal immunoglobulin G1 antibody that works as a tumor necrosis factor (TNF) receptor blocker, thereby neutralizing the biological function of TNF [1]. Reference adalimumab (Humira®; AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany) [2] is a widely used biological agent and is approved for use in a variety of inflammatory indications, including rheumatoid arthritis and psoriatic arthritis [2,3]. However, the development of, and treatment with, biologics represent a significant cost [4], and this has led to the development of several approved biosimilars by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) [2,5]. Biosimilars are highly similar in structure and function to the existing approved reference biological product. The stepwise comparative approach outlined in the FDA and EMA guidelines specifies that biosimilars should demonstrate no clinically meaningful differences in quality, safety and efficacy compared to the reference product [6,7]. Additionally, demonstration of bioequivalence for at least one of the reference product’s indications can lead to approval for the other indications, through the concept of extrapolation [6,7].

AVT02 is a biosimilar to the reference adalimumab with a high concentration (100 mg/mL) dosage and a citrate free formulation, matching the newest formulation of the reference product [2,5]. The higher concentration formulation is well tolerated by patients and is associated with less injection site pain [8]. AVT02 is currently approved in Europe, Canada, Switzerland, and the UK, and remains under development in other jurisdictions. Similar to reference adalimumab, AVT02 is also available to patients either as a prefilled syringe (PFS) or autoinjector (AI) device. Previous studies with a PFS have established bioequivalence between AVT02 and reference adalimumab in terms of pharmacokinetic (PK) parameters [9] and efficacy [10]. In healthy volunteers, the three primary PK parameters met bioequivalence for all pairwise comparisons between AVT02 and the US-licensed and EU-approved reference product adalimumab [9]. In patients with moderate to severe chronic plaque psoriasis, comparable efficacy at Week 16 in Psoriasis Area and Severity Index score percent improvement from baseline was demonstrated for AVT02 compared to reference adalimumab (91.6% for AVT02-treated subjects versus 89.6% for reference adalimumab) [10]. Furthermore, highly similar immunogenicity and safety profiles were observed between AVT02 and reference adalimumab in both studies [9,10].

The purpose of this study was to compare the PK, safety, tolerability, and immunogenicity of AVT02 when administered either via PFS or with a newly developed AI in healthy adult subjects. As per FDA and EMA recommendations, this study was designed to fulfil the requirements to demonstrate bioequivalence between the two devices.

2. Patients and methods

2.1. Study design and subjects

This randomized, open-label, 2-arm, parallel-group study (NCT03983876) was conducted at two sites in New Zealand (Christchurch, NZ; Auckland, NZ). The study consisted of a screening period, admission and treatment period, assessment period and end of study (EOS) visit. Healthy subjects eligible for inclusion were male or female adults aged 18–55 years, with body mass index (BMI) 18.5–32.0 kg/m². Subjects were excluded from the study if they had evidence of clinically relevant pathology, were unable to follow protocol instructions in the opinion of the investigator, had a history of relevant drug and/or food allergies, or had a known history of previous exposure to adalimumab or any other anti-TNF-α molecules.

Subjects were randomized (1:1) using an electronic case report forms system (Viedoc), and according to a computer-generated randomizations schedule prepared by a statistician prior to study start. Randomization was stratified by low, medium and high body weight categories. All subjects who were randomized into the study, regardless of which treatment the subject actually received, were included in the full analysis set. Demographic data and other baseline characteristics are presented for the full analysis set.

Subjects received a single dose (40 mg in 0.4 mL;100 mg/mL) of AVT02 on Day 1 by s.c. administration via PFS (AVT02-PFS group) or an AI (AVT02-AI group). This dose was selected as it represents the approved therapeutic dose of adalimumab used for all indications and is on the ascending linear part of the dose-concentration curve, providing a level of sensitivity able to detect small PK differences between PFS and AI [9]. AVT02 was administered to the abdomen, in bed, in a supine or semi-supine position. Subjects fasted for at least 4 hours (water was allowed) before administration of AVT02 by a member of the clinical team. Baseline assessments were performed on Day 1, prior to dosing.

The study was conducted in accordance with the protocol, the ethical principles derived from international guidelines including the Declaration of Helsinki, applicable International Council for Harmonization Good Clinical Practice Guidelines, New Zealand Medicines, and Medical Devices Safety Authority (Medsafe) regulations, and applicable laws and regulations. The study protocol, all study protocol amendments, participant information and Informed Consent Forms were reviewed and approved by each site’s independent ethics committee at each study site prior to implementation in the study. Written informed consent was obtained from each subject before participation in the study.

2.2. Pharmacokinetic analysis

The PK set included all randomized subjects who received the full dose of the study drug and who had at least one evaluable PK parameter. Assessments were based on the actual treatment received if this differed from the treatment allocated at randomization. PK blood samples were collected on Day 1 (pre-dose), and at the following time points post-dose: 8 hours, and on Days, 2, 3, 4, 5, 6, 7, 8, 9, 12, 15, 22, 29, 36, 43, 50, 57, and 64. PK parameters were derived using noncompartmental methods (Phoenix WinNonlin™ v8.1 and/or SAS) and calculated from serum concentration-time data. The primary PK parameters used to demonstrate bioequivalence of AVT02 administered via PFS or AI were maximum serum concentration (C_max), area under the serum concentration-time curve from time zero (pre-dose) to the time of the last quantifiable concentration (AUC_0-t) and area under the serum concentration-time curve from time zero (pre-dose) extrapolated to infinity, where t is the last time point with a concentration above the lower limit of quantification: AUC_0-t + C_t/ elimination rate constant (K_el) (AUC_0-inf). The secondary PK parameters assessed were time to maximum serum concentration (T_max), K_el, elimination half-life (T_1/2), volume of distribution (V_Z/F) and apparent clearance (CL/F). Quantitation of serum adalimumab biosimilar concentrations was performed using a validated sandwich assay on 96-well microtiter plates using Meso Scale Discovery electrochemiluminescence technology. This was designed and validated as a one assay setup as per current guidelines [11,12] and recommendations [13]. PK parameters and bioequivalence assessments are presented for the PK set.

2.3. Safety evaluations

The safety set included all randomized subjects who received any amount of study drug and was based on the actual treatment received if this differed from the treatment allocated at randomization. Day 1 local injection site reaction (ISR) assessments took place 15 minutes, 30 minutes, 1 hour, 2 hours, and 8 hours post-dose. Safety parameters assessed included treatment-emergent adverse events (TEAEs), clinical laboratory assessments (hematology, clinical chemistry, coagulation, urinalysis), physical examination findings and ISRs. All safety data are presented for the safety set.

2.4. Immunogenicity

The immunogenicity set included all randomized subjects who received any amount of study drug and who had at least one evaluable post-dose immunogenicity result reported (i.e. positive or negative for presence of anti-drug antibodies [ADAs]) and was based on the actual treatment received if this differed from the treatment allocated at randomization. Blood sampling for immunogenicity was collected on Day 1, 30 minutes prior to injection, and at Days 9, 15, 29 and 64. Immunogenicity assessments included ADAs and neutralizing antibodies (NAbs). The detection of ADAs and NAbs was each performed as a one assay setup for anti-AVT02 and anti-reference-adalimumab following current recommendations [14]. A multi-tiered approach was used consisting of a screening assay, confirmation assay, titration assay and neutralizing assay to evaluate immunogenicity as per the FDA and EMA guidelines [15,16]. ADA and NAb assessments are presented for the immunogenicity set.

2.5. Statistical analysis

The log-transformed primary endpoints (C_max, AUC_0–t and AUC_0–inf) were analyzed by analysis of variance (ANOVA) with treatment as a fixed effect. Bioequivalence was assessed using the ratio of the geometric least squares (LS) means and corresponding 2-sided 90% confidence interval (CI) for each of the three serum adalimumab biosimilar PK endpoints: C_max, AUC_0-t, and AUC_0-inf. This method corresponded to the two 1-sided test procedure, with each 1-sided t-test at the 5% significance level. Equivalence was concluded if the 90% CI for the ratio of geometric LS means were entirely contained within the prespecified bioequivalence margins of 80% to 125%. The planned total sample size (N = 204) was based on the criteria that the 90% CI for the ratio between the geometric means of the three primary PK parameters fell within 80% and 125%. Power calculations showed that, assuming the maximum true ratio of the means to be 1.03, a sample size of 204 patients was needed to achieve 90% power to show bioequivalence.

Demographics, serum concentrations and safety data were summarized using descriptive statistics. Baseline was defined as the last available, valid, non-missing assessment (scheduled or unscheduled) prior to dosing. If subjects withdrew from the study prior to completion for any reason, all data compiled up to the point of discontinuation were used for analysis. If subjects withdrew prematurely from study treatment, their data were to be included in all analyses regardless of the duration of treatment. There was no imputation for missing safety or immunogenicity data, unless otherwise stated. Missing PK concentrations were not imputed, except if the Day 1 pre-dose concentration was missing, then a value of zero was imputed for this time point.

All statistical analyses were performed using SAS v9.4 (SAS Institute, Inc., Cary, North Carolina). The PK parameters were computed using Phoenix WinNonlin™ v8.1 (Certata, L.P. Princeton, New Jersey, US) and/or SAS. Graphics were prepared using the same version of SAS.

3. Results

3.1. Patient disposition

Between 1 July 2019 and 3 December 2019, 207 subjects were randomized to the study, with 102 assigned to the AVT02-PFS group and 105 to the AVT02-AI group (Figure 1). Of the randomized subjects, three subjects were not dosed (two subjects in the AVT02-PFS group and one in the AVT02-AI group). Patient characteristics between the two groups were generally balanced, with similar demographics and baseline characteristics (Table 1). The overall mean ± standard deviation age of the subjects was 26.9 ± 8.2 years: 26.3 ± 7.3 years in the AVT02-PFS group and 27.4 ± 9.0 years in the AVT02-AI group. Overall, the proportion of female subjects (56.0%) was slightly higher than male subjects (44.0%), with a similar distribution across both groups. The majority of female subjects were of childbearing potential (95.7%) in both groups. The overall mean BMI was 24.8 kg/m² and was similar between treatment groups. Randomization was stratified by low (50.0 to 81.9 kg), medium (82.0 to 94.9 kg), and high (95.0 to 140.0 kg) body weight categories. The majority of dosed subjects (71.6%) belonged to the low weight category and the distribution of subjects in each category was well balanced between treatment groups.

Figure 1. Patient disposition. The three subjects (two in the AVT02-PFS group and one in the AVT02-AI group) who did not receive AVT02 were withdrawn from the study. AI: autoinjector; PFS: prefilled syringe.

Table 1. Baseline characteristics (Full analysis set).

Characteristic	AVT02-PFS N = 102	AVT02-AI N = 105	Total N = 207
Age (years); mean ± SD	26.3 ± 7.3	27.4 ± 9.0	26.9 ± 8.2
Male/Female (participants); %	45.1/54.9	42.9/57.1	44.0/56.0
Women of childbearing potential (participants); n (%)	55 (98.2)	56 (93.3)	111 (95.7)
Race (participants); n (%)
Asian	12 (11.8)	12 (11.4)	24 (11.6)
Black or African American	2 (2.0)	0	2 (1.0)
White	72 (70.6)	70 (66.7)	142 (68.6)
Other*	16 (15.7)	23 (21.9)	39 (18.8)
Ethnicity; n (%)
Hispanic/Latino	8 (7.8)	6 (5.7)	14 (6.8)
Not Hispanic/Latino	90 (88.2)	97 (92.4)	187 (90.3)
Not reported/Unknown	4 (3.9)	2 (2.0)	6 (2.9)
Height (cm); mean ± SD	170.7 ± 8.7	172.4 ± 9.4	171.6 ± 9.1
Weight (kg); mean ± SD	72.4 ± 13.6	74.4 ± 13.0	73.4 ± 13.3
BMI (kg/m^2); mean ± SD	24.7 ± 3.4	24.9 ± 3.2	24.8 ± 3.3

*Includes Native Hawaiian/other Pacific Islander, Multiple, and Other. Age (years) is relative to the date the ICF was signed. n: number of subjects in each category; N: total number of subjects in the relevant population; %: percentage of subjects in each category calculated relative to the total number of subjects in the relevant population. Percentage of females of childbearing potential and reasons for not being of childbearing potential calculated relative to the total number of female subjects in the relevant population. AI: autoinjector; BMI: body mass index; ICF: informed consent form; PFS: prefilled syringe; SD: standard deviation.

3.2. PK results

Following a single 40 mg s.c. dose of AVT02, mean adalimumab serum concentrations, observed up to Day 64 of the study, were comparable between the AVT02-PFS and AVT02-AI groups. Following mean peak serum adalimumab biosimilar concentrations, the slopes of the mean elimination phase were also similar between treatment groups, with slightly lower mean concentrations observed for the AVT02-PFS group (Figure 2).

Figure 2. Mean serum Adalimumab biosimilar concentrations over time (semi-logarithmic, PK set). Lower limit of quantification = 7.5 ng/mL. Concentrations reported as below the lower limit of quantification (ÃLLOQ) are set to zero for the calculation of summary statistics. Mean concentration values of zero are excluded from printing on log concentration scale. AI: autoinjector; PFS: prefilled syringe

The primary PK parameters were similar across the two groups. The geometric mean C_max were similar between the two groups (3570 ng/mL for the AVT02-PFS group and 3586 ng/mL for the AVT02-AI group), with a moderate and identical geometric coefficient of variance percentage (CV%) of 38% for both groups (Table 2). The geometric mean values for AUC_0-t and AUC_0-inf were comparable between groups, although slightly higher mean values and slightly lower geometric mean CV% were observed for the AVT02-AI group compared to the AVT02-PFS group in both parameters (Table 2). The 90% CIs for the ratios of geometric LS means for the primary PK parameters C_max, AUC_0-t, and AUC_0-inf were all contained within the prespecified margins of 80% and 125% (Table 3). The CV% of serum adalimumab biosimilar concentrations for all time points were comparable across treatments (Supplementary Table 1).

Table 2. Summary of PK parameters by device (PK set).

	Median (Range)	Geometric Mean (Geometric CV%)
Treatment	Tmax (h)	Cmax (ng/mL)	AUC0-t (h$\cdot$ng/mL)	AUC0-inf (h$\cdot$ng/mL)	Kel (1/h)	T1\2 (h)	CL/F (mL/h)	Vz/F (L)
AVT02-PFS (N = 99)	168 (48–503)	3570 (38%)	1,961,000 (59%)	2,131,000 (61%)	0.0048 (98%)	144.9 (98%)	18.77 (61%)	3.924 (70%)
AVT02-AI (N = 99)	168 (72–672)	3586 (38%)	2,104,000 (57%)	2,286,000 (59%)	0.0045 (105%)	153.0 (105%)	17.50 (59%)	3.863 (73%)

Lower limit of quantification was 7.5 ng/mL. AI: autoinjector; AUC: area under the curve; AUC_0-t: area under the serum concentration-time curve from time zero (pre-dose) to the time of the last quantifiable concentration; AUC_0-inf: area under the serum concentration-time curve from time zero (pre-dose) extrapolated to infinity; CL/F: apparent total serum clearance; C_max: maximum serum concentration; CV%: coefficient of variance percentage; K_el: terminal elimination rate constant; PFS: prefilled syringe; T_1/2: apparent terminal half-life; T_max: time to C_max; V_z/F: apparent volume of distribution.

Table 3. Bioequivalence assessment of Adalimumab primary PK parameters (PK set).

		Ratio of geometric LS means (%) (90% CI)
Parameter	n (AVT02-AI vs AVT02-PFS)	AVT02-AI/AVT02-PFS
Cmax (ng/mL)	99 vs 99	100.45 (92.18, 109.45)
AUC0-t (h·ng/mL)	99 vs 99	107.31 (94.55, 121.79)
AUC0-inf (h·ng/mL)	97 vs 95	107.22 (94.00, 122.30)

Results are based on an analysis of variance model with treatment as a fixed effect. The data were logarithmically transformed prior to the analysis then transformed back for the result presentation. AI: autoinjector; AUC: area under the curve; AUC_0-t: area under the serum concentration-time curve from time zero (pre-dose) to the time of the last quantifiable concentration; AUC_0-inf: area under the serum concentration-time curve from time zero (pre-dose) extrapolated to infinity; CI: confidence interval; C_max: maximum serum concentration; LS: least squares; PFS: prefilled syringe; SD: standard deviation.

The median T_max and the geometric means for the other secondary PK parameters (K_el, t_½, V_z/F, and CL/F) were similar between the two groups (Table 2). Systemic absorption of adalimumab had a median T_max of 168 hours after AVT02-PFS administration (range: 48 to 503 hours) and AVT02-AI administration (range: 72 to 672 hours) (Table 2). The geometric CV% for T_max was 44–46%. Systemic elimination of adalimumab was consistent between the two groups, with slow apparent total serum clearance (geometric mean CL/F values <20 mL/h), a long T_1/2 (geometric mean values >140 h), similar K_el, and geometric mean V_z/F values of approximately 3.9 L (Table 2).

3.3. Safety

A total of 204 subjects (100 in the AVT02-PFS group and 104 in the AVT02-AI group) received a single s.c. dose of AVT02. Treatment with a single dose of AVT02 40 mg administered using a PFS or AI was safe and well tolerated in healthy subjects during this study. Safety results are shown in Table 4. The frequency of TEAEs was similar between the two groups (85.0% in the AVT02-PFS group and 84.6% in the AVT02-AI group). Three subjects (1.5% overall, two in AVT02-PFS group and one in the AVT02-AI group) reported four serious TEAEs during the study. The frequency of TEAEs of special interest was comparable between treatment groups (17.0% in the AVT02-PFS group and 14.4% in the AVT02-AI group). The frequency of local administration site reaction adverse events of special interest was low, and the frequency of these events was similar between treatment groups. The most frequently reported local administration site reaction was injection site erythema. No TEAEs leading to study discontinuation or serious TEAEs leading to death occurred during the study.

Table 4. Summary of safety data by treatment group (Safety set).

Parameter	AVT02-PFS N = 100		AVT02-AI N = 104		Total N = 204
	Subjects, n (%)	Events, n	Subjects, n (%)	Events, n	Subjects, n (%)	Events, n
Patients with 1≥ TEAE	85 (85.0)	232	88 (84.6)	232	173 (84.8)	464
Patients with 1≥ serious TEAE	2 (2.0)	2	1 (1.0)	2	3 (1.5)	4
Patients with 1≥ TEAESI	17 (17.0)	19	15 (14.4)	19	32 (15.7)	38
System organ class MedDRA preferred term
Infections and Infestations	56 (56.0)	74	47 (45.2)	61	103 (50.5)	135
Upper respiratory tract infection	41 (41.0)	46	36 (34.6)	44	77 (37.7)	90
Viral upper respiratory tract infection	4 (4.0)	4	7 (6.7)	7	11 (5.4)	11
Nasopharyngitis	5 (5.0)	5	0	0	5 (2.5)	5
Nervous system disorders	34 (34.0)	47	32 (30.8)	42	66 (32.4)	89
Headache	32 (32.0)	44	31 (29.8)	41	63 (30.9)	85
General disorders and administration site conditions	26 (26.0)	34	22 (21.2)	30	48 (23.5)	64
Injection site erythema	11 (11.0)	11	12 (11.5)	12	23 (11.3)	23
Catheter site related reaction	6 (6.0)	6	4 (3.8)	4	10 (4.9)	10
Respiratory, thoracic and mediastinal disorders	17 (17.0)	19	20 (19.2)	26	37 (18.1)	45
Oropharyngeal pain	6 (6.0)	6	6 (5.8)	7	12 (5.9)	13
Nasal congestion	4 (4.0)	4	7 (6.7)	7	11 (5.4)	11
Skin and subcutaneous tissue disorders	7 (7.0)	9	12 (11.5)	16	19 (9.3)	25
Rash	2 (2.0)	2	7 (6.7)	9	9 (4.4)	11

A TEAE is defined as any AE which commenced or worsened in severity on or after the start of AVT02 administration. AEs were coded using MedDRA Version 21.1. n: number of subjects in each category (subjects with multiple events in each category are counted only once per category); N: total number of subjects in the relevant population; %: percentage of subjects in each category calculated relative to the total number of subjects in the relevant population. AE: adverse event; AI: autoinjector; MedDRA: Medical Dictionary for Regulatory Activities; PFS: prefilled syringe; TEAE: treatment-emergent adverse event; TEAESI: treatment-emergent adverse event of special interest.

3.4. Immunogenicity

The onset and frequencies of ADA and NAb development over time were similar in both treatment groups (Table 5). Formation of binding ADAs progressively increased over the duration of the study and were detectable at the end of study visit on Day 64 in 100.0% and 97.0% of subjects in the AVT02-PFS and the AVT02-AI groups, respectively. Of those subjects positive for ADAs, a further 85.7% and 86.5% tested positive for NAbs in the AVT02-PFS and AVT02-AI groups, respectively. As expected, there was a lag time between positive detection of ADAs and formation of NAbs in both groups.

Table 5. Summary of immunogenicity results by treatment group (Immunogenicity set).

			Number of subjects (%)
			ADA Detection			NAb Detection
Treatment	Study Day	N	Sample not collected/analysed	Negative	Positive	Negative	Positive
AVT02 AI	Day 1	104	0 (0)	88 (84.6)	16 (15.4)	16 (100)	0 (0)
AVT02 AI	Day 9	103	1 (1.0)	49 (47.6)	53 (51.5)	52 (98.1)	1 (1.9)
AVT02 AI	Day15	101	2 (2.0)	21 (20.8)	78 (77.2)	77 (98.7)	1 (1.3)
AVT02 AI	Day 29	100	1 (1.0)	6 (6.0)	93 (93.0)	73 (78.5)	20 (21.5)
AVT02 AI	Day 64/EOS	99	0 (0)	3 (3.0)	96 (97.0)	13 (13.5)	83 (86.5)
AVT02 PFS	Day 1	100	0 (0)	88 (88.0)	12 (12.0)	10 (83.3)	2 (16.7)
AVT02 PFS	Day 9	100	0 (0)	41 (41.0)	59 (59.0)	55 (93.2)	4 (6.8)
AVT02 PFS	Day15	100	1 (1.0)	16 (16.0)	83 (83.0)	79 (95.2)	4 (4.8)
AVT02 PFS	Day 29	99	1 (1.0)	7 (7.1)	91 (91.9)	68 (74.7)	23 (25.3)
AVT02 PFS	Day 64/EOS	98	0 (0)	0 (0)	98 (100)	14 (14.3)	84 (85.7)

Day 1 sample was collected prior to dose administration. The NAb assay was only performed for samples positive for ADAs. Unscheduled and early termination samples were excluded from data summaries. The denominator for the percent frequency of NAb detection is the total number of positive ADA detections for the respective study day. ADA: anti-drug antibody; AI: autoinjector; EOS: End of study; NAb: neutralizing antibody; PFS: Pre-filled syringe.

4. Discussion

Regulatory bodies including the FDA and EMA mandate biosimilar developers to provide comparative data, evaluated in a stepwise manner, that demonstrate high similarity in chemical structure, biological function, efficacy, safety and immunogenicity to the reference biological medicine, with no clinically meaningful differences [6,7]. Furthermore, assessment of delivery devices is requested to ensure clinical attributes such as PK are not impacted [17]. Reference adalimumab and biosimilars (including AVT02) are typically administered by s.c. injection via PFS or AI, with the availability of different devices accommodating differing patient needs [18].

In the current study, the primary objective was met, and bioequivalence was demonstrated between AVT02-PFS and AVT02-AI following a single s.c. administration of 40 mg AVT02 in healthy subjects. While the average age of the study participants (mean 26.9 ± 8.2) is younger than the typical real-life population [19], the primary endpoint – detection of any difference in PK parameters C_max, AUC_0-t, and AUC_0-inf – is most effectively assessed in a younger population without co-morbidities and complications of disease which may influence study results. Real-life use in participants with rheumatoid arthritis has been assessed in another study [20].

The PK profile similarity of AVT02 and reference adalimumab administered via PFS has been demonstrated in a previous study of healthy subjects without comorbidities [9]. The current study was designed to demonstrate bioequivalence of AVT02 administered via PFS or AI. The bioequivalence criteria were met for all three PK parameters tested. The 90% CIs of the ratios of geometric LS means for the primary PK parameters C_max, AUC_0-t, and AUC_0-inf were all contained within the prespecified bioequivalence margins of 80% and 125%, demonstrating systemic exposure after AVT02-AI administration is equivalent to exposure after AVT02-PFS administration. Furthermore, the results for the secondary PK endpoints support the bioequivalence results for the primary PK endpoints.

Overall, the safety and tolerability profile of AVT02 in this study is consistent with that observed in previous studies with AVT02 [9,10]. Similar safety profiles were observed between the AVT02-PFS and AVT02-AI groups, with similar frequency of local administration site reactions. The frequency of TEAEs reported were similar across both groups, with 84.8% of subjects overall reporting at least one TEAE during the study. ISRs were reported by 8.8% of subjects (9.0% in the AVT02-PFS group and 8.7% in the AVT02-AI group). All local ISRs were Grade 1 to 2 in severity; no Grade 3 or Grade 4 reactions were observed. The most common TEAEs were upper respiratory tract infections and headaches, consistent with the known side effects of reference adalimumab [2] and those reported for other adalimumab biosimilars [21–23]. In addition, the safety profiles of AVT02-PFS and AVT02-AI were comparable in terms of TEAEs. Infections and Infestations was also the most-frequently-reported TEAE in the previously published PK study conducted with PFS, also in healthy volunteers [9] and with similar variability (34.6% AVT02 participants, 34.9% EU-reference product participants, and 43.5% US-reference product participants). Therefore, the variation between those treated with PFS and those treated with AI in the present study are considered to be within expected and demonstrated margins, and to have no clinically meaningful impact.

The comparable immunogenicity profile, specifically the time of onset and frequencies and development of ADAs and NAbs, between AVT02-PFS and reference adalimumab has been previously established in healthy adults [9] and psoriatic patients [10]. This study further demonstrates that AVT02 delivered by AI had an immunogenicity profile similar to that observed with a PFS.

As the study was conducted in healthy adults to ensure that the sensitivity to detect small differences in PK parameters between the two groups was optimal, the ease of use of the delivery devices for patients with limited dexterity was not evaluated. However, this has been established in a separate study [20]. In addition, as the study was powered to assess differences in PK profile between the two groups, small differences in safety and immunogenicity could have been missed in the relatively small sample size.

5. Conclusions

The primary objective was met and the observed results demonstrated PK similarity between a single s.c. 40 mg (100 mg/mL) dose of AVT02 using a PFS or AI device in healthy subjects. AVT02 was generally well tolerated in healthy subjects when administered using an AI device, with a safety and immunogenicity profile similar to that observed with AVT02 administered using a PFS. Overall, the results of this study demonstrated bioequivalence between AVT02 administered by an AI or by a PFS. Results from this study support patients being provided with a selection of devices and bringing choice and flexibility to their treatment regimen.

Declaration of interests

C Wynne and C Schwabe are employees of, and hold shares in New Zealand Clinical Research, which received payment for carrying out the study. H Stroissnig, R Dias, J Sobierska, H Otto, A Sattar, HN Haliduola, E Edwald, and F Berti are employees of Alvotech. E Guenzi was an employee of Alvotech at the time of the study. 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.

Author contributions

H Stroissnig, R Dias, J Sobierska, E Guenzi, H Otto, A Sattar, HN Haliduola, E Edwald and F Berti conceived and designed the study; C Wynne and C Schwabe recruited patients and were involved in data acquisition; H Stroissnig, R Dias, J Sobierska, H Otto, A Sattar, HN Haliduola, E Edwald and F Berti were involved in the analysis and interpretation of the data; all authors contributed to drafting the paper and revising it critically for intellectual content. All authors have read and agreed to the published version of the manuscript.

Ethical approval

The study was conducted in accordance with the protocol, the ethical principles derived from international guidelines including the Declaration of Helsinki, applicable International Council for Harmonization Good Clinical Practice Guidelines, New Zealand Medicines, and Medical Devices Safety Authority (Medsafe) regulations, and applicable laws and regulations. The study protocol, all study protocol amendments, participant information and Informed Consent Forms were reviewed and approved by each site’s independent ethics committee at each study site prior to implementation in the study. Written informed consent was obtained from each subject before participation in the study.

Acknowledgments

The authors thank the subjects who participated in the study and all the investigators who contributed. Medical writing support was provided by Sola Lawal and Anna Chapman-Barnes (eluSCIdate ltd, Meggen, Switzerland) and funded by Alvotech. This work was presented at EULAR 2022 in Copenhagen as Wynne C, Stroissnig H, Dias R, et al AB1586-PARE Multi-Center, Randomized, Open-Label, 2-Arm Parallel Study to Compare the Pharmacokinetics, Safety and Tolerability of AVT02 Administered Subcutaneously Via Prefilled Syringe or Autoinjector in Healthy Adult Volunteers. Annals of the Rheumatic Diseases 2022;81:1891-1892.

Data availability statement

The datasets generated and/or analyzed during the current study are available from the sponsor on reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14712598.2022.2131391

Additional information

Funding

This study was funded by Alvotech Swiss AG.