A randomized, adaptive design, double-blind, 3-arm, parallel study assessing the pharmacokinetics and safety of AVT02, a high-concentration (100 mg/mL) Adalimumab biosimilar, in healthy adult subjects (ALVOPAD FIRST)

ABSTRACT

Background

This study (ALVOPAD FIRST) assessed bioequivalence, safety, and immunogenicity of AVT02, an adalimumab biosimilar, compared with reference product adalimumab (EU- and US-approved Humira®).

Methods

Healthy subjects (N = 392) were randomized 1:1:1 to receive one 40 mg dose of AVT02, EU-reference product, or US-reference product subcutaneously. An interim analysis was planned when ~30 subjects per arm had completed the study, to optimize final sample size. The primary PK parameters were C_max, AUC_0-t, and AUC_0-inf. Bioequivalence was demonstrated if the 90% confidence intervals (CI) for the ratio of geometric means for the primary pharmacokinetic (PK) parameters were all contained within the prespecified margins of 80% and 125%. Safety and immunogenicity were assessed until Day 64.

Results

The 90% CI for the ratio of geometric means for the primary PK parameters, based on Fisher’s Combination test analysis, were all contained within the prespecified bioequivalence margins of 80% and 125%, supporting the demonstration of bioequivalence between AVT02 and both EU- and US-reference product. The safety and immunogenicity profiles were comparable across all three treatment arms.

Conclusion

PK bioequivalence was supported between AVT02, US-licensed- and EU-approved-reference product adalimumab. Similar safety and immunogenicity were also demonstrated.

Trial Registration

The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03849313).

KEYWORDS:

• Adalimumab
• adaptive design
• AVT02
• bioequivalence
• biosimilar
• pharmacokinetics

1. Introduction

Adalimumab is a recombinant, fully human monoclonal immunoglobulin G1 (IgG1) antibody that binds specifically and with high affinity to the soluble and transmembrane forms of TNF-α thereby inhibiting the binding of TNF-α with its receptor and inhibiting TNF-α’s biological function. The reference product Humira (adalimumab 50 mg/mL) was approved by the United States (US) Food and Drug Administration in February 2002 and by the European Medicines Agency in January 2003 for the treatment of rheumatoid arthritis and is currently approved in a variety of inflammatory diseases including juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, chronic psoriasis, hidradenitis suppurativa and juvenile idiopathic arthritis [1,2]. More recently (from 2016), the European Medicines Agency (EMA) for European Union (EU), Food and Drug Administration (FDA) for US and Pharmaceutical and Medical Devices Agency for Japan, as well as other major Regulatory Agencies, have approved a higher concentration (100 mg/mL) in a new formulation that is well tolerated by patients and is associated with less injection site pain [2,3].

Nevertheless, the high cost of reference product adalimumab may preclude some patients from being able to access the treatment, especially considering prolonged use is indicated to treat the chronic conditions for which the product is prescribed [4–6]. A similar product that provides comparable safety and efficacy at reduced cost would fulfil a broader medical need as a more cost-effective treatment in all settings for the approved indications. While it is not possible to produce a truly identical copy of a biological product, a candidate biosimilar can be approved by Regulatory Authorities if it is highly similar in structure and function and demonstrates no clinically meaningful differences compared to the reference product with respect to quality, safety, and efficacy [7–9]. To date, the FDA have licensed six adalimumab biosimilars and the EMA have approved twelve, of which four overall have subsequently been withdrawn [10,11].

Alvotech is developing AVT02, a biosimilar of high-concentration (100 mg/mL) reference product which contains adalimumab (ATC code L04AB04), to be administered by prefilled syringe or by autoinjector. Like reference product adalimumab, AVT02 is a recombinant, fully human monoclonal IgG1 antibody. The amino acid sequences of AVT02 and reference product adalimumab are identical. The buffer used in the formulation of both AVT02 and high concentration reference product adalimumab is citrate-free, which has been shown to be associated with significantly improved adherence and persistence compared with citrate-containing adalimumab [12]. AVT02 was approved by the European Commission in December 2021 and remains under development in other jurisdictions [13].

The study reported here aimed to establish three-way bioequivalence and safety of AVT02 compared with EU-approved and US-licensed reference product 100 mg/mL adalimumab after a single dose administered in healthy subjects (ALVOPAD FIRST). The innovative adaptive design of the study optimized sample size even with limited availability of information on the pharmacokinetic (PK) profile of the new reference product formulation.

2. Patients and methods

2.1. Study design and subjects

This clinical study was a randomized, adaptive, double-blind, three-arm, parallel study to assess the pharmacokinetics, safety, tolerability, and immunogenicity of a single dose of AVT02 compared with EU-approved and US-licensed reference product 100 mg/mL adalimumab in healthy adult subjects (NCT03849313; ALVOPAD FIRST). This study was conducted at three study sites in New Zealand and Australia. Additionally, while ethnicity is not a factor influencing PK in adalimumab [2], the study aimed to enroll at least 15% of Japanese subjects to satisfy a specific regulatory request from the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan [14].

Due to the limited information on the variability of PK parameters for the high concentration formulation (100 mg/mL) of adalimumab, a two-stage adaptive design was used in this study to mitigate the risk of underpowering the study. Stage 1 of the study was complete when 90 subjects (approximately 30 subjects per treatment group) completed the study. Following an interim analysis, the sample size was reevaluated for Stage 2 of the study to ensure an optimal number of enrolled subjects. An independent consultant was responsible for the sample size re-estimation, only receiving masked treatment codes at the group level (A, B, and C), and did not have access to individual subject actual treatment codes. For the power calculation for the sample size for Stage 2, see Supplemental Information.

Key inclusion criteria were male and female healthy adults, aged 18–55 years, with a body mass index of 17.0 to 32.0 kg/m². Key exclusion criteria included previous exposure to anti-TNFα molecules including adalimumab, previous or concurrent clinically relevant pathologies (e.g. malignancies, demyelinating disorders, herpes zoster, or hepatic, gallbladder, pancreatic diseases and congestive heart failure), presence of chronic obstructive pulmonary disease, subjects with a recent infection requiring hospitalization or IV antibiotic use (within the 6 months prior to dosing) or oral or systemic antibiotics (within the 4 weeks prior to dosing), subjects who had a positive test for tuberculosis (TB) or a known history of active or latent inadequately treated TB, and subjects with clinically significant lab abnormalities.

Subjects were randomized to treatment groups in a 1:1:1 ratio (AVT02:EU-reference product:US-reference product). Randomization was stratified by 2 factors (weight and ethnicity) but consisted of 3 strata as follows: non-Japanese subjects ≤80 kg, non-Japanese subjects >80 kg, and Japanese subjects. A computer-generated randomization schedule was prepared by an independent, unblinded statistician prior to the start of the study. The study drug was administered in accordance with the randomization list. The Investigator, site staff (other than pharmacists and unblinded dosing team), Sponsor, Sponsors’ delegates (if applicable), and subjects were all blinded to treatment.

The day of dosing was scheduled up to 28 days after Screening had taken place. Subjects who completed the Screening assessments and fulfilled all of the eligibility criteria were entered into the study.

Subjects were confined to the study site from Day −1 to Day 3, which was 48 hours post dose. On Day 1, subjects received a single 40 mg dose of one of AVT02, EU-reference product, or US-reference product high concentration 100 mg/mL formulation as a subcutaneous (SC) injection. Subjects returned to the study site for an ambulant visit to conduct assessments on Days 4, 5, 6, 7, 8, 9, 12, 15, 22, 29, 36, 43, 50, and 57, with an end of study visit on Day 64.

The dose selected (40 mg in 0.4 ml; 100 mg/mL) for administration in this study is the approved therapeutic dose of adalimumab used to treat patients and on the ascending linear part of the dose–concentration curve, thus sensitive enough to detect small PK differences between test and reference product.

Study drug was administered by the study staff at the study site, ensuring treatment compliance. Administration of the product was performed in the clinical center by the investigator or designee trained to inject this product, based on the established guidance for the reference product [1,2]. In accordance with all applicable regulatory requirements, the Investigator or designated site staff maintained investigational product accountability records throughout the course of the study. The amount of investigational product received from the Sponsor and amount administered to subjects were documented.

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 of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines, New Zealand Medicines and Medical Devices Safety Authority (Medsafe) regulations, Australia Therapeutic Goods Administration (TGA) regulations, and all other applicable laws and regulations. In addition, the study was approved by two independent ethical committees: Southern Health and Disability Ethics Committee (New Zealand) and The Alfred (Australia).

2.2. Pharmacokinetic analysis

The PK population included all randomized subjects who received any amount of study drug and who had at least 1 evaluable PK parameter (n = 380) and was based on the actual treatment received if this differed from that to which the subject was randomized. An evaluable profile allowed the determination of 1 or more PK parameters and was determined at the discretion of the blinded pharmacokineticist.

PK blood samples were collected pre-dose (within the hour prior to dosing), and at the following time points post-dose: 8 hours, and at Days 1, 2, 3, 4, 5, 6, 7, 8, 11, 14, 21, 28, 35, 42, 49, 56, and 63. Samples for the determination of adalimumab were analyzed using a sandwich assay on 96-well microtiter plates using Meso Scale Discovery (MSD) electrochemiluminescence (ECL) technology, an appropriate validated bioanalytical method [15–17]. The lower limit of quantification was 7.5 ng/mL.

Serum adalimumab concentrations were listed for each subject and summarized with descriptive statistics (sample size [N], mean, SD, coefficient of variation (CV) as a percent [CV%], median, minimum, maximum, and geometric mean) by treatment group and nominal PK sampling time point. Serum concentrations of adalimumab that were below the limit of quantification were designated a value of zero for the summary of concentration–time data, except for geometric mean, where they were excluded from the calculation.

Pharmacokinetic parameters were derived using noncompartmental methods (Phoenix™ WinNonlin® v8.1 and/or SAS). The concentration–time data comprised maximum serum concentration obtained directly from the observed concentration versus time data (C_max), time to C_max, taken directly from the data (T_max), area under the serum concentration–time curve (AUC) up to time t, where t was the last time point with concentrations above the lower limit of quantification (AUC_0-t), total AUC after extrapolation from time t to time infinity, where t was the last time point with a concentration above the lower limit of quantification: AUC_0-t + Ct/K_el (AUC_0-inf), terminal elimination rate constant (K_el), apparent terminal half-life (t_1/2), apparent volume of distribution during terminal phase after subcutaneous administration (V_z/F), and apparent total serum clearance of drug after subcutaneous administration (CL/F).

2.3. Safety evaluations

The safety population included all randomized subjects who received any amount of study drug (n = 390) and was analyzed according to the actual treatment received if this differed from that to which the subject was randomized.

Routine safety parameters, including clinical laboratory safety tests, vital sign measurements, 12-lead electrocardiogram (ECG) results, and physical examination findings were assessed throughout the study. The frequency, category (per system organ class and preferred term), and severity of adverse events (AEs), including adverse drug reactions (ADRs), adverse events of special interest (AESI; identified from the known profile of the reference product [1]) and severity of injection-site reactions (ISRs), were assessed. Adverse events were reported from the time of randomization to study completion for all subjects who received the study drug.

Evaluation of ISRs was done by clinical staff following subcutaneous administration of study drug. The injection site was monitored for pain, tenderness, erythema, and swelling. Each ISR was categorized using an intensity grading scheme, from 0 (absent) to 4 (potentially life-threatening). If an ISR was graded as at least 1 (mild, corresponding to no interference of pain in activity, mild discomfort to touch, and erythema and swelling of size 2.5–5.0 cm), then it was reported as an AE. Assessment of the injection site reaction continued until the AE had resolved.

The final safety follow-up visit was conducted at Day 64, 9 weeks after receiving the dose of study drug.

2.4. Immunogenicity

The immunogenicity population included all randomized subjects who received any amount of study drug, who had at least 1 evaluable post dose immunogenicity result (positive or negative for presence of anti-drug antibodies [ADAs]) reported (n = 390), and was based on the actual treatment received, if this differed from that to which the subject was randomized.

Immunogenicity blood samples were collected pre-dose (within the 30 minutes prior to dosing), and on Days 9, 15, 29, and 64. Samples for the determination of ADAs and neutralizing antibodies (NAbs) were both analyzed using a sandwich assay on 96-well microtiter plates using MSD ECL technology; an appropriate bioanalytical method [18].

A multi-tiered strategy consisting of a screening assay, confirmation assay, titration assay and neutralizing assay was performed for the evaluation of immunogenicity as recommended by FDA and EMA [19,20]. The ADA and NAb assays were each designed as a one-assay-approach to detect anti-AVT02 and anti-reference product-adalimumab antibodies in a one assay setup following current recommendations [18].

Individual immunogenicity sample collection and ADA results (including NAb results, if available) are listed for all subjects. Detection of ADAs (positive or negative) was summarized with frequency counts by treatment group and nominal study day. The ADA titer/concentration values were also summarized if >20% of subjects within a single treatment group had positive ADA results (if available).

2.5. Statistical analysis

All statistical analyses were performed using SAS® v9.4 (SAS Institute, Inc., Cary, North Carolina). The primary bioequivalence analysis between AVT02 and EU-reference product, between AVT02 and US-reference product, and between EU-reference product and US-reference product was performed using PK parameters derived from the full PK concentration dataset (i.e. samples collected up to Day 64). The primary PK parameters used for the demonstration of bioequivalence were C_max, AUC_0-t, and AUC_0-inf.

As mentioned in Section 2.1, a two-stage adaptive design was used in this study. When 90 subjects (31 subjects each from Groups A and B, and 28 subjects from Group C) completed Stage 1 of the study, an interim analysis was performed, and the overall required study sample size was estimated to be 390 (including the 90 subjects from Stage 1) to maintain a study-wise power of 80%. Therefore, Stage 2 of the study was conducted to randomize an additional 300 subjects (100 per treatment group).

In a trial with two-stage adaptive design, for each pairwise treatment comparison and each PK parameter, we can consider the null hypothesis to be tested as:

$H_{01}\cap H_{02}$

where H₀₁ and H₀₂ are the null hypothesis for Stage 1 and Stage 2 of the trial, respectively. Under the null hypothesis, the p-values for the hypothesis tests relating to H₀₁ and H₀₂ are based on non-overlapping samples and assumed to be stochastically independent and uniformly distributed on [0, 1]. At the end of the trial, the Stage 1 and Stage 2 data should be kept distinct in the analysis rather than pooling together, as pooling the data from the two parts will not control the Type I error rate at its nominal level [21]. Fisher’s Combination (FC) test is a well-known approach with good properties, and it uses the product of the p-values from Stage 1 and Stage 2 of the trial [21].

Let p₁ and p₂ be the one-sided p-values calculated from the Stage 1 and Stage 2 data, respectively, in relation to specific null and alternative hypotheses. For example, p₁ relates to:

${\mathrm{H}}_{01}:\frac{G{M}_{AVT02}}{G{M}_{Humira}}\le 0.8{\mathrm{H}}_{11}:\frac{G{M}_{AVT02}}{G{M}_{Humira}}>0.8$

where GM denotes geometric mean. Under the null hypothesis (at the boundary), and based on the uniform (0, 1) distribution of the one-sided p-values it follows that

$-2\mathrm{l}\mathrm{n}(p_1{p}_2)\sim {\chi }_4^2$

where ${\chi }_4^2$ is the ${\chi }^2$ distribution with 4 degrees of freedom. Small values for p₁ and p₂ support rejection of the null hypothesis – this translates into a large value for the test statistic $-2\mathrm{l}\mathrm{n}(p_1{p}_2)$ . At the end of the trial, Fisher’s criterion leads to rejection of H₀ if

$p_1{p}_2\le c_{\alpha }=exp\left[-\frac{1}{2}{\chi }_4^2\left(1-\alpha \right)\right]$

where ${\chi }_4^2\left(1-\alpha \right)$ is the 100%(1 – α)-quantile of of the central ${\chi }^2$ distribution with 4 degrees of freedom, is the critical value to reject the null hypothesis, is the overall significance level for the trial. For overall one-sided $\alpha$ = 0.05, the corresponding critical value $c_{\alpha }$ = 0.0087, i.e. at the end of the trial, every null hypothesis can be rejected if for each pairwise treatment comparison and each PK parameter there is statistical significance at the one-sided 5% level. The FC test strongly controls the Type I error rate at 5% by following this procedure.

A closed formula for the confidence interval (CI) that linked directly with the two FC tests for each pairwise treatment comparison and each PK parameter was not available; therefore the 90% CIs were calculated indirectly through the one-sided p-values arising from the FC tests for each of the three pairwise treatment comparisons and each of the three PK parameters. In this approach, the confidence interval is constructed by looking at the coverage probability for the parameter of interest [22,23]. A 90% CI is equivalent to two one-sided tests at the 5% level of significance [24].

A sensitivity analysis was conducted on the complete clinical trial data using conventional methods which ignore the adaptive nature of the design, based on an analysis of variance model with treatment and demographic randomization strata as fixed effects. The Test (T) to Reference (R) ratios of the geometric least-squares (LS) means (T/R) and corresponding two-sided 90% CIs for each of the three primary PK parameters: C_max, AUC_0-t, and AUC_0-inf were presented.

3. Results

3.1. Subject disposition

Between 20 March 2019 and 27 February 2020, 620 subjects were screened and 392 were randomized in a 1:1:1 ratio (AVT02: 130 subjects; EU-reference product 100 mg/mL: 130 subjects; US-reference product 100 mg/mL: 132 subjects). Two randomized subjects did not receive investigational product and discontinued the study; one in the AVT02 group had out-of-range blood pressure values, and one in the US-reference product group experienced syncope, both on Day 1 prior to dosing. One subject who had been randomized to the EU-reference product group received the investigational product allocated to a subject in the AVT02 group due to a dosing error. The disposition of subjects is shown in Figure 1.

Figure 1. Disposition of study subjects.

a. A subject randomized to the EU-reference product group received the IP allocated to a subject in the AVT02 group due to a dosing error. Therefore, a total of 130 subjects actually received AVT02 and 129 subjects actually received EU-reference product. b. The 2 randomized subjects (1 each in the AVT02 and US-reference product groups) who did not receive the IP discontinued the study.

The distribution of dosed subjects according to the predefined randomization strata was well balanced across treatment groups. The majority of subjects (64.6%) were non-Japanese weighing ≤80 kg, 22.1% of subjects were non-Japanese weighing >80 kg, and 13.3% were Japanese.

Subject demographics were generally well-balanced across treatment groups (Table 1). The overall mean age of the subjects was 27.8 years (range, 18 to 53 years): 27.1 years in the AVT02 group, 28.5 years in the EU-reference product group, and 27.8 years in the US-reference product group. The proportion of female subjects (55.1%) was slightly higher than male subjects (44.9%), with a comparable distribution observed across the 3 treatment groups. The overall mean BMI was 24.1 kg/m² and was similar across treatment groups.

Table 1. Demographic and baseline characteristics (full analysis set)

	Statistic	AVT02 (N = 130)	EU-reference product (N = 129)	US-reference product (N = 131)	Overall (N = 390)
Age (years)	N	130	129	131	390
	Mean	27.1	28.5	27.8	27.8
	SD	6.76	8.94	8.17	8.00
Gender
Male	n (%)	57 (43.8)	55 (42.6)	63 (48.1)	175 (44.9)
Female	n (%)	73 (56.2)	74 (57.4)	68 (51.9)	215 (55.1)
Females of Childbearing Potential
Yes	n (%)	72 (98.6)	72 (97.3)	64 (94.1)	208 (96.7)
No	n (%)	1 (1.4)	2 (2.7)	4 (5.9)	7 (3.3)
Race
Asian	n (%)	28 (21.5)	26 (20.2)	28 (21.4)	82 (21.0)
Black or African American	n (%)	0 (0)	3 (2.3)	0 (0)	3 (0.8)
Caucasian/ White	n (%)	84 (64.6)	78 (60.5)	88 (67.2)	250 (64.1)
Native Hawaiian or other Pacific Islander	n (%)	4 (3.1)	4 (3.1)	3 (2.3)	11 (2.8)
Multiple	n (%)	3 (2.3)	4 (3.1)	2 (1.5)	9 (2.3)
Other	n (%)	11 (8.5)	14 (10.9)	10 (7.6)	35 (9.0)
Ethnicity
Japanese	n (%)	17 (13.1)	17 (13.2)	18 (13.7)	52 (13.3)
Non-Japanese	n (%)	113 (86.9)	110 (85.3)	111 (84.7)	334 (85.6)
Not reported^a	n (%)	0 (0)	2 (1.6)	1 (0.8)	3 (0.8)
Unknown^a	n (%)	0 (0)	0 (0)	1 (0.8)	1 (0.3)
Height (cm)	n	130	129	131	390
	Mean	171.45	170.37	169.64	170.49
	SD	9.516	8.790	9.558	9.303
Weight (kg) at Screening	n	130	129	131	390
	Mean	71.00	70.52	69.62	70.38
	SD	13.123	12.626	13.690	13.135
Weight Group at Screening
≤80 kg	n (%)	100 (76.9)	98 (76.0)	100 (76.3)	298 (76.4)
>80 kg	n (%)	30 (23.1)	31 (24.0)	31 (23.7)	92 (23.6)
Strata^a at randomization
Non-Japanese ≤80 kg	n (%)	84 (64.6)	83 (64.3)	85 (64.9)	252 (64.6)
Non-Japanese >80 kg	n (%)	29 (22.3)	29 (22.5)	28 (21.4)	86 (22.1)
Japanese	n (%)	17 (13.1)	17 (13.2)	18 (13.7)	52 (13.3)
BMI (kg/m^2)	n	130	129	131	390
	Mean	24.04	24.19	24.07	24.10
	SD	3.295	3.265	3.557	3.368

BMI = body mass index; ICF = Informed Consent Form; SD = standard deviation.

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.

Age (years) is relative to the date ICF was signed.

^aSubjects whose ethnicity was documented as ‘Not Reported’ or ‘Unknown’ in the eCRF were considered as ‘Non-Japanese’ for the purpose of stratified randomization.

Four subjects, two subjects in each of EU-reference product and US-reference product groups, tested negative for tuberculosis at Screening but were found to have positive results at the Day 64 end of study visit. For two of the subjects (one in each of EU-reference product and US-reference product groups), a retest 3 to 5 days later showed a negative result. For the remaining two subjects, the positive results were considered clinically significant and the 2 events were reported as treatment-emergent adverse events (TEAEs) and TEAEs of special interest. There were two subjects who had a negative pregnancy test at Screening who subsequently became pregnant, and both were withdrawn from the study.

In September 2019, the sponsor undertook a sample size re-estimation following an interim analysis of unblinded data for the first 90 subjects who had completed an end of study visit, comprising 31 subjects each from Groups A and B, and 28 subjects from Group C (Stage 1 of the study).

During evaluation of the data available for the interim analysis, one outlier subject was identified in the data. From the observed concentrations and the T_max, it was clear that there was vascular compromise for at least part of the dose. This subject was therefore removed from the interim analysis dataset and the statistical analysis, together with data from 5 randomly selected additional subjects (for a total of 2 subjects excluded from each arm) in order to preserve the blind.

Evaluations were based on summary statistics calculated by the independent consultant (Supplementary material, Table S1). The values for power are calculated based on the alpha levels and projections regarding realistic assumptions for Stage 2.

Assuming a sample size of 100 subjects per group in Stage 2, the levels of power for each pairwise comparison for AUC_0-inf ranged from 83.5% to 92.8% (Supplementary material, Table S2). These levels of power provide a solid justification for the choice of 100 subjects to be randomized per group in Stage 2.

Mean protocol compliance was 98.0% (n = 384/392) overall, comprising 98.5% (n = 128/130) in the AVT02 group, 97.7% (n = 127/129) in the EU-reference product group, and 97.7% (129/131) in the US-reference product group. None of the subjects who discontinued the study after dosing (n = 8) withdrew due to a TEAE.

3.2. PK results

Concentration–time profiles were similar following a single 40 mg SC dose of either AVT02, EU-reference product or US-reference product. The mean absorption profile and the profile around mean peak serum adalimumab concentrations (i.e. from Day 1 to Day 12 [264 hours post-dose]) were similar for all 3 treatment groups, with mean EU-reference product concentrations over this period being slightly lower than those observed for AVT02 and US-reference product (Figure 2 and Table S3). Following mean peak serum adalimumab concentrations, the slopes of the mean elimination phase were also similar across the 3 treatment groups.

Figure 2. Mean serum adalimumab concentrations over time by treatment (semi log; pharmacokinetic population).

Notes: Lower limit of quantification = 7.5 ng/mL.Concentrations reported as below the limit of quantification (<LLOQ) are set to zero for the calculation of summary statistics. Mean concentration values of zero are excluded from printing on log concentration scale.

The CV% of serum adalimumab concentrations for all time points were comparable across treatments. The CV% values were ≥50% during initial drug absorption up to Day 3 (48 hours post-dose), and then reduced to a range of 30% to 50% up to Day 22. From Day 29 onwards, CV% continually increased, with values greater than 100% from Day 50 and beyond (Table S3).

The primary PK parameters were similar across all treatment groups in Stage 2 of the study (Table 2). The geometric mean C_max was 3355 ng/mL in the AVT02 group, 3239 ng/mL in the EU-reference product group, and 3365 ng/mL in the US-reference product group. The geometric mean AUC_0-t was comparable across treatment groups (2,018,000 h·ng/mL in the AVT02 group, 1,971,000 h·ng/mL in the EU-reference product group, 1,954,000 h·ng/mL in the US-reference product group), as was geometric mean AUC_0-inf (2,159,000 h·ng/mL in the AVT02 group, 1,971,000 h·ng/mL in the EU-reference product group, 2,101,000 h·ng/mL in the US-reference product group). The geometric CVs% for all 3 primary PK parameters were further comparable across treatment groups.

Table 2. Summary of serum pharmacokinetic parameters for adalimumab by treatment (pharmacokinetic population)

	Median(Range)	Geometric Mean (Geometric CV%)
	Tmax(h)	Cmax(ng/mL)	AUC0-t(ng·h/mL)	AUC0-inf(ng·h/mL)	Kel(1/h)	t1/2(h)	CL/F(mL/h)	Vz/F(L)
AVT02 (N = 130)	192.0(48–672)	3355(41%)	2,018,000(48%)	2,159,000(53%)	0.00398(107%)	174.1(107%)	18.53(53%)	4.654(77%)
EU-reference product (N = 129)	168.0(75–504)	3239(38%)	1,832,000(52%)	1,971,000(52%)	0.00432(95%)	160.6(95%)	20.30(52%)	4.702(71%)
US-reference product (N = 131)	192.0(24–506)	3365(41%)	1,954,000(51%)	2,101,000(53%)	0.00416(91%)	166.6(91%)	19.04(53%)	4.577(60%)

AUC_0-inf = Area under the serum of the concentration–time curve from time zero (predose) extrapolated to infinity; AUC_0-t = Area under the serum concentration–time curve from time zero (predose) to the time of the last quantifiable concentration; CL/F = apparent total serum clearance; C_max = maximum serum concentration; CV% = coefficient of variation as a percent; K_el = terminal elimination rate constant; N = Total number of subjects in the relevant population; t_½ = apparent terminal half-life; T_max = time to C_max; V_z/F = apparent volume of distribution.

Lower limit of quantification was 7.5 ng/mL.

The 90% CI for the ratio of geometric means for the primary PK parameters of C_max, AUC_0-t, and AUC_0-inf, calculated in conjunction with the one-sided p-values from the FC test analysis, were all contained within the prespecified bioequivalence margins of 80% and 125%, supporting the demonstration of bioequivalence between AVT02 and both EU-reference product and US-reference product (Table 3). A sensitivity analysis based on the calculation of 90% confidence intervals, ignoring the adaptive nature of the trial design, supported the primary bioequivalence analyses.

Table 3. Overview of bioequivalence assessment of adalimumab primary pharmacokinetic parameters (pharmacokinetic population)

	Combined Geometric Mean Ratio (90% CI)^a
	AVT02/EU-reference product	AVT02/US-reference product	EU-reference product/US-reference product
Cmax (ng/mL)	1.05 (0.96, 1.13)	1.01 (0.93, 1.09)	0.96 (0.89, 1.05)
AUC0-t (ng·h/mL)	1.10 (1.00, 1.23)	1.03 (0.93, 1.15)	0.94 (0.84, 1.04)
AUC0-inf (ng·h/mL)	1.11 (0.99, 1.24)	1.04 (0.92, 1.16)	0.94 (0.84, 1.05)

ANOVA = analysis of variance; AUC_0-inf = Area under the serum concentration–time curve from time zero (predose) extrapolated to infinity; AUC_0-t = Area under the serum concentration–time curve from time zero (predose) to the time of the last quantifiable concentration; CI = confidence intervals; C_max = maximum serum concentration; FC = Fisher’s combination.

a. 90% CI*: FC method: p-values for Stages 1 and 2 data (P1 and P2) were recalculated using a range of limits (instead of 0.8 and 1.25) until the combined p-value* for the FC test equaled 0.05 – these final limits were the 90% CI for the Combined Geometric Mean Ratio

Results are based on an ANOVA model with treatment and randomization strata as a fixed effect. The data were logarithmically transformed prior to the analysis and then transformed back for the result presentation.

Secondary PK parameters were also similar across treatment groups (Table 2). The geometric CV% for T_max was 45% to 48% for all treatments, with T_max values ranging from 24 to 672 hours. Systemic elimination of adalimumab was consistent across the 3 treatment groups, with slow apparent total serum clearance (geometric mean CL/F values 18.53 to 20.30 mL/h) and a long terminal half-life (geometric mean values 160.6 to 174.1 hours), geometric mean K_el ranging from 0.0040 to 0.0043 1/h, and geometric mean V_z/F of 4.6 to 4.7 L. The geometric CV% for the elimination PK parameters was >50% and similar for all 3 treatment groups.

Systemic exposure to adalimumab appeared to be body weight dependent and potentially ethnicity dependent (Supplementary material, Table S4). When adjusted for differences in body weight, across all three treatment groups, there were no clinically meaningful differences observed in systemic exposure to adalimumab in terms of C_max, AUC_0-t, and AUC_0-inf based on ethnicity (Supplementary material, Table S5), with any observed differences likely due to inter-subject variability.

3.3. Safety

A total of 390 subjects received a single 40 mg SC dose of investigational product on Day 1. As discussed in Section 3.1, one subject randomized to the EU-reference product group had a dosing error and received a single dose of AVT02. Therefore, based on their actual treatment, 130 subjects received AVT02, 129 subjects received EU-reference product, and 131 subjects received US-reference product (Figure 1).

Overall, 80.0% of subjects reported at least 1 TEAE during the study, comprising 79.2% in the AVT02 group, 79.8% in the EU-reference product group, and 80.9% in the US-reference product group (Table 4). At least 1 treatment-related TEAE was reported by 34.6% of subjects overall, comprising 34.6% in the AVT02 group, 38.0% in the EU-reference product group, and 31.3% in the US-reference product group. Most TEAEs were mild in severity (75.9%), with four subjects (1.0%) reporting severe TEAEs; two in the AVT02 group (one event of lymphocyte count decreased and one event of hypoalbuminemia) and two in the US-reference product group (one event of abdominal tenderness and one event of liver function test increased). None of the severe TEAEs were considered treatment-related. TEAEs of special interest were reported by 14.9% of subjects, the majority of which were reported as mild in severity and none of which were classified as severe. The frequency of TEAEs of special interest was comparable across treatment groups. Six subjects (1.5% overall; 2 in AVT02 group, 1 in EU-reference product group, 3 in US-reference product group) reported 6 TEAEs that were Grade 3 or above laboratory abnormalities, 3 of which (2 in the AVT02 group and 1 in the US-reference product group) were severe but not treatment-related, and 1 of which was classified as moderate and was judged possibly treatment-related (neutrophil count decreased). There were no TEAEs which led to discontinuation of the study. No serious TEAEs were reported, and there were no deaths.

Table 4. Treatment-emergent adverse events (safety set)

	AVT02N = 130		EU-reference productN = 129		US-reference productN = 131		OverallN = 390
	Subjects, n (%)	Events, n	Subjects, n (%)	Events, n	Subjects, n (%)	Events, n	Subjects, n (%)	Events, n
Adverse event category
Any TEAE	103 (79.2)	256	103 (79.8)	269	106 (80.9)	300	312 (80.0)	824
Treatment-related TEAEs	45 (34.6)	84	49 (38.0)	71	41 (31.3)	71	135 (34.6)	226
Maximum severity of TEAEs
Mild	95 (73.1)		96 (74.4)		105 (80.2)		296 (75.9)
Moderate	17 (13.1)		25 (19.4)		16 (12.2)		58 (14.9)
Severe	2 (1.5)		0 (0.0)		2 (1.5)		4 (1.0)
TEAEs of special interest	19 (14.6)	23	21 (16.3)	23	18 (13.7)	21	58 (14.9)	67
TEAE leading to early withdrawal	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0
Treatment-related TEAE leading to early withdrawal	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0
TESAEs leading to early withdrawal	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0
Treatment-related TESAEs leading to early withdrawal	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0
TESAEs	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0
Treatment-related TESAEs	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0
Death	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0	0 (0.0)	0
System organ classMedDRA-preferred term
Infections and infestations	45 (34.6)	57	45 (34.9)	60	57 (43.5)	64	147 (37.7)	181
Upper respiratory tract infection	35 (26.9)	39	34 (26.4)	39	35 (26.7)	38	104 (26.7)	116
Nervous system disorders	42 (32.3)	54	36 (27.9)	49	41 (31.3)	61	119 (30.5)	164
Headache	37 (28.5)	46	32 (24.8)	43	36 (27.5)	51	105 (26.9)	140
General disorders and administration site conditions	27 (20.8)	31	32 (24.8)	37	26 (19.8)	31	85 (21.8)	99
Injection site erythema	16 (12.3)	16	10 (7.8)	10	9 (6.9)	9	35 (9.0)	35
Influenza like illness	7 (5.4)	8	5 (3.9)	5	3 (2.3)	3	15 (3.8)	16
Injection site pain	4 (3.1)	4	1 (0.8)	1	7 (5.3)	8	12 (3.1)	13
Gastrointestinal disorders	19 (14.6)	23	26 (20.2)	29	27 (20.6)	39	72 (18.5)	91
Nausea	6 (4.6)	8	5 (3.9)	5	11 (8.4)	11	22 (5.6)	24
Vomiting	0 (0)	0	2 (1.6)	2	7 (5.3)	7	9 (2.3)	9
Respiratory, thoracic and mediastinal disorders	20 (15.4)	29	15 (11.6)	17	25 (19.1)	28	60 (15.4)	74
Oropharyngeal pain	11 (8.5)	14	5 (3.9)	5	11 (8.4)	11	27 (6.9)	30
Nasal congestion	3 (2.3)	3	5 (3.9)	6	7 (5.3)	7	15 (3.8)	16
Musculoskeletal and connective tissue disorders	14 (10.8)	17	21 (16.3)	26	13 (9.9)	15	48 (12.3)	58
Back pain	7 (5.4)	7	5 (3.9)	5	4 (3.1)	4	16 (4.1)	16

AE = adverse event; IP = investigational product; MedDRA = Medical Dictionary for Regulatory Activities; TEAE = treatment-emergent AE.

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; E = Number of TEAEs in each category; % = Percentage of subjects in each category calculated relative to the total number of subjects in the relevant population.

A TEAE is defined as any AE which commence or worsened in severity on or after IP administration. Adverse events were coded using MedDRA Version 21

TEAEs reported by at least 5% of subjects in any group are reported in Table 4. At the System Organ Class level, the subject frequency of TEAEs in the AVT02 group was either similar to, or lower than, that observed in the EU-reference product and US-reference product groups. The most frequently reported TEAEs per preferred term were headache, upper respiratory tract infection, injection site erythema, oropharyngeal pain, nausea, back pain, influenza like illness, nasal congestion, and injection site pain.

The most frequently reported treatment-related TEAEs overall were injection site erythema, headache, upper respiratory tract infection, injection site pain, nausea, and influenza like illness. The frequency of local administration site reactions was 12.6% overall, and the frequency of these events was comparable across treatment groups: 13.8% in the AVT02 group, 10.9% in the EU-reference product group, and 13.0% in the US-reference product group. All injection site reactions were Grade 1 or 2 in severity; all were also reported as TEAEs of special interest, and all were considered related to the study drug. The most frequently reported local administration site reaction was injection site erythema (9.0% overall). Other administration site reactions reported included pain, macule (a flat, distinct, discolored area of skin), bruising, hypersensitivity, pruritis, and rash. Overall, local tolerability was similar across treatment groups, with small overall differences in tolerability profile which were not clinically meaningful.

TEAEs of Grade 3 or above in laboratory abnormalities were infrequent, occurring in 1.5% of subjects. Three subjects had severe events: lymphocyte count decreased, and hypoalbuminemia (AVT02 group) and liver function test increased (US-reference product group). These events were not treatment-related. One moderate Grade 2 event (neutropenia) in the EU-reference product group and one moderate Grade 3 event (neutrophil count decreased) in the US-reference product group were considered treatment-related by the Investigator.

There were no clinically meaningful findings or observations of note in vital signs or physical examinations. Analyses of ECG parameters did not reveal any clinically meaningful effect of the study drug in healthy subjects.

3.4. Immunogenicity

The onset and frequency of ADA and NAb development over time were similar in all treatment groups (Table 5). At baseline (i.e. pre-dose on Day 1), the frequency of subjects who were positive for binding ADAs was similar in the AVT02 (6.2%), EU-reference product (3.9%), and US-reference product (5.3%) groups and was not clinically meaningful. Formation of ADAs progressively increased over the duration of the study, with a similar frequency of ADA-positive subjects at Day 64 across treatment groups: 96.1% in the AVT02 group (n =124/129); 96.0% in the EU-reference product group (n =121/126); and 95.3% in the US-reference product group (n =123/129).

Table 5. Summary of immunogenicity (immunogenicity population)

		Number of Subjects (%)
		ADA Detection			NAb Detection
Study Day	N	Sample not collected/ analyzed	Negative	Positive	Negative	Positive
AVT02
Day 1 (predose)	130	0 (0)	122 (93.8)	8 (6.2)	8 (100)	0 (0)
Day 9	130	1 (0.8)	84 (64.6)	45 (34.6)	44 (95.7)	2 (4.3)
Day 15	130	0 (0)	41 (31.5)	89 (68.5)	88 (98.9)	1 (1.1)
Day 29	130	1 (0.8)	24 (18.5)	105 (80.8)	90 (85.7)	15 (14.3)
Day 64/ EOS	129	0 (0)	5 (3.9)	124 (96.1)	24 (19.4)	100 (80.6)
EU-reference product
Day 1 (predose)	129	0 (0)	124 (96.1)	5 (3.9)	5 (100)	0 (0)
Day 9	129	0 (0)	53 (41.1)	76 (58.9)	71 (93.4)	5 (6.6)
Day 15	128	4 (3.1)	24 (18.8)	100 (78.1)	97 (97.0)	3 (3.0)
Day 29	127	1 (0.8)	18 (14.2)	108 (85.0)	96 (88.9)	12 (11.1)
Day 64/ EOS	126	0 (0)	5 (4.0)	121 (96.0)	16 (13.1)	106 (86.9)
US-Reference product
Day 1 (predose)	131	0 (0)	124 (94.7)	7 (5.3)	5 (71.4)	2 (28.6)
Day 9	131	0 (0)	89 (67.9)	42 (32.1)	40 (95.2)	2 (4.8)
Day 15	131	2 (1.5)	42 (32.1)	87 (66.4)	85 (97.7)	2 (2.3)
Day 29	130	1 (0.8)	24 (18.5)	105 (80.8)	88 (83.8)	17 (16.2)
Day 64/ EOS	129	0 (0)	6 (4.7)	123 (95.3)	16 (13.0)	107 (87.0)

ADA = antidrug antibody; NAb = neutralizing antibody; EOS = End-of-study.

Notes:

The NAb assay was only performed for samples positive for ADAs, except for 1 subject in the AVT02 group (Day 9 sample) and 1 subject in the EU-reference product group (EOS sample), whose ADA results were negative and NAb was performed (with negative NAb results).

Early termination samples were excluded from the data summary.

The denominator for the percent frequency of NAb detection is the total number of NAb results for the respective treatment and study day.

In subjects positive for ADAs, the frequency of subjects who tested positive for NAbs also increased over the duration of the study, with the highest frequency of NAb positivity reported at Day 64 across all 3 treatment groups (Table 5). At Day 64, the frequency of NAb-positive subjects was comparable across treatment groups: 80.6% in the AVT02 group, 86.9% in the EU-reference product group, and 87.0% in the US-reference product group. A time lag was observed between positive detection of ADAs and formation of NAbs in all 3 treatment groups.

At Day 64, the median ADA titer in the AVT02 and EU-reference product groups (both groups, 128.0) was numerically lower compared with the US-reference product group (256.0; Supplementary material, Table S6).

4. Discussion

Establishing biosimilarity requires a stepwise approach, designed to establish that the quality, safety, and efficacy of the proposed biosimilar are highly similar to the reference product and do not result in any clinically meaningful differences compared with the reference product [25]. Demonstrating a comparable pharmacokinetic profile between an investigational biosimilar and a reference product is typically a first step in the clinical assessment of a new candidate and represents a critical aspect of the scientific justification to allow extrapolation of safety and efficacy data from one indication of a new biosimilar to other indications of the reference product [8].

The primary endpoint was met in this study to establish three-way bioequivalence of AVT02, an adalimumab biosimilar, and both EU-approved and US-licensed reference product. The 90% CI for the ratio of geometric means for the primary PK parameters of C_max, AUC_0-t, and AUC_0-inf were all contained within the prespecified bioequivalence margins of 80% and 125%, supporting the demonstration of bioequivalence. The primary analysis was substantiated by a sensitivity analysis, and all secondary PK endpoints further affirmed the primary result. Additionally, all subgroup analyses supported the overall primary analysis.

This study enrolled just under 15% Japanese subjects, which allowed subgroup analysis per ethnicity, and showed that, when adjusted for body weight, no noticeable differences were observed in systemic exposure to adalimumab between Japanese and non-Japanese subjects. Compliance of all subjects was high, with 98.0% of volunteers completing the study, contributing to the robustness of the data set.

Notably, the study demonstrated successful use of an adaptive design, which allowed enrollment of an optimal number of subjects to the study (Supplementary material, Table S1 and Table S2) in spite of limited availability of information on the PK profile of the higher concentration 100 mg/mL reference product adalimumab, which is not unusual following market approval of a new formulation. This innovative approach reduced the risk of over- or under-powering the study, notwithstanding a scarcity of reference data. The FC test was used in this study to strongly control the Type I error rate at its nominal level. It is important to emphasize that FC test is a more appropriate approach than pooling the data from the Part 1 and Part 2 of the trial, which may lead to Type I error inflation.

The safety profiles of AVT02 and both reference product adalimumab products were comparable with treatment being generally well tolerated. Overall, 80% of subjects reported at least 1 TEAE during the study, and subject frequency of TEAEs was similar across treatment groups. The most frequently reported drug reactions (incidence >10%) across clinical trials in patients receiving reference product adalimumab at therapeutic doses are infections (e.g. upper respiratory, sinusitis), injection site reactions, headache and rash, and this was consistent with results in this study [1]. The subject frequency of local administration site reactions was 12.6% overall, and the frequency comparable across groups. It should be noted that many adverse effects, like herpes zoster and other infections, occur only with long-term treatment in patients on the reference product. Those adverse events are not expected to be seen after single-dose administration in healthy volunteers.

Immunogenicity of a biological can reduce a product’s exposure thereby reducing its clinical efficacy. Reduced exposure can also have an important impact on PK and safety profiles [26]. Demonstrating a similar immunogenicity profile for a biosimilar to its reference product is therefore essential to the establishment of ‘no clinically meaningful differences’ as required by the key regulatory guidelines [7,8]. A single dose of investigational product in this population can reveal important signals like transient immunogenicity, or key differences between the candidate biosimilar and the reference product, and in this study, immunogenicity was measured up to Day 64. The onset and frequency of ADA and NAb development over time were similar in all treatment groups in this study. Over 95% of subjects in the immunogenicity population had at least one positive ADA result by end of study at Day 64, with over 80% of those subjects additionally testing positive for NAbs. The results observed in this study, while different from historical studies using different assays with reference product adalimumab, are nevertheless comparable with adalimumab studies using a similar assay setup [27,28]. Different assays lead to variability in the incidence of ADA+ subjects with reference product adalimumab [29–37]. This study utilized a homogeneous, microtiter plate based, bridging assay format using MSD ECL, which is highly sensitive, with a pre-analytical acidic dissociation step further rendering the assay highly drug tolerant. The same sensitive/highly drug tolerant platform of microtiter plate based, competitive ligand binding assay format using MSD ECL was used for detection of NAbs, resulting in rates of NAb development that are likewise higher than other published studies using different platforms [29–38]. In addition to the choice of assay, the cut point threshold chosen for a positive result will influence the overall result. But, importantly, the immunogenicity profile was comparable across all three treatment arms in this study, indicating that immunogenicity is comparable when treated with AVT02 rather than reference product adalimumab (either EU- or US-sourced), and this was also observed in a confirmatory efficacy study with AVT02 in a relevant patient population [39]. As reported in the literature, the frequency of preexisting ADAs was low and similar across groups [39–43].

These data support the assessment of PK biosimilarity of AVT02 with its 100 mg/mL reference product and complement the recently published clinical study of efficacy, safety and immunogenicity in subjects with moderate-to-severe chronic plaque psoriasis, which showed comparable objective and subjective measures of efficacy in the short and long term, in switched and continued treatment groups, as well as similar safety, tolerability, and immunogenicity profiles [39]. This confirmatory efficacy and safety study, and the PK study reported here, formed the basis of the clinical assessment of AVT02 which, along with robust structural and functional data, contributed to the recent market approval of AVT02 in Europe [13]. The clinical development program of AVT02 continues with an interchangeability study comparing multiple switches between AVT02 and EU-reference product adalimumab versus continued treatment with the EU-reference product (NCT04453137), as well as a study on auto-injector real-life handling in patients (NCT04224194).

5. Conclusions

This study supported the finding of PK bioequivalence between AVT02, US-licensed- and EU-approved-reference product adalimumab. The safety, tolerability, and immunogenicity profiles were comparable across all three treatment arms.

Author contributions

Christopher Wynne, Heimo Stroissnig. Joanna Sobierska, Eris Guenzi, Hendrik Otto, Abid Sattar, Halimu N. Haliduola, Richard Kay, and Fausto Berti were involved in the conception and design of the study. Christian Schwabe, Charlotte Lemech, Joanna Sobierska and Roshan Dias were involved in the provision of study materials and patients and acquisition of the data. Christopher Wynne, Heimo Stroissnig, Joanna Sobierska, Hendrik Otto, Abid Sattar, Halimu N. Haliduola, and Fausto Berti did the analysis and/or the interpretation of the data. All authors revised the report critically. All authors approved the final version.

Declaration of Interests

Christopher Wynne and Christian Schwabe are employees of, and hold shares in, New Zealand Clinical Research that received payment for carrying out the study. Charlotte Lemech is an employee of Scientia Clinical Research that received payment for carrying out the study. Heimo Stroissnig, Roshan Dias, Joanna Sobierska, Eric Guenzi, Hendrik Otto, Abid Sattar, Halimu N. Haliduola, and Fausto Berti are employees at Alvotech. Richard Kay’s company has received consultancy fees in relation to this study and in other studies conducted by Alvotech, but no consultancy fees have been received in relation to the writing of this manuscript.

Reviewer disclosures

One referee is an employee of Mount Sinai and receives research funds from: Abbvie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant Sciences, Eli Lilly, Incyte, Janssen Research & Development, LLC, Ortho Dermatologics, Regeneron, and UCB, Inc., and is a consultant for Aditum Bio, Almirall, AltruBio Inc., AnaptysBio, Arcutis, Inc., Aristea Therapeutics, Arrive Technologies, Avotres Therapeutics, BiomX, Boehringer-Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Dr. Reddy’s Laboratories, Evelo Biosciences, Evommune, Inc., Facilitatation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Helsinn Therapeutics, Hexima Ltd., LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica. One reviewer receives research grants from Pfizer, AbbVie, and BMS. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Acknowledgments

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

Supplemental data

Supplemental data for this article can be accessed here.

Additional information

Funding

This study was funded by Alvotech.