‘Totality of Evidence’ Approach in the Development of GP2017, an Approved Adalimumab Biosimilar

Abstract

Introduction

Hyrimoz^®, (GP2017 [SDZ-ADL]), is a biosimilar to Humira^® (REF-ADL). SDZ-ADL was approved in 2018 by both the United States Food and Drug Administration (US FDA) and European Medicines Agency (EMA) for the indications of REF-ADL not protected by orphan exclusivity. In 2023, the US FDA and EMA also approved a citrate-free high-concentration formulation (HCF) of SDZ-ADL.

Totality of Evidence—the approach

Approval of SDZ-ADL was based on data gathered using the US FDA, EMA and World Health Organization (WHO)-recommended step-wise Totality of Evidence approach. This approach is a robust dataset confirming high confidence in analytical, functional, pharmacokinetic (PK) and clinical biosimilarity between the biosimilar and reference medicine determined through analytical and clinical investigation.

Evidence of biosimilarity

Evidence supporting the biosimilarity of SDZ-ADL and REF-ADL was reported at each stage of investigation. Comprehensive comparative analytical and functional assessments demonstrated that SDZ-ADL was analytically indistinguishable from REF-ADL in required critical quality attributes, including receptor binding. Phase I clinical data showed PK similarity of SDZ-ADL and REF-ADL in healthy volunteers, with similar safety, tolerability and immunogenicity profiles. Phase III confirmatory efficacy and safety studies, ADACCESS (included in US/EU dossiers) and ADMYRA (separate to US/EU dossiers), both confirmed that SDZ-ADL’s efficacy, safety, and immunogenicity matched REF-ADL in all patient groups with no clinically meaningful differences. More recently, this data package was the basis for a citrate-free HCF of SDZ-ADL to be developed, and its PK, safety and immunogenicity were confirmed against the initially approved formulation of SDZ-ADL.

Conclusion

Overall, the Totality of Evidence provided for biosimilar adalimumab, SDZ-ADL, confirmed the analytical, functional and clinical similarity of SDZ-ADL to REF-ADL, supporting its regulatory approval and providing a data bridge with which to evaluate and support the approval of citrate-free HCF SDZ-ADL for clinical use.

Plain Language Summary

A biosimilar is a type of medicine that is designed to match the structure and function of a ‘reference’ biologic medicine. Hyrimoz^® (SDZ-ADL) is a biosimilar of the adalimumab reference medicine, Humira^® ([REF-ADL]). SDZ-ADL was approved in the US and Europe in 2018. For SDZ-ADL to be approved, a collection of evidence needed to be created, called the ‘Totality of Evidence.’ The purpose of this collection of data is to show there is a high confidence that the new biosimilar medicine matches the reference medicine, from the structure of the medicine to the effect of the medicine on the human body. For SDZ-ADL, this investigation started with comparing the physical structure and other functional properties of SDZ-ADL versus REF-ADL and ended with clinical studies in both healthy volunteers and in patients with diseases treated with adalimumab. This Totality of Evidence gathered for biosimilar adalimumab, SDZ-ADL, confirmed the similarity of SDZ-ADL to REF-ADL and therefore supported the approval of SDZ-ADL. In 2018, a citrate-free high-concentration version (high concentration formulation [HCF]) of REF-ADL was launched that matched REF-ADL. HCF REF-ADL has since become the primary formulation of REF-ADL used in practice. In 2023, a HCF version of SDZ-ADL was also approved in the US and EU based on evidence confirming that HCF SDZ-ADL matched SDZ-ADL. As SDZ-ADL had been previously confirmed to match the reference medicine, this meant that HCF SDZ-ADL could be directly compared against SDZ-ADL to confirm biosimilarity and support its approval.

Key Summary Points

Hyrimoz® (GP2017 [SDZ-ADL]) is a biosimilar to reference adalimumab (Humira® [REF-ADL]) and was approved in 2018 by both the United States Food and Drug Administration and European Medicines Agency based on the Totality of Evidence.

Comprehensive comparative analytical and functional assessments demonstrated that SDZ-ADL was analytically indistinguishable from REF-ADL, and confirmatory clinical studies established the clinical similarity between the two medicines in healthy volunteers and patients with immune-mediated disorders.

A citrate-free high-concentration formulation of SDZ-ADL (HCF-SDZ-ADL) was also approved in 2023 in the US and Europe.

Comparable pharmacokinetics and matching safety and immunogenicity between HCF-SDZ-ADL and SDZ-ADL were confirmed within a Phase I bridging study.

Introduction

Humira^® (Adalimumab; AbbVie Inc., North Chicago, IL, USA [REF-ADL]) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody targeting tumor necrosis factor alpha (TNF-α) [1, 2]. Adalimumab is highly specific for TNF-α, binding to no other member of the TNF superfamily. Adalimumab is a potent antagonist of TNF-α, neutralizing both its soluble and transmembrane forms, with a half-life of approximately 10–20 days [2].

REF-ADL is approved for the treatment of immune-mediated inflammatory rheumatic diseases (rheumatoid arthritis [RA], juvenile idiopathic arthritis, axial spondyloarthritis [EU only; including ankylosing spondylitis] and psoriatic arthritis), inflammatory bowel diseases (Crohn’s disease and ulcerative colitis), dermatologic conditions (psoriasis and hidradenitis suppurativa) and uveitis [1, 3]. REF-ADL was first approved for use in 2002 at a concentration of 50 mg/ml [4], with the primary product patent expiring in the US in 2016 and in Europe in 2018, allowing the development of cost-effective adalimumab biosimilars [5]. In 2018, a citrate-free high-concentration formulation (HCF [concentration 100 mg/ml]) of REF-ADL (HCF REF-ADL) was launched with its development based on direct comparison to REF-ADL (Fig. 1) [6, 7]. Since its approval, HCF REF-ADL has become the preferred formulation of REF-ADL used in clinical practice [6, 8].

Fig. 1.

Order of comparisons in the development of the Sandoz adalimumab biosimilar formulations and the high concentration formulation of REF-ADL. HCF REF-ADL and SDZ-ADL were directly compared against the reference medicine, REF-ADL, to confirm equivalence prior to their respective approvals. HCF SDZ-ADL was directly compared against SDZ-ADL prior to its approval. Thus, by extension, all SDZ biosimilar formulations and the reference high concentration formulation of adalimumab were directly or indirectly confirmed to be comparable to the reference medicine prior to approval. HCF high concentration formulation, REF-ADL reference adalimumab, SDZ-ADL Sandoz biosimilar adalimumab

Many regulators, including the United States Food and Drug Administration (US FDA) and European Medicines Agency (EMA), have strict procedures for the development of biosimilars. The US FDA, EMA and World Health Organization (WHO) request stringent regulatory processes to ensure that the proposed biosimilar medicine has robust evidence of equivalent therapeutic efficacy, safety and quality to the reference medicine [9–11]. The main goal of the US/European biosimilar development approach is to compare the biosimilar medicine and reference medicine by using a step-wise approach referred to as the ‘Totality of Evidence’ approach [12], which first determines structural and functional similarity at the analytical level followed by demonstration of similar pharmacokinetic (PK), efficacy, safety and immunogenicity at the clinical level. To do this, extensive head-to-head comparability studies of the biosimilar and the reference medicine, based on critical quality attributes, are performed [9, 10, 12, 13]. These characterize analytical (physical and chemical) and functional (biologic and pharmacologic) properties that can impact the PK, safety and immunogenicity of a biosimilar [9, 14]. Preclinical studies may be included with the intent to address potential residual uncertainties; however, these are rarely required, with the WHO and US FDA guidance now stating that preclinical in vivo assessment is not a requirement [11, 15, 16]. At the clinical level, comparative studies are conducted to assess PK, safety and immunogenicity profiles of the biosimilar medicine compared with the reference medicine [9, 15]. Assessment of immunogenicity is relevant when developing biologic medicines, including biosimilars, because of the potential that some agents possess to cause an unwanted immune response, which can impact treatment outcomes [9, 10]. Finally, confirmatory clinical studies may be conducted, comparing the efficacy, safety and immunogenicity in a sensitive patient population. As these studies assess biosimilarity to the reference medicine, they are equivalence studies in design [9, 10]. For physicians who are used to prescribing treatment based on the results of Phase III clinical trials for new drugs, it is vital to understand that biosimilar clinical studies are designed solely to confirm the biosimilarity of the two medicines and not to reconfirm the efficacy and safety of the reference biologic, as these qualities will have been fully established during the development of the reference medicine [17, 18].

Sandoz biosimilar adalimumab, GP2017 (Hyrimoz^®; [SDZ-ADL]), has been developed as a biosimilar to REF-ADL following the strict requirements of health authorities (Figs. 1 and 2). SDZ-ADL was approved by both the US FDA and EMA in 2018 for the indications of REF-ADL that were not protected by orphan exclusivity. Approval was given for SDZ-ADL across these indications following clinical investigation in patients with plaque psoriasis (ADACCESS) and moderate-to-severe RA (ADMYRA) based on the principle of extrapolation, the scientific and regulatory process of granting a clinical indication to a medicine without conducting clinical safety and efficacy study in that specific indication [19–21]. US access to SDZ-ADL was granted in July 2023, following a biosimilar entry delay of several years after approval due to extended late-stage patent restrictions associated with the reference manufacturer [22–24].

Fig. 2.

‘Totality of Evidence’ approach for the biosimilar adalimumab SDZ-ADL. HCF high concentration formulation, PD pharmacodynamics; PK pharmacokinetics, REF-ADL reference adalimumab, SDZ-ADL Sandoz biosimilar adalimumab

A citrate-free HCF (100 mg/ml) of SDZ-ADL was approved by the US FDA and EMA in 2023 [25, 26] based on comprehensive PK comparison to the initial SDZ-ADL formulation (Fig. 1). As seen with REF-ADL and HCF REF-ADL, HCF SDZ-ADL increases the drug concentration from 50 mg/ml in the initially approved formulation to 100 mg/ml, thus decreasing injection volume and potentially the number of injections, which can improve patient convenience [27]. Additionally, there is concern among healthcare professionals regarding the use of citrate buffer due to the apparent potential to induce injection site pain at concentrations > 50 mM in adalimumab formulations; the citrate-free formulation avoids this potential issue [27, 28].

Here, we present the Totality of Evidence based on previously conducted analytical, functional, PK and clinical studies that confirm the biosimilarity of SDZ-ADL to REF-ADL. Furthermore, we present clinical trial data relating to the use of SDZ-ADL in additional patient populations conducted to support worldwide registration and provide further efficacy and safety data, as well as the PK, safety and immunogenicity data for citrate-free HCF SDZ-ADL (Fig. 2), aligning the regulatory Totality of Evidence package with the clinical totality for SDZ-ADL to date.

Totality of Evidence for SDZ-ADL

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Analytical Characterization

Analytical characterization, comparing the structure and function of the biosimilar medicine to its reference medicine, formed the foundation of establishing biosimilarity in the target-directed development of SDZ-ADL [9–11].

Following US FDA and EMA guidelines, critical quality attributes were identified for REF-ADL (i.e., physical, chemical and biologic features of the reference medicine that can impact safety, efficacy and immunogenicity), and these attributes were evaluated for SDZ-ADL regarding pre-specified limits/ranges to determine similarity to US-licensed and EU-approved REF-ADL (US-REF-ADL; EU-REF-ADL, respectively) [29–31]. Attributes relating to primary and higher-order structure as well as post-translational modifications were assessed. Binding to recombinant TNF-α, as well as a panel of human Fc gamma and neonatal Fc receptors, was analyzed using surface plasmon resonance-based assays [30].

State-of-the-art analytics confirmed matching analytical and functional profiles between SDZ-ADL and REF-ADL (Table 1) [30, 31]. Comparing multiple batches of each US- and EU-REF-ADL and SDZ-ADL, TNF-α binding curves of SDZ-ADL and REF-ADL were superimposable, indicating a high degree of similarity in target binding affinity, with a binding specificity range for SDZ-ADL of 92–124% and 78–114% for REF-ADL (Fig. 3a) [30, 31]. Peptide mapping of SDZ-ADL and REF-ADL showed superimposable ultraviolet (UV) chromatograms, a matching peptide pattern and identical primary sequence of SDZ-ADL and REF-ADL [31]. Analysis of protein structure by circular dichroism spectroscopy in the far- and near-UV spectral regions (assessing secondary and tertiary protein structure, respectively), showed that SDZ-ADL and REF-ADL have an indistinguishable 3D structure with all measures superimposable [31]. Adalimumab is an IgG1 antibody and mediates effector functions, so in vitro pharmacologic characterization of SDZ-ADL included evaluation of Fc receptor binding profiles, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Cell-based bioassays, including those evaluating TNF-α neutralization (Fig. 3b), TNF-α binding, Fc gamma receptor and neonatal Fc, ADCC and CDC showed matching potency for SDZ-ADL and REF-ADL [30, 31].

Table 1.

Overview of analytical and functional characterization of SDZ-ADL

Methodology	Analysis of	SDZ-ADL matches REF-ADL?
Analytical characterization
Peptide mapping (HPLC followed by UV/visible spectroscopy)	Primary protein sequence	✓
CD spectroscopy  Far (190–230 nm)  UV spectrum  Near (250–350 nm)  UV spectrum	Secondary/tertiary protein structure	✓
H/DX mass spectrometry	Higher order (up to quaternary) structure	✓
X-ray crystallography	Higher order (up to quaternary) structure	✓
Functional characterization
SPR	TNF-α binding	✓
Reporter gene assay	TNF-α neutralization	✓
Pharmacologic functional assays	Relative potency	✓

CD circular dichroism, H/DX hydrogen/deuterium exchange, HPLC high-performance liquid chromatography, REF-ADL reference adalimumab, SDZ-ADL Sandoz biosimilar adalimumab, SPR surface plasmon resonance, TNF tumor necrosis factor, UV ultraviolet

Fig. 3.

Analytical characterization of SDZ-ADL. a TNF-α binding curves of SDZ-ADL and REF-ADL (curves depict the multiple batches of REF-ADL analyzed to define the development target), b TNF-α neutralization reporter gene assay for SDZ-ADL and REF-ADL. Figures reproduced courtesy of Schiestl M and Roesli C. United European Gastroenterology Week. 2016:P0844. REF-ADL reference adalimumab; SDZ-ADL Sandoz biosimilar adalimumab; TNF tumor necrosis factor

Overall, analytical characterization of SDZ-ADL demonstrated biosimilarity of the structure and function of the biosimilar medicine to its reference medicine with little residual uncertainty. These data formed the core data required for regulatory approval and the basis for all subsequent trials.

Preclinical Assessments

Non-clinical studies based on animal data are no longer required by the US FDA or EMA for approval of biosimilar medicines, but they may be run to address any residual uncertainties or to further support the evidence for biosimilarity [15, 16]. Preclinical studies were conducted for SDZ-ADL as they were recommended to be included in the data package at the time of initial development.

The current review is focused on the foundational analytical and confirmatory clinical data for SDZ-ADL. However, in brief, while there was limited residual uncertainty following the analytical investigation, preclinical studies were performed to obtain information on the toxicity, local tolerance and PK profile of SDZ-ADL compared to REF-ADL. Similar mean serum concentration of SDZ-ADL and REF-ADL was reported following a single 3 mg/kg subcutaneous (SC) dose in rabbits [30]. At the same dose in a transgenic mouse model of spontaneous polyarthritis, similar improvement in preventing arthritic symptoms, as well as joint damage as measured by histopathologic scoring, was evident in all parameters tested (body weight, in-life arthritic and histopathologic evaluations) for both SDZ-ADL and EU-REF-ADL compared with the age-matched placebo-treated group [30].

Clinical Studies

The regulatory Totality of Evidence for SDZ-ADL included GP17-102, a device study comparing autoinjector versus prefilled syringe, the pivotal GP17-104 PK clinical study in healthy volunteers and the confirmatory ADACCESS (NCT02016105) study in a sensitive patient population (moderate-to-severe plaque psoriasis), all of which were performed as part for the original submission for SDZ-ADL [20, 32]. A further comparative study, ADMYRA (NCT02744755), was conducted for worldwide registration purposes to generate additional safety, efficacy and immunogenicity data in a relevant population (moderate-to-severe RA) [21]. Most recently, a PK bridging study was performed in pursuit of the citrate-free HCF for SDZ-ADL (Table 2) [27]. Each of these studies is discussed in turn below.

Table 2.

Overview of SDZ-ADL clinical studies

Study	Study population	N	REF-ADL origin	Dose	PK	PD	Efficacy	Safety	Immunogenicity
GP17-102a [32]	Healthy volunteers	108	n/a	40 mg SC	✓	–	–	✓	✓
GP17-104 [32, 37]	Healthy volunteers	318	US & EU	40 mg SC	✓	–	–	✓	✓
HCF PK bridgingb [27]	Healthy volunteers	330	n/a	40 mg SC	✓	–	–	✓	✓
GP17-301 ADACCESS [20]	Patients with moderate-to-severe psoriasis, with or without psoriatic arthritis	465	US & EU	Initial dose 80 mg SC Followed by 40 mg SC	✓d	n/a	✓	✓	✓
GP17-302c ADMYRA [21]	Patients with moderate-to-severe RA	353	US	40 mg SC	n/a	n/a	✓	✓	✓

HCF high concentration formulation n/a not applicable, PD pharmacodynamics, PK pharmacokinetics, RA rheumatoid arthritis, REF-ADL reference adalimumab, SC subcutaneous, SDZ-ADL Sandoz biosimilar adalimumab

^aDevice PK bridging study

^bHCF PK bridging study which was conducted following the approval of SDZ-ADL

^cRA study not part of US/EU dossier. ^dTrough serum drug concentrations were collected

PK Studies

SDZ-ADL

To demonstrate SDZ-ADL similarity to REF-ADL in humans, a Phase I study, GP17-104, was conducted to verify that the biosimilar behaved in the same way within the body as the reference medicine. As the SDZ-ADL PK similarity study was conducted using a prefilled syringe, and as patients were offered treatment with an autoinjector in addition to the prefilled syringe, a device PK bridging study, GP17-102, was also conducted.

GP17-104: PK Study [32]

The pivotal, single-center, double-blind, parallel group, three-arm, GP17-104 study was conducted to investigate PK similarity among SDZ-ADL, US-REF-ADL, and EU-REF-ADL in healthy males (N = 318). Primary endpoints were the maximum observed serum concentration (C_max) and area under the concentration-time curve (AUC) measured from time of dosing and extrapolated to infinity (AUC_0–inf), with secondary endpoints comparing AUC from time of dosing to last quantifiable concentration (AUC_0–last) and to 360 h post-dose (AUC_0–360h), safety, tolerability and immunogenicity. Most subjects in this study were white (96.2%); other parameters including age, body weight and body mass index (BMI) were well balanced across the treatment arms. Full details of this study have been reported elsewhere [32].

The primary endpoint was met for both C_max and AUC_0–inf, and all 90% confidence intervals (CIs) of the ratios of the geometric least square means were contained within the predefined PK similarity margin of 0.8–1.25, demonstrating that the SDZ-ADL serum concentration-time profile matched both US-REF-ADL and EU-REF-ADL (Fig. 4a). This outcome was also seen across all pairwise comparisons of secondary PK endpoints, AUC_0–360h and AUC_0–last, demonstrating PK similarity of SDZ-ADL to both US-REF-ADL and EU-REF-ADL.

Fig. 4.

PK outcomes in the GP17-104 and GP17-102 studies. a PK pairwise comparisons between SDZ-ADL, US-REF-ADL, and EU-REF-ADL in the GP17-104 study, b PK parameters for a single dose of SDZ-ADL administered by autoinjector or prefilled syringe, in the GP17-102 study. Figures reproduced courtesy of von Richter O, et al. Expert Opin Biol Ther. 2019;19:1075–1083. AI autoinjector, AUC area under the concentration–time curve, AUC_0–360h AUC measured from time to dosing to 360 hours post-dose, AUC_0–inf AUC measured from time of dosing and extrapolated to infinity, AUC_0–last AUC up to the last measurable concentration, CI confidence interval, C_max maximum observed serum concentration, GP2017 SDZ-ADL, EU Humira EU REF-ADL, PFS prefilled syringe, PK pharmacokinetic, REF-ADL reference adalimumab, SDZ-ADL Sandoz biosimilar adalimumab, US Humira US REF-ADL

There were no relevant differences in immunogenicity, safety and tolerability among the three treatment groups. Immunogenicity assessments found anti-drug antibody (ADA) rates of 58% with SDZ-ADL and ~ 70% in both US-REF-ADL and EU-REF-ADL groups, with similar ADA development kinetics over 72 days post-dose across all three treatments. Treatment-emergent adverse events (TEAEs) were reported at similar rates among groups, with two serious adverse events (SAEs) reported—one case of angioedema with SDZ-ADL (considered related to study treatment) and one case of femoral neck fracture with US-REF-ADL (not considered related to study treatment).

In summary, pivotal PK clinical data demonstrated the PK similarity of SDZ-ADL and REF-ADL in healthy volunteers. SDZ-ADL was generally safe and well tolerated; no new safety signals were reported, and immunogenicity profiles were comparable between the biosimilar and reference medicines [32].

GP17-102: Device PK Bridging Study [32]

This single-center, open-label study compared injection of SDZ-ADL (40 mg/0.8 ml) with autoinjector versus prefilled syringe (randomized 1:1) in 108 healthy male subjects (N = 108). The primary endpoints were C_max and AUC_0–360h in healthy volunteers weighing 50–94.9 kg, with secondary endpoints assessing further PK outcomes (AUC_0–last, AUC_0–inf) across weight categories, plus safety, tolerability and immunogenicity.

Subjects had a mean age of approximately 32 years. Patients were stratified by body weight into two categories: 83% were in the primary weight category (50–94.9 kg) with 17% in the heavy weight category (95–140 kg). Baseline characteristics were well balanced between the two groups. Full details of this study have been reported elsewhere [32].

Primary (C_max and AUC_0–360h) and secondary AUC (AUC_0–last, AUC_0–inf) parameters were similar for a single dose of 40 mg/0.8 ml SDZ-ADL administered by either autoinjector or prefilled syringe and remained within the standard bioequivalence margin of 0.8–1.25 (Fig. 4b). When assessed for immunogenicity, 69% of subjects in the autoinjector group and 72% of subjects in the pre-filled syringe group had at least one ADA-positive result, with most ADAs being neutralizing. Safety assessments demonstrated that type and incidence of TEAEs were similar in both treatment groups. In conclusion, use of autoinjector versus prefilled syringe for injection of SDZ-ADL was not shown to affect PK, safety or immunogenicity outcomes [32].

SDZ-ADL Citrate-Free HCF Formulation

Phase I HCF Citrate-Free Formulation PK Bridging Study [25, 27]

A Phase I PK bridging study was conducted as part of the development of the HCF SDZ-ADL formulation to compare the high concentration variant (100 mg/ml) with SDZ-ADL in its approved formulation (50 mg/ml) [25, 27]. Both SDZ-ADL and HCF REF-ADL were compared to approved REF-ADL prior to their approvals [7, 20, 21, 27]. Thus, demonstrating matching activity for proposed HCF SDZ-ADL against SDZ-ADL means that HCF SDZ-ADL would also match REF-ADL and HCF REF-ADL (Fig. 1).

Citrate-free HCF SDZ-ADL (100 mg/ml; total dose 40 mg/0.4 ml) was assessed in a randomized, double-blind, parallel, two-arm PK bridging study in healthy volunteers against the initially approved SDZ-ADL formulation (50 mg/ml; total dose 40 mg/0.8 ml) (N = 330) [27]. The C_max and AUC_0–inf and AUC_0–360h of the concentration-time curve were the primary outcomes of interest, with secondary endpoints measuring concentration-time curve AUC_0–last, percentage of AUC_0–inf extrapolated from the time of last observed concentration to infinity (%AUC_extrap), elimination half-life (t_1/2), time taken to reach the maximum serum concentration (t_max) and slope of the serum concentration curve in the terminal elimination phase, immunogenicity, safety and local tolerability of both formulations.

The study included subjects aged 18–55 years old, weighing 65–110 kg, with a BMI of 20–29.9 kg/m² and no previous exposure to adalimumab (reference or biosimilar) and other biologics during the last 9 months prior to screening. Demographics and baseline characteristics of the enrolled subjects were well balanced between the two treatment groups, including body weight and BMI. Full details of this study have been reported elsewhere [25, 27].

PK results were comparable between SDZ-ADL and HCF SDZ-ADL, with the geometric mean ratio 90% CIs of HCF SDZ-ADL and SDZ-ADL formulations for C_max, AUC_0–inf, AUC_0–360h and AUC_0–last all within the pre-defined comparability margin of 0.80–1.25 (Fig. 5); similar mean adalimumab serum concentration-time profiles were also reported between groups.

Fig. 5.

Forest plot of PK endpoints (PK analysis set) in the HCF PK bridging study. Figure reproduced courtesy of von Richter O, et al. Expert Opin Biol Ther. 2022; https://doi.org/10.1080/14712598.2022.2117546. PK analysis set included all subjects who received the study treatment and completed the study without a major protocol deviation that had a relevant impact on PK data (n = 300). ANCOVA analysis performed for PK parameter including treatment as a fixed effect and baseline body weight (at Day − 1) as a covariate. ANCOVA analysis of covariance, AUC_0–360h AUC measured from time to dosing to 360 h post-dose, AUC_0–inf AUC measured from time of dosing and extrapolated to infinity, AUC_0–last AUC up to the last measurable concentration, C_max maximum serum concentration, CI confidence interval, GP2017 SDZ-ADL, HCF high concentration formulation, LS least squares, n number of subjects by treatment group with evaluable PK parameter data, PK pharmacokinetics

Single-dose administrations of HCF SDZ-ADL and SDZ-ADL were well tolerated, with comparable overall rates of TEAEs between treatment groups; there were no reports of deaths or other SAEs. One subject receiving HCF SDZ-ADL and three subjects receiving SDZ-ADL discontinued because of TEAEs (TEAEs not reported). Immunogenicity assessments revealed comparable proportions of subjects with positive ADA responses and with neutralizing antibodies between HCF SDZ-ADL and SDZ-ADL formulation groups, both overall and at all individual visits.

In summary, similarity assessment of citrate-free HCF SDZ-ADL met all its primary objectives, demonstrating comparable PK and showing similar safety and immunogenicity between the two concentrations [27].

SDZ-ADL Initial Formulation

ADACCESS [20]

ADACCESS (NCT02016105) was a multicenter, randomized, double-blind, comparator-controlled confirmatory clinical study of SDZ-ADL in patients with chronic plaque psoriasis (N = 465), which was included in the US and EU approval dossiers [20].

The study included an innovative design comprising four treatment periods with multiple switches between SDZ-ADL and REF-ADL (up to four times total). In Treatment Period 1 (Randomization to Week 17), patients were randomized to receive an initial dose of 80 mg subcutaneous (SC) SDZ-ADL or REF-ADL, followed by 40 mg/0.8 ml of the same treatment every other week, starting 1 week after the initial dose until Week 15. Patients with a Week 16 Psoriasis Area and Severity Index score improvement of ≥ 50% (PASI 50) were eligible for Treatment Period 2. These patients were randomized 2:1 to continue their original treatment until Week 35 or to receive either SDZ-ADL or REF-ADL during three alternating 6-week periods. During the Week 35–51 extension period, all patients received the treatment originally assigned at randomization.

The study enrolled adults aged ≥ 18 years with active, clinically stable, moderate-to-severe chronic plaque psoriasis diagnosed ≥ 6 months prior to baseline with PASI score ≥ 12, Investigator’s Global Assessment (IGA) score ≥ 3 and ≥ 10% body surface area affected by plaque-type psoriasis. A total of 465 patients were randomized in Treatment Period 1: 231 to SDZ-ADL and 234 to REF-ADL, with balanced patient baseline demographics between the two groups. Full details for this study have been published elsewhere [20].

The primary endpoint of ADACCESS was to assess the proportion of patients who achieved a 75% improvement in PASI score (PASI 75) at Week 16 (prespecified equivalence margin of ± 18%), with a key secondary endpoint of percentage change from baseline to Week 16 in continuous PASI score (prespecified equivalence margin of ± 15%). Other secondary endpoints included further PASI response rates, IGA response, health-related quality of life (QoL), safety, tolerability and immunogenicity across treatment arms [20].

Results from Treatment Period 1 confirmed the clinical efficacy of SDZ-ADL matched REF-ADL; patients receiving SDZ-ADL had similar PASI 75 responses at Week 16 compared to REF-ADL, with 95% CIs contained within ± 18%, confirming efficacy (Fig. 6a). Similarly, therapeutic equivalence was shown for mean percent change in PASI from baseline to Week 16, with 95% CIs contained within the prespecified ± 15%.

Fig. 6.

Primary and supportive efficacy analyses. a Primary efficacy analysis and b logistic regression analysis on PASI 75 response at Week 16 in the ADACCESS study. *Equivalence margin of ±18%. Figures reproduced courtesy of Blauvelt A, et al. Br J Dermatol. 2018;179:623–631. CI confidence interval, EP extension period, PASI Psoriasis Area and Severity Index, REF-ADL reference adalimumab, SDZ-ADL Sandoz biosimilar adalimumab, SE standard error, TP treatment period

Safety and tolerability were comparable between groups, with similar and low proportions of patients with AEs, SAEs, treatment-related SAEs, AEs of special interest, AEs requiring study drug interruption and discontinuations due to AEs. Nasopharyngitis was the most commonly reported AE over Treatment Period 1, seen in 5.6% of patients receiving SDZ-ADL and 6.4% of patients receiving REF-ADL. Similar rates of patients with at least one positive ADA result were observed between groups, and approximately 80% of ADAs were neutralizing in both groups.

Patients with 50% improvement in PASI score at Week 16 were re-randomized in a 2:1 ratio at Week 17 to either remain on their initial study treatment or undergo a sequence of three treatment switches between SDZ-ADL and REF-ADL until Week 35; 379 patients were re-randomized to continue SDZ-ADL (n = 126) or REF-ADL (n = 127) or to switch to/from REF-ADL or SDZ-ADL (n = 63 per group) with patient characteristics remaining balanced between arms. Clinical outcomes remained consistent, with mean absolute PASI score over time (Fig. 6b), mean change from baseline in PASI score and mean serum drug concentration all comparable between arms throughout the switch and extension periods.

Safety assessments demonstrated a similar overall incidence of AEs of special interest (i.e. all warnings and precautions given in the REF-ADL label) in all treatment groups. In Treatment Period 1, similar rates of overall infections and infestations were seen with SDZ-ADL (2.6%) and REF-ADL (3.8%). Vulvovaginal mycotic infection was seen in both groups (0.4% and 0.9%, respectively), oral herpes (0.9%) was reported with SDZ-ADL, and oral candidiasis (0.9%), tinea pedis (0.9%) and herpes zoster (0.4%) were each reported with REF-ADL. Over Treatment Period 2, overall rates of infections and infestations remained similar, 3.2% and 4.7% in those continuing SDZ-ADL and REF-ADL and 3.2% and 1.6% in patients switching to REF-ADL and SDZ-ADL, respectively. Individual infection and infestation AEs of special interest were seen at low rates across treatment groups.

Benign, malignant and unspecified neoplasms were reported in 1.7% and 2.1% of patients receiving SDZ-ADL and REF-ADL, respectively, in Treatment Period 1, with basal cell carcinoma observed in 1.3% and 0.9%, respectively. In Treatment Period 2, overall rates of neoplasms were 3.2% in patients who switched treatment (from either REF-ADL to SDZ-ADL, or SDZ-ADL to REF-ADL) and 2.4% in those who continued REF-ADL; no cases were seen in patients who continued SDZ-ADL. Blood and lymphatic system disorders were reported in 0.4% and 1.3% of patients receiving SDZ-ADL and REF-ADL, respectively, in Treatment Period 1. In Treatment Period 2, overall rates were 2.4% and 1.6% in patients who continued SDZ-ADL and REF-ADL, respectively, and 3.2% and 1.6% of patients who switched to REF-ADL and SDZ-ADL, respectively.

Most injection site reactions (ISRs) were mild to moderate in severity with no incident considered to be serious. The proportions of patients developing ADAs after the first treatment switch were similar in all treatment groups. In both the switched and continued treatment groups, most patients positive for ADA also tested positive for neutralizing antibodies (75–100%) (Table 3).

Table 3.

Immunogenicity in the ADACCESS study [20]

	TP1 (randomization to Week 17)		TP2 + EP (Week 17 to Week 51)
	SDZ-ADL (n = 231)	REF-ADL (n = 234)	SDZ-ADL → REF-ADL (n = 63)	Continued SDZ-ADL (n = 126)	REF-ADL → SDZ-ADL (n = 63)	Continued REF-ADL (n = 127)
Negative	139/220 (63.2)	145/220 (65.9)	32/60 (53.3)	79/123 (64.2)	37/61 (60.7)	67/122 (54.9)
Positive	81/220 (36.8)	75/220 (34.1)	28/60 (46.7)	44/123 (35.8)	24/61 (39.3)	55/122 (45.1)
Neutralizing	65/81 (80.2)	60/75 (80.0)	21/28 (75.0)	38/44 (86.4)	24/24 (100.0)	47/55 (85.5)

Figure reproduced courtesy of Blauvelt A, et al. Br J Dermatol. 2018;179:623–631

EP extension period, REF-ADL reference adalimumab, SDZ-ADL Sandoz biosimilar adalimumab, TP treatment period

In summary, the confirmatory clinical ADACCESS study showed no clinically meaningful differences in efficacy and safety among patients who received continued SDZ-ADL or REF-ADL or in those who experienced multiple switches between REF-ADL and SDZ-ADL. This also extended to comparable immunogenicity among patients consistently treated with SDZ-ADL and REF-ADL and patients undergoing repeated treatment switches [20].

ADMYRA [21]

The ADMYRA comparative efficacy and safety clinical study (NCT02744755) was conducted to support worldwide registration purposes of SDZ-ADL. The study enrolled patients with moderate-to-severe RA who had an inadequate response to disease modifying anti-rheumatic drugs (DMARDs); the study was initiated immediately following completion of ADACCESS [21].

ADMYRA evaluated the effect of a single switch from REF-ADL to SDZ-ADL at Week 24 on efficacy, safety and immunogenicity; enrolled patients were randomized to SDZ-ADL for 48 weeks (n = 177) or REF-ADL followed by a Week 24 switch to SDZ-ADL (n = 176). Treatment Period 1 covered baseline to Week 24, and Treatment Period 2 continued to Week 48. The design of the 48-week, multicenter, randomized, double-blind, comparator-controlled, confirmatory study resembled that of the REF-ADL ARMADA trial [21, 33].

Patients were aged ≥ 18 years, with confirmed diagnosis of RA (as assessed by ACR 1987 or ACR/EULAR 2010 modified criteria) at least 6 months prior to baseline, with active disease defined as Disease Activity Score 28 for Rheumatoid Arthritis with C-Reactive Protein (DAS28-CRP) score ≥ 3.2 at screening. Patients with inadequate clinical response to 10–25 mg/week methotrexate following dose escalation and patients who had failed a DMARD treatment (alone or with methotrexate) were included after an appropriate wash-out period.

The primary study endpoint of ADMYRA was change from baseline in DAS28-CRP score at Week 12, with the associated key secondary endpoint of time-weighted averaged change from baseline in DAS28-CRP until Week 24. Additional secondary endpoints assessed further DAS28-CRP parameters including absolute change from baseline in DAS28 score, proportion of patients with moderate or good EULAR response based on DAS-28-CRP, patients achieving EULAR remission (DAS28-CRP < 2.6), ACR20/50/70 response rates, changes in CRP and elevated erythrocyte sedimentation rate, along with safety and immunogenicity.

Patient demographics and baseline characteristics were balanced and comparable between both treatment groups during Treatment Periods 1 and 2 (SDZ-ADL vs REF-ADL; ‘continued SDZ-ADL’ vs ‘REF-ADL to SDZ-ADL’), except for minor differences in gender distribution between the treatment groups in Treatment Period 1. There were no clinically relevant differences between treatment groups in the baseline disease characteristics or with prior RA medication. Full details for this study have been published previously [21].

After 24 weeks, 325 patients (SDZ-ADL, n = 159; REF-ADL to SDZ-ADL, n = 166) entered Treatment Period 2, with 303 completing this period (SDZ-ADL, n = 145; REF-ADL to SDZ-ADL, n = 158). The primary endpoint of least square means difference from baseline in DAS28-CRP scores over 12 weeks was within the pre-specified equivalence margin of ± 0.6; − 2.16 in patients receiving SDZ-ADL and − 2.18 in patients receiving REF-ADL (difference 0.02, 95% CI: − 0.24, 0.27). Similarly, the time-weighted average change from baseline in DAS28-CRP until Week 24 was comparable between SDZ-ADL and REF-ADL, with 95% CIs within the pre-specified equivalence margin (± 0.6), demonstrating therapeutic equivalence between SDZ-ADL and REF-ADL.

Looking out to 48 weeks, mean change in DAS28-CRP score was similar between patients receiving continued SDZ-ADL versus those who switched from REF-ADL to SDZ-ADL. At baseline, mean DAS28-CRP for patients who received SDZ-ADL and patients who switched from REF-ADL to SDZ-ADL was 5.74 and 5.73, respectively. At all subsequent assessments up to 48 weeks, the difference in the change from baseline between the two treatment groups was < 0.1, well within the pre-defined equivalence margin.

Median duration of study drug exposure was similar between groups throughout the 48-week study duration. Rates of TEAEs (including moderate or severe TEAEs) and overall incidence of TEAEs of special interest were comparable between study groups across both treatment periods. During Treatment Period 1, from initiation to Week 24, the most common system organ classes of AEs (reported in ≥ 10% of either group) were infections and infestations (35.6% and 36.9% of patients receiving SDZ-ADL and REF-ADL, respectively), musculoskeletal and connective tissue disorders (11.9% and 8.0%, respectively) and gastrointestinal disorders (11.9% and 9.7%, respectively). All other system organ classes have incidences of < 10% in each treatment arm. During Treatment Period 2, starting at Week 24, the only system organ class of AEs reporting incidence in ≥ 10% of either group was infections and infestations, with 15.7% in patients who continued SDZ-ADL and 16.3% in patients who switched from REF-ADL to SDZ-ADL.

The SDZ-ADL group had a lower proportion of patients with ISRs in Treatment Period 1 compared with the REF-ADL group (4% [7/177] and 6.3% [11/176], respectively); all reported cases of ISR (except two) in the REF-ADL group were suspected to be study drug-related. ISRs were similar, and low between those who received continued SDZ-ADL and those who switched from REF-ADL to SDZ-ADL (0.6% [1/159] and 1.2% [2/166], respectively); all ISRs during this period were suspected to be study drug-related. All ISRs were mild/moderate, with no cases of study drug discontinuation due to an ISR.

The study reported a similar incidence of ADAs between groups over 48 weeks, with no meaningful difference in incidence of neutralizing ADAs (Table 4). After the single switch at Week 24, similar rates of patients tested ADA-positive in the SDZ-ADL and REF-ADL to SDZ-ADL switch groups.

Table 4.

Immunogenicity in the ADMYRA study [21]

N (%)	Week 24		Week 48
	Continued SDZ-ADL	REF-ADL/switched SDZ-ADL	Continued SDZ-ADL	REF-ADL/switched SDZ-ADL
Incidence of ADAs	36 (24.0)	42 (26.3)	40 (24.2)	43 (25.6)
Incidence of neutralizing ADAs	26 (72.2)	34 (81.0)	29 (72.5)	34 (79.1)

ADA anti-drug antibody, REF-ADL reference adalimumab, SDZ-ADL Sandoz biosimilar adalimumab

This additional comparative clinical study demonstrated that in patients with moderate-to-severe RA and inadequate response to DMARDs, SDZ-ADL demonstrated efficacy, safety and immunogenicity profiles matching REF-ADL. This comparable efficacy was sustained after switching from REF-ADL to SDZ-ADL, with no impact on safety and immunogenicity [21].

Supplementary Clinical Outcomes

While not considered part of the regulatory requirements for demonstration of biosimilarity, patient-reported outcomes (PROs) and QoL assessments provide additional evidence to support similarity of clinical data to help create a full picture of the impact of a treatment on patients. PRO and QoL assessments were included in both ADACCESS and ADMYRA, demonstrating that treatment with SDZ-ADL and REF-ADL resulted in comparable improvements in both PROs and QoL, and these outcomes were not affected by treatment switching [34]. These improvements were seen across psoriasis, psoriatic arthritis and RA as measured by the Dermatology Life Quality Index, European Quality of Life 5-Dimension Health Status questionnaire, Health Assessment Questionnaire-Disability Index scores, Functional Assessment of Chronic Illness Therapy-Fatigue, Patient Global Assessment of Disease and patient assessment of RA pain [34].

Discussion

The Totality of Evidence is the fundamental approach for biosimilar development. It provides a robust dataset of the evidence required for high confidence in biosimilarity between the proposed biosimilar and its reference medicine [12]. These data comprising the Totality of Evidence establish that patients and healthcare providers alike can expect to see the same clinical outcomes when using biosimilars that have been approved by regulators with strict development process criteria compared to their reference medicines [9, 10–12].

The Totality of Evidence presented here for SDZ-ADL established its biosimilarity to REF-ADL from analytical assessment through to clinical confirmatory studies in healthy participants and sensitive patient populations [20, 21, 27, 30–32]. First, comprehensive comparative analytical and functional characterization, which forms the foundation of biosimilar development (Fig. 1), using state-of-the-art techniques revealed matching analytical and functional profiles of SDZ-ADL to both US-licensed and EU-approved REF-ADL [12, 30, 31]. Analytical investigation demonstrated that TNF-α binding curves of SDZ-ADL and REF-ADL had a high degree of similarity in target binding affinity; similarly, cell-based bioassays (including for TNF-α neutralization, TNF-α binding, Fc gamma receptor and neonatal Fc, ADCC and CDC) demonstrated matching potency of SDZ-ADL and REF-ADL. Following the foundational analytical investigation conducted in line with biosimilar development recommendations, several clinical studies were carried out to ensure any residual uncertainties were addressed [30, 31].

The pivotal PK study, GP17-104, confirmed similarity in PK parameters between SDZ-ADL and REF-ADL in healthy volunteers. SDZ-ADL matched REF-ADL across primary and secondary endpoints, C_max, AUC_0–inf, AUC_0–last, while also demonstrating that SDZ-ADL’s safety, tolerability and immunogenicity profiles matched those of REF-ADL [32]. The reported PK activity of SDZ-ADL was not affected by administration by prefilled syringe or autoinjector, as shown in GP17-102 [32].

The Phase III confirmatory efficacy and safety clinical study, ADACCESS, reported no clinically meaningful differences in efficacy, safety or immunogenicity among patients with psoriasis who received continued SDZ-ADL and REF-ADL or those treated with multiple switches between REF-ADL and SDZ-ADL [20]. ADMYRA supported this outcome, demonstrating matching efficacy and safety profiles, and no impact of treatment choice on immunogenicity outcomes between patients with RA receiving SDZ-ADL, and those switching from REF-ADL to SDZ-ADL [21]. Alongside matching treatment efficacy, SDZ-ADL has been shown to affect comparable improvements to REF-ADL in PROs and QoL across plaque psoriasis, psoriatic arthritis and RA indications [34].

Additional device and formulation development was enabled by the prior positive evidence, with the development of SDZ-ADL, HCF SDZ-ADL and HCF REF-ADL providing a valuable illustration of extrapolation between formulation concentrations (Fig. 1) [35]. Both HCF REF-ADL and SDZ-ADL were directly compared against the reference medicine, REF-ADL, confirming their equivalence prior to their respective approvals [20, 21, 27]. Having confirmed via the Totality of Evidence approach that SDZ-ADL matched REF-ADL in functional, PK and clinical activity, SDZ-ADL acted as the comparator for a pivotal PK bridging study to confirm comparable PK, safety and immunogenicity for citrate-free HCF SDZ-ADL (100 mg/ml) [27]. Therefore, both SDZ biosimilar formulations and high concentration formulation reference adalimumab were all either directly or indirectly confirmed to be comparable to the reference medicine. HCF SDZ-ADL was not directly compared to HCF REF-ADL prior to approval, but both high-concentration formulations are ultimately based on the initially approved formulation of REF-ADL.

Biosimilar medicines can be more affordable than their reference medicines because of focused clinical development programs. They have shown significant benefits in reducing pressure on healthcare systems, which in turn can lead to increased access to biologic therapy to treat more patients in an earlier phase of their disease [36].

Conclusion

The approval of biosimilar adalimumab, GP2017, by the US FDA and EMA was based on a robust analytical and functional similarity dataset, supported by demonstration of PK similarity in a pivotal study in healthy volunteers. Clinical data from studies in healthy volunteers and patients supported the biosimilarity of SDZ-ADL to REF-ADL, with demonstration of similar efficacy and comparable safety and immunogenicity data. The totality of the evidence presented here assures patients and prescribers that both SDZ-ADL and HCF SDZ-ADL are effective alternative adalimumab biosimilars that provide similar efficacy and safety as their reference medicine; this equivalence subsequently allows healthcare providers to take advantage of any potential cost saving as applicable in their own setting.

Author Contributions

Norman Gaylis, Charlotte Both, Lena Lemke, Oliver von Richter and Paul Yamauchi contributed to the creation of the review at all stages of development. All authors critically reviewed and approved the final version of the manuscript. All authors were in compliance with ICMJE criteria.

Funding

The manuscript, journal Rapid Service Fee and Open Access Fee were funded/sponsored by Hexal AG (a Sandoz company).

Data Availability

Data sharing is not applicable to this review article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Norman Gaylis is an investigator for Alumis, AbbVie, Acelyrn, Amgen, AstraZeneca, Biogen, BMS, Gallopagos, Gilead, Horizon, IGM Sciences, LG Chem, F. Hoffmann-La Roche/Genentech and SetPoint Medical. Charlotte Both is an employee of Grünenthal GmbH. Lena Lemke is an employee of Hexal AG (A Sandoz company). Oliver von Richter is an employee of Hexal AG (A Sandoz company). Paul Yamauchi is an investigator, advisor, and/or speaker for Amgen, AbbVie, Janssen, Novartis, Boehringer Ingelheim, Lilly, Regeneron, Sanofi, LEO Pharma, Pfizer, Sun Pharma, BMS.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.