FormalPara Key Summary Points

SB5 is an approved adalimumab biosimilar with equivalent pharmacokinetics and efficacy, and comparable safety and immunogenicity to reference adalimumab demonstrated in randomized controlled clinical trials enrolling patients with rheumatoid arthritis.

“Real-world” evidence confirms the effectiveness and safety of SB5 for the treatment of immune-mediated inflammatory diseases for which reference adalimumab has been approved.

In both controlled and “real-world” settings, SB5 was not associated with reduced efficacy/effectiveness or clinical complications in both naïve and switched patients compared to reference adalimumab.

The quality of SB5 is tightly controlled and consistent over time, and its unique self-injection device is preferred over other autoinjectors by both patients and healthcare professionals.

Introduction

Adalimumab is a fully human recombinant immunoglobulin G1 (IgG1) monoclonal antibody that binds to the pro-inflammatory cytokine tumor necrosis factor (TNF) and inhibits its receptor interaction. In the USA, adalimumab is indicated for the treatment of immune-mediated inflammatory disorders such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), adult and pediatric Crohn’s disease (CD), adult and pediatric ulcerative colitis (UC), psoriasis (PsO), hidradenitis suppurativa (HS), and uveitis. Approved by the US Food and Drug Administration (FDA) in 2002, adalimumab has a well-established long-term safety and efficacy profile [1].

In 2016, the main patent for adalimumab (Humira®, AbbVie Inc., North Chicago, Illinois, USA) expired, opening the opportunity to launch biosimilars. With settlement agreements in place, nine adalimumab biosimilars approved by the FDA have been marketed in the USA as of August 2023 (Table 1) [2].

Table 1 FDA-approved adalimumab biosimilars
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Biosimilars are biological products with equivalent efficacy and comparable safety and immunogenicity to a reference product [3, 4]. Biosimilars undergo stringent regulatory review and their approval requires comprehensive evidence of the similarity to the approved reference biologic. Upon approval, biosimilars may introduce market competition and reduce the cost of medications, thereby expanding patients’ access to effective treatment [5,6,7,8].

An approved biosimilar can be designated as an interchangeable biosimilar product if it meets additional requirements outlined by the FDA [9]. An interchangeability designation allows pharmacists to substitute the interchangeable biosimilar for its reference product, or vice versa, without the intervention of the prescribing healthcare professional [10]. This process, commonly referred to as pharmacy-level substitution, is regulated by state pharmacy laws and is similar to how reference drugs are substituted for generic drugs [9]. To date, interchangeable biosimilar products are only available for three different reference products, including adalimumab, which was the second biologic to have an interchangeable biosimilar product [2, 11].

SB5 (Hadlima™ in the USA and Imraldi™ in the European Union (EU), Samsung Bioepis, Republic of Korea) is an adalimumab biosimilar with equivalent pharmacokinetics (PK) and efficacy to its reference product as demonstrated in clinical trials [12,13,14,15]. Regulatory approval was granted in the EU in 2017 and in the USA in 2019 on the basis of the “totality of the evidence”. Initially, clinical data was obtained from patients with RA. By extrapolation, the approval was extended to include additional indications such as JIA, PsA, AS, adult and pediatric CD, UC, PsO, and HS (Table 2). In the USA, SB5 has been approved as both low-concentration formulation (40 mg/0.8 mL [SB5-LC]) containing citrate and as high-concentration formulation (40 mg/0.4 mL [SB5-HC]) without citrate [16]. Currently, a phase IV study in patients with plaque psoriasis is ongoing aiming to support the granting of an interchangeability designation [NCT05510063] (Fig. 1).

Table 2 Highlights of the FDA Prescribing Information of Hadlima (SB5)
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Fig. 1
figure 1

Study design of the SB5 phase IV interchangeability study. ADL, reference adalimumab; EOS, end of study; F/U, follow-up; PASI50, 50% reduction in the Psoriasis Area and Severity Index; PK, pharmacokinetics

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The objective of this review is to aggregate and analyze available data and information on the biosimilarity of SB5 to reference adalimumab (ADL). To this end, the “totality of the evidence” from clinical trials and real-world studies is summarized, an overview of the control measures taken during the last 10 years to ensure the consistency of quality of SB5 is provided, and the unique characteristics of the SB5 autoinjector are explored. 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.

Stepwise Approach to Build the “Totality of the Evidence” Demonstrating Biosimilarity

Rather than demonstrating efficacy and safety de novo, biosimilar clinical development programs rely on confirming the similarity between a proposed biosimilar product and its reference product. Critical elements in the biosimilar development program include establishing the key product quality attributes of these complex biopharmaceuticals, demonstrating equivalent PK/pharmacodynamic profiles and clinical efficacy with comparable safety, and immunogenicity profiles to the reference product [17]. Once the “totality of the evidence” supports biosimilarity of the proposed biosimilar to its reference product, regulatory guidance allows for extrapolation of the data to all indications of use for which the reference product is approved, provided there is sufficient scientific justification considering the pathophysiology of each disease [18, 19].

The clinical development program of SB5 was built around three randomized controlled clinical trials:

  • A randomized, single-blind, three-arm, parallel group, single-dose, PK, clinical equivalence study using the SB5-LC formulation conducted in healthy subjects. In this study, a total of 189 subjects were randomized to either receive SB5, EU-sourced adalimumab (EU-ADL), or USA-sourced adalimumab (US-ADL). Each group featured 63 subjects [15].

  • A randomized, double-blind, multinational, 52-week, pivotal, comparative efficacy study using the SB5-LC formulation conducted in patients with moderate to severe RA [12, 13]. A total of 542 patients were initially randomized to SB5 (N = 269) or ADL (N = 273). After 24 weeks, the patients in the ADL group were re-randomized to either continue ADL (N = 129; ADL/ADL) or switch to SB5 (N = 125, ADL/SB5).

  • A randomized, single-blind, two-arm, parallel-group, single-dose, PK, clinical equivalence study in healthy male subjects comparing the SB5-LC and SB5-HC formulations. A total of 188 healthy subjects were randomized (94 subjects in each group) [20].

Pharmacokinetics

Equivalent PK of SB5 to ADL had initially been demonstrated in the clinical equivalence study with healthy subjects using the SB5-LC formulation (40 mg/0.8 mL). For all pairwise comparisons, 90% confidence intervals (CI) of the geometric least squares mean (LSMean) ratios of area under the concentration–time curve from time zero to infinity (AUCinf; SB5 vs EU-ADL, 0.990 [0.885–1.108]; SB5 vs US-ADL, 1.001 [0.890–1.126]), maximum serum concentration (Cmax; SB5 vs EU-ADL, 0.957 [0.870–1.054]; SB5 vs US-ADL, 0.972 [0.881–1.073]), and AUC from time zero to the last quantifiable concentration (AUClast; SB5 vs EU-ADL, 1.027 [0.915–1.153]; SB5 vs US-ADL, 1.025 [0.911–1.153]) were contained within the predefined equivalence margins of 0.8–1.25 [15]. Consistent with these findings in healthy subjects, the pivotal comparative efficacy study successfully confirmed the equivalence in terms of PK in patients with moderate-to-severe RA as trough concentrations (Ctrough) for SB5 and ADL were similar up to week 24 [12]. Furthermore, the SB5-HC citrate-free formulation (40 mg/0.4 mL) showed equivalent PK compared to the initially used SB5-LC citrate-containing formulation (40 mg/0.8 mL) in the dedicated PK clinical equivalence study. The LSMean ratios for AUCinf and Cmax were 0.920 and 0.984, respectively, with the corresponding 90% CIs well within the predefined bioequivalence margins of 0.80–1.25 [20].

Safety

No clinically meaningful differences in clinical safety of SB5 and ADL were detected in randomized controlled trials. In the pivotal comparative efficacy study conducted in patients with moderate to severe RA, types and characteristics of the reported treatment-emergent adverse events (TEAEs) were consistent with the known safety profile of ADL. In the SB5 and ADL groups, 35.8% and 40.7% of patients experienced TEAEs up to week 24, respectively. Serious adverse events (SAEs) were reported in three patients (1.1%) treated with SB5 and eight patients (2.9%) treated with ADL. No deaths were reported for patients in the SB5 group, whereas two patients in the ADL group died during the study. Both deaths were considered not to be related to the study drug [12]. Switching from ADL to SB5 at week 24 did not result in an increased number of adverse events (AEs) [13]. In the clinical equivalence study conducted in healthy subjects using the SB5-LC formulation, the number of patients experiencing TEAEs was comparable across treatment groups (SB5, 57.1%; EU-ADL, 46.0%; US-ADL, 61.9%), most TEAEs were considered mild to moderate in intensity, and no discontinuations of study drug due to TEAEs were reported. Two subjects (SB5, n = 1 [1.6%]; US-ADL, n = 1 [1.6%]) had SAEs, but neither event was considered to be related to the study drug [15]. The clinical equivalence study dedicated to the comparison of the SB5-LC and SB5-HC formulations revealed comparable safety profiles for the two different formulations. All TEAEs were mild or moderate in intensity and no patient withdrew from the study because of a TEAE [20]. Overall, the combined safety data from all the studies in the SB5 clinical development program were comparable for SB5 and ADL and for the two different SB5 formulations.

Efficacy

The pivotal clinical equivalence study conducted in patients with moderate-to-severe RA provided data demonstrating the equivalent efficacy of SB5 and ADL. At week 24, the proportions of patients meeting the American College of Rheumatology 20% (ACR20) improvement criteria were 72.4% and 72.2% for SB5 and ADL, respectively, with an adjusted difference of 0.1% (95% CI 7.83, 8.13). The remission rates of the Disease Activity Score in 28 joints using the Erythrocyte Sedimentation Rate (DAS28-ESR) (SB5, 21.6% [mean change, − 2.74] vs. ADL, 19.8% [mean change, − 2.68]) and of the Simplified Disease Activity Index (SDAI) (SB5, 11.0% [mean change, − 25.98] vs. ADL, 14.4% [mean change, − 25.00]) confirmed the equivalent efficacy of SB5 and ADL at week 24 [12]. At week 52, 77.8% of patients treated with SB5 and 73.4% of patients treated with ADL achieved an ACR20 response, indicating that the equivalent efficacy of SB5 and ADL was maintained over an extended treatment period. The observed similarity in long-term efficacy up to week 52 between SB5 and ADL was again corroborated by the results of additional efficacy endpoints such as the remission rates of the DAS28-ESR (SB5, 30.4% [mean change, − 3.05] vs. ADL, 29.0% [mean change, − 2.92]) and the SDAI (SB5, 22.3% [mean change, − 29.0] vs. 18.5% [mean change, − 27.8]). Importantly, switching from ADL to SB5 at week 24 did not result in a reduction of efficacy, with 78.8% of switched patients meeting the ACR20 at week 52. The DAS28-ESR and SDAI remission rates at week 52 were 28.8% (mean change, − 3.02) and 19.5% (mean change, − 28.2), respectively, for patients switching from ADL to SB5 at week 24 [13].

Immunogenicity

An important component of the “totality of the evidence” approach demonstrating equivalence of a biosimilar candidate to its reference product is to demonstrate that there are no clinically meaningful differences in immunogenicity. In each of the clinical studies mentioned above, the immunogenicity profile of SB5 was comparable to that of ADL. In the pivotal comparative efficacy study conducted in patients with moderate-to-severe RA, 33.1% of patients treated with SB5 and 32.0% of patients treated with ADL developed anti-drug antibodies (ADAs) to adalimumab up to week 24 [12]. The incidences of overall ADAs remained comparable across treatment groups up to week 52, including those patients who switched from ADL to SB5 at week 24 [13]. In the single-dose clinical equivalence study in healthy subjects using the SB5-LC formulation, the overall incidence of ADAs to adalimumab after dosing was 98.4%, 95.2%, and 100.0% in subjects treated with SB5, EU-ADL, and US-ADL, respectively [15]. In the clinical equivalence study comparing single doses of the two different formulations of SB5 in healthy male subjects, the overall incidence of post-dose ADAs was similar for both formulations, with 93.6% of subjects in the SB5-HC group and 94.7% of subjects in the SB5-LC group having detectable ADAs post dose [20].

Overall, the clinical development program of SB5 provides comprehensive data about the equivalence of SB5 and ADL and corroborates the similarity between the two different SB5 formulations.

Real-World Evidence

Gathering real-world data (RWD) is an important means to confirm the findings of randomized clinical trials, which are conducted in controlled settings, and to provide data for the extrapolation of the approval of a biosimilar for use in indications held by the reference product. Observational studies have generated RWD that confirm the comparability of the effectiveness and safety of SB5 to that of ADL in both adalimumab-naïve and adalimumab-experienced patients across major indications (Table 3).

Table 3 Post-approval observational studies of SB5
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Rheumatologic Diseases

Several observational studies were conducted in patients with rheumatologic diseases such as RA, AS, and PsA, who were treated with SB5 [21,22,23].

Two observational studies investigated switching from ADL to SB5 [21, 22]. The first (Bruni et al. [21]), which focused on safety, enrolled 172 patients with inflammatory arthritis, including 34 patients with RA, 59 patients with PsA, and 61 patients with AS. All enrolled patients previously had received at least 6 months of treatment with ADL before switching to SB5. During the follow-up period of up to 18 months, 65 (37.8%) patients reported AEs, most of which were flares of disease activity (n = 46). The remainder were infections (n = 19), of which one (0.6%) was reported to be an SAE of severe infection requiring hospitalization. The probability of persisting on SB5 treatment was generally high, with 94.7% and 85.1% after 6 and 12 months, respectively [21]. The second (Müller-Ladner et al. [22]), known as the “PROPER Study,” was a 48-week analysis of data from patients with RA, PsA, AS, CD, or UC, who had switched from ADL to SB5. The inflammatory arthritis cohort of this study consisted of 496 patients, who were enrolled at centers across Europe and followed up to week 48 after the switch to SB5. Effectiveness of treatment was maintained throughout the study: the mean DAS28 score of patients with RA was 2.3 at baseline and 2.4 at week 48; the Hannover Functional Ability Questionnaire (FFbH) for patients with RA was 80.0 at baseline and 77.1 at week 48; the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for patients with AS was 2.58 at baseline and 2.65 at week 48; and the Psoriatic Arthritis Response Criteria (PsARC) tender joint count (TJC) and swollen joint count (SJC) for patients with PsA were 1.7 and 0.7 at baseline and 1.9 and 0.7 at week 48, respectively. SAEs were reported in 17 patients, of which two were considered to be related to SB5 treatment. Overall treatment persistence was high with 397 (81.5%) of the 487 patients who completed the full 48 weeks of the study having remained on SB5 throughout the study [22].

Another observational study (Parisi et al. [23]) evaluated sequential switching from ADL to the adalimumab biosimilar ABP501 and subsequently to SB5 in 127 patients with RA, PsA, or AS. Disease activity, as measured by DAS28, Disease Activity in Psoriatic Arthritis (DAPSA), or BASDAI remained stable over 3 years. One year after the switch from ABP501 to SB5, 82.1%, 78.7%, and 77.5% of patients with AS, RA, and PsA, respectively, remained on treatment with SB5 [23].

Taken together, RWD from patients with inflammatory arthritis confirm the comparability of SB5 with ADL; sequential switching from ADL to another adalimumab biosimilar and subsequently to SB5 revealed similar effectiveness of SB5 after two switches with that after a single switch. Effectiveness and safety data in these observational studies are consistent with those of randomized clinical trials, and no new safety concerns were identified.

Inflammatory Bowel Diseases

The effectiveness and safety of SB5 has also been confirmed in patients with inflammatory bowel diseases (IBDs), CD, and UC in several observational studies [24,25,26].

In one study (Lukas et al. [24]), 93 patients with IBD who switched from ADL to SB5 were compared to 93 patients who continued treatment with ADL. There were no clinically meaningful differences between SB5 and ADL in disease activity, PK, safety, and immunogenicity. At weeks 0 and 10, the levels of C-reactive protein (CRP) and fecal calprotectin of patients treated with SB5 were comparable to those of patients treated with ADL, reflecting similar disease activity in the two cohorts. Both CD activity as measured by the Harvey-Bradshaw Index (HBI) and UC activity as measured by the partial Mayo score were similar among patients treated with SB5 to those of patients treated with ADL. Ctrough levels at week 0 (SB5, 14.2 μg/mL vs. ADL, 14.8 μg/mL) and at week 10 (SB5, 13.0 μg/mL vs. ADL, 13.7 μg/mL) were comparable, confirming similarity of the PK profiles of SB5 and ADL, which had previously been observed in randomized controlled trials. Throughout the study, observed AEs were comparable for patients treated with SB5 and ADL, and two patients in each cohort tested positive for ADAs. Of note, more patients in the SB5 cohort reported injection site pain during drug administration compared to the ADL cohort, and the median visual analogue scale (VAS) score for SB5 injections (3 [1; 5]) was higher than that for ADL injections (0 [0; 0]) [24].

A second observational study (Tapete et al. [25]) assessed the effectiveness and safety of SB5 in a cohort of patients with IBD who were in stable remission and who switched from ADL to SB5 (switching cohort) and in a cohort of patients with IBD who initiated SB5 treatment without receiving prior treatment with ADL (naïve cohort) [25]. In the naïve cohort, 66.7% (32/48) patients reached the 12-month follow-up, at which time 60.4% (29/48) of patients were in clinical remission. Loss of response was the most common reason for discontinuation. Throughout the study, mean fecal calprotectin (baseline, 665 mg/kg; month 12, 231 mg/kg) and CRP (baseline, 1.2 mg/dL; month 12, 0.57 mg/dL) levels decreased. In the switching cohort, 81.6% (80/98) reached the 12-month follow-up with an overall remission rate of 74.5% (73/98). No statistically significant differences in fecal calprotectin and CRP levels were observed throughout the study. Of the 146 patients in both cohorts, 53 (36.3%) reported AEs. The most common AE was severe injection site pain (24.7%), which was reported more frequently by patients in the switching cohort. Excluding injection site pain, the AE profiles of the two cohorts were otherwise comparable. In 17 of the patients in the switching cohort, Ctrough and ADA levels were measured before the switch from ADL to SB5 and at 3 and 6 months after switching and were similar [25].

Another retrospective observational study (Derikx et al. [26]) conducted in a cohort of 481 patients with IBD in the National Health Service (NHS) Lothian (Scotland) analyzed the effectiveness and safety of SB5 in a switched cohort (n = 256) and a naïve cohort (n = 225) [26]. The median follow-up duration was 13.7 months for the switched cohort and 8.3 months for the naïve cohort. Treatment persistence was similar in both cohorts, with 35.2% (90/256) and 36% (81/225) of patients discontinuing SB5 in the switched and naïve cohort, respectively. AEs and loss of response were the main reasons for discontinuing SB5 in both cohorts. The median CRP and fecal calprotectin levels, HBI, and partial Mayo scores were similar throughout the study period in patients who switched from ADL to SB5. In the naïve cohort, 22% (40/182) of the patients who underwent therapeutic drug monitoring developed ADAs. Similar proportions of patients in the switched cohort had ADAs before (10.1% [21/207]) and after (10.5% [27/256]) switching to SB5. In the naïve cohort, the median Ctrough level measured 3 months after SB5 initiation was 9.4 μg/mL. Although several patients in the switched cohort underwent dose adjustments, Ctrough levels remained stable throughout the observational period (Ctrough before switching, 10.1 μg/mL; Ctrough before week 52, 7.8 μg/mL). SB5 dosing was suspended or discontinued because of AEs experienced by 17.3% (31/225) of patients in the naïve cohort and by 19.9% (51/256) of patients in the switched cohort. Infections (n = 17) were the AEs most commonly reported in the naïve cohort, whereas injection site pain (n = 34) was the AE most commonly reported in the switched cohort [26].

Overall, observational studies confirm the clinical equivalence of SB5 and ADL in patients with IBD. Switching from ADL to SB5 was not associated with clinical complications and did not affect treatment success. Injection site pain was the only AE that was observed more frequently among patients switching from ADL to SB5 compared to patients continuing treatment with ADL [24,25,26]. Multiple factors related to the product formulation, such as pH, volume and excipients, or to the injection process might contribute to injection site pain [27]. The observational studies described in this review were conducted with SB5-LC which contains citrate. In a clinical equivalence study that compared the SB5-LC and SB5-HC formulations, the incidence of injection site reactions in the SB5-HC group was lower than that in the SB5-LC group (4 subjects [4.3%] vs. 10 subjects [10.6%]) [20].

Psoriasis and Hidradenitis Suppurativa

Three observational studies evaluated the treatment of PsO with SB5 [28,29,30], and a small case series reported use of SB5 to treat HS [31].

The first study (Loft et al. [28]) assessed the outcome of mandatory nonmedical switching from ADL to an approved adalimumab biosimilar (either SB5 or GP2017) in patients with psoriasis. A cohort of patients who switched from ADL to an adalimumab biosimilar (n = 348 [SB5, n = 162; GP2017, n = 186]) was compared to a cohort of patients who did not switch treatment and remained on ADL throughout the follow-up duration (n = 378). The primary outcome was the 1-year drug retention rate, which was similar between the two cohorts (biosimilar cohort, 92.0% [95% CI 89.0%; 94.9%] vs. ADL cohort, 92.1% [95% CI 89.4%; 94.8%]). Similar proportions of patients discontinued treatment in the biosimilar cohort (8% [28/248]) and in the ADL cohort (7.9% [30/378]), most commonly because of insufficient effect or AEs. A larger proportion of patients who switched from ADL to an adalimumab biosimilar reported AEs (n = 29 [9.1%]) than did those who remained on ADL (n = 18 [5.0%]). Disease activity and Dermatology Life Quality Index (DLQI) remained unchanged throughout the study period in both cohorts. No clinically meaningful difference was detected between the adalimumab biosimilars SB5 and GP2017 [28].

The second study (Killion et al. [29]) was a single-center retrospective cohort study that analyzed 100 patients with moderate to severe PsO who had switched from ADL to either of the adalimumab biosimilars SB5 or ABP501. After 16 weeks of follow-up, 81% of patients were still being treated with a biosimilar, whereas 19% of patients had switched back to ADL because of AEs. Among patients who continued treatment with SB5 at week 16, 91% of patients had improvements in Psoriasis Area and Severity Index (PASI) and 90% had improvements in DLQI compared to baseline. Patients who switched back to ADL experienced resolution of the AE or loss of efficiency that caused them to discontinue the biosimilar [29].

Another observational study (Girolomoni et al. [30]) enrolled 1059 patients with PsO who were treated with SB5 from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR); 1043 patients were adalimumab naïve and 16 patients were switched from ADL to SB5. The persistence rates of SB5 at years 1, 2, and 3 were 79.7%, 73.5%, and 72.1%, respectively. Median PASI and DLQI improved from baseline to year 1. The most common reasons for SB5 discontinuation were inefficacy (10.6%) followed by AEs (9.9%) [30].

HS is a chronic, relapsing inflammatory skin condition for which currently available conventional synthetic drugs are ineffective in treating severe forms of the disease. The introduction of biologic drugs to treat HS revolutionized the management of this condition. Since adalimumab is the only biologic agent approved to treat HS, the availability of adalimumab biosimilars should expand patients’ access to this medication [32]. In a case series (Ricceri et al. [31]) of 11 patients with moderate to severe HS, the four adalimumab-naïve patients experienced clinical improvement when treated with SB5. Clinical remission rates did not change over 36 weeks in the seven patients who switched from ADL to SB5, and the incidence of AEs was not affected by switching from ADL to SB5 [31].

Taken together, the available observational studies conducted in patients with inflammatory dermatologic diseases reveal no clinically meaningful differences in efficacy or safety of SB5 compared to its reference product, and corroborate that switching from ADL to SB5 is not associated with a significant increase in AEs or loss of efficacy.

Uveitis

Two observational studies reported that SB5 is an effective and safe treatment for uveitis that reduces rates of relapse and improves or preserves visual acuity in both adalimumab-naïve patients and those that have switched from ADL to SB5 [33, 34].

One retrospective study (Sota et al. [34]) assessed the clinical outcomes of SB5 in 26 adalimumab-naïve patients with uveitis. In 47 studied eyes, the rate of uveitis relapses decreased from 121/100 patient-years during the year before SB5 initiation to 4/100 patient-years during the first year of treatment with SB5. By the end of the follow-up (median duration 16.50 months), uveitis was inactive in all but one studied eye. The mean (± SD) letter score of best-corrected visual acuity (BCVA) increased significantly from baseline (7.7 ± 3.41) to the last follow-up (8.9 ± 2.46), while the mean (± SD) daily dosage of co-administered glucocorticoids decreased from 18.33 ± 10.33 to 5.75 ± 2.29 mg/day. Two subjects discontinued SB5 treatment, resulting in a drug retention rate of 92% at both 12 and 20 months of follow-up. One patient reported an injection site reaction, which was considered to be a mild AE [34].

The other observational study (Fabiani et al. [33]) reported the outcome of switching from ADL to SB5 in 20 patients with uveitis (33 eyes). In patients treated with ADL, ocular flares occurred in three patients during the 12 months before switching to SB5. But, after the switch, no patient treated with SB5 experienced an ocular flare. Disease activity did not increase significantly after switching from ADL to SB5. No patient treated with SB5 experienced an ocular flare and no patient experienced an SAE after switching from the ADL to SB5 [33].

Consistency of Product Quality

Whereas small molecules are manufactured by chemical synthesis, biologic medications are produced by living organisms. Since there is variation among proteins manufactured in living cells, biologics from different production lots differ from one another (lot–lot variation) [35]. Monitoring and minimizing lot–lot variations is necessary to ensure the effectiveness and safety of the biological product. In a clinical study of SB3, a biosimilar of the anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab, different lots of reference trastuzumab (Herceptin®, TRZ) varied in efficacy [36]. Analysis of physicochemical and biological properties of lots of TRZ using state-of-the-art methods revealed two sequential drifts in the levels of afucosylated and high mannose N-glycans, which affected Fc gamma receptor 3a (FcγRIIIa) binding activity and antibody-dependent cell-mediated cytotoxicity (ADCC) activity [36] (Fig. 2). In a comparative efficacy clinical trial with SB3, these downward drifts of ADCC among the lots of TRZ reduced event-free survival and overall survival of patients with breast cancer [37] (Fig. 3).

Fig. 2
figure 2

Trend of biologic activities of Herceptin®. a Relative FcγRIIIa binding activity of Herceptin® (n = 98); b relative ADCC activity of Herceptin® (n = 102). Dotted line shows the min–max range of expiry date before August 2018, 1st drift and 2nd drift periods. Boxplot shows the interquartile range, median and outlier (◊). Statistical significance was assessed with one-way ANOVA (*P ≤ 0.05); ADCC, antibody dependent cell-mediated cytotoxicity; ANOVA, analysis of variance; FcγRIIIa, Fc gamma receptor IIIa. The figure and caption have been adapted from Kim et al. [36]

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Fig. 3
figure 3

Event-free survival and overall survival among patients receiving reference TRZ, by ADCC status. a Event-free survival by ADCC status, drifted TRZ vs non-drifted TRZ. b Overall survival by ADCC status, drifted TRZ vs non-drifted TRZ. Tick marks represent censored patients. HRs with corresponding 95% CIs and P values were estimated using a stratified Cox proportional hazards regression model. Non-drifted TRZ, patients who were never exposed to any vials from a drifted TRZ lot during the neoadjuvant period. Drifted TRZ, patients who were exposed to at least one vial from a drifted TRZ lot during the neoadjuvant period. ADCC, antibody-dependent cell-mediated cytotoxicity; CI, confidence interval; HR, hazard ratio; TRZ, trastuzumab reference product. The figure and caption have been adapted from Pivot et al. [37]

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SB5 has undergone process changes since production started, such as transfer of manufacturing sites and the introduction of a new formulation. The quality attributes of SB5 have been tightly controlled and monitored since production started. Between 2013 and 2022, the purity, charge variants, and functional activities of 93 batches of SB5 drug product have been analyzed. The TNF binding activity and TNF neutralizing potency, which have a direct effect on the efficacy of adalimumab, ranged from 86% to 108% (mean ± SD, 99 ± 4%) and from 88% to 119% (mean ± SD, 98 ± 4%), respectively, across different SB5 batches. None of the batches showed a relevant drift in biological activity (Fig. 4). Overall, critical quality attributes of all analyzed batches of SB5 were consistent over time and well within the acceptable ranges of variation that had been agreed upon with regulatory agencies [38].

Fig. 4
figure 4

Biological activities in SB5 batches. a Fluorescence resonance energy transfer (FRET)-based competitive inhibition binding assay. b Cell-based NFκB-luc reporter gene assay. The figure and caption have been adapted from Lee et al. [38]

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Device Features

The SB5 pen device has design attributes that differ from those of the ADL pen. The SB5 pen device has a square shape with rounded edges and a nonslip surface. Its needle gauge (29G) is small to reduce injection pain. The initiation mechanism does not require pressing a button, an audible indicator “clicks” at the start and end of dose administration, and an enlarged medication viewing window allows the patients to confirm that injection is complete (Table 4) [1, 16]. The SB5 pen device was compared to the ADL pen and the reference etanercept (Enbrel®, ETN) MyClic® pen in two survey studies, which were conducted in Germany and the UK, each of which enrolled nurses (N = 101) and patients (N = 151) [39]. The first study compared the SB5 and ADL pens whereas the second study compared the SB5 and ETN pens. Patients had a confirmed diagnosis of RA, PsA, axial spondyloarthritis, UC, or CD, and were required to have been self-injecting ADL for more than 3 months at the time of screening. Nurses were eligible to participate if they had extensive experience with autoinjector devices and at least 1 year of experience as practicing nurse/nurse practitioner, rheumatology specialist nurse, or gastroenterology specialist nurse. To compare the different autoinjector devices, participants were given show cards providing instructions for use of the autoinjectors before being allowed to handle training versions of the respective pen devices [39].

Table 4 Comparison of pen device features of SB5 and ADL
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In the first study, most patients (78%) and nurses (85%) preferred the SB5 pen over the ADL pen. The main attributes prompting preference of the SB5 pen were convenient and easy to use/inject/handle (nurses, 60%; patients, 63%), fits well and does not slip in hand (nurses, 43%; patients, 40%), has an initiation mechanism that requires no thumb trigger button (nurses, 41%; patients, 30%), has a large and visual control that is suitable for hearing-impaired patients (nurses, 42%; patients, 27%), has a double click that is suitable for visually impaired patients (nurses, 49%; patients, 38%), and requires removal of only one cap (nurses, 34%; patients, 33%). Most participants preferred the SB5 pen to the ADL pen because of its ease of use, ease of grip, ease of dose administration, and feedback after administering a full dose. Notably, 87% of nurses would recommend the SB5 pen over the ADL pen, and 79% of patients would choose the SB5 pen over the ADL pen to continue treatment [39].

The SB5 pen was also preferred over the ETN pen by 79% of patients and 86% of nurses in the second study. The main attributes prompting preference of the SB5 pen were convenient and easy to use/inject/handle (nurses, 45%; patients, 65%), fits well and does not slip in hand (nurses, 57%; patients, 51%), and has an automatic start that requires no thumb trigger button (nurses, 45%; patients, 27%). Its ease of use, ease of grip, ease of dose administration, ease of assessing clarity, feedback after administering a full dose, and audio signals made the SB5 pen the preferred option over the ETN pen. Overall, 81% of nurses would recommend the SB5 pen over the ETN pen, and 79% of patients would choose the SB5 pen over the ETN pen to continue treatment [39].

Limitations

The primary focus of this review was to aggregate, analyze, and present available data about SB5. Studies were identified for inclusion by searching PubMed using the keywords “SB5,” “Imraldi,” “Hadlima,” or “Adalloce” in combination with “adalimumab biosimilar.” However, because it is not a systematic review, studies were not evaluated for the quality of their methodology as a criterion for inclusion or exclusion from this review. Thus, as with other narrative reviews, the authors’ selections of studies to include or exclude influenced the conclusions.

Conclusion

SB5 is an adalimumab biosimilar with similar quality attributes, PK, efficacy, safety, and immunogenicity to ADL. Although injection site pain was the most common AE after switching from ADL to citrate-containing, low concentration SB5 (SB5-LC), the availability of citrate-free, high concentration SB5 (SB5-HC) is expected to reduce the rate of injection site pain. Both patients and healthcare professionals have preferred the SB5 autoinjector over other autoinjectors. Overall, available data support that SB5 is both safe and effective in clinical practice across immune-mediated inflammatory diseases for which adalimumab is indicated.