REVIEW

A Review of the Totality of Evidence Supportingthe Development of the First Adalimumab BiosimilarABP 501

Richard Markus . Helen J. McBride . Monica Ramchandani .

Vincent Chow . Jennifer Liu . Dan Mytych . Gary Fanjiang

Received: December 21, 2018 / Published online: June 10, 2019� The Author(s) 2019

ABSTRACT

ABP 501 [United States: AMJEVITATM (adali-mumab-atto); European Union: AMGEVITA�

(adalimumab)] is the first approved biosimilarto adalimumab [reference product (RP)], amonoclonal antibody (mAb) targeting tumornecrosis factor-alfa (TNF-a). ABP 501 hasreceived approval for use in indications thatadalimumab RP is approved for, except thoseprotected by regulatory exclusivity. A system-atic step-wise totality of evidence (TOE)approach formed the basis of approval of ABP501; this involved methodical accumulation ofscientifically robust comparative data support-ing similarity in analytical, preclinical, andclinical [pharmacokinetics (PK)], efficacy, safetyand immunogenicity) evaluations. As a foun-dational first step, comprehensive analyticalassessments demonstrated that ABP 501 isstructurally and functionally similar to adali-mumab RP in critical quality attributes. Pre-clinical assessments confirmed similar activityin assessing mechanisms of action and toxicol-ogy. Clinical evaluation included a phase 1 PK

equivalence study in healthy subjects and twocomparative phase 3 studies that evaluated ABP501 and adalimumab RP in two sensitive patientpopulations, plaque psoriasis (PsO) andrheumatoid arthritis (RA). The PK profiles ofABP 501 and adalimumab RP were similar inhealthy subjects as well as patients with PsOand RA. The pivotal phase 3 study in patientswith PsO demonstrated that ABP 501 was clin-ically similar to adalimumab RP in terms ofefficacy, safety and immunogenicity in both theprimary and transition phases. The pivotalphase 3 study in patients with RA also estab-lished clinical similarity between ABP 501 andadalimumab RP; an open-label extension of thisstudy demonstrated sustained efficacy over anadditional 72 weeks, with no new safety orimmunogenicity concerns with ABP 501 treat-ment. Overall, the TOE supported the conclu-sion that ABP 501 is highly similar toadalimumab RP and provided scientific justifi-cation for extrapolation to all the approvedindications of adalimumab RP not protected byexclusivities.Funding: Amgen Inc.

Keywords: ABP 501; Adalimumab; Ankylosingspondylitis; Biosimilar; Inflammatory boweldisease; Juvenile idiopathic arthritis; Plaquepsoriasis; Psoriatic arthritis; Rheumatoidarthritis; Totality of evidence

Enhanced Digital Features To view enhanced digitalfeatures for this article go to: https://doi.org/10.6084/m9.figshare.7998434.

R. Markus � H. J. McBride � M. Ramchandani �V. Chow � J. Liu � D. Mytych � G. Fanjiang (&)Amgen Inc., Thousand Oaks, CA, USAe-mail: Gary.Fanjiang@amgen.com

Adv Ther (2019) 36:1833–1850

https://doi.org/10.1007/s12325-019-00979-6

INTRODUCTION

ABP 501 [United States (US): AMJEVITATM

(adalimumab-atto); European Union (EU):AMGEVITA� (adalimumab); Amgen Inc.,Thousand Oaks, CA, USA] is the first approvedbiosimilar to adalimumab (HUMIRA�; AbbVieInc., North Chicago, IL, USA), a humanimmunoglobulin G1 (IgG1) monoclonal anti-body (mAb) that specifically binds to both sol-uble (sTNFa) and membrane-bound tumornecrosis factor-alfa (mbTNFa), a pleotropicproinflammatory cytokine that plays a centralrole in the pathogenesis of multiple inflamma-tory diseases. Depending on the target cellengaged, binding of soluble TNFa with its cog-nate cell surface receptors, TNF receptor 1 andTNF receptor 2, leads to induction of either geneexpression via the nuclear factor kappa B-me-diated pathway and production of inflamma-tory cytokines or cell death [1]. The primarymechanism of action of adalimumab is bindingand neutralization of soluble TNFa, therebyblocking subsequent TNFa signaling and thepromotion of inflammation. Moreover, thebinding of adalimumab to membrane-boundTNFa also triggers induction of effector func-tions including antibody-dependent cell-medi-ated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) as well asinduction of reverse signaling, which may berelevant for the observed efficacy of adali-mumab in patients with inflammatory boweldisease (IBD) [2].

ABP 501 is approved by the Food and DrugAdministration (FDA) and European MedicinesAgency (EMA) for all the requested indicationsof adalimumab (HUMIRA�; AbbVie, Chicago,IL, USA; AbbVie, Ludwigshafen, Germany); afew indications were not requested due to reg-ulatory exclusivity [3, 4]. In the US, the indica-tions include moderately to severely activerheumatoid arthritis (RA), moderately toseverely active juvenile idiopathic arthritis (inpatients aged 4 years and older), psoriaticarthritis (PsA), ankylosing spondylitis (AS),adult moderately to severely active Crohn’sdisease (CD), moderately to severely activeulcerative colitis (UC), and moderate to severe

chronic plaque psoriasis (PsO) [3]. In the EU,ABP 501 is additionally approved for two otherindications, i.e., moderate to severe hidradenitissuppurativa and adult non-infectious interme-diate, posterior and panuveitis [4].

A biosimilar is a biological therapeutic that ishighly similar to an already approved originatorreference product (RP). Different regulatoryauthorities consistently define biosimilars asbeing highly analytically similar to the origi-nator RP, with no clinically meaningful differ-ences in purity, potency, pharmacokinetics(PK), pharmacodynamics (PD), clinical efficacy,safety and immunogenicity, notwithstandingthe presence of minor differences in clinicallyinactive components [5–7].

Biosimilars are a distinct category of prod-ucts different from small molecule generic drugs[5, 6, 8]. Whereas generics are chemically syn-thesized and identical to their RP, biologicssuch as mAbs and recombinant proteins arestructurally and functionally complex entitiesthat require development of unique cell linesand manufacturing processes in living systems.Thus, biosimilars are ‘‘similar’’ to their RP; it isimpossible to produce biosimilars that areidentical to the originator RP. Because the pro-prietary manufacturing processes of originatorRP are not known, it is important to character-ize multiple lots of RP and to understand thecritical quality attributes (CQAs) to match. Thischaracterization aids in designing a biosimilarthat has similar identified CQAs, through opti-mization of the unique cell line and manufac-turing processes used by the biosimilarmanufacturer. During the normal manufactur-ing process of biologics, post-translationalmodifications occur on the protein produced ina living cell system; such modifications canconfer minor structural, and in some cases,functional differences in the biosimilar mole-cule. These modifications, although minor,should be evaluated for potential impact offunctional similarity [5, 6]. For the establish-ment of biosimilarity, the biosimilar mustdemonstrate that any structural differences donot confer clinically meaningful differences andthat there is no gain of new functionality.Moreover, biologics have an intrinsic potentialfor immunogenicity, which should be

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specifically evaluated during clinical develop-ment, as there are currently no in vitro assess-ments capable of predicting clinicalimmunogenicity.

Due to the complexity of biologics produc-tion and characterization, the regulatory path-way for biosimilars is different from that forgenerics; US and EU biosimilar guidance recom-mend that biosimilars demonstrate similaritybased on a step-wise totality of evidence (TOE)approach, which begins with the demonstrationof analytical (structural and functional) similar-ity followed by preclinical pharmacology andclinical PK and PD (if applicable) evaluations;and finally, clinical efficacy, immunogenicity,and safety as compared to the RP [5, 6, 8].Building this TOEoccurs in several stages (Fig. 1).The first step involves a comprehensive analyti-cal and functional characterization that serves asthe foundation for the establishment of biosim-ilarity. A meaningful assessment of analyticalsimilarity requires extensive and robust studiesusing multiple state-of-the-art analytical tech-niques and a full evaluation of all known andplausible mechanisms of action of the RP. Thenext step may involve preclinical assessments,particularly if there are uncertainties regardingobserved structural and/or functional differ-ences that a preclinical study could address. Suchpreclinical assessments could include animalstudies to compare the toxicology, toxicokinet-ics, or PD characteristics of the biosimilar ascompared to the RPwith the goal of reducing any

residual uncertainty remaining from the ana-lytical similarity assessment. This is then fol-lowed by assessment of phase 1 comparativehumanPK (and PDwhere applicable) studies; thefinal step is confirmatory clinical evaluation ofthe proposed biosimilar in a sensitive patientpopulation to demonstrate similar efficacy,immunogenicity and safety as compared to theRP. A robust analytical characterization withminimal differences in structural and functionalassessments provides justification for reducedregulatory requirements for clinical evaluations,which allows the program to proceed directly tophase 3 comparative clinical evaluations afterdemonstration of PK/PD biosimilarity.

This review presents the step-wise processthat was used to generate the robust TOE lead-ing to the approval of ABP 501 as the firstbiosimilar to adalimumab. The adalimumab RPused for the analytical and clinical PK assess-ments presented in the current review wasacquired from the US and EU. This was neces-sary because RP is defined as that approved inthe local jurisdiction (i.e., US and EU); thus,ABP 501 must be separately shown to be similarto the adalimumab RP approved in the US andEU. However, recognizing the complexity andcost associated with fulfilling such a require-ment, both regulatory agencies allow the use offoreign-sourced comparators in comparativeclinical studies, contingent upon establishing ascientific rationale or ‘‘scientific bridge’’ thatdemonstrates that the foreign-sourced RP is

Fig. 1 ABP 501 development program: stepwise ‘‘totality-of-the-evidence’’ approach for biosimilarity demonstration. PDpharmacodynamics, PK pharmacokinetics, PsO plaque psoriasis, RA rheumatoid arthritis

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similar to the locally-sourced RP in analyticaland clinical PK/PD assessments [5, 6]. This thenprovides sufficient justification for the use of asingle comparator in the confirmatory clinicalstudy(ies).

This article is based on previously conductedstudies and does not contain any new studieswith human participants or animals performedby any of the authors.

ANALYTICAL CHARACTERIZATION

Similarity assessments start with risk-rankingthe CQA based on scientific understanding ofhow each product quality attribute impactssafety, efficacy, immunogenicity, and/or PK andPD. The testing strategy and evaluationapproaches are designed to incorporate state-of-the-art analytical methods, and assessment cri-teria are established considering the criticalityof the attribute being measured. Statisticalconsiderations are used to establish objectiveassessment criteria to aid in the interpretationof biosimilarity. The result is a scientificallyjustified analytical similarity assessment thatdemonstrates that a proposed biosimilar isstructurally and functionally similar to a RP.

The ABP 501 similarity assessment testingplan was designed to comprehensively assessanalytical and functional similarity and ensurethe detection and understanding of any differ-ences between ABP 501 and the adalimumab RP[9]. Physicochemical similarity of adalimumabRP and ABP 501 was demonstrated throughextensive analytical characterization incorpo-rating orthogonal analytical techniques toassess product quality attributes in multiplecategories, including general properties, pri-mary structure including amino acid sequenceand post-translational modifications, higher-order structure, purity, product- and process-related impurities, particles and aggregates, andthermal-forced degradation profiles [9]. Toensure an objective conclusion of structuralsimilarity between ABP 501 and the adali-mumab RP, comprehensive statistical approa-ches were used to confirm similarity [10].Functional similarity was evaluated for allestablished and plausible mechanisms of action

of ABP 501 and adalimumab RP using primary(potency) and orthogonal measures to supportthat the minor analytical differences observeddid not impact the activity of ABP 501 [11].

Structural Similarity

The primary structure of ABP 501 was shown tobe similar to the adalimumab RP based oncomparative assessments including peptidemapping which confirmed identical amino acidsequences (Fig. 2a). Post-translational modifica-tions including C- and N-terminus modifica-tion, deamidation, and oxidation were detectedamong the products at similar levels [9]. More-over, glycan mapping established that ABP 501and the adalimumab RP had similar glycosyla-tion profiles in terms of major glycans impor-tant to functional activities and PKcharacteristics, including afucosylated and highmannose glycans (Fig. 2b).

The higher-order structure was also found tobe highly similar between ABP 501 and adali-mumab RP [9]. In addition, assessments of levelsand characteristics of different sizes of particlesand aggregates, which identifies any subvisibleand submicron particles and impurities thatcould impact immunogenicity and safety con-cerns, were determined to be low and similar forAPB 501 and adalimumab RP. Product- andprocess-related impurities that result from thedifferent manufacturing processes were alsofound to be similar. Analyses of relevant host-cell impurities, including host-cell protein andhost-cell DNA, were found to be well controlledfor ABP 501. Overall, general properties of ABP501 and adalimumab RP, including proteinconcentration and volume, all met the pre-specified criteria for analytical similarity. Due tothe different formulation of ABP 501 as com-pared with the adalimumab RP (of note, theregulatory guidance allows for a different for-mulation for proposed biosimilars [5, 6]), ther-mal degradation behavior of ABP 501 was foundto be non-inferior compared to that of adali-mumab RP, as evidenced by decreased forma-tion of high molecular weight species in ABP501 compared to adalimumab under forceddegradation conditions. Taken together, these

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results from the similarity assessment demon-strated that ABP 501 was highly analyticallysimilar to adalimumab RP.

Functional Similarity

As a critical component of the TOE for biosim-ilar development, functional similarity assess-ments of ABP 501 versus adalimumab RP wereconducted. As the primary mechanism of actionof adalimumab and ABP 501 is the binding andneutralization of sTNFa, this activity was mea-sured in multiple assays, including those

resulting in caspase activation, cytokine andchemokine production, and in cell death [11].

The results demonstrated similarity betweenABP 501 and adalimumab RP in binding to bothsTNFa and mbTNFa; these results were furtherconfirmed by comparing the binding kinetics ofABP 501 and adalimumab RP using surfaceplasmon resonance. Both ABP 501 and adali-mumab RP showed similarity in neutralizationof sTNFa activity, reflecting the inhibition ofsTNFa-induced proinflammatory signaling. Thepotency of ABP 501 was demonstrated to bestatistically equivalent to adalimumab RP, as

Fig. 2 Structural similarity: comparison of primary structure of ABP 501 with adalimumab (US and EU) [9]: a reducedpeptide map. b glycan map

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assessed by inhibition of TNFa-induced apop-tosis (Fig. 3a). ABP 501, adalimumab (US), andadalimumab (EU) were also similar in terms ofinhibition of TNFa-induced IL-8 secretion, withEC50 values ranging from 192 to 294 pM, 131 to253 pM, and 168 to 225 pM, respectively(Fig. 3b). Moreover, ABP 501 and adalimumabRP were unable to neutralize lymphotoxinalpha bioactivities, the most closely relatedcytokine to TNFa, indicating specificity forTNFa with no gain of function for ABP 501.

Given that adalimumab is an IgG1 and medi-ates effector functions (ADCCandCDC) thatmayplay a role in efficacy in the IBD indications, anevaluation of Fc receptor binding profiles andeffector function was conducted, which includedbinding to Fc-gamma receptors FccRIa, FccRIIa(131H), FccRIIIa (158Vand158F), andneonatal Fcreceptor (FcRn) [11]. Importantly, to confirmsimilarity in activation of Fc-mediated effectorfunction, ABP 501 and adalimumab RP weredemonstrated to be similar in terms of inductionof ADCC and CDC (Fig. 3c, d) [11].

Additionally, binding to mbTNFa can alsoresult in other outcomes including inhibition ofproliferation in a mixed lymphocyte reaction(MLR) through induction of regulatory macro-phages, in addition to reverse signaling andapoptosis of mbTNFa expressing immune cells;thus, these activities were also assessed [12].Both ABP 501 and adalimumab RP were shownto similarly inhibit proliferation in an MLRassay and showed similar mean relative activityin reverse signaling (Fig. 3e).

Overall, the comprehensive assessment offunctional activity, including all establishedand plausible mechanisms of action of adali-mumab, demonstrated high similarity betweenABP 501 and adalimumab RP. The similarfunctional activity of ABP 501 supports the TOEfor biosimilarity and the scientific justification

Fig. 3 Functional similarity: comparison of ABP 501 withadalimumab (US and EU): a potency: inhibition ofTNFa-induced apoptosis [11]; b potency: inhibition ofTNFa-induced IL-8 secretion [11]; c effector functionactivity: induction of ADCC [11]; d effector functionactivity: induction of CDC [11]; e reverse signaling [12]

c

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for extrapolation to all non-studied indicationsapproved for adalimumab.

NON-CLINICAL STUDIES IN VIVO

A repeat dose toxicology study was conductedwith ABP 501 and adalimumab (US) RP in thecynomolgus monkey model. In this study of1-month duration, weekly doses of ABP 501 andthe adalimumab RP showed similar expectedlymphoid changes,which includeddecreased sizeandnumber of germinal centers in axillary lymphnodes, mesenteric lymph nodes, and tonsil.Repeat-dose toxicokinetics were also conductedas part of the toxicology study (unpublished data,Amgen Inc.). Mean toxicokinetic parameters andserum concentration-time profiles at day 1 andagain following the last dosewere similar betweenABP 501 and adalimumab RP.

CLINICAL PHARMACOLOGY

To further confirm similarity, a phase 1 ran-domized, single-blind, single-dose, three-arm,parallel-group study was conducted to demon-strate the PK equivalency of ABP 501 withadalimumab RP after administration of a single40-mg subcutaneous (SC) dose in healthy sub-jects [13]. Healthy volunteers provided the mosthomogenous population to detect any differ-ences between ABP 501 and the adalimumabRP. The adalimumab RP in this study wasacquired from both EU (adalimumab EU) andthe US (adalimumab US) to complete the sci-entific bridge described above. Primary end-points were area under the serumconcentration–time curve from time 0 extrapo-lated to infinity (AUCinf) and the maximumobserved serum concentration (Cmax); sec-ondary objectives were assessments of safety,tolerability, and immunogenicity.

A total of 203 healthy male and femaleadults were dosed and included in the safetyand PK analyses. The geometric mean ratios(GMRs) for PK parameters were similar betweenABP 501 and adalimumab (US) as well asbetween ABP 501 and adalimumab (EU). The90% confidence intervals (CIs) for the GMRs of

AUCinf and Cmax were within the protocol-specified standard PK equivalence criteria of0.80–1.25, indicating PK similarity between ABP501 and adalimumab (US) as well as ABP 501and adalimumab (EU) (Fig. 4).

Treatment-emergent adverse events (TEAEs),regardless of causality, were mild to moderateand were balanced between the treatmentgroups. The most common TEAEs were head-ache, oropharyngeal pain, sinus congestion,nasopharyngitis, and nausea. In terms ofimmunogenicity, the incidence of anti-drugantibodies (ADAs) was similar among the studygroups. PK parameters were affected by the ADAstatus, with a decrease in the study drug half-lifereported in ADA-positive subjects comparedwith ADA-negative subjects; however, theimpact was similar for both ABP 501 and theadalimumab RP [13]. In addition, population PKmodeling confirmed the PK similarity of ABP501 and adalimumab RP for both ADA-negativeand ADA-positive subjects [14]. Overall, theseresults demonstrated PK similarity between ABP501 and adalimumab RP.

CLINICAL EVALUATION

The final step that completes the TOE forbiosimilarity demonstration is clinical confir-mation of similar efficacy, safety, and

Fig. 4 ABP 501 phase 1 study: PK results [23]

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immunogenicity of ABP 501 with the adali-mumab RP.

Two randomized phase 3 clinical studieswere conducted for ABP 501, one in patientswith moderate to severe PsO (NCT01970488)and the other in patients with moderate tosevere RA also receiving methotrexate(NCT01970475). In addition, the RA study wasfollowed by an open-label extension (OLE)study that evaluated the safety and efficacy ofABP 501, such that the total evaluation of thesafety of ABP 501 reached 2 years of treatment(NCT02114931). A single comparator was usedin these clinical studies: EU-authorized RP inthe PsO study and FDA-licensed RP in the RAstudy. This is because, as discussed earlier, ascientific bridge was considered to have beenestablished during the analytical and phase 1 PKevaluations, thereby justifying the use of a sin-gle RP in the ABP 501 clinical program.

DEMONSTRATION OF CLINICALEQUIVALENCE IN MODERATETO SEVERE PLAQUE PSORIASIS

This was a randomized, double-blind, multi-center, active-controlled, phase 3 trial, thatincluded a 4-week screening period, followed by1:1 randomization to receive ABP 501 or adali-mumab RP treatment for 16 weeks [15, 16].Patients were administered ABP 501 and adali-mumab RP at an initial loading dose of 80 mgsubcutaneously (SC) on week 1/day 1, followedby 40 mg SC every 2 weeks (starting at week 2)for 16 weeks. Patients with 50% improvementfrom baseline in psoriasis area and severityindex score (PASI 50) at week 16 remained onthe study and were rerandomized 1:1 to con-tinue on study until 52 weeks. Patients whoreceived ABP 501 in the first randomizationcontinued ABP 501 treatment, and those whoreceived adalimumab RP initially were reran-domized to either continue adalimumab RP orswitch to ABP 501. All patients receivedassigned treatment every 2 weeks until week 48,followed by a 4-week safety follow-up period.The final efficacy assessments were performed atweek 50; the end-of-study visit was at week 52.

Eligible patients had stable moderate to sev-ere PsO for C 6 months, had inadequatelyresponded to or were unable to tolerate/re-ceive C 1 conventional systemic therapy, haddisease involvement of C 10% of body surfacearea (BSA), a PASI score C 12 and a staticPhysician’s Global Assessment (sPGA) of at leastmoderate severity (sPGA range: 0–5) [15, 16].

The primary efficacy endpoint was the per-cent improvement in PASI score from baselineto week 16. Secondary endpoints included PASIpercent improvement from baseline at week 32and week 50; PASI 50, C 75% improvement inPASI score from baseline (PASI 75), C 90%improvement in PASI score from baseline (PASI90), and 100% improvement in PASI score frombaseline (PASI 100) responses; sPGA response ofclear (0) or almost clear (1); and mean change inaffected BSA from baseline at weeks 16, 32, and50 [15, 16]. Safety assessments included moni-toring for TEAEs and serious adverse events(SAEs), laboratory data, vital signs, andimmunogenicity.

A total of 350 patients were randomized onstudy (ABP 501, n = 175; adalimumab, n = 175)and a total of 326 patients completed the trial toweek 16. At week 16, 308 patients were reran-domized to continue through to week 52(ABP 501/ABP 501, n = 152; adalimumab RP/adalimumab RP, n = 79; adalimumab RP/ABP501, n = 77).

Primary Efficacy and Safety AnalysisResults: Initial 16-Week Period

At week 16, the percent improvement in PASIscore from baseline was similar between the twogroups, with a least-square mean difference of- 2.18 (95% CI, - 7.39 to 3.02) (Fig. 5a) [15].Since the 95% CIs of the primary endpoint werewithin the prespecified margin (- 15 to 15),clinical equivalence between ABP 501 andadalimumab RP was demonstrated. Key sec-ondary efficacy endpoints, including the pro-portion of patients achieving PASI 50, PASI 75,PASI 90, PASI 100, sPGA clear/almost clear, andBSA affected at week 16, were also similarbetween the two treatment groups.

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During the initial 16-week treatment period,the incidences of TEAE (67.2% vs. 63.6%) anddiscontinuations due to TEAEs (4% vs. 2.9%)were similar between the ABP 501 and adali-mumab RP groups (Table 1) [15]. AEs occurringin C 5% of patients in any treatment groupwere nasopharyngitis, headache, and upperrespiratory tract infection. Other TEAEs ofinterest included infections, serious infections,hypersensitivity, and injection-site reactions.

A sub-analysis of patients with a medicalhistory of psoriatic arthritis also showed thatthe efficacy, safety, immunogenicity, and PK forABP 501 and adalimumab RP were similar andconsistent with the primary study results [17].

Single Transition Results: 16–52 Weeks

Following the single planned switch fromadalimumab RP to ABP 501 at week 16, the

rerandomized patients achieved similar meanPASI percent improvement from baseline toweek 16 in the ABP 501/ABP 501, adalimumabRP/adalimumab RP, and the adalimumab RP/ABP 501 groups [16]. In the rerandomizedpopulation, percent improvement in PASI,PASI 50/75/90/100 responses were similar acrossthe three groups from week 16 to the end of thestudy (week 52), with no significant differencebetween groups (Fig. 5b). Also, sPGA positiveresponses achieved in the transition phase weresimilar at all timepoints, across all groups, andto the pre-switch results. Similarly, among thererandomized population, changes from base-line in percent BSA were similar across the threegroups at weeks 16, 32, and 50.

After week 16 and through week 52 (follow-ing rerandomization), similar percentages ofpatients experienced C 1 TEAE between thethree groups (Table 1) [16]. Imbalances in C 5%TEAEs were noted for nasopharyngitis, head-ache, diarrhea and back pain. The most com-mon AEs of interest were nasopharyngitis andupper respiratory tract infection. Overall, eventsof hypersensitivity were low and included con-tact dermatitis (ABP 501/ABP 501, n = 4), all ofwhich were noted to be unrelated to treatment,rash (ABP 501/ABP 501, n = 3) and urticaria(adalimumab RP/ABP 501, n = 2). These did notrepresent any clinically meaningful differencesbetween treatment groups. Changes in liverenzymes occurred in 13 patients—the groupthat continued on ABP 501 after rerandomiza-tion (ABP 501/ABP501 group) had a greaterproportion of patients with increased liverenzymes including alanine aminotransferase(ALT), aspartate aminotransferase (AST), andgamma-glutamyltransferase (GGT) in contrastto the other two groups (adalimumab RP/ABP501 and adalimumab RP/adalimumab RP). Inthe latter two groups, changes in liver enzymeswere grade 1 or 2 in severity and were resolvedby the end of study in all but one case of ele-vated GGT. Injection site reactions were notedin five patients and appeared to be comparablebetween the ABP 501/ABP 501 and adalimumabRP/adalimumab RP groups; the majority ofthese events were ascribed to injection-site pain.Over the course of the study, no deaths and no

Fig. 5 Phase 3 trial data in moderate to severe PsO:percentage improvement in psoriasis area and severityindex (PASI) scores: a primary efficacy results: baseline toweek 16 [15]; b overall efficacy results: baseline to week 52[16]

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cases of demyelinating disease, heart failure, orlupus-like syndromes were reported.

DEMONSTRATION OF CLINICALEQUIVALENCE IN MODERATETO SEVERE RHEUMATOIDARTHRITIS

A randomized, double-blind, active comparator-controlled equivalence study was conducted tocompare the clinical efficacy, safety, andimmunogenicity of ABP 501 with adalimumabRP and to establish clinical similarity in adali-mumab-naive adult patients with moderate tosevere RA who had an inadequate response tomethotrexate (MTX) [18]. This study includedpatients with a diagnosis of moderate to severeRA [per 2010 American College of Rheumatol-ogy/European League Against Rheumatism cri-teria (ACR/EULAR) criteria] for C 3 months,active RA (C 6 swollen joints and C 6 tender

joints) at screening and baseline, an erythrocytesedimentation rate C 28 mm/hour serum C-re-active protein (CRP)[1.0 mg/dL with positiv-ity for rheumatoid factor or anticycliccitrullinated peptide antibodies at screening.Additionally, patients must have received MTX(dose of 7.5–25 mg/week) for C 12 consecutiveweeks before receiving the investigational drug,which they continued for the study duration.Enrolled patients were randomized 1:1 toreceive either ABP 501 or adalimumab RP 40 mgSC on day 1 and then every 2 weeks untilweek 22. Assessments for the primary endpointoccurred at week 24. Safety and immunogenic-ity assessments were made at week 26, whileADA levels were measured at baseline and atweeks 4, 12, and 26. The primary efficacy end-point was the risk ratio (RR) of achieving a 20%improvement from baseline in the AmericanCollege of Rheumatology (ACR) core set ofmeasurements (ACR20) at week 24. Secondaryefficacy endpoints included assessments of

Table 1 Clinical evaluations of ABP 501 vs. adalimumab RP in moderate to severe PsO: summary of clinical safety

Initial 16-week periodPapp et al. [15]

Rerandomized treatment, weeks 16–52Papp et al. [16]

ABP 501(n = 174)

Adalimumab(n = 173)

ABP 501/ABP501(n = 152)

Adalimumab/Adalimumab(n = 79)

Adalimumab/ABP 501(n = 77)

Any TEAE 117

(67.2%)

110 (63.6%) 108 (71.1%) 52 (65.8%) 54 (70.1%)

SAEs 6 (3.4%) 5 (2.9%) 4 (2.6%) 4 (5.1%) 4 (5.2%)

TEAEs leading to

discontinuations

7 (4.0%) 5 (2.9%) 4 (2.6%) 1 (1.3%) 2 (2.6%)

Adverse events of interest

Infections 59 (33.9%) 58 (33.5%) 67 (44.1%) 29 (36.7%) 37 (48.1%)

Nasopharyngitis 25 (14.4%) 27 (15.6%) 25 (16.4%) 14 (17.7%) 18 (23.4%)

Headache 13 (7.5%) 18 (10.4%) 5 (3.3%) 8 (10.1%) 2 (2.6%)

Malignancies 1 (0.6%) 1 (0.6%) 1 (0.7%) 0 0

Hypersensitivity 8 (4.6%) 7 (4.0%) 8 (5.3%) 2 (2.5%) 3 (3.9%)

Haematological reactions 0 3 (1.7%) 0 1 (1.3%) 1 (1.3%)

Liver enzyme elevations 4 (2.3%) 2 (1.2%) 9 (5.9%) 2 (2.5%) 2 (2.6%)

TEAE treatment-emergent adverse event, SAE serious adverse event

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disease activity score 28-joint count-CRP(DAS28-CRP), the RR for achieving 20%(ACR20), 50% (ACR50), and 70% (ACR70)improvement in ACR core set of measurementsat various time points throughout the study.Other endpoints assessed in this study includedthe risk differences (RD) for ACR20, ACR50, andACR70. Key measures for safety assessmentincluded TEAEs, SAEs and incidence of ADAs.

A total of 526 patients were randomized andtreated with study drug (ABP 501, n = 264;adalimumab RP, n = 262) [18]. Baseline demo-graphics and clinical characteristics were similarbetween groups; mean baseline DAS28-CRPscores were 5.66 for the ABP 501 group and 5.68for the adalimumab RP group. The majority ofpatients were female (81.0%) and white(95.1%), and mean age was 55.9 years (range:21–80 years) with a mean of 9.39 years since RAdiagnosis. Prior use of biologics for RA andbaseline use of RA medications was balancedacross groups; a majority of patients in bothgroups (ABP 501, 73.1%; adalimumab RP,71.8%) were treatment-naive for prior use ofbiologics for RA.

Clinical Efficacy

At week 24, a similar proportion of patients inthe ABP 501 (74.6%) and adalimumab RP(72.4%) groups met the ACR20 response

criteria, with an RR (two-sided 90% CI) of 1.039(0.954, 1.133) for ABP 501 versus adalimumabRP (Fig. 6) [18]. The 90% CI (0.954, 1.133) fellwithin the predefined equivalence margin(0.738, 1.355), demonstrating clinical similaritybetween ABP 501 and adalimumab RP. In addi-tion, the RD for ACR20 at week 24 between theABP 501 and adalimumab RP groups was 2.604(two-sided 90% CI, - 3.728, 8.936). The pro-portion of ACR20 responders was comparablebetween the two treatment groups at weeks 2and 8.

A similar proportion of patients achievedACR50 and ACR70 response criteria at week 24with ABP 501 versus adalimumab RP (Fig. 6).The percentage of ACR50 and ACR70 respon-ders was similar between treatment groupsthroughout the study. Additionally, the meanchange from baseline in DAS28-CRP was - 2.32for both ABP 501 and adalimumab RP groups atweek 24. A similar decrease in mean changefrom baseline in DAS28-CRP was noted in bothgroups throughout the study, indicating simi-larly reduced disease activity. For both groups, agreater percentage of patients achieved DAS28-CRP remissions over time from weeks 2 to 18(range, ABP 501: 6.3–31.1%; adalimumab RP:2.8–27.1%). At week 24, 30.5% in the ABP 501group and 35.5% of patients in the adalimumabRP group reached the criteria of DAS28-CRPremission, further substantiating clinical

Fig. 6 Phase 3 trial data in moderate to severe RA: percentage of patients achieving ACR20, ACR50, and ACR75 [18]

Adv Ther (2019) 36:1833–1850 1843

efficacy equivalence between ABP 501 and theadalimumab RP.

Safety

Overall, similar proportions of patients reportedTEAEs in the ABP 501 and adalimumab RPgroups (50.0% vs. 54.6%) (Table 2) [18]. TEAEsreported by C 3% of patients werenasopharyngitis (6.4% vs. 7.3%), headache(4.5% vs. 4.2%), arthralgia (3.0% vs. 3.4%),cough (2.7% vs. 3.1%), and upper respiratorytract infection (1.5% vs. 3.8%). A total of 27SAEs in 23 patients were reported throughoutthe study, with similar incidence in the ABP 501(n = 10; 3.8%) and adalimumab RP (n = 13;5.0%) groups. Sepsis (n = 2; ABP 501) was theonly SAE reported for[ 1 patient, whichresolved by the end of the study. There were nodeaths in this study. Adverse events of interestthat occurred during the study were mostly ofgrade 1 or 2 severity and included infections,malignancies, hypersensitivity, and liverenzyme elevations (Table 2). Two malignancies(basal cell carcinoma and squamous cell carci-noma) were reported in one subject in the ABP501 group, and another (squamous cell carci-noma of the skin) was reported in one subject in

the RP group. Events of hypersensitivity occur-ring in[2 patients included rash, erythema-tous rash, and allergic dermatitis. Overall, 2.3%of patients in the ABP 501 and 5.0% of patientsin the adalimumab groups experienced injec-tion-site reactions. Although elevations in liverenzymes were reported, none led to prematurestudy discontinuation and none were associatedwith increases in bilirubin.

Open-Label Extension Study in Moderateto Severe RA

An open-label, single-arm extension of thephase 3 study in RA (NCT02114931, ParentStudy) was designed to further evaluate thesafety, efficacy, and immunogenicity for anadditional 72 weeks in patients with moderateto severe RA [19]. All subjects who had com-pleted the week 26 visit received ABP 501 40 mgevery other week starting on day 1 of the OLEstudy. Primary outcomes were the incidence ofTEAEs, severe adverse events (SAEs), clinicallysignificant changes in laboratory analytes, andADA incidence. Secondary outcomes includedthe percentage of participants with an ACR20response and change from parent study baselinein DAS28-CRP, at OLE study baseline and weeks

Table 2 Clinical evaluations of ABP 501 vs. adalimumab RP in moderate to severe RA: clinical safety

Phase 3 studyCohen et al. [18]

OLE studyCohen et al. [19]

ABP 501(n = 264)

Adalimumab(n = 262)

ABP 501(n = 467)

Any TEAE 132 (50.0%) 143 (54.6%) 297 (63.7%)

SAEs 10 (3.8%) 13 (5.0%) 46 (9.9%)

AEs leading to discontinuations 7 (2.7%) 2 (0.8%) 8 (1.7%)

Adverse events of interest

Infections 61 (23.1%) 68 (26.0%) 190 (40.8%)

Malignancies 1 (0.4%) 1 (0.4%) 8 (1.7%)

Hypersensitivity 14 (5.3%) 10 (3.8%) 20 (4.3%)

Haematological reactions 5 (1.9%) 5 (1.9%) 5 (1.1%)

Liver enzyme elevations 13 (4.9%) 10 (3.8%) 25 (5.4%)

AE adverse events, TEAE treatment-emergent adverse event, OLE open-label extension, SAE serious adverse event

1844 Adv Ther (2019) 36:1833–1850

4, 24, 48, and 70. A total of 494 (93.9%) subjectscompleted the parent study; of these, 467 sub-jects who completed the week 26 visit wereenrolled and 466 received treatment in the OLEstudy.

Clinical EfficacyAt baseline, the overall ACR20 response rate was73.3%, which was sustained at subsequentweeks (Fig. 7) [19]. The mean change frombaseline of the parent study was - 2.25 atbaseline of the extension study. The meanchange from baseline in DAS28-CRP of theparent study remained unchanged throughoutthe extension study. Also, the proportion ofACR20 responders was similar in the patientcohort that continued on ABP 501 and thosewho had transitioned from adalimumab RP toABP 501. The efficacy, as assessed by ACR20 andDAS28-CRP, was maintained throughout theextension period and was similar among thosepatients who continued on ABP 501 and thosewho had transitioned from adalimumab RP toABP 501.

SafetyOverall, 63.7% of all patients experienced C 1TEAE during the extension study; however, theincidence rates of TEAEs were similar in thegroup that continued ABP 501 from the parentstudy to the OLE study (ABP 501/ABP 501,62.4%) and in those that transitioned fromadalimumab RP to ABP 501 (adalimumab RP/ABP 501, 65.0%) [19]. Consistent with the par-ent study, common TEAEs that occurred inC 5% of overall patients included nasopharyn-gitis (9.2%), upper respiratory tract infection

(8.6%), bronchitis (6.4%), pharyngitis (4.1%)and urinary tract infection (3.6%). Throughoutthe study, a total of 59 SAEs in 46 patients(9.9%) were reported, with similar rates in theadalimumab RP/ABP 501 (8.9%) and ABP501/ABP 501 (10.9%) cohorts. SAEs reported formore than one patient were osteoarthritis(n = 5), RA (n = 2), myocardial infarction(n = 2), and cataract (n = 3). Common AEs ofinterest during the study were infections,malignancies, hypersensitivity, hematologicalreactions, and liver enzyme elevations (Table 2).The most common infection was nasopharyn-gitis (adalimumab RP/ABP 501: 10.5%, ABP501/ABP 501: 7.9%); other infections includedupper respiratory tract infection, bronchitis,pharyngitis, urinary tract infection, sinusitis,oral herpes, tonsillitis, laryngitis, andpneumonia.

IMMUNOGENICITY IN ALL THREESTUDIES

Immunogenicity assessments were carried outin all three clinical studies. The development ofbinding and neutralizing antibodies was similarbetween ABP 501 and adalimumab RP in boththe PsO and RA patient populations; these dataare presented in Table 3 [15, 16, 18, 19]. Addi-tionally, in the PsO study, despite the singletransition switch from adalimumab RP toABP 501 at week 16, the proportion of patientsthat developed binding and neutralizing anti-bodies was generally similar across groups overthe entire 52 weeks of treatment, i.e., frombaseline to study end (Table 3) [16]. Further, in

Fig. 7 OLE trial data in moderate to severe RA: percentage of patients achieving ACR20 [19]

Adv Ther (2019) 36:1833–1850 1845

the OLE study which included patients who hadtransitioned from adalimumab to ABP 501, thedevelopment of binding and neutralizing anti-bodies was also similar.

In the phase 3 RA study, the incidence ratesof binding antibodies and neutralizing anti-bodies were similar between the two treatmentgroups throughout the study (Table 3) [18]. Inthe OLE study, relative to the OLE baseline, asimilar proportion of patients were positive forbinding antibodies and neutralizing antibodies,across the treatment groups anytime through-out the study (Table 3) [18]. Although the inci-dence rates of binding and neutralizing ADAsincreased over time from the parent studybaseline, the rates were maintained throughoutthe OLE study, with no differences in the adal-imumab RP/ABP 501 and ABP 501/ABP 501groups. Overall, no immunogenicity-relatedconcerns were observed with ABP 501 duringthe 2 years of combined treatment [20].

It is important to note that, in the threeclinical studies, a highly sensitive and drug-tolerant electrochemiluminescence (ECL) assaywas used to assess ADA status. This may explainthe higher rates of ADAs in these studies com-pared with those reported for adalimumab RP inthe original studies. Of note, the rates werehigher for both ABP 501 and adalimumab RP.The sensitivity of the ECL ADA binding assaywas\ 25 ng/mL in the presence of 25 lg/mL ofthe drug, with detection of 25 ng/mL ADAs[13, 21]. The ADA status in historical pivotaltrials of adalimumab RP had been determinedby ELISA assay, which is a less-sensitive assaythat does not permit detection of ADAs in thepresence of the drug [22]. The same ECL assaywas used in all clinical studies of ABP 501 (phase1, phase 3 and OLE) for the determination ofADAs and neutralizing antibodies.

INJECTION-SITE REACTIONSAND INJECTION-SITE PAINASSESSMENTS IN THE TWO PHASE3 STUDIES

An exploratory objective of both phase 3 studieswas to assess patient perception of injection-site

Table3

Immun

ogenicityof

ABP501vs.adalim

umab

RPin

moderateto

severe

RA

andPsO

Mod

erateto

severe

RA

Mod

erateto

severe

PsO

Phase

3stud

yCoh

enet

al.[18]

OLEstud

yCoh

enet

al.[19]

Phase

3stud

y:16-week

Pappet

al.[15]

Phase

3stud

y:po

strerand

omization

Pappet

al.[16]

ABP501

(%)

Adalim

umab

RP(%

)ABP501

(%)

Adalim

umab

RP(%

)ABP501

(%)

Adalim

umab

RP(%

)ABP501/ABP

501(%

)Adalim

umab

RP/A

dalim

umab

RP(%

)

Adalim

umab

RP/A

BP501

(%)

Binding

antibody

38.3

38.2

54.1

48.9

55.2

63.6

68.4

74.7

72.7

Neutralising

antibody

9.1

11.1

14.4

13.9

9.8

13.9

13.8

20.3

24.7

1846 Adv Ther (2019) 36:1833–1850

pain and injection-site reactions. Assessmentswere carried out within 5 min of injection atbaseline, and weeks 4, 8, and 12, and measuredusing the validated 100-mm horizontal visualanalog scale questionnaire [23, 24]. In the phase3 study of patients with plaque PsO, the per-ception of pain was lower in the ABP 501 group(range 3.3–4.5 mm) compared with the adali-mumab RP group (range 12.4–19.3 mm) at eachtime point including baseline. Overall, meanpain scores decreased over time in both treat-ment groups, from 4.5 mm at baseline to3.3 mm at week 12 in the ABP 501 group andfrom 19.3 mm at baseline to 12.4 mm at week12 in the adalimumab RP group. Similarly,injection-site reactions were lower in the ABP501 group compared with the adalimumab RPgroup; adverse events in the ABP 501 groupincluded injection-site hematoma, injection-site reaction, and injection-site erythema.

Similar to the findings of the PsO assessment,the perception of pain was lower in the ABP 501group (range 10.0–10.7 mm) compared with theadalimumab RP group (range 16.1–21.4 mm) inthe RA study [23, 24]. The mean pain scoresremained nearly the same from baseline to week12 in the ABP 501 group; however, the scoresdecreased over time in the adalimumab RPgroup, from 21.4 mm at baseline to 16.1 mm atweek 12. Injection-site reactions were also lowerin the ABP 501 group compared with the adal-imumab RP group. The relevant events in theABP 501 group included injection-site reactionand injection-site erythema, whereas those inthe adalimumab RP group included injection-site erythema and injection-site reaction,injection-site pruritus, injection-site eczema,injection-site reaction hematoma, injection-sitehypersensitivity, and injection-site pain; theevent of injection-site eczema led to discontin-uation of adalimumab RP.

The adalimumab RP used in the clinicalstudies contained citrate which has been linkedto injection-site pain [25]. Therefore, thereduced perception of pain and injection-sitereactions observed in the ABP 501 group may beattributed to the absence of citrate in the ABP501 formulation. Potentially, the absence ofinjection site pain could result in increasedcompliance with ABP 501 treatment [25].

OVERALL CLINICAL SUMMARY

The clinical confirmation component of theTOE for demonstration of ABP 501 similarity toadalimumab RP included a phase 1 PK equiva-lence study and two comparative phase 3 piv-otal studies that evaluated the efficacy, safety,and immunogenicity of ABP 501 and adali-mumab RP in two sensitive patient populations,PsO and RA.

In both phase 3 pivotal studies in PsO andRA, clinical efficacy of ABP 501 was demon-strated to be similar to the adalimumab RP. TheOLE results further supported the clinical simi-larity between ABP 501 and adalimumab RP inRA by demonstrating that the efficacy wasmaintained over 72 weeks. Moreover, efficacywas similar among patients who continued onABP 501 and those who had transitioned fromadalimumab RP to ABP 501.

In terms of safety, there were no clinicallymeaningful differences in AEs or laboratoryabnormalities in the two phase 3 pivotal stud-ies, and no new safety signals emerged in theOLE study, supporting the long-term safety ofABP 501 for at least 2 years. Reports of hyper-sensitivity were also similar between the treat-ment arms. Malignancies occurred at a similarrate in both treatment arms and diseasesettings.

Immunogenicity was also shown to be simi-lar between ABP 501 and adalimumab RP in thetwo comparative phase 3 studies as well as inthe OLE study. Transition from the RP to ABP501 did not impact immunogenicity, withsimilar rates of antibody formation in the ABP501/ABP 501 and adalimumab RP/ABP 501cohorts.

EXTRAPOLATION

The concept of extrapolation is unique tobiosimilars and refers to seeking approval forbiosimilar use in indications for which theadalimumab RP is approved without having toperform clinical trials in each of those indica-tions [5, 6]. The scientific justification forextrapolation is based on the establishment ofbiosimilarity based on the TOE generated

Adv Ther (2019) 36:1833–1850 1847

during development of the biosimilar program,including analytical, functional, non-clinical,and clinical data. Then, the mechanism ofaction, safety, immunogenicity, PK and evalu-ation of any other clinical risks for the RP areevaluated across the approved indications todetermine if there are any differences that couldpreclude extrapolation. If none are identified,then extrapolation is supported based on a sci-entific justification of the above points and ispredicated upon a determination of biosimilar-ity to the RP.

As discussed in this review, ABP 501 is similarto adalimumab RP based on a comprehensiveanalytical and functional assessment and showssimilar non-clinical performance. In clinicalevaluations, ABP 501 exhibits similar PK profilesin healthy subjects as well as in subjects with RAand PsO. Additionally, ABP 501 shows similarefficacy, safety, and immunogenicity in both RAand PsO patient populations. Of note,immunogenicity was similar in patients takingMTX as a concomitant medication (RA study) aswell as those not on immunosuppressive med-ications (PsO study). Taken together, these datasupport the conclusion of biosimilarity. With-out identified differences in the mechanism ofaction, PK, safety, or immunogenicity of the RPacross the approved indications of adalimumab,extrapolation to all approved indications of theadalimumab RP (i.e., AS, PsA, UC, and CD) isalso supported. In fact, ABP 501 receivedapproval for use in all indications approved forthe adalimumab RP, except those protected byregulatory exclusivity.

OVERALL CONCLUSIONS

The regulatory pathway for demonstration ofsimilarity between a proposed biosimilar and itsRP requires a systematic stepwise approach, inwhich evidence of similarity of structure, func-tion, PK (and PD where appropriate), clinicalefficacy, safety, and immunogenicity is built bymethodical accumulation of scientificallyrobust comparative data between the proposedbiosimilar and its RP. The sum of these results,referred to as the TOE in support of biosimilar-ity, forms the basis of approval of a biosimilar.

In accordance with this TOE approach, allevaluations demonstrated that ABP 501 and itsadalimumab RP are highly similar (including2 years of clinical data in RA and 1 year in PsO).Additionally, a single switch from adalimumabRP to ABP 501 was safe and without loss ofefficacy. The results presented here led to theapproval of ABP 501 as the first biosimilar toadalimumab.

ACKNOWLEDGEMENTS

The authors wish to thank Teresa Born, ScottKuhns, and Jyoti Velayudhan for their contri-butions to pre-clinical evaluations.

Funding. Sponsorship of ABP 501 studiesdescribed in this review, the article processingcharges and the Open Access fee were funded byAmgen Inc., Thousand Oaks, CA, USA. Allauthors had full access to the articles reviewedin this manuscript and take complete responsi-bility for the integrity and accuracy of thismanuscript.

Editorial Assistance. Editing assistance wasfunded by Amgen Inc. and provided by SabbyMuneer, PhD, from Innovation Communica-tions Group, Inc., New York, NY, USA, underthe guidance of Monica Ramchandani, PhD,Amgen Inc.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Richard Markus is an Amgenemployee and stockholder.Helen J.McBride is anAmgen employee and stockholder. MonicaRamchandani is an Amgen employee and stock-holder. Vincent Chow is an Amgen employeeand stockholder. Jennifer Liu is an Amgenemployee and stockholder. Dan Mytych is anAmgen employee and stockholder. Gary Fan-jiang is an Amgen employee and stockholder.

1848 Adv Ther (2019) 36:1833–1850

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any new studies withhuman participants or animals performed byany of the authors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the currentreview.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercialuse, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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