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BIOLOGICS |
From ZymoGenetics, Seattle, Washington (Dr Nestorov, Dr Visich) and Merck Serono International S.A. (an affiliate of Merck KGaA, Darmstadt, Germany), Geneva, Switzerland (Dr Munafo, Dr Papasouliotis).
Address for correspondence: Ivan Nestorov, ZymoGenetics, Inc, 1201 Eastlake Avenue East, Seattle, WA 98102; e-mail: intv{at}zgi.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: APRIL • atacicept • BLyS • pharmacokinetics • rheumatoid arthritis • TACI-Ig
Atacicept is a recombinant fusion protein that binds and neutralizes the activity of B lymphocyte stimulator (BLyS, CD257), a key cytokine regulating B cell maturation, proliferation, and survival, and its homologue, a proliferation-inducing ligand (APRIL, CD256).10 Both BLyS and APRIL are members of the tumor necrosis factor (TNF) family produced by a wide variety of cell types and act on B cells to enhance survival, proliferation, antigen presentation, and class-switch recombination at various stages of B cell development.11,12 Both ligands bind to 2 TNF-receptor family members, transmembrane activator and CAML interactor (TACI) and B cell maturation antigen (BCMA).13 BLyS also binds specifically to B cell activating factor receptor (BAFF-R), another TNF-receptor family member.14
Depending on the stage of maturation and activation state of the B cell, APRIL and BLyS receptors are expressed on the B cell surface to varying degrees. Immature transitional-type 1 B cells weakly express TACI, but this expression is upregulated in immature transitional type 2 B cells, marginal zone B cells, and activated B cells; TACI, however, is not expressed by germinal center B cells.15 In comparison, plasma cells, plasmablasts, and tonsillar germinal center B cells each strongly express BCMA.15-17 BAFF-R, which is expressed earlier in B cell development, is present on the majority of peripheral B cells, but expression decreases as the B cells differentiate to the plasma cell stage. TACI has also been reported to be expressed on the surface of activated T cells,18,19 although this has been under some debate.15 BAFF-R seems to be expressed on activated/memory/regulatory subsets of T cells and may serve as a mediator of T cell costimulation and/or survival.15,20
The important role for BLyS in the pathogenesis of autoimmune disorders is supported by the observation that transgenic mice expressing high levels of BLyS exhibit immune cell disorders and display symptoms similar to those in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome.10,21 In addition, BLyS and APRIL serum levels are, on average, elevated in patients with RA, SLE, and Sjögren's syndrome,22-24 although there is considerable overlap in the ranges of BLyS and APRIL serum concentrations observed, for example, in patients with RA compared with healthy controls. Of interest, the levels of both BLyS and APRIL are higher in RA synovial fluid than in blood, particularly in the case of significant joint inflammation, suggesting that these ligands may play an important role in the inflamed synovial compartment.23-26
In addition to elevated levels of BLyS and APRIL homotrimers, circulating heterotrimeric complexes of BLyS and APRIL have also been shown to be elevated in serum from patients with systemic immune-based rheumatic diseases (including SLE, RA, Reiter's syndrome, psoriatic arthritis, polymyositis, and ankylosing spondylitis) and are able to induce B cell proliferation in vitro.26,27 Interestingly, only atacicept, but not BCMA-immunoglobulin (Ig) or BAFF-R-Ig, can apparently neutralize these heterotrimers.27
Atacicept contains the BLyS/APRIL-binding extracellular portion of the TACI molecule fused to the Fc portion of human IgG1, and it is designed to neutralize BLyS, APRIL, and heterotrimers and to prevent them from binding to their receptors on lymphocytes. Decreasing the levels of BLyS and APRIL in vivo is expected to result in a decrease in circulating mature B cells and Ig-secreting cells, leading to a consequent drop in Ig levels.
In a phase I study with healthy male volunteers (n = 23) who received a single subcutaneous dose of atacicept (2.1 mg, 70 mg, 210 mg, or 630 mg) or placebo and were monitored over 7 weeks, atacicept was well-tolerated with no clinically significant changes in vital signs or laboratory parameters at all doses during the study.28 Treatment-emergent adverse events (AEs) were mainly mild or moderate in severity, and all were transient, resolving without any clinical sequelae. There was no evidence of any relationship between atacicept dose and the incidence of AEs. Serum pharmacokinetic (PK) profiles of atacicept were nonlinear, and the drug demonstrated a dose-dependent biological effect on IgM levels. In these healthy volunteers, a single atacicept dose did not appear to have an effect on IgG levels.
To evaluate a variety of single and multiple doses of atacicept administered over a 1- and 3-month period in patients with RA, we conducted a randomized, double-blind, placebo-controlled, escalating-dose phase Ib study. A general description of the study results with detailed safety outcomes has been described previously by Tak et al.29 The purpose of this article is to present a detailed description of the PK profiles and biomarker results from the study, as well as the emerging relationships between atacicept exposure and biological activity.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Except for the first 6-hour sampling in the single-dose cohorts, PK samples on dosing days were specified nominally as troughs. Unbound BLyS and APRIL concentrations were measured in serum at baseline. IgG, IgM, IgA, and RFs (IgA-, IgM- and IgG-RF) were assessed in the blood as markers of biological activity. The biomarkers were measured at the same times as the PK markers (except the 6-hour and study days 3-5 in cohorts 1-5 and study days 2, 3-5, 86, and 99 in cohort 6).
Assays
Pharmacokinetic Assays
The PK variables free atacicept, atacicept-BLyS complex, and composite atacicept (free atacicept plus that complexed with BLyS) were measured using enzyme-linked immunosorbent assays (ELISAs). To this end, either biotin-conjugated mouse monoclonal antibodies (mAbs) specific for atacicept (ZymoGenetics, Seattle, Washington) or goat-biotinylated polyclonal antibodies (pAbs) specific for either BLyS (R&D Systems, Minneapolis, Minnesota) or atacicept (R&D Systems) were incubated together with patient, standard, or control samples diluted 1:10 for 1 hour in streptavidin precoated microplates (Adaltis, Montreal, Canada). After washing, horseradish peroxidase (HRP)-conjugated mouse mAbs directed against atacicept for the detection of free atacicept or atacicept-BLyS complex and, in the case of the composite ELISA, against atacicept and BLyS (ZymoGenetics) were incubated at room temperature for 1 hour. After washing, tetramethylbenzidine (TMB) was added as HRP substrate (Sigma-Aldrich, St Louis, Missouri). The reaction was halted after 20 minutes using 0.5 M sulfuric acid and the absorbance recorded at 450 nm. The analyte concentration of a patient sample was recalculated using the standard curve, applying a polynomial second-order fitting algorithm. All samples were measured in triplicate. Assay performance criteria of a precision of <15% coefficient of variation (CV) for standard samples and <20% for patient samples were accepted. The lower limits of quantification (LLOQs) of the assays were 31.2 ng/mL serum for free atacicept, 10 U/mL serum for atacicept-BLyS complex (1 U/mL corresponding to 1.82 ng/mL atacicept-0.44 ng/mL BLyS in a 3:1 molar ratio), and 50 ng/mL serum for the composite analytes. The mean spiking recoveries performed to test the accuracy for low, medium, and high analyte concentrations in samples from patients with RA corresponded to recovery rates of 82.5% to 97.0%, 93.9%, and 102.0% to 125.8% in the 3 assays, respectively.
Biomarker Assays
BLyS was measured by ELISA. Biotinylated mAbs specific for BLyS were incubated together with patient, standard, or control samples (diluted 1:10) for 1 hour in streptavidin precoated microplates. After washing, anti-BLyS and HRP-conjugated mouse mAbs were incubated at room temperature for 1 hour. After washing, TMB was added as an HRP substrate. The reaction was stopped after 20 minutes using 0.5 M sulfuric acid and the absorbance recorded at 450 nm. The analyte concentration of a patient sample was recalculated using the standard curve, applying a polynomial second-order fitting algorithm. All samples were measured in triplicate. Assay performance criteria of a precision of <20% CV were an accepted measurement in patient samples. The LLOQ was 1.56 ng/mL BLyS in serum. The mean spiking recoveries for a low, medium, and high concentration of analytes in samples from patients with RA corresponded to recovery rates of 101% to 113%.
Data Analysis Methods
Concentration-time profiles were subjected to noncompartmental analysis (NCA; WinNonlin software, Version 5.0.1). Individual NCA-derived parameters were also analyzed statistically. Biomarker (IgM, IgG, or IgA) data were converted into a "change from base-line" format, and then the individual biomarker-time profiles were also subjected to NCA. The resulting NCA-derived measures for exposure (PK) and response were thus analyzed together to explore the existing exposure-response relationships.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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(terminal half-life, [hours]), Cmax and tmax (maximum concentration [ng/mL] and time of the maximum concentration [hours]), AUC
(area under the concentration-time curve to infinity [mg·h/L]), and AUC336 (AUC from time 0 hours to time 336 hours [mg·h/L]) are presented in Tables II, III and IV, respectively. The PK profiles of free drug after the first dose display a multiphasic behavior with at least 3 discernible phases: absorption phase; (at least 1) fairly rapid distribution phase(s), which is over by the second week after administration; and a prolonged terminal phase. The t and, hence, AUC estimates vary significantly across the doses. A significant number of measurements from the terminal portion in the lowest dose cohort are under the LLOQ, which, together with the sampling scheme, may influence the estimation of t in cohort 1. Despite the large intersubject variability observed, which is typical for protein drugs, tmax, Cmax, and AUC336 estimates are consistent within the same dose level in single- and multiple-dose cohorts (eg, comparing cohorts 1-2 and 3-4).
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Free BLyS Serum Concentrations
Free BLyS serum concentrations were quantified at baseline. Of the 73 patients, 21 (29%) had baseline BLyS levels below the level of quantification (1.6 ng/mL with the current BLyS assay). Patients (n = 52) with quantifiable BLyS concentrations yielded a mean (standard deviation) baseline value of 2.6 ng/mL (1.0 ng/mL; geometric mean, 2.5 ng/mL). The median baseline BLyS level from all patients was 2.1 ng/mL (range from LLOQ to 5.9 ng/mL).
Pharmacokinetics in Synovial Fluid
Only 4 patients had their synovial fluid analyzed for free and composite atacicept, atacicept-BLyS complex, and free BLyS; of those, only 2 (from cohort 4) had both predose and day 29 samples taken and analyzed. Both patients with samples at day 29 yielded detectable free atacicept (48.4 ng/mL and 28.8 ng/mL), composite atacicept (282.5 ng/mL and 326.4 ng/mL), and atacicept-BLyS complex levels (199.3 U/mL and 189.9 U/mL) in synovial fluid. These values were comparable to the measured serum concentrations in the same individuals at the same time point (148 ng/mL and 95.4 ng/mL for free atacicept, 616 ng/mL and 525 ng/mL for composite atacicept, and 337 U/mL and 344 U/mL for the atacicept-BLyS complex, respectively), indicating that the drug distributes into this major site of action for RA and binds there to its ligands.
Baseline BLyS levels in the synovial fluid of the 4 patients were significantly higher than the levels observed in serum (for the same patients) and ranged between 6 and 17.4 ng/mL (data not shown).
Biological Activity
The median concentration-time profiles for IgM, IgA, and IgG are given in Figures 4, 5 and 6. All 3 Igs monitored showed prompt decreases following the first dose of atacicept, which continued with repeated dosing. As expected, IgM levels turned out to be most reactive to atacicept, dropping more than 50% from baseline in the highest exposure (cohort 6). IgA levels dropped by approximately 40%, whereas IgG levels decreased by approximately 20% of their baseline values in the same cohort. Nadirs were generally attained within a few weeks (at a median of 21-35 days) after the last dose for cohorts 1 to 5. Likewise, for cohort 6, the nadir was presumably reached between the last scheduled injection and 6 weeks thereafter, but no sample was taken during that period, and the maximum observed decrease was just prior to the last injection (day 84). After the cessation of dosing, all Ig profiles started to return toward baseline. At 12 weeks after the last dose, Ig levels were at, or close to, the baseline values for the single- and 3-dose cohorts. However, for cohort 6, return of the Ig antibodies to baseline was not yet completed by the end of the 12-week follow-up period. With the 7 biweekly atacicept doses in cohort 6, all 3 biomarkers gradually and consistently decreased toward steady state. The shape of the curves indicates that although IgM (Figure 4) and IgA (Figure 5) profiles were approaching steady state at the end of the 3 months of treatment, IgG profiles (Figure 6) were still dropping at this time. Atacicept administration decreased RF levels, most consistently (Figure 7), although baseline values differed considerably across groups, and placebo response was much more variable than for nonspecific Igs. It is notable that the differential in response between the nonspecific IgM, IgA, and IgG levels is not observed with the respective RF profiles: in the active treatment arm of cohort 6, maximum decreases from baseline of 41% to 44% were observed for all 3 RF classes. Within 2 to 3 months after treatment cessation, RF values had essentially returned to baseline levels, again in keeping with the large variability observed.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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According to the most recent tendencies of drug development science, we have adopted a rigorous investigational plan for atacicept, centering on the MoA cascade and focusing in the early stage of development on the early biomarkers of target binding, inhibition, and subsequent biological activity of the molecule.
This exploratory phase Ib trial showed that atacicept was well tolerated locally and systemically in patients with RA.29 Clear signs of atacicept biological activity in RA, very much in line with its MoA, have been observed on the numerous biomarkers monitored throughout the study.
After subcutaneous administration, atacicept displayed multiphasic PK with a fairly rapid absorption, followed by at least 1 distribution phase and a long terminal elimination phase. Signs of nonlinearity were observed, characterized by a more than dose-proportional increase in free drug exposure and saturated (less than dose-proportional) increase in atacicept-BLyS complex exposure. Such behavior is expected and supports the hypothesis that the PK of atacicept are mediated by its ligands. Overall, the PK of atacicept, albeit nonlinear, were consistent and predictable across the doses and between single and multiple doses.
It is important to consider the fact that minimal accumulation of free atacicept was observed with multiple doses, whereas the accumulation of atacicept-BLyS complex continued throughout the whole dosing period (up to 7 biweekly doses for cohort 6). On one hand, this may be evidence for the presence of a considerable initial load of soluble free BLyS and APRIL both systemically and in the periphery, which starts to get inhibited and to redistribute once the predose equilibrium is disrupted by the administration of the drug. The elevated baseline BLyS levels measured in this study speak in favor of this hypothesis. On the other hand, prolonged complex accumulation may imply significant rates of endogenous generation of the free ligands (again both in the blood circulation and in the peripheral tissues). The long time to steady-state attainment (atacicept-BLyS complex profile keeps rising after 3 months of biweekly dosing; Figure 3b) supports such a hypothesis. Published data regarding the rate of serum BLyS increase after rituximab administration30 seem to provide additional evidence that endogenous BLyS production plays an important role in BLyS inhibition.
The saturable kinetics of atacicept was first observed and reported with single atacicept doses applied to healthy volunteers in a first phase I study.27 The complex saturation indicates that BLyS inhibition is also saturable—a fact that should be considered and exploited when selecting therapeutic dosage regimens. Indeed, with saturable binding, increasing the amount of free atacicept administered (ie, the dose) beyond the amount necessary for saturation would not lead to a significant increase in the atacicept-BLyS complex profiles and, hence, would not bring about additional benefit in terms of target ligand inhibition. Therefore, achieving a saturation of binding to BLyS and APRIL represents an appropriate objective when screening dosage regimens for atacicept. It should be emphasized that the appropriate saturation of BLyS (and APRIL) inhibition needs to be maintained over time, which will require a dynamic balance between the complex and largely uncharacterized processes of endogenous BLyS and APRIL generation and redistribution and the kinetics of atacicept. Such a balance can be achieved only by an appropriate design of the dosing regimen in terms of dose levels and dosing frequency.
A well-defined relationship between atacicept cumulative dose and Ig antibody response has been established by noncompartmental methods; such a relationship was also first detected with single atacicept doses in healthy volunteers.28 In this study, all 3 Igs monitored showed prompt decreases following the first dose of atacicept. Following 7 biweekly dosing, all 3 biomarkers of antibody response gradually and consistently decreased toward steady state. IgM and IgA profiles were approaching steady state at the end of the 3-month treatment period, and IgG profiles were still dropping at this time (it should be noted, however, that the biological half-life of IgG is about 4 to 5 times that of both IgM and IgA). The observation that dosing frequency also seems to play at least as important a role as dose level in the response of all 3 biomarkers (Figure 8) also speaks in support of the hypothesized importance of the distribution and endogenous generation processes of both drug and ligands in achieving a desired level of BLyS and APRIL inhibition at steady state. It can be assumed that agents targeting endogenously generated soluble proteins may benefit from more frequent administration, which will inhibit the freshly secreted ligands in a timely manner.
As IgA-RF, IgM-RF, and IgG-RF may be associated with the pathogenesis of RA and/or the severity of disease, the observed decreases in RFs may have clinical relevance. The fact that, in contrast to the nonspecific Igs, no differential sensitivity of the RF kinetics to atacicept was observed may indicate that the RF-secreting B cells are specifically affected by the drug-induced BLyS and APRIL inhibition. In addition, the detection of atacicept in the synovial fluid of patients with RA demonstrates availability of the drug at the site of joint inflammation. These observations deserve further detailed research to fully understand the effect of atacicept on the pathology of RA.
The good tolerability,28 marked biological activity of atacicept treatment in line with its MoA, and the other positive trends observed so far provide the rationale for further development of this novel therapeutic approach aimed at interfering with the humoral response in patients with RA. The contemporary drug development science paradigm31,32 requires that, at each step, newly generated information is appended to the already existing knowledge while the drug knowledge base is updated, expanded, and improved to be subsequently used for informed design of the next step in a typical "learn and confirm" cycle. In accordance to that paradigm, we chose to observe and analyze a multitude of exposure (free and composite atacicept), specific binding (atacicept-BLyS complex), biological activity (Igs and immune system cell counts28), and disease-related markers (RFs) in an early (phase Ib) study with very complex design (sequential, dose escalating). Analyzing the wealth of data generated in a rigorous way and extracting the information they contain will enable us to define dose ranges and regimens for the further trials that will be needed to characterize the safety profile of atacicept and to enhance the understanding of its MoA, confirm initial indications of clinical efficacy, and define its optimal clinical use.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The Institutional Review Boards and Ethics Committees that approved the study were as follows: Ethics Committee of Institute Niska Banja (Prof L. Branko), Serbia; Ethics Committee of the Institute of Rheumatology Belgrade (Prof N. Damjanov), Serbia; Ethics of Human Research Committee Queen Elizabeth Hospital (Dr A. M. Hoby), Australia; Ethics Committee under the Federal Body for the Control of Quality, Efficacy, Safety of Medical Products (Prof F. I. Komarov), Russia; Local Ethics Committee for Clinical Trial (Prof A. A. Matyushenko), Russia; Medical Ethics Committee (Prof J. D. Bos), the Netherlands; Leeds (East) Research Ethics Committee (Dr Dear), UK.
The authors also thank Stacey Dillon, Julie Hill, Ciara Rossier, and Jane Gross for valuable discussions and contributions to the manuscript.
Financial disclosure: Financial support was provided by ZymoGenetics, Seattle, Washington and Merck Serono International S.A. (an affiliate of Merck KGaA, Darmstadt, Germany), Geneva, Switzerland. I. Nestorov and J. Visich are employees of ZymoGenetics. A. Munafo and O. Papasouliotis are employees of Merck Serono International S.A.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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