1. Top of page
  2. Abstract
  8. Acknowledgements


To assess the efficacy, safety, and biologic activity of atacicept in patients with rheumatoid arthritis (RA) in whom the response to treatment with tumor necrosis factor antagonists was inadequate.


The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial (AUGUST I) was a multicenter, phase II, double-blind, placebo-controlled dose-finding study involving 256 patients randomized 1:1:1:1 to receive atacicept (25 mg, 75 mg, or 150 mg) or placebo twice weekly for 4 weeks, then weekly for 21 weeks, with a 13-week treatment-free followup period (week 38). The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20% improvement in disease severity, using the C-reactive protein level.


No statistically significant differences were observed in the efficacy end points at week 26 (P = 0.410 for overall treatment effect). However, atacicept significantly reduced immunoglobulin and rheumatoid factor (RF) levels, but not anti–citrullinated protein antibody levels, in a dose-dependent manner, with levels returning toward baseline values during followup. The effects of treatment on IgG-RF and IgA-RF were more pronounced than the effects on total IgG and IgA. Adverse events (AEs), including serious AEs, leading to withdrawal were more common among patients treated with atacicept compared with placebo. AEs were variable in nature, and no dose-dependent trends were observed. The frequency of infection-related AEs was similar across treatments. No notable effect of treatment on immunization status (protective versus nonprotective titer) was observed after initiation of treatment.


This study did not meet the primary efficacy end point. However, clear biologic activity consistent with the proposed mechanism of action was observed. The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA. The safety of atacicept was considered acceptable in this patient population.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder characterized by joint inflammation, which can result in progressive destruction of articular and periarticular structures (1). Disease-modifying antirheumatic drugs (DMARDs) such as methotrexate are used to help control RA, and although early, aggressive treatment with DMARDs improves patient outcomes (2), RA is still associated with long-term morbidity and premature death. The introduction of biologic agents has represented a considerable advance in the treatment of RA, but treatment-free remission is still not achieved in most patients (3). In many cases, the disease is resistant to existing therapies, or patients may be unable to continue treatment because of intolerance. Therefore, the need for novel treatments of RA remains.

B cells may play an important role in the pathogenesis of RA, possibly through the production of proinflammatory cytokines and antigen presentation (4). In addition, B cells produce autoantibodies such as rheumatoid factor (RF) and anti–citrullinated protein antibodies (ACPAs), both of which are characteristic of the disease and are associated with disease severity. The B cell–depleting agent rituximab (anti-CD20) has been shown to be beneficial in RA (5, 6), while other B cell–targeting agents with differing mechanisms of action are under investigation.

APRIL (a proliferation-inducing ligand) and B lymphocyte stimulator (BLyS; also called BAFF) play key roles in B cell proliferation and survival (7, 8). APRIL promotes B cell and plasma cell activation and survival and plays important roles in immunoglobulin class switching and antigen presentation (9–11). BLyS promotes B cell survival and maturation (12–15). APRIL and BLyS form homotrimers and heterotrimers, which can be present at elevated levels in the serum of patients with autoimmune diseases including RA, Sjögren's syndrome, and systemic lupus erythematosus (SLE) (16–18). Both APRIL and BLyS homotrimers bind 2 receptors expressed by B lymphocytes, TACI and BCMA. BLyS also binds to the BAFF receptor, and APRIL binds to the proteoglycan receptor. Only the TACI and BCMA receptors bind these heterotrimers (17, 19). In light of the potential role of BLyS and APRIL in autoimmune diseases, targeting these cytokines is a rational approach to therapy. Indeed, neutralization of BLyS and APRIL in an animal model of RA has been shown to reduce disease activity (20, 21).

Atacicept is a soluble, fully human, recombinant fusion protein consisting of a modified human immunoglobulin Fc domain and the extracellular portion of the TACI receptor, which includes the ligand-binding domain. Atacicept binds to and sequesters both BLyS and APRIL (20), thereby reducing B cell maturation and survival, plasma cell numbers, and immunoglobulin levels. The numbers of memory B cells and B cell progenitors are not reduced (22).

Several phase I studies of subcutaneous and intravenous atacicept have been completed, including a safety study in healthy volunteers and dose-escalating studies in patients with SLE, RA, or B cell malignancies (22–26). In all 5 phase I studies reported to date, atacicept raised no unexpected safety concerns over a range of doses. Furthermore, atacicept was shown to reduce immunoglobulin and RF levels in patients with RA (26) and to reduce levels of mature B cells and serum immunoglobulin in patients with SLE (22). However, a recent phase II study of mycophenolate mofetil versus the combination of mycophenolate mofetil plus atacicept in patients with lupus nephritis was terminated early because of an unexpected incidence of infectious complications (27).

The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial I (AUGUST I) study described here assessed the efficacy, safety, and biologic activity of 3 doses of atacicept in patients with RA in whom tumor necrosis factor (TNF) antagonist therapy had failed to induce an adequate response.


  1. Top of page
  2. Abstract
  8. Acknowledgements

Study design and treatment.

AUGUST I ( NCT00430495) was a multicenter, phase II, randomized, double-blind, placebo-controlled, dose-finding study. The study was approved by the review boards of the participating institutions and conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice, and all applicable local regulatory requirements. All patients gave written informed consent prior to undergoing any assessments that did not constitute routine medical care. Additional contributors to the AUGUST I Study are listed in Appendix A.

Patients were randomized 1:1:1:1 (stratified by region and sex) to receive atacicept (25 mg, 75 mg, or 150 mg, subcutaneously) or placebo twice weekly for 4 weeks (loading period) and then weekly for 21 weeks, with a 13-week treatment-free followup period.

Patient population.

Patients (ages ≥18 years) with RA (diagnosed according to the American College of Rheumatology [ACR] criteria [28]) were recruited to the study. Patients attending routine outpatient rheumatology clinics were eligible for enrollment if they presented with active RA (defined as ≥8 swollen joints [of 66 joints counted], ≥8 tender joints [of 68 joints counted], and a C-reactive protein [CRP] level of ≥10 mg/liter and/or an erythrocyte sedimentation rate [ESR] of ≥28 mm/hour), and a disease duration of at least 1 year. Patients had to be receiving at least 1 conventional DMARD, previously have had an inadequate response to TNFα antagonist therapy, and were positive for RF and/or ACPA (as measured by an anti–cyclic citrullinated peptide test); steroid treatment had to be at a stable dosage of ≤10 mg/day.

Exclusion criteria included the following: treatment with biologic agents for B cell modulation within 2 years prior to study day 1; treatment with abatacept, anakinra, or tocilizumab within 3 months prior to study day 1; treatment with etanercept within 28 days or with adalimumab or infliximab within 60 days prior to study day 1; participation in any interventional clinical trial within 3 months (or 5 half-lives of the investigational compound, whichever was longer) of study day 1; treatment with methotrexate dosages of >25 mg/week; change in the nonsteroidal antiinflammatory drug dosing regimen within 28 days prior to study day 1; serum IgG levels of <6 gm/liter; immunization with live vaccines or immunoglobulin treatment within 1 month prior to study; and an opportunistic infection within 28 days prior to study day 1, a history of chronic infections requiring repeated antibiotic treatment, or any current active infection.

Randomization and blinding.

This was a double-blind study. All study medication was supplied in identical vials and treatment kits, each containing sufficient study medication for 4 administrations. Treatment kits were labeled by the manufacturer with only a unique kit number. The 3 doses of atacicept were dispensed in 3 different volumes (0.25 ml, 0.75 ml, and 1.5 ml), and randomization to placebo included assignment to one of these volumes.

At baseline (study day 1), patients were randomized by the permuted-blocks method, stratified by region (North America, Western Europe, Eastern Europe, Rest of World) and sex, using an interactive voice response system (IVRS), to 1 of 3 atacicept doses or placebo. Blinded treatment kits corresponding to each patient's assigned treatment were obtained using an IVRS. Requests for treatment kits and dispensing were handled by a trial pharmacist, independent trial nurse, or other member of the center's staff not involved in the trial evaluation. To minimize the risk of unblinding by potential injection-site reactions, efficacy assessors were not involved in the collection of data regarding local tolerability.

Study end points.

The primary end point was the proportion of patients at week 26 with a response according to the ACR criteria for 20% improvement, assessed using the CRP level (ACR20-CRP) (29). Secondary end points included ACR50-CRP and ACR70-CRP responses and change from baseline to week 26 in the Disease Activity Score in 28 joints (DAS28) (30) using the CRP level. Safety end points included the nature, incidence, and severity of adverse events (AEs), clinical laboratory tests, and vaccine immunization status based on titers of anti-pneumococcus, anti-diphtheria, and anti–tetanus toxoid. Additional end points included the ESR and changes over time in the levels of CRP, immunoglobulins (including IgM, IgA, and IgG), RF, and ACPAs.


Assessments were performed at baseline and weeks 2 (study day 8 in this study), 4, 8, 12, 16, 20, and 26 (the treatment period). An additional followup assessment was carried out 13 weeks after the final dose of the study drug was administered (week 38). All laboratory analyses were performed centrally, except for the ESR assessment, which was performed locally. Efficacy was assessed using the ACR core disease activity measures (31) (ACR20-CRP, ACR50-CRP, and ACR70-CRP responses, DAS28 and DAS28-CRP [calculated based on ACR-CRP measures]), the ESR, European League Against Rheumatism (EULAR)–CRP responses, and the CRP level. Biologic activity was assessed at each study visit using standard laboratory techniques to determine serum levels of immunoglobulin. RF levels were assessed using EIA-3584 (IgG), EIA-3585 (IgM), and EIA-3586 (IgA) kits (DRG Diagnostics) and the Roche Tina-quant RF II Immunoturbidimetric Assay (Cobas System). ACPA levels were measured using an Immunoscan CCPlus Kit (Euro-Diagnostica). AEs were assessed continuously throughout the study.

Sample size calculation.

Sample size calculations were based on the assumption of an ACR20-CRP placebo response rate of 20% and a difference of ≥25% for one atacicept arm versus placebo. The study was powered to allow an 80% chance of detecting a true-positive treatment effect versus placebo.

Statistical analysis.

Efficacy analyses were performed using the intent-to-treat population, originally defined as all randomized patients and revised to include all randomized patients who received at least 1 dose of study drug. The safety population included all patients who received at least 1 treatment dose and for whom safety data were available. Nonresponder imputation was used for patients who withdrew prematurely from the study or for whom only incomplete data were available.

The primary end point was analyzed using a logistic regression model for pairwise comparison of each atacicept group versus placebo. Both stratification factors (region and sex) were included for the primary analysis and other relevant statistical analyses. The null hypothesis assumed that the proportion of patients with an ACR20-CRP response at week 26 would be similar across the placebo group and all atacicept dose groups. The primary efficacy end point would be considered to be met if at least 1 atacicept dose was shown to be significantly more beneficial than placebo (P < 0.05), rejecting the null hypothesis. A statistical procedure for multiple comparisons was applied to avoid inflation of the Type I error. This procedure consisted of a global test of the treatment effect (Wald's test as provided by the logistic regression model), followed by pairwise comparisons versus placebo, provided the overall treatment effect was statistically significant. For secondary end point analyses, logistic regression was used for analysis of binary outcomes, and analysis of covariance was used for analysis of continuous outcomes. The numbers of AEs leading to withdrawal in the active-treatment and placebo groups were compared using the pairwise Fisher's exact test.


  1. Top of page
  2. Abstract
  8. Acknowledgements

Patient disposition and characteristics.

Recruitment took place in 22 countries between January 2007 and September 2008. Similar proportions of patients were recruited from the 4 predefined regions: 66 patients (26%) were from North America, 60 patients (24%) were from Western Europe, 68 patients (27%) were from Eastern Europe, and 60 patients (24%) were from Rest of World (Brazil, Argentina, Lebanon). Patient disposition from the time of enrollment to week 26 is shown in Figure 1. Of 456 patients screened, 256 were enrolled in the study and randomized to treatment, although 2 of these patients did not receive treatment. Of the 254 treated patients, 152 (60%) completed the study; the reasons for discontinuations are shown in Figure 1. The baseline characteristics of the patients (Table 1) were balanced across treatment groups; 76–88% of patients received methotrexate during the study.

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Figure 1. Patient disposition from the time of screening to week 26.

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Table 1. Baseline patient demographics and disease characteristics*
CharacteristicPlacebo (n = 62)Atacicept 25 mg (n = 66)Atacicept 75 mg (n = 62)Atacicept 150 mg (n = 64)
  • *

    Except where indicated otherwise, values are the mean ± SD. ACPA = anti–citrullinated protein antibody; anti-TNF = anti–tumor necrosis factor; DAS28-CRP = Disease Activity Score in 28 joints using the C-reactive protein level; SJC = swollen joint count; TJC = tender joint count; ESR = erythrocyte sedimentation rate; HAQ = Health Assessment Questionnaire.

  • Data were missing for 1 patient.

  • Data were missing for 2 patients.

Age, years53.1 ± 12.553.4 ± 13.155.3 ± 12.053.5 ± 10.1
Female sex, no. (%)51 (82)54 (82)53 (85)53 (83)
Weight, kg73.7 ± 16.975.7 ± 18.772.0 ± 16.678.4 ± 16.9
Region, no. (%)    
 North America16 (26)17 (26)16 (26)17 (27)
 Western Europe14 (23)16 (24)15 (24)15 (23)
 Eastern Europe17 (27)17 (26)17 (27)17 (27)
 Rest of World15 (24)16 (24)14 (23)15 (23)
Disease duration, years12.3 ± 6.612.6 ± 7.714.2 ± 8.712.3 ± 9.2
Rheumatoid factor positive, no. (%)59 (97)64 (100)58 (94)63 (100)
ACPA positive, no. (%)57 (98)66 (100)54 (89)56 (90)
Oral corticosteroid treatment, no. (%)43 (69)46 (70)47 (76)43 (67)
Methotrexate treatment, no. (%)47 (76)58 (88)47 (76)52 (81)
No. of previous anti-TNF agents, no. (%)    
 141 (66)48 (73)36 (59)39 (62)
 215 (24)11 (17)18 (30)17 (27)
 36 (10)7 (11)7 (12)7 (11)
DAS28-CRP6.0 ± 1.06.2 ± 0.86.1 ± 0.96.3 ± 0.8
SJC (66 joints assessed)17.5 ± 10.517.4 ± 7.917.3 ± 7.419.3 ± 11.6
TJC (68 joints assessed)24.3 ± 12.228.7 ± 14.130.1 ± 14.931.0 ± 14.7
CRP, mg/liter24.3 ± 23.329.1 ± 25.729.8 ± 31.228.8 ± 22.6
ESR, mm/hour44.6 ± 21.446.1 ± 18.650.2 ± 27.249.9 ± 20.0
HAQ disability index score1.8 ± 0.562.0 ± 0.551.8 ± 0.581.8 ± 0.59

Clinical efficacy.

At week 26, the proportion of patients with an ACR20-CRP response was not significantly different across treatment groups (placebo 29%, atacicept 25 mg 30%, atacicept 75 mg 27%, atacicept 150 mg 39%). The corresponding relative risks versus placebo, with 95% confidence intervals (95% CIs), were as follows: for atacicept 25 mg, 1.06 (95% CI 0.65–1.74), for atacicept 75 mg, 0.98 (95% CI 0.58–1.64), and for atacicept 150 mg, 1.44 (95% CI 0.92–2.24) (P = 0.410 for overall treatment effect). Some regional variation in the ACR20-CRP response rates was observed. Among placebo-treated patients, response rates at week 26 were as follows: 13% in North America, 21% in Western Europe, 41% in Eastern Europe, and 40% in Rest of World. An exploratory analysis revealed no baseline characteristic that could account for this regional variation (data not shown). In addition, exploratory analyses did not identify any patient subgroup (based on demographics, disease severity, and disease history) in which atacicept had a significant effect on the ACR20-CRP response rate (data not shown).

The proportion of patients with an ACR50-CRP or ACR70-CRP response at week 26 also showed no significant differences between treatment groups. A summary of the primary and secondary efficacy outcomes is shown in Table 2.

Table 2. Primary and secondary efficacy outcomes*
OutcomePlaceboAtacicept 25 mgAtacicept 75 mgAtacicept 150 mg
  • *

    Values for the American College of Rheumatology criteria for 20% improvement in disease activity using the C-reactive protein level (ACR20-CRP), the Disease Activity Score in 28 joints (DAS28), and the European League Against Rheumatism (EULAR) responses are the percentage of patients at week 26; values for the erythrocyte sedimentation rate and the CRP level are the median percentage reduction from baseline to week 26.

ACR20-CRP response29302739
ACR50-CRP response7141111
ACR70-CRP response0650
DAS28 response ≤3.210111013
DAS28 response ≤2.62655
EULAR response rated good/moderate42323653
Erythrocyte sedimentation rate3283129

Biologic activity.

At week 26, atacicept was associated with significant reductions from baseline in the levels of IgM and IgA at all doses and in the level of IgG at the 2 higher doses, compared with placebo (Table 3). The observed decreases in the levels of IgM, IgA, and IgG increased with increasing doses (Figure 2), with near-maximum reductions achieved within 12 weeks. Throughout the study, median IgG levels remained above the lower limit of normal (data not shown), and no patient had IgG levels below the predefined discontinuation threshold of 3 gm/liter during the study.

Table 3. Changes in immunoglobulin and rheumatoid factor (RF) levels from baseline to week 26*
25 mg75 mg150 mg
  • *

    Values are the median (interquartile range) percent.

IgM−0.1 (−11.4, 9.0)−33.3 (−48.8, −21.0)−58.6 (−71.8, −46.3)−70.0 (−78.0, −52.5)
IgM-RF9.6 (−19.5, 64.8)−21.4 (−44.4, 31.3)−55.6 (−76.6, −14.3)−56.4 (−71.4, −11.0)
IgA2.5 (−2.4, 9.1)−21.7 (−35.5, −13.6)−39.0 (−50.3, −31.9)−52.5 (−61.7, −39.4)
IgA-RF11.1 (−22.4, 59.3)−31.7 (−50.7, −3.5)−55.8 (−76.5, −32.1)−65.5 (−79.1, −42.9)
IgG−0.6 (−5.5, 9.5)−15.9 (−24.4, −8.2)−22.7 (−39.9, −15.6)−30.3 (−39.1, −22.4)
IgG-RF0.0 (−30.0, 33.2)−27.2 (−55.2, 3.0)−57.3 (−72.5, −30.0)−54.9 (−74.0, −26.7)
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Figure 2. Effect of atacicept on immunoglobulins. Values are the median percentage change from baseline in IgM, IgA, and IgG in the completers population.

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Significant reductions in IgM-RF levels were seen at week 26 with atacicept doses of 75 mg and 150 mg, but not 25 mg, compared with placebo (see Table 3). Higher doses were associated with similar significant reductions in the levels of IgA-RF (see Table 3). These effects on IgG-RF and IgA-RF were more pronounced than those on total IgG and total IgA, respectively (Figure 3). The effects on immunoglobulin and RF were reversible, with levels returning toward baseline values during the off-treatment followup period.

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Figure 3. Effect of atacicept on immunoglobulin rheumatoid factor (RF). Values are the median percentage change from baseline in IgM-RF, IgA-RF, and IgG-RF in the completers population.

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The median percentage changes in ACPA titers from baseline to week 26 were as follows: for placebo, −6.8% (interquartile range [IQR] −28.0, 12.5), for atacicept 25 mg, −11.6% (IQR −35.8, 5.0), for atacicept 75 mg, −22.9% (IQR −37.1, 5.2), for atacicept 150 mg, 0.0% (IQR −34.1, 8.1). However, these changes were not statistically significant, and no clear dose effect on ACPA levels was observed.


Overall, 66% of the patients receiving placebo and 71% of the patients receiving atacicept reported at least 1 AE during the 38-week study period. The most commonly reported AEs occurred with similar frequency across all treatment groups. However, total AEs, AEs leading to discontinuation, and serious AEs (SAEs) were more frequent in the atacicept groups (Table 4).

Table 4. Incidence of treatment-emergent and posttreatment adverse events and serious adverse events during the 38-week treatment period*
 Placebo (n = 62)Atacicept 25 mg (n = 66)Atacicept 75 mg (n = 62)Atacicept 150 mg (n = 64)
  • *

    Values are the number (%) of patients in the safety population (patients receiving at least 1 treatment dose and having safety data). Coding was performed using the Medical Dictionary for Regulatory Activities, version 11.1.

  • The patient died of intestinal occlusion 145 days after administration of the last dose of study medication.

  • The patient had a history of cardiac problems and died of acute cardiorespiratory arrest.

All adverse events41 (66)49 (74)42 (68)46 (72)
Serious adverse events3 (5)9 (14)8 (13)5 (8)
Events leading to discontinuation of treatment2 (3)12 (18)8 (13)7 (11)
Death1 (2)1 (2)
Serious adverse events according to system/organ class    
 Musculoskeletal and connective tissue disorders1 (2)2 (3)3 (5)
 Injury, poisoning, and procedural complications1 (2)2 (3)2 (3)
 Cardiac disorders2 (3)1 (2)
 Infections and infestations1 (2)2 (3)
 Gastrointestinal disorders1 (2)1 (2)
 Endocrine disorders1 (2)1 (2)
 General disorders and administration-site conditions2 (3)
 Nervous system disorders1 (2)1 (2)
 Investigations1 (2)
 Blood and lymphatic system disorders1 (2)
 Immune system disorders1 (2)
 Pregnancy, puerperium, and perinatal conditions1 (2)
 Reproductive system and breast disorders1 (2)
 Respiratory, thoracic, and mediastinal disorders1 (2)
 Skin and subcutaneous tissue disorders1 (2)
 Surgical and medical procedures1 (2)

The number of patients with SAEs over 38 weeks in each group was as follows: for placebo, n = 3; for atacicept 25 mg, n = 9; for atacicept 75 mg, n = 8; for atacicept 150 mg, n = 5. There were no dose-dependent trends in SAEs. Although there were more discontinuations owing to AEs in the atacicept groups than in the placebo group (placebo 3%, atacicept 25 mg 18%, atacicept 75 mg 13%, atacicept 150 mg 11% [P < 0.01, atacicept 25 mg versus placebo; P = 0.10, atacicept 75 mg versus placebo; P = 0.16, atacicept 150 mg versus placebo]), these AEs were variable in nature and did not suggest any trends. Evaluation of laboratory test results, vital signs, and electrocardiography results did not reveal any trends or new safety concerns.

There was no notable difference in the number of patients with infection-related AEs between the atacicept and placebo groups (for placebo, n = 20 [32%], for atacicept 25 mg, n = 22 [33%], for atacicept 75 mg, n = 12 [19%], for atacicept 150 mg, n = 22 [34%]). Three patients were considered to have serious infection-related AEs, all of whom were receiving atacicept. One patient who received the 25-mg dose was reported to have relapsing fever; this was considered unlikely to be related to the study treatment. Three serious infection-related AEs (bronchitis, Stenotrophomonas infection, and pyopneumothorax) were reported in 2 patients who received the 150-mg dose; these SAEs were considered possibly to be related to the study treatment.

One patient (in the group receiving atacicept 75 mg) died during the course of the study due to acute cardiorespiratory arrest, although this incident was considered by the investigator unlikely to be related to treatment. One patient died of postoperative sepsis 145 days after receiving the last dose of atacicept 25 mg (i.e., after the last formal followup visit); this was considered possibly related to the study treatment.

Effect of atacicept on protective immunity.

Modest reductions were seen from baseline to week 26 in the median titers of antibodies against diphtheria (for placebo, −8.7% [IQR −37.5, 0], for atacicept 25 mg, −16.0% [IQR −50.0, 0], for atacicept 75 mg, −6.6% [IQR −50.0, 0], for atacicept 150 mg, −19.1% [IQR −50.0, 0]) and pneumococcus (for placebo, −4.2% [IQR −26.4, 14.2], for atacicept 25 mg, −17.4% [IQR −35.3, 5.0), for atacicept 75 mg, −17.8% [IQR −40.5, 7.5], for atacicept 150 mg, −24.2% (IQR −40.3, −12.4]), consistent with those seen for total IgG. These reductions were statistically significant only at the 150-mg dose (for diphtheria, P = 0.029; for pneumococcus, P = 0.011 versus placebo). No notable reduction was seen in the titers of antibodies against tetanus toxoid. There were no notable trends in shifts in immunization status at week 26 (protective versus nonprotective titer; data not shown).


  1. Top of page
  2. Abstract
  8. Acknowledgements

In this phase II trial of patients with RA and an inadequate response to TNF antagonist therapy, the primary end point based on ACR20-CRP response rates at 26 weeks was not met: no statistically significant treatment benefit of atacicept compared with placebo was observed. The secondary end points also showed no evidence of clinical efficacy, although biologic activity consistent with the proposed mechanism of action of atacicept (32) was seen. At all atacicept doses, the reduction in the ESRs was proportionally greater than the reduction in CRP levels. It is possible that the effects on immunoglobulin levels may have contributed to the reductions in the ESR, which may help to explain the difference between these 2 measures.

Atacicept significantly reduced immunoglobulin and RF levels in a dose-dependent manner. The effects of atacicept on immunoglobulin were reversible: immunoglobulin and RF levels returned toward baseline values during the 13-week treatment-free followup period. The observation of a proportionally greater reduction in IgG-RF and IgA-RF levels compared with total IgG and IgA levels suggests that some autoantibody-secreting cells may have greater sensitivity to BLyS and APRIL inhibition compared with other antibody-secreting cells. However, a clear-cut reduction in ACPA levels in patients treated with atacicept compared with placebo was not observed.

It should be noted that clinical and biologic responses to atacicept were assessed in different patient populations. The clinical response was assessed in all randomized patients who received at least 1 dose of study drug, with patients who withdrew from treatment imputed as nonresponders. In comparison, patients who withdrew during the study were not included in the evaluation of biologic activity, which was assessed in patients who completed treatment.

Consistent with our findings, potent biologic effects with only modest clinical efficacy have also been reported in patients with RA receiving the anti-BLyS antibody, belimumab (33). Atacicept blocks APRIL in addition to BLyS (8), and APRIL supports plasma cells in the absence of BLyS (34). Therefore, it would be reasonable to hypothesize that the reduction in plasma cell numbers achieved with atacicept, but not belimumab (33), in patients with RA may have additional clinical effects. However, the results of our study do not permit a firm conclusion as to whether mature B cells or short-lived plasma cells are key factors in RA.

The discrepancy between biologic and clinical effects could be explained by the presence of a delay between biologic effects and their clinical manifestation. However, clinical efficacy associated with decreased levels of both RF and ACPAs has been demonstrated at 6 months after initiation of treatment with the B cell–targeting therapy, rituximab, in RA (35, 36), suggesting that the 26-week treatment period in our study was of sufficient duration to evaluate clinical benefit. Rituximab (37) and atacicept (34, 38) target different B cell populations, and rituximab may interfere with antigen presentation, cytokine production, and the direct stimulation of T cells by B cells, in addition to its effects on autoantibody production (5), all of which may be relevant for its clinical efficacy. Thus, comparing the time course of the effects of rituximab and atacicept may not be informative.

It is conceivable that atacicept treatment did not modulate the humoral response at the site of inflammation sufficiently to achieve clinical benefit. Previous studies in RA have indicated that levels of APRIL and BLyS are elevated in synovial fluid relative to serum and have identified both antibody-secreting plasma cells and APRIL-secreting cells within the RA synovium (39, 40), suggesting that local inhibition of autoimmune responses may be required for clinical effects.

Phase I studies of atacicept in patients with RA have demonstrated that atacicept does enter the synovial compartment and form complexes with BLyS (26, 41). However, these observations were made in very small numbers of patients, and whereas one study demonstrated lower levels of atacicept in the synovial fluid than in the circulation (26), the other showed local and systemic levels to be comparable (41). Nevertheless, the possibility that atacicept may affect cells in the synovial compartment to a lesser extent than it affects those in the periphery cannot be excluded at this stage. It is noteworthy that a lack of response to rituximab treatment has been associated with persistent plasma cell infiltration of the synovial tissue, highlighting the importance of an effect on plasma cells at the site of inflammation (36).

Finally, although we cannot exclude the possibility that an even stronger effect on RF levels would have translated into clinical benefit, it is also possible that other mechanisms play a greater role in the inflammatory process in RA. It may, for instance, be necessary to induce a marked reduction in ACPA levels to achieve clinical benefit when interfering with the humoral response, because ACPA-containing immune complexes could induce TNF production by macrophages (42).

The safety of atacicept was considered acceptable in this patient population. Importantly, only small differences were seen in the incidence of infection-related AEs between patients receiving placebo and those receiving atacicept. Both the absolute number and the proportion of patients with serious infections were low: only 3 patients (1.6%) had infection-related SAEs, all of whom received atacicept (1 patient in the 25-mg group [1.5%] and 2 patients in the 150-mg group [3%]). There were no infection-related SAEs in the placebo group or the atacicept 75-mg group. Therefore, additional studies would be needed to characterize the risk of serious infections in this population. Although AEs and SAEs were more common in the atacicept groups than the placebo group, the incidence of the most frequent AEs was similar across all groups, no trends in AEs were identified, and the incidence of SAEs did not increase with the atacicept dose. Despite reductions in immunoglobulin levels, median IgG levels remained above the lower limit of normal throughout the study, and no patient had IgG levels <3 gm/liter. Modest decreases in titers of antibodies against diphtheria and pneumococcus (but not tetanus) were observed at week 26. Treatment had no notable impact on patient immunization status, although its clinical relevance to actual protection against infection remains unclear.

The findings described herein must be interpreted in the context of the limitations of this trial. The trial population was limited to patients for whom therapy with TNF antagonists had previously failed, a patient group traditionally considered to have disease that is refractory to treatment. The effects of atacicept in TNF antagonist–naive patients with RA with an inadequate response to methotrexate have been studied in a separate trial (AUGUST II), in which a statistically significant treatment effect was seen in some secondary end points, but not the primary end point (ACR20-CRP response rate) (43, 44). Effects in other patient subpopulations, such as those who are treatment naive, are currently unknown. In heterogeneous diseases such as RA, it is reasonable to speculate that treatments may be most effective in specific patient subgroups. For example, atacicept may be of benefit to patients with elevated BLyS and APRIL levels; improved patient profiling may, therefore, help to identify patients who would benefit from atacicept in the future.

In addition, regional differences were observed in ACR20-CRP response rates, and regional variations in placebo response rates were also seen. Because there is no evidence to suggest that RA is a different disease in different parts of the world, differences in key outcomes are more likely to reflect differences in patient management prior to the study, background medications, and possible variation in subjective elements of the various measurement tools. Higher-than-expected levels of placebo response could occur in situations such as those in which patients had poor adherence to the permitted background medication prior to study entry or because patients may have had limited access to treatment prior to study entry. Strategies to identify such noncompliance and reduce potential causes of regional variability should be considered when planning future multinational studies.

The biologic effects of atacicept demonstrated here are consistent with the known mechanism of action of this drug. Although this study did not show a clinical benefit of atacicept in patients with RA that was refractory to TNFα antagonist treatment, the effects on serum immunoglobulin, and evidence of differential suppression of autoantibody levels, suggest that atacicept could be a rational treatment in autoantibody-mediated diseases.


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  2. Abstract
  8. Acknowledgements

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Genovese had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Genovese, Kinnman, Pena Rossi.

Acquisition of data. Genovese, Kinnman, Tak.

Analysis and interpretation of data. Genovese, Kinnman, de La Bourdonnaye.


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  2. Abstract
  8. Acknowledgements

This trial was sponsored by Merck Serono SA – Geneva, which, in collaboration with ZymoGenetics, Inc., is developing atacicept for various indications. Merck Serono SA – Geneva and ZymoGenetics Inc. facilitated the study design and the writing of the manuscript and reviewed and approved the manuscript prior to submission. The authors independently collected the data, interpreted the results, and had the final decision to submit the manuscript for publication. Publication of this article was not contingent upon approval by the study sponsor.


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  2. Abstract
  8. Acknowledgements

We thank Andy Shepherd, PhD, and Andrea Plant, PhD (Caudex Medical; supported by Merck Serono SA – Geneva) for their assistance in the preparation of the manuscript. We also thank Stephen Wax (EMD Serono, Inc.) for his input and contribution to the manuscript. The manuscript was critically reviewed for accuracy by Eleni Stavridi, Catherine Barbey, Corrine Barrra, Ralf Gleixner, and Henry Hess (Merck Serono SA – Geneva) and Jennifer Johnson (ZymoGenetics Inc.).


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  2. Abstract
  8. Acknowledgements


Additional contributors to this study are as follows: J. Barreira, M. A. Lazaro, J. Velasco, D. Zoruba, A. M. Babini, O. Messina, G. Tate, E. Lucero, A. Rio Pedre, I. Strusberg, A. Berman (Argentina); P. Geusens, M. Malaise, F. Van Den Bosch (Belgium); M. Scheinberg, C. Zerbini (Brazil); S. Alimanska, B. Oparanov, I. Sheytanov, A. Toncheva (Bulgaria); A. Beaulieu, A. Chow, A. Bookman (Canada); K. Pavelka, E. Dokoupilová, H. Brabcová, P. Vavrincova, P. Vitek (Czech Republic); L. Paimela (Finland); R. M. Flipo, F. Lioté, M. Dougados (France); J. Wollenhaupt (Germany); L. Settas, F. Skopouli (Greece); R. Perricone, B. Seriolo, F. Trotta, G. Valentini (Italy); I. Thurayya Arayssi, H. Awada (Lebanon); E. Brouwer, M. D. Posthumus, J. M. W. Hazes (The Netherlands); A. Dudek, S. Jeka, J. Lacki, S. Sierakowski, L. Sczepanski, J. Szechinski, A. Filipowicz-Sosnowska (Poland); J. C. Da Silva, M. Viana de Queiroz (Portugal); H. Bolosiu, C. Codreanu, D. Nemes, M. Suta, V. Stoica (Romania); J. Rovenský, H. Raffayova (Slovakia); J. J. Gómez Reino, V. R. Valverde, E. Collante Estevez, E. M. Mola, J. Gratacos (Spain); R. van Vollenhoven, M. Bokarewa (Sweden); J. Dudler, J. Von Kempis (Switzerland); M. Sebai, R. Ettlinger, J. Fiechtner, M. A. Goldberg, H. Kenney, E. J. Kopp, M. Lowenstein, W. Shergy, N. Wei, J. Huffstutter, M. Miniter, N. Singer, R. Trapp, R. White, Y. Sherrer, A. Deodhar, A. Dikranian, N. Straniero, J. Taborn, V. Hanna, M. Niemer, J. Neal, A. Nussbaum, J. Starr, R. Levin, C. Pritchard (USA).