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Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosusResults of a multicenter phase ib double-blind placebo-controlled dose-escalating trial.

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ARTHRITIS & RHEUMATISM
Vol. 56, No. 12, December 2007, pp 4142–4150
DOI 10.1002/art.23047
© 2007, American College of Rheumatology
Reduced B Lymphocyte and Immunoglobulin Levels After
Atacicept Treatment in Patients With
Systemic Lupus Erythematosus
Results of a Multicenter, Phase Ib, Double-Blind, Placebo-Controlled,
Dose-Escalating Trial
Maria Dall’Era,1 Eliza Chakravarty,2 Daniel Wallace,3 Mark Genovese,2 Michael Weisman,3
Arthur Kavanaugh,4 Kenneth Kalunian,4 Patricia Dhar,5 Emmanuelle Vincent,6
Claudia Pena-Rossi,6 David Wofsy,1 and the Merck Serono and
ZymoGenetics Atacicept Study Group
Objective. To assess the safety and tolerability of
atacicept in patients with systemic lupus erythematosus
(SLE) and the biologic effect of atacicept on B lymphocyte and immunoglobulin levels. Atacicept is a TACI-Ig
fusion protein that inhibits B cell stimulation by binding to B lymphocyte stimulator and a proliferationinducing ligand.
Methods. This phase Ib, double-blind, placebocontrolled, dose-escalating trial comprised 6 cohorts of
patients treated with atacicept or placebo in a 3:1 ratio
of active drug to placebo (n ⴝ 8 per group; n ⴝ 7 in
cohort 5). Cohorts 1–4 received a single subcutaneous
dose of placebo or either 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or
9 mg/kg of atacicept. Cohorts 5 and 6 received weekly
doses of placebo or either 1 mg/kg or 3 mg/kg of
atacicept for 4 weeks. Patients were followed up for 6
weeks (cohorts 1–4) or 9 weeks (cohorts 5 and 6).
Patients with mild-to-moderate SLE were enrolled.
Results. Biologic activity of atacicept was demonstrated by dose-dependent reductions in immunoglobulin
levels and in mature and total B cell numbers. This effect
was most pronounced in the repeated-dose cohorts and
was sustained throughout the followup period. There were
no changes in the numbers of T cells, natural killer cells,
or monocytes. Mild injection-site reactions occurred more
frequently among the atacicept group than the placebo
group. There were no differences in the frequency or type
of adverse events and no severe or serious adverse events
in patients treated with atacicept.
Conclusion. Atacicept administered subcutaneously was well tolerated and demonstrated biologic activity
consistent with the proposed mechanism of action.
Supported by Merck Serono International SA (an affiliate of
Merck KGaA, Darmstadt, Germany) and ZymoGenetics Inc. Research conducted at the University of California, San Francisco, was
supported in part by a grant from the state of California. Research
conducted at Stanford University was supported in part by the
National Center for Research Resources, NIH (grant M01-RR00070). Dr. Genovese’s work was supported by Merck Serono International SA and the Lupus Clinical Trials Consortium.
1
Maria Dall’Era, MD, David Wofsy, MD: University of
California, San Francisco; 2Eliza Chakravarty, MD, Mark Genovese,
MD: Stanford University, Palo Alto, California; 3Daniel Wallace, MD,
Michael Weisman, MD: Cedars-Sinai Medical Center, Los Angeles,
California; 4Arthur Kavanaugh, MD, Kenneth Kalunian, MD: University of California, San Diego; 5Patricia Dhar, MD: Wayne State
University, Detroit, Michigan; 6Emmanuelle Vincent, PhD, Claudia
Pena-Rossi, MD, PhD: Merck Serono International SA, Geneva,
Switzerland.
Drs. Dall’Era and Wofsy have received consulting fees (less
than $10,000) from Merck Serono. Dr. Genovese has received consulting fees, speaking fees, and/or honoraria (less than $10,000) from
Merck Serono. Dr. Weisman has received consulting fees, speaking
fees, and/or honoraria (less than $10,000 each) from Amgen, Wyeth,
Genentech, Bristol-Myers Squibb, and UCB and has received research
grants from Amgen, Abbott, Centocor, Wyeth, Genentech, BristolMyers Squibb, Human Genome Sciences, UCB, and Bio-Rad. Dr.
Dhar has received consulting fees, speaking fees, and/or honoraria
(less than $10,000 each) from the Lupus Research Institute and the
Arthritis Foundation.
Address correspondence and reprint requests to Maria
Dall’Era, MD, Division of Rheumatology, University of California,
San Francisco, 533 Parnassus Avenue, U 384, Box 0633, San Francisco,
CA 94143. E-mail: maria.dallera@ucsf.edu.
Submitted for publication April 23, 2007; accepted in revised
form August 24, 2007.
Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by the pro4142
ATACICEPT TREATMENT OF SLE
duction of autoantibodies to a variety of nuclear antigens. B cells are currently thought to play an important
role in SLE pathogenesis through both antibodydependent and antibody-independent mechanisms.
Thus, B cells have emerged as rational targets for drug
development in SLE (1).
Several B cell–directed strategies have been proposed as possible therapies for SLE. Some of these
strategies are designed to eliminate B cells through the
use of B cell–directed monoclonal antibodies (mAb)
(2–5), while others interfere with B cell stimulation
(6–8) or seek to selectively target autoantibodyproducing B cells (9–11). Attempts to inhibit B cell
stimulation have focused primarily on receptor–ligand
interactions that involve molecules called B lymphocyte
stimulator (BLyS; trademark of Human Genome Sciences, Rockville, MD) and APRIL. BLyS and APRIL
are members of the tumor necrosis factor family of
cytokines, which are critical for B cell survival and
development. Both molecules bind to TACI and BCMA,
while BLyS also binds to BAFF receptor (BAFF-R) and
APRIL interacts with proteoglycans.
Mounting evidence in animal models and in
humans supports an important role of BLyS and APRIL
in the development of autoimmune disease. Transgenic
mice that overexpress BLyS display B cell expansion and
polyclonal hypergammaglobulinemia (12–14). Some of
these mice develop a lupus-like phenotype consisting of
anti–double-stranded DNA (anti-dsDNA) antibodies,
immunoglobulin deposition in the kidneys, and accelerated development of glomerular disease (15).
Studies in humans also suggest a role of BLyS
and APRIL in systemic autoimmune diseases. Patients
with SLE have increased serum levels of BLyS that
correlate positively with levels of anti-dsDNA antibodies
(16–18). Serum levels of APRIL are elevated in patients
with SLE as compared with healthy individuals and
patients with rheumatoid arthritis (19). BLyS and
APRIL have been detected in the synovial fluid of
patients with inflammatory arthritis (20).
These compelling observations in mice and humans have led to the development of several BLyS
antagonists. One of these agents, atacicept (previously
referred to as TACI-Ig), is a recombinant fusion protein
comprising the extracellular domain of the TACI receptor joined to a human IgG1 Fc domain. Atacicept blocks
B cell stimulation by both BLyS and APRIL. Several
lines of investigation provide support for the expectation
that atacicept will have potent effects in vivo. First,
transgenic mice that express atacicept have few mature
B cells and reduced concentrations of immunoglobulin
(8). Second, treatment of lupus-prone female (NZB ⫻
4143
NZW)F1 (NZB/NZW) mice with atacicept delays the
development of proteinuria and increases survival (12).
Finally, in a direct comparison of the efficacy of murine
atacicept and BAFF-R-Ig (a BLyS-only inhibitor) in
lupus-prone female NZB/NZW mice, only atacicept
reduced the serum levels of IgM, decreased the frequency of plasma cells in the spleen, and inhibited the
IgM response to a T cell–dependent antigen, suggesting
a role of APRIL in these processes (21). In light of these
encouraging preclinical data, we examined the biologic
effects, pharmacokinetics, pharmacodynamics, and
safety of atacicept in a phase Ib, double-blind, doseescalating trial in patients with SLE.
PATIENTS AND METHODS
Study design. This study (study code 25050) was a
multicenter, phase Ib, placebo-controlled, dose-escalating,
single- and repeated-dose trial of atacicept in patients with
mild-to-moderate SLE. Informed consent was obtained from
all patients in accordance with the human subjects Institutional
Review Boards of all the participating universities.
Six cohorts comprising 8 patients each were treated with
subcutaneously administered atacicept or matching placebo in a
3:1 ratio of those taking active drug and those taking placebo (an
additional patient was enrolled in cohort 5 to replace a patient
who was withdrawn because of a protocol violation). Cohorts 1–4
received a single subcutaneous dose of placebo or 0.3 mg/kg, 1
mg/kg, 3 mg/kg, or 9 mg/kg of atacicept, respectively. Cohorts 5
and 6 received subcutaneous doses of placebo or 1 mg/kg or 3
mg/kg of atacicept, respectively, once a week for 4 weeks. Patients
were followed up for 6 weeks (cohorts 1–4) or 9 weeks (cohorts 5
and 6). Outcome measures included: systemic and local tolerability of atacicept; frequency of adverse events (AEs); pharmacokinetics and pharmacodynamics of atacicept, including effects on
lymphocyte subpopulations and immunoglobulin levels; and measures of SLE disease activity.
Selection of study patients. All patients enrolled in the
study were required to have fulfilled at least 4 of the 11
classification criteria for SLE as defined by the American
College of Rheumatology (22) and as updated in 1997 (23).
Patients also were required to be between the ages of 18 and 70
years, with a body mass index of 18–40 kg/m2. Patients with
Safety of Estrogens in Lupus Erythematosus: National Assessment modification of the Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI) scores of 0–10 at
screening were eligible for the trial (24,25). Patients with a
SELENA–SLEDAI score ⬎10 were excluded, based on the
rationale that their baseline therapy should be modified to
provide better disease control. Patients treated with immunosuppressive medications, such as azathioprine, methotrexate,
mycophenolate mofetil, and cyclophosphamide, during the 8
weeks prior to enrollment were excluded. In addition, patients
treated with ⬎20 mg/day of prednisone or who were experiencing a change in prednisone dosage during the 4 weeks prior
to the start of the trial were excluded. For patients being
treated with hydroxychloroquine or nonsteroidal antiinflammatory drugs, stable dosages were required during the 4 weeks
prior to the trial. Patients were required to meet the following
4144
hematologic criteria for safety: hemoglobin value ⬎8.5 mg/dl,
white blood cell count ⬎2.5 ⫻ 109/liter, and platelet count
⬎75 ⫻ 109/liter. Patients with neurologic symptoms suggestive
of central nervous system lupus, congestive heart failure, a
history of cancer other than treated basal cell or squamous cell
carcinoma of the skin, or the presence of significant liver or
kidney disease were excluded from the study. Patients were
also excluded if they had been previously treated with biologic
agents or had a history of recurrent or active infections, such as
human immunodeficiency virus, tuberculosis, hepatitis B virus,
or hepatitis C virus.
Assessment of pharmacokinetics. The pharmacokinetics of the study medication were assessed by measuring serum
levels of free atacicept, atacicept–BLyS complex, and composite atacicept (defined as free atacicept plus atacicept–BLyS
complex). Serum levels of each of these components were
quantified using an enzyme-linked immunosorbent assay
(ELISA). Serum was incubated with a biotin-conjugated mAb
specific for atacicept (free or total atacicept detection) or BLyS
(atacicept–BLyS complex detection) immobilized on a
streptavidin-coated microplate. After washing, an ataciceptspecific mAb conjugated to horseradish peroxidase (HRP) was
added. For detection of total atacicept, a BLyS-specific mAb
conjugated to HRP was also added at this stage. In all 3 assays,
serum atacicept levels were detected and quantified using
standard chemiluminescence methods.
Assessment of pharmacodynamics. The pharmacodynamics of the study medication were assessed by measuring
serum levels of immunoglobulins (IgG, IgM, IgA), C3 complement, and antinuclear antibodies (ANAs), as determined by
flow cytometric analysis of lymphocyte subsets (see below).
Levels of immunoglobulins and C3 were measured using
standard methods. ANAs were measured using the AtheNA
Multi-Lyte ANA test system (Zeus Scientific, Raritan, NJ).
Flow cytometry. A panel of peripheral blood mononuclear cell types (B cell and T cell subsets, natural killer [NK]
cells, and monocytes) was assessed in antibody-stained peripheral blood samples, using 4-color flow cytometry. The
analysis included: total T cells (CD45⫹,CD3⫹), T helper cells
(CD45⫹,CD3⫹,CD4⫹,CD8–), T cytotoxic/suppressor cells
(CD45⫹,CD3⫹,CD4–,CD8⫹), total B cells (CD19⫹), mature
B cells (CD19⫹,IgD⫹,CD27–), monocytes (CD45⫹,CD3–,
CD14⫹,CD56–), and NK cells (CD45⫹,CD3–,CD14–,
CD56⫹). A contract research organization (Esoterix, Groningen, The Netherlands) performed blood sample processing,
antibody staining, and acquisition, analysis, and quality control
of data. ZymoGenetics (Seattle, WA) performed further analysis and quality control on B cell subsets. For B cell subsets,
the analysis gate was enlarged to include small and large
lymphocytes, with the latter being similar in size to monocytes.
Measurement of antitetanus antibodies. In the
repeated-dose cohorts only, vaccine immunization status was
assessed by measuring titers of antibodies to tetanus toxoid on
days 1 and 29 and at the poststudy visit.
Measurement of the immune response to atacicept.
Assays for binding and neutralizing antibodies to atacicept
were performed on samples taken at baseline and at the final
poststudy visit. Quantification of anti-atacicept antibodies was
performed using a bridging ELISA based on streptavidinprecoated plates. For each unknown and control sample, the
T:U ratio was calculated (T ⫽ treated, representing postdose
or spiked sample [control samples only], and U ⫽ untreated,
DALL’ERA ET AL
representing predose sample). Test samples were considered
positive for the presence of antibody to atacicept if the T:U
ratio was ⱖ1.3, corresponding to a minimum sensitivity of
250 ng of control antibody per milliliter (rabbit IgG to
atacicept).
Clinical assessments. Medical history was obtained at
study inclusion, and a physical examination was conducted on
a weekly basis. Hematologic and serum chemistry profiles were
performed on a weekly basis and were evaluated using the
Common Toxicity Criteria of the National Cancer Institute
(26). Blood samples for pharmacokinetic evaluations were
collected on a weekly basis for repeated-dose cohorts and on
day 1 at 4 and 8 hours after dosing, days 2, 3, 4, and 8, and on
a weekly basis thereafter for the single-dose cohorts. Blood
samples for pharmacodynamic evaluations were drawn on a
weekly basis in the repeated-dose cohorts and on days 2, 3, and
8 and on a weekly basis thereafter in the single-dose cohorts.
Electrocardiogram after day 4 was performed every 2 weeks in
the single-dose cohorts and on a weekly basis in patients
receiving repeated doses of the study drug.
For practical reasons, there was a difference in collection of local tolerability data between the single-dose and
repeated-dose cohorts. Local tolerability of injections was a
solicited event and was actively assessed in the single-dose
cohorts. Clinically significant local tolerability reactions were
to be reported as AEs. In repeated-dose cohorts, local reactions were reported as AEs, but injection sites were not
routinely evaluated.
Measures of disease activity. Although the study was
not powered to determine the impact of treatment on disease
activity, the following disease activity measurements were
obtained to provide preliminary efficacy data. SELENA–
SLEDAI scores were determined at baseline and on days 29
and 43 (cohorts 1–4) or on days 22 and 64 (cohorts 5 and 6).
Anti-dsDNA antibody and C3 levels were measured at baseline
and on days 15, 29, and 43 (cohorts 1–4) or on days 15, 22, 29,
43, and 64 (cohorts 5 and 6).
RESULTS
Clinical characteristics. Forty-nine patients with
mild-to-moderate SLE participated in the study from
June 2004 through March 2006 at 5 centers. Characteristics of the study patients are shown in Tables 1 and 2.
Among the patients in the single-dose cohorts, 90.6%
were female, 71.9% were Caucasian, and their median
age was 45.5 years (range 23–64 years). Within the
repeated-dose cohorts, 100% were female, 70.6% were
Caucasian, and their median age was 49.0 years (range
26–64 years). Clinical manifestations of SLE at baseline
included the following: arthritis (90%), photosensitivity
(65%), malar rash (51%), oral ulcers (47%), serositis
(41%), hematologic (35%), discoid lupus (31%), renal
involvement (16%), and neurologic involvement (10%).
The median duration of disease was 11.2 years in the
single-dose cohorts and 11.0 years in the repeateddose cohorts. At study entry, 36% of patients were
receiving corticosteroids, and 59% of patients were
ATACICEPT TREATMENT OF SLE
4145
Table 1. Baseline demographic and clinical characteristics of patients in the single-dose cohorts*
Atacicept
Age, years
Female, no. (%)
BMI, kg/m2
Race, no. (%)
Caucasian
Black
Asian
Other
No. of ACR criteria met,
no. (%) of patients
4
5
6
7
8
9
10
Disease duration, years
SELENA–SLEDAI score
Placebo
(n ⫽ 8)
0.3 mg/kg
(n ⫽ 6)
1 mg/kg
(n ⫽ 6)
3 mg/kg
(n ⫽ 6)
9 mg/kg
(n ⫽ 6)
All
(n ⫽ 32)
43.5 (26–61)
8 (100)
25.0 (18.1–39.6)
46.5 (23–64)
6 (100)
27.9 (20.2–36.9)
35.0 (24–54)
6 (100)
23.6 (21.3–27.7)
55.5 (44–63)
5 (83.3)
26.8 (23.2–31.1)
41.0 (30–60)
4 (66.7)
22.6 (20.8–32.1)
45.5 (23–64)
29 (90.6)
25.4 (18.1–39.6)
6 (75.0)
1 (12.5)
0
1 (12.5)
5 (83.3)
0
0
1 (16.7)
5 (62.5)
2 (25.0)
1 (12.5)
0
0
0
0
10.3 (1.2–28.6)
2.0 (0–7)
2 (33.3)
2 (33.3)
1 (16.7)
1 (16.7)
0
0
0
9.6 (3.4–34.6)
2.0 (0–7)
3 (50.0)
0
2 (33.3)
1 (16.7)
4 (66.7)
0
1 (16.7)
1 (16.7)
2 (33.3)
2 (33.3)
0
1 (16.7)
0
1 (16.7)
0
12.4 (0.4–36)
2.0 (0–8)
3 (50.0)
0
0
1 (16.7)
1 (16.7)
0
1 (16.7)
12.3 (5.1–25.2)
1.0 (0–6)
5 (83.3)
0
0
1 (16.7)
23 (71.9)
1 (3.1)
3 (9.4)
5 (15.6)
2 (33.3)
2 (33.3)
1 (16.7)
0
1 (16.7)
0
0
5.0 (0.8–46.5)
3.0 (2–8)
14 (43.8)
8 (25.0)
3 (9.4)
3 (9.4)
2 (6.3)
1 (3.1)
1 (3.1)
11.2 (0.4–46.5)
2.0 (0–8)
* Except where indicated otherwise, values are the median (range). BMI ⫽ body mass index; ACR ⫽ American College of Rheumatology;
SELENA–SLEDAI ⫽ Safety of Estrogens in Lupus Erythematosus: National Assessment modification of the Systemic Lupus Erythematosus
Disease Activity Index.
receiving hydroxychloroquine. Stable dosages of these
medications were continued for the duration of the
study.
Disposition of the study patients. Thirty-two
patients were enrolled in the single-dose cohorts and 17
patients were enrolled in the repeated-dose cohorts. All
of the patients except for 2 completed the trial. One
patient in the 1-mg/kg atacicept repeated-dose group
(cohort 5) withdrew and was replaced after day 8, when
a protocol violation was discovered (history of melanoma). One patient in the repeated-dose placebo group
in cohort 6 was lost to followup after day 8.
Table 2. Baseline demographic and clinical characteristics of patients in the repeated-dose cohorts*
Atacicept
Age, years
Female, no. (%)
BMI, kg/m2
Race, no. (%)
Caucasian
Black
Other
No. of ACR criteria met,
no. (%) of patients
4
5
6
7
8
Disease duration, years
SELENA–SLEDAI score
Placebo once
weekly for 4 weeks
(n ⫽ 4)
1 mg/kg once
weekly for 4 weeks
(n ⫽ 7)
3 mg/kg once
weekly for 4 weeks
(n ⫽ 6)
All
(n ⫽ 17)
59.0 (42–63)
4 (100)
32.7 (28.4–36.9)
51.0 (26–64)
7 (100)
25.3 (21.8–42.6)
42.5 (36–49)
6 (100)
28.1 (17.7–39.3)
49.0 (26–64)
17 (100)
29.1 (17.7–42.6)
4 (100)
0
0
2 (50.0)
1 (25.0)
0
1 (25.0)
0
13.3 (6–26)
1 (0–6)
4 (57.1)
1 (14.3)
2 (28.6)
4 (66.7)
1 (16.7)
1 (16.7)
1 (14.3)
4 (57.1)
0
1 (14.3)
1 (14.3)
16.8 (2.8–36.8)
2 (0–6)
2 (33.3)
2 (33.3)
1 (16.7)
1 (16.7)
0
9.0 (5–27)
4 (0–6)
12 (70.6)
2 (11.8)
3 (17.6)
5 (29.4)
7 (41.2)
1 (5.9)
3 (17.6)
1 (5.9)
11.9 (2.8–36.8)
3 (0–6)
* Except were indicated otherwise, values are the median (range). BMI ⫽ body mass index; ACR ⫽ American College of
Rheumatology; SELENA–SLEDAI ⫽ Safety of Estrogens in Lupus Erythematosus: National Assessment modification of the
Systemic Lupus Erythematosus Disease Activity Index.
4146
Figure 1. Pharmacokinetics of free atacicept when administered as A,
a single dose or B, repeated doses in patients with systemic lupus
erythematosus. Pharmacokinetic parameters were measured before
each dose and no sooner than 1 week after the last dose (see Patients
and Methods for details). Values are the median.
Atacicept pharmacokinetics. Evidence of nonlinear pharmacokinetics, consistent with saturable binding
pharmacokinetics of ligand–receptor interactions, was
demonstrated (Figure 1). Free and composite atacicept
concentration–time profiles displayed multiphasic pharmacokinetics with fairly rapid absorption, with a time to
maximum concentration of ⬃24 hours after the first dose,
and an initial distribution phase lasting 7–14 days. Low
accumulation of free atacicept was observed in the
repeated-dose cohort; the accumulation of composite atacicept was marginally higher and the atacicept–BLyS
complex was found to accumulate throughout the dosing
period.
Effect of atacicept on B lymphocytes. Treatment
with atacicept was associated with an initial, transient
increase in mature and total B cells, followed by a
sustained, dose-related reduction (Figure 2). In the
single-dose 3 mg/kg and 9 mg/kg groups (data not
shown) and in the repeated-dose groups (Figure 2), a
reduction in mature B cells of ⬃35% from baseline was
seen on day 29. In the single-dose groups, this reduction
was sustained through day 43; in the repeated-dose
groups, a reduction of ⬃60% was seen on day 43 and was
sustained at 45–60% through to the last assessment on
day 64. The patterns observed for total B cells were
similar to those for mature B cells. In the 3-mg/kg
single-dose group (data not shown), a reduction in total
B cells of ⬃30% from baseline was seen on day 29, which
was sustained through day 43; in the repeated-dose
groups, reductions of ⬃40–50% were seen on day 43 and
were sustained at 35–60% through to the last assessment
on day 64 (Figure 2). There were no significant changes
DALL’ERA ET AL
in the number of total T cells, T helper cells, T
suppressor/cytotoxic cells, monocytes, or NK cells.
Effect of atacicept on immunoglobulin levels.
Dose-dependent reductions in immunoglobulin levels were
observed in the atacicept-treated patients (Figure 3). This
effect was most notable in the repeated-dose groups. IgM
levels showed the greatest declines with treatment, reaching nearly 50% on day 43 in the 3-mg/kg repeated-dose
group. IgA levels decreased by ⬃33% in the 3-mg/kg
repeated-dose group on day 29, and IgG levels decreased
by ⬃16% in the 3-mg/kg repeated-dose group on day 36.
Nadirs occurred between days 15 and 29 in the single-dose
cohorts and between days 29 and 43 in the repeated-dose
cohorts. Thereafter, values began to return to baseline. The
last observed values were ⬃5–30% below baseline in the
single-dose cohorts (with the exception of the 0.3-mg/kg
group, in which IgM values were above baseline) and
8–45% below baseline in the repeated-dose cohorts.
IgM levels dropped below the lower limit of
normal during treatment (range 0.31–0.39 mg/ml) in a
total of 6 patients (1 in each cohort). However, for all of
these patients, levels were already low at baseline,
varying from 0.42 to 0.81 mg/ml (normal range 0.4–2.3).
IgM values had returned to normal by the end of the
study for 3 of the patients who received single doses.
In terms of IgG levels, a decrease below the lower
limit of normal occurred only in 1 patient; this patient
Figure 2. Effect of atacicept versus placebo on B lymphocyte numbers
in patients with systemic lupus erythematosus. A, Mature B cells
(CD19⫹,IgD⫹,CD27–), gated on small and large lymphocytes. B,
Total B cells (CD19⫹), gated on small and large lymphocytes. Values
are the median percentage change in absolute numbers from baseline.
ATACICEPT TREATMENT OF SLE
4147
between the placebo and atacicept groups (Table 3). At
least 1 AE was reported by 78% of patients in the
single-dose cohorts and by 77% of patients in the repeateddose cohorts. All reported events except 1 were graded as
mild or moderate in severity: 107 events were graded as
mild, 33 were graded as moderate, and 1 was graded as
severe (paresthesia in a patient in the repeated-dose placebo group). There were no treatment withdrawals or
withdrawals from the trial because of AEs.
Overall, 42% of patients receiving placebo and
35% of patients receiving atacicept experienced an
infection-related event. The most frequently reported
infectious AEs were upper respiratory tract infections (6
patients, 3 receiving placebo and 3 receiving atacicept),
rhinitis (none receiving placebo and 5 receiving atacicept), and sinusitis (1 receiving placebo and 2 receiving
atacicept). No infection-related event was reported as
severe or serious, and all patients recovered without
complications. Two patients experienced serious AEs;
both were in the placebo groups. One patient was
hospitalized because of ventricular bigeminy and pyrexia, and the other patient was hospitalized because of
acute right-sided paresthesia. There were no severe or
serious AEs in patients treated with atacicept.
Local tolerability. For the single-dose cohorts,
the injection sites were assessed systematically; symptoms were noted, but none was reported as an AE. In the
repeated-dose cohorts, local tolerability was assessed
through AE reporting. All of the injection-site AEs
reported, therefore, occurred in patients in the
repeated-dose cohorts. Overall, mild injection-site reactions occurred more frequently in patients receiving
atacicept than in patients receiving placebo. Mild
injection-site redness was observed in 2 of the 8 patients
Figure 3. Levels of immunoglobulin present after treatment with
atacicept in patients with systemic lupus erythematosus. A, IgM levels
in patients receiving single or repeated doses. 1⫹ 8h ⫽ 8 hours after
the dose. B, IgG and C, IgA levels in patients receiving repeated doses.
Values are the median percentage change in absolute levels from
baseline.
Table 3.
Types of adverse events occurring in ⱖ3 patients
Adverse event
had received a single 0.3-mg dose. IgG levels dropped
from 7.55 mg/ml at baseline (normal range 7–16) to 6.31
mg/ml on day 8. IgG levels in this patient had returned
to normal by day 15. It is important to note that 7
patients had IgG levels below the lower limit of normal
at baseline and that these levels decreased during treatment. However, no patient had IgG levels below 4 mg/ml
at any point during the study.
Adverse events. There were no statistical differences in the frequency or type of AEs, including infections,
Rhinitis
Fatigue
Nausea
Headache
Upper respiratory tract infection
Peripheral edema
Arthritis
Arthralgia
Prolonged prothrombin time
Dizziness
Depression
Sinusitis
Vaginal mycosis
Pain in extremity
No. (%) of
No. (%) of
atacicept-treated placebo-treated
patients
patients
(n ⫽ 37)
(n ⫽ 12)
5 (13.5)
5 (13.5)
5 (13.5)
4 (10.8)
3 (8.1)
3 (8.1)
3 (8.1)
3 (8.1)
3 (8.1)
2 (5.4)
2 (5.4)
2 (5.4)
2 (5.4)
2 (5.4)
0
1 (8.3)
1 (8.3)
0
3 (25.0)
0
2 (16.7)
0
0
1 (8.3)
1 (8.3)
1 (8.3)
1 (8.3)
1 (8.3)
4148
in the single-dose placebo group. Mild-to-moderate
injection-site redness, bruising, and swelling were noted
in all of the atacicept single-dose groups, without notable differences between doses except for redness, which
was less frequent in the 0.3-mg/kg group (affecting only
1 patient). Injection-site redness was observed in 50% of
all of the patients who were receiving atacicept. No
itching was reported, and no severe injection-site reactions were observed. Three local injection-site reactions
were reported as AEs: a mild injection-site hemorrhage
in a patient in the placebo group and moderate
injection-site rashes in 2 patients in the repeated-dose
atacicept group.
SLE exacerbations. A total of 4 exacerbations of
SLE were reported during the trial. One patient in the
placebo group experienced increased arthralgias and
was treated with corticosteroids and adrenocorticotropic
hormone. One patient in the atacicept 0.3-mg/kg group
experienced increased arthritis and rash 11 days after
dosing; this was treated with acetaminophen, corticosteroids, and azathioprine. One patient in the atacicept
1-mg/kg group experienced a new mouth ulcer 4 weeks
after dosing; no treatment was required. One patient in
the atacicept 3-mg/kg repeated-dose group experienced
pleuritic chest pain 3 days after the first dose, which
required treatment with ibuprofen.
Findings of laboratory and other assessments.
There was no evidence of hematologic, hepatic, or renal
toxicity in any patient treated with atacicept. There were
no differences in blood pressure, heart rate, temperature, or electrocardiographic findings between the placebo and atacicept groups.
Anti-atacicept antibody response. No patient developed detectable binding antibodies to atacicept.
Antitetanus protective antibodies. Twelve subjects (3 assigned to placebo and 9 assigned to atacicept)
had detectable levels of antitetanus antibodies at baseline. Levels posttreatment were available in 11 of these
patients. None of these patients experienced a decrease
in antibody levels into the nonprotective range. Antibody titers of ⬍0.1 IU/ml are considered nonprotective,
and levels ⬎0.49 IU/ml are considered protective; patients with titers falling between these values are said to
be in the intermediate range.
Five patients receiving atacicept and 2 receiving
placebo who had protective levels of antibodies at
baseline continued to have levels within the protective
range. One patient receiving atacicept who had a protective level of antibodies at baseline showed
intermediate-range levels on day 29, which then returned to the protective range on day 64. Two patients
receiving atacicept who had baseline levels of antibodies
DALL’ERA ET AL
in the intermediate range continued to have levels within
the intermediate range. One patient receiving atacicept
who had baseline levels of antibodies in the intermediate
range showed protective levels on days 29 and 64. One
patient receiving atacicept who had nonprotective levels
of antibodies at baseline and on day 29 had levels in the
protective range on day 64.
Effect of atacicept on SELENA–SLEDAI scores.
The majority of patients had mild SLE disease activity at
baseline; the median SELENA–SLEDAI score was 2.0
in the single-dose cohorts and 3.0 in the repeated-dose
cohorts. However, 12 patients (3 receiving placebo, 6
receiving single-dose atacicept, and 3 receiving
repeated-dose atacicept) had baseline SELENA–
SLEDAI scores of ⱖ6, denoting moderate disease activity. To evaluate a possible trend in the effect of atacicept
on disease activity, we determined how many of those 12
patients experienced a reduction of ⬎3 points in the
SELENA–SLEDAI score by the end of the trial. Our
choice of 3 points was based on a study of 230 patients
with SLE, which determined that meaningful improvement in a patient’s clinical disease activity correlated
with a reduction in the SELENA–SLEDAI score of ⬎3
(27). Using this criterion, we observed that 1 of the 3
patients from the placebo group, 2 of the 6 patients from
the single-dose cohorts, and 2 of the 3 patients from the
repeated-dose cohorts experienced clinically meaningful
improvements in disease activity.
We also determined how many of the 12 patients
with baseline SELENA–SLEDAI scores of ⱖ6 achieved
a SELENA–SLEDAI score of 0 at the end of the study.
Interestingly, 2 of the 3 patients in the repeated-dose
cohorts achieved a SELENA–SLEDAI score of 0, compared with 2 of the 6 patients in the single-dose cohorts
and none of the 3 patients in the placebo cohorts. While
these data are encouraging, they are insufficient to draw
conclusions regarding efficacy, which will be assessed in
a subsequent phase II/III trial.
Effect of atacicept on C3 complement levels. Only
8 patients in this study had low C3 levels at baseline (1
receiving placebo, 5 receiving single-dose atacicept, and
1 each receiving 1 mg/kg and 3 mg/kg repeated-dose
atacicept). Hypocomplementemia persisted in all 6 of
the patients receiving placebo and single-dose atacicept,
whereas C3 levels normalized in both of the patients
receiving repeated-dose atacicept.
Effect of atacicept on anti-dsDNA antibodies.
Since this phase Ib study was conducted in patients with
relatively mild disease, only 5 patients had anti-dsDNA
antibodies at baseline (2 receiving placebo and 1 each
receiving single-dose 0.3 mg/kg, 1 mg/kg, and 3 mg/kg
atacicept). Each of these patients also had anti-dsDNA
ATACICEPT TREATMENT OF SLE
antibodies at the end of the study. None of the patients
in the repeated-dose cohorts had detectable anti-dsDNA
antibodies at baseline.
DISCUSSION
The primary objectives of this study were 1) to
assess the short-term safety and tolerability of single and
repeated subcutaneous doses of atacicept in patients
with mild-to-moderate SLE and 2) to determine the
biologic effects of atacicept on B lymphocyte numbers
and immunoglobulin levels. Treatment with atacicept
was well tolerated, although mild injection-site reactions
were observed more commonly in the atacicept groups
than in the placebo group. The impact of atacicept on B
cell and immunoglobulin levels documents a potent
biologic effect that supports the hope that this approach
may be effective in autoantibody-mediated autoimmune
diseases such as SLE.
Interest in the role of B cells in the pathogenesis
of SLE has led to the development of several potential
therapeutic agents that specifically target B cells by
distinct mechanisms. Rituximab (anti-CD20) and
epratuzumab (anti-CD22) deplete B cells by mAbmediated mechanisms. In contrast, atacicept and belimumab (anti-BLyS) deprive B cells of signals necessary
for growth and development, thereby causing partial
depletion of B cells and reducing immunoglobulin production.
Belimumab is a mAb to BLyS. As such, it inhibits
B cell stimulation by BLyS, but not by APRIL. Belimumab was recently studied in a phase II, randomized,
double-blind, placebo-controlled trial in 449 patients
with active SLE (7). Although this trial did not meet its
primary end points in the overall study population,
subsequent subset analysis suggested possible benefit. It
is expected that this issue will be clarified in 2 upcoming
phase III trials. A potentially important distinguishing
feature between atacicept and belimumab is the fact that
atacicept binds to both BLyS and APRIL, while belimumab is a mAb directed solely against BLyS. In
addition, the receptors for BLyS and APRIL are expressed differentially on B cells according to their
developmental stage. TACI is strongly expressed by
transitional type 2 B cells, marginal-zone B cells, and
activated B cells, whereas BCMA is preferentially expressed by plasma cells, plasmablasts, and tonsillar germinal center B cells (28). Thus, the various proposed B
cell–directed therapies may well differ in their potency
and in their safety profiles. Atacicept may be more
potent than belimumab because of its ability to block
both BLyS and APRIL; however, it remains to be
4149
determined whether this difference will result in a better
risk/benefit ratio. Similarly, atacicept may be safer than
rituximab or epratuzumab because it might spare patients severe and prolonged B cell depletion. How this
difference will translate in terms of relative risk and
benefit, however, also remains to be determined in
controlled clinical trials.
It is reassuring that there were no differences in
the frequency of infections between the atacicept and
placebo groups. The most commonly reported infectious
AE was upper respiratory tract infection (3 patients
receiving atacicept and 3 patients receiving placebo).
Despite the overall reductions in immunoglobulin levels
observed in this study, it is encouraging that all patients
maintained protective levels of antitetanus antibodies.
Additionally, immunogenicity against atacicept was not
detected, even though the majority of patients were not
receiving concomitant antimetabolic or cytotoxic
therapies.
This small study was not powered to reach definitive conclusions regarding the effect of atacicept on
measures of disease activity. In addition, for ethical
reasons, only patients with mild-to-moderate SLE were
enrolled in this phase Ib study. Nevertheless, reassuring
trends were observed in complement levels and
SELENA–SLEDAI scores. These very preliminary indications will be the subject of systematic investigation in
a phase II/III trial.
ACKNOWLEDGMENTS
We thank Steve Lund, NP, and Anne Marie Duhme,
RN (Clinical Trial Center, University of California, San Francisco), for their contributions to the study design and protocol
development. We are indebted to the Rosalind Russell Medical Research Center for Arthritis for their support of the
Clinical Trials Center at the University of California, San
Francisco.
AUTHOR CONTRIBUTIONS
Dr. Dall’Era 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 design. Dall’Era, Chakravarty, Genovese, Vincent, Pena-Rossi,
Wofsy.
Acquisition of data. Dall’Era, Chakravarty, Wallace, Genovese, Kavanaugh, Kalunian, Dhar, Vincent, Pena-Rossi, Wofsy.
Analysis and interpretation of data. Dall’Era, Genovese, Kavanaugh,
Kalunian, Vincent, Pena-Rossi, Wofsy.
Manuscript preparation. Dall’Era, Chakravarty, Wallace, Genovese,
Weisman, Kavanaugh, Kalunian, Vincent, Pena-Rossi, Wofsy.
Statistical analysis. Vincent, Pena-Rossi.
ROLE OF THE STUDY SPONSOR
A committee composed of the study investigators and members of the Merck Serono and ZymoGenetics Study Group was
4150
DALL’ERA ET AL
responsible for the design of the study protocol. Merck Serono was
responsible for collecting data from the study sites and for preparing
and maintaining the study database. The study investigators had full
access to the study data and were responsible for data analysis and
manuscript preparation. The manuscript was reviewed by Merck
Serono and ZymoGenetics prior to submission.
15.
16.
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APPENDIX A: THE MERCK SERONO AND
ZYMOGENETICS ATACICEPT STUDY GROUP
Members of the Merck Serono and ZymoGenetics Atacicept
Study Group are as follows: Nasreen Alam, PhD, Annette Dubois,
MA, Nils Kinnman, MD, PhD, and Marie Picard, MS (Merck Serono
International SA, Geneva, Switzerland); Alessandro Bortolotti, PhD
(Industria Farmaceutica Serono SpA, Rome, Italy); Laura O’Grady,
BS (EMD Serono, Rockland, MA); and Julieann Hill, MS, Ivan
Nestorov, PhD, and Elisabeth Salmon, MS (ZymoGenetics Inc.,
Seattle, WA).
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