Annals of Oncology 18: 1216–1223, 2007
Published online 29 April 2007
A phase I/II study of galiximab (an anti-CD80 monoclonal
antibody) in combination with rituximab for relapsed or
refractory, follicular lymphoma
J. P. Leonard1*?, J. W. Friedberg2?, A. Younes3, D. Fisher4, L. I. Gordon5, J. Moore6,
M. Czuczman7, T. Miller8, P. Stiff9, B. D. Cheson10, A. Forero-Torres11, N. Chieffo12,
B. McKinney13, D. Finucane14& A. Molina12
1Division of Hematology/Oncology, Weill Medical College of Cornell University and NewYork-Presbyterian Hospital, New York, NY;2Lymphoma Clinical Research, James
P. Wilmot Cancer Center, University of Rochester, Rochester, NY;3Division of Cancer Medicine Department of Lymphoma and Myeloma, M.D. Anderson Cancer
Center, Houston, TX;4Department of Hematologic Malignancies, Dana Farber Cancer Institute, Boston, MA;5Division of Hematology/Oncology, Northwestern
University, Chicago, IL;6Division of Hematology—Oncology, Duke University, Durham, NC;7Departments of Hematologic Oncology and Bone Marrow Transplantation,
Roswell Park Cancer Institute, Buffalo, NY;8Section of Hematology/Oncology, University of Arizona, Tucson, AZ;9Division of Hematology/Oncology, Loyola University
Medical Center, Chicago, IL;10Department of Hematology, Georgetown University Hospital, Washington, DC;11Division of Hematology/Oncology, University of
Alabama at Birmingham, Birmingham, AL;12Department of Hematology/Oncology - Medical Research;13Department of Biostatistics;14Department of Medical Writing,
Biogen Idec Inc., San Diego, CA, USA
Received 7 November 2006; revised 21 February 2007; accepted 22 February 2007
Background: Galiximab is a monoclonal antibody that targets CD80, a costimulatory molecule constitutively
expressed on follicular and other lymphomas. Modest single-agent clinical activity and tolerability were demonstrated
in a phase I study in relapsed or refractory, follicular non-Hodgkin’s lymphoma (NHL). A phase I/II study was
conducted to evaluate galiximab in combination with a standard course of rituximab. Safety, pharmacokinetics, and
efficacy were evaluated.
Patients and methods: Patients with follicular NHL who had relapsed or failed primary therapy were enrolled.
Rituximab-refractory patients (no response or a response with time to progression <6 months) were excluded. Patients
received 4 weekly i.v. infusions of galiximab (125, 250, 375, or 500 mg/m2) and rituximab (375 mg/m2). International
Workshop Response Criteria (IWRC) were used to evaluate response.
Results: Seventy-three patients received treatment. All had received at least one prior lymphoma therapy; 40% were
rituximab naive. Infusions were delivered in an outpatient setting and were well tolerated. The most common
study-related adverse events (AE) were lymphopenia, leukopenia, neutropenia, fatigue, and chills. The overall
response rate at the recommended phase II dose of galiximab (500 mg/m2) was 66%: 19% complete response, 14%
unconfirmed complete response, and 33% partial response. The median progression free survival was 12.1 months.
Combination therapy did not appear to alter pharmacokinetics.
Conclusion: These results indicate that galiximab can be safely combined with a standard course of rituximab. This
doublet biologic approach offers the potential to avoid or delay chemotherapy or to integrate with other lymphoma
therapies. A phase III, randomized study evaluating clinical benefit of rituximab versus the combination has been
Key words: galiximab, lymphoma, monoclonal antibody, rituximab, CD80
Treatment of follicular non-Hodgkin’s lymphoma (NHL)
is characteristically associated with a high rate of initial
response, followed by relapse. Subsequent remissions occur,
but at a progressively lower rate and with progressively
shorter durations . Despite improvements in response
rates with more aggressive combination regimens, the
increased toxicity and/or logistics of administration with
these regimens limit their use in a significant number of
patients [2–5]. The introduction nearly a decade ago of
therapeutic monoclonal antibodies provided patients with an
alternative. Single-agent rituximab (anti-CD20 antibody) has
demonstrated response rates of ?50% with a favorable safety
profile in relapsed or refractory, low-grade or follicular B-cell
NHL . Studies investigating maintenance/extended
treatment with rituximab have shown prolonged progressive
*Correspondence to: Dr J. P. Leonard, Weill Medical College of Cornell University and
NewYork-Presbyterian Hospital, Starr Building, Room 340, 520 East 70th Street,
New York, NY 10021 USA. Tel: +1 212-746-2932; Fax: +1 212-746-3844;
?These authors contributed equally to this work and share first authorship.
ª 2007 European Society for Medical Oncology
by guest on September 13, 2015
free survival (PFS) and event free survival (EFS) in indolent
NHL [7, 8]. Antibody combination therapies are also
under development to improve clinical response and/or to
extend remission without increasing toxicity. Galiximab,
an anti-CD80 antibody, is one such therapy.
Galiximab was developed as a macaque–human chimera
(human constant regions and primate variable regions)
to minimize immunogenicity and is structurally
indistinguishable from human antibodies . It binds
specifically to CD80, which is transiently expressed on the
surface of activated B cells and antigen-presenting cells
including dendritic cells, but is constitutively expressed on
a variety of NHLs, including follicular lymphoma; thus,
CD80 is an attractive target for lymphoma therapy [10–14].
Preclinical studies indicate that targeting this antigen has
antitumor effects. In vitro, cross-linking CD80 with
anti-CD80 antibodies on lymphoma cells has been shown to
inhibit cell proliferation, up-regulate proapoptotic molecules,
and induce antibody-dependent cell-mediated cytotoxicity
(ADCC) . In vivo, galiximab delays progression and
prolongs survival in a human lymphoma xenograft/severe
combined immunodeficiency (SCID) mouse model .
Previous clinical studies with galiximab have shown
promising results. A phase I/II, single-agent, dose escalation,
multiple-dose study demonstrated that 4 weekly infusions
of galiximab (125, 250, 375, or 500 mg/m2) were well
tolerated. Modest single-agent activity was observed
[11% overall response rate (ORR)] and nearly half of all
patients had a decrease in tumor burden .
Galiximab in combination with the anti-CD20 monoclonal
antibody rituximab has also been evaluated. In vitro,
combination therapy increased ADCC over that observed
with either agent alone. Treatment with galiximab or
rituximab in SCID mice with human SKW NHL xenografts,
which express both CD80 and CD20, increased survival over
untreated controls, and the combination of the two
antibodies appeared more effective than either agent alone
. These observations provided the rationale for
developing galiximab in combination with rituximab as
a targeted therapy for the treatment of patients with relapsed
or refractory, follicular NHL.
Herein, we report results from a multicenter, phase I/II
clinical study evaluating galiximab in combination with
a standard course of rituximab in patients with relapsed or
refractory, follicular NHL.
patients and methods
The primary objective of the study was to characterize the safety profile
and define the recommended phase II dose of galiximab in combination
with rituximab in patients with relapsed or refractory, follicular NHL.
Secondary objectives included the evaluation of pharmacokinetics (PK),
efficacy, and immunogenicity.
Adult patients (‡18 years) with histologically confirmed, follicular NHL
who had relapsed or failed primary therapy were eligible for this study.
Patients were required to have progressive disease after at least one prior
standard therapy. Patients who were rituximab-refractory [defined as no
response to prior rituximab or prior rituximab-containing regimen or
a response with a time to progression (TtP) of <6 months] were not
eligible for this study. Previously published studies have demonstrated
that CD80 is universally expressed on lymphoma cells; therefore, CD80
expression was not a requirement for study eligibility. Patients were not
permitted to have had radiotherapy, biological therapy, chemotherapy,
prednisone, or other immunosuppressive therapy within 3 weeks before
the first scheduled treatment. Inclusion criteria also required patients to
have a World Health Organization performance status of two or less;
bidimensionally measurable disease with at least one lesion ‡2.0 cm in
a single dimension; and adequate hematological, renal, and hepatic
function. Patients were excluded if they had central nervous system
lymphoma, chronic lymphocytic leukemia, a prior diagnosis of aggressive
NHL or mantle-cell lymphoma, active opportunistic infection, serious
nonmalignant disease, or were human immunodeficiency virus positive.
Concomitant treatment with additional lymphoma treatments or other
investigational drugs was not permitted during the study.
The study was conducted in accordance with the Declaration of
Helsinki. Written informed consent was obtained from all patients, and
each participating clinical site received approval from its Institutional
This was an open-label, multicenter, dose escalation, phase I/II study.
In phase I, patients were enrolled into four treatment groups using
a standard 3 + 3 dose escalation design for galiximab (125, 250, 375,
or 500 mg/m2). Subjects received 4 weekly i.v. infusions of rituximab
(375 mg/m2) and galiximab (Figure 1). For safety reasons, the first
infusions of rituximab and galiximab were given on separate days. The
first infusion of rituximab was given on day 1, and subjects were
monitored for infusion-related events known to occur. The first infusion
of galiximab was given on day 3. Thereafter, rituximab and galiximab
were given on the same infusion day (days 8, 15, and 22). Enrollment
Figure 1. Overview of study schedule. Patients received infusions of rituximab on day 1, galiximab on day 3, and rituximab and galiximab on days
8, 15, and 22. Patients were followed every week until day 50 and every 3 months thereafter until month 24. Subjects were then contacted every 6 months as
part of long-term follow-up.
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into a higher dose cohort was not permitted until three patients in
the previous treatment group were at least 12 days beyond their first
infusion of galiximab with no dose-limiting toxic effects (DLTs)
reported. If one of three patients experienced DLT, an additional three
patients were to be enrolled in the treatment group and no further DLT
(i.e. one of six patients) were observed before dose escalation could
proceed. If two of three patients experienced DLT, additional patients
were not to be enrolled in that treatment group and the preceding dose
of galiximab in combination with rituximab was to be the recommended
phase II dose. DLT was defined as grade 3 toxicity not associated with an
infusion, grade 4 toxicity, or adverse reactions that prevented completion
of an infusion within 48 h. In phase II, enrollment was expanded to
treat ?60 patients at the dose recommended from phase I.
Following the administration of study treatment, patients entered
a follow-up period (through month 48). All patients who withdrew
from the study early or were alive at the end of the 48-month study
period were followed, at 6-month intervals, for continuation of
response (if applicable), initiation of a subsequent lymphoma therapy,
Study treatment was administered as i.v. infusions in an outpatient
setting. Rituximab was given according the package insert directions.
The median infusion duration for galiximab was 1 h. Doses were
individually formulated according to assigned treatment group and the
patient’s body surface area. In calculating the dose, there was no
downward adjustment to ?ideal? body weight.
study end points
safety. Safety evaluations included physical examinations, clinical adverse
events (AEs), hematology, blood chemistry, immunology, vital sign
measurements, and urinalysis. AEs were encoded using MedDRA
(version 8.0) and graded using the National Cancer Institute Common
Toxicity Criteria (version 2.0). Immunology evaluations included
immunoglobulin concentrations (immunoglobulin G, immunoglobulin M,
and immunoglobulin A), T- and B-lymphocyte subsets (CD3+, CD3+CD4+,
CD3+CD8+, CD19+), antigaliximab antibody formation, and
antihuman chimeric antibody (HACA) formation. Antigaliximab
and HACA formation were evaluated at baseline and months 3, 6, 9,
and 12 post-treatment using an enzyme-linked immunosorbent assay
pharmacokinetics. Serum samples to evaluate galiximab and rituximab
concentrations were obtained before and after the completion of each
infusion and posttreatment up to month 12. Data were analyzed using
noncompartmental methods. PK parameters evaluated included maximum
observed concentration (Cmax), elimination half-life (t1/2), and area under
the concentration–time curve (AUC).
efficacy. Disease assessments were carried out by comprehensive scans
(computed tomography or magnetic resonance imaging) and physical
examination at study entry, 1 month after completion of galiximab
treatment (day 50), every 3 months thereafter for years 1 and 2, and
every 6 months for years 3 and 4. Response to treatment was analyzed
using the IWRC for NHL . The primary efficacy end point was ORR
at the recommended phase II dose of galiximab. Secondary efficacy end
points included complete response (CR) rate, unconfirmed complete
response (CRu) rate, partial response (PR) rate, duration of response,
TtP, time to next anticancer therapy, overall survival (OS), EFS, and PFS.
Phase I was to include three to six subjects at up to four dose levels
for a total of 12–24 subjects. In phase II, additional subjects were to
be enrolled for a total of 60 per protocol subjects treated at the
recommended phase II dose. With a sample size of 60 per protocol
subjects, the precision of the objective ORR estimate, reflected by the
width of the 95% confidence interval (CI), would range from 20% to 26%.
Patients were considered assessable for safety and efficacy if they
received any part of an infusion of study treatment. Patients were
considered assessable for PK analyses if they received four infusions of
galiximab and had sufficient data available for calculation of PK
Summary descriptive statistics were used for all continuous variables
(n, mean, standard deviation, median, minimum, maximum) and
categorical variables (n, %). All CIs for proportions were calculated
using the methodology for inference about a single proportion. For
Kaplan–Meier median estimates, a 95% CI was calculated on the basis
of the sign test proposed by Brookmeyer and Crowley .
From 27 November 2002 to 05 March 2004, 75 patients with
relapsed or refractory, follicular lymphoma were enrolled at
18 clinical sites in the United States. Of the 75 patients
enrolled, 72 received all scheduled infusions of study
treatment (three at 125 mg/m2, three at 250 mg/m2, three at
375 mg/m2, and 63 at 500 mg/m2), one patient discontinued
treatment after three infusions due to disease progression
(500 mg/m2group), and two patients withdrew from the
study before treatment.
A summary of baseline characteristics for all treated
patients is presented in Table 1. The median age of patients
was 59 years. All had progressed after a median of two prior
treatment regimens; 29 (40%) were rituximab naive. The
majority of patients had disease stage III/IV (88%).
Distribution by Follicular Lymphoma International
Prognostic Index (FLIPI) risk group was good (23%),
intermediate (41%), and poor (36%). The median time
from diagnosis to study entry was 4.4 years.
Seventy-three patients were evaluated for safety and
efficacy. Efficacy is also reported for the 64 patients treated at
the recommended phase II dose of galiximab (500 mg/m2).
Fifteen patients remain on study in long-term follow-up;
the median follow-up is 25 months (1–34.8 months) as of
17 May 2006.
clinical adverse events
Antibody infusions were well tolerated. No DLTs were
reported at any dose, and no patient withdrew from the
study due to toxicity.
AEs of possible, probable, or unknown relationship to
study treatment are presented in Table 2. Seventy (96%)
patients experienced at least one study-related AE; the most
common were lymphopenia (48%), leukopenia (36%),
fatigue (36%), chills (27%), and neutropenia (22%). Eighteen
(25%) patients experienced grade 3 study-related AEs. One
(1%) patient experienced a grade 4 study-related AE
(neutropenia), which was classified as ?possibly? related to
study treatment. The patient was treated with filgrastim and
the event resolved.
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Thirteen serious adverse events (SAEs) were reported in
six patients. One patient experienced SAEs considered
possibly related to the first administration of rituximab
(grade 1 hypotension and nausea and grade 3 vomiting).
The rituximab infusion was interrupted until the events
resolved. All other SAEs were considered by investigators to
be unrelated to study treatment.
Twenty-six (36%) patients experienced an infection during
the study. The most common infections were upper
respiratory tract infections (7%), nasopharyngitis (6%),
pneumonia (6%), and urinary tract infections (6%). The
majority of infections were grade 1 or 2. Four grade 3
infections were experienced by three patients: pneumonia,
bronchitis, sinusitis, and central line infection. None were
considered by the investigator to be related to study
treatment, and all resolved with medication. No patient
experienced a grade 4 infection.
immunological parameters and lymphocyte
Detailed analyses of changes in immunological parameters
and lymphocyte subsets were carried out. Median serum
Table 1. Summary of baseline patient characteristics by treatment group
125 (n = 3)
Total (N = 73)
250 (n = 3) 375 (n = 3)500 (n = 64)
Sex, n (%)
Disease stage, n (%)
Years from diagnosis
FLIPI risk group, n (%)
WHO performance status, n %)
Extranodal involvement, n (%)
Maximum diameter of largest tumor (cm)
Bone marrow involvement, n (%)
No. of prior lymphoma regimens
All treatment groups received 375 mg/m2of rituximab.
FLIPI, Follicular Lymphoma International Prognostic Index; WHO, World Health Organization.
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immunoglobulin concentrations and T- and B-lymphocyte
subset counts fluctuated throughout the study, but remained
within the normal range with the exception of CD19+B-cell
counts. Median CD19+cell counts decreased below the
normal range by study day 8 (median of 0 cell counts). CD19+
counts returned to normal in the majority of patients with
measurements at study month 12. No patient developed
detectable antigaliximab antibody or HACA titers
For galiximab, Cmaxand AUC values were proportional to
the administered dose. Concentrations were measurable in
most patients up to 6 months after dosing at 500 mg/m2,
but seldom thereafter. Figure 2 shows the mean serum
concentrations of galiximab and rituximab over time for the
500 mg/m2galiximab treatment group. The mean half-life
for 500 mg/m2galiximab was 25.8 days, and the mean
half-life for rituximab was 27.3 days.
The primary efficacy end point was ORR at the recommended
phase II dose of galiximab. The ORR in the 500-mg/m2
galiximab treatment group was 66% (42 of 64 treated
patients; 95% CI, 52.6–76.8%) with a 19% CR rate,
14% CRu rate, and 33% PR rate. An additional 28%
(18 of 64) had stable disease [The appendix of the protocol
defined stable disease as £50% decrease in the sum of the
products of the greatest diameters (SPD) of the 6 largest
dominant nodes or nodal masses, but £50% increase from
nadir in the SPD] as their best response. The median PFS
was 12.1 months. The ORR for patients who were rituximab
naive was 70% (19 of 27) with a median PFS of 15.4 months.
The ORR for all treatment groups was 63% (46 of 73) with
a median PFS of 11.7 months. In some patients, response
improved over time between the 1- and 4-month scans. A
summary of efficacy end points for the 500-mg/m2galiximab
treatment group and for overall is presented in Table 3.
The median OS has not been reached to date. Of the 73
patients treated, 63 (86%) patients remain alive and 10 have
died. Nine deaths occurred off study; six were attributed to
disease progression and two were from unknown causes.
One death occurred on study. The subject had a history of
dyspnea, dry cough, sleep apnea, obesity, hypertension, and
diabetes. He received all infusions of study treatment and
experienced respiratory failure and died 9 days after his
last infusion. The investigator classified the event as
Table 2. Incidence of most common (‡5%)aand all grade 3 and 4 study-related adverse eventsb
Total N (%)
Any adverse event
Tumour lysis syndrome
aIncidence ‡5% of total patients evaluated and all grade 3 and 4 events. Each patient counted only under the worst grade experienced.
bAdverse events of probable, possible, or unknown relationship to study treatment.
cCytopenias were based on laboratory nadir grades.
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unrelated to study treatment. The cause of death was
reported as respiratory failure due to chronic obstructive
pulmonary disease, most likely related to obesity; however,
a potential relationship to study treatment cannot be
definitively ruled out.
A therapeutic goal in the management of follicular NHL is
to extend remission without increasing toxicity. Many
standard of care therapies are limited by their toxicity
profiles and/or logistics of administration. The benefit of
targeted therapies, such as monoclonal antibodies, is
a potential for lower toxicity of treatment. Galiximab is an
investigational monoclonal antibody that targets CD80,
a costimulatory molecule universally expressed on NHL and
Hodgkin’s cells [10–14, 20–22]. Because galiximab’s safety
profile and mechanism of action differ from chemotherapeutic
agents and other monoclonal antibodies, galiximab offers the
potential for integration with other lymphoma therapies.
This clinical study employs a doublet of two biologic agents
(antibodies against CD20 and CD80) in follicular lymphoma,
an approach that offers the potential to avoid or delay
chemotherapy (and its associated toxic effects) or to integrate
it with other lymphoma therapies. The current approved
schedule for rituximab is weekly times four; therefore, a
weekly dosing schedule with combination therapy was chosen
based on the ease of administration for patients and clinicians.
The favorable safety profile of galiximab is notable,
particularly, with respect to the lack of myelosuppression
typical with standard chemotherapies, radiotherapy, and
other antibody therapies [2, 3, 23–25]. The ease of galiximab
administration was also favorable; galiximab infusions were
delivered in an outpatient setting and were well tolerated.
The toxicity profile of rituximab is well known, and the
addition of galiximab to rituximab in this current study did
not appear to increase the overall incidence of AEs or alter
the AE profile. Additionally, the median serum half-life of
rituximab when administered in this combination is similar
to that observed in several recent studies of rituximab
Figure 2. Mean galiximab and rituximab serum concentrations over time (500 mg/m2galiximab in combination with 375 mg/m2rituximab; N = 64).
Table 3. Summary of objective response rates and time-to-event variables
galiximab + rituximab
group (n = 64)
groups (N = 73)
rate n (%)
Duration of response
Time to progression
Progression free survival
Event free survival
Time to next
41 (64) 45 (62)
CR, complete response; CRu, unconfirmed complete response;
PR, partial response; SD, standard deviation; PD, progressive disease;
CI, confidence interval.
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monotherapy [26–28]. Laboratory correlative studies showed
no evidence of T-cell depletion following galiximab
monotherapy  or galiximab in combination with
rituximab. Transient B-cell depletion was observed in this
current study, but not in the galiximab monotherapy study
and was attributed to the use of rituximab in the combination
regimen. The pattern of transient B-cell depletion is similar
to that seen with rituximab monotherapy. A reasonable
concern would be that targeting the CD80 antigen could
impair antigen-presenting function. However, we could find
no evidence of this. Since galiximab is a primatized antibody,
the risk of immunogenicity is low compared with murine
and some chimeric antibodies, which can potentially restrict
repeated administration. To confirm this, no patient
developed HACA or antigaliximab antibodies, no secondary
malignancies or lymphoproliferative disorders have been
reported, and there was no significant increase in infections
compared with rituximab monotherapy.
Galiximab monotherapy produced modest clinical activity
(11% ORR) . Combination therapy with rituximab
produced an ORR of 66% with a median PFS of
12.1 months. There appeared to be a trend for patients in
lower FLIPI risk groups and rituximab-naive patients to have
better clinical outcome as measured by ORR and PFS. Three
historical rituximab monotherapy studies using a standard
course of rituximab monotherapy in follicular NHL showed
an ORR of 58%, with a median PFS of 9.4 months [29–31].
A phase III, randomized, double-blind study comparing
galiximab in combination with rituximab with rituximab
and placebo for the treatment of relapsed and refractory,
follicular NHL has been initiated. In addition, accrual has
recently been completed in an investigator-sponsored Cancer
and Leukemia Group B study evaluating efficacy after
up-front galiximab plus rituximab therapy (weekly for
4 weeks) followed by extended dosing with rituximab and
galiximab (every 2 months times four) in previously
untreated follicular NHL patients.
Defining an optimal phase II dose with biologic therapy is
challenging. The maximum tolerated dose was not reached in
this study, and dose escalation with galiximab was feasible
up to 500 mg/m2. This dose was demonstrated to be safe and
active in the single-agent, phase 1 study, and we did not
observe additional efficacy or an increase in toxicity in the
combination study when the galiximab dose was escalated
from 375 to 500 mg/m2. Patients did not appear to be
underdosed, as evident by the PK profile. Therefore, the
500 mg/m2dose was considered to be a reasonable dose to
evaluate in phase II. However, we recognize that higher or
lower doses may also be effective. Additional studies are
planned to explore alternative dosing schedules. Potential
future directions also include evaluating maintenance therapy
with this combination regimen in follicular NHL and
galiximab, rituximab, plus chemotherapy for follicular and
diffuse aggressive NHL.
We would like to acknowledge Margaret Whiteley and the
Biogen Idec 114-21 study management team and the
investigational site coordinators. This study was supported
by Biogen Idec Inc. This work was presented in part at the
9th International Conference on Malignant Lymphoma
(June 2005) and the Annual Meeting of the American Society
of Hematology (December 2005). The following authors
have indicated a financial interest. JPL, JWF acted as
a consultant or advisor for Biogen Idec within the last
2 years. JPL, DF, LIG, and JM received honoraria from
Biogen Idec. LIG, TM, AF-T, and MC received research
funding from Biogen Idec. NC, BM, DF, and AM are
employees of Biogen Idec and own stock.
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