Evaluation of the safety and
immunogenicity of synthetic A?42
(AN1792) in patients with AD
A.J. Bayer, MB; R. Bullock, MA, MRCPsych; R.W. Jones, FRCP, FFPM; D. Wilkinson, FRCPsych;
K.R. Paterson, FRCP; L. Jenkins, PhD; S.B. Millais, BSc, PgDip (Tox); and S. Donoghue, PhD
Abstract—Background: A?42-immunization reduces plaque burden and improves cognition in transgenic mouse models
of Alzheimer disease (AD). This phase 1 study evaluated the safety, tolerability, and immunogenicity of AN1792 (human
aggregated A?42) in patients with mild to moderate AD. Methods: Twenty patients were enrolled into each of four dose
groups and randomly assigned to receive IM AN1792 (50 or 225 ?g) with QS-21 adjuvant (50 or 100 ?g) or QS-21 only
(control) in a 4:1 active:control ratio on day 0 and at weeks 4, 12, and 24. Patients could receive up to four additional
injections of a polysorbate 80 modified formulation at weeks 36, 48, 60, and 72. Safety, tolerability, immunogenicity, and
exploratory evidence of efficacy were evaluated. Results: Treatment-related adverse events were reported in 19 (23.8%)
patients, but no relationship was observed between AN1792 dose and incidence. One patient developed meningoencepha-
litis that was diagnosed after death (not directly related to study treatment) and 219 days after discontinuing from the
study. Five deaths occurred during the study follow-up, but none was considered to be directly related to study treatment.
During the period of the first four injections, 23.4% of AN1792-treated patients had a positive anti-AN1792 antibody titer
(an anti-AN1792 antibody titer of ?1:1,000). This increased to 58.8% after additional injections with the modified
formulation. Disability Assessment for Dementia scores showed less decline among active compared with control patients
at week 84 (p ? 0.002). No treatment differences were observed in three other efficacy measures. Conclusions: AN1792 ?
QS-21 elicited a positive antibody response to A?42 in more than half of this elderly study population.
Therapeutic options for treatment of Alzheimer dis-
ease (AD) have so far focused on modifying neuro-
transmitter systems, in particular the cholinergic
system, to maximize the remaining activity in af-
fected neuronal circuits.1,2However, these ap-
proaches are likely to treat only the symptoms of AD
without altering the underlying disease process or
slowing disease progression.
AD is characterized pathologically by the presence
of cerebral ?-amyloid (A?) plaques (with A?42 as the
major peptide constituent), neurofibrillary tangles,
and neuronal loss.3Furthermore, genetic linkage in-
dicates that mutations affecting A? production are
causative for some cases of AD.4-6The notion of A? as
an AD-causing factor has also been supported by
experiments showing fibrillary tangle formation af-
ter intracerebral microinjections of A? into P301L
mutant tau transgenic mice,7and an influence of
APP or A? on tangle formation in double mutant
tau/APP mice.8Accordingly, several strategies for re-
moving or reducing the pathologic amyloid burden in
AD are under investigation.3
Active immunization with human aggregated
A?42 (AN1792) effectively reduces cerebral A?
plaque burden in mice that express mutations impli-
cated in familial AD.9-11In young PDAPP mice, im-
almost entirely prevented the development of A?
plaques, neuritic dystrophy, and gliosis.9Further-
more, immunizing older PDAPP mice (with an exist-
ing extensive plaque burden) markedly reduced the
extent and progression of AD-like neuropathology.10
Additional material related to this article can be found on the Neurology
Web site. Go to www.neurology.org and scroll down the Table of Con-
tents for the January 11 issue to find the title link for this article.
See also pages 10 and 129
From the University Department of Geriatric Medicine (A.J. Bayer), University of Wales College of Medicine, Cardiff; Kingshill Clinical Research Unit (R.
Bullock), Victoria Hospital, Swindon; The Research Institute for the Care of the Elderly (Dr. Jones), St Martins Hospital, Bath; Thornhill Research Unit (Dr.
Wilkinson), Moorgreen Hospital, Southampton; Department of Clinical Pharmacology (Dr. Paterson), Royal Infirmary, Glasgow, UK; Clinical Biostatistics,
Wyeth Research (Dr. Jenkins), Collegeville, PA; and Clinical Development (S.B. Millais and Dr. Donoghue), Elan Pharma Limited, Stevenage, UK.
The study was sponsored by Elan Pharmaceuticals, Inc.
A.J. Bayer, R. Bullock, and Drs. Jones, Wilkinson, and Paterson have received grants or honoraria from Elan Pharmaceuticals, Inc. S.B. Millais and Dr.
Donoghue are full-time employees of Elan Pharma Limited, in which Dr. Donoghue also holds equity. Dr. Jenkins is a full-time employee of, holds equity in,
and has received honoraria from Wyeth Research.
Received December 3, 2003. Accepted in final form July 20, 2004.
Address correspondence and reprint requests to Dr. A. Bayer, University Department of Geriatric Medicine, Academic Centre, University of Wales College of
Medicine, Llandough Hospital, Penarth Road, Cardiff, South Glamorgan, CF64 2XX, UK; e-mail: firstname.lastname@example.org
Copyright © 2005 by AAN Enterprises, Inc.
Immunization also resulted in improvements in cog-
nitive performance, with12,13or without14a reduction
of cerebral amyloid deposits. These studies strongly
suggest A? immunization as a potential disease-
modifying therapeutic strategy for patients with AD.
Immunization of A? is the first immunotherapeu-
tic approach to AD to enter clinical studies. The aim
of the current study was to determine the safety,
tolerability, and immunogenicity of four dose combi-
nations of AN1792 ? QS-21 (adjuvant) vs QS-21
alone as a control, in patients with mild to moderate
AD, and to determine the optimal dosing regimen for
a larger phase 2a study. Clinical assessment mea-
sures were also included to explore the potential effi-
cacy of AN1792 ? QS-21, although the study was not
powered to detect differences in efficacy between
Patients and methods.
?85 years, lived with their caregivers, and met the criteria for a
diagnosis of probable AD as defined by the criteria of the National
Institute of Neurologic and Communicative Disorders and
Stroke–AD and Related Disorders Association.15Additional crite-
ria included a score of 14 to 26 on the Mini-Mental State Exami-
nation (MMSE),16a Rosen-Modified Hachinski Ischemic score ?4,
and written, informed consent at time of entry into the study. The
local independent ethics committee for each study site approved
the protocol, amendments, and informed consent forms before
study initiation. The study was conducted in accordance with the
International Conference on Harmonisation Tripartite Guideline
Eligible patients were aged
on Good Clinical Practice and in compliance with the Declaration
of Helsinki and subsequent revisions.17An independent Safety
Monitoring Committee assessed safety data throughout the study.
This was a multicenter, phase 1, randomized,
multiple-dose, dose escalation, double-blind study conducted at four
study sites in the United Kingdom and involved 80 patients with
mild to moderate AD. Twenty patients were enrolled in each of four
dose groups and randomly assigned in a double-blind manner to
receive treatment in a 4:1, active:control ratio (within each dose
group patients were randomly assigned in blocks of five using statis-
tical random number tables generated through the Clinical Trials
Materials Group at Elan). During the conduct of the study, the code
was not to be shared with the sponsor, the investigators, or study site
personnel (other than the study pharmacist who was unblinded to
treatment), unless specifically required for safety reasons. In each
dose group, treatment was administered as a 1 mL intradeltoid injec-
tion of QS-21 (immunogenic adjuvant, surface-active saponin, Aquila
Biopharmaceuticals, Inc.) alone or in combination with AN1792 at
weeks 0, 4, 12, and 24. The doses for each group were as follows:
Group A, AN1792 50 ?g ? QS-21 50 ?g or QS-21 50 ?g alone; Group
B, AN1792 50 ?g ? QS-21 100 ?g or QS-21 100 ?g alone; Group C,
AN1792 225 ?g ? QS-21 50 ?g or QS-21 50 ?g alone; Group D,
AN1792 225 ?g ? QS-21 100 ?g or QS-21 100 ?g alone. Study
assessments were performed at weeks 1, 2, 4, 6, 8, 12, 14, 16, 20, 24,
26, 28, 32, 39, 52, and 65 after the first immunization.
After an interim data review to assess tolerability and immu-
nogenicity, the study protocol was amended to add an optional
extension phase (up to a total of 84 weeks after the first injection)
that permitted patients to receive additional study injections at
weeks 36, 48, 60, and 72. In the extension phase, the formulation
of active and control immunizations was modified by the addition
of 0.4% polysorbate 80 (PS-80) to improve product stability. Pa-
tients from Groups B, C, and D could receive up to four additional
injections, and patients from Group A could receive up to three
additional injections (because of the timing of the amended proto-
Figure 1. Flow chart of study patients. Early withdrawals from the study and the reasons for withdrawal are listed. †A
maximum of three injections was allowed in the extension phase because of the timing of the protocol amendment; ††pa-
tients did not receive injection 8 due to the sponsor’s decision to halt further dosing of AN1792. ‡One patient died from
carcinoma of the lung after completing treatment according to the original protocol. *One patient died from pulmonary
embolism after withdrawing from the study; **both patients died (cerebrovascular accident, chest infection) after with-
drawing from the study.
January (1 of 2) 2005
col). The study schedule was amended so that assessment visits
after week 32 took place at weeks 36, 38, 40, 44, 48, 50, 52, 56, 60,
62, 64, 68, 72, 74, 76, 80, and 84. In some patients, week 64 visits
actually occurred during week 65.
The primary outcome measures were
safety and tolerability, which were monitored throughout the trial
by adverse event (AE) reporting, physical and neurologic examina-
tions, vital signs, and routine laboratory evaluations (biochemical
and hematologic tests and urinalyses). The secondary outcome
measure was the immunogenicity of the four dose combinations as
assessed by ELISA analysis of serum samples. The ELISA was
able to detect immunoglobulins (Ig) of the IgG, IgM, and IgA
classes against AN1792 and had a lower limit of detection of a
titer of 1:100 ELISA units. Based on preclinical studies, a positive
response was defined as an anti-AN1792 antibody titer ?1:1,000.
Anti-AN1792 antibody responders were defined as patients with
an antibody titer ?1:1,000 at 4 weeks after an injection or a titer
?1:5,000 at any time point after an injection.
Exploratory evaluations of efficacy were assessed using four
scales: two cognitive scales, the AD Assessment Scale–Cognitive
Subscale (ADAS-Cog; score range 0 to 70, higher score indicates
greater impairment),18and the MMSE (score range 0 to 30, lower
score indicates greater impairment)16; a global rating scale, the
AD Cooperative Study–Clinical Global Impression of Change
(ADCS-CGIC; 7-point scale rating an independent investigator’s
assessment of change from baseline, higher score indicates greater
impairment)19; and a functional disability scale, the Disability As-
sessment for Dementia (DAD).20The total DAD score is the sum of
28 items expressed as a percentage of all items answered; it con-
tains items related to basic self-care and instrumental activities of
daily living and can range from 0 to 100%, with lower scores
indicating greater impairment.
As this trial was designed to explore the
safety of AN1792 ? QS-21, 16 control and 64 treated patients
were deemed adequate to demonstrate initial safety. No formal
power calculations were made with respect to the ability to detect
significant treatment differences on any efficacy measures. Pa-
tients in Groups A, B, C, and D were combined into a single active
group and a single control group for safety and exploratory effi-
All efficacy variables were analyzed at day 0, week 32, week 64
(data for patients with week 65 visits were combined with week 64
data for analyses), and week 84. Analyses were also conducted at
a final visit time point, which consists of data from each patient’s
last observation carried forward (LOCF; only post-baseline values
were carried forward). Exploratory efficacy was evaluated in the
intent-to-treat (ITT) population (all patients who had at least one
baseline efficacy evaluation and at least one postinjection efficacy
evaluation; patients who had no post-baseline efficacy evaluations
were excluded from the ITT population).
ADAS-Cog, MMSE, and DAD data were analyzed using analy-
sis of covariance (ANCOVA) with baseline as the covariate and
treatment and center as main effects. ADCS-CGIC data were an-
alyzed using analysis of variance (ANOVA) with treatment and
center as main effects. In addition, the Cochran-Mantel-Haenszel
test using equally spaced scores for the ordered levels of the re-
sponse variable was used to evaluate the effect of treatment on
study and received study treatment: 64 received AN1792 ?
QS-21, 16 received QS-21 alone (figure 1). A total of 64
patients entered the protocol extension phase (51 patients
from the active treatment group and 13 from the control
group), during which up to a further four injections of the
PS-80 modified formulation were administered. Study en-
rollment began in April 2000 and the final observations
were made in June 2002. Patient demographics, baseline
characteristics, and concomitant medications are summa-
rized in table 1.
Exposure and concomitant medications.
tients received at least two injections of study treatment
and 91.3% received all four injections scheduled in the
original protocol. Of the 64 patients who entered the proto-
col extension phase, 89.1% received seven injections and
51.6% received all eight injections. For these injections,
Eighty patients were enrolled in the
All 80 pa-
Table 1 Patient demographics, baseline characteristics, and concomitant medications
QS-21 AN1792 ? (QS-21)
n ? 8
n ? 8
50 ?g ?
n ? 16
50 ?g ?
n ? 16
225 ?g ?
n ? 16
225 ?g ?
n ? 16
Mean age (SD), y70.3 (10.5)72.5 (8) 74.3 (6.6)74.1 (5.6)72.3 (6.7) 71.7 (8.2)
Mean weight (SD), kg 73.6 (11.2)68.1 (12.6)73 (9.6)66.6 (13.3)73 (15)70.7 (13.6)
White (%) 8 (100)8 (100)16 (100)16 (100)16 (100)16 (100)
Mean duration of AD (SD), y 4.4 (2) 3 (1.2)3.7 (2.6) 4.3 (2.1)4.1 (2.3) 3.8 (1.9)
Family history of AD (%) 4 (50) 2 (25)6 (37.5) 6 (37.5)8 (50)7 (43.8)
Mean MMSE scores (SD)20.5 (4.9)19.0 (3.7)20.6 (3.8)21.9 (2.6)20.8 (3.2)20.4 (3.8)
Mean Rosen-modified Hachinski
Ischemic total score (SD)
0.4 (0.7)0.3 (0.7) 0.3 (0.5)0.4 (0.6) 0.9 (1.5)1.2 (1.2)
Concomitant medications (%)
Donepezil hydrochloride*8 (100)4 (50)11 (68.8) 14 (87.5) 9 (64.3) 14 (87.5)
Galantamine01 (12.5)01 (6.3)1 (6.3) 0
Rivastigmine tartrate†0 1 (12.5)1 (6.3)2 (12.5)00
Ginkgo biloba1 (12.5)3 (37.5)2 (12.5)2 (12.5)3 (18.8)1 (6.3)
Vitamin E2 (25)1 (12.5)2 (12.5)1 (6.3)4 (25)1 (6.3)
* Also includes patients reported as receiving donepezil: some patients may be counted twice.
† Also includes patients reported as receiving rivastigmine: some patients may be counted twice.
AD ? Alzheimer disease; MMSE ? Mini-Mental State Examination.
January (1 of 2) 2005
0.4% PS-80 was added to the AN1792 formulation to im-
prove stability. The 13 patients in Group A who entered
the protocol extension phase could only receive up to seven
injections (at weeks 0, 4, 12, 24, 48, 60, and 72) due to the
timing of the protocol amendment. Patients in Group D
could also only receive up to seven injections because of the
sponsor’s decision to suspend further treatment with
AN1792 following the reporting of encephalitis in several
patients in an ongoing phase 2a study of AN1792. Details
of these cases have been published.21
The most frequently used concomitant medications in-
cluded donepezil hydrochloride (75% of patients in the ac-
tive group and 75.1% in the control group), influenza
vaccine (50% and 31.5%), aspirin (39.1% and 43.8%), and
paracetamol (acetaminophen) (23.4% and 50%).
Safety and tolerability results.
reported in 97.5% of patients during the study period (ta-
ble 2 and table E-1 on the Neurology Web site). The most
frequently reported AEs were accidental injury (38.8%),
infection (31.3%), and confusion (31.3%); these events were
reported at a similar frequency in the active and control
groups (see table 2). In the majority of patients, the maxi-
mum intensity of AEs was either mild (active: 21.9% and
control: 25%) or moderate (54.7% and 56.3%).
AEs that were considered treatment related by the in-
vestigators were reported in 28.1% of patients who re-
ceived active treatment, compared with 6.3% of patients in
the control group (table E-2 on the Neurology Web site);
the majority were mild in intensity. The most frequently
reported treatment-related AE in patients receiving active
treatment was injection site pain (15.6%; see table E-2). No
relationship was observed between the AN1792 dose and
the incidence of treatment-related AEs.
Five (6.3%) patients (mean age 74 years) died during
the study period; these deaths were due to arterial anom-
aly, pulmonary embolus, cerebrovascular accident, infec-
tion (all in the active treatment group), and carcinoma of
the lung (control group). No deaths were considered to be
directly related to study treatment. Non-fatal serious AEs
(SAEs) were reported in 22 (27.5%) patients (26 events in
the active group and 9 in control patients) during the
study (see table E-1). Four patients had non-fatal SAEs
that were considered related to study treatment; these
events were rash, confusion and syncope, encephalitis, and
worsening of dementia. The encephalitis case was diag-
nosed histologically after the patient’s family consented to
an autopsy; the results have been previously reported.22
This patient had experienced dizziness and disorientation,
and showed signs of functional deterioration on day 288,
approximately 36 days after study injection 5 (the first
dose of the altered formulation of AN1792 50 ?g ? QS-21
100 ?g with 0.4% PS-80). These symptoms were initially
attributed to a primary CNS neoplasm, and the patient
was treated with dexamethasone. As a consequence of
these symptoms, she was withdrawn from the study on
day 380. The patient subsequently died from a pulmonary
embolism secondary to deep vein thrombosis 347 days af-
ter administration of the last study injection (injection 5)
and 219 days after her withdrawal from the study. At the
postmortem examination, there were no signs of a CNS
T-lymphocyte meningoencephalitis were present.22
A total of 10 patients (9 active [14.1%] and 1 control
Adverse events.AEs were
[6.3%]) prematurely withdrew from the study due to AEs
(see table E-1). The AEs resulting in discontinuation were
hostility (4 patients), depression (2 patients), hallucina-
tions (2 patients), accidental injury (2 patients), and infec-
tion (2 patients); some patients reported more than one
AE. Treatment-related AEs (hostility, n ? 3; hallucina-
tions, n ? 1) led to discontinuation in four patients (3
active [4.7%] and 1 control [6.3%]).
No apparent dose-related trends were observed in the
clinical laboratory measures studied. A total of 20 (25%)
patients developed one or more clinically important abnor-
mal laboratory values (table 3); these were reported more
Table 2 Summary of treatment-emergent adverse events reported
by ?10% patients overall during treatment with AN1792 ? QS-
21 or QS-21 alone
n ? 80
n ? 64
n ? 16
Body as a whole65 (81.3)51 (79.7)14 (87.5)
Accidental injury31 (38.8) 25 (39.1)6 (37.5)
Back pain 9 (11.3)8 (12.5) 1 (6.3)
Headache 10 (12.5)7 (10.9) 3 (18.8)
Infection25 (31.3) 20 (31.3) 5 (31.3)
Injection site pain 10 (12.5)10 (15.6)0
Malaise10 (12.5) 8 (12.5) 2 (12.5)
Pain14 (17.5)10 (15.6) 4 (25)
Cardiovascular 34 (42.5) 26 (40.6)8 (50)
Hypertension11 (13.8) 6 (9.4)5 (31.3)
Digestive system 32 (40)28 (43.8) 4 (25)
Hematologic and lymphatic 16 (20)13 (20.3) 3 (18.3)
Ecchymosis 9 (11.3)7 (10.9) 2 (12.5)
Metabolic and nutritional 20 (25)14 (21.9) 6 (37.5)
Peripheral edema10 (12.5) 7 (10.9)3 (18.8)
Musculoskeletal18 (22.5) 13 (20.3)5 (31.3)
Arthralgia9 (11.3) 6 (9.4)3 (18.8)
Nervous system 54 (67.5)43 (67.2)11 (68.8)
Agitation 13 (16.3)11 (17.2) 2 (12.5)
Confusion 25 (31.3)20 (31.3) 5 (31.3)
Depression11 (13.8)11 (17.2)0
Dizziness 12 (15)8 (12.5) 4 (25)
Hallucinations10 (12.5) 8 (12.5)2 (12.5)
Hostility 13 (16.3) 9 (14.1) 4 (25)
Respiratory system 32 (40)25 (39.1) 7 (43.8)
Cough increased 15 (18.8)11 (17.2) 4 (25)
Pharyngitis14 (17.5)9 (14.1) 5 (31.3)
Skin and appendages 18 (22.5) 16 (25)2 (12.5)
Rash11 (13.8)9 (14.1) 2 (12.5)
Special senses14 (17.5) 12 (18.8)2 (12.5)
Urogenital25 (31.3)21 (32.8) 4 (25)
Urinary tract infection14 (17.5) 12 (18.8)2 (12.5)
Any adverse event78 (97.5) 62 (96.9)16 (100)
Values are n (%).
January (1 of 2) 2005
frequently in AN1792-treated patients than in control pa-
tients. However, only one of these abnormalities (a moder-
ate event of increased alkaline phosphatase that was
reported in a patient receiving QS-21 100 ?g alone) was
considered to be treatment related by the investigator.
Mean decreases in blood pressure, especially systolic
pressure, were observed immediately following each injec-
tion in the active treatment group. The greatest decreases
were typically observed 60 minutes after an injection, with
mean systolic blood pressure changes after an injection of
?1.2 mm Hg at week 0, ?6.8 mm Hg at week 24, and ?8.8
mm Hg at week 72 among patients receiving active treat-
ment. Changes in blood pressure after control injections
were ?2.9 mm Hg at week 0, ?2.4 mm Hg at week 24, and
?3.0 mm Hg at week 72.
Control patients had anti-
AN1792 antibody titers that were below the lower limit of
detection (?1:100) at nearly all time points. No control
patients developed a positive anti-AN1792 antibody titer
(?1:1,000) at any time during the study. Among study
patients who received active treatment (n ? 64), no posi-
tive anti-AN1792 antibody titers were reported within 2
weeks after injection 1. After injection 2, one positive anti-
body titer (in the AN1792 225 ?g ? QS21 50 ?g dose
group) was reported. More positive anti-AN1792 antibody
titers became evident after injections 3 and 4 (see table 3,
supplementary figure E-1). A notable increase in the pro-
portion of patients with positive anti-AN1792 antibody ti-
ters was observed after injection 5 for all dose groups
except AN1792 50 ?g ? QS-21 50 ?g. Patients in this
latter dose group did not receive injection 5 because of the
timing of the amended protocol. Of all patients who re-
ceived AN1792 (n ? 64), 53.1% had a positive anti-AN1792
antibody titer at some point during the study. Of those
who entered the protocol extension (n ? 51), 58.8% of
patients had a positive antibody response and 56.9% were
considered anti-AN1792 antibody responders at some point
during the study (see table 3). Of the 13 AN1792-treated
patients who did not enter the protocol extension, 15.4%
were considered anti-AN1792 antibody responders.
Measures of efficacy—exploratory results.
scores showed similar increases in the active and control
groups during the study (figure 2A, table E-3 on the Neu-
rology Web site), indicating a decline in cognition. No sig-
nificant treatment effects were observed at any visit.
Similarly, no significant treatment effects on MMSE were
observed at any visit, as MMSE scores showed declines
from baseline in both active and control groups during the
study period (figure 2B, see table E-3).
Reductions in DAD scores (worsening functional ability)
were observed throughout the study (figure 2C, see table
E-3). At week 64, patients in the active treatment group
showed marginally less decline than control patients (ad-
justed mean values ?11.68 vs ?22.23, p ? 0.077). The
difference between treatment groups was significant at
week 84 (?14.15 vs ?36.42, p ? 0.002) and at the final
visit (?12.64 vs ?34.13, p ? 0.001).
Figure 2D displays the frequency distribution of ADCS-
CGIC scores by treatment at week 84; observed mean rat-
ings (SD) for active and control groups were 5.36 (1.19) in
the active group and 5.31 (1.32) in the control group (see
table E-3). No significant treatment differences on the
ADCS-CGIC were observed at any visit.
course of this study to preclude the initiation of a
larger phase 2a trial; however, one patient died ap-
proximately 1 year after her last injection; although
the death was not directly attributable to study
treatment, the patient was found to have evidence of
encephalitis at autopsy.
Positive anti-AN1792 antibody titers were re-
ported in patients treated with AN1792 ? QS-21,
but not with QS-21 alone. There appeared to be a
correlation between dose and positive anti-AN1792
antibody titer, as a greater proportion of patients
who were treated with the higher dose of AN1792
(225 ?g) had a positive anti-AN1792 antibody titer at
some point during the study than patients treated
No safety concerns arose during the
Table 3 Summary of anti-AN1792 antibody responders among the population of patients who entered the protocol extension
AN1792 ? (QS-21)
50 ?g ? (50 ?g),
n ? 10
50 ?g ? (100
?g), n ? 15
225 ?g ? (50
?g), n ? 15
225 ?g ? (100
?g), n ? 11Total, n ? 51
200 1 (6.7)0 1 (2)
3 2 (20)2 (13.3) 4 (26.7)0 8 (15.7)
4 2 (20) 2 (13.3)5 (33.3) 2 (18.2)11 (21.6)
5 0*5 (33.3) 8 (53.3)3 (27.3)16 (31.4)
6 2 (20)5 (33.3)9 (60) 4 (36.4)20 (39.2)
7 2 (20) 6 (40) 10 (66.7)6 (54.5) 24 (47.1)
8 2 (20)7 (46.7) 9 (60) 5 (45.5)†23 (45.1)
Overall 2 (20)7 (46.7)13 (86.7)7 (63.6)29 (56.9)
* Injection 5 not given; † Injection 8 not given.
Patients were considered responders if they had an antibody titer of ?1:1,000 at 4 weeks after an injection or a titer of ?1:5,000 at any
time point after an injection.
January (1 of 2) 2005
with AN1792 50 ?g (77% vs 40%). The increase in
the number of anti-AN1792 antibody responders af-
ter injection 5 may reflect the increased cumulative
exposure to the antigen or enhanced immunogenicity
associated with the addition of PS-80 to the formula-
tion. As AN1792 225 ?g ? QS-21 50 ?g resulted in
the highest percentage of anti-AN1792 antibody re-
sponders of the four doses tested, this dose was se-
(manuscript in preparation).
Although active treatment induced an immuno-
genic response in approximately one-half of patients,
it is apparent that a considerable proportion of el-
derly individuals did not mount an immune response
to the current formulation. Accordingly, it may be
necessary to modify the adjuvant or other aspects of
the formulation to achieve a higher response rate
and thus a more useful therapeutic entity. Given the
acknowledged difficulties of stimulating an immune
response in elderly individuals, the use of passive
immunization may be an attractive alternative ap-
proach to AD immunotherapy.
The overall incidence of AEs occurring during the
study was similar between active and control treat-
ment groups. However, the incidence of treatment-
related AEs was higher in patients who received
active treatment, although most AEs were mild or
moderate in intensity. The incidence of severe
treatment-related AEs and treatment-related SAEs
was similar between active and control groups.
As an ad hoc evaluation, we also summarized AEs
according to anti-AN1792 antibody titers. Several
AEs occurred in patients who had a positive anti-
AN1792 antibody titer with twice the incidence rate
than in patients with a negative anti-AN1792 anti-
body titer. These events (including rash, asthenia,
Figure 2. Summary of changes in efficacy measures for patients who received AN1792 ? QS-21 or QS-21 alone. (A) Alz-
heimer Disease Assessment Scale–Cognitive Subscale (ADAS-Cog); (B) Mini-Mental State Examination (MMSE); (C) Dis-
ability Assessment for Dementia (DAD); (D) frequency distribution of AD Cooperative Study–Clinical Global Impression
of Change (ADCS-CGIC) scores at week 84. Data presented are adjusted mean changes (? standard error of the adjusted
mean change) from baseline; ADAS-Cog, MMSE, and DAD scores were evaluated by analysis of covariance, ADCS-CGIC
scores were evaluated by analysis of variance. For patients with week 65 visits, data were combined with those of patients
with week 64 visits for ADAS-Cog, MMSE, and DAD. **p ? 0.002 and ***p ? 0.001 vs QS-21 alone; all other compari-
sons were not significant at the 0.05 level.
January (1 of 2) 2005
tremor, abnormal gait, flu syndrome, infection, injec-
tion site pain and inflammation, pain, and periph-
eral edema) primarily affected the nervous system
and the body as a whole. Conversely, the following
AEs occurred in patients who had a negative anti-
AN1792 antibody titer with twice the incidence than
in patients with a positive anti-AN1792 antibody ti-
ter: headache, dyspepsia, fecal incontinence, ecchy-
mosis, hostility, insomnia, prostatic disorder, breast
neoplasm, and hematuria. Some of these events may
have been associated with the progression of AD;
others might be expected when following an elderly
population for ?18 months.
No relationship was observed between AN1792
dose and the number of patients who reported
treatment-related AEs. However, several SAEs, in-
cluding confusion, convulsion, and encephalitis (di-
agnosed after death), were considered to be possibly
related to treatment with AN1792. Some of these
AEs led to premature discontinuation from the
study: one patient receiving active treatment with-
drew because of confusion and hallucinations and
three patients (two in the active treatment group
and one in the control group) withdrew because of
hostility. In addition, three patients who received
active treatment had convulsions during the study;
two of these cases were severe. Five patients (mean
age 74 years) died during the study follow-up, but no
deaths were considered to be directly related to
study treatment. One of these cases was the patient
who died on day 599 after a pulmonary embolism,
and was found at autopsy to have evidence of a me-
ningoencephalitic reaction.22The patient died 347
days after administration of the last (fifth) injection
of study treatment and 219 days after leaving the
study. The death occurred a few weeks after cases of
encephalitis21resulted in the sponsor halting dose
administration in a phase 2a study of AN1792. In
this latter study, all patients who had encephalitis
had received the AN1792 ? QS-21 formulation con-
taining PS-80. Studies are presently underway to
understand the etiology of encephalitis in relation to
AN1792 ? QS-21 and to develop alternative immu-
notherapeutic approaches for AD.
The autopsy report of the patient who died after
participating in the current study indicated that
there were extensive areas of neocortex with very
few A? plaques in relation to the density of tangles
and neuropil threads, and in some of these areas,
A?-immunoreactivity was associated with micro-
glia.22These findings resemble the changes seen af-
ter A? immunotherapy in mouse models of AD10-13,23
and suggest that the immune response generated
against AN1792 may have elicited the clearance of
A? plaques in this patient.
This phase 1b study was not powered to demon-
strate differences between groups on any of the clin-
exploratory measures of efficacy showed no signifi-
cant differences among treatment groups during the
study period, but interestingly, the decline from
Indeed,three of the
baseline in DAD scores (caregiver assessment) ap-
peared slower among patients receiving AN1792 ?
QS-21 compared with those in the control group.
These differences emerged approximately 18 months
after the study began; however, data from only a
small number (n ? 12) of control patients were avail-
able for analysis at this timepoint. Further studies in
larger cohorts of patients are needed to determine
the efficacy of AN1792 ? QS-21.
The authors thank the patients, families, and carers of those who
participated. They also thank Helen Cartwright, Carol Hall, Dr.
Venkatesh, Dr. Jill Mann, Catriona Rainsford, Jo Waring, and Viv
Hopkins for their help and Dr. Edgar Fenzl (Elan Pharma Lim-
ited, Stevenage, UK) for assistance with the study and review of
(Macclesfield, UK) assisted in the development of the manuscript:
Mary Gaskarth made substantial contributions to the analysis
and interpretation of data and the drafting of the article; Delyth
Clemett made substantial contributions to the analysis and inter-
pretation of data, revision of the article for important intellectual
content, and assisted with the final approval of the version to be
1. Francis PT, Palmer AM, Snape M, et al. The cholinergic hypothesis of
Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychia-
2. O’Brien JT, Ballard CG. Drugs for Alzheimer’s disease. BMJ 2001;323:
3. Selkoe DJ, Schenk D. Alzheimer’s disease: molecular understanding
predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol
4. Citron M, Oltersdorf T, Haass C, et al. Mutation of the beta-amyloid
precursor protein in familial Alzheimer’s disease increases beta-protein
production. Nature 1992;360:672–674.
5. Hardy J, Duff K, Hardy KG, et al. Genetic dissection of Alzheimer’s
disease and related dementias: amyloid and its relationship to tau. Nat
6. Suzuki N, Cheung TT, Cai XD, et al. An increased percentage of long
amyloid beta protein secreted by familial amyloid beta protein precur-
sor (beta APP717) mutants. Science 1994;264:1336–1340.
7. Gotz J, Chen F, van Dorpe J, et al. Formation of neurofibrillary tangles
in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 2001;
8. Lewis J, Dickson DW, Lin WL, et al. Enhanced neurofibrillary degener-
ation in transgenic mice expressing mutant tau and APP. Science 2001;
9. Games D, Bard F, Grajeda H, et al. Prevention and reduction of AD-
type pathology in PDAPP mice immunized with A beta 1–42. Ann NY
Acad Sci 2000;920:274–284.
10. Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-?
attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Na-
ture 1999;400:173–177. Letter.
11. Sigurdsson EM, Scholtzova H, Mehta PD, et al. Immunization with a
nontoxic/nonfibrillar amyloid-? homologous peptide reduces Alzhei-
mer’s disease-associated pathology in transgenic mice. Am J Pathol
12. Janus C, Pearson J, McLaurin J, et al. A? peptide immunization re-
duces behavioural impairment and plaques in a model of Alzheimer’s
disease. Nature 2000;408:979–982. Letter.
13. Morgan D, Diamond DM, Gottschall PE, et al. A? peptide vaccination
prevents memory loss in an animal model of Alzheimer’s disease. Na-
ture 2000;408:982–985. Letter.
14. Dodart JC, Bales KR, Gannon KS, et al. Immunization reverses mem-
ory deficits without reducing brain A? burden in Alzheimer’s disease
model. Nat Neurosci 2002;5:452–457.
15. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alz-
heimer’s disease: report of the NINCDS-ADRDA Work Group under the
auspices of Department of Health and Human Services Task Force on
Alzheimer’s Disease. Neurology 1984;34:939–944.
16. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state:” a practical
method for grading the cognitive state of patients for the clinician.
J Psychiatr Res 1975;12:189–198.
17. World Medical Association. World Medical Association Declaration of
Helsinki. 2002. Available at: http://www.wma.net/e/policy/b3.htm#
paragraphe29. Accessed March 03, 2004.
January (1 of 2) 2005
18. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s Download full-text
disease. Am J Psychiatry 1984;141:1356–1364.
19. Schneider LS, Olin JT, Doody RS, et al. Validity and reliability of the
Alzheimer’s Disease Cooperative Study–Clinical Global Impression of
Change. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis
Assoc Disord 1997;11 suppl 2:S22–S32.
20. Gauthier S, Gelinas I, Gauthier L. Functional disability in Alzheimer’s
disease. Int Psychogeriatr 1997;9 suppl 1:163–165.
21. Orgogozo J-M, Gilman S, Dartigues J-F, et al. Subacute meningoen-
cephalitis in a subset of patients with AD after A?42 immunization.
22. Nicoll JAR, Wilkinson D, Holmes C, et al. Neuropathology of human
Alzheimer disease after immunization with amyloid-? peptide: a case
report. Nat Med 2003;9:448–452.
23. Bard F, Cannon C, Barbour R, et al. Peripherally administered antibod-
ies against amyloid ?-peptide enter the central nervous system and
reduce pathology in a mouse model of Alzheimer disease. Nat Med
ALERT: NEUROLOGY NOW USING ONLINE PEER REVIEW AND
MANUSCRIPT SUBMISSION SYSTEM
Neurology is now using an online peer review and manuscript submission system called Bench?Press.
Authors should upload all original submissions via the Neurology website (www.submit.neurology.org). The
Instructions to Authors detail the submission process and adjusted specifications.
January (1 of 2) 2005