U.S. patent application number 14/085048 was filed with the patent office on 2014-03-20 for composition comprising vlp and amyloid beta peptide.
This patent application is currently assigned to NOVARTIS AG. The applicant listed for this patent is Thomas BLATTLER, Ana GRAF, Paolo PAGANETTI, Matthias STAUFENBIEL. Invention is credited to Thomas BLATTLER, Ana GRAF, Paolo PAGANETTI, Matthias STAUFENBIEL.
Application Number | 20140079730 14/085048 |
Document ID | / |
Family ID | 33523293 |
Filed Date | 2014-03-20 |
United States Patent
Application |
20140079730 |
Kind Code |
A1 |
GRAF; Ana ; et al. |
March 20, 2014 |
COMPOSITION COMPRISING VLP AND AMYLOID BETA PEPTIDE
Abstract
The present invention relates to novel uses of a construct
consisting of virus-like particle (VLP) structure chemically
coupled to a fragment of the A.quadrature.-1-42 peptide and its
pharmaceutically acceptable salts (hereinafter CONSTRUCT), in
particular to dosage regimens, modes of and dosage forms for the
administration of a CONSTRUCT for the treatment of patients
suffering from dementia. in particular dementia of the A
Inventors: |
GRAF; Ana; (Riehen, CH)
; STAUFENBIEL; Matthias; (Lorrach, DE) ; BLATTLER;
Thomas; (Bockten, CH) ; PAGANETTI; Paolo;
(Basel, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRAF; Ana
STAUFENBIEL; Matthias
BLATTLER; Thomas
PAGANETTI; Paolo |
Riehen
Lorrach
Bockten
Basel |
|
CH
DE
CH
CH |
|
|
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
33523293 |
Appl. No.: |
14/085048 |
Filed: |
November 20, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13892552 |
May 13, 2013 |
8617566 |
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14085048 |
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12971534 |
Dec 17, 2010 |
8460676 |
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13892552 |
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Current U.S.
Class: |
424/196.11 |
Current CPC
Class: |
A61P 25/28 20180101;
A61K 2039/6075 20130101; A61K 39/0007 20130101; A61K 38/22
20130101; A61K 47/6901 20170801; A61K 45/06 20130101; A61K 39/385
20130101; A61P 25/16 20180101; A61K 38/162 20130101; A61K 9/0019
20130101; A61K 2039/5258 20130101; A61P 25/00 20180101 |
Class at
Publication: |
424/196.11 |
International
Class: |
A61K 39/385 20060101
A61K039/385; A61K 45/06 20060101 A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 5, 2004 |
GB |
0424563.5 |
Claims
1. A combination for reducing the severity or delaying onset of
dementia in human patients according to the method of claim 1,
comprising: between 5 to 1000 .mu.g of a construct consisting of a
virus like particle structure chemically coupled to a fragment of
the A.beta.-1-42 peptide or its pharmaceutically acceptable salts
and, at least one agent selected from the list of nootropic agent,
antidepressants, antipsychotics, antioxydative treatments, vitamin
E, lipid-lowering agents, hormone substitution, amyloid lowering
agents, aggregation inhibitors, chelators, immunomodulatory
agents.
2. A combination according to claim 1 wherein: (i) the nootropic
agent is selected from nootropic plant extracts, calcium
antagonists, cholinesterase inhibitors, dihydroergotoxin,
nicergoline, piracetame, purine derivatives, pyritinol, vincamine,
vinpocentine and memantine; (ii) the antidepressant is selected
from SSRIs, SNRIs, NRIs; (iii) the antipsychotic is risperidone;
(iv) the antioxydative treatments is selegiline; (v) the
lipid-lowering agents is a statins; (vi) the hormone substituent is
estrogen; (vii) the amyloid lowering agent is an abeta secretase
inhibitors; (viii) the aggregation inhibitor is a beta-sheet
blocker; or (ix) the immunomodulatory agent is glatiramer
acetate.
3. A commercial package comprising a combination according to claim
1, and further comprising instructions for simultaneous, separate
or sequential use thereof in the treatment of dementia.
Description
[0001] The present invention relates to novel uses of a construct
consisting of virus-like particle (VLP) structure chemically
coupled to a fragment of the A.beta.-1-42 peptide and its
pharmaceutically acceptable salts (hereinafter CONSTRUCT), in
particular to dosage regimens, modes of and dosage forms for the
administration of a CONSTRUCT for the treatment of patients
suffering from dementia, in particular dementia of the Alzheimer's
type, especially mild to moderate or severe Alzheimer's Disease
(AD), and vascular dementia with amyloid angiopathy to a method of
isolating immune cells, especially antibody producing cells, and
antibodies as well as there genes or fragments thereof generated by
the immune system of a warm-blooded animal, especially a human, in
response to the administration of the CONSTRUCT, the production of
such antibodies and the pharmaceutical use of such antibodies.
[0002] The present invention relates to novel uses of a construct
consisting of virus-like particle (VLP) structure chemically
coupled to a fragment of the A.beta.-1-42 peptide and its
pharmaceutically acceptable salts (hereinafter CONSTRUCT), in
particular to dosage regimens, modes of and dosage forms for the
administration of a CONSTRUCT for the treatment of patients with
increased Are-level , including but not limited to patients with
dementia associated with Parkinson's disease, Lewy Body
dementia.
[0003] The present invention also relates to novel uses of a
construct consisting of virus-like particle (VLP) structure
chemically coupled to a fragment of the A.beta.-1-42 peptide and
its pharmaceutically acceptable salts (hereinafter CONSTRUCT), in
particular to dosage regimens, modes of and dosage forms for the
administration of a CONSTRUCT for the prophylactic treatment of
subjects at risk of developing AD, including but not limited to
subjects with mild cognitive impairment , subjects with genotypes
known to be associated with AD, such as ApoE4, subjects with
Trisomy 21 and subjects with surrogate markers indicating risk for
AD.
[0004] Considerable evidence has been accumulated suggesting that
the .beta.-amyloid peptide--the major component of senile amyloid
plaques--plays a causal role in AD. Successful disease-modifying
therapy for AD is likely to include products that affect the
deposition of .beta.-amyloid in the brain. A.beta.-specific
antibodies, actively generated by the immune system or passively
administered, consistently reduce plaque burden in different
transgenic mouse models for A.beta.-amyloidosis. A first clinical
attempt to stimulate the immune system of AD patients to generate
A.beta.-antibody, however, had to be suspended due to unacceptable
side effects (meningoencephalitis in 6% of treated patients,
Orgogozo J M, Gilman 5, Dartigues J F, Laurent B, Puel M, Kirby L
C, Jouanny P, Dubois B, Eisner L, Flitman 5, Michel B F, Boada M,
Frank F, Hock C (2003)] Subacute meningoencephalitis in a subset of
patients with AD after A.beta.42 immunization, Neurology; 61:
46-54.).
[0005] Surprisingly, lesser adverse immune reactions and a lesser
incidence of microhemorrhages are observed with the CONSTRUCTS
disclosed herein. In particular, no adverse immune reaction nor
increased incidence of microhemorrhages, is observed with
CONSTRUCTS consisting of a VIP chemically coupled to the
A.beta.-1-6 peptide.
[0006] In a first aspect of the present invention, it was
surprisingly found that the CONSTRUCT advantageously can be applied
subcutaneously to warm-blooded animals, especially humans,
suffering from dementia.
[0007] In another aspect of the present invention, it was
surprisingly found that the CONSTRUCT advantageously can be applied
intramuscularly, intranasally and orally to warm-blooded animals,
especially humans, suffering from dementia.
[0008] In a second aspect, the present invention provides a dosage
form for subcutaneous administration of the CONSTRUCT. The
preferred dosage form for subcutaneous administration of the
CONSTRUCT is an aqueous solution containing Phosphate Buffer Saline
(PBS), between 0.25 and 0.75 mg/mL CONSTRUCT, preferably between
0.4 and 0.6 mg/mL, e.g. 0.5 mg/mL CONSTRUCT, and no further
excipients. The dosage form can be kept frozen until shortly before
usage. The dosage form is administered preferably by subcutaneous
injection with a syringe to the warm-blooded animal, especially
into the abdomen. For thawing of the dosage form, the dosage form
can be kept at ambient temperature for about between 15 minutes and
45 minutes, e.g. 30 minutes. Preferably, before withdrawing drug
substance, the vials are gently inverted several times for
dispersion of potential sub-visual particles.
[0009] The CONSTRUCTS as employed in the present invention are
known as such. For example, WO 00/3227 to Cytos discloses a
technology for providing a construct comprising a core-particle
such as a VLP), a linker and an antigen, all together forming an
ordered and repetitive antigen array. WO 02/056907 to Cytos and
Novartis describes constructs comprising a VLP comprising
recombinant proteins of a bacteriophage, such as Q.beta., a linker
and an antigen, e.g. A.beta.1-42 or a fragment thereof, all
together forming an ordered and repetitive antigen array.
Preferably, a CONSTRUCT as used herein consists of capsid proteins
of a RNA bacteriophage, more preferably of capsid proteins of the
RNA bacterio-phage Q.beta., self-assembled into a highly ordered
VLP structure chemically coupled with a bivalent linker to a
fragment of the A.beta.1-42 peptide, more preferably to
A.beta.-1-6. The CONSTRUCT can be prepared, purified and
administered as disclosed in WO 00/3227, WO 02/056907 or
WO2004/016282, especially in Example 13, which patent filings as
well as the references cited therein are incorporated by reference
into the present patent application, especially the end products of
the Examples.
[0010] The term "treatment" as used herein relates in particular to
a treatment aiming to halt pathogenic processes that lead to
disease progression and/or has symptomatic effects.
[0011] The term "prophylactic treatment" as used herein relates in
particular to a treatment aiming to halt pathogenic processes
leading to disease.
[0012] The term "dementia of the Alzheimer's type" as used herein
relates in particular to a disease as defined according to the
Diagnostic and Statistical Manual of Mental Disorders, 4th edition
(DSM-IV) criteria.
[0013] In a third aspect, the present invention relates to a method
of treatment of dementia in human patients comprising administering
5 to 175 .mu.g preferably 15 to 125 .mu.g, more preferably about 25
to 100 .mu.g, e.g. 50 .mu.g or 75 .mu.g, of the CONSTRUCT to human
patients in need thereof about every 4 to 8 weeks, preferably about
every 5 to 7 weeks, in particular about every 6 weeks.
[0014] In a fourth aspect the present invention relates to a method
of treatment of dementia in human patients comprising administering
5 to 1000 .mu.g, preferably 5 to 300 .mu.g, more preferably about
50 to 200, most preferably 50-150 .mu.g, e.g. 50 .mu.g or 75 .mu.g,
100 .mu.g, 125 .mu.g, 150 .mu.g of the CONSTRUCT to human patients
in need thereof about every 4 to 8 weeks, preferably about every 5
to 7 weeks, in particular about every 6 weeks. Frequency of
injection can vary depending on the patient response.
[0015] For example the frequency of administration can vary if the
injection has to be administered according to antibody titers.
[0016] The usefulness of the CONSTRUCTS in the treatment of the
above-mentioned disorders can be confirmed in suitable clinical
studies, e.g. those described in the Examples, e.g. applying a
total daily dosage of 25 to 100 pg CONSTRUCT to patients every 4 to
8 weeks.
[0017] Suitable clinical studies are in particular randomized,
double-blind, placebo-controlled, parallel studies in Alzheimer's
patients or open label studies.
[0018] In a further aspect, the present invention pertains to a
combination comprising at least one CONSTRUCT and at least one
nootropic agent, preferably one cholinesterase-inhibitor, or
memantine.
[0019] The term "nootropic agent" as used herein includes, but is
not limited to nootropic plant extracts, calcium antagonists,
cholinesterase inhibitors, dihydroergotoxin, nicergoline,
piracetame, purine derivates, pyritinol, vincamine and
vinpocetine.
[0020] The term "nootropic plant extracts" as used herein includes,
but is not limited to extracts from Ginkgo leafs. The term "calcium
antagonists" as used herein includes, but is not limited to
cinnarizine and nimodipine. The term "cholinesterase inhibitors" as
used herein includes, but is not limited to donepezil
hydrochloride, rivastigmine and galantamine hydrobromide. The term
"purine derivates" as used herein includes, but is not limited to
pentifyilin.
[0021] Extracts from Ginkgo leafs can be administered, e.g., in the
form as marketed, e.g. under the trademark Ginkodilat.TM. according
to the information provided by the package insert. Cinnarizine can
be administered, e.g., in the form as marketed, e.g. under the
trademark Cinnarizin forte-ratiopharm.TM. Nimodipine can be
administered, e.g., in the form as marketed, e.g. under the
trademark Nimotop.TM.. Donepezii hydrochloride can be administered,
e.g., in the form as marketed, e.g. under the trademark
Aricept.TM.. Rivastigmine can be prepared as disclosed in U.S. Pat.
No. 5,602,176. It can be administered, e.g., in the form as
marketed, e.g. under the trademark Exelon.TM.. Galantamine
hydrobromide can be administered, e.g., in the form as marketed,
e.g. under the trademark Reminyl.TM.. Dihydroergotoxin can be
administered, e.g., in the form as marketed, e.g. under the
trademark Hydergin.TM.. Nicergoline can be administered, e.g., in
the form as marketed, e.g. under the trademark Sermion.TM..
Piracetam can be administered, e.g., in the form as marketed, e.g.
under the trademark Cerebroforte.TM., Pentifyllin can be
administered, e.g., in the form as marketed, e.g. under the
trademark Cosaldon.TM.. Pyritinol can be administered, e.g., in the
form as marketed, e.g. under the trademark Encephabol.TM..
Vinpocetin can be administered, e.g., in the form as marketed, e.g.
under the trademark Cavinton.TM.. Memantine can be administered,
e.g., in the form as marketed, e.g. under the trademarks Axura.TM.
or Namenda.TM..
[0022] The structure of the active agents identified by code nos.,
generic or trade names may be taken from the actual edition of the
standard compendium "The Merck Index" or from databases, e.g.
Patents International (e.g. IMS World Publications). The
corresponding content thereof is hereby incorporated by
reference.
[0023] Hence, the present invention pertains also to a combination
comprising a CONSTRUCT of the invention, and at least one nootropic
agent selected from the group consisting of nootropic plant
extracts, calcium antagonists, cholinesterase inhibitors,
dihydroergotoxin, nicergoline, piracetame, purine derivates,
pyritinol, vincamine and vinporetine or memantine, in which the
active ingredients are present in each case in free form or in the
form of a pharmaceutically acceptable salt and optionally at least
one pharmaceutically acceptable carrier, for simultaneous, separate
or sequential use, especially for use in a method of treating
dementia.
[0024] Such a combination is preferably a combined preparation.
[0025] Other agents can be used in combination with the CONSTRUCT,
for example: antidepressants such as SSRIs, SNRIs, NRIs,
antipsychotics such as risperidone, antidiabetic treatments such as
insulin or metformin, antioxidative treatments such as selegiline,
vitamin E, anti-inflammatory treatments such as NSAIDs,
lipid-lowering agents such as statins, hormone substitution such as
estrogens, amyloid lowering agents such as abeta secretase
inhibitors, aggregation inhibitors such as beta-sheet blockers,
chelators, immunomodulatory agents such as glatiramer acetate.
[0026] The term "a combined preparation", as used herein defines
especially a "kit of parts" in the sense that the active
ingredients as defined above can be dosed independently or by use
of different fixed combinations with distinguished amounts of the
ingredients, i.e., simultaneously or at different time points. The
parts of the kit can then, e.g., be administered simultaneously or
chronologically staggered, that is at different time points and
with equal or different time intervals for any part of the kit of
parts. Preferably, the time intervals are chosen such that the
effect on the treated disease in the combined use of the parts is
larger than the effect which would be obtained by use of only any
one of the active ingredients.
[0027] Hence, the present invention also provides [0028] the use of
a combination as disclosed herein for the preparation of a
medicament for the treatment of dementia, in particular Alzheimer's
disease; and [0029] a commercial package comprising a combination
as disclosed herein together with instructions for simultaneous,
separate or sequential use thereof in the treatment of dementia, in
particular Alzheimer's disease.
[0030] In one preferred embodiment of the invention, the
combination partner (b) is a cholin-esterase inhibitor, especially
rivastigmine, or memantine.
[0031] If the combination partners are administered as separate
dosing forms, a dosage and mode of administration can be applied as
provided in the package inserts. In particular, the following
dosages of the combination partners (b) can be administered to the
patient:
[0032] Cinnarizine may be administered to a patient in a total
daily dosage of between about 75 to about 150 mg.
[0033] Nimodipine may be administered to a patient in a total daily
dosage of between about 60 to about 120 mg.
[0034] Donepezil hydrochloride may be administered to a patient in
a total daily dosage of between about 5 mg and 10 mg.
[0035] Rivastigmine may be administered to a patient in a total
daily dosage of between about 6 and about 12 mg.
[0036] Galantamine may be administered to a patient in a total
daily dosage of between about 12 and 24 mg, e.g. 12 mg twice
daily.
[0037] Dihydroergotoxin may be administered in the form of its
methansulfonate to a patient in a total daily dosage of between
about 4 mg and 10 mg, e.g. about 8 mg.
[0038] Nicergoline may be administered in the form of its tartrate
by intramuscular injection to a patient in a total daily dosage of
between about 4 mg and 8 mg.
[0039] Piracetam may be administered to a patient in a total daily
dosage of between about 1200 and 5000 mg, e.g. 4800 mg/day.
[0040] Pentifyllin may be administered to a patient in a total
daily dosage of between about 400 and 800 mg.
[0041] Pyritinol may be administered in the form of its
hydrochloride to a patient in a total daily dosage of about 600
mg.
[0042] Vinpocetin may be administered to a patient in a total daily
dosage of between about 10 and 15 mg.
[0043] Memantine may be administered to a patient in the form of
memantine hydrochloride in a total daily dosage of about 20 mg.
[0044] In a further aspect, the present invention provides human
monoclonal antibodies against A.beta.1-42 induced by the CONSTRUCT,
preferably A.beta. antibodies recognizing the N-terminus of
A.beta.1-42.
[0045] An efficient method to make human monoclonal antibodies from
B cells isolated from the blood of a human patient is described by
Etisabetta Traggial, Stephan Becker, Kanta Subbarao, Larissa
Kolesnikova, Yasushi Uematsu, Maria Rita Gismondo, Brian R Murphy,
Rino Rappuoli & Antonio Lanzavecchia in Nature Medicine 10,
871-875 (2004), which publication is included by reference into the
present specification.
EXAMPLES
[0046] In the following Examples 1 to 4, male and female patients
are included aged between 50 to 80 years (both inclusive), with
mild to moderate AD as confirmed by a MMSE score of 16 to 26 (both
inclusive), who are outpatients with caregivers (living together
or, if living alone, with daily contact), who meet the DSM-IV
criteria for dementia of the Alzheimer's type, and who satisfy the
criteria for a clinical diagnosis of probable AD according to the
National institute of Neurological and Communicative Disorders and
Stroke (NINCDS-ADRDA), Each patient participates in a 4-week
screening period (Day -28 to Day -1), a baseline period (pre-dose
on Day 1 in week 0), three single dose treatments under ambulatory
conditions in weeks 0, 6 and 18 (Days 1, 43, 127), ten additional
ambulatory visits in bi- to four weekly intervals in weeks 2, 4, 8,
12, 16, 20, 22, 26, 30, and 34 (i.e. on Study Days 15, 29, 57, 85,
113, 141, 155, 183, 211 and 239), and two additional ambulatory
visits in week 42 and 52 (i.e. on Study Days 295 and 365). Safety
assessments include general physical examinations, neurological
examinations, 12-lead electrocardiograms (ECGs), vital signs,
standard clinical laboratory evaluations (hematology, blood
chemistry, urinalysis), special immunological laboratory
evaluations in blood and cerebrospinal fluid (CSF), cerebral
magnetic resonance imagings (MRIs), as well as adverse event and
serious adverse event monitoring. Further, patients and caregivers
are instructed (verbally and in writing) to look for any unexpected
deterioration in health status.
[0047] A.beta.-antibody response is measured by determination of
the AS-antibody titer (lgG and lgM) in serum and CSF using ELISA
methods. The ex vivo A.beta.-antibody binding properties in serum
and CSF is explored by immunological methods on human and
.beta.-amyloid precursor protein (APP) transgenic mouse brain
tissue. The VLP-antibody titer response in serum is measured to
investigate the immune response to the carrier compound in relation
to the immune response to A.beta.. Exploratory pharmacodynamic
assessments include the following assessments; 1) determination of
disease related markers in CSF (A.beta. peptides and its isoforms,
tau protein and its isoforms, phospho-tau) and plasma (A.beta.
peptides and isoforms); 2) volumetric MRIs, and 3)
neuropsychological test battery, mini-mental state examination
(MMSE), clinical dementia rating (CDR) and Alzheimer's Disease
Cooperative Study--Activities of Daily Living (ARCS-ADL), 4)
Positron emission tomography (PET) with .sup.11C-Pittsburgh
Compound-B (.sup.11C-PIB) which is a novel beta-arnyloid selective
tracer developed for m vivo detection of .beta.-amyloid plaques in
the brain and .sup.18F-fluorodeoxyglucose (.sup.18FDG)
[0048] Responders are defined as those patients who show a
significant increase of A.beta.-specific antibody titers above
baseline and who show an antibody isotype switch from lgM to lgG in
serum at latest after the 3rd injection. A.beta.-specific antibody
titers are defined as titers above lower limit of quantification
(LLOQ) in a validated enzyme-linked immunosorbent assay (ELISA)
assay detecting specific antibodies relative to a standard serum as
calibrator.
Example 1
A Single or Multi Center, Randomized, Double-Blind,
Placebo-Controlled Study in Patients with Mild to Moderate
Alzheimer's Disease (AD) with Three Subcutaneous Injections of 25
.mu.g of CONSTRUCT
[0049] A total of 30 patients is randomized to receive three s.c.
injections of the CONSTRUCT or placebo. 24 patients receive the
active drug CONSTRUCT and 6 patients receive placebo under
double-blind conditions. Three s.c. injections of 25 .mu.g
CONSTRUCT or placebo are administered to each patient in weeks 0, 6
and 18.
Example 2
A Single or Multicenter, Randomized, Double-Blind,
Placebo-Controlled Study in Patients with Mild to Moderate
Alzheimer's Disease (AD) with Three Subcutaneous Injections of 50
.mu.g of CONSTRUCT
[0050] A total of 30 patients is randomized to receive three s.c.
injections of the CONSTRUCT or placebo. 24 patients receive the
active drug CONSTRUCT and 6 patients receive placebo under
double-blind conditions. Three s.c. injections of 50 pg CONSTRUCT
or placebo are administered to each patient in weeks 0, 6 and
18.
Example 3
A Single or Multicenter, Randomized, Double-Blind,
Placebo-Controlled Study in Patients with Mild to Moderate
Alzheimer's Disease (AD) with Three Subcutaneous Injections of 100
.mu.g of CONSTRUCT
[0051] A total of 30 patients is randomized to receive three s.c.
injections of the CONSTRUCT or placebo. 24 patients receive the
active drug CONSTRUCT and 6 patients receive placebo under
double-blind conditions. Three s.c. injections of 100 .mu.g
CONSTRUCT or placebo are administered to each patient in weeks 0, 6
and 18.
Example 4
Determination of Antibody Titers in Serum
[0052] Blood samples are taken by direct venipuncture. A total of
10 mL venous blood is collected in plain barrier tubes. The sample
are allowed to clot during 45 minutes at room temperature and then
centrifuged for 10 minutes at approximately 2500 g. Serum tubes are
frozen within 60 min after venipuncture and kept at <-70.degree.
C. pending analysis.
Example 5
A Single or Multicenter, Randomized, Double-Blind,
Placebo-Controlled Study in Patients with Mild to Moderate
Alzheimer's Disease AD with Three Subcutaneous Injections of 150
.mu.g of CONSTRUCT
[0053] A total of 30 patients is randomized to receive three s.c.
injections of the CONSTRUCT or placebo. 24 patients receive the
active drug CONSTRUCT and 6 patients receive placebo under
double-blind conditions. Three s.c. injections of 150 .mu.g
CONSTRUCT or placebo are administered to each patient in weeks 0, 6
and 18.
Example 6
A Single or Multicenter, Randomized, Double-Blind,
Placebo-Controlled Study in Patients with Mild to Moderate
Alzheimer's Disease (AD) with Three Subcutaneous Infections of 300
.mu.p of CONSTRUCT
[0054] A total of 30 patients is randomized to receive three s.c.
injections of the CONSTRUCT or placebo. 24 patients receive the
active drug CONSTRUCT and 6 patients receive placebo under
double-blind conditions. Three s.c. injections of 300 .mu.g
CONSTRUCT or placebo are administered to each patient in weeks 0, 6
and 18.
* * * * *