Note: Descriptions are shown in the official language in which they were submitted.
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USE OF PIMAYANSERIN IN THE TREATMENT OF PARKINSON AND SYMPTOMS THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application
Nos.
60/938,985, filed May 18, 2007, and 60/942,990, filed June 8, 2007, both of
which are
= incoxporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] The present invention relates to the fields of chemistry and medicine.
More particularly, disclosed herein are methods of administering and using
pimavanserin.
Description of the Related Art
100031 Parkinson's disease (PD) is a common progressive neurodegenerative
disorder; its clinical diagnosis is based on the presence of a core set of
neurological
symptoms including rest tremor, bradykinesia, rigidity, and disturbances of
balance and
posture. Patients also experience a number of nomnotor symptoms that are
equally important
to address. These include psychosis and behavioral disturbances, pain, sensory
complaints,
depression, and dementia. Among these, perhaps the most significant with
respect to
morbidity and quality of life, and the most difficult to treat, is psychosis.
Psychotic
symptoms occur in 20% to 40% of patients with PD in advanced stages of the
disease.
Parkinson's disease psychosis (PDP) manifests primarily as hallucinations
(predominantly
visual) and delusions (usually associated with a paranoid theme focused on the
partner);
initial symptoms are frequently a sense of presence or passage. 'l'he
prevalence of psychosis
in PD may be more common in patients with dementia.
[0004] Development of psycliosis in a patient with PD is progressive and often
devastating as it is prognostic of nursing home placement, poses enormous
stress on
caregivers, and markedly increases the risk of mortality in the patient
population. There is no
proven safe and effective course of treatment for PDP. Dose reduction of
dopaminergic
treatment is frequently standard practice when psychotic symptoms first
present, but this
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practice does not always diminish psychosis and provides only short-term
antipsychotic
beneftt. In addition, it usually resuIts in increased motor function deficits.
[0005] Sleep problems are common in patients with PD. Some studies suggest
that over 80% of PD patients have difficulty staying asleep. Common sleep
problems in PD
patients include nocturnal sleep disruption, excessive daytime sleepiness,
restless legs
syndrome, rapid eye movement sleep behavior disorder, sleep apnea, sleep
walking, sleep
talking, nightmares, sleep terrors and panic attacks.
[0006] Antipsychotics and dopamine receptor antagonists can be effective in
ameliorating psychotic symptoms. Unfortunately, many of these compounds
significantly
worsen motor function in PD patients secondary to their hypo-dopanainergie
state.
[00071 Absorption and pharmacakinetics of drugs can be altered by food intake.
For some drugs, it is recommended that they be taken with a meal, whereas
other drugs must
be taken on an empty stomach.
SUMMARY OF THE INVENTION
(0008] One embodiment disclosed herein includes a kit comprising a
pharmaceutical composition, prescribing information, and a container, wherein
the
pharmaceutical composition comprises a therapeutically effective amount of
pimavanserin
and the prescribing information advises a patient that the pharmaceutical
composition can be
taken with or without food.
[0049] Another embodiment disclosed herein includes a kit comprising a
pharmaceutical composition, prescribing information, and a container, wherein
the
pharmaceutical composition comprises a therapeutically effective amount of
pimavanserin
and the prescribing information advises a patient that food does not affect
either the rate or
extent of absorption of pimavanserin.
[0010j Another embodiment disclosed herein includes a method for providing
pimavanserin therapy to a patient, including providing a therapeutic dose of
pimavanserin to
the patient and advising the patient that pimavanserin can be taken with or
without food.
[0011J Another embodiment disclosed herein includes a method for providing
pimavanserin therapy to a patient, including providing a therapeutic dose of
pimavanserin to
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the patient and advising the patient that food does not affect either the rate
or extent of
absorption of pimavanserin.
[00121 Anotlier embodiment disclosed herein includes a method of administering
pimavanserin to a, patient, wherein the administering comprises providing a
pharmaceutical
composition comprising pimavanserin to the patient in a container associated
with printed
labeling advising the patient that the pharmaceuticai composition can be taken
with or
without food.
[00131 Another embodiment disclosed herein includes a method of administering
pimavanserin to a patient, wherein the administering comprises providing a
pharmaceutical
composition comprising pimavanserin to the patient in a container associa#od
with printed
labeling advising the patient that food does not affect either the rate or
extent of absorption of
pimavanserin.
10014] Another embodiment disclosed herein includes a method of treating
Parkinson's disease psychosis that includes administering pimavanserin to a
Parlcinson's
disease patient exhibiting symptoms of psychosis.
[0015] Another embodiment disclosed herein includes a method of treating a non-
motor symptom of Parkinson's disease that includes administering pimavansserin
to a
Parkinson's disease patient in, an amount sufficient to ameliorate the non-
motor symptom.
100161 Another embodiment disclosed herein includes a method of ameliorating a
sleep disorder in a subject suffering from Parkinson's disease that includes
administering
pimavanserin to a Parkinson's disease subject suffeiing from a sleep disorder.
(0017) Another embodiment disclosed herein includes a method of ameliorating a
sleep disorder and psychosis in a subject suffering fFom Parkinson's discase
that includes
administering pimavanserin to a Parkinson's disease subject suffering from a
sleep disorder
and exhibiting one or more symptoms of psychosis.
[00181 Another embodiment disclosed herein includes a method of ameliorating
psychosis in a Parkinson's disease patient having dementia that includes
administering
pimavanserin to a Parkinson's disease patient exhibiting one or more symptoms
of psychosis
and one or more symptoms of dementia.
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[0019] Another embodiment disclosed herein includes a method of decreasing day
time sleepiness that includes administering pimavanserin to a subject
suffering from day time
sleepiness.
[0020] Another embodiment disclosed herein includes a method of improving the
quality of life of a caregiver that includes administering pimavanserin to a
Parkinson's
disease patient under the care of the caragiver.
[0021] Another embodiment disclosed hercin includes a method of decreasing
mortality in a Parkinson's disease patient that includes administering
pimavanserin to the
patient in an amount sufficient to decrease risk of mortality.
BRIEF DESCRIP7'lON OF THE DRAWINGS
100221 FIGURE 1 is a graph showing plasma concentrations of pimavanserin
administered with and without food.
[0023] FIGURE 2 is graph showing Cmax values for pimavanserin ada-inistered
with and without food.
[0024] FIGURE 3 is a graph showing AUC values for pimavanserin administered
with and without. food.
100251 FIGURE 4A is a bar graph illustrating the change in baseline in the
UPDRS Parts II and III scale upon administration of pimavanserin or placcbo.
[0026] FIGURE 4B is a bar graph illustrating the UPDRS Parts II and III scale
at
baseline and after 28 days of administration of pimavanserin or placebo.
[0027] FIGURE 5A is a bar graph illustrating the change in baseline in the
UPDRS Part I scale upon administration of pimavanserin or placebo.
[0028] FIGURE 5B is a bar graph illustrating the UPDRS Part I scalc at
baseline
and after 28 days of administration of pimavanserin or placebo.
[0029] FIGURE 6A is a bar graph illustrating the change in baseline in the
Total,
Hallucinations, and Delusions SAPS scale upon administraiion of pimavanserin
or placebo.
[0030] FIGURE 6B is a bar graph illustrating the Total SAPS scale at baseline
and after 28 days of administration of pimavanserin or placebo.
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[0031] FIGURE 6C is a bar graph illustrating the Hallucinations SAPS scale at
baseline and after 28 days of administration of pimavanserin or placebo..
[0032] FIGURE 6D is a bar graph illustrating the Delusions SAPS scale at
baseline and after 28 days of administration of pitnavanserin or placebo.
[0033] FIGURE 7A is a bar graph illustrating the change in baseline in the CGI
scale upon administration of pimavanserin or placebo.
[8034] FIGURE 7B is a bar graph illustrating the CGI `scale at baseline and
after
28 days of administration of pimavanserin or placebo.
[0035] FIGURE 7C is a bar graph illustrating the percent of subjects
experiencing
either an increase or decrease in CGI scale upon administration of
pimavanserin or placebo,
[0036] FIGURE 8A is a bar graph illustrating the change in baseline in the
UPDRS Part IV scale upon administration of pimavanserin or placebo.
[0037] FIGURE 8B is a bar graph illustrating the UPDRS Part IV scale at
baseline and after 28 days of administration of pimavanserin or placebo.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMh'NT
[0038] Pimavanserin, which is also known as N-(1-methylpiperidin-4-yl)-N-(4-
fluorophenylmethyl}N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide, N-[(4-
fluorophenyl)methyl]-N-(l -methyl-4-piperidinyl)-N'-[[4-(2-
methylpropoxy)phenyl]methyl}
urca, 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)-3-[4-(2-
methylpropoxy)benzyl]urea, or
ACP-103 has the structure of Formula (I):
CM3
N
F ~, O~
N y N ~ `
O
{I}
[0391 Methods suitable to make pimavanserin are known and described, for
example, in U.S. Application Publication Nos. 2004-0213816, filed January 15,
2004, and
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2007-0260064, filed May 15, 2007, both of which are incorporated herein by
reference in
their entirety.
10040] Pimavanserin exhibits activity at serotonin receptors, and acts as an
inverse agonist of the 5-HT2A receptor. Experiments performed on cells
transiently
expressing the human phenotype of the 5-HT2A receptor have shown that
pimavanserin
attenuates the signaling of such receptors in the absence of additional
ligands acting upon the
receptor. Pimavanserin has thus been found to possess inverse agonist activity
at the 5-HT2A
receptor and is able to attenuate the basal, non-agonist-stimulated,
constitutive signaling
responses that this receptor displays. The observation that pimavanscrin is an
inverse agonist
of the 5-HT2A receptor also indicates that it has the ability to antagonize
the activation of 5-
HT2A rcceptors that is mediatod by endogenous agonists or exogenous synthetic
agonist
ligands. Pimavanserin exhibits high affinity for the 5-HT2A receptor with a
pKj > 9. In vivo
human and non-human animal studies have further shown that pimavanserin
exhibits anti-
psychotic, anti-dyskinesia, and anti-insomnia activity. Such properties of
pimavausexin are
described in U.S. Patent Publication No. 2004-0213816, filed January 15, 2004
and entitled,
"SELECTIVE SEROTONIN 2A/2C RECEPTOR INVERSE AGONISTS AS
THERAPEUTICS FOR NEURODEGENERATIVE DISEASES," which is incorporated
herein by reference in its entirety, including any drawings.
100411 Pimavanserin exhibits selective activity at the 5-IIT2A receptor.
Specifically, pimavanserin lacks functiona.l activity (pEC50 or pK; < 6) at 31
of the 36 human
monoaminergic receptors including 5-HT1A, 5-HT1B, 5-HTID, 5-HT1E, 5-HT1F, 5-
HT2B,
5-HT3, 5-HT4, 5-HT6A, 5-HT'7A, adrenergic-alA, -adrenergic-aiB, adrenergic-
a.1D,
adrenergic-a2A, adrenergic-a2B, adrenergic-P2, dopamine-D1, dopamine-D2,
dopamine-D3,
dopamine-D4, histamine-H1, histamine-H2, and histamine-H3. Thus, pimavanserin
provides
high affinity at 5-HT2A receptors with little to no affuiity to most other
monoaminergic
receptors.
100421 In addition, pimavanserin exhibits high stability, good oral
bloavailability,
and a long half-life, Specifically, pimavanserin exhibited a slow clearance
rate from in vitro
human microsomes (< 10 L/min=mg) and a half-life of approximately 55 hours
upon oral
administration to humans.
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[0043) Various forms of pimavanserin can be used in the methods described
herein. For example, a number of salts and crystalline forms of pimavanserin
can be used,
Exemplary salts include the tartrate, hemi-tartrate, citrate, fumarate,
maleate, nwate,
phosphate, succinate, sulphate, and edisylate (ethanedisulfonate) salts.
Pimavanserin salts
including the aforementioned ions, among others, are described in U.S. Patent
Publication
No. 2006-0111399, filed September 26, 2005 and entitled "SALTS OF N-(4-
FLUO1tOBENZYL}N-(1-METHYLPIPERIDIN-4-YL)-N' -(4-(2-
METHYLPROPYLOXY)PHENYLMETHYL)CARBAMIDE AND THEIR
PREPARATION," which is incorporated herein by reference in its entirety. Two
crystalline
forms of the t,artrate salt are referred to as crystalline Fonn A and Form C,
respectively, and
are described in U.S. Patent Publication No. 2006-0106063, filed September 26,
2006 and
entitled "SYNTHBSIS OF N-(4-FLUOROBENZYL}N-(1-METHYLPIPERIDIN-4-YL)-N'-
(4-(2-METHYLPROPYLOXY)PHENYLMETHYL)CARBAMIDE AND ITS TARTRATE
SALT AND CRYSTALLINE FORMS," which is incorporated herein by reference in its
entirety. Pimavanserin (including, for example, the tartrate salt) may be
formulated into
tablets, such as is described in more detail in U.S. Patent Publication Nos.
2007-0260064,
filed May 15, 2007 and 2007-0264330, filed May 15, 2007, each entitled
"PHARMACEUTICAL FORMULATIONS OF PIMAVANSERIN," which are incorporated
herein by reference in their entireties.
[0044] Similarly, isolated, substantially pure metabolites of pimavanserin can
also
be used. Suitable metabolites that can be used have the chemical structures of
Formulae (II)
through (V) shown below.
OH
\ I N N \ ~
y
O
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N a \ I
(III)
N
F ~ I / ( O
N
y
0
F ~ ~ O~oH
N
y
(V)
[0045] Compounds of Formulae (II), (III), (IV), and (V) as described herein
may
be prepared in various ways. General synthetic routes to the compounds of
Formulae (II),
(III), (IV), and (V) are shown in Schemes A-D. 'I'he routes shown are
illustrative only and
are not intended, nor are they to be construed, to limit the scope of this
invention in any
manner whatsoever. Those skilled in the art will be able to recognize
modifications of the
disclosed synthesis and to devise alteraate routes based on the disclosures
herein; all such
modifications and alternate routes are within the scope of this invention.
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~
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Scheme A
N
9 O=C=N
NH F
~
+ N I
I
0
F
O
[0046] Scheme A shows a general reaction scheme for forming the compound of
Formula (11). As shown in Scheme A, the secondary amine and isocyanate can be
combined
to produce the 4-methoxybenzyl derivative of the compound of Formula (lI). The
methoxy
group can be converted to a hydroxy group using methods known to those skilled
in the art,
for example, using a boron trihalide to form the compound of Formula (11).
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Scheme B
FyC`
O~ + ~ / F -----
N2N N
O
A-ieobuloxybenryl iw.ysnd9
F3C
N
N N~. ~~ ~ I N
[0047] An exemplary method for synthesizing the compound of Formula (III) is
shown in Scheme B. The protected 4-piperidoinone and 4-fluorobenzylamine can
be undergo
reductive amination to form N-(4-fluorobenzyl)-4-amino-l-
triflnoroacetylpiperidine. The
resulting secondary amine can then be reacted with the appropriate isocyanate
to form the
nitrogen-protected carbamide. The acyl protecting group can be cleaved off
using an alkali
metal salt such as potassium carbonate to form the compound of Formula (III).
Scheme C
OH
F ~ OH F ~/~
N
y
0
[00481 One method for synthesizing the compound of Formula (IV) is shown in
Scheme C. The compound of Formula (II) can be reacted with isobutylene oxide
to form the
compound of Formula (IV) via a nucleophilic ring opening of the epoxide.
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Scbgmt D
f OH
~ ~~ x OH v v N
Ny N y
[0049] Scheme D shows a general reaction scheme for forming the compound of
Formula (V). As shown in Scheme D, the compound of Formula (II) can be
reacted. with a
halohydrin to form the compound of Formula (V). All the compounds described
hetein can
be purified using methods known to those skilled in art. Furthermore,
isolated, substantially
pure metabolites of pimavanserin, compounds of formulae (II), (QI), (IV) and
(V), are
described in U.S, Provisional Patent Application No. 60/974,426, filed
September 21, 2007
and entitled "N-SUBSTITUTED PIPERIDINE DERIVATIVES AS SEROTONIrI
RECEPTOR AGENTS," which is incorporated herein by reference in its entirety.
[0050] Unless otherwise indicated, pimavanserin as used herein inchtdes the
free
base of the compound, all of its salts, hydrates, solvates, polymorphs, and
isolated,
substantially pure metabolites thereof, either individually or in combination.
In an
embodiment, the form of pimavanserin that is used is its tartrate salt:
Food Effects
[0051] It was surprisingly discovered that administration of pimavanserin with
or
without food results in no significant difference in pharmacokinetics.
Accordingly, in some
embodiments, pimavanserin is administered to a patient either with or without
food. In some
embodiments, a therapeutic dose of pimavanserin is provided to a patient and
the patient is
advised, either in writing or orally, that the dose can be taken with or
without food. In some
embodiments, the patient is advised that food does not affect either the rate
or extent of
absorption of pimavanserin. In some embodiments, the advising to the patient
is via printed
labeling associated with a container comprising a pimavanserin dosage form.
One
embodiment includes a kit comprising a pimavanserin pharmaceutical dosage
form, a
container, and prescribing informaxion containing the advice discussed above.
[0052] In some embodiments, pimavanserin is administered in combination with
an additional antipsychotic agent along with the advice noted above. For
example, in some
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embodiments, pimavanserin is administered in combination with risperidone,
which itself can
be taken with or without food without a significant difference in
pharmacokinetics.
Parkinson's Disease Psychosis
[0053] It was also discovered that pimavanserin can be used to treat non-motor
symptoms of. Parkinson's disease.. In various embodiments, the non-motor
symptoms include
one or more of depression, dementia, apathy, hallucinations, dribbling saliva,
constipafion,
pain, genitourinary problems, and sleep disorders. Non-motor symptoms of
Parkinson's
disease may be measured using the NMSQUEST questionnaire known to those of
skill in the
art. Accordingly, in one embodiment, piunavanserin is administered to a
Parkinson's pataent
to improve non-motor symptoms as demonstrated on a NMSQUEST questionnaire.
[0054] It was discovered that one non-motor symptom that pimavanscrin is
effective in trealang is Parkinson's disease psychois (PDP). Thus, one
embodiment includes a
method of trealing Parkinson's disease psychosis by administering pimavanserin
to a
Parkinson's disease patient exhibiting symptoms of psychosis. In some
embodiments, the
Parkinson's disease psychosis treated by pimavanserin is not drug induced. In
one
embodiment, the administration is sufficient to result in a decrease in the
Scale for
Assessment of Positive Symptoms (SAPS) for the patient. In one embodiment, the
administration is sufficient to decrease the severity and/or frequency of
hallucinations. ln one
embodiment, the administration is sufficient to decrease the severity and/or
frequency of
delusions. In various embodiments, the administration results in at least
about a 10%, 20%,
30%, 40%, or 50% decrease in the SAPS total score, hallucinations sub-score,
and/or
delusions sub-score. In some embodiments, the reduction of Parkinson's disease
psychosis is
fiirther demonstrated by a decrease in the Clinical Global Impression (CGI)
scale. In various
embodiments, the administration results in at least about a 5%, 10%, 15%, or
20'/o decrease
in the Ct31 scale. In some embodiments, the reduction of Parkinson's disease
psychosis is
demonstrated by a decrease in Part I (Mentation, Behavior, and Mood) of the
Unified
Parkinson's Disease Rating Scale (UPDRS). In various embodiments, the
administration
results in at least about a 10 %, 20%, 30%, or 40% decrease in Part I of the
UPDRS.
[0055] Another non-motor symptom of Parkinson's disease is day time
sleepiness. In one embodiment, pimavanscrin is administered to a Parkison's
disease patient
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to decrease day time sleepiness. In one embodiment, the reduction in day time
sleepiness is
demonstrated by an improvement in the SCOPA-Sleep scale,
[0056] Some embodiments include improving the quality of life of a caregiver
by
administering pimavanserin to a Parkinson's disease patient under the care of
the caregiver.
In one embodiment, the administration is sufficient to result in a decrease in
the Caregiver
Burden Scale for the caregiver.
[0057] In one embodiment, the administration of pimavanserin does not cause a
significant worsening of motor symptoms. In one embodiment, the lack of
significant
worsening of motor symptoms is demonstrated by the lack of significant
worsening in the
Unified Parkinson's Disease Rating Scale (UPDRS), particularly in Parts II
(Activities in
Daily Living) and III (Motor Examination) of the scale. In various
embodiments, the
administration of pimavanserin at dosages sufficient to improve Parkiason's
disease
psychosis results in a change in UPDRS score for Parts II and III of less than
about 15%,
10%, 5%, or 3%.
[0058] In one embodiment, the administration decreases the mortality of a
Parkinson's disease patient. In one embodiment, the Parkinson's disease
patient suffers from
Parkinson's disease psychosis.
[00591 ' The dosage of pimavanserin administered as described above may be any
suitable dosage to achieve an efficacious result. In some embodiments,
pimavanserin is
administered from about 5 mg to about 100 mg once daily. In one embodiment,
about 40 mg
of pimavanserin is administered once daily. In one embodiment, about 10 mg of
pimavanserin is administered once daily. In one embodiment, about 20 mg of
pimavanserin
is administered once daily.
[0060] In some embodiments of the methods described above, pimavanserin is
co-administered with an anti-parkinsonisni agent. In one cmbodiment, the anti-
parkinsonism
agent comprises levodopa. In one embodiment, the anti-parkinsonism agent is
SINEMET
(carbidopa-levodopa combination). In one embodiment, the anti-parkinsonism
agent is
rasagiline.
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EXAMPLES
~nWle 1- Food Effect
[0061] The study was conducted as a single-ecntcr, randomized, open-label,
three-
way incomplete crossover design in 8 subjects. Subjects checked in on Day -1
and wrre
housed for a total of 5.5 days for each treatment. On Day 1, all subjects
received a single
pimavanserin dose (100 mg) under either fasted or fed conditions. Serial
pharmacokinetic
samples were collected up to 216 hours postdose. Pimavanserin was administered
as
follows:
Treaxinent A: 100 mg pimavanserin (5 mL of a 20-mg/mL pimavanserin
solution) via nasogastric tube under fasted conditions,
Treatment B: 100 mg pimavanscrin (5 x 20-mg tablets) orally under fasted
conditions,
Treatment C: 100 mg pimavanserin (5 x 20-nig tablets) orally under fed
conditions.
[0062] Two subjects each were randomized to receive one of the following
treatment sequenccs: ABC, CBA, BAC, or CAB. For the fed treatment, the single
oral dose
of pimavanserin was administered immediately following a high-fat breakfast.
The
treatments were separated by at least 14 days.
[0063] Pimavanserin was administered as a solution via a polyvinyl chloride
(PVC) nasogastric tube or as a 20-mg tablet. For the solution, powder
pimavanserin was
reconstituted with water to a concentration of 20 mg/mL. After ingestion, the
subject was
asked to drink sufficient water to allow a total volume of 240 mL to be
ingested. The
pimavanserin tablets were administercd with 240 mL of water.
Subjects
[00641 Healthy, young, nonsmoking males between the ages of 18 to 45 years
with a body mass index (BMI) of 19 - 28 kg/mz were selected for participation
in this study.
Subjects were excluded if they had a significant organ abnormality or disease,
abnormal vital
signs or clinical laboratory evaluations upon screening or had a serious
physical illness within
one year prior to study start. Subjects also were excluded from participation
in the study if
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they had any history of renal, hepatic, gastrointestinal, cardiovascular, or
hematologic
disease, seizure, epilepsy, severe head injury, multiple sclerosis, or other
known neurological
condition, hepatitis B or C (or a positive test for hepatitis B surface
antigen or hepatitis C
antibody) or human immunodeficiency virus (HIV), or alcohol or drug abuse (or
a positive
urine drug or alcohol test at screening), or were considering or scheduled to
undergo any
surgical procedure during the duration of the study. Furthermore, any subject
who had
donated plasma or blood within 30 days of study start, who required treatment
With
medications within 14 days of study start, who had received any known hepatic
or renal
clearance altering agents within a period of 3 mozltlis prior to study start,
who ingested any
investigational medication or used any investigational device within 3 months
prior to study
start, or who required a special diet were excluded. Subjects were required to
have mental
capacity sufficient to provide legal consent.
10065) A total of 8 healthy, nonsmoking male subjects were enrolled in the
study.
The mean age of enrolled subjects was 28.3 7.4 years (range 19 to 40 years)
with an
average weight of 74.96 11.75 kg (range 63.0 to 96.9 kg) and an average
height of 176.38.f
8.19 orn (range 163.0 to 189.0 cm). Body mass index averaged 24.1 2.3 kg/tna
(range 21 to
28 kg/m). Of the 8 healthy male subjects who participated, 7 (87.5%) were
White and 1
(12.5%) was of a race other than White, Black, Asian, or Oriental.
Procedures
100661 Screening procedures including medical history, physical examination,
12-
lead ECG,. clinical laboratory evaluations, vital signs, urine drug screen,
and serology
screening were performed before check-in of each treatment period along with
inclusion/exclusion criteria. Informed consent was only obtained once before
the first
treatment period. The results of the urine drug screen were reviewed prior to
the start of the
study on Day 1.
[0067] All subjects scheduled to receive Treatment A or B (fasted) began
fasting
after the evening snack on Day -1 and continued to fast overnight for 10
hours. Pimavanserin
was administered after the 10-hour fast. Subjects scheduled to receive
Treatment C(fcd)
were given a high-fat breakfast 30 minutes prior to dosing on Day 1. Treatment
C subjects
were required to consume the entire breakfast within 25 minutes (i.e., within
5 minutes of
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drug administration). The high-fat breakfast consisted of 2 eggs fried in
butter, 2 strips of
bacon, 2 pieces of buttered toast, 4 ounces of hash brown potatoes, and 8
ounces of whole
milk (approximately 55 g fat, 33 g protein, and 58 g carbohydrate). The exact
time of all
dose administrations and breakfast times were accurately recorded for Day 1 of
each
treatment period. Lunch on Day I of each study period was served 4 hours after
dosing for
all subjects. All other meals were served at the same time for all subjects
and were identical
within a given meal time for all dose groups in the 3 periods. Water was
allowed ad libitum
beginning 2 hours after dosing.
[0068] Blood samples were collected for determination of plasma pimavanserin
concentrations and for clinical laboratories. All subjects with
pharmacolcinetic parameter
data from at least one treatment period were included in the statistical
analysis. A high
performance liquid chromatography/tandem mass spectrometric (LC/MS/MS) method
for the
quantitative determination of pimavanserin concentrations in heparinized human
plasma was
validated. The validated method had a standard curve range of 0.5 to 500 ng/mL
for this
analybc using 100 L of heparinized human plasma.
[00691 The following variables were collected during the study to assess
safety
and inclusion criteria: modified physical examinations; medical history and
demographics
including age, gender, race, height, and weight were collected at baseline
(screening); vital
signs, including 3-positional blood pressure and pulse rate (5-minutes supine,
1-minute
sitting, and 3-minutes standing), respiratory rate, and oral temperature, were
collected, 12-
lead ECGs were recordcd, and standard ECG parameters including QRS, PR, QT,
and QTc
intervals were measured. In addition, continuous lead-II ECG monitoring was
perforrtied for
the first 12 hours following the pimavanserin dose (the continuous lead-II
monitoring was
inl.arrupted during neurological exams, collection of 12-lead ECGs, and at
times when
subjects used the restroom facilities). HepB, HepC, and HIV antibody tests
were performed
at screening. Qualitative urine drug (cocaine, opiates, aniphetamines,
alcohol,
benzodiazepines, barbiturates, and urine creatinine) and alcohol tests were
perfonned at
screening and upon check-in to each treatment period.
[00701 Clinical laboratories were measured after an 8-hour fast and included
the
following; Hematology: hematocrit, hemoglobin, red blood cell count with
indices (mean
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,. . ... . . . _ . . . . . . . ..._ . ...::,..,...5:.5-:_'n..,.. . ....: .. .
.. . . .. . . . ... .
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corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular
hemoglobin
concentration), white blood cell count and differential (neutrophils,
lymphocytes, monocytes,
eosinophils, and basophils) reported as absolute values, and platelets
(platelet count,
prothrombin time and activated partial thromboplastin time); Serum Chemistry:
albumin,
alkaline phosphatase, blood urea nitrogen, gamma-glutamyl transferase,
calcium, creatinine,
glucose, cholesterol (including high-density lipoprotein and low-density
lipoprotein
cholesterol), triglycerides, phosphate, potassium, aspartate transaminase,
alanine
transaminase, lactic dehydrogenase, sodium, chloride, bilirubin (total,
direct, indirect), total
protein, and uric acid; Urinalysis: macroscopic (pH, specific gravity,
glucose, protein,
ketones, and blood) and microscopic (RBCs/hpf, WBCs/hpf, bacteria, casts,
epithelial cells,
mucous threads, and crystals).
Pharmacokinetic Analy,,l,s's
[00711 Pharmacokinetic parameters were calculated from plasma concentrations
of pimavanserin as a free base by noneompartmental techniques using WinNonlin
Professional Version 4.01 (Pharsight Corp., Mountain View, California).
Graphics were
prepared using SAS for Windows Version 8.2 (SAS Institute, Cary, North
Carolina) or
SigmaPlot 7.101 (SPSS, Inc., Chicago, Illinois). All calculations of the
plasma
pharmacokinetics were based on actual sampling times.
(0072] Treatment comparisons were evaluated for the natural log-transformed
AUC 0-ao, AUC 0-z, and Cmax. Analysis of variance (ANOVA), with terms for
sequence,
subject within sequence, period, and treatment were performed for each
parameter. From this
ANOVA, least-squares means for each treatment, estimated treatment
differences, and 90%
confidence intervals for treatment differences were calculated. These log-
transformed results
were transformed to the original scale by exponentiation to obtaun adjusted
means, treatment
ratios, and 90% confidcnce intervals for these ratios. To assess relative
bioavailability of the
tablet formulation, the pimavanserin ratio of pharmacokinetic parameters
following
administration of tablets and solution to fasted subjects was calculated.
Solution was used as
a reference. To assess the effect of a high-fat meal on the PK of
pimavanserin, the PK
parameters of tablet `fed' treatment were compared with the PK parameters of
tablet 'fasted'
treatment, where tablet `fasted' was used as the reference. The primary
statistical comparison
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was based on AUC 0-oo and Cmax. The hypothesis of no food effect on PK of
pimavanserin
was accepted if the 90% confidence interval of ratios of AUC 0-co and Cmax
fell within the
interval from 70 to 143%.
Results
[0073] Intersubject variability of concentrations was generally less than 50%.
Mean pimavanserin plasma concentrations reached a maximum at approximately 6
hours
postdose and then declined monoexponentially. There was little difference in
systemic
exposure across treatments.
[0074] Median Tmax was 6 hours for Treatment A and Treatment B and 10.5
hours for Treatment C. Mean Cmax was approximately 51 ng/mL, 57 ng/mL, and 52
ng/mL,
respectively, for Treatments A, B, and C. The mean pharmacokinetic profile of
each
treatment group is shown in Figure 1 and the individual and mean Cmax for each
treatment
are shown in Figure 2. Mean AUC 0-oo values for Treatments A, B, and C were
3847, 3871,
and 4269 ngxh/mL, respectively. Individual and mean AUC 0-0o for each
treatment are
shown in Figure 3. Values of half-life and oral clearance were similar across
treatments.
[0075] Statistical pairwise comparisons were performed for the following
pairs:
Treatment B/Treatment A and Treatment C/Treatment B. Table 1 lists plasma
pimavanserin
pharmacokinetic parameters following single oral or nasogastric administration
of 100 mg
pimavanserin under different treatment conditions. Ninety-percent confidence
interval (90%
CI) was within the 80 - 125% interval for each comparison indicating
bioequivalence of
tablet formulation and solution, and the absence of food effect on
pimavansetin
pharmacokinetics. Relative bioequivalence of the tablet formulation was 99.7%.
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Table 1. Plasma pimavanserin pharmacokinetic parameters following single oral
or
nasogastric administration of 100 mg pimavanserin.
100 mg Pimavans rin
Solution Tablets TabieM
Parameter Statistics Fasted Fasted Fed
(Nn8) (N=B) (N'8)
Cmax (ng/mL) Mean 51.39 57.01 52.15
CV% 15.6 18.0 20.6
Tmax (h) Median 6 8 10.5
Range 6-12 6-6 6-24.02
AUC 0-ao (h*ng/mL) Mean 3847 3871 4289
CV% 16.2 22.2 29.9
T1/2 (h) Mean 59.96 57.8 56.79
CV% 14.9 13.1 16.9
CLpo (L/h) Mean 26.65 26.83 25.28
CV% 15.0 19.5 28.5
DisCus. iO-D
[0076] There was no effect of food on pimavanserin pharmacokineties. Relative
bioequivalence of the tablet formulation to the dose solution was 99.7%. The
pharmacokinetic profile of pimavanserin was consistent across treatment
groups.
Pimavanserin demonstrated a median Tmax of 6 hours and a mean half life
between 55 and
60 hours. After a dose of 100 mg piniavanserin, the mean Cmax was between 50
and 60
ng/mL and the mean AUC 0-oo ranged between 3800 and 4300 h*ng/mL.
[0077] A high fat meal did not affect systemic exposure of ACP-103 when
administered as a tablet formulation indicating that food does not alter its
absorption,
exposure or clearance. In addition, the generally mild adverse events reported
were similar
across fed and fasted conditions.
Example 2- Parkinson's Disease Phase II studv
[0078] This study was conducted as an inpatient single-center, randomized,
double-blind, placebo-controlled, escalatiiig dose study in sequential groups.
Two different
groups of 6 subjects were enrolled in each dose level and received either
placebo (N=2) or
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pimavanserin (N= 4/dose; 25 mg or 100 mg). The starting dose for this study
was 25 mg,
based on a quarter of the maximum tolerated dose (MTD) in healthy subjects
(100 mg). An
interim analysis of safety variables was conducted after 10 days of multiple
dosing for the
first group to decide on a dose for the second group. Additionally, the
pharmacoltinetics
(PK) of pimavanserin following the 24-hour serial blood/plasma collection ou
Day I was
evaluated in the first dose level to compare pimavanserin exposure in
Parkinon's disease
subjects with that of healthy subjects and before escalating to the second
dose level. No
subject participated more than once.
Subjects
(0079] Male and female subjects of any age and any race in otherwise good
health
with a clinical diagnosis of idiopathic Parkinson's disease (defined as the
presence of at least
three of the following cardinal features: rest tremor, rigidity, bradykinesia
and/or akinesia,
postural and balance abnormalities typical of Parkinson's disease, and the
absence of
alternative explanations or atypical features) were eligible to participate in
the study. Discase
severity was assessed by the Hoehn and Yahr's (H/Y Staging) scale and subjects
were
excluded if they exhibited stage V. Females must have been of non-childbearing
potent,ial or
must have complied witli double-barrier protection methods against eonception.
All subjects
were required to have a minui-mental status exam (MMSA) score of equal to or
greater than
25 and to have been on stable anti-Parkinson's medication for at least I week
prior to Day 1
of the study. All concomitant medications remained stable for the duration of
the study.
Subjects were excluded if they had a terminal illness, a ciinically
signif'icant pre-morbid
psychiatric condition, or the presence or recent histoiy within previous 3
months of
significant hematological, renal, laepatic, endocrinologieal, neurological
(other than
Parkinson's disease) or cardiovascular disease. Concomitant or recent use of
antipsychotics,
selective serotonin reuptake inhibitors, or other neuropsychiatric drugs other
than those
approved for Parkinson's disease as well as known hepatic or renal clearance
altering agents
were excluded. History or positive testing for drugs of abuse, hepatitis B or
C, human
inununodefieiency virus (HTV) infection was also reason for exclusion.
Subjects were
required to provide informed consent before participating in the study.
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[0080] A total of 12 subjects were enrolled in tlvs study and all 12 subjects
completed study procedures with no major protocol deviations. Subject
demographics across
dose groups were similar with the exception of weiglit and BMI. The 100-mg
pimavanserin
dose group was composed of subjects whose mean weight was approximately 17
pounds less
than the placebo group and 13 pounds less than the 25-mg pimavanserin dose
group and the
mean BMI for the 100-mg pimavanserin dose group was approximately 8% less than
the
placebo group and 21% less than the 25-mg pimavanserin dose group.
[0081] Eight (66.7%) subjects were male and 4(33.3%) were female. The mean
age of enrolled subjects was 65,0 f 8.1 years (range 48 to 78 years) with an
average weight of
79.53 18.11 kg (range 60.0 to 124.7 kg) and an average height of 167.30 f
8.13 cm (range
150.0 to 177.8 cm). Body mass index averaged 28.59 7.16 kg/m2 (range 22.0 to
45.2
kglm2 ). Of the 12 subjects, 8 (66.7%) were Caucasian, 2 (16.7%) were
Hispanic, 1(8.3%)
was African American, and 1 (8.3%) was Iranian.
[0082] Eleven (91.7%) subjects tested negative for urine drug and alcohol
screens
at Day -1. One subject tested positive for benzodiazepine and received a
waiver to
participate in the study.
Studv Procedures
[0083] Subjects were screened within 21 days of receipt of study medication.
Subjects were admitted to the hospital on Day -1 and were confined for a total
of 19 days and
18 nights. Following check-in on Day -1, select safety and pharmacodynamic
measurements
were collected for all subjects at approximately the same time as the
anticipated pimavanserin
Tmax on subsequent dosing days.
[0084] On Days I through 14, subjects received daily oral doses of study
medication in the morn.ing. Study medication consisted of visually matching
coated tablets
containing 5-mg, 20-mg, or placebo (e.g., subjects in the 25 mg group ingested
one 5-mg
tablet and one 20-mg tablet or two placebo tablets; subjects in the 100 mg
group ingested five
20-mg tablets or five placebo tablets), Each dose was administered with a
total of 240 mL of
water 1 h after breakfast was completed.
100851. On Day 1, serial blood samples were collected pre-dose (0 h) and 2, 4,
6,
9, 12, and 24 h after study medication administration, Blood samples were
collected also
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pre-dose on Days 7, 10 and 13 for determination of trough plasma levels. On
Day 14, seiiai
blood samples were collected pre-dose (0 h) and 2, 4, 6, 9, 12, 24, 48, 72,
96, 144, and 216 b
after study medication administration. Vital signs, electrocardiogram (ECO)
measurements,
neurological assessments, and clinical laboratory tests (measured after an 8 b
fast) were
collected periodically throughout the study period. In addition, 48-hour
continuous 2-lead
Holter monitoring was performed from Day -1 (24 hours prior to dose
administration on Day
1) to Day 2 (24 hours following the fust dose of pimavanserin or placebo) and
again over two
dosing intervals from Day 7 to Day 9 of the study. Reported or observed
adverse events were
collected.
Data Ana~ysis
[0086] PK parameters calculated from plasma concentrations following the
single-dose pimavanserin administration on Day I of each treatment period
included the
following: maxinnum plasma concentration (Cmax), time to maximum plasma
concentration
(Tmax), and area under the plasma conccntration time curve from time zero to
the end of the
dosing interval (ti) used for multiple dosing (24 hours), calculated by linear-
trapezoidal
summation [AUC(0-ti)]. Parameters to be calculated from plasma concentrations
following
the last dose on Day 14 included the following: maximum steady-state plasma
concentration
(Cmax,ss), minimum steady-state plasma concentration (Cmin,ss), average steady-
state
plasma concentration (Cavg,ss) calculated as AUC(0-i)ss divided by the dosing
interval (ti),
time to maximiun steady-state plasma concentration (Tniax,ss), time to minimum
steady-state
plasma concentration (Tmin,ss), area under the plasma concentration-time curve
from time
zero to the end of the steady-state dosing interval (-c=24 hours) calculated
by linear
trapezoidal summation [AUC({}-ti),ss], steady-state elimination raze constant
(Xz,ss)
determined by linear regression of the terminal points of the log-linear
plasma concentration
time curve, steady-state terminal half-life (tl/2,ss) determined as ln(2)/
Xz,ss, apparent oral
clearance (CLpo,ss) calculated by Dose / AUC(0-i)ss, percent fluctuation
(%Fluct) calculated
as (Cmax,ss-Cmin,ss)/Ca.vg,ss*100%, accumulation ratio [AR(1)] calculated as
AUC(0-
'c)ss/AUC(0-ti), and accumulation ratio [AR(2)], calculated as Cmax,ss/Cmax.
The weight
of the dose of the pimavanserin dibasic salt (1005.2 g/mol) was adjusted to
the weight as free
base (427.561 g/mol) by the following correction factor: 2* 427.561/1005.2 =
0.851.
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[0087] All available safety data from subjects receiving at least one dose of
study
medication were included in the safety analyses. The frequency of adverse
events was
tabulated. Baseline, within study and end of study, and change from baseline
laboratory, vital
signs, and ECG parameters were summarized, Shift tables were prepared for
laboratory
parameters.
Results
[0088) Mean pimavanserin concentrations in plasma were measurable at 2 h
following administration of 25 mg and 100 mg on Day 1. The time to reach the
maximum of
mean pimavanserin concentrations in plasma on Day 1 occurred at approximately
9 hours
following administration of 25 mg pimavanserin and 12 hours following
administration of
100 mg pimavanserin. Mean pimavanserin concentrations in plasrna on Day 1 were
quantifiable for 24 hours post-dose following 25-mg and 100-mg pimavanserin
administration.
[00891 Following multiple doses of 25 mg and 100 mg pimavanserin, the mean
pre-dose pimavanserin concentrations in plasma were measurable on Day 14. The
time to
reach the maximum of mean pimavanserin concentrations in plasma on Day 14
occurred at
approximately 9 h for both the 25 mg and 100 mg pimavanserin doses. Mean
pimavanserin
concentrations in plasma on Day 14 were quantifiable for 312 hours postdose
following 25
mg and 100 mg administration.
[00901 Intersubject variability of concentrations, measured by percent
coefficient
of variation (CV%), was generally less than 50% for the 25 mg pimavanserin
dose, except for
the beginning of the study (up to 6 hours postdose on Days 1 and 14) and (from
72 hours to
end of study) after the last dose. Intersubject variability was generally
lower for the 100 mg
pimavanserin dose than the 25 mg pimavanserin dose.
[0091) An analysis of the mean trough concentrations of pimavanserin over the
14-day dosing period (inclusive of the 24-hour sample collected on Day 15) for
each dose
group indicated that steady state was essentially reached within 10 to 13 days
of dosing.
Statistical analysis of trough concentrations collected on Days 7, 10, 13, 14,
and 15 indicated
that the trough concentration reached steady state by Day 7. Mean trough
concentrations on
Day 7 were approximately 20% of those observed on Days 14 and 15. Due to the
small
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sample size (N = 4 per dose group), the statistical analysis failed to discern
these small
differences in trough concentrations between Day 7 and subsequent PK sampling
days.
100921 The pimavanserin concentration-time data in plasma were analyzed by
noncornpartmental analysis using actual sampling collection times, Median Tmax
was 10.58
and 10.53 h on Day 1 for the 25 mg and 100 mg pimavanserin doses,
respectively. Following
administration of 25 mg and 100 mg pimavanserin, mean Cmax values on Day 1
were 11.37
and 43.65 ng/mL, respectively, and mean Cmax appeared to increas'e in
proportion with
escalating dose. Mean AUC(0-t) values were 198.5 and 761.5 ngxh/mL on Day l
following
administration of 25 mg and 100 mg pimavanserin, respectively. A 4-fold
increase in
AUC(0-t) was observed for the 100 mg pimavanserin dose compared with the 25 mg
pima.vanserin dose, which suggested AUC(0-t) on Day I increased in proportion
to dose.
[0093] On Day 14, median Tmax,ss values were 7.50 and 9.00 hours for the 25
mg and 100 nig piniavanserin doses, respectively. Compared with the range of
Tmax on Day
1, the range of Tmax on Day 14 was narrower (4.00 to 12.00 hours). Mean
Cmax,ss values
were 53.00 and 142.8 ng/mL; mean Cmin,ss values were 39.08 and 97.15 ng/mL;
and mean
Cavg,ss values were 46.70 and 121.8 ng/mL for the 25 mg and 100 mg doses,
respectively.
An approximately 2.6-fold increase in these pharmacokinetic parameters was
observed as
dose increased 4-fold. This ratio was consistent with the comparison of mean
AUC(0-t),ss
between the 100 mg and 25 mg doses (2920 versus 1121 ngxh/mL). IIowever,
considering
the small sample size (N=4) in this study, no inferences of dose
proportionality can be made.
[0094] Mean t 1/2,ss was 77.2 hours for the 25 mg dose and 50.9 hours for 100
mg
dose and appeared to be independent of dose. Mean oral clearance (CLpo,ss) was
21.23 and
29.43 L/h for the 25 mg and 100 mg doses, respectively. There was little
fluctuation between
maximum and minimum concentrations in this study. The meam percent
fluctuation, 31%
and 39%, was similar between the 25 mg and 100 mg pimavanserin doses,
respectively.
[0095] The mean Cmax,ss to Cmax ratio was 4.8 and 3.5 for 25 mg and 100 mg
pimavanserin, respectively. '1'he mean AUC(0-t),ss to AUC(0-t) ratio was 5.8
and 4.1 for 25
mg and 100 mg, respectively. A significant accumulation of pimavanserin on Day
14 was
observed for both dose groups.
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[0096] Adverse events were monitored continuously throughout the 19-day
confinement period and through the end of study and follow-up. Overall,
adverse events
were generally mild in intensity. There were no dose-related increases in any
adverse events
and a maximally tolerated dose was not reached. No serious adverse events
occurred during
the conduct of this study.
[00971 There were no clinically meaningful changes or trends observed in
clinical
laboratory data, hematology analytes, serum chemistry analytes, urinalysis
results, or vital
sign values with administration of increasing doses of pimavanserin. Safety
values were
snnilar between pimavanserin-treated subjects and placebo subjects. Twelve
(100.0%)
subjects experienced at least one episode of abnormal lead-Il Holter ECG
monitoring
conducted on Day -1 to Day 1 (48 hours) and Day 7 to Day 9 (48 hours).
However, only one
of these abnormal lead-II Holter readings was considered to be of clinical
significance and
that one event occurred in a subject who had received placebo. No adverse
events were
reported from the 12-lead machine-read ECG results, and no subject experienced
HR, PR,
QRS, QT, QTcB, or QTcF intervals that were considered to be clinically
significant. There
were no subjects who experienced a QT, QTcB, or QTcF interval that exceeded
500 msec
and there were no subjects who experienced a borderline or prolonged QTcB or
QTcF that
was associated with a >60 msec change from baseline in any treatment group.
Neurological
examinations and motor function evaluation revealed no clinically significant
findings for
pimavanserin.
Discussion
[0098] The pharmacokinetic results obtained with pimavanserin in patients with
Parkinson's disease were consistent with those obtained in a previous multiple
dose study in
young healthy male subjects. Inter-subject variability of pimavanserin
pharmacokinetics was
low in patients with Parkinson's disease irrespective of any confounding
disease state and/or
conc:omitant medications. The accumulation was consistent with the 50- to 80-
hour half-life
observed in this study and with data from the previous multiple dose study. By
Day 7, mean
trough concentrations were within approximately 20% of those obtained on Day
15, and
steady state was reached within 10 to 13 days of once daily administration of
pimavanserin.
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[0099) Pimavanserin appeared to be safe and well tolerated in patients with
Parkinson's disease and did not worsen motor function. The present study
suggests that
pimavanserin exhibits pharmacokinetics consistent with once daily
administration and is well
tolerated in an older patient population with Parkinson's disease.
Ex=Rle 3 - Parkinson's Disease Psychosis Phase II study
[0100] A phase II study was conducted to measure the antipsychotic efficacy
and
safety of pimavanserin in patients with Parkinson's disease suffering from
treatment-induced
psychosis. The trial enrolled 60 patients at multiple clinical sites. The
study involved once-
daily oral administration of either pimavanserin or placebo for a 28-day
period to patients
who also received their stable dopamine replacement therapy. The design of the
study
permitted escalation of the initia120 mg dose of pimavanserin to 40 mg and
then to 60 mg at
two scheduled intervals during the study. Fewer patients on pimavanserin were
escalated to
higher doses as compared to placebo-treated patients, and the mean total dose
of
pimavanserin was significantly less than the mean total dose of placebo
(p=0.05). This
difference in dose escalation between the two groups as indicated by
physicians' answers to a
trial questionnaire was mainly due to positive clinical responses in those
patients who were
not ewAlated rather than any dose limitation due to tolerability.
101011 Thc primary endpoint of the clinical trial was niet by the
demonstration
that there was no statistical difference between the pimavanserin-treated
group and the
placebo-treated group in motoric function as measured by subsections Parts II
(Activities in
Daily Living) and III (Motor Examination) of the Unified Parkinson's Disease
Rating Scale
(UPDRS - discussed in more detail in Example 4) (p=0.22). The primary endpoint
evaluated
absolute change from baseline to study day 28 between the pimavanserin and
placebo groups
on the UPDRS for the intent-to-treat population. Figure 4A depicts the change
from baseline
in the UPDRS Parts II and III for the pimavanserin and placebo arms. Figure 4B
depicts the
UPDRS Pails II and IIl score at baseline and Day 28, The study was designed
with 95%
statistical power to detect a clinically meaningful 5 point difference between
pimavanserin
and placebo as measured by subsections Parts II and III of the UPDRS. This
lack of statistical
significance between pimavanserin and placebo-treated groups showed that
pimavanserin did
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not worsen motor functions in patients with Parkinson's disease suffering from
treatment-
induced psychosis.
[0102] The study also included secondary endpoints of antipsychotic efficacy
using three different rating scales: Part I of the UPDRS, which measures
mental impairments,
including an item rating severity of psychosis; the Scale for the Assessment
of Positive
Symptoms (SAPS - discussed in more detail in Example 4), which measures
hallucinations
and delusions; and the Clinical Global Impression - Severity of Illness scale
(CGI-S -
discussed in more detail in Example 4), which reflects a general assessment of
a patient's
overall severity of mental illness. Figure 5A depicts the change from baseline
in the UPDRS
Part I score for the pimavanserin and placebo arms. Figure 5B depicts the
UPDRS Part I
score at baseline and Day 28. Pimavanserin demonstrated statistically
significant
improvement compared to placebo on the UPDRS Part I(p<0.05) and this result
was
attributable to effects on hallucinations and delusions.
[0103] Figure 6A depicts the change from baseline in the total SAPS scale as
well
as the hallucinations ar:d delusions subscales. Figure 6B depicts the total
SAPS scores at
baseline and at Day 28. Similarly, Figures 6C and 6D depict the hallucinations
and delusions
subscales, respectively, at baseline and Day 28. Pimavanserin showed a
statistical trend
compared to placebo on total SAPS score (p<0.09) as measured by the absolute
change from
baseline. Post-hoc analyses showed a signiftcant difference from placebo for
pimvanserin
using a relative percent change from baseline analysis for the SAPS (p=0.05).
[0104] Figure 7A depicts the change from baseline in the CGI-S scale for the
two
treatment arms. Figure 7B depicts the CGI-S scores at baseline and at Day 28.
Pimvanserin
did not show a significant effect as compared to placebo on the CGI-S.
However, more
patients in the pimvanserin-treated group (42%) showed a reduction in CGI-S
score as
compared to patients in the placebo-treated group (18%) as shown in Figure 7C.
10105] Table 2 shows the mean baseline scores and mean change scores from
baseline to study day 28 for the pirnvanserin and placebo-treated groups.
Negative figures
under mean change indicate improvements, The p-values reflect the difference
between
pimvanserin and placebo (n.s.=not significant).
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Table 2. Parkinson's disease psychosis efficacy measures.
ACP-103 Placebo
n=24 n=28 p-value
Mean Mean Mean Mean
Baseline Chan e Baseline Change
UPDRS Part I 6.6 -1.5 6.3 -0.5 <0.05
SAPS Total 16.7 -5.6 17.9 -1.2 ~ <0.09
CGI-S 4.3 -0.6 3.8 0 n.s.
[0106] The study also assessed other complications of Parkinson's disease
therapy
using the UPDRS Part IV, which measures clinical fluctuations (i.e., on/off
periods),
dyskinesias, and other complications common to the dopaminergic treatments
used in
Parkinson's therapy. Figure 8A depicts the change from baseline in the UPDRS
Part IV score
for the two treatment arms. Figure 8B shows the absolute UPDRS Part IV scores
at baseline
and at Day 28. Pimavanserin showed a statistical trend for improvement versus
placebo on
the UPDRS Part IV (p<0.06), suggesting that it may be useful in treating a
variety of
dysfunctions in Parkinson's disease.
[0107] Pimavanserin was safe and well tolerated in patients with Parkinson's
disease suffering from treatment-induced psychosis. There were no treatrnent-
relat.ed serious
adverse events in the study as designated by the investigators. Most of the
adverse events
were mild to moderate in nature and the frequency of adverse events was
generally similar
across the pimavanscrin and placebo-treated groups. Pimavanserin was safe
across a wide
variety of clinical meastires assessed throughout the study, including ECO,
vital signs,
hematology, urinalysis and clinical chemistry.
Example 4 - Parlsinson's Disease Psychosis Phase III study
[0108] A double-blind, placebo-controlled, multicenter, phase III study is
conducted that includes administering pimavanserin to patients having
Parkinson's disease
psychosis. Pimavanserin is administered at two dose levels (10 mg and 40 mg)
over a
6-week treatment period and each of the active arms are compared to a single
placebo ann
with approximately 93 subjects randomized to each arrn. The trial is conducted
on an
outpatient basis with visits conducted at screening, on Study Day I
(Baseline), Study Day 8,
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Study Day 15, Study Day 29, and Study Day 42. A follow-up visit (Study Day 70)
is
performed 4 weeks after the last day investigational drug is administered for
those subjects
who do not continue into the open-label extension protocol.
[0109] Treatment duration is six weeks. Subjects are screened no more thait 21
days prior to start of treatment and may have a follow-up visit 4 weeks after
the last day on
which investigational diug is administered. Thus the maximum duration of the
study for
each subject is 13 weeks. Pimavanserin or matching placebo is administered in
tablet form,
once daily by mouth in either 10 mg (2x 5mg tablets) or 40 mg (2x 20 mg
tablets) doses.
Su bjects
[0110] The study population includes subjects who are male or female of 40
years
of age or older with a clinical diagnosis of idiopathic Parkinson's disease
with a minimum
duration of 1 year, defined as the presence of at least three of the following
cardinal features,
in the absence of alternative explanations or atypical features: rest tremor,
rigidity,
bradykinesia and/or akinesia, and postural and gait abnormalities. The
subjects have the
presence of visual and/or auditory hallucinations, and/or delusions,
occurri.ng during the four
weeks prior to the screening visit. These symptoms are severe enough to
warrant treatment
with an antipsychotic agent. The psychotic symptoms are present for >1 month
and have
developed after PD diagnosis was established. Subjects are on a stable dose of
anti-
Parkinson's medication for 1 month prior to Study Day 1(Baseline) and during
the triaL
Q2ncomitant TherW
101111 Concomitant medications are kept to a minimum during the study.
Subjects are on a stable dose of anti-Parkinson's medication for at least one
month prior to
Study Day 1(Baseline) and remain on this stable dose throughout the study.
Screening Assessments
Mini Mental State Examination (MMSE)
[0112] The mini-mental state examination (MMSE) is a brief 30-point
questionnaire that is used to quantitatively assess cognition (Folstein M,
Folstein S, McHugh
P. Mini-Mental State. A practical method for grading the cognitive state of
patients for the
clinician. J Psych Res 1975;12:189-' 98), The MMSE test includes simple
questions.and
problems in a number of areas: the time and place of the test, repeating lists
of words,
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arithmetie, language use and comprehension, and copying a drawing. It can be
used to screen
for cognitive innpairment, to estimate the severity of cognitive impairment at
a given point in
time, to follow the course of cognitive changes in an individual over time,
and to document
an individual's response to treatment.
Neuropsychiatric InventqrX,fbIPI)
[0113] The Neuropsychiatric Inventory (NPI) was developed to assess
psychopathology in dementia patients (Cuminings JL, Mega M, Gray K, Rosenberg-
Thompson S, Carusi DA and Gombein J (1994). The Neuropsychiatric Inventory:
comprehcnsive assessment of psychopathology in dementia. Neurology, 44: 2308-
2314). It
evaluates 12 neuropsychiatric disturbances common in dementia: delusions,
hallucinations,
agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition,
abemant motor
behavior, night-time behavior disturbances, and appetite and eating
abnormalities. At
screening, the degree of the patient's psychosis is evaluated using the
hallucinations and
delusions domains of the NPI such that their total scare (frequency x severity
of
hallucinations + frequency x severity of delusions) is greater than or equal
to 4.
Assessment of Efficacy
Prim Endpoint - Scale for Assessment of Positive 5ymptom (, APW
[0114] The primary endpoint is a measure of the decrease in the severity
and/or
frequency of hallucinations and delusions, the core symptoms of PDP. The
primary endpoint
is assesscd using the SAPS (Andreason, N., Scale for the Positive Assessment
of Positive
Symptoms. Iowa City, IA, University of Iowa, 1984). The SAPS was designed to
measure
positive psychotic symptoms, especially in schizophrenia. Positive symptoms
include
dclusions, hallucinations, abnormalities in language and behavior, and
disordered thought
processes. Two of the SAPS subscales, Hallucinations and Delusions, are used
in this trial.
The selection of these domains is based principally on their relevance to the
specific
symptomatology of the PDP population, their utility for assessing the severity
(reflective of
frequency and duration) of these symptoms, and their high inter-rater
reliability.
[0115] A centralized rater service is used to control for inter-rater
variability
across sites, and to obtaiii a "blinded" rating of subject symptom severity
and change. A
remote blinded rater (i.e,, mental health evaluator) from the centralized
service conducts the
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SAPS in real-time using videoconference technology. The remote rater is blind
to the study
design, entrance criteria, visit number and treatment assignment. This SAPS
assessment is
administered at Study Day i(Baseline), Study Day 8, Study Day 15, Study Day,
29, and
Study Day 42.
[0116] The primary endpoint is the mean change in the combined SAPS
Hallucinations and Delusions scores from Baseline (Study Day 1) to Study Day
42. The
comparisons of interest is between the two pimavanserin dose arms and the
placebo arm
assuming the null hypothesis of no difference in change from Baseline (Study
Day 1). The
comparison is tested using the least square means from an ANOVA model.
Beca.use of the
potential increase in type I error due to multiple comparisons of two
pimavanserin dose arms
with placebo, Holm's sequential testing procedure is used. The most
significant of the two
comparisons of the primary endpoint uses an a=0.025 significance level. If
this comparison
is significant at that level, the second comparison is tested using an a=0.05
significance level.
The primary analysis uses the ITT population.
[0117) Secondary analyses on the primary endpoint is performed on the per
protocol population. Each component of the score, hallucinations and
delusions, is analyzed
separately for those subjects who have measurable baseline (Study Day 1)
scores. The SAPS
Hallucinations and Delusions score and each individual componcnt is also
evaluated at the
other study time points: Study Day 8, Study Day 15 and Study Day 29. Covariate
and
stratified analyses is performed to assess the effect of duration of illness,
duration of PD
treatment, and pretreatment MMSE level on the SAPS total and individual
hallucination and
delusion endpoints.
Secpndar~ Endpoints
(0118] The secondary efficacy endpoirrts are designed to address the effect of
pimavanscrin on motor symptoms of PD and clinical global impression of
severity of
psychosis and improvement iui psychosis. The Unified Parkinson's Disease
Rating Scale
(UPDRS) Parts II & III evaluation are analyzed by constructing 2-sided 95%
confidence
intervals on the difference between the pimavanserin dose arms and placebo
mean change
from Baseline (Study Day 1). The other secondary endpoint (Clinical Global
Impression
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Scale (CGI)) is summarized with descriptive statistics for each treatment arm.
Group
comparisons are assessed using ANOVA on the change from Baseline (Study Day
1).
Unified Parkinson's Discase Rating Scale (UPDRS)
[0119] The effect of pimavanserin on motor symptoms of PD are evaluated to
ensum that pimavanserin efficacy does not come at the expcnse of unacceptable
worsening of
Parkinsonism. The UPDRS is a comprehensive battery of motor and behavioral
indices
derived from the Columbia Scale (Fahn S, Elton RL, and Members of the UPDRS
Development Committee (1987). Unified Parkinson's Disease Rating Scale. In:
Fahn S,
Marsden CD, Calne DB, Lieberman A, eds: Recent developments in Parldnson's
disease.
Florhanm Park, NJ: Macmillan Health Care Information; pp 153-163), providing
explicit
rating criteria that have undergone considerable testing for reliability. All
six parts of the
UPDRS are administered at screening, on Study Day 1(Baseline) and on Study Day
42 to
evaluate the subject's PD; the evaluation on screening and Study Day 42 are
for descriptive
purposes. Only Parts II (Activities in Daily Living) and III (Motor
Examination) are
administered on Study Day 8, Study Day 15, and Study Day 29.
Clinical Global Impression Scale (CGII
[0120] The Clinical Global Impression (CGI) Scale (Guy, W., ECDFU
Assessment Manual for Psychopharmacology - Revised (DHEW Pubi No ADM 76-338).
Rockville MD, U.S. Department of IIealth, Education, and Welfare Public Health
Service,
Alcohol, Drug Abuse, and Mental Health Administration, NIMH Psychopharmacology
Research Branch, Division of Extramural Research Programs, 1976, p. 218-222)
is used to
analyze longitudinal changes (mean and percentage changes from Study Day
1(Baseline))
with an emphasis on severity and improvemcnt of psychosis. This scale has been
used
previously in subjects with PDP. The CGI allows the Investigator to determine,
in a global
sense, how severely psychotic these subjects are in the context of other PD
subjects (CGI -
Severity; CGI-S) and how much improvement is seen (CGI - Improvement; CGI-I).
This
instrument is a reliable scale that allows the Investigator to ignore baseline
dementia,
personality traits, and a"reasonable" degree of an.xiety that usually
accompanies clinical
motor fluctuations and other peculiar aspects of PD.
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Additional Efficacy Assessments
101211 The Caregiver Burden Scale, SCOPA-Sleep, and NMSQuest measures are
summarized with descriptive statistics for each treatment arm. Group
comparisons are
assessed using ANOVA on the change from Baseline (Study Day 1).
Caregiver Burden Solc
[01221 The Caregiver Burden Scale is administered to the subject's attending
caregiver. It allows assessment of the potential for pimavanserin to
ameliorate the stress on
caregivers (Zarit SH, Reever KE, Bach-Peterson J. Relatives of the impaired
elderly:
correlates of feeling of burden. Gerontologist 1980; 20:649-55). This self-
administered
22-item questionnaire is commonly used in caregivers of the dementia patient
population,
most specifically in caregivers of subjects with Alzheimer's disease.
Nonetheless, it has baen
reported to have high reliability in PD.
SCaPA-Sleeu
[0123] Sleep fragmentation is common in subjects with PD and may lead to
daytime sleepiness. PD subjects also wake up frequently during the night,
because of the
muscle pain associated with PD. The effect of pimavanserin on sleep in
subjects is evaluated
using the SCOPA-Sleep scale (Marinus J; Visser M; van Hilten JJ et al.
Assessment of sleep
and sleepiness in parkinson's disease. SLEEP 2003;26(8):1049-54).
NMS uest
[0124] The non-motor symptoms questionnaire (NMSQuest) is also used. The
NMSQuest was developed specifically for subjects Nvith PD; this newly
developed
questionnaire is self-adniinistered and enables a comprehensive assessment of
the range of
non-motor symptoms (NMS) such as depression, dementia, apathy, hallucinations,
dribbling
saliva, constipation, pair., genitourinary problems, and sleep disorders
(Chaudhuri, KR,
lviartinez-Martin, P., Shapira, A.H., et al., IntYrnational niulticenter pilot
study of the first
comprehensive self completed nonmotor symptoms questionnaire for Parkinson's
disease:
Thc NMSQuest study. Mov Disord, 2006).
Result
[0125] The ctudy indicates that pimavanserin (e.g., 10 nag or 40 mg
administered
once daily) is effective in treating Parkinson's disease psychosis, including
decreasing the
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severity and/or frequency of hallucinations and/or delusions. Specifically, an
improvement
in mean change in the combined SAPS Hallucinations and Delusions scores from
Baseline
(Study Day 1) to Study Day 42 is observed, indicating efficacy in treating
Parkinson's disease
psychosis. Further evidence is provided by an improvement in the CGI scale. In
addition,
the Parts II and III of the UPDRS measure does not significantly worsen from
Baseline to
Study Day 42, indicating that pimavanserin improves Parkinson's disease
psychosis without
significant worsening of Parkinsonism.
[01261 Finally, general improvement in non-motor symptoms is evidenced by an
improvement in the self-administered NMSQuest questionnaire. Specific
improvement in
sleep patterris is evidenced by improvement in the SCOPA-Sleep scale.
Administration of
pimavanserin also relieves burden on the primary care giver as evidenced an
improvement in
the Caregiver Burden Scale,
[01271 Although the invention has been described with reference to embodiments
and examples, it should be understood that numerous and various modifications
can be made
without departing from the spirit of the invention. Accordingly, the invention
is limited only
by the following claims.
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