USE OF PIMAVANSERIN 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 incorporated 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

[0003] 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 nonmotor 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. The prevalence of psychosis in PD may be more common in patients with dementia.

[0004] Development of psychosis 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

practice does not always diminish psychosis and provides only short-term antipsychotic benefit. In addition, it usually results 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-dopaminergic state.

[0007] Absorption and pharmacokinetics 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.

[0009] 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.

[0010] 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.

[0011] 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 food does not affect either the rate or extent of absorption of pimavanserin.

[0012] 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 associated with printed labeling advising the patient that the pharmaceutical composition can be taken with or without food.

[0013] 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 associated with printed labeling advising the patient that food does not affect either the rate or extent of absorption of pimavanserin.

[0014] Another embodiment disclosed herein includes a method of treating Parkinson's disease psychosis that includes administering pimavanserin to a Parkinson'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 pimavanserin to a Parkinson's disease patient in an amount sufficient to ameliorate the non-motor symptom.

[0016] 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 suffering from a sleep disorder.

[0017] Another embodiment disclosed herein includes a method of ameliorating a sleep disorder and psychosis in a subject suffering from Parkinson's disease that includes administering pimavanserin to a Parkinson's disease subject suffering from a sleep disorder and exhibiting one or more symptoms of psychosis.

[0018] 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.

[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 caregiver.

[0021] Another embodiment disclosed herein 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 DESCRIPTION OF THE DRAWINGS

[0022] 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 administered with and without food.

[0024] FIGURE 3 is a graph showing AUC values for pimavanserin administered with and without food.

[0025] FIGURE 4A is a bar graph illustrating the change in baseline in the UPDRS Parts II and IH scale upon administration of pimavanserin or placebo.

[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 scale 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 administration 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.

[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 pimavanserin or placebo.

[0033] FIGURE 7A is a bar graph illustrating the change in baseline in the CGI scale upon administration of pimavanserin or placebo.

[0034] 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 8 A 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 EMBODIMENT [0038] Pimavanserin, which is also known as N-(l-methylpiperidin-4-yl)-N-(4- fluorophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl)ca rbamide, N- [(4- fluorophenyl)methyl]-N-(l-methyl-4-piperidinyl)-N'-[[4-(2-me thylpropoxy)phenyl]methyl]- urea, 1 -(4-fluorobenzyl)- 1 -(I -methylpiperidin-4-yl)-3-[4-(2-methylpropoxy)benzyl]urea, or ACP-103 has the structure of Formula (I):

[0039] Methods suitable to make pimavanserin are known and described, for example, in U.S. Application Publication Nos. 2004-0213816, filed January 15, 2004, and

2007-0260064, filed May 15, 2007, both of which are incorporated herein by reference in their entirety.

[0040] 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 pimavanserin is an inverse agonist of the 5-HT2A receptor also indicates that it has the ability to antagonize the activation of 5- HT2A receptors that is mediated 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 antipsychotic, anti-dyskinesia, and anti-insomnia activity. Such properties of pimavanserin 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.

[0041] Pimavanserin exhibits selective activity at the 5-HT2A receptor. Specifically, pimavanserin lacks functional activity (ρEC ₅₀ or pKj < 6) at 31 of the 36 human monoaminergic receptors including 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2B, 5-HT3, 5-HT4, 5-HT6A, 5-HT7A, adrenergic-αlA, adrenergic-αlB, adrenergic-αlD, adrenergic-α2A, adrenergic-α2B, adrenergic- β2, dopamine-Dl, dopamine-D2, dopamine-D3, dopamine-D4, histamine-Hl, histamine-H2, and histamine-H3. Thus, pimavanserin provides high affinity at 5-HT2A receptors with little to no affinity to most other monoaminergic receptors.

[0042] In addition, pimavanserin exhibits high stability, good oral bioavailability, and a long half-life. Specifically, pimavanserin exhibited a slow clearance rate from in vitro human microsomes (< 10 μL/min-mg) and a half-life of approximately 55 hours upon oral administration to humans.

[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, malate, 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- FLUOROBENZYL>N-(l-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 tartrate salt are referred to as crystalline Form A and Form C, respectively, and are described in U.S. Patent Publication No. 2006-0106063, filed September 26, 2006 and entitled "SYNTHESIS OF N-(4-FLUOROBENZYL>N-(l-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.

(II)

(III)

(IV)

(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. The 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 alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of this invention.

Scheme A

[0046] Scheme A shows a general reaction scheme for forming the compound of Formula (II). As shown in Scheme A, the secondary amine and isocyanate can be combined to produce the 4-methoxybenzyl derivative of the compound of Formula (II). 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 (II).

Scheme B

4-isobu1oxybenzyl isocyanate

[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-trifluoroacetylpiperidine. 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

[0048] 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.

Scheme D

[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 herein can be purified using methods known to those skilled in art. Furthermore, isolated, substantially pure metabolites of pimavanserin, compounds of formulae (II), (III), (IV) and (V), are described in U.S. Provisional Patent Application No. 60/974,426, filed September 21, 2007 and entitled "N- SUB STITUTED PIPERIDINE DERIVATIVES AS SEROTONIN RECEPTOR AGENTS," which is incorporated herein by reference in its entirety.

[0050] Unless otherwise indicated, pimavanserin as used herein includes 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 information 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

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, constipation, 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, pimavanserin is administered to a Parkinson's patient to improve non-motor symptoms as demonstrated on a NMSQUEST questionnaire.

[0054] It was discovered that one non-motor symptom that pimavanserin is effective in treating is Parkinson's disease psychois (PDP). Thus, one embodiment includes a method of treating 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. In 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 further 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% decrease in the CGI 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, pimavanserin is administered to a Parkison's disease patient

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 IH (Motor Examination) of the scale. In various embodiments, the administration of pimavanserin at dosages sufficient to improve Parkinson'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.

[0059] 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-parkinsonism agent. In one embodiment, 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.

EXAMPLES Example 1 - Food Effect

[0061] The study was conducted as a single-center, randomized, open-label, three- way incomplete crossover design in 8 subjects. Subjects checked in on Day -1 and were 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:

Treatment A: 100 mg pimavanserin (5 mL of a 20-mg/mL pimavanserin solution) via nasogastric tube under fasted conditions,

Treatment B: 100 mg pimavanserin (5 x 20-mg tablets) orally under fasted conditions,

Treatment C: 100 mg pimavanserin (5 x 20-mg tablets) orally under fed conditions.

[0062] Two subjects each were randomized to receive one of the following treatment sequences: 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 administered with 240 mL of water.

Subjects

[0064] Healthy, young, nonsmoking males between the ages of 18 to 45 years with a body mass index (BMI) of 19 - 28 kg/m ² 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

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 months 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.

[0065] 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 ± 8.19 cm (range 163.0 to 189.0 cm). Body mass index averaged 24.1 ± 2.3 kg/m ² (range 21 to 28 kg/m ² ). 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

[0066] 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 (fed) 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

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 1 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 pharmacokinetic 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 analyte using 100 μL of heparinized human plasma.

[0069] 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 recorded, and standard ECG parameters including QRS, PR, QT, and QTc intervals were measured. In addition, continuous lead-II ECG monitoring was performed for the first 12 hours following the pimavanserin dose (the continuous lead-II monitoring was interrupted 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, amphetamines, alcohol, benzodiazepines, barbiturates, and urine creatinine) and alcohol tests were performed at screening and upon check-in to each treatment period.

[0070] Clinical laboratories were measured after an 8-hour fast and included the following: Hematology: hematocrit, hemoglobin, red blood cell count with indices (mean

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 Analysis

[0071] Pharmacokinetic parameters were calculated from plasma concentrations of pimavanserin as a free base by noncompartmental 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 O-oo, 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 obtain adjusted means, treatment ratios, and 90% confidence 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

Al-

was based on AUC 0-∞ 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/niL, 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-w 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 pimavanserin pharmacokinetics. Relative bioequivalence of the tablet formulation was 99.7%.

Table 1. Plasma pimavanserin pharmacokinetic parameters following single oral or nasogastric administration of 100 mg pimavanserin.

100 tng Pimavanserin

Solution Tablets Tablets

Parameter Statistics Fasted Fasted Fed

(N=B) (N=8) (N=8)

Cmax (πg/mL) Mean 51.39 57.01 52.15 CV% 15.6 18.0 20.6

Tmax (h) Median 6 6 10.5 Range 6-12 6-6 6-24.02

AUC 0-α> (h*ng/nriL) Mean 3847 3871 4269 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 26.55 26.83 25.28

CV% 15.0 19.5 28.5

Discussion

[0076] There was no effect of food on pimavanserin pharmacokinetics. 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 pimavanserin, 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 study

[0078] This study was conducted as an inpatient single-center, randomized, double-blind, placebo-controlled, escalating dose study in sequential groups. Two different groups of 6 subjects were enrolled in each dose level and received either placebo (N-2) or

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 pharmacokinetics (PK) of pimavanserin following the 24-hour serial blood/plasma collection on Day 1 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. Disease 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 potential or must have complied with double-barrier protection methods against conception. All subjects were required to have a mini-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 1 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 clinically significant pre-morbid psychiatric condition, or the presence or recent history within previous 3 months of significant hematological, renal, hepatic, endocrinological, 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 immunodeficiency virus (HIV) infection was also reason for exclusion. Subjects were required to provide informed consent before participating in the study.

[0080] A total of 12 subjects were enrolled in this study and all 12 subjects completed study procedures with no major protocol deviations, Subject demographics across dose groups were similar with the exception of weight 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 ± 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 ± 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 kg/m2 ). 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.

Study 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 1 through 14, subjects received daily oral doses of study medication in the morning. 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.

[0085] 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

pre-dose on Days 7, 10 and 13 for determination of trough plasma levels. On Day 14, serial blood samples were collected pre-dose (0 h) and 2, 4, 6, 9, 12, 24, 48, 72, 96, 144, and 216 h after study medication administration. Vital signs, electrocardiogram (ECG) measurements, neurological assessments, and clinical laboratory tests (measured after an 8 h 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 first 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 Analysis

[0086] PK parameters calculated from plasma concentrations following the single-dose pimavanserin administration on Day 1 of each treatment period included the following: maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and area under the plasma concentration time curve from time zero to the end of the dosing interval (τ) used for multiple dosing (24 hours), calculated by linear- trapezoidal summation [AUC(O-τ)], 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-τ)ss divided by the dosing interval (τ), time to maximum steady-state plasma concentration (Tmax,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 (t=24 hours) calculated by linear trapezoidal summation [AUC(0-τ),ss], steady-state elimination rate constant (λz,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)/ λz,ss, apparent oral clearance (CLpo,ss) calculated by Dose / AUC(0-τ)ss, percent fluctuation (%Fluct) calculated as (Cmax,ss-Cmin,ss)/Cavg,ss*100%, accumulation ratio [AR(I)] calculated as AUC(O- τ)ss/AUC(0-τ), 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.

[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 plasma on Day 1 were quantifiable for 24 hours post-dose following 25-mg and 100-mg pimavanserin administration.

[0089] 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.

[0090] Inter subject 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

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.

[0092] The pimavanserin concentration-time data in plasma were analyzed by noncompartmental 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 increase in proportion with escalating dose. Mean AUC(O-t) values were 198.5 and 761.5 ng ^χ h/mL on Day 1 following administration of 25 mg and 100 mg pimavanserin, respectively. A 4-fold increase in AUC(O-t) was observed for the 100 mg pimavanserin dose compared with the 25 mg pimavanserin dose, which suggested AUC(O-t) on Day 1 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 mg pimavanserin 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 ng ^χ h/niL). However, considering the small sample size (N=4) in this study, no inferences of dose proportionality can be made.

[0094] Mean tl/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 mean 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. The mean AUC(0-t),ss to AUC(O-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.

[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.

[0097] 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 similar between pimavanserin-treated subjects and placebo subjects. Twelve (100.0%) subjects experienced at least one episode of abnormal lead-II 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 ₃ 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 concomitant 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.

[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.

Example 3 - Parkinson's Disease Psychosis Phase II study fOlOO] 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 initial 20 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 escalated rather than any dose limitation due to tolerability.

[0101] The primary endpoint of the clinical trial was met 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 Parts II and III 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

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 (pθ.05) and this result was attributable to effects on hallucinations and delusions.

[0103] Figure 6 A depicts the change from baseline in the total SAPS scale as well as the hallucinations and delusions sub scales. 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 significant 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.

[0105] Table 2 shows the mean baseline scores and mean change scores from baseline to study day 28 for the pimvanserin 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).

Table 2. Parkinson's disease psychosis efficacy measures.

[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 treatment-related 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 pimavanserin and placebo-treated groups. Pimavanserin was safe across a wide variety of clinical measures assessed throughout the study, including ECG, vital signs, hematology, urinalysis and clinical chemistry.

Example 4 - Parkinson's Disease Psychosis Phase HI 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 arm with approximately 93 subjects randomized to each arm. The trial is conducted on an outpatient basis with visits conducted at screening, on Study Day 1 (Baseline), Study Day 8,

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 than 21 days prior to start of treatment and may have a follow-up visit 4 weeks after the last day on which investigational drug 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.

Subjects

[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, occurring 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.

Concomitant Therapy

[0111] 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 (MMSB)

[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: 189-198). The MMSE test includes simple questions and problems in a number of areas: the time and place of the test, repeating lists of words,

arithmetic, language use and comprehension, and copying a drawing. It can be used to screen for cognitive impairment, 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 Inventory (NPI)

[0113] The Neuropsychiatric Inventory (NPI) was developed to assess psychopathology in dementia patients (Cummings JL, Mega M ₅ Gray K, Rosenberg- Thompson S, Carusi DA and Gornbein J (1994). The Neuropsychiatric Inventory: comprehensive 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, aberrant 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 score (frequency x severity of hallucinations + frequency x. severity of delusions) is greater than or equal to 4.

Assessment of Efficacy

Primary Endpoint - Scale for Assessment of Positive Symptoms (SAPS)

[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 assessed 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 delusions, 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 obtain a "blinded" rating of subject symptom severity and change. A remote blinded rater (i.e., mental health evaluator) from the centralized service conducts the

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 1 (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. Because 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 α=0.025 significance level. If this comparison is significant at that level, the second comparison is tested using an α=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 component 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.

Secondary Endpoints

[0118] The secondary efficacy endpoints are designed to address the effect of pimavanserin on motor symptoms of PD and clinical global impression of severity of psychosis and improvement in 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

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 Disease Rating Scale fUPDRS)

[0119] The effect of pimavanserin on motor symptoms of PD are evaluated to ensure that pimavanserin efficacy does not come at the expense 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 Parkinson's disease. Florham 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 (CGI)

[0120] The Clinical Global Impression (CGI) Scale (Guy, W., ECDEU Assessment Manual for Psychopharmacology - Revised (DHEW Publ No ADM 76-338). Rockville MD, U.S. Department of Health, 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 improvement 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 anxiety that usually accompanies clinical motor fluctuations and other peculiar aspects of PD.

Additional Efficacy Assessments

[0121] 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). Carefiiver Burden Scale

[0122] 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 been reported to have high reliability in PD.

SCOPA-Sleep

[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). NMSOuest

[0124] The non-motor symptoms questionnaire (NMSQuest) is also used. The NMSQuest was developed specifically for subjects with PD; this newly developed questionnaire is self-administered and enables a comprehensive assessment of the range of non-motor symptoms (NMS) such as depression, dementia, apathy, hallucinations, dribbling saliva, constipation, pain, genitourinary problems, and sleep disorders (Chaudhuri, KR, Martinez-Martin, P., Shapira, A. H., et al., International multicenter pilot study of the first comprehensive self completed nonmotor symptoms questionnaire for Parkinson's disease: The NMSQuest study. Mov Disord, 2006).

Result

[0125] The study indicates that pimavanserin (e.g., 10 mg or 40 mg administered once daily) is effective in treating Parkinson's disease psychosis, including decreasing the

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.

[0126] Finally, general improvement in non-motor symptoms is evidenced by an improvement in the self-administered NMSQuest questionnaire. Specific improvement in sleep patterns 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.

[0127] 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.