Putative Cognitive Enhancer VU319

Alzheimer's Disease (AD) is a chronic and irreversible neurodegenerative disease characterized by the deterioration of memory and other cognitive functions, progressive impairments in normal daily living, and severe neuropsychiatric symptoms and behavioral disturbances1,2. Currently, there is no available prevention or cure for AD. Therapeutic strategies for the cognitive impairments in AD involve only symptomatic treatments, primarily through enhancement of cholinergic neurotransmission using AChEIs1,2.

This first trial will be First-in-Human single ascending dose (SAD) phase 1 trial in healthy volunteers. One dose will be selected for expansion and evaluation of the effect of food on bioavailability. This Phase I trial, if successful, would serve as the basis for the design of multiple ascending dose (MAD) Phase I trial.

Primary objectives To establish the safety and tolerability of single dose (up to VU319 steady state) VU319 administration in healthy volunteers To establish the maximum tolerated dose of single dose (up to VU319 steady state) VU319 administration in healthy volunteers To characterize the plasma pharmacokinetics and urinary excretion of VU319 and metabolite after single dose oral administration in healthy volunteers Secondary objectives To establish the effect of food on the bioavailability and pharmacokinetic parameters of VU319 in healthy volunteers Exploratory Objectives To gain preliminary evidence that tolerable doses of VU319 engage central M1 receptors by 1) altering/enhancing cognitive performance, and 2) enhancing cortical event related potentials (ERP) as a measure of increased cognitive function in healthy volunteers This will be a double blind, randomized, placebo controlled, and sequential dose escalation in male or female healthy volunteers. Gender will be balanced to the extent possible. Volunteers will receive oral VU319 single dose administration in the fasted state. Subjects meeting entry criteria will be enrolled in successive dose escalating cohorts of 8 subjects each (2 placebo and 6 active drug per dose level). The dose levels will be tested sequentially until the Maximum Tolerated Dose (MTD) is reached, or saturation of exposure occurs, or sustained VU319 plasma level above the safe daily exposure determined from animal toxicokinetic studies is achieved.

The food effect sequence will be double blind, placebo controlled, two sequences, balanced and sequential cross-over in 12 healthy male or female volunteers (2 placebo and 10 active drug). Volunteers will receive oral VU319 single dose administration repeated once under either the fed (i.e. high fatty meal per FDA recommendations) or fasted state. The order of the two periods will be randomized and balanced with 6 subjects receiving treatment in the fed/fast or fast/fed order, respectively.

Clinical safety endpoints include adverse event and symptoms data, vital signs (HR, BP, Respiratory Rate, body weight), 12-lead ECG changes, and laboratory safety assessments (hematology, plasma biochemistry, coagulation, urinalysis).

Inclusion criteria

• Men and women aged 18 through 55 years, inclusive.
• Body mass index 18 through 32 kg/m2
• Determined as healthy based on screening medical history, physical examination, vital signs, complete neurological examination and 12-lead ECG (QTc interval with Fridericia's correction method recorded on screening and predose must be less than 450 msec for male and less than 470 in females).
• Clinical laboratory test result without clinically significant abnormalities at screening and at admission.
• Negative tests for Hepatitis B surface antigen, hepatitis C virus antibodies and human immunodeficiency virus (HIV-1 or HIV-2) antibody at screening.
• Nonsmokers (use of any nicotine containing product) or ex-smokers (have ceased smoking for at least 6 months and do not use any drug for smoking cessation).
• Negative screen for alcohol and drugs of abuse at screening and admission.
• For Women: Must have no child-bearing potential by reason of surgery or at least 1 year post-menopausal (i.e. 12 months without menstrual period), or menopause confirmed with an estradiol level of < 30 pg/mL and follicle-stimulating hormone level of > 40 IU/L at screening.
• For Men: Must be infertile (at least 3-months post-vasectomy), or truly abstinent of heterosexual intercourse, or heterosexual partner is not of child-bearing potential, or must agree to use an effective method of contraception (condom or occlusive cap with spermicidal foam/gel/film/cream/suppository) through the study and for 28 days after last dose of study drug.
• Able and willing to be available for the duration of the study.
• Willing and able to give written informed consent to participate.
• Able to understand and comply with protocol instructions.
• Agrees not to receive any vaccination within 21 days prior to admission and through Day 7 after final discharge.
• Agrees not to use nonprescription drugs, including vitamins, antacids, and herbal and dietary supplements within 7 days prior to admission and through 7 days after final discharge. Acetaminophen may be used at doses of ≤ 1 g/day, and ibuprofen may be used at doses of ≤ 1.2 g/day starting no earlier than 48 hours after discharge.
• Agrees not to use nicotine-containing products from screening through 48 hours after discharge.
• Agrees not to consume alcohol for the 72 hours prior to admission and through 48 hours after discharge.
• Agrees not to eat grapefruit or drink grapefruit juice within 7 days prior to admission and through 24 hours after discharge.
• Agrees to not drink caffeinated drinks from 72 hours prior to admission to discharge.
• Agrees not to eat or drink (except water) for 8 hours before and 4 hour after dosing for all SAD cohort participants (applicable to the Food Effect Cohort participants only for the fasted dose).
• Agrees to eat the high-fat standard breakfast 30 minutes pre-dose for participants in Food Effect Cohort.

Exclusion criteria

• Individuals with significant previous or ongoing disease or disorder, on the basis of history, physical exam, ECG, and laboratory tests, including for example: Cardiovascular diseases; hypertension; cancer or neoplasia; diabetes; hepatic, endocrine, metabolic, respiratory, renal, gastrointestinal (except appendectomy), dermatological or hematological disorders, Axis I or II psychiatric, substance use, or cognitive disorders.
• Clinically significant infection or inflammation at time of screening or admission.
• Clinically significant abnormalities upon physical/neurological exam at screening.
• Acute gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea) at time of screening or admission
• History of seeking advice from a physician or counselor for abuse or misuse of alcohol, non-medical drugs, medicinal drugs or other substance abuse, for example, solvents.
• Any current or previous use of Class A drugs such as illicit opiate use, cocaine, ecstasy, LSD, and amphetamines (Class B). Volunteers that admit to occasional past use of cannabis will not be excluded as long as they have a negative drugs-of-abuse test at screening and admission and have been abstinent for at least 3 months.
• An alcoholic intake greater than 21 units per week or unwillingness to stop alcohol consumption for the duration of the study. Note: 1 unit = 8 g ethanol (250 mL of beer, 1 glass wine [100 mL], 1 measure spirits [30 mL]).
• Use of medication (including OTC and oral contraceptive agents) within 14 days of admission that may affect the safety of the subject or any study assessment, in the opinion of the investigator.
• Use of prescribed centrally active or psychoactive agents within 28 days from admission.
• Requirement for any medication that would need to be continued during the study.
• Use of any investigational medication within 3 months prior to the start of this study or scheduled to receive an investigational drug during the course of this study.
• Have participated in more than 2 clinical trials within the 12 months prior to screening
• History of blood donation in the last 3 months.
• History of severe allergies or multiple adverse drug reactions.
• Any condition, which compromises ability to give informed consent or to communicate with the investigator as required for the completion of this study.
• The subject has been previously enrolled in the study.