Bisnorcymserine in Healthy Adult Volunteers

Objective: Alzheimer s disease (AD) is a progressive neurodegenerative disease that impairs
memory and other cognitive abilities, as well as behavior and the ability to function
independently. It is the most common cause of dementia among older people. Alzheimer s
disease is characterized by deficits in several neurotransmitter systems, most prominently
acetylcholine (Ach). The cholinergic deficit in the AD brain is associated with the cognitive
and functional symptoms in AD. Restoring this deficit in the cholinergic system is one proven
approach for symptomatic treatment in AD. The action of Ach in the brain is terminated mainly
by two enzymes called cholinesterases (ChEs): acetylcholinesterase (AChE) and
butyrylcholinesterase (BChE). Inhibitors of these enzymes therefore augment the activity of
surviving Ach neurons in AD. All ChEs inhibitors currently approved for the treatment of AD
mainly inhibit AChE and, secondarily and to a varying extent, BChE. Reversible and
brain-specific BChE inhibitors have been developed as a class of drugs called cymserine
analogs. Scientists at the NIA/NIH have developed a novel BChE inhibitor called
Bisnorcymserine (BNC). Pre-clinical evidence suggests that BNC may be a safe treatment for
Alzheimer s disease. Based on this, we propose this first-in-human study to evaluate the
safety, tolerability and pharmacokinetics of single doses of BNC tartrate administered
orally.

Study population: Healthy volunteers aged 55 years and older.

Design: Double blind placebo-controlled Phase I clinical Trial of single oral doses of BNC
doses in an ascending schedule: 20, 40mg, 80 mg, 160 mg, 270 mg and 380 mg. Each dose will be
tested in groups of 8 subjects. Six subjects in each cohort will receive active drug and two
will receive placebo. Subjects will be kept in the unit and followed clinically and with
laboratory tests for adverse effects for 32 hours; they will return for a follow-up visit to
assess safety in about 7 days. A Data Safety Monitoring Board will evaluate the safety and
tolerability associated with each dose level before the next higher dose is tested in a new
cohort. All research will be performed at the National Institute on Aging (NIA) Clinical
Research Unit located on the 5th floor of MedStar Harbor Hospital.

- INCLUSION CRITERIA:

- Age greater than or equal to 55 years.

- Mini Mental State Examination (MMSE) > 27 at screening and at Visit 2-Day 1.

- Women who are able to become pregnant must have a negative urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) at screening and prior to
study drug administration

- Both men who are able to father children and women of childbearing potential must be
willing to use an adequate method of contraception (see section 7) to avoid conception
throughout the study and for up to 30 days of study drug administration.

- Body mass index (BMI) of 18.5 to 34.0, inclusive, and a total body weight of > 50 kg
(110 pounds).

- Participants should be in good general physical and mental health as determined by
medical history, a baseline physical examination, vital signs, clinical laboratory
tests and electrocardiogram (EKG). Participants may have common age-related disorders
(such as hypertension, type II diabetes, dyslipidemia, hypothyroidism) as long as
these disorders are under good control by diet or medications.

- Able to sign own consent

EXCLUSION CRITERIA:

- Any clinically significant medical and psychiatric condition (including asthma active
within the last 10 years or COPD, and drug abuse and dependency).

- Subject has used any tobacco products in the past 3 months.

- A history of significant allergy to any drug or systemic allergic disease (e.g.,
urticaria, atopic dermatitis).

- Pregnant or lactating females.

- Subject with a positive urine test for drugs of abuse at screening or at admission to
the clinic on study Day 1.

- Subject has consumed any alcohol within 48 hours prior to Visit 2; and cannot or is
unwilling, thereafter to abstain from drinking alcohol for the remainder of the
subject s study participation.

- Subject is positive for HIV, hepatitis B surface antigen or hepatitis C antibody tests
at screening.

- Any clinically significant laboratory abnormality. These include:

- CBC: WBC < 3000 /mm^3; Hb < 12 g/dL; Liver function tests: ALT, AST, Bilirubin
(total, direct, indirect), Alkaline Phosphatase > 1.5 x the upper normal limit of
the laboratory

- Serum Creatinine > 1.5 mg/dL; Serum Glucose >150mg/dL

- Resting supine blood pressure outside of a systolic blood pressure range of
90-140 mmHg or a diastolic blood pressure outside a range of 50-90 mmHg on two
consecutive measurements taken up to 10 minutes apart.Resting supine heart rate
greater than 100 bpm or less than or equal to 55 55 bpm on two consecutive
measurements taken up to 10 minutes apart.

- Any clinically significant abnormality on screening 12-lead EKG (e.g., heart
block, conduction disorders, ventricular and/or atrial arrhythmias).

- Routine or PRN consumption of the following herbal/dietary supplements are not
permitted, if used within 2 weeks before the screening visit at doses higher than the
recommended daily intake: Omega-3 fatty acids (> 1000 mg/day), Vitamin E (>
400IU/day). Ginkgo biloba, St. John's wort and ginseng are not permitted, if used at
any dose within 2 weeks before the screening visit.

- Medications that are excluded are:

- Insulin

- Anti-parkinsonian medications (such as levodopa/carbidopa, amantadine,
bromocriptine, pergolide, selegiline)

- Typical or atypical neuroleptics

- Narcotic analgesics at any dose within 4 weeks prior to screening.

- Long-acting benzodiazepines or barbiturates (such as clonazepam, diazepam,
phenobarbital) within 4 weeks prior to screening

- Short-acting anxiolytics or sedative hypnotics more frequently than 2 times per
week within 4 weeks prior to screening (sedative hypnotics should not be used
within 102 hours of study drug administration)

- Medications with known significant cholinergic or anticholinergic side effects
(such as pyridostigmine, tricyclic antidepressants, meclizine, oxybutynin) within
4 weeks prior to screening

- Anti-convulsants (such as phenytoin, Phenobarbital, carbamazepine) within 2
months prior to screening

- Medications for Alzheimer s disease (such as donepezil or memantine)

- Beta-Blockers

- Corticosteroids (Systemic)

- Neuromuscular-Blocking Agents (non-depolarizing)

- Succinylcholine

- Any other drug (including prescription, over the counter medications and
supplements) that may pose a risk to the subject or produce overlapping side
effects with the study medication. Participants will not be taken off of
medications for the purpose of this study.

- Donation or loss of 400 mL or more of blood within 56 days prior to and subsequent to
screening.

- Participation in another research study involving an investigational drug within 30
days or 5 half-lives, whichever is longer.

- Known allergy or hypersensitivity to the investigational study drug and to the
microcrystalline cellulose used as placebo.