Multiple Ascending Dose Study of TC-5619 in Elderly Subjects With Alzheimer's Disease

• Pharmacokinetic profiles [ Time Frame: Group 1: Days 1, 2, 28-32; Group 2: Day 1, 2, 4, 8, 10-14 ] [ Designated as safety issue: Yes ]
  Plasma concentrations (pharmacokinetic profiles) of TC-5619-238 over time (Groups 1 & 2) and urine (Group 2) samples after multipe doses
• Markers of inflammation in cerebrospinal fluid [ Time Frame: Group 1: Days 1, 2, 28-32; Group 2: Day 1, 2, 4, 8, 10-14 ] [ Designated as safety issue: No ]
  Changes in markers of inflammation in cerebrospinal fluid (Group 1 only)
• Markers of inflammation in plasma [ Time Frame: Group 1: Days 1, 2, 28-32; Group 2: Day 1, 2, 4, 8, 10-14 ] [ Designated as safety issue: No ]
  Dose related changes in markers of inflammation in plasma over time (Groups 1 & 2)

This is a Phase 1, multi-center, study design that will examine the safety, tolerability, maximum tolerated dose, and pharmacokinetics of TC-5619-238 in elderly subjects with and without Alzheimer's Disease.

This is a multi-center study design to establish the safety, tolerability, maximum tolerated dose, and pharmacokinetics of the alpha-7 receptor agonist TC-5619-238 in elderly subjects with Alzheimer's Disease. In addition, the study may provide preliminary evidence supporting the potential therapeutic benefits of using TC-5619-238 in subjects with Alzheimer's Disease, including modulation of systemic- and neuro-inflammation.

30 subjects (20 active, 10 placebo) w/Alzheimer's Disease will receive 28 days of dosing with 25mg of TC-5619-238 or placebo. Subjects will have an initial 3-day in-clinic assessment, followed by 23 days of out-patient treatment, and a final in-clinic assessment period of 6 days. CSF and plasma collection pre-dose on Days 1 and 28, PK will be collected on Days -1, 1, 2, 28-32.

Group 2 (without Alzheimer's Disease): First cohort will receive a daily dose of 50mg or matching placebo. Cohorts 2 and 3 will receive doses of 100mg and 150mg (or matching placebo), respectively. Subjects will have a screening period (Days -14 to -1), 11 days of in-clinic dosing (Days -1 to Day 10), 4 days in-clinic post-treatment follow-up (Days 11-14) and 1 day end-of-study safety assessment (Day 15). Each cohort will include 6 elderly subjects on active treatment and 2 elderly subjects on placebo treatment. Cohort dose escalation to next highest dose will occur after a safety assessment of tolerability for the cohort, plus a preliminary PK assessment on half of the treated subjects. Plasma collection pre-dose on Days 1, 2, 4, 8, and 10-14.

• Drug: TC-5619-238
  TC-5619-238 is supplied as a blend of active pharmaceutical ingredient (API) with excipients in a hard gelatin capsule (gelatin and titanium dioxide). Excipients used are microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
• Drug: Placebo
  Supplied as a blend of API with excipients in a hard gelatin capsule (gelatin and titanium dioxide). Excipients used are microcrystalline cellulose, colloidal silicon dixoide, croscarmellose sodium, and magnesium stearate.

• Placebo Comparator: Placebo
  Intervention: Drug: Placebo
• Active Comparator: TC-5619-238
  TC-5619-238 (tosylate sale) will be provided as a 25mg dose strength in hard gelatin capsules.
  Intervention: Drug: TC-5619-238

Inclusion Criteria (Groups 1 & 2):

• Normal body mass index (BMI)
• Non-smoking for a minimum of 3 months
• Subjects must be in reasonably good health, based on medical history, physical examination, vital signs, and ECG.

Group 1 Only:

• Subjects a Mini Mental State Examination score between 12-22, inclusive.
• Diagnosis of probable Alzheimer's Disease according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria
• Subjects must have a reliable caregiver.

Exclusion Criteria (Groups 1 & 2):

• Subjects with clinically significant heart disease, pulmonary disease, diabetes, neurologic or psychiatric disease (Group 1 subjects must have Alzheimer's Disease), or any other illness that could interfere with interpretation of study results.
• Subjects with a past or current history of seizures cannot participate.
• Current use of donepezil, rivastigmine or galantamine.