Safety Study of AV-101 to Treat Capsaicin-Induced Pain

Healthy subjects will be randomized into three dose cohorts (360, 1,080, and 1,440 mg) to
receive daily oral doses of AV-101 for 14 consecutive days. Each cohort has 12 subjects on
active drug and 4 subjects on placebo. Safety, PK, and antihyperalgesic effects of treatment
with AV-101 will be assessed.

At the screening visit between Day -28 and Day -7 before randomization, 250 μg of capsaicin
will be intradermally delivered into the volar aspect of one forearm. Subjects must report a
pain score of at least 4 out of 10 to qualify for the study. On Day 1 and Day 14 the
following data are collected: (1) neurosensory testing (thermal sensation, thermal pain,
touch, and mechanical pain) on the forearm; (2) neurocognitive evaluation; and (3) 12-lead
electrocardiogram, blood pressure, heart rate, respiratory rate, and temperature. PK samples
will be collected on Days 1, 2, 14, and 15. The capsaicin-induced pain will be assessed at
screening, on Day 1, and Day 14. An intradermal injection of capsaicin into the forearm on
Day 1 and Day 14 will be followed by the efficacy measures. On Day 1 before administration
of the first dose, subjects will be given a paper diary to record daily self-administration
of each dose, concomitant medications, and adverse events during the 14-day treatment
period.

Inclusion Criteria:

- A subject will be eligible for participation in the full study only if all of the
following criteria are met:

1. Be male or female, aged 21 to 60 years inclusive, healthy, able and willing to
provide written informed consent to participate in the study.

2. Be able to read and speak English sufficiently to understand and follow the
study instructions, including completion of pain intensity rating scales.

3. For males, must use birth control (condom) to prevent fathering children; for
females must be nonlactating, not pregnant, and using a reliable contraception
method (e.g., abstinence, intrauterine device, hormonal birth control, or double
barrier method [male condom, female condom, or diaphragm plus a spermicidal
agent such as contraceptive foam, jelly, or cream]).

4. Have a visual analog pain score of at least 4 out of 10 at screening.

Exclusion Criteria:

- Subjects will be excluded from the study if any one or more of the following
conditions apply:

1. History of peripheral neuropathy or any chronic pain condition.

2. History of significant hepatic, ophthalmic (including previous or current
cataract), cardiovascular, renal, gastrointestinal, hematological, neurological,
endocrine (including diabetes), metabolic, pulmonary, or psychiatric disease.
Significance will be determined by the principal investigator.

3. Clinically significant abnormality on the screening electrocardiogram that in
the judgment of the investigator would place the subject at risk of cardiac
adverse event as a result of capsaicin injection or administration of AV-101.

4. Cognitive or psychiatric disorders that may diminish compliance with study
procedures.

5. Dermatopathology, skin hypersensitivity, or skin lesions in the areas of
capsaicin application.

6. Allergy to capsaicin or the study medication.

7. Current tobacco use.

8. Use of chemotherapy agents or history of cancer, other than resolved skin
cancer, within 5 years before the screening visit.

9. History of drug or alcohol abuse within 1 year before screening.

10. History of AIDS, testing as HIV positive, or use of antiretroviral therapy.

11. Use of, within 4 weeks before study drug dosing, any investigational drug, any
epidural or intrathecal agent, corticosteroids, topical anesthetics, topical
analgesics, central alpha agents (e.g., clonidine), alpha blockers (e.g.,
praxosin, terazosin), beta blockers, calcium channel blockers, or ACE
inhibitors.

12. Use within 7 days before and during the entire period of study drug dosing of
long-acting nonsteroidal anti-inflammatory drug (NSAIDs) such as piroxicam or
naproxen.

13. Use within 36 hours before and during the entire period of study drug dosing of
NSAIDs, aspirin, acetaminophen, antihistamines, sympathomimetics (e.g.,
pseudoephedrine and ephedrine), caffeine or alcohol.