Evaluate the Analgesic Efficacy and Safety of VVZ-149 Injections for Post-Operative Pain Following Laparoscopic Colorectomy

VVZ-149 is a dual antagonist of GlyT2 and 5HT2A. GlyT2 blockage increases inhibitory synaptic
transmission by glycine in the spinal cord, resulting in a reduction of pain transmissions to
the brain. 5HT2A blockage decreases descending serotonergic facilitatory modulation on pain
transmission by the brain and reduces nociceptor activation in peripheral nerves, which are
primary sources of pain in post-surgical pain. VVZ-149 has been shown to have comparable
efficacy to morphine in well controlled (blind, complete randomization with a positive
control) animal studies using rat models of post-operative pain and formalin-induced pain.
The PK/PD study in animals indicates that therapeutic plasma concentration in human subjects
will be 600-1,900 ng/ml. A clinical Phase 1 study performed in healthy subjects has shown no
clinically significant adverse events up to a plasma concentration level of 3,261 ng/ml other
than brief symptoms of mild nausea or dizziness, and mild somnolence when the plasma exposure
level is more than 2,000 ng/ml. A clinical Phase 2 study performed in laparoscopic
gastrectomy patients showed that patients who received VVZ-149 had reduced opioid consumption
after surgery compared to those who received placebo, without any significant drug-related
adverse events.

Inclusion Criteria:

- Subjects undergoing planned laparoscopic colorectal surgery.

- Ability to provide written informed consent.

- Ability to understand study procedures and communicate clearly with the investigator
and staff.

- American Society of Anesthesiologists (ASA) risk class of I to III.

Exclusion Criteria:



- Emergency or unplanned surgery.

- Repeat operation (e.g., previous surgery within 30 days for same condition).

- Cancer-related condition causing preoperative pain in site of surgery.

- Surgical duration (from incision to end of closure) > 5 hours.



- Women with childbearing potential (age 18-55) must undergo blood pregnancy test at
screening and then a urine pregnancy test preoperatively on day of surgery. Women with
a positive pregnancy test will be excluded. Women of childbearing potential must agree
to use at least one effective contraceptive method upon enrollment and for 30 days
following the last dose of the investigational product.

- Women who are pregnant or breastfeeding.

- Chronic pain diagnosis (e.g., ongoing pain at baseline with NRS ≥ 4/10).

- Unstable or poorly controlled psychiatric condition (e.g., untreated PTSD, anxiety, or
depression) Subjects who take stable doses of antidepressants and anti-anxiety drugs,
or procedure-related anti-anxiety drugs may be included.

- Unstable or acute medical condition (e.g., unstable angina, congestive heart failure,
renal failure, hepatic failure, AIDS).

- Body weight under 55 kg.



- Renal or hepatic impairment.

- History of alcohol, opiate or other drug abuse or dependence within 12 months prior to
Screening (TICS alcohol/drug screen will be performed at Screening).

- Ongoing or recent (within 30 days prior to surgery) use of opioids or antipsychotics.
However, subjects who receive procedure-related opioids (i.e., for a preoperative
colonoscopy) may be included.

- Alcohol consumption within 24 hours of surgery.

- Use of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen within 24 hours
of surgery. Exception: use of aspirin for cardiovascular prophylaxis is acceptable.

- Use of herbal agents or nutraceuticals (i.e., chaparral, comfrey, germander, jin bu
huan, kava, pennyroyal, skullcap, St. John's wort, or valerian) within 7 days prior to
surgery.



- Use of neuraxial or regional anesthesia related to the surgery.

- Use of local anesthetic wound infiltration > 20 ml of 1% lidocaine

- Use of ketamine, gabapentin, pregabalin, or lidocaine (>1 mg/kg) intra or
peri-operatively, or within 24 hours of surgery.

- Subjects with known allergies to hydromorphone.

- Subjects who received another investigational drug within 30 days of scheduled
surgery.

- Subjects who have long PR (>200 msec) or prolonged QTc (> 450 msec for males and > 470
msec for females) at Screening.