A phase 1, randomized, double-blind, placebo-controlled study evaluating the pharmacokinetics of capsule and tablet formulations of VX-150, including the effects of food and milk, the relative bioavailability of the tablet formulation, and the drug-drug interaction between VX-150 and Midazolam, in healthy adults

VX 150 (also called study compound) is a new investigational drug.
Investigational means the study compound is not approved for use and is still
being tested for safety and effectiveness. This study compound may eventually
be used for the treatment of pain. VX 150 is a blocker of sodium channels
(Nav), specifically the NaV1.8 channel. Sodium channels are channels present in
the outer layer of cells, which allow sodium ions to enter the cell in certain
circumstances. The NaV1.8 channel is primarily present in neurons that sense
pain and it plays an important role in pain signaling.

The purpose of Part A of the study is to investigate to what extent VX-150 is
tolerated when administered as a single dose (capsule). The effect of taking
the dose with food and milk on how quickly and to what extent VX-150 is
absorbed, distributed, broken down and eliminated from the body will be
investigated (this is called pharmacokinetics).

The purpose of Part B of the study is to investigate on how quickly and to what
extent VX-150 is absorbed, distributed, broken down and eliminated from the
body when administered for 11 or 14 days (capsule). In addition, the
interaction between VX-150 or placebo in combination with midazolam will be
investigated. Midazolam is a Food and Drug Administration (FDA)-approved,
commercially available short acting sedative used prior to diagnostic or
surgical procedures.

The purpose of Part C of the study is to investigate to what extent VX-150 is
tolerated when administered as a single dose (tablet and capsule). The effect
of taking the dose with food and milk on how quickly and to what extent VX-150
is absorbed, distributed, broken down and eliminated from the body will be
investigated.

Part A:
The actual study will consist of 1 period during which the volunteer will stay
in the clinical research center in Groningen (Location UMCG) for 20 days (19
nights).

The volunteer will receive VX-150 twice under fasted conditions, once under fed
conditions and once with milk, as a capsule with 240 milliliters of (tap)
water.

Part B:
For Group 1, the actual study will consist of 1 period during which the
volunteer will stay in the clinical research center in Groningen (Location
UMCG) for 14 days (13 nights).

The volunteer will receive the study compound (midazolam, VX-150 or placebo)
under fed conditions, as a capsule or syrup (for midazolam only) with 240
milliliters of (tap) water. The volunteer will receive the study compound after
an overnight fast (at least 8 hours no eating and drinking).

For Group 2, the actual study will consist of 1 period during which the
volunteer will stay in the clinical research center in Groningen (Location
UMCG) for 16 days (15 nights).

The volunteer will receive the study compound (VX-150 or placebo) under fasted
condition, as a capsule with 240 milliliters of (tap) water. The volunteer will
receive the study compound after an overnight fast (at least 8 hours no eating
and drinking). Fasting will continue until 4 hours after administration of the
study compound. Then the volunteer will receive a lunch.

Part C:

The actual study will consist of 1 period during which the volunteer will stay
in the clinical research center in Groningen (Location UMCG) for 25 days (24
nights). However, based on the results of dosing on Day 1 and Day 6 it can be
decided not to conduct dose administrations on Day 16 and Day 21. In that case,
the volunteer will stay in the clinical research for 15 days (14 nights).

During the study the volunteer will receive VX-150 twice under fasted
conditions, once under fed conditions and once with milk, as a capsule or
tablet with 240 milliliters of (tap) water.

Part A:

Sequence Treatment Day 1 Treatment Day 6 Treatment Day 11 Treatment Day 16
1 750 mg once (fasted) 1250 mg once (fasted) 1250 mg once (fed) 1250 mg
once (milk)
2 1250 mg once (fasted) 750 mg once (fasted) 1250 mg once (milk) 1250 mg
once (fed)

Part B:

Group Day(s) Treatment Dosage Form How often
1 -1 - midazolam 2 mg - syrup once
1-10 - VX-150 1250 mg*) or matching placebo (fed) - oral capsule
once daily
11 - VX-150 1250 mg*) or matching placebo (fed), and - oral capsule
once
- midazolam 2 mg (fed) - syrup

2 1-14 - VX-150 1750 mg*) or matching placebo (fasted) - oral capsule once
daily

*) The dose level of VX-150 may be increased or decreased based on the data
from Part A of the study. The volunteer will be informed by an amendment if the
dose will change.

Part C:

Sequence Treatment Day 1 Treatment Day 6 Treatment Day 16*) Treatment Day
21*)
1 1500 mg once 1500 mg once 1500 mg once 1500 mg once
(fasted) as a capsule (fasted) as a tablet (fed) as a tablet
(milk) as a tablet
2 1500 mg once 1500 mg once 1500 mg once 1500 mg once
(fasted) as a tablet (fasted) as a capsule (milk) as a tablet
(fed) as a tablet

*) The dosing on Day 16 and Day 21 will only proceed if data from Day 1 and Day
6 supports further evaluation of the tablet dosage form.

For Part A, B and C:

VX-150
As of November 15, 2016 approximately 141 healthy subjects, and 124 patients
with osteoarthritis have received at least one dose of VX-150. Based on limited
experience so far, there are no known side effects for the study compound.
Overall, the study compound has been well tolerated in humans. There were some
adverse events that occurred in subjects taking the study compound or an
inactive placebo, but we do not know whether they were due to the study
compound or other conditions. Some of these adverse events included:

• Headache
• Muscle or joint aches
• Rash
• Dizziness
• Fatigue
• Runny nose

Continued (blinded) analyses of 124 patients treated with osteoarthritis are
ongoing. Safety observations included 5 serious adverse events in 3 subjects
(pain in jaw with dyspnea, urinary tract infection, and urinary tract infection
with sepsis (infection in the blood)), all of which were considered not related
or unlikely related to study drug by the investigator. The most common adverse
events that occurred in 4 or more subjects were headache (6 subjects), joint
pain (6 subjects), dizziness (4 subjects), urinary tract infection (4
subjects), nasopharyngitis (4 subjects), and rash (4 subjects).

The study compound has been studied in laboratory animals (rats, dogs and
monkeys). There have been no harmful side effects or toxicities at any tested
dose level. Decreased body weight and lower food consumption were observed in
rats exposed to high doses of the study compound. These adverse effects and
possibly others, still unknown, adverse effects may occur during the study.

And also for Part B:

Midazolam
Midazolam is already on the market. Midazolam is a short-acting sedative used
prior to invasive diagnostic or surgical procedures. The most commonly reported
side effects include the following:
• Nausea
• Vomiting
• Skin rash
• Agitation
• Prolonged sleepiness
• Abnormal heart beat
• Laryngospasm (sudden violent closure of the voice box)
• Rhonchi (rattling in the chest)
• Serious respiratory problems including respiratory depression, airway
congestion or blockage and low oxygen level

• Less commonly reported adverse events include the following:
• Stopped breathing
• Decreased blood pressure
• Increased heart rate
• Hiccups
• Gagging
• Drooling
• Salivation
• Bad mood
• Excitation
• Aggression
• Mood swings
• Hallucinations (seeing or hearing things that are not there)
• Dizziness
• Confusion
• Lack of coordination
• Impaired speech
• Saying or doing things that you would not normally do
• Double vision
• Loss of balance
• Blurred vision

Midazolam has a boxed warning from the FDA because it can cause breathing
difficulties. Midazolam has been associated with severe breathing
difficulties, including slowed breathing, inability to breathe, airway
obstruction and low oxygen most often when used together with other central
nervous system depressants (for example, pain medications). A significant
decrease in the rate of your breathing can cause death if not treated
correctly. If breathing is too slow after taking the study compound, the
responsible physician will treat the volunteer, based upon PRA standard
procedures. The single 2 mg oral dose of Midazolam is a standard dose used in
drug-drug interaction studies and is less than the usual therapeutic dose of 10
to 20 mg. The dose is expected to be safe and well tolerated even when
co-administered with VX-150.