MLN3126 Single Rising Dose Study

The drug tested in this study is called MLN3126. The study evaluated the safety,
tolerability, pharmacokinetics (PK), pharmacodynamics and the potential effect of food on
the PK of MLN3126 and its M-I metabolite following single oral dose administrations.

This study planned to enroll approximately 48 healthy participants, who were to be enrolled
in 1 of the 6 dose cohorts or matching placebo in an ascending fashion. Participants were
randomly assigned to MLN3126 or placebo within each cohort- which remained undisclosed to
the participant and study doctor during the study (unless there was an urgent medical need):

- Cohort 1 - MLN3126 300 mg or matching placebo

- Cohort 2 - MLN3126 600 mg or matching placebo

- Cohort 3 - MLN3126 1000 mg or matching placebo

- Cohort 3 - MLN3126 1000 mg or matching placebo (fed regimen)

- Cohort 4 - MLN3126 1500 mg or matching placebo

- Cohort 5 - MLN3126 2000 mg or matching placebo

- Cohort 6 - Did not taken place due to termination of the study

All participants were asked to take the required tablets at the same time throughout the
study.

This single-centre trial was conducted in The United States. Participants were confined to
the clinic for 5 days, and were contacted by telephone on day 14 (±2days) for a follow-up
assessment.

This study was terminated after completion of Cohort 5 due to findings of study site
non-compliance to Good Clinical Practice (GCP) regarding study documentation. There were no
safety concerns.

Inclusion Criteria:

1. In the opinion of the investigator, the participant was capable of understanding and
complying with protocol requirements.

2. The participant or, when applicable, the participant's legally acceptable
representative signed and dated a written, informed consent form and any required
privacy authorization prior to the initiation of any study procedures.

3. Is a male or female adult, aged 18 to 55 years, inclusive, at the time of informed
consent and study drug dosing.

4. Is a healthy adult male or female subject as evidenced by their medical history,
complete physical examination, vital signs, ECG, and safety laboratory evaluations.

5. Weighed at least 45 kg (99 lbs) and had a body mass index (BMI) between 18 and 30.0
kg/m2 inclusive at Screening.

6. A male participant who was nonsterilized and sexually active with a female partner of
childbearing potential agreed to use adequate contraception from signing of informed
consent throughout the duration of the study and for 12 weeks after last dose. In
addition, participants were advised not to donate sperm during this period.

7. A female participant of childbearing potential who was sexually active with a
nonsterilized male partner agreed to use routinely adequate contraception from
signing of informed consent throughout the duration of the study to their next
postconfinement menstruation. In addition participants were advised not to donate ova
during this period.

Exclusion Criteria:

Any participant who meets any of the following criteria will not qualify for entry into
the study:

1. Has received any investigational compound within 30 days prior to the first dose of
study medication.

2. Is an immediate family member, study site employee, or in a dependent relationship
with a study site employee who is involved in the conduct of this study (eg, spouse,
parent, child, sibling) or may consent under duress.

3. Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary,
hepatic, renal, metabolic, GI, or endocrine disease or other abnormality, which may
impact the ability of the participant to participate or potentially confound the
study results.

4. Has a known hypersensitivity to any component of the formulation of MLN3126.

5. Has a positive urine drug result for drugs of abuse at Screening or Check-in (Day
-1).

6. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol
abuse (defined as 4 alcoholic beverages per day) within 1 year prior to the Screening
visit or is unwilling to agree to abstain from alcohol and drugs throughout the
study.

7. Has taken any excluded medication, supplements, or food products listed in the
Excluded Medications and Dietary Products section of the protocol.

8. If female, the participant is pregnant or lactating or intending to become pregnant,
or intending to donate ova, before or during, the study; including the timeframe to
participant's next postconfinement menstruation after participating in this study.

9. If male, the participant intends to donate sperm during the course of this study or
for 12 weeks thereafter.

10. Has evidence of current cardiovascular, central nervous system, hepatic,
hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious
allergy, asthma hypoxemia, hypertension, seizures, or allergic skin rash. There is
any finding in the participant's medical history, physical examination, or safety
laboratory tests giving reasonable suspicion of a disease that would contra indicate
taking MLN3126 or a similar drug in the same class, or that might interfere with the
conduct of the study. This includes, but is not limited to, peptic ulcer disease,
seizure disorders, and cardiac arrhythmias.

11. Has current or recent (within 6 months) GI disease that would be expected to
influence the absorption of drugs (ie, a history of malabsorption, any surgical
intervention known to impact absorption [eg, bariatric surgery or bowel resection],
esophageal reflux, peptic ulcer disease, erosive esophagitis or frequent [more than
once per week] occurrence of heartburn).

12. Has a history of cancer or other malignancy, except basal cell carcinoma that has
been in remission for at least 5 years prior to Day 1.

13. Has a positive test result for hepatitis B surface antigen, antibody to hepatitis C
virus, at Screening or a known history of human immunodeficiency virus infection.

14. Has used nicotine-containing products (this includes, but is not limited to,
cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28
days prior to Check-in Day -1. Cotinine test is positive at Screening or Check-in
(Day -1).

15. Has poor peripheral venous access.

16. Has donated or lost 450 mL or more of his or her blood volume (including
plasmapheresis), or had a transfusion of any blood product within 45 days prior to
Day 1.

17. Has a Screening or Check-in (Day -1) abnormal (clinically significant) ECG. Entry of
any subject with an abnormal (not clinically significant) ECG must be approved, and
documented by signature by the principal investigator or medically qualified
subinvestigator.

18. Has abnormal Screening or Check-in (Day -1) laboratory values that suggest a
clinically significant underlying disease or participant with the following
laboratory abnormalities: alanine aminotransferase (ALT) and/or aspartate
aminotransferase (AST) >1.5×ULN.

19. Has QT interval with Fridericia correction method (QTcF) >430 ms for men and >450 ms
for women or PR outside the range of 120 to 220 ms confirmed upon repeat testing
within a maximum of 5 minutes, at the Screening Visit or Check-in (Day -1).