Double-blind, placebo-controlled, multiple ascending-dose study to investigate the safety and tolerability of AZ01 in healthy volunteers.

The drug to be given, AZ01, is a new, investigational compound that may
eventually be used for the treatment of Multiple Sclerosis. Multiple Sclerosis
is a disease of suspected autoimmune cause, in which the body's immune response
attacks a person's central nervous system (brain and spinal cord), affecting
the ability of nerve cells in the brain and spinal cord to communicate with
each other.
Interferon-beta (IFN-beta) has been established as standard of care in the
treatment of Multiple Sclerosis. IFN-beta is an endogenous compound involved in
inflammation processes. Though the currently available IFN-beta products
provide significant benefit, its non-desirable effects (like flu-like illness,
headache and fever) and the short activity requiring frequent injections (from
3 times weekly to weekly) may limit their utility. AZ01, a different form of
INF-beta with an extended activity, was designed to address these issues.

Primary:
- assess safety and tolerability and determine the maximum tolerated dose (MTD)
of repeated doses or a single dose of AZ01 given as a subcutaneous (SC) or
intravenous (IV) dose in healthy subjects. Dosing will not exceed the maximum
feasible dose, determined for this study to be 10 mg.

Secondary:
- evaluate the pharmacokinetic (PK) profile of AZ01 with repeated doses or a
single dose;
- evaluate biomarkers of AZ01 activity with repeated doses or a single dose of
AZ01.

Design:
This is a single-center, double-blind, placebo-controlled study with 3
successive escalating cohorts, each containing 8 subjects each. Five
additional cohorts were subsequently added to evaluate the safety, PK and PD of
AZ01 that had been manufactured with improved purification processes. In
Cohorts A through E, eight subjects will be randomly assigned at a 3:1 ratio
(AZ01:placebo) to receive study drug at 14 day intervals for a total of 3
doses. Eight subjects in Cohort F will be randomly assigned at a 3:1 ratio
(AZ01:placebo) to receive a three doses of study drug on Days 1, 19 and 43.
Eight subjects in Cohort G will receive two doses of study drug on Days 1 and
15. Eight subjects in Cohort H will receive one intravenous dose of 0.5 mg
study drug on Day 1. Eight subjects in Cohort I will receive one intravenous
dose of maximum 3.0 mg study drug on Day 1.

Cohort G:
Procedures and assessments
Screening and follow-up:
Medical history, medication history, clinical laboratory, physical examination,
ECG, vital signs (including blood pressure, pulse, oral temperature and
respiratory rate), TSH and pregnancy test (females only); at eligibility
screening: drug screen, anti-HBsAg, anti HCV, anti-HIV 1/2, weight, height and
BMI; to be repeated upon first admission: physical examination, weight, ECG,
vital signs (including blood pressure, pulse, oral temperature and respiratory
rate), clinical laboratory, alcohol and drug screen, medical history,
medication history, and pregnancy test (females only); to be repeated upon each
admission: urine drug screen; at follow up: AEs.

Observation period:
In clinic from -17 h up to 72 h after drug administration on Day 1 followed by
ambulatory visits on Days 6, 8 and 11, in clinic from -17 h up to 24 h after
drug administration on Day 15 followed by ambulatory visits on Day 20, 22, 25,
29, 32, 36 and 40; follow-up on Day 43.

Blood sampling
Serum/plasma samples:
AZ01 concentration: pre-dose on Days 1 and 15; post-dose at 6 and 12 hours on
Days 1 and 15; at 24 hours post-dose on Days 2, and 16; at 36 hours post-dose
on Days 2 and 16; and once on Days 3, 4, 6, 8, 11, 17, 18, 20, 22, 25, 29, 32,
36, 40, and 43.
Antibodies to AZ01: pre-dose on Days 1 and 15; and on Day 43; subjects with
measurable antibodies at Day 43 will be asked to be tested approximately every
3 months until either test is negative or 12 months after last dose.
Biomarker analysis: pre-dose on Days 1and 15; post-dose at 12 hours on Days
1and 15; at 24 hours post-dose on Days 2, and 16; at 36 hours post-dose on Days
2 and 16; and once on Days 3, 4, 6, 8, 11, 17, 18, 20, 22, 25, 29, 32, 36, 40,
and 43.
Whole blood samples:
Biomarker analysis: pre-dose on Days 1and 15; post-dose at 12 hours on Days
1and 15; at 24 hours post-dose on Days 2, and 16; at 36 hours post-dose on Days
2 and 16; and once on Days 3, 4, 6, 8, 11, 17, 18, 20, 22, 25, 29, 32, 36, 40,
and 43.

Safety assessments:
Medical and medication history: Complete review at Screening. Interim review
at Check-in; pre-dose Days 1 and 15; Days 2 and 16 (at 24 h post-dose); and in
addition once on Days 3, 4, 8, 17, 18, 22, 29, and 43.

Physical examination: Screening, Check-In, Day 15 (pre-dose) and Day 43
(follow-up).

12-lead ECG: Screening; Check-in; Day 15 (pre-dose); Days 3 and 17 (48 hours
post-dose); Day 43 (follow-up).

Vital signs: Screening; Check-in; Days 1 and 15 (pre-dose; and 2, 6, and 12
hours post-dose); Days 2 and 16 (24 and 36 hours post-dose); Days 3, 4, 17, and
18 (prior to discharge); and Days 8, 22, 29, and 43 (follow-up).

Adverse events:Days 1 and 15 (pre-dose; and 2, 6, and 12 hours post-dose); Days
2 and 16 (24 and 36 hours post-dose); Days 3, 4, 17, and 18 (prior to
discharge); and Days 8, 22, 29, and 43 (follow-up).

Bioanalysis:
- analysis of plasma AZ01 samples using a validated method by Sponsor
- analysis of antibodies to AZ01 samples using a validated method by Sponsor
- biomarker analysis using a validated method by Sponsor

Cohort H and I:
Procedures and assessments
Screening and follow-up:
Medical history, medication history, clinical laboratory, physical examination,
ECG, vital signs (including blood pressure, pulse, oral temperature and
respiratory rate), TSH and pregnancy test (females only); at eligibility
screening: drug screen, anti-HBsAg, anti HCV, anti-HIV 1/2, weight, height and
BMI; to be repeated upon first admission: physical examination, weight, ECG,
vital signs (including blood pressure, pulse, oral temperature and respiratory
rate), clinical laboratory, alcohol and drug screen, medical history,
medication history, and pregnancy test (females only); to be repeated upon each
admission: urine drug screen; at follow up: AEs.

Observation period:
In clinic from -17 h up to 72 h after drug administration on Day 1 followed by
ambulatory visit on Days 6, 8, 11, 15, 18, 22 and follow-up on Day 29.

Blood sampling
Serum/plasma samples:
AZ01 concentration: pre-dose on Day 1; post-dose at 6 and 12 hours on Day 1;
at 24 hours post-dose on Day 2 at 36 hours post-dose on Day 2; and once on Days
3, 4, 6, 8, 11, 15, 18, 22, and 29.
Antibodies to AZ01: pre-dose on Day 1; Day 8; Day 15; Day 22; and on Day 29;
subjects with measurable antibodies at Day 29 will be asked to be tested
approximately every 3 months until either test is negative or 12 months after
last dose.
Biomarker analysis: pre-dose on Day 1; post-dose at 12 hours on Day 1; at 24
hours post-dose on Day 2; at 36 hours post-dose on Day 2; and once on Days 3,
4, 6, 8, 11, 15, 18, 22, and 29.

Whole blood samples:
Biomarker analysis: pre-dose on Day 1; post-dose at 12 hours on Day 1; at 24
hours post-dose on Day 2; at 36 hours post-dose on Day 2; and once on Days 3,
4, 6, 8, 11, 15, 18, 22, and 29.

Safety assessments:
Medical and medication history: Complete review at Screening. Interim review
at Check-in; pre-dose Day 1; Day 2 (at 24 h post-dose); and in addition once on
Days 3, 4, 8, 15, 22, and 29.

Physical examination: Screening, Check-In, and Day 29 (follow-up).

12-lead ECG: Screening; Check-in; Day 3 (48 hours post-dose); Day 29
(follow-up).

Vital signs: Screening; Check-in; Day 1 (pre-dose; and 2, 6, and 12 hours
post-dose); Day 2 (24 and 36 hours post-dose); Days 3 and 4, (prior to
discharge); and Days 8, 15, 22, and 29 (follow-up).

Adverse events: Day 1 (pre-dose; and 2, 6, and 12 hours post-dose); Day 2 (24
and 36 hours post-dose); Days 3 and 4 (prior to discharge); and Days 8, 15, 22,
and 29 (follow-up).

Bioanalysis:
- analysis of plasma AZ01 samples using a validated method by Sponsor
- analysis of antibodies to AZ01 samples using a validated method by Sponsor
- biomarker analysis using a validated method by Sponsor

Study Medication:
Active substance : AZ01
Activity : unknown
Indication : unknown
Strength : 1.5 mg/mL
Dosage form : SC injection


Treatments:
Cohort G: 7.5 mg dose of AZ01 manufactured with improved purification process
administered as five SC injections of AZ01 or placebo on each dosing day (Days
1 and 15).
Cohort H: 0.5 mg dose of AZ01 manufactured with improved purification process
administered as one IV dose on one dosing day (Day 1).
Cohort I: Maximum 3.0 mg dose of AZ01 manufactured with improved purification
process administered as one IV dose on one dosing day (Day 1).

Light bleeding and possibly an infection may occur.