Phase I, single-centre, randomised, placebo-controlled, double-blinded study, with single ascending dose and multiple dose at maximum tolerated dose, evaluating the safety, tolerability and pharmacokinetics of ALX-0171, administered by pulmonary inhalation, in healthy male volunteers

The purpose of the study is to investigate how safe the compound is and how
well the compound is tolerated when administrated by pulmonary inhalation. The
study will also investigate how quickly and to what extent the compound is
absorbed and eliminated from the body (this is called pharmacokinetics).
Furthermore, the study will investigate if an immune response will occur in the
body.

This study is not intended to improve your health, but is necessary for the
further development of the new compound.

- to determine the safety and tolerability of escalating single doses and
multiple doses of ALX-0171
- to evaluate the dose-limiting toxicity (DLT) level of ALX-0171 and determine
the maximum tolerated dose (MTD)
- to evaluate the PK of escalating single doses and multiple doses of ALX-0171
- to evaluate the effect of ALX-0171 on exploratory (safety-related) biomarkers
- to assess the systemic and local immunogenicity of ALX-0171

DESIGN:
A single-centre, randomised, placebo-controlled, double-blinded study, with
single ascending dose (SAD) and multiple dose (MD) at MTD administered by
pulmonary inhalation in healthy male subjects

In the first SAD cohort two subjects (one active and one placebo) will be dosed
minimum 24 hours prior to the remaining two subjects (one active and one
placebo), all remaining cohorts are randomised in a 3:1 ratio

Study drug escalation will be done as follows:
single doses of ALX-0171 or placebo will be escalated until a study drug
related dose limiting toxicity occurs (CTCAE grade 3 or more, excluding
hypersensitivity reactions) and/or until the CMD of 3 mg/kg is reached.

In case that CTCAE grade 2 treatment emerging toxicity is seen in *2/4 or *3/8
subjects or 1 or 2 DLT an additional 4 subjects (3 active and 1 placebo) will
be recruited. In case a DLT is observed in * 3 Subjects, the MTD is defined as
the dose level below the dose at which of subjects have experienced a DLT.

In the MD part sixteen subjects are dosed in a 3:1 ratio and dosed twice daily
for five Days

SAD
PROCEDURES AND ASSESSEMENTS:
Screening and follow-up: clinical laboratory, physical examination (lung
auscultation included), lung function tests (spirometry, DLCO), exploratory
biomarkers: exhaled NO, 12-lead ECG, vital signs

at eligibility screening: medical history, Chest (thorax) X-ray, bronchial
(methacholine) challenge test, body weight and height, drug and alcohol screen,
HBsAg, anti HCV, anti-HIV 1/2, SAD 5 and 6 only: sputum induction

to be repeated upon submission: clinical laboratory, physical examination (lung
auscultation included), exhaled NO, alcohol breath test

at follow up only: immunogenicity, alcohol breathe test

at second follow up (SAD 5 and 6 only): sputum induction

Observation period: one period in clinic from -17 h up to 72 h after drug
administration on Day 1 followed by ambulatory visits on Days 5, 6 and 14 ± 1

Blood sampling: for pharmacokinetics of ALX-0171: pre-dose and 0.5, 1, 3, 6,
10, 12, 24, 30, 36, 48, 60, 72, 96 and 120 h post dose
for immunogenicity: pre-dose and Day 14 ± 1 post dose

Spirometry : pre-dose and 0.25, 0.5, 1, 2, 6, 10, 12, 24, 36, 48, 60 and 72 h
post dose

DLCO: 10, 24, 48 and 72 h post dose

Exhaled NO: 24, 48, 72, 96 and 120 h post dose

Alcohol breath test: 96 and 120 h post dose

Safety assessments:
adverse events: throughout the study;
physical examination: 72 h post dose;
lung auscultation: pre-dose and 0.25 and 1h post dose;
vital signs: pre-dose and 0.5, 1, 12, 24, 48 and 72 h post dose;
12-lead ECG: pre-dose and 0.5, 6, 10, 12, 24, 48 and 72 h post dose;
clinical chemistry: 24 and 72 h post dose;
limited safety lab: 12 h post dose;
exploratory safety lab: pre-dose and 12, 24, 48 and 72 h post dose

MD
PROCEDURES AND ASSESSEMENTS:
Screening and follow-up: clinical laboratory, physical examination (lung
auscultation included), lung function tests (spirometry, DLCO), exploratory
biomarkers: exhaled NO, 12-lead ECG, vital signs

at eligibility screening: medical history, Chest (thorax) X-ray, bronchial
(metacholine) challenge test, body weight and height, drug and alcohol screen,
HBsAg, anti HCV, anti-HIV 1/2, sputum induction

to be repeated upon submission: clinical laboratory, physical examination (lung
auscultation included), exhaled NO, alcohol breath test

at follow up only: immunogenicity, alcohol breathe test

at second follow up: sputum induction

Observation period: one period in clinic from -17 h up to 72 h after first drug
administration on Day 5 followed by ambulatory visits on Days 9, 10 and 12 ± 1

Blood sampling: for pharmacokinetics of ALX-0171: pre morning dose and 0.5, 3,
6, 10, 12 (= pre second dose) and 4 h post second dose on Day 1 and pre morning
dose on Days 2-4 and pre morning dose on Day 5 and 1, 3, 6, 10, 12, 16 and 24 h
(Day 6) post morning dose of Day 5
for immunogenicity: pre morning dose on Day 1 and on Day 12 ± 1 post dose of
Day 1

Spirometry: pre morning dose and 0.25, 0.5, 1, 2, 6, 10, 12 (=pre second dose)
and 0.25, 0.5, 1, 2 and 4 h post second dose on Day 1 and pre morning dose and
0.25, 0.5, 1, 2, 6, 10, 12 (=pre second dose) and 0.25, 0.5, 1, 2 and 4 h post
second dose on Days 2-5 and 24, 36, 48, 60 and 72 h post morning dose on Day 5

DLCO: 10 h post morning dose on Day 1 and pre morning dose on Days 2-4 and pre
morning dose and 2 h post second dose on Day 5 and 72 h post morning dose on
Day 5 (=Day 8)

Exhaled NO: pre morning dose on Days 2-5 and 24, 48, 72, 96 and 120 h post
morning dose on Day 5

Safety assessments:
adverse events: throughout the study;
physical examination: 72 h (= Day 8) post dose on Day 5;
lung auscultation: pre morning dose and 0.25, 1, 12 (= pre second dose) and
0.25 and 1 h post second dose on Day 1 and pre morning dose and 0.25, 1, 12 (=
pre second dose) and 0.25 and 1 h post second dose on Days 2-4 and pre morning
dose and 0.25, 1, 12 (= pre second dose) and 0.25 and 1 h post second dose on
Day 5 and 24 and 48 h post dose on Day 5;
vital signs: pre morning dose and 0.5, 1, 12 (= pre second dose) and 0.5, 1 and
4 h post second dose on Days 1-5;
12-lead ECG: pre morning dose and 12 (= pre second dose) and 2 and 4 h post
second dose on Day 1 and pre morning dose and 4 h post second dose on Days 2-4
and pre morning dose and 1, 3, 6, 12 (= pre second dose) and 4 h post second
dose on Day 5 and 24, 48 and 72 h post morning dose on Day 5;
clinical chemistry: pre morning dose on Days 2-5 and 24 and 72 h post morning
dose on Day 5;
limited safety lab: 12 h post morning dose (= pre second dose) on Days 1-5;
exploratory safety lab: pre morning dose and 12 h (= pre second dose) on Day 1
and pre morning dose on Days 2-5 and 24, 48 and 72 h post morning dose on Day 5

Bioanalysis: analysis of plasma ALX-0171 samples using a validated method by
sponsor

Study Medication
Active substance: ALX-0171
Activity: Inhibition of the fusion (F) protein of hRSV
Indication: treatment of human respiratory syncytial virus (hRSV) infection
Strength: 50 mg/ml
Dosage form: nebuliser solution

Treatment(s)
SAD
Cohort 1: a single dose of 2.1 mg/ subject ALX-0171 or placebo on Day 1
Cohort 2: a single dose of 7 mg/ subject ALX-0171 or placebo on Day 1
Cohort 3: a single dose of 21 mg/ subject ALX-0171 or placebo on Day 1
Cohort 4: a single dose of 70 mg/ subject ALX-0171 or placebo on Day 1
Cohort 5: a single dose of 140 mg/ subject ALX-0171 or placebo on Day 1
Cohort 6: a single dose of 210 mg/ subject ALX-0171 or placebo on Day 1

MAD
Cohort 7: a single dose of X mg/ subject ALX-0171 or placebo twice daily on
Days 1-5

Procedures: pain, light bleeding, heamatoma, possibility of an infetcion
Lungfunction tests: short of breath

See E9