A Randomized, Double-Blind, Placebo-Controlled, Single-Dose, Dose-Escalation STUDY of MORAb-022 in Healthy SUBJECTS and Subjects with Rheumatoid Arthritis.

The drug to be given, MORAb-022 is a new, investigational compound that may
eventually be used for the treatment of rheumatoid arthritis (RA). RA is a
chronic, systemic inflammatory disorder that may affect many tissues and
organs, but principally attacks the joints producing an inflammatory reaction
(synovitis) that often progresses to destruction of the soft tissue of the
joints. RA can also produce diffuse inflammation in the lungs, pericardium (a
double-walled sac that contains the heart), pleura (tissue that surrounds the
lungs), and sclera (white part of the eye), and also elevations of the skin,
most common in subcutaneous tissue under the skin. Although the cause of
rheumatoid arthritis is unknown, autoimmunity plays a decisive role in its
chronic character and progression.
MORAb-022 is a human monoclonal antibody and is a therapeutic antibody being
developed for the treatment of autoimmune diseases including rheumatoid
arthritis.

Primary:
to evaluate the safety and tolerability of single escalating intravenous (IV)
doses of MORAb-022 in healthy subjects and subjects with rheumatoid arthritis
(RA)

Secondary:
- to evaluate the pharmacokinetics (PK) of single escalating IV doses of
MORAb-022 in healthy subjects and subjects with RA
- to explore the pharmacodynamic (PD) effect of single escalating IV doses of
MORAb-022 in healthy subjects and subjects with RA
- to assess the effect of single escalating IV doses of MORAb-022 on the
disease activity score (DAS) and American College of Rheumatology scores (ACRn)
of subjects with RA

Design:
A randomized, double-blind, placebo-controlled, single-ascending dose study in
healthy male and/or female subjects and subjects with RA; Groups 1-3 will
consist of six healthy male and/or healthy female subjects each receiving a
single iv infusion of MORAb-022 or placebo (four verum and two placebo); Groups
4-6 will consist of eight healthy male and/or healthy female subjects each
receiving a single iv infusion of MORAb-022 or placebo (six verum and two
placebo); at the first dose level two subjects (one verum and one placebo) will
be dosed and monitored for twenty-four hours before the next two subjects will
be dosed (no more than two subjects will be dosed each day in Group 1); in
parallel with dose escalation in healthy subjects, there will be a dose
escalation of MORAb-002 in three cohorts (Groups 7-9) of four RA patients each
receiving a single iv infusion of MORAb-022 or placebo (three verum and one
placebo).

Procedures and assessments
Screening and follow-up:
Clinical laboratory, SP-D level, physical examination, pulmonary function test
(PFT), vital signs (including body temperature and respiratory rate), weight,
12-lead ECG; at eligibility screening: chest X-ray, medical history, alcohol
and drug screen, GM-CSF autoAb, height, PPD test, HBsAg, anti HCV, anti-HIV 1/2
and serum pregnancy test (females only); physical examination, weight, vital
signs (including body temperature and respiratory rate), 12-lead ECG (in
triplicate), clinical laboratory, alcohol and drug screen, urine pregnancy test
(females only), PFT and SP-D level to be repeated upon admission; follow-up on
Day 85; the follow-up visit will be repeated every 2 weeks until MORAb-022 has
been cleared 90% from the body.

Observation period:
One period in clinic from -17 h up to 48 h for healthy volunteers (HV) and 24
hr for RA patients after drug administration and ambulatory visits on Days 5,
8, 15, 29, 43 and 57 and a telephonic contact on Day 71.

Blood sampling:
- for pharmacokinetics of MORAb-022 in plasma: pre-dose and 0.25, 0.5 (end of
infusion/post-start infusion), 0.75 (post-start infusion), 1, 2, 4, 8 and12 h
post-dose (post-start infusion) and once on Days 2, 3 (HV only), 5, 8, 15, 29,
43, 57 and 85 (follow-up)
- for pharmacodynamics of cytokines, IL-1, IL-6, TNF-* and IFN-*: pre-dose and
24 h post-dose and once on Days 3, 8, 15, 29, 43, 57 and 85 (follow-up)
- for pharmacodynamics of antibodies to MORAb-022: pre-dose and once on Days 57
and 85 (follow-up)
- for pharmacodynamics of CD11b in plasma: pre-dose and 8 h post-dose and once
on Days 2, 5, 8, 15, 29, 43, 57 and 85 (follow-up)
- for pharmacodynamics of circulating GM-CSF: pre-dose and 0.25, 0.5, 0.75, 2,
4 and 8 h post-dose and once on Days 3 (HV only), 5, 8, 15, 29, 43, 57 and 85
(follow-up)
- for pharmacodynamics of T-cell profile: pre-dose and 4 and 24 h post-dose
- for pharmacodynamics of CRP and SAA (RA patients only): pre-dose and 8 h
post-dose and once on Days 2, 5, 8, 15, 29, 43, 57 and 85 (follow-up)
- for DNA: once on Day -1
- for RNA: once on Day -1, post-dose on Day 1 and once on Days 2, 3, 5, 15 ,
43, 57 and 85 (follow-up)

DAS, ACRn and VAS scores (RA patients only):
Once on Day -1 and post-dose on Days 2, 5, 8, 15, 29, 43, 57 and 85 (follow-up).

Safety assessments:
Adverse events: throughout the study; vital signs (including body temperature
and respiratory rate): pre-dose and 1, 2, 4 and 8 h post-dose and once on Days
5, 8, 15, 29, 43 and 57; 12-lead ECG: pre-dose and 2 and 8 h post-dose and once
on Days 3 (HV only), 8, 15, 29 and 57; clinical laboratory: 24 h post-dose and
once on Days 5, 8, 15, 29, 43 and 57; SP-D level: 24 h post-dose and once on
Days 5, 8, 15, 29, 43 and 57; PFT: post-dose on Day 1 and once on Days 2, 3 (HV
only), 5, 8, 15, 29, 43 and 57; local tolerability at infusion site:
continuously on Day 1 and once on Days 2, 5, 8, 15, 29, 43, 57 and 85
(follow-up).

Bioanalysis:
- analysis of plasma MORAb-022 samples using a validated method by PRA
- analysis of cytokines, IL-1, IL-6, TNF-* and IFN-* samples using validated
methods by PRA
- analysis of antibodies to MORAb-022 samples using a validated method by PRA
- analysis of plasma CD11b samples using a validated method by PRA
- analysis of GM-CSF samples using a validated method by PRA
- analysis of GM-CSF auto Ab samples using a validated method by PRA
- analysis of T-cell profile using a validated method by PRA
- analysis of CRP samples using a clinical chemistry method by PRA
- analysis of SAA and SP-D samples using validated methods by PRA
- analysis of DNA samples using a validated method by Sponsor
- analysis of RNA and proteomics samples using a validated method by Sponsor

Study Medication
Active substance: MORAb-022
Activity: human monoclonal antibody targeting GM-CSF
Indication: rheumatoid arthritis (RA)
Strength: unknown
Dosage form: iv infusion

Treatments
Healthy subjects
Group 1: a single 30-min iv infusion of 0.0085 mg/kg (absolute dose of
approximately 0.6 mg) MORAb-022 or placebo on Day 1
Group 2: a single 30-min iv infusion of 0.042 mg/kg (absolute dose of
approximately 3 mg) MORAb-022 or placebo on Day 1
Group 3: a single 30-min iv infusion of 0.12 mg/kg (absolute dose of
approximately 10 mg) MORAb-022 or placebo on Day 1
Group 4: a single 30-min iv infusion of 0.36 mg/kg (absolute dose of
approximately 30 mg) mg MORAb-022 or placebo on Day 1
Group 5: a single 30-min iv infusion of 0.7 mg/jkg (absolute dose of
approximately 60 mg) MORAb-022 or placebo on Day 1
Group 6: a single 30-min iv infusion of 1.4 mg/kg (absolute dose of
approximately 120 mg) MORAb-022 or placebo on Day 1

RA patients
Group 7: a single 30-min iv infusion of 0.36 mg/kg MORAb-022 or placebo on Day 1
Group 8: a single 30-min iv infusion of 0.7 mg/kg MORAb-022 or placebo on Day 1
Group 9: a single 30-min iv infusion of 1.4 mg/kg MORAb-022 or placebo on Day 1

Procedures:
Pain, light bleeding, heamatoma, possibly an infection.

Medication:
There is no side effect information for humans as MORAb-022 has not been given
to humans before. In a previous study with monkeys, in which MORAb-022 was
administered daily in very high doses over a period of 4 weeks, the following
adverse effects were observed: increase in monocyte counts, increase in liver
weights, increase in macrophage infiltration in the lung and a decrease in
weight, length and coiling of uterine glands.
An adverse effect, associated with the activity of the compound is Pulmonary
Alveolar Proteinosis (PAP). PAP is a rare lung disease and symptoms include
dyspnea (shortness of breath), cough, low grade fever and weight loss. Although
theoretically these symptoms may occur, this has not been observed yet in
preclinical studies.
In the healthy volunteer part, up till cohort 4, MORAb-022 has been well
tolerated. There are no significant adverse events reported.