A randomized, double blind, placebo controlled, multi-centre study to assess the pharmacodynamics, pharmacokinetics, safety and tolerability of BYM338 in chronic obstructive pulmonary disease patients with cachexia (CBYM338X2204)

Muscle loss and dysfunction in COPD is linked to an increase in myostatin
levels, poor physical performance, decreased sense of well being and increased
mortality. The causes of muscle dysfunction in COPD are remain to be clearly
established. Possibilities include physical inactivity, hypoxia, nutritional
insufficiency, systemic inflammation and hormonal insufficiency.
Apart from pulmonary rehabilitation no pharmacologic or non-pharmacologic
interventions have been shown to improve muscle dysfunction associated with
COPD. Pulmonary rehabilitation increases muscle strength, physical performance
and quality of life in COPD patients, without a concomitant improvement in
airflow obstruction, indicating that improvement in the muscle dysfunction per
se can be clinically beneficial in these patients.
Imaging data demonstrate that the muscle loss in COPD particularly involves the
thigh and calf. Studies have demonstrated an association between the loss of
skeletal muscle in the lower limbs and symptoms and reduced function in COPD
patients. The 25-30% loss of muscle mass observed in COPD patients can manifest
as 20-30% lower quadriceps strength. Although muscle wasting can occur in all
stages of COPD, it tends to be more marked with more severe disease.
Myostatin, a member of the TGF-* family, is a protein that negatively regulates
skeletal muscle mass. Inhibition of myostatin increases muscle mass and
strength. The absence of myostatin in developing animals results in a
hypermuscular phenotype with an increased number and size of muscle fibers. In
the adult, myostatin is produced in skeletal muscle and circulated in the blood
in part as a latent inactive complex.
BYM338 is a fully human monoclonal antibody developed to bind competitively to
activin receptor type II B with greater affinity than myostatin, its natural
ligand.
The purpose of this study is to determine the effects of two doses of BYM338
(week 1 and 8) on skeletal muscle volume, mass, strength and physical function
in COPD patients with associated muscle wasting (cachexia). In addition, this
study will generate data on the pharmacokinetics, safety and tolerability of
BYM338 in COPD patients with cachexia and its effect on pulmonary function
measures in this population. The extended study duration will provide
information on the duration of BYM-induced changes in skeletal muscle and
patient function.

Primary: Assess the effect of i.v. infusions of BYM338 on muscle volume of the
thigh (assessed by MRI) at 4, 8, 16 and 24 weeks, compared to placebo, in COPD
patients with pulmonary cachexia.
Secondary: Effect on 6-minute walk test, safety and tolerability, PK and
immunogenicity.
Several exploratory objectives (see protocol page 29).

Randomized, double blind, placebo controlled, phase II study. First study in
COPD patients.
Randomization (1:1) to
* two i.v. doses of BYM338 (week 1 and 8)
* Placebo.
60 patients.
Follow-up 24 weeks
Internal DMB.

Treatment with BYM338 or placebo.

Risk: Adverse effects of study medication.
Burden: Study duration approx. 6 months. 13 visits. Duration 2-4 h.
2 i.v. infusions (250 mL), duration 2 hours, 4 hours observation thereafter.
Physical examination 8x.
Blood draw during 13 visits, 10-60 ml per occasion and approx. 400 ml in total.
Optional pharmacogenetic blood testing (10 ml).
Urine tests 13x.
Pulmonary function 8x
ECG 10x.
Muscle strength: respiratory: 5x, grip/leg/quadriceps/6 minute walk test/timed
up and go 6x.
Physical Monitoring device 6 x(24 h).
DXA whole body muscle mass 6x.
MRI thigh 5x.
Muscles biopsy (optional) 3x.
Questionnaires severity of symptoms, quality of life 6x.
Diary muscle symptoms.