A randomized, double-blind, placebo-controlled, multicenter, parallel group, dose-finding, pivotal, phase IIb/III study to evaluate the efficacy, safety and tolerability of intravenous BYM338 at 52 weeks on physical function, muscle strength, and mobility and additional long-term safety up to 2 years in patients with sporadic inclusion body myositis (CBYM338B2203)

Sporadic inclusion-body myositis (sIBM) is a very rare disease. The estimated
prevalence is 15-71 per million for all ages, and 51 per million over age 50.
Men are more often affected than women (2:1). The etiology is unknown. sIBM is
refractory to any treatments despite evidence of possibly secondary
degenerative and inflammatory features.
The disease is characterized by the insidious and asymmetric onset of proximal
and distal muscle weakness. Lower extremity complaints come typically in the
form of difficulty arising from chairs, and walking upstairs or downstairs. As
the disease progresses, lower extremity weakness leads to frequent falls. In
addition there is early onset of hand and finger weakness which eventually
impairs activities of daily living (e.g. writing, feeding, bathing, dressing,
brushing teeth). Of other important symptoms, dysphagia occurs in at least 40%
of patients due to esophageal and pharyngeal muscle involvement. Disease
progression is relatively slow but virtually all patients with sIBM require a
wheelchair, by about ten years of onset.
No treatments have been found to slow or reverse the progression of muscle
weakness in sIBM. Patients with sIBM have not demonstrated a clinically
meaningful response to agents used traditionally to treat inflammatory
myopathies, including corticosteroids, methotrexate, azathioprine or
cyclophosphamide. Intravenous immunoglobulin is used off-label in some centers,
but there is no evidence to support its longterm effectiveness. Similar overall
conclusions can be drawn on the efficacy of different immunotherapies such as
the anti-T lymphocyte inhibitor, the anti-TNF medication (etanercept) and
beta-inteferon 1A. Oxandrolone is still in an explorative phase and further
data are required before reaching conclusions on its potential benefits.
Therefore, there is currently a clear, unmet medical need in the treatment of
patients with sIBM.
Myostatin, a member of the TGF-* family, is a protein that negatively regulates
skeletal muscle mass. Inhibition of myostatin increases muscle mass and
strength.
BYM338 is a fully human monoclonal antibody developed to bind competitively to
activin receptor type II B with greater affinity than myostatin and activin,
its natural ligands. BYM338 is formulated for both i.v. and s.c. administration.
Since sIBM causes dramatic skeletal muscle atrophy, treatments that target
atrophy pathways in muscle, like BYM338, may be effective in this disease. Data
from study CBYM338X2205 on 14 patients with sIBM (11 active, 3 placebo) showed
statistically significant increases in BYM338 relative to placebo for both
muscle volume and lean body mass after a single dose of BYM338 30 mg/kg i.v.
was administered.
The purpose of the present dose-finding study is to demonstrate that at least
one dose regimen of BYM338 in sIBM patients improves physical function and
mobility when compared to placebo after 52 weeks of treatment.

Primary: to demonstrate that at least one dose regimen of BYM338 in sporadic
inclusion body myositis patients will increase the distance traveled as
measured by change from baseline at Week 52 of the 6 minute walking distance
test relative to placebo.
Secondary: Quadriceps muscle strength, Sporadic Inclusion Body Myositis
Functional Assessment, falls, lean body mass, Short Physical Performance
Battery. Dose-reponse in 6 minute walk test. Safety and tolerability.
Several exploratory objectives (see protocol page 19).

Randomized, double blind, placebo controlled, phase II study.
Randomization (1:1:1:1) to
* BYM338 10 mg/kg i.v. infusion every 4 weeks
* BYM338 3 mg/kg i.v. infusion every 4 weeks
* BYM338 1 mg/kg i.v. infusion every 4 weeks
* Placebo, administered as i.v. infusion every 4 weeks
Treatment duration until the last patient has completed the week 48 evaluation.
Maximal treatment duration approx. 2 years.
Post-treatment follow-up 8 weeks after last dose of study medication.
240 patients.
A maximum of 20% of patients with baseline 6 minute walk distance >400 meters
will be
randomized.
Independent Data Monitoring Committee.

Treatment with BYM338 or placebo.

Risk: Adverse effects of study medication.
Burden: Study duration approx. 1-2 years. 18-31 visits. Duration 4-8 h.
13-26 i.v. infusions (100 mL), duration at least 30 min.
Every visit:
* Physical examination.
* Columbia Suicide Rating Scale.
Every visit 1st year and every 12 weeks thereafter:
* Blood draw, 20-30 ml per occasion.
Every 8 weeks:
* Evaluation muscle strength
* 6 minute walk test
* Quadriceps strength
* Hand grip strength
* Short test battery balance, speed, getting up from a chair.
Every 12 weeks:
* ECG
* DEXA scan (approx. 0,02 mSv per occasion)
Every 24 weeks:
* Echocardiogram
* Videofluoroscopy (in case of dysphagia approx. 0,2 mSv (LUMC), c.q. 0,9 mSv
(AMC))
Every 8-24 weeks:
* Questionnaires (severity of symptoms, dysphagia, quality of life)
Full study period:
* Diary (number of falls)
Optional:
* Blood and urine sampling pharmacogenetics, biomarkers. 12 blood samples
(27-35 ml) during treatment period.