Extension of the CBYM338B2203 phase IIb/III study to evaluate the long-term efficacy, safety and tolerability of intravenous BYM338 in patients with sporadic inclusion body myositis

Inclusion-body myositis inclusion-body myositis (sIBM) is a very rare disease.
The estimated prevalence is 15-71 per milliorn 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-13 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.

This extension trial is designed to provide additional placebo-controlled data
(Treatment Period 1) to further evaluate the efficacy, safety, and tolerability
of three doses of BYM338 as well as long-term safety, tolerability, and
efficacy data (Treatment Period 2) for patients who enroll from the core study
(CBYM338B2203).

Main Objective:
To evaluate the long-term safety and tolerability of BYM338 in the treatment of
sIBM and to further evaluate the effect of three BYM338
dose regimens against placebo in increasing the distance traveled as measured
by the 6 Minute Walking Distance Test (6MWD).

Secondary Objectives:
- To describe the long-term evolution of quadriceps muscle strength using
quadriceps Quantitative Muscle Testing (QMT)
- To describe physical function reported by patients using the Sporadic
Inclusion Body Myositis Functional Assessment (sIFA)
- To report the incidence of self-reported falls and self-reported injurious
falls (falls that result in any subject injury) which are a subset of all
selfreported falls
- To describe physical performance using the Short Physical Performance Battery
(SPPB)
- To characterize muscle changes using magnetic resonance imaging (MRI) from a
subset of patients
- To investigate the development of immunogenicity against BYM338

The extension study consists of a Screening epoch, during which patient
eligibility will be assessed, followed by a Treatment Period 1 epoch, which is
double-blind and placebo-controlled (according to randomisation used in
Corestudy), and a Treatment Period 2 epoch, which is open-label. A
Post-treatment Follow-up epoch is also provided for patients who discontinue
prematurely.
Treatmentperiod 1:
BYM338 1 mg/kg i.v.: every 4 weeks
BYM338 3 mg/kg i.v.: every 4 weeks
BYM338 10 mg/kg i.v.: every 4 weeks
Placebo: every 4 weeks
Duration: max 1 year

Treatmentperiod 2:
BYM33 optimal dosing, depending on the results from the corestudie, i.v.: every
4 weeks
Duration: untill BYM338 will be commercially available on the Dutch market or
untill sponsor stops the study.

Posttreatment Follow up visits after 3 and 6 months of last dose will be
applicable for subjects who duiscontinue the study prematurely.

240 patients.

DMC is in place.

BYM338 i.v. or placebo i.v. (treatment period 1).
BYM338 i.v. (treatment period 2)

Risk: adverse events studymedication and risk study procedures.

Burden:
Studyduration 2 years, visits 4-weekly. Duration 1-4 hours per visit.

26 i.v. infusions (100 ml), duration 30 min minimal.

Every visit (as of week 4):
* Columbia Suicide Rating Scale.
* Weight
* Pregnancytest (urine, when applicable)

At screening visit and Day 1, results of assessments done in the core study
will be taken and these assessments are not extra performed in the context of
this extension study and so not listed below.

Treatmentperiod 1:
* Physical examination (2x).
* Bloodpressure, heart rate and body temperature (2x)
* Blood collection, 20 ml per visit (2x).
* Evaluation muscle/physical activity (5x)
* 6 minute walktest (2x)
* Quadriceps strenght (2x)
* Pinch strength (2x)
* Short test battery balance, speed, getting up from a chair (2x)
* ECG (5x)
* Questionnaire ((Dietary assessment Nutrition Status (PIQ)): 5x
* Questionnaires (severity of symptoms, dysphagia, quality of life) (2x)

Treatmentperiod 2:
* Physical examination (3x).
* Bloodpressure and heart rate (3x)
* Body temperature (3x)
* Blood collection, 20 ml per visit (2x).
* Evaluation muscle/physical activity (4x)
* 6 minute walktest (1x)
* Quadriceps strenght (1x)
* Pinch strength (1x)
* Short test battery balance, speed, getting up from a chair (1x)
* ECG (3x)
* Questionnaire ((Dietary assessment Nutrition Status (PIQ)): 4x
* Questionnaires (severity of symptoms, dysphagia, quality of life) (1x)

Throughout study period:
* Diary (number of falls)

Optional substudy:
MRI (2x during total duration study)