A double-blind, placebo-controlled, randomized clinical pharmacology study to evaluate the prevention effect and the recovery-promoting effect of a single subcutaneous administration of GYM329 on disuse muscle atrophy in healthy male volunteers.

Muscular atrophies and muscular dystrophies (e.g., spinal muscular atrophy
[SMA], Duchenne muscular dystrophy [DMD], Becker muscular dystrophy [BMD],
facial scapulohumeral muscular dystrophy [FSHD]) are a heterogeneous group of
inherited disorders characterized by markedly reduced muscle strength and
muscle function accompanied by muscle tissue changes, including degeneration,
fibrosis, and muscle fiber size variation. Although of various etiologies and
severities (SMA and DMD lead to premature death), all of the conditions cause
significant physical disability, resulting in a lifelong need for physical
rehabilitation and reduced quality of life. In most cases, the major
pathologies cannot be adequately managed due to a lack of effective treatments.
GYM329 is a humanized monoclonal antibody discovered by Chugai Pharmaceutical
Co., Ltd. that binds to human latent myostatin to block its conversion to
mature myostatin. The development of GYM329 is intended as a treatment for
patients with muscle wasting diseases such as SMA, DMD, BMD and FSHD. GYM329
was engineered to have antibody-recycling and antigen-sweeping capabilities.
GYM329 was developed using a novel technology called Sequential Monoclonal
Antibody Recycling Technology (SMART-Ig) that combines four different
innovative antibody engineering technologies. The four antibody engineering
technologies consist of pH-dependent antigen binding, antibody charged
engineering technology-Fc domain (ACT-Fc) technology (binding to neonatal Fc
receptor at neutral pH), isoelectric point Fc domain (pI-Fc) technology
(modification of the isoelectric point of the Fc region), and selective binding
technology-Immunoglobulin (TwoB-Ig) technology (binding to Fcγ receptor IIb).
The combination of these engineering technologies functions to prolong
elimination half-life (antibody recycling) and accelerate antigen clearance
through enhanced uptake of drug-target complex (antigen sweeping) [1]. GYM329
is therefore expected to promote effective clearance of antigens, allowing for
lower and less frequent doses than similar antibodies produced without the use
of this technology. GYM329 is a subcutaneous formulation that is currently
being evaluated in an ongoing Phase I clinical trial (Study BP40484) in healthy
volunteers, including Japanese volunteers. Refer to the Investigator's Brochure
for details on nonclinical and clinical studies.

The primary objectives for this study are:
To evaluate the preventive effect of GYM329 on disuse muscle atrophy in healthy
male volunteers through changes in muscle strength following a single
subcutaneous administration prior to unilateral thigh and lower leg
immobilization
To evaluate the recovery-promoting effect of GYM329 from disuse muscle atrophy
in healthy male volunteers through changes in muscle strength following a
single subcutaneous administration after unilateral thigh and lower leg
immobilization

The secondary objectives for this study are:
To evaluate the safety, tolerability, PK, and immunogenicity of GYM329 in
healthy male volunteers following a single subcutaneous administration prior to
or after unilateral thigh and lower leg immobilization
To evaluate changes in thigh muscle volume in healthy male volunteers following
a single subcutaneous administration of GYM329 prior to or after unilateral
thigh and lower leg immobilization
To evaluate serum PD biomarkers in healthy male volunteers following a single
subcutaneous administration of GYM329 prior to or after unilateral thigh and
lower leg immobilization

In this study, healthy male volunteers will receive either GYM329 or placebo by
subcutaneous injection at two time points, before and after 2 weeks of
unilateral thigh and lower leg immobilization, in an investigator- and
subject-blinded, randomized, placebo-controlled, parallel-group design.

96 mg GYM329 or placebo by subcutaneous injection

Since the study is being executed in healthy volunteers, there are no
anticipated benefits of the IMP. Please see the IB for further
information.