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Locally Acting ACE-083 Increases Muscle Volume in Healthy Volunteers

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Introduction: ACE-083 is a locally acting follistatin-based therapeutic that binds myostatin and other muscle regulators and has been shown to increase muscle mass and force in neuromuscular disease mouse models. This first-in-human study examined these effects. Methods: In this phase 1, randomized, double-blind, placebo-controlled, dose-ranging study in healthy postmenopausal women, ACE-083 (50-200 mg) or placebo was administered unilaterally into rectus femoris (RF) or tibialis anterior (TA) muscles as 1 or 2 doses 3 weeks apart. Results: Fifty-eight postmenopausal women were enrolled; 42 ACE-083 and 16 placebo. No serious adverse events (AEs), dose-limiting toxicities, or discontinuations due to AEs occurred. Maximum mean (± standard deviation [SD]) increases in RF and TA muscle volume were 14.5±4.5% and 8.9±4.7%, respectively. No significant changes in mean muscle strength were observed. Discussion: ACE-083 was well tolerated and resulted in significant targeted muscle growth. ACE-083 may have the potential to increase muscle mass in a wide range of neuromuscular disorders. This article is protected by copyright. All rights reserved.
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LOCALLY ACTING ACE-083 INCREASES MUSCLE VOLUME IN HEALTHY
VOLUNTEERS
CHAD E. GLASSER, PharmD,
1
MICHAEL R. GARTNER, MD,
2
DAWN WILSON, BS,
1
BARRY MILLER, MS,
1
MATTHEW L. SHERMAN, MD,
1
and KENNETH M. ATTIE, MD
1
1
Acceleron Pharma, 128 Sidney Street, Cambridge, Massachusetts, 02139, USA
2
Celerion, Lincoln, Nebraska, USA
Accepted 25 February 2018
ABSTRACT: Introduction: ACE-083 is a locally acting follistatin-
based therapeutic that binds myostatin and other muscle regu-
lators and has been shown to increase muscle mass and force
in neuromuscular disease mouse models. This first-in-human
study examined these effects. Methods: In this phase 1, ran-
domized, double-blind, placebo-controlled, dose-ranging study
in healthy postmenopausal women, ACE-083 (50–200mg) or
placebo was administered unilaterally into rectus femoris (RF)
or tibialis anterior (TA) muscles as 1 or 2 doses 3 weeks apart.
Results: Fifty-eight postmenopausal women were enrolled, 42
ACE-083 and 16 placebo. No serious adverse events (AE),
dose-limiting toxicities, or discontinuations resulting from AEs
occurred. Maximum (mean 6SD) increases in RF and TA mus-
cle volume were 14.5% 64.5% and 8.9% 64.7%, respectively.
No significant changes in mean muscle strength were
observed. Discussion: ACE-083 was well tolerated and resulted
in significant targeted muscle growth. ACE-083 may have the
potential to increase muscle mass in a wide range of neuro-
muscular disorders.
Muscle Nerve 000:000–000, 2018
ACE-083 is a recombinant fusion protein consisting
of a modified form of human follistatin linked to
the human immunoglobulin G2 Fc domain. The
protein functions as a trap for ligands within the
transforming growth factor bsuperfamily (princi-
pally growth differentiation factor [GDF]8 [myosta-
tin], GDF11, and activins A and B) that inhibit
skeletal muscle growth and differentiation.
1,2
ACE-083 is designed to act locally in the muscle
into which it is injected by having increased residence
time in muscle and rapid inactivation after entering
the circulation. It has been shown to increase muscle
volume as well as peak tetanic force of the injected
muscle in wild-type mice as well as in mouse models
of myogenic and neurogenic neuromuscular diseases,
including mdx (Duchenne muscular dystrophy
model), superoxide dismutase 1 (amyotrophic lateral
sclerosis model), and trembler-J (Charcot–Marie–
Tooth disease model).
3–6
These studies support clini-
cal development of ACE-083 as a potential treatment
for a wide range of neuromuscular disorders, in par-
ticular those with focal and/or asymmetric muscle
involvement.
The primary objective of this first-in-human
study of ACE-083 was to evaluate the safety and tol-
erability of single and multiple doses of ACE-083
as a local muscle injection. This study also investi-
gated the magnitude and duration of the pharma-
codynamic (PD) effects of ACE-083 on muscle
volume and strength as well as the pharmacokinet-
ics (PK) of ACE-083 in the circulation.
MATERIALS AND METHODS
Study Design. This study was approved by the Chesapeake
Institutional Review Board 6940 Columbia Gateway Drive,
Suite 110, Columbia, MD, and conducted in accordance with
good clinical practices, the Declaration of Helsinki, and appli-
cable national and local regulations and requirements. All
participants provided written informed consent, and the
study is registered at clinicaltrials.gov (NCT02257489).
This was a phase 1, randomized, double-blind, placebo-
controlled, dose-ranging study conducted at a single study
center (Celerion, Lincoln, NE) that enrolled healthy post-
menopausal women between October 6, 2014 and April 25,
2016. In total, 7 cohorts were enrolled, each with 8 or 9 ran-
domized participants (6 active and 2 placebo in cohorts 1–
5; 6 active and 3 placebo in cohorts 6 and 7).
Determination of the starting dosage level of ACE-083
was based on nonclinical toxicity and pharmacology studies
in various animal species. In cohorts 1–3, ACE-083 (50 mg/
ml; Acceleron Pharma, Cambridge, MA) was injected into the
rectus femoris (RF) as a single dose (50, 100, or 200 mg per
muscle), and in cohorts 4 and 5 it was injected as 2 doses on
days 1 and 22 (100 or 200 mg per muscle). In cohorts 6 and
7, ACE-083 was injected into the tibialis anterior (TA) as 2
doses on days 1 and 22 (100 or 150 mg per muscle). ACE-083
(or placebo) was administered unilaterally in the right side
only. Electromyography guidance was used to administer
each dose as 2 or 4 equal-volume injections (0.5–1.0 ml per
injection), depending on the dose, by using a 26-gauge Myo-
ject needle (Natus, Pleasanton, CA) into predefined muscle
locations along the length of the muscle.
Additional supporting information may be found in the online version of
this article.
Abbreviations: ADA, antidrug antibody; AE, adverse event; ECG, electro-
cardiogram; GDF, growth differentiation factor; LC-MS/MS, liquid
chromatography-mass spectrometry assay; LLOQ, lower limit of quantita-
tion; PD, pharmacodynamic; PK, pharmacokinetic; RF, rectus femoris;
SAE, serious adverse advent; TA, tibialis anterior
Key words: ACE-083; muscular dystrophy; muscle volume; myostatin;
neuromuscular disease
Conflicts of Interest: K. M. Attie, C. E. Glasser, B. Miller, and M. L.
Sherman are all employees of Acceleron Pharma. D. Wilson was an
employee of Acceleron Pharma at the time of the study. M. R. Gartner
was an employee of Celerion at the time of the study.
Correspondence to:K. M. Attie; e-mail: kattie@acceleronpharma.com
This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs License, which permits use and dis-
tribution in any medium, provided the original work is properly cited, the
use is non-commercial and no modifications or adaptations are made.
V
C2018 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.
Published online 27 February 2018 in Wiley Online Library (wileyonlinelibrary.
com). DOI 10.1002/mus.26113
ACE-083 Increases Muscle Volume MUSCLE & NERVE Month 2018 1
Participants were followed for 12 weeks after their final
dose. Study visits included physical exams, safety and bio-
marker assessments, MRI scans, and strength assessments.
Participant Eligibility. Eligible participants were healthy
postmenopausal women aged 45–75 years with a body mass
index range of 18.5–32 kg/m
2
. Participants who had
received any medication that could affect muscle, including
hormone replacement therapy, systemic glucocorticoid ther-
apy, statin medication, insulin, or any other investigational
therapy within 3 months prior to study enrollment were
excluded. Participants who had received any therapies
affecting bleeding risk within 1 week prior to enrollment
were also excluded. In addition, because muscle changes
were a key endpoint, participants unwilling or unable to
maintain their baseline level of physical activity throughout
the study were excluded.
Randomization and Blinding. The randomization sched-
ule was computer generated. The pharmacist at the site and
a selected research associate were unblinded to the partici-
pant treatment assignments. Participants, the investigators,
the sponsor, and all other site personnel remained blinded
to treatment assignments throughout the study until the
database was locked.
Assessments and Endpoints. Safety. Safety end points
were assessed at baseline and regularly throughout the study.
They included evaluation of adverse events (AE), injection site
reactions, clinical laboratory tests (including hematology,
chemistry, urinalysis, and biomarkers), electrocardiograms
(ECG), vital signs, antidrug antibody (ADA), and physical
examinations (see Supp. Info. Table 1). AEs were coded
according to the Medical Dictionary for Regulatory Activities
v17.1 and were recorded regardless of causality.
A safety review team comprising the principal investigator,
medical monitor, and a neuromuscular specialist unaffiliated
with either the study or the sponsor met periodically through-
out the study and reviewed blinded data from each cohort to
make recommendations regarding dose selection, dose escala-
tion, enrollment, and overall safety monitoring. Dose-limiting
toxicity was defined as a serious AE (SAE) possibly or probably
related to study drug or an AE, injection-site reaction, ECG
abnormality, laboratory variable abnormality, or vital sign
abnormality, possibly or probably related to study drug that was
either grade 3 (National Cancer Institute-Common Terminol-
ogy Criteria for Adverse Events v4.0) or clinically significant in
the judgment of the investigator.
Pharmacokinetics. An enzyme-linked immunosorbent
assay with a lower limit of quantitation (LLOQ) of 100 ng/ml
was performed on serum from all cohorts; however, detection
of inactive breakdown products led to inconclusive results and
discontinuation of this assay. A liquid chromatography-mass
spectrometry assay (LC-MS/MS) with an LLOQ of 10 ng/ml
was developed specifically to measure intact ACE-083 with
higher sensitivity. The LC-MS/MS assay was performed only on
serum samples from cohorts 6 and 7 because of limited sample
volumes from earlier cohorts. PK samples were collected on
days 1, 2, 5, 8, 15, 22, 23, 26, 29, 33, 36, 40, 43, 50, 64, 78, and
92; multiple samples (predose, 3 h postdose, and 6 h postdose)
were obtained on days 1 and 22.
Pharmacodynamics. Key PD assessments included
MRI of the thigh (RF cohorts) and lower leg (TA cohorts)
to measure muscle volume and intramuscular fat. The
boundaries of the injected muscle on each cross-sectional
image were identified by a blinded technologist and
reviewed and approved by the blinded radiologist assigned
to the study. The volume of the injected muscle was calcu-
lated by using an automated task developed and validated
by the imaging vendor (VirtualScopics, Rochester, NY).
Muscle strength of the knee extensors (RF cohorts) and
ankle dorsiflexors (TA cohorts) was measured by both
hand-held dynamometer (microFET2; Hoggan Scientific,
Salt Lake City, UT) and fixed system (Biodex System 3 Pro;
Biodex Medical Systems, Shirley, NY). Each strength assess-
ment was performed by the same blinded clinical evaluator,
as outlined in the clinical evaluator manual. Knee extension
was performed with the participant sitting and at 90 8of
flexion; ankle dorsiflexion was performed with the partici-
pant supine and the ankle in the neutral state. The partici-
pant was instructed to flex as hard as possible for 5 s, 3
times, with 30–60 s rest between each measurement. The
best of the 3 attempts was recorded.
Statistical Analysis. No formal a priori power analysis for
sample size was conducted. Baseline was defined as the last
assessment prior to dosing on study day 1. For each partici-
pant, change and percentage change from baseline were
calculated for each PD endpoint; treated and contralateral
limbs were compared. PD changes in active dosage groups
were compared to the pooled placebo group by analysis of
covariance. In addition, Dunnett’s test was performed to
assess trends in muscle volume changes. Safety and PK varia-
bles of ACE-083 were summarized by using descriptive statis-
tics. Fisher’s exact test was used to compare the proportions
of selected AEs among treatment and muscle groups.
RESULTS
In total, 58 postmenopausal women were
enrolled including 42 randomized to ACE-083 and
16 randomized to placebo. One participant was
not evaluated for PD because of missing posttreat-
ment MRI scans (see Supp. Info. Fig. 1 for the
study CONSORT diagram). Demographics and
baseline characteristics by muscle and treatment
group are summarized in Table 1. The median age
and range was similar between ACE-083- and pla-
cebo-treated groups; most participants were white
and not Hispanic or Latino.
Safety and Tolerability. There were no SAEs, dose-
limiting toxicities, grade 3 or higher AEs, or discon-
tinuations resulting from AEs. AEs considered
related to treatment and occurring in 10% of
ACE-083-treated participants are shown in Table 2,
by muscle and treatment group. AEs involving the
injection site accounted for the majority of AEs
reported for both ACE-083- and placebo-treated par-
ticipants. Injection site pain was the most common
AE. Other injection site AEs, reported in approxi-
mately 10%–20% of ACE-083-treated participants,
are described in Table 2. Most of these events were
mild in intensity and occurred at the time of or
immediately after dosing and were resolved shortly
thereafter. There was no statistically significant
difference in the incidence of injection site reaction
2ACE-083 Increases Muscle Volume MUSCLE & NERVE Month 2018
or hemorrhage in the ACE-083 groups compared
with placebo.
Noninjection site AEs considered related to treat-
ment are also shown in Table 2. Each had a similar
incidence in ACE-083 and placebo groups. There was
no statistically significant difference in the incidence
of myalgia between ACE-083 and placebo. There
were statistically significant differences in the inci-
dence of muscle twitching (P50.01), pain in extrem-
ity (P<0.001), and muscle tightness (P50.02)
between the RF and TA cohorts, but there was no sig-
nificant difference in limb discomfort. There were
no notable correlations between AE incidence and
increasing dosage or number of injections.
No trends in vital signs, ECG, clinical laboratory
tests, or physical examination were noted. Three
participants had confirmed positive ADA results, 2
of which occurred at the last time point at low
titers (40, 80) and returned to negative. One par-
ticipant had varying titers of ADA (40–2,560) that
decreased to 80 at 12 weeks after the last dose and
were not associated with any clinical manifesta-
tions; this participant was lost to follow-up.
Pharmacokinetics. PK results were available for
cohorts 6 and 7. Serum ACE-083 levels were
detectable only during the first day after dosing,
with most values close to the LLOQ. Only 14 of
252 (5.6%) samples from 6 of 12 (50%) ACE-
083-treated participants were above the LLOQ;
thus, limited PK variables could be estimated
(Table 3).
Pharmacodynamics. Muscle Volume According to
MRI. Increases in muscle volume of the injected
muscle were observed after administration of
ACE-083 to both the RF and TA muscles, with
Table 2. Related AEs reported in 10% of ACE-083-treated participants overall
RF cohorts 1–5 TA cohorts 6–7 Overall
AE preferred term
ACE-083,
n530
Placebo,
n510
ACE-083,
n512
Placebo,
n56
ACE-083,
n542
Placebo,
n516
Injection site AEs, n(%)
Injection site pain 27 (90) 10 (100) 11 (92) 6 (100) 38 (90) 16 (100)
Injection site discomfort 4 (13) 1 (10) 4 (33) 3 (50) 8 (19) 4 (25)
Injection site reaction 5 (17) 1 (10) 1 (8) 0 (0) 6 (14) 1 (6)
Injection site hemorrhage 4 (13) 0 (0) 1 (8) 0 (0) 5 (12) 0 (0)
Injection site warmth 1 (3) 2 (20) 3 (25) 1 (17) 4 (10) 3 (19)
All other AEs, n(%)
Pain in extremity 6 (20) 2 (20) 12 (100) 5 (83) 18 (43) 7 (44)
Muscle twitching 8 (27) 3 (30) 0 (0) 0 (0) 8 (19) 3 (19)
Muscle tightness 2 (7) 1 (10) 4 (33) 2 (33) 6 (14) 3 (19)
Limb discomfort 3 (10) 2 (20) 1 (8) 0 (0) 4 (10) 2 (13)
Myalgia 3 (10) 0 (0) 1 (8) 0 (0) 4 (10) 0 (0)
AE, adverse event; RF, rectus femoris; TA, tibialis anterior.
Table 1. Demographic summary
RF cohorts 1–5 TA cohorts 6–7 Overall
Variable
ACE-083,
n530
Placebo,
n510
ACE-083,
n512
Placebo,
n56
ACE-083,
n542
Placebo,
n516
Sex, n(%)
Women 30 (100) 10 (100) 12 (100) 6 (100) 42 (100) 16 (100)
Race, n(%)
White 29 (97) 10 (100) 12 (100) 5 (83) 41 (98) 15 (94)
Black 1 (3) 0 (0) 0 (0) 1 (17) 1 (2) 1 (6)
Ethnicity, n(%)
Not Hispanic or Latino 29 (97) 10 (100) 11 (92) 6 (100) 40 (95) 16 (100)
Hispanic or Latino 1 (3) 0 (0) 1 (8) 0 (0) 2 (5) 0 (0)
Age, y
Median 56.0 57.5 55.5 57.5 56.0 57.5
Minimum, maximum 45, 70 55,73 49, 62 45,65 45, 70 45, 73
BMI, kg/m
2
Median 25.0 26.2 28.3 24.8 25.9 25.1
Minimum, maximum 19.2, 31.5 22.3, 29.6 21.5, 31.6 23.8, 31.4 19.2, 31.6 22.3, 31.4
BMI, body mass index; RF, rectus femoris; TA, tibialis anterior; y, years.
ACE-083 Increases Muscle Volume MUSCLE & NERVE Month 2018 3
effects in the contralateral noninjected muscle sim-
ilar to placebo-injected muscles. Percentage
changes in right (injected) muscle volume for
each cohort at 3 and 8 weeks after the last dose
are shown in Figures 1 and 2. The maximum
(mean 6SD) increase in muscle volume at 3 weeks
after the last dose was 14.5% 64.5% in the RF
(cohort 5, 200 mg 32 doses) and 8.9% 64.7% in
the TA (cohort 7, 150 mg 32 doses). At the high-
est dose levels in both muscles at 8 weeks after the
last dose, increases in muscle volume were
observed, but the increases were not statistically
significant.
The dose of ACE-083 relative to the size of the
muscle was estimated for each participant by divid-
ing the dose of ACE-083 administered by the base-
line muscle volume of the injected muscle
determined by MRI for cohorts 4–7 (Fig. 2).
Observed percentage change in muscle volume
correlated with the estimated ACE-083 dose within
each muscle (milligrams ACE-083/gram of mus-
cle), with r50.77–0.78. Dose levels >1.0 mg/g
muscle were associated with increases in muscle
volume exceeding 5%. No significant changes in
intramuscular fat were observed.
Strength. No statistically significant changes in
strength of the injected side were observed by
either hand-held dynamometry or fixed system.
Although the TA is the primary muscle contribut-
ing to dorsiflexion, changes in dorsiflexion
strength were not observed. For example, mean
percentage changes from baseline for muscle
strength fixed system measurements after multiple
doses of ACE-083 (100 mg 32 and 150 mg 32)
administered in the TA of the right leg showed
marked variability in both treated and untreated
sides, with mean percentage changes on the
treated side ranging from 22.75% to 15.22%, and
no consistent trends were observed compared with
placebo.
DISCUSSION
The number of active and placebo-treated par-
ticipants in this study is considered appropriate for
Tab le 3. Summary of ACE-083 LC-MS/MS PK observations in the TA
Variable
Cohort 6, 100 mg Cohort 7, 150 mg
Dose 1, n56 Dose 2, n56 Dose 1, n56 Dose 2, n56
Participants with at least
1 sample >LLOQ, n(%)
1 (17) 0 (0) 4 (67) 3 (50)
C
max
Minimum (ng/ml) BLQ BLQ BLQ BLQ
Maximum (ng/ml) 13.3 BLQ 25.8 37.2
T
max
(postdose)
Minimum (h) 3 NC 3 3
Maximum (h) 3 NC 24 6
BLQ, below limit of quantification; C
max
, maximum measured plasma concentration; LC-MS/MS, liquid chromatography-mass spectrometry; LLOQ, lower
limit of quantitation (10 ng/ml in this assay); NC, not calculated; PK, pharmacokinetic; TA, tibialis anterior; T
max
, time of the maximum measured plasma
concentration.
FIGURE 1. Mean 6SEM percentage change from baseline in muscle volume according to MRI in the right (ACE-083-injected) muscle
at 3 weeks and 8 weeks after the last dose. (A) Rectus femoris. (B) Tibialis anterior. *P<0.05, **P<0.001, Dunnett’s test vs.
placebo.
4ACE-083 Increases Muscle Volume MUSCLE & NERVE Month 2018
early-stage clinical studies and was both feasible
and sufficient to achieve the primary objective of
the study. Single and multiple doses of ACE-083 as
a local muscle injection into the RF or TA muscle
were generally safe and well tolerated. AEs consid-
ered related to treatment consisted primarily of
events at the injection site occurring in both active-
and placebo-treated participants as well as transient
pain in extremity, muscle twitching, and muscle
tightness. PK data collected in this study support
the localized therapeutic effect of ACE-083 with lit-
tle to no systemic exposure beyond 24 h postdose.
Muscle volume as assessed by MRI increased
with escalating doses of ACE-083 in the RF and TA
compared with placebo-treated participants. With
only 2 doses administered 3 weeks apart, these
increases reached maximum changes from baseline
at 3 weeks after the last dose that have not previ-
ously been seen with other muscle agents. No
change in intramuscular fat was observed; however,
minimal intramuscular fat was noted on baseline
MRI scans.
Significant changes in strength were not
detected. This finding could be related to several
factors. First, the participants included in this
phase 1 study were healthy individuals with no
muscle atrophy or strength deficits at baseline. Sec-
ond, the RF muscle only accounted for approxi-
mately 13% of the total quadriceps muscle volume
in these participants, making quantifiable improve-
ments in knee extension strength unlikely. Finally,
a maximum of 2 doses was administered; an
extended duration of treatment and observation
may be required to elicit a measurable improve-
ment in strength.
In future studies with ACE-083, many of these
limitations will be addressed. For example, studies
will be longer in treatment duration. In neuromus-
cular diseases in which atrophy and weakness of
specific muscles can have a devastating impact on
a patient’s daily activities and overall quality of life,
substantial increases in muscle volume may be
associated with quantifiable improvements in
strength and function. In diseases with elevated fat
fraction,
7,8
ACE-083 treatment may reasonably be
expected to reduce intramuscular fat.
9
The concentrated effect of locally acting ACE-083
resulted in an amount of muscle growth not previ-
ously achieved. For comparison, GDF8 (myostatin)-
directed compounds (e.g., LY2495655, stamulumab
[MYO-029], domagrozumab [PF-06252616], BMS-
986089) have led to muscle volume increases in the
1%–6% range.
7–10
Studies with muscle volume
changes in this range were typically not associated
with clinically meaningful changes in strength or
function, although some studies did show trends
favoring improvement.
A phase 2 trial evaluating bimagrumab, an acti-
vin receptor antibody, in patients with sporadic
inclusion body myositis (n514) showed a mean
increase from baseline in lean mass of approxi-
mately 5%–6%, which was associated with an
approximately 7% increase from baseline in 6-min
walk distance in the treated group.
11
However, a
phase 3 trial using lower dosage levels (n5251)
showed a mean increase from baseline in lean
mass of approximately 2.8% at the highest dosage
level and an approximate corresponding mean
increase from baseline in 6-min walk distance of
<5%.
12,13
This suggests that the threshold to
achieve clinical benefit is likely greater than 5%
and that ACE-083, in comparison to other thera-
pies, has a greater likelihood of achieving this
threshold in patients. The ability of ACE-083 to
bind multiple ligands, including GDF8, GDF11,
and activins as well as acting locally at high con-
centrations in the muscle (where these ligands act
in largely a paracrine/autocrine manner), may
account for the greater increases in muscle volume
observed here.
14
FIGURE 2. Correlation between right (ACE-083-injected) muscle volume increase at 3 weeks after last dose and ACE-083 dosage per
gram muscle (according to MRI for each participant). (A) Rectus femoris cohorts 4 and 5. (B) Tibialis anterior cohorts 6 and 7.
ACE-083 Increases Muscle Volume MUSCLE & NERVE Month 2018 5
The promising degree of muscle growth
observed in this phase 1 healthy volunteer study sup-
ports further evaluation of the impact of ACE-083
on dystrophic or atrophic muscle. Previous studies
in Duchenne muscular dystrophy with a systemic
myostatin inhibitor
15
have suggested that increases
in lean body mass can be achieved in dystrophic
muscle, whereas the present study suggests that
changes are possible even in healthy muscle, as may
be found in primarily neuropathic diseases. Two
studies of ACE-083 are currently ongoing and
actively enrolling patients with facioscapulohumeral
muscular dystrophy (NCT02927080), and Charcot–
Marie–Tooth disease (NCT03124459).
The authors thank Steven A. Greenberg for providing medical
review assistance as part of the safety review team; Sharon Wagner
(Celerion) and VirtualScopics for study conduct, participant
recruitment and treatment, and data acquisition; ICON, Algo-
rithme, and qPharmetra for antidrug antibody and pharmacoki-
netic data analyses; Bryan Health for facilities and personnel; and
Susan Pandya, MD, Ashley Leneus, Amelia Pearsall, Brian Vidal,
Xiaosha Zhang, Jade Sun, and Carrie Barron from Acceleron
Pharma for trial management, data management, statistical analy-
sis, and writing support.
Ethical Publication Statement: We confirm that we have read the
Journal’s position on issues involved in ethical publication and
affirm that this report is consistent with those guidelines.
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6ACE-083 Increases Muscle Volume MUSCLE & NERVE Month 2018
... 3,7 ACE-083 is a locally acting investigational drug containing a modified form of human follistatin that binds growth differentiation factor (GDF) 8 (myostatin), activin A, and other negative regulators of skeletal muscle in the transforming growth factor-β superfamily. 8,9 ACE-083 has been engineered and developed as a ligand trap of negative regulators of skeletal muscle growth such as activin and myostatin, in addition to other ligands. Intramuscular administration of ACE-083 causes dose-dependent, localized hypertrophy of the injected skeletal muscle in wild-type mice and mouse models of CMT without systemic muscle effects. ...
... 9 In a phase 1 study, ACE-083 increased muscle mass locally in healthy volunteers to a greater extent than systemically acting myostatin inhibitors. 8 Increases in muscle mass were also observed in patients with facioscapulohumeral muscular dystrophy (FSHD), with the most common adverse events (AEs) being injection-site reactions (ISRs) and myalgia. 10 The objective of this phase 2 study was to evaluate the safety and tolerability of ascending doses of ACE-083 (part 1) and to determine whether treatment with ACE-083 increases muscle volume of the injected muscles compared with placebo after 6 months of randomized treatment followed by 6 months of open-label extension (part 2). ...
Article
Objective To determine whether locally acting ACE-083 is safe, well tolerated, and increases muscle volume, motor function, and quality of life (QoL) in adults with Charcot-Marie-Tooth disease (CMT) type 1. Methods This phase 2 study enrolled adults with CMT1 or CMTX (N=63). Part 1 was open-label and evaluated safety and tolerability of different dose levels of ACE-083 for use in Part 2. Part 2 was a randomized, placebo-controlled, 6-month study of 240 mg/muscle ACE-083 injected bilaterally in the tibialis anterior muscle, followed by a 6-month, open-label extension in which all patients received ACE-083. Pharmacodynamic endpoints included total muscle volume (TMV; primary endpoint), contractile muscle volume (CMV), and fat fraction. Additional secondary endpoints included 6-minute walk test, 10-meter walk/run, muscle strength, and QoL. Safety was assessed with treatment-emergent adverse events (TEAEs) and clinical laboratory tests. Results In Part 1 (n=18), ACE-083 was generally safe and well tolerated at all dose levels, with no serious AEs, TEAEs ≥Grade 3, or death reported. In Part 2 (n=45 enrolled, n=44 treated), there was significantly greater change in TMV with ACE-083 compared with placebo (LS mean difference: 13.5%; p = 0.0096). There was significant difference between ACE-083 and placebo for CMV and change in ankle dorsiflexion strength. Fat fraction and all other functional outcomes were not significantly improved by ACE-083. Moderate-to-mild injection-site reactions were the most common TEAEs. Conclusions Despite significantly increased TMV and CMV, patients with CMT receiving ACE-083 in tibialis anterior muscles did not demonstrate greater functional improvement compared with those receiving placebo. Classification of evidence This study provides Class II evidence that intramuscular ACE-083 is safe, well tolerated, and increases total muscle volume after 6 months of treatment in adults with CMT1 or CMTX.
... 1,6 ACE-083 is a recombinant fusion protein composed of modified human follistatin linked to the human immunoglobulin G2 Fc domain that functions as a ligand trap for the transforming growth factor (TGF)-β superfamily, particularly activins and myostatin, which inhibit skeletal muscle growth and regeneration. 7 In animal models, ACE-083 caused localized muscle hypertrophy and improved function. 8 In a phase 1 study, locally injected ACE-083 increased muscle volume in healthy volunteers, was generally well tolerated, and was largely undetectable in serum. ...
... 8 In a phase 1 study, locally injected ACE-083 increased muscle volume in healthy volunteers, was generally well tolerated, and was largely undetectable in serum. 7 The aim of this study was to evaluate safety, tolerability, and efficacy of ACE-083 in participants with FSHD. ...
Article
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Introduction/aims: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. Methods: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. Results: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions. Discussion: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.
... Acceleron has led the field with at least 4 ligand traps being tested in clinical trials ( Table 2). ACE-083 is a modified 291 amino acid follistatin lacking 24 C-terminal residues (FS291) and is linked to the human IgG2 Fc domain (326,327). Another similar drug, FST288-Fc, has also been tested in animals (328), although its developmental status is not described on the corporate website. All of the other traps are IgG chimeras with the extracellular domains (ECDs) of wild-type or modified ActRIIb, ActRIIa, or the ActRIIb:ALK4 complex (Table 1) and are based upon wildtype receptor ECD isoforms with differing affinities for different ligands (21). ...
... ACE-536 is being developed to treat chronic anemia (eg, thalassemia, myelodysplastic syndrome, myelofibrosis), not muscle wasting disease, and has already obtained an FDA approval on strong preclinical and clinical trial results (342,343). By contrast, clinical development of both ACE-083 and ACE-2494 has been suspended, the former for not significantly enhancing metrics of muscle function or quality of life (326) and the latter because of antidrug antibodies among study participants. Such results are discouraging, especially to the neuromuscular disease community as ACE-083 studies with mdx and Trembler-J mice, models for DMD and Charcot-Marie Tooth disease, respectively, produced highly promising results (327). ...
Article
Full-text available
Muscle wasting disease indications are among the most debilitating and often deadly noncommunicable disease states. As a comorbidity, muscle wasting is associated with different neuromuscular diseases and myopathies, cancer, heart failure, chronic pulmonary and renal diseases, peripheral neuropathies, inflammatory disorders and of course, musculoskeletal injuries. Current treatment strategies are relatively ineffective and can at best only limit the rate of muscle degeneration. This includes nutritional supplementation and appetite stimulants as well as immunosuppressants capable of exacerbating muscle loss. Arguably, the most promising treatments in development attempt to disrupt myostatin and activin receptor signaling as these circulating factors are potent inhibitors of muscle growth and regulators of muscle progenitor cell differentiation. Indeed, several studies demonstrated the clinical potential of “inhibiting the inhibitors”, increasing muscle cell protein synthesis, decreasing degradation, enhancing mitochondrial biogenesis and preserving muscle function. Such changes can prevent muscle wasting in various disease animal models yet many drugs targeting this pathway failed during clinical trials, some from serious treatment-related adverse events and off-target interactions. More often, however, failures resulted from the inability to improve muscle function despite preserving muscle mass. Drugs still in development include antibodies and gene therapeutics, all with different targets and thus, safety, efficacy and proposed use profiles. Each is unique in design and, if successful, could revolutionize the treatment of both acute and chronic muscle wasting. They could also be used in combination with other developing therapeutics for related muscle pathologies or even metabolic diseases.
... The creation of FSHD-specific therapeutics has been understandably hampered by these challenges, and in the interim, easier avenues have been explored, including compensatory treatments to improve muscle strength or health [29][30][31][32][33][34][35][36] (ClinicalTrials.gov Identifiers: NCT02927080, NCT02603562), immunomodulation (ClinicalTrials.gov ...
Article
Full-text available
Facioscapulohumeral muscular dystrophy (FSHD) is arguably one of the most challenging genetic diseases to understand and treat. The disease is caused by epigenetic dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead to chromatin relaxation and, in the context of a permissive allele, pathogenic misexpression of DUX4 in skeletal muscle. The complex nature of the locus and the fact that FSHD is a toxic, gain-of-function disease present unique challenges for the design of therapeutic strategies. There are three major DUX4-targeting avenues of therapy for FSHD: small molecules, oligonucleotide therapeutics, and CRISPR-based approaches. Here, we evaluate the preclinical progress of each avenue, and discuss efforts being made to overcome major hurdles to translation.
... A phase II trial (ClinicalTrials.gov NCT03124459) has been recently completed that employed ACE-083, which is a molecule that is able to generate muscle hypertrophy by inhibiting myostatin and other muscle regulators [77]. A total of 62 CMT1 and CMTX1 patients were treated with periodic injections of ACE-083 into the tibialis anterior muscles, which indeed produced a muscle volume increase; however, this did not translate into a significant amelioration in functional and quality of life measures as compared to shamtreated patients. ...
Article
Full-text available
There is still no effective drug treatment available for Charcot-Marie-Tooth neuropathies (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment of pain; fatigue and cramps are frequent complaints that are difficult to treat. The challenge is to find disease-modifying therapies. Several approaches, including gene silencing, to counteract the PMP22 gene overexpression in the most frequent CMT1A type are under investigation. PXT3003 is the compound in the most advanced phase for CMT1A, as a second-phase III trial is ongoing. Gene therapy to substitute defective genes or insert novel ones and compounds acting on pathways important for different CMT types are being developed and tested in animal models. Modulation of the Neuregulin pathway determining myelin thickness is promising for both hypo-demyelinating and hypermyelinating neuropathies; intervention on Unfolded Protein Response seems effective for rescuing misfolded myelin proteins such as P0 in CMT1B. HDAC6 inhibitors improved axonal transport and ameliorated phenotypes in different CMT models. Other potential therapeutic strategies include targeting macrophages, lipid metabolism, and Nav1.8 sodium channel in demyelinating CMT and the P2X7 receptor, which regulates calcium influx into Schwann cells, in CMT1A. Further approaches are aimed at correcting metabolic abnormalities, including the accumulation of sorbitol caused by biallelic mutations in the sorbitol dehydrogenase (SORD) gene and of neurotoxic glycosphingolipids in HSN1.
... ACE-083 treatment also showed a significant effect on local muscle hypertrophy and increased focal force generation in targeted muscle in a mouse model.26 In a phase growth but did not improve muscle strength.27 Similar to the phase I result, there is a significant increase in patient's muscle volume, but no significant improvement on any of the functional outcomes results in early terminations of its phase II trials in patients with FSHD (NCT02927080, terminated in 2019) and CMT (NCT03124459, terminated in 2020).Besides injection of follistatin fusion proteins, the intramuscular gene transfer of various FST isoforms to promote muscle hypertrophy has been proved in various animal models.28-30 ...
Article
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Sarcopenia is a comprehensive degenerative disease with the progressive loss of skeletal muscle mass with age, accompanied by the loss of muscle strength and muscle dysfunction. As a new type of senile syndrome, sarcopenia seriously threatens the health of the elderly. The first‐line treatment for sarcopenia is exercise and nutritional supplements. However, pharmacotherapy will provide more reliable and sustainable interventions in geriatric medicine. Clinical trials of new drugs targeting multiple molecules are ongoing. This article focuses on the latest progress in pharmacotherapeutic approaches of sarcopenia in recent years by comprehensively reviewing the clinical outcomes of the existing and emerging pharmacotherapies as well as the molecular mechanisms underlying their therapeutic benefits and side effects. Signaling of the pharmacotherapies of sarcopenia.
Article
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Myostatin (MSTN) is a well-reported negative regulator of muscle growth and a member of the transforming growth factor (TGF) family. MSTN has important functions in skeletal muscle (SM), and its crucial involvement in several disorders has made it an important therapeutic target. Several strategies based on the use of natural compounds to inhibitory peptides are being used to inhibit the activity of MSTN. This review delivers an overview of the current state of knowledge about SM and myogenesis with particular emphasis on the structural characteristics and regulatory functions of MSTN during myogenesis and its involvements in various muscle related disorders. In addition, we review the diverse approaches used to inhibit the activity of MSTN, especially in silico approaches to the screening of natural compounds and the design of novel short peptides derived from proteins that typically interact with MSTN.
Chapter
Duchenne muscular dystrophy (DMD) is a severe, progressive, genetic muscle wasting disorder arising from the absence of the membrane stabilizing protein, dystrophin, that renders muscle fibers susceptible to damage and degeneration. Since the discovery of the dystrophin gene, research efforts have focused on the development of regenerative gene- and cell-based therapies for DMD, although many obstacles need to be overcome before they can be considered for clinical application. The development of adjunct therapies that can slow the pathologic progression, preserve muscle mass, enhance muscle regeneration, and promote muscle growth, is therefore essential. Rehabilitation through physical exercise or muscle contraction protocols may help attenuate muscle weakness and dysfunction in DMD, with evidence supporting rehabilitation as an adjunct treatment to gene- and cell-mediated therapies. This chapter summarizes the current state of research for DMD therapy and explores the potential for combined regenerative and rehabilitation therapies to improve outcomes for DMD patients.KeywordsDuchenne muscular dystrophyGene therapyCell therapyRehabilitationExercise
Chapter
Sarcopenia is recognized today as a real public health issue. In order to reduce its public health burden, screening for sarcopenia is essential to act early and thus prevent the occurrence of adverse health events. Screening for sarcopenia also avoids the need for unnecessary resource-consuming diagnostic procedures. Several screening tools for sarcopenia exists: the SARC-F questionnaire, the calf circumference, the SARC-F-CalF, the Mini Sarcopenia Risk Assessment, the Ishii score, the equation of Yu, the screening grid of Goodman, the chair and stand test, the finger-ring test, the gripBMI, the Tawaïn Risk Score for sarcopenia, and the red flag method. As the choice of a screening instrument is quite large, it can sometimes be difficult for the clinician to determine which one is the most suitable. Studies have therefore been carried out to compare the performance of different screening tools for sarcopenia. Statistically, the Ishii score offers the best performance (with an area under the curve of 0.914). SARC-F-CalF also exhibits interesting properties. Overall, all of the screening tools for sarcopenia are very effective in detecting the absence of the disease (i.e., high specificity). It is, however, important to remember that the choice of a screening tool is made on the basis of the performance of the tool and also on the basis of other criteria such as its ease of implementation, its reliability, and its acceptability by the population. Therefore, in view of these criteria, the screening tool recommended by scientific societies remains the SARC-F, which is easy to use, reliable, and very well accepted.
Chapter
Sarcopenia is the age-related decline in muscle mass and strength and is associated with increased risk of adverse health outcomes including falls, morbidity, loss of independence, disability and mortality. Despite important efforts to find effective pharmacological treatment, to this date there are no official approved drugs for the treatment of sarcopenia, with “lifestyle” interventions (i.e. physical activity and nutrition with protein and amino acids supplements) being the only recommended therapy to address this condition. In this chapter, we reviewed principal pharmacological drugs developed for the treatment of sarcopenia. Phase I and II studies addressing safety and efficacy of inhibitors of the myostatin pathways with monoclonal antibodies and follistatin have showed encouraging results in preventing muscle loss, although more clinical trials are required to evaluate their effects in people with sarcopenia. Hormonal replacement therapy with androgens and oestrogens has also demonstrated interesting results. However, hormonal replacement therapy was also characterized by many adverse effects. Targeting different factors implicated in the development of sarcopenia, such as chronic systemic inflammation, may be crucial for the treatment of this condition, albeit further studies are still needed. Nevertheless, a novel potential approach to prevent and revert sarcopenia may relay in hybrid therapies combining myostatin/activin inhibitors and/or hormonal therapy with physical exercise and nutritional supplements, although future studies are needed in order to be able to derive strong guidelines and standard treatment approaches to treat sarcopenia.
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Growth and differentiation factor 8 (GDF8) is a TGF-β superfamily member, and negative regulator of skeletal muscle mass. GDF8 inhibition results in prominent muscle growth in mice, but less impressive hypertrophy in primates, including man. Broad TGF-β inhibition suggests another family member negatively regulates muscle mass, and its blockade enhances muscle growth seen with GDF8-specific inhibition. Here we show that activin A is the long-sought second negative muscle regulator. Activin A specific inhibition, on top of GDF8 inhibition, leads to pronounced muscle hypertrophy and force production in mice and monkeys. Inhibition of these two ligands mimics the hypertrophy seen with broad TGF-β blockers, while avoiding the adverse effects due to inhibition of multiple family members. Altogether, we identify activin A as a second negative regulator of muscle mass, and suggest that inhibition of both ligands provides a preferred therapeutic approach, which maximizes the benefit:risk ratio for muscle diseases in man.
Article
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Background: A substantial impediment to progress in trials of new therapies in neuromuscular disorders is the absence of responsive outcome measures that correlate with patient functional deficits and are sensitive to early disease processes. Irrespective of the primary molecular defect, neuromuscular disorder pathological processes include disturbance of intramuscular water distribution followed by intramuscular fat accumulation, both quantifiable by MRI. In pathologically distinct neuromuscular disorders, we aimed to determine the comparative responsiveness of MRI outcome measures over 1 year, the validity of MRI outcome measures by cross-sectional correlation against functionally relevant clinical measures, and the sensitivity of specific MRI indices to early muscle water changes before intramuscular fat accumulation beyond the healthy control range. Methods: We did a prospective observational cohort study of patients with either Charcot-Marie-Tooth disease 1A or inclusion body myositis who were attending the inherited neuropathy or muscle clinics at the Medical Research Council (MRC) Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK. Genetic confirmation of the chromosome 17p11.2 duplication was required for Charcot-Marie-Tooth disease 1A, and classification as pathologically or clinically definite by MRC criteria was required for inclusion body myositis. Exclusion criteria were concomitant diseases and safety-related MRI contraindications. Healthy age-matched and sex-matched controls were also recruited. Assessments were done at baseline and 1 year. The MRI outcomes-fat fraction, transverse relaxation time (T2), and magnetisation transfer ratio (MTR)-were analysed during the 12-month follow-up, by measuring correlation with functionally relevant clinical measures, and for T2 and MTR, sensitivity in muscles with fat fraction less than the 95th percentile of the control group. Findings: Between Jan 19, 2010, and July 7, 2011, we recruited 20 patients with Charcot-Marie-Tooth disease 1A, 20 patients with inclusion body myositis, and 29 healthy controls (allocated to one or both of the 20-participant matched-control subgroups). Whole muscle fat fraction increased significantly during the 12-month follow-up at calf level (mean absolute change 1.2%, 95% CI 0.5-1.9, p=0.002) but not thigh level (0.2%, -0.2 to 0.6, p=0.38) in patients with Charcot-Marie-Tooth disease 1A, and at calf level (2.6%, 1.3-4.0, p=0.002) and thigh level (3.3%, 1.8-4.9, p=0.0007) in patients with inclusion body myositis. Fat fraction correlated with the lower limb components of the inclusion body myositis functional rating score (ρ=-0.64, p=0.002) and the Charcot-Marie-Tooth examination score (ρ=0.63, p=0.003). Longitudinal T2 and MTR changed consistently with fat fraction but more variably. In muscles with a fat fraction lower than the control group 95th percentile, T2 was increased in patients compared with controls (regression coefficients: inclusion body myositis thigh 4.0 ms [SE 0.5], calf 3.5 ms [0.6]; Charcot-Marie-Tooth 1A thigh 1.0 ms [0.3], calf 2.0 ms [0.3]) and MTR reduced compared with controls (inclusion body myositis thigh -1.5 percentage units [pu; 0.2], calf -1.1 pu [0.2]; Charcot-Marie-Tooth 1A thigh -0.3 pu [0.1], calf -0.7 pu [0.1]). Interpretation: MRI outcome measures can monitor intramuscular fat accumulation with high responsiveness, show validity by correlation with conventional functional measures, and detect muscle water changes preceding marked intramuscular fat accumulation. Confirmation of our results in further cohorts with these and other muscle-wasting disorders would suggest that MRI biomarkers might prove valuable in experimental trials. Funding: Medical Research Council UK.
Article
Introduction: ACE-031 is a fusion protein of activin receptor type IIB and IgG1-Fc, which binds myostatin. It aims to disrupts its inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD). Methods: ACE-031 was administered subcutaneously every 2-4 weeks to DMD boys in a randomized, double-blind, placebo-controlled, ascending dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics. Results: ACE-031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6 minute walk test (6MWT) distance in ACE-031 groups compared to decline in placebo (not statistically significant) was noted, as was a trend for increased lean body mass, bone mineral density (BMD), and reduced fat mass. Conclusion: ACE-031 demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non-muscle-related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD. This article is protected by copyright. All rights reserved.
Article
Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor β superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical ndings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging.
Article
Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor β superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging. (Circ Res.
Article
Background: Myostatin inhibits skeletal muscle growth. The humanised monoclonal antibody LY2495655 (LY) binds and neutralises myostatin. We aimed to test whether LY increases appendicular lean body mass (aLBM) and improves physical performance in older individuals who have had recent falls and low muscle strength and power. Methods: In this proof-of-concept, randomised, placebo-controlled, double-blind, parallel, multicentre, phase 2 study, we recruited patients aged 75 years or older who had fallen in the past year from 21 investigator sites across Argentina, Australia, France, Germany, Sweden, and the USA. Eligible patients had low performance on hand grip strength and chair rise tests, tested with the procedure described by Guralnik and colleagues. Participants were stratified by country, age, hand grip strength, and performance on the chair rise test, and were randomly assigned (1:1) by a computer-generated random sequence to receive subcutaneous injections of placebo or 315 mg LY at weeks 0 (randomisation visit), 4, 8, 12, 16, and 20, followed by 16 weeks observation. The primary outcome was change in aLBM from baseline to 24 weeks. We measured physical performance as secondary outcomes (four-step stair climbing time, usual gait speed, and time to rise five times from a chair without arms, or with arms for participants unable to do it without arms) and exploratory outcomes (12-step stair climbing test, 6-min walking distance, fast gait speed, hand grip strength, and isometric leg extension strength). Efficacy analyses included all randomly assigned patients who received at least one dose and had a baseline and at least one subsequent measure. The primary analysis and all other tests of treatment effect (except physical performance tests) were done at a two-sided alpha level of 0·05. Tests of treatment effect on physical performance tests were done at a pre-specified two-sided alpha level of 0·1. This trial is registered with ClinicalTrials.gov, number NCT01604408. Findings: Between June 19, 2012, and Dec 12, 2013, we screened 365 patients. 99 were randomly assigned to receive placebo and 102 to receive LY. Treatment was completed in 85 (86%) of patients given placebo and in 82 (80%) given LY. At 24 weeks, the least-squares mean change in aLBM was -0·123 kg (95% CI -0·287 to 0·040) in the placebo group and 0·303 kg (0·135 to 0·470) in the LY group, a difference of 0·43 kg (95% CI 0·192 to 0·660; p<0·0001). Stair climbing time (four-step and 12-step tests), chair rise with arms, and fast gait speed improved significantly from baseline to week 24 with differences between LY and placebo of respectively -0·46 s (p=0·093), -1·28 s (p=0·011), -4·15 s (p=0·054), and 0·05 m/s (p=0·088). No effect was detected for other performance-based measures. Injection site reactions were recorded in nine (9%) patients given placebo and in 31 (30%) patients given LY (p<0·0001), and were generally mild, and led to treatment discontinuation in two patients given LY. Interpretation: Our findings show LY treatment increases lean mass and might improve functional measures of muscle power. Although additional studies are needed to confirm these results, our data suggest LY should be tested for its potential ability to reduce the risk of falls or physical dependency in older weak fallers. Funding: Eli Lilly and Company.
Conference Paper
To investigate a new therapeutic strategy for inherited asymmetrical myopathies, we generated a modified cysteine knot ligand trap of TGFβ superfamily members, ACE-083, which acts locally to increase skeletal muscle mass. ACE-083 binds to activin and myostatin and inhibits their signaling. Unlike ActRIIB-Fc, ACE-083 does not bind to ligands BMP9/10. To demonstrate the ability of ACE-083 to increase muscle mass locally, we used a murine model of muscular dystrophy. Six week old C57BL/10ScCN-Dmdmdx/J (mdx) and wild-type mice received intramuscular injections into the left gastrocnemius muscle of ACE-083 (100 μg, 50 μL, biw) or vehicle (PBS, 50 μL, biw) for 4 weeks. Each injection corresponded to a dose of approximately 5 mg/kg. After 4 weeks of treatment muscles were collected to evaluate the effect of ACE-083. In the left gastrocnemius muscle injected with 100 μg ACE-083, mdx mice had increased muscle mass 16% (p < 0.01) and wild-type mice 34% (p < 0.001) compared to the non-injected, contralateral legs. Histologically, muscles injected with ACE-083 underwent hypertrophy with no signs of hyperplasia and no alteration in muscle fiber type distribution. Over the course of the study there were no significant differences in body weight between ACE-083 or vehicle treated mice. In addition, pectoral and femoris muscles were examined to determine if there was a systemic effect of locally-administered ACE-083. There was no significant increase in muscle size in the pectoral (p = 0.838) or the femoris (p = 0.62) muscles in either treatment group. Furthermore, we determined there was no active ACE-083 in the serum following local injections, minimizing potential off target effects in other organs. These preclinical results demonstrate that ACE-083 can effectively increase muscle mass locally following direct injection into target muscles. Therefore, local inhibition of activin and myostatin using ACE-083 represents a promising therapeutic approach for the treatment of asymmetric myopathies.
Article
Objective: To study activin signaling and its blockade in sporadic inclusion body myositis (sIBM) through translational studies and a randomized controlled trial. Methods: We measured transforming growth factor β signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase. Results: Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied (p = 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg +6.5% compared with placebo, p = 0.024; left leg +7.6%, p = 0.009) and lean body mass (+5.7% compared with placebo, p = 0.014). Subsequently, bimagrumab-treated patients had improved 6-minute walking distance, which peaked at 16 weeks (+14.6%, p = 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions. Conclusions: Transforming growth factor β superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM. Classification of evidence: This study provides Class I evidence that for patients with inclusion body myositis, bimagrumab increases thigh muscle volume at 8 weeks.