Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD)

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02927080

Enrollment

Registered

2016-10-06

Start date

2016-11-30

Completion date

2019-10-09

Last updated

2022-09-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Facioscapulohumeral Muscular Dystrophy

Keywords

FSHD

Brief summary

Study A083-02 is a multi-center, Phase 2 study to evaluate the safety, tolerability, pharmacodynamics (PD), efficacy, and pharmacokinetics (PK) of locally-acting ACE-083 in patients with Facioscapulohumeral muscular dystrophy (FSHD) to be conducted in two parts. Part 1 is open-label, dose-escalation and Part 2 is randomized, double-blind, and placebo-controlled.

Detailed description

Part 1 (dose escalation, open-label) Part 1 will consist of up to 6 cohorts of patients and will evaluate multiple ascending dose levels of ACE-083 administered unilaterally or bilaterally to either the tibialis anterior (TA) or biceps brachii (BB) muscle(s). Patients in each cohort will be enrolled in a 4-week screening period before beginning treatment. A Safety Review Team (SRT) will meet to review data for each cohort when at least 4 patients within a cohort have completed their Day 43 visit prior to dose escalation of the next cohort. Study duration for Part 1 for each patient will be approximately 24 weeks, including a 4-week screening period, a 12-week treatment period, and an 8-week follow-up period after the last dose. Part 2 (randomized, double-blind, placebo-controlled, with open-label extension) Prior to the initiation of Part 2, a review of safety and efficacy data from Part 1 will be conducted to determine whether cohorts for one or both muscles will be pursued in Part 2, as well as the recommended dose level for each muscle. A total of up to 56 new patients (28 patients per muscle) may be enrolled and randomized (1:1) to receive either ACE-083 (n=14/muscle) or placebo (n=14/muscle) bilaterally to either the TA or BB muscles (but not both). Patients will receive blinded study drug once every three weeks for approximately 6 months (9 doses). Patients who complete the double-blind treatment period will immediately roll over to open-label treatment with ACE-083, receiving the same dose of active drug, bilaterally in either the TA or BB muscle, once every three weeks for approximately 6 months (8 doses). In Part 2, the SRT will periodically review blinded safety data for each muscle treated. Study duration for Part 2 for each patient will be approximately 15 months, including a 1-month screening period, a 12-month treatment period (6-month double-blind, placebo-controlled and a 6-month open-label extension), and a 2-month follow-up period after the last dose

Interventions

DRUGACE-083

Recombinant fusion protein.

DRUGACE-083 or placebo

Recombinant fusion protein or normal saline.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: 1. Age ≥ 18 years 2. Genetically confirmed Facioscapulohumeral muscular dystrophy type 1 (FSHD1) or FSHD2 (or a first-degree relative with genetically confirmed FSHD1 or FSHD2) and clinical findings meeting FSHD criteria 3. Part 1 TA cohorts: 1. 6-minute walk distance (6MWD) ≥ 150 meters (without a brace) 2. Mild to moderate weakness in left and/or right ankle dorsiflexion Part 1 BB cohorts: a. Mild to moderate weakness in left and/or right elbow flexion Part 2 TA cohorts: 1. 6MWD ≥ 150 and ≤ 500 meters (without a brace) 2. Mild to moderate weakness in left and right ankle dorsiflexion Part 2 BB cohorts: a. Mild to moderate weakness in left and/or right elbow flexion 4. Females of childbearing potential must have negative urine pregnancy test prior to enrollment and use highly effective birth control methods during study participation. Hormonal birth control use must be stable for at least 14 days prior to Day 1. Males must agree to use a condom during any sexual contact with females of childbearing potential while participating in the study even if he has undergone a successful vasectomy. Key

Exclusion criteria

1. Current/ active malignancy (e.g., remission less than 5 years duration), with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 squamous cell carcinomas of the skin 2. Symptomatic cardiopulmonary disease, significant functional impairment, or other co morbidities that in the opinion of the investigator would limit a patient's ability to complete strength and/or functional assessments on study 3. Renal impairment (serum creatinine ≥ 2 times the upper limit of normal,(ULN)) 4. Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≥ 3 times ULN 5. Increased risk of bleeding (i.e., due to hemophilia, platelet disorders, or use of any anti-coagulation/platelet modifying therapies up to 2 weeks prior to Study Day 1; low dose aspirin \[≤ 100 mg daily\] is permitted) 6. Major surgery within 4 weeks prior to Study Day 1 7. Chronic systemic corticosteroids (≥ 2 weeks) within 4 weeks before Study Day 1 and for duration of study; intra-articular/topical/inhaled therapeutic or physiologic doses of corticosteroids are permitted 8. Androgens or growth hormone within 6 months before Study Day 1 and for duration of study; topical physiologic androgen replacement is permitted 9. Any condition that would prevent MRI scanning or compromise the ability to obtain a clear and interpretable scan of the TA or BB muscles, as applicable (e.g., pacemaker, knee/hip replacement, or metallic implants)

Design outcomes

Primary

Measure	Time frame	Description
Safety and Tolerability (Incidence of Adverse Events)	From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2	The number of participants that had a least one Treatment Emergent Adverse Event for the duration of each of the respective study parts.
Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).	From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2	The number of participants that had a least one Treatment Emergent Adverse Event with CTCAE Grade 3 or Higher for the duration of each of the respective study parts.
Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2	The number of participants that had a least one Treatment Emergent Adverse Event that led to dose interruption, dose reduction and/or drug withdrawn.
Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	Time Frame: From initiation of treatment to Study Visit Day 190	Total Muscle Volume (TMV)of the treated muscle in Patients with FSHD administered ACE-083 or placebo During Part 2 (randomized, controlled portion) from Baseline to Day 190. Total Muscle volume was measured by Magnetic Resonance Imaging (MRI). MRI was performed bilaterally on the tibialis anterior and the biceps brachii on Day 1, Day Day 43, Day 106, and Day 190. Baseline and Day 190 total muscle volume, means and standard deviations are reported.
Percent Change of Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	Time Frame: From initiation of treatment to Study Visit Day 190	Percent Change of Total Muscle Volume (TMV)of the treated muscle in Patients with FSHD administered ACE-083 or placebo During Part 2 (randomized, controlled portion) from Baseline to Day 190. Total Muscle volume was measured by Magnetic Resonance Imaging (MRI). MRI was performed bilaterally on the tibialis anterior and the biceps brachii on Day 1, Day Day 43, Day 106, and Day 190. Percent Change from Baseline to Day 190 total muscle volume, mean and standard deviation is reported.

Secondary

Measure	Time frame	Description
Change From Baseline in Facioscapulohumeral Muscular Dystrophy-health Index (FSHD-HI), Patient-reported Outcome (PRO) Measures Part 2 (Randomized, Controlled Portion)- Total Score	Time Frame: From initiation of treatment (Study Day 1) to Study Visit Day 190	The facioscapulohumeral muscular dystrophy-health index (FSHD-HI) is a disease-specific patient-reported outcome (PRO) tool assessed by health-related quality of life and disease burden. The FSHD-HI questionnaire was designed to measure both overall FSHD health-related quality-of-life and 14 separate subdomains designed and based on patient interviews to measure total FSHD health-related quality-of-life, including both motor impairment and the social and emotional impact of FSHD. The 116 questions are combined into a total score, the score is transformed onto a percentage scale; with a range of 0-100, with 100 representing maximal disability, and lower scores representing decreasing disability, 0 representing no disability. The mean and standard deviation for baseline and day 190 are reported as is the absolute change from baseline to Day 190 during the randomized controlled portion of Part 2.
ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Tibialis Anterior (TA) Bilaterally) Day 2, 24-hours After Dose	Day 2, 24-hours after dose	Pharmacokinetic assessment included ACE-083 serum concentration collection and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. Timepoints that have data are reported; Day 2, 24-hours after dose is reported.
ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Tibialis Anterior (TA) Bilaterally) Day 85, 6-hours After Dose	Study Day 85 (6 hours post-dose)	Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 86, 6-hours post-dose is reported.
ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Biceps Brachii (BB) Unilateral) Day 1, 6-hours Post-dose	Study Day 1, 6-hours post-dose	Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 1, 6-hours post-dose, is reported.
Percent Change in Total Muscle Volume (TMV) in Muscle in Patients With FSHD Administered ACE-083 During Part 1 (Open-label, Dose-escalation Portion)	Time Frame: From initiation of treatment to Study Visit Day 106	Percent Change in Total Muscle Volume (TMV) in muscle in patients with FSHD administered ACE-083 During 1 (open-label, dose-escalation portion) from Baseline to Day 106. Total Muscle volume was measured by Magnetic Resonance Imaging (MRI). MRI was performed bilaterally on the tibialis anterior and the biceps brachii on Day 1, Day Day 43, and Day 106, change from Baseline and Day 106 reported.
ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Tibialis Anterior (TA) Bilaterally) Day 2, 24- Hours Post-dose	Day 2, 24-hours post-dose	Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 2, 24-hours post-dose is reported.
ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Tibialis Anterior (TA) Bilaterally) Day 86, 24- Hours Post-dose	Day 86, 24-hours post-dose	Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 86, 24-hours post-dose is reported.
ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Biceps Brachii (BB) Bilaterally) Day 2, 24- Hours Post-dose	Day 2, 24-hours post-dose	Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 2, 24-hours post-dose is reported.
ACE-083 Serum Concentration Following Local Intramuscular Administration (240 mg Biceps Brachii (BB) Bilaterally) Day 86, 24 Hours Post-dose	Day 86, 24- hours post-dose	Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 86, 24-hours post-dose is reported.
ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Biceps Brachii (BB) Unilateral) Day 85, 4-hours Post-dose	Study Day 85, 4-hours post-dose	Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported.
Absolute Change in Fat Fraction (FF) of the Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	Time Frame: From initiation of treatment to Study Visit Day 190	Absolute change in Fat Fraction (FF) of the muscle in patients with FSHD administered ACE-083 or Placebo During Part 2 (randomized, controlled portion) from Baseline to Day 190. Absolute change in intramuscular fat fraction in the tibialis anterior and biceps brachii were measured by Magnetic Resonance Imaging (MRI). MRI was performed bilaterally on the tibialis anterior and the biceps brachii on Day 1, Day Day 43, Day 106, and Day 190, change from Baseline and Day 190 reported.
Percent Change From Baseline in Function of Tibialis Anterior, Part 2 (Randomized, Controlled Portion)	From initiation of treatment (Study Day 1) to Study Visit Day 190	Percent change from baseline in function of Tibialis Anterior during Part 2 assessed by: 6-minute walk test, 10 meter walk/run and 4-stair climb (ascend)
Percent Change From Baseline in Strength of Biceps Brachii, Part 2, Randomized-controlled	From initiation of treatment (Study Day 1) to Study Visit Day 190	Elbow flexion strength measured by hand-held dynamometry (quantitative muscle testing), maximum voluntary isometric contraction (MVIC).
Percent Change From Baseline in Performance of the Upper Limb (PUL) Mid-Level Elbow Dimension, Part 2, Randomized-controlled	From initiation of treatment (Study Day 1) to Study Visit Day 190	Percent Change from Baseline in Performance of the Upper Limb (PUL) Mid-Level Elbow Dimension, Part 2, Randomized-controlled, PUL from baseline to end of treatment (Day 190). The Performance of the Upper Limb is an assessment specifically designed for patients with Duchenne muscular dystrophy. The measures used in this study was a subset of the assessment. PUL was assessment by measures of high-level of movement (lifting weights of 50g, 200g, 500g and 1000g at shoulder height and above shoulder height) and mid-level movement by performing tasks with and without weights: hand to mouth with and without weights (50, 200g), hand to table, moving weights on table (100g, 200g, 500g and 1000g), lift light and heavy cans, stack light and heavy cans, remove lid from container, tearing paper).

Countries

Canada, Spain, United States

Participant flow

Recruitment details

First subject enrolled 22 November 2016, last subject completed 09 October 2019. The study was divided into parts; Part 1 was an open-label dose escalation study and had 6 cohorts and Part 2 was a randomized double-blind placebo controlled trial. Participants were recruited from 23 study centers in 3 countries (US, Canada and Spain).

Participants by arm

Arm	Count
ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150mg ACE-083 150 mg TA unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein	6
ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200mg ACE-083 200 mg TA unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein	6
ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200mg ACE-083 200 mg TA bilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein	6
ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg ACE-083 150 mg BB unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein	6
ACE-083 (Part 1, Cohort 2b) Biceps Brachii (BB) 200 mg ACE-083 200 mg BB unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein	7
ACE-083 (Part 1, Cohort 3b) Biceps Brachii (BB) 240 mg ACE-083 240 mg BB unilaterally, once every 3 weeks for up to 5 doses. Drug: ACE-083 Recombinant fusion protein	6
Placebo (Part 2, DB-PC) Tibialis Anterior (TA) Double-Blind, Placebo-Controlled Placebo- TA bilaterally, once every 3 weeks for up to 9 doses. Drug: Placebo Normal saline	15
ACE-083 (Part 2, DB-PC) Tibialis Anterior (TA) 240 mg Double-Blind, Placebo-Controlled ACE-083 240 mg TA bilaterally, once every 3 weeks for up to 9 doses. Drug: ACE-083 Recombinant fusion protein.	14
Placebo (Part 2, DB-PC) Biceps Brachii (BB) Double-Blind, Placebo-Controlled Placebo- BB bilaterally, once every 3 weeks for up to 9 doses. Drug: Placebo Normal saline	15
ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) Double-Blind, Placebo-Controlled ACE-083 240 mg BB bilaterally, once every 3 weeks for up to 9 doses. Drug: ACE-083 Recombinant fusion protein	14
Total	95

Withdrawals & dropouts

Period	Reason	FG001	FG004	FG006	FG007	FG008	FG009
Overall Study	Adverse Event	1	0	0	1	0	1
Overall Study	Other	0	0	1	0	1	0
Overall Study	Study terminated by Sponsor	0	0	6	7	2	3
Overall Study	Willingness to comply with protocol	0	0	0	0	0	1
Overall Study	Withdrawal by Subject	0	1	1	1	0	2

Baseline characteristics

Characteristic	ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200mg	ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200mg	ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg	ACE-083 (Part 1, Cohort 2b) Biceps Brachii (BB) 200 mg	ACE-083 (Part 1, Cohort 3b) Biceps Brachii (BB) 240 mg	ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150mg	Placebo (Part 2, DB-PC) Tibialis Anterior (TA)	ACE-083 (Part 2, DB-PC) Tibialis Anterior (TA) 240 mg	Placebo (Part 2, DB-PC) Biceps Brachii (BB)	ACE-083 (Part 2, DB-PC) Biceps Brachii (BB)	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants	1 Participants	2 Participants	1 Participants	6 Participants
Age, Categorical Between 18 and 65 years	6 Participants	6 Participants	5 Participants	6 Participants	6 Participants	6 Participants	15 Participants	13 Participants	13 Participants	13 Participants	89 Participants
Age, Continuous	43.7 years STANDARD_DEVIATION 16.9	50.7 years STANDARD_DEVIATION 7.6	52.2 years STANDARD_DEVIATION 10.8	48.3 years STANDARD_DEVIATION 17.6	41.2 years STANDARD_DEVIATION 14	46.7 years STANDARD_DEVIATION 4.3	41.3 years STANDARD_DEVIATION 14.5	50.9 years STANDARD_DEVIATION 11.4	46.3 years STANDARD_DEVIATION 17.2	46.7 years STANDARD_DEVIATION 10.8	46.6 years STANDARD_DEVIATION 13.4
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	5 Participants	6 Participants	6 Participants	7 Participants	5 Participants	6 Participants	14 Participants	14 Participants	14 Participants	14 Participants	91 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	2 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	2 Participants	3 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants	0 Participants	3 Participants
Race (NIH/OMB) More than one race	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	5 Participants	6 Participants	6 Participants	6 Participants	6 Participants	6 Participants	14 Participants	12 Participants	12 Participants	12 Participants	85 Participants
Region of Enrollment Canada	1 participants	2 participants	0 participants	0 participants	1 participants	0 participants	1 participants	3 participants	6 participants	5 participants	19 participants
Region of Enrollment Spain	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	5 participants	4 participants	3 participants	1 participants	13 participants
Region of Enrollment United States	5 participants	4 participants	6 participants	7 participants	5 participants	6 participants	9 participants	7 participants	6 participants	8 participants	63 participants
Sex: Female, Male Female	3 Participants	4 Participants	2 Participants	3 Participants	2 Participants	3 Participants	7 Participants	8 Participants	3 Participants	4 Participants	39 Participants
Sex: Female, Male Male	3 Participants	2 Participants	4 Participants	4 Participants	4 Participants	3 Participants	8 Participants	6 Participants	12 Participants	10 Participants	56 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk	EG010 affected / at risk	EG011 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 6	0 / 6	0 / 6	0 / 7	0 / 6	0 / 15	0 / 14	0 / 15	0 / 14	0 / 27	0 / 26
other Total, other adverse events	6 / 6	6 / 6	5 / 6	6 / 6	7 / 7	6 / 6	12 / 15	14 / 14	13 / 15	14 / 14	22 / 27	22 / 26
serious Total, serious adverse events	0 / 6	0 / 6	0 / 6	0 / 6	0 / 7	0 / 6	0 / 15	1 / 14	1 / 15	1 / 14	1 / 27	0 / 26

Outcome results

Primary

Percent Change of Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)

Percent Change of Total Muscle Volume (TMV)of the treated muscle in Patients with FSHD administered ACE-083 or placebo During Part 2 (randomized, controlled portion) from Baseline to Day 190. Total Muscle volume was measured by Magnetic Resonance Imaging (MRI). MRI was performed bilaterally on the tibialis anterior and the biceps brachii on Day 1, Day Day 43, Day 106, and Day 190. Percent Change from Baseline to Day 190 total muscle volume, mean and standard deviation is reported.

Time frame: Time Frame: From initiation of treatment to Study Visit Day 190

Population: The Per Protocol Set: All patients enrolled/randomized in the study who received at least one dose of the study drug (includes placebo) with no major protocol violations.

Arm	Measure	Value (MEAN)	Dispersion
ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150 mg	Percent Change of Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	5.46 percent change	Standard Deviation 7.32
ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200 mg	Percent Change of Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	14.20 percent change	Standard Deviation 10.72
ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200 mg	Percent Change of Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	1.07 percent change	Standard Deviation 8.08
ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg	Percent Change of Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	20.41 percent change	Standard Deviation 16.64

Comparison: D190 Percent change from baseline in TMVp-value: 0.013890% CI: [3.17, 15.92]ANCOVA

Comparison: D190 Percent change from baseline in TMVp-value: <0.000190% CI: [9.75, 23.02]ANCOVA

Primary

Safety and Tolerability (Incidence of Adverse Events)

The number of participants that had a least one Treatment Emergent Adverse Event for the duration of each of the respective study parts.

Time frame: From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2

Population: The safety set population is all participants that received at least one dose of ACE-083 or placebo during the study.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150 mg	Safety and Tolerability (Incidence of Adverse Events)	6 Participants
ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200 mg	Safety and Tolerability (Incidence of Adverse Events)	6 Participants
ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200 mg	Safety and Tolerability (Incidence of Adverse Events)	5 Participants
ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg	Safety and Tolerability (Incidence of Adverse Events)	6 Participants
ACE-083 (Part 1, Cohort 2b) Biceps Brachii (BB) 200 mg	Safety and Tolerability (Incidence of Adverse Events)	7 Participants
ACE-083 (Part 1, Cohort 3b) Biceps Brachii (BB) 240 mg	Safety and Tolerability (Incidence of Adverse Events)	6 Participants
Placebo (Part 2, DB-PC) Tibialis Anterior (TA)	Safety and Tolerability (Incidence of Adverse Events)	12 Participants
ACE-083 (Part 2, DB-PC) Tibialis Anterior (TA) 240 mg	Safety and Tolerability (Incidence of Adverse Events)	14 Participants
Placebo (Part 2, DB-PC) Biceps Brachii (BB)	Safety and Tolerability (Incidence of Adverse Events)	13 Participants
ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) 240 mg	Safety and Tolerability (Incidence of Adverse Events)	14 Participants

Primary

Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)

The number of participants that had a least one Treatment Emergent Adverse Event that led to dose interruption, dose reduction and/or drug withdrawn.

Time frame: From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2

Population: The safety set population is all participants that received at least one dose of ACE-083 or placebo during the study.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose interruption	0 Participants
ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose reduction	0 Participants
ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Drug Withdrawal	0 Participants
ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose reduction	1 Participants
ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Drug Withdrawal	1 Participants
ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose interruption	0 Participants
ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Drug Withdrawal	0 Participants
ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose interruption	0 Participants
ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose reduction	0 Participants
ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Drug Withdrawal	0 Participants
ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose interruption	0 Participants
ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose reduction	0 Participants
ACE-083 (Part 1, Cohort 2b) Biceps Brachii (BB) 200 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Drug Withdrawal	0 Participants
ACE-083 (Part 1, Cohort 2b) Biceps Brachii (BB) 200 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose reduction	0 Participants
ACE-083 (Part 1, Cohort 2b) Biceps Brachii (BB) 200 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose interruption	0 Participants
ACE-083 (Part 1, Cohort 3b) Biceps Brachii (BB) 240 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose reduction	0 Participants
ACE-083 (Part 1, Cohort 3b) Biceps Brachii (BB) 240 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose interruption	0 Participants
ACE-083 (Part 1, Cohort 3b) Biceps Brachii (BB) 240 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Drug Withdrawal	0 Participants
Placebo (Part 2, DB-PC) Tibialis Anterior (TA)	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose interruption	0 Participants
Placebo (Part 2, DB-PC) Tibialis Anterior (TA)	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose reduction	0 Participants
Placebo (Part 2, DB-PC) Tibialis Anterior (TA)	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Drug Withdrawal	0 Participants
ACE-083 (Part 2, DB-PC) Tibialis Anterior (TA) 240 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose reduction	1 Participants
ACE-083 (Part 2, DB-PC) Tibialis Anterior (TA) 240 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose interruption	0 Participants
ACE-083 (Part 2, DB-PC) Tibialis Anterior (TA) 240 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Drug Withdrawal	0 Participants
Placebo (Part 2, DB-PC) Biceps Brachii (BB)	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose interruption	0 Participants
Placebo (Part 2, DB-PC) Biceps Brachii (BB)	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose reduction	0 Participants
Placebo (Part 2, DB-PC) Biceps Brachii (BB)	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Drug Withdrawal	0 Participants
ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) 240 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Drug Withdrawal	1 Participants
ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) 240 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose interruption	0 Participants
ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) 240 mg	Safety and Tolerability (Severity of Adverse Events- Dose Interruption, Reduction and/or Drug Withdrawal)	Dose reduction	0 Participants

Primary

Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).

The number of participants that had a least one Treatment Emergent Adverse Event with CTCAE Grade 3 or Higher for the duration of each of the respective study parts.

Time frame: From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2

Population: The safety set population is all participants that received at least one dose of ACE-083 or placebo during the study.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150 mg	Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).	0 Participants
ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200 mg	Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).	1 Participants
ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200 mg	Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).	0 Participants
ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg	Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).	0 Participants
ACE-083 (Part 1, Cohort 2b) Biceps Brachii (BB) 200 mg	Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).	0 Participants
ACE-083 (Part 1, Cohort 3b) Biceps Brachii (BB) 240 mg	Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).	0 Participants
Placebo (Part 2, DB-PC) Tibialis Anterior (TA)	Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).	0 Participants
ACE-083 (Part 2, DB-PC) Tibialis Anterior (TA) 240 mg	Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).	1 Participants
Placebo (Part 2, DB-PC) Biceps Brachii (BB)	Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).	1 Participants
ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) 240 mg	Safety and Tolerability (Severity of Adverse Events, Grade 3 or Higher).	1 Participants

Primary

Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)

Total Muscle Volume (TMV)of the treated muscle in Patients with FSHD administered ACE-083 or placebo During Part 2 (randomized, controlled portion) from Baseline to Day 190. Total Muscle volume was measured by Magnetic Resonance Imaging (MRI). MRI was performed bilaterally on the tibialis anterior and the biceps brachii on Day 1, Day Day 43, Day 106, and Day 190. Baseline and Day 190 total muscle volume, means and standard deviations are reported.

Time frame: Time Frame: From initiation of treatment to Study Visit Day 190

Population: The Per Protocol Set: All patients enrolled/randomized in the study who received at least one dose of the study drug (includes placebo) with no major protocol violations.

Arm	Measure	Group	Value (MEAN)	Dispersion
ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150 mg	Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	Baseline Total Muscle Volume (TMV)	79708.77 mm3	Standard Deviation 4507.67
ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150 mg	Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	Day 190 Total Muscle Volume (TMV)	81761.70 mm3	Standard Deviation 43533.71
ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200 mg	Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	Day 190 Total Muscle Volume (TMV)	95739.04 mm3	Standard Deviation 20689.98
ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200 mg	Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	Baseline Total Muscle Volume (TMV)	85159.90 mm3	Standard Deviation 22382.2
ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200 mg	Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	Baseline Total Muscle Volume (TMV)	104788.87 mm3	Standard Deviation 58681.86
ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200 mg	Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	Day 190 Total Muscle Volume (TMV)	109489.17 mm3	Standard Deviation 56130.61
ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg	Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	Baseline Total Muscle Volume (TMV)	89133.23 mm3	Standard Deviation 48264.27
ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg	Total Muscle Volume (TMV) of the Treated Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	Day 190 Total Muscle Volume (TMV)	102131.94 mm3	Standard Deviation 54608.84

Secondary

Absolute Change in Fat Fraction (FF) of the Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)

Absolute change in Fat Fraction (FF) of the muscle in patients with FSHD administered ACE-083 or Placebo During Part 2 (randomized, controlled portion) from Baseline to Day 190. Absolute change in intramuscular fat fraction in the tibialis anterior and biceps brachii were measured by Magnetic Resonance Imaging (MRI). MRI was performed bilaterally on the tibialis anterior and the biceps brachii on Day 1, Day Day 43, Day 106, and Day 190, change from Baseline and Day 190 reported.

Time frame: Time Frame: From initiation of treatment to Study Visit Day 190

Population: The Per Protocol Set: All patients enrolled/randomized in the study who received at least one dose of the study drug (includes placebo) with no major protocol violations.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
ACE-083 (Part 1, Cohort 1a) Tibialis Anterior (TA) 150 mg	Absolute Change in Fat Fraction (FF) of the Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	-0.32 Percent change	Standard Error 0.888
ACE-083 (Part 1, Cohort 2a) Tibialis Anterior (TA) 200 mg	Absolute Change in Fat Fraction (FF) of the Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	-3.05 Percent change	Standard Error 0.946
ACE-083 (Part 1, Cohort 3a) Tibialis Anterior (TA) 200 mg	Absolute Change in Fat Fraction (FF) of the Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	1.03 Percent change	Standard Error 0.955
ACE-083 (Part 1, Cohort 1b) Biceps Brachii (BB) 150 mg	Absolute Change in Fat Fraction (FF) of the Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)	-0.22 Percent change	Standard Error 0.978

Comparison: D190 Absolute change from baseline in FF for the TA group administered ACE-083 when compared to Placebo in part 2p-value: 0.035990% CI: [-4.86, -0.59]ANCOVA

Comparison: D190 Absolute change from baseline in FF for the BB group administered ACE-083 when compared to Placebo in part 2p-value: 0.358290% CI: [-3.49, 0.99]ANCOVA

Secondary

ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Biceps Brachii (BB) Unilateral) Day 1, 6-hours Post-dose

Pharmacokinetic assessment included ACE-083 serum concentration and on a dosing day had a ±15 minute window for post-dose sample collection, based on the time of the first injection. The timepoints for which data is available are reported. Day 1, 6-hours post-dose, is reported.

Time frame: Study Day 1, 6-hours post-dose