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

Part 1 (dose escalation, open-label) Part 1 will consist of up to 6 cohorts (A to F) of
patients and will evaluate multiple ascending dose levels of ACE-083 in either the tibialis
anterior (TA) or biceps brachii (BB) muscle. 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.

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 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.

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

Key Inclusion Criteria:

1. Age ≥ 18 years

2. Genetically-confirmed 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
anticoagulation/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)