Principal Investigator: Russell Butterfield
Keywords: FSHD (Facioscapulohumeral Muscular Dystrophy) , Muscular Dystrophy Department: Pediatric Administration
IRB Number: 00095257 Co Investigator: Russell Butterfield
Specialty: Neurology
Sub Specialties: Muscular Dystrophy
Recruitment Status: Recruiting

Contact Information

zBryan  Gardner

Brief Summary

This is a multicenter, Phase 2 study to evaluate the safety, tolerability, pharmacodynamics (PD), efficacy, and pharmacokinetics (PK) of ACE-083 in patients with FSHD, to be conducted in two parts. Part 1 is open-label, dose-escalation (3 months) and Part 2 is randomized, double-blind, placebo-controlled (6 months) followed by an open-label extension (6 months). Patients who have signed the informed consent form (ICF) and meet the eligibility criteria will be enrolled into the study.

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 in either the tibialis anterior (TA) or biceps brachii (BB) muscle. Patients in each cohort will be enrolled in a 1 month screening period before beginning treatment.

Cohorts 1a and 1b will be treated in parallel. The dose level in Cohort 1a will be 150 mg (3 mL) administered by multiple injections unilaterally into the TA muscle, once every 3 weeks for up to 5 doses. Patients in Cohort 1b will be similarly treated in the BB muscle. The estimated tissue exposure of ACE-083 (mg/g muscle) is expected to be similar for the TA and the BB, as the two muscles are relatively similar in size.

For Cohorts 2a and 2b, the decision to enroll patients and the dose levels that will be administered will be based upon Safety Review Team (SRT) review of safety and, if necessary, imaging data collected in prior cohorts. The planned dose level for Cohorts 2a and 2b is 200 mg, with a maximum possible dose level of 250 mg, to be selected following SRT review of data from prior cohorts.

For Cohorts 3a and 3b, the decision to enroll patients, dose level (maximum 250 mg), muscle tested (TA and/or BB), and unilateral or bilateral dosing will be based upon SRT review of safety and imaging data collected in prior cohorts.

The SRT will meet to review data for each cohort when at least 4 patients within a cohort have completed their Day 43 visit (SRT meetings for a and b cohorts can occur separately or together, depending on recruitment). The SRT may recommend treatment of the remaining patients at the current dose level or escalation to a higher dose level for the next cohort;  an intermediate (lower) dose level or no treatment of additional patients or cohorts. Recommendations made by the SRT may be relevant to both the TA and BB or specific to one or the other muscle, as safety findings and dose escalation may be specific to each muscle.

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 per muscle) or placebo (n=14 per 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)

Detailed Description

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

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 criteria1
3. Part 1 For TA cohorts:
   a. 6-minute walk distance ≥ 150 meters, without a brace
   b. Left and/or right ankle dorsiflexion Medical Research Council (MRC) manual muscle testing (MMT) grade 3 to 4+, inclusive 
Note: Contralateral side may be MRC MMT grade 3 to 5
   Part 1 For BB cohorts:
     a. Left and/or right elbow flexion MMT, MRC grade of 3 to 4+, inclusive
                               Note: Contralateral side may be any MRC MMT grade

Part 2 TA cohorts:

  1. 6MWD ≥ 150 and ≤ 500 meters (without a brace); a maximum of 20% of  enrolled patients with 6MWD ≥ 450 meters will be included
  2.  Left and right ankle dorsiflexion MRCMMT grade 3 to 4+, inclusive 

Part 2 BB cohorts:

  1. Left and right elbow flexion MRC MMT grade 3 to 4+, inclusive 
4. Females of childbearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥ 24 consecutive months) must have negative urine pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation and for 8 weeks following the last dose of ACE-083. Males must agree to use a latex condom during any sexual contact with females of childbearing potential while participating in the study and for 8 weeks following the last dose of ACE-083, even if he has undergone a successful vasectomy. Patients must be counseled concerning measures to be used to prevent pregnancy prior to the first dose of ACE-083. Hormonal birth control use must be stable for at least 14 days prior to Day 1.
5. Ability to adhere to the study visit schedule/procedures, and to understand and comply with protocol requirements
6. Signed written informed consent

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 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 ≥ 1.5 times the upper limit of normal [ULN])
4. Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≥ 2 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 before randomization; 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 change in medications potentially affecting muscle strength or function within 4 weeks before randomization and for duration of study(e.g., creatinine, CoQ10, systemic beta-adrenergic agonists)
10. Previous exposure to any investigational agent potentially affecting muscle volume, strength, or function within 5 half-lives of last dose or 4 weeks of study day 1 if half-life is unknown
11. Significant change in physical activity or exercise (e.g., significant increase or decrease in intensity) within 8 weeks before Study Day 1
12. 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)
13. Known active substance abuse, including alcohol
14. History of sensitivity to protein pharmaceuticals

15. Female that is lactating/breast-feeding