Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease Types 1 and X

This is a multicenter, phase 2 study to evaluate the safety, tolerability, pharmacodynamics (PD), efficacy, and pharmacokinetics (PK) of ACE-083 in patients with Charcot-Marie-Tooth Disease Type 1 and Type X (CMT1 and CMTX), to be conducted in two parts. Part 1 is non-randomized, open-label, dose-escalation and Part 2 is randomized, double-blind, and placebo-controlled.

Part 1 (non-randomized, open-label, dose-escalation)

Part 1 will consist of up to 3 cohorts of 6 patients each and will evaluate multiple ascending dose levels of ACE-083 administered bilaterally once every 3 weeks for up to 5 doses in the tibialis anterior (TA) muscle. Patients in each cohort will be enrolled in a 4-week screening period before beginning treatment.

Part 2 (randomized, double-blind, placebo-controlled) Prior to the initiation of Part 2, a review of safety and efficacy data from Part 1 will be conducted by the Safety Review Team (SRT) to determine the recommended dose level (maximum 250 mg/muscle). A total of up to 40 new patients may be enrolled and randomized (1:1 randomization) to receive either ACE 083 (n=20) or placebo (n=20) bilaterally by injection into both TA muscles once every 3 weeks for up to 17 doses.

Study duration for Parts 1 and 2 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 will be 15 months, including 4-week screening, 6 months double blind placebo-controlled, 6 months open-label and 8 week follow-up.

Key Inclusion Criteria

1. Age ≥ 18 years

2. Diagnosis of CMT1 or CMTX confirmed by:

   1. Clinical presentation and electrodiagnostics
   2. Genetically-confirmed CMT1 or CMTX for the patient or first-degree relative

3. Part 1:

   1. Six-minute walk distance (6MWD) of at least 150 meters (without a brace or walker)
   2. Independent ambulation for at least 10 meters, without a brace
   3. Left and right ankle plantar flexion MRC grade 4+ to 5, inclusive

   Part 2:

   1. 6MWD ≥ 150 and ≤ 500 meters (without a brace or walker); a maximum of 20% of enrolled patients with 6MWD ≥ 450 meters will be included
   2. Left and right ankle plantar flexion MRC grade 4- to 5, inclusive

4. Left and right ankle dorsiflexion Medical Research Council (MRC) manual muscle testing (MMT) grade 3 to 4+ inclusive. No more than 12 of the 40 subjects may have a grade of 3 or 3+ on one or both sides.

5. Females of childbearing potential must have negative urine pregnancy test prior to enrollment and use highly effective birth control methods during study participation and for 8 weeks following the last dose of ACE-083. Males must agree to use a 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.

6. Ability to adhere to the study visit schedule/procedures, and to understand and comply with protocol requirements

7. Signed written informed consent

Key Exclusion Criteria

1. History of active malignancy, 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, significant orthopedic or neuropathic pain, 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. Type 1 or type 2 diabetes mellitus
4. Thyroid disorder unless condition is stable with no change in treatment for at least 4 weeks before the first dose and no expected change for duration of study
5. Renal impairment (serum creatinine ≥ 2 times the upper limit of normal (ULN])
6. Aspartate transaminase (AST) and/or alanine transaminase (ALT) ≥ 3 times ULN
7. 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 and for duration of study; low dose aspirin [≤ 100 mg daily] is permitted)
8. Severe deformity or ankle fixation that would sufficiently limit passive range of motion to affect assessment of dorsiflexion strength
9. Major surgery within 4 weeks prior to Study Day 1
10. Chronic pharmacologic doses of systemic corticosteroids (≥ 2 weeks) within 4 weeks before Study Day 1 and for duration of study; intra-articular/topical/inhaled/intranasal physiologic doses of systemic corticosteroids are permitted
11. Androgens, growth hormone, insulin or oral hormone replacement therapy within 6 months before Study Day 1 and for duration of study; topical physiologic androgen replacement is permitted
12. Any change in medications potentially affecting muscle strength or function within 4 weeks of Study Day 1 and for duration of study (e.g., creatinine, CoQ10, systemic beta-adrenergic agonists)
13. Previous exposure to any investigational agent potentially affecting muscle volume, muscle strength, or muscle or nerve function within 5 half-lives of last dose plus an additional 8-week washout period (or 12 weeks prior to Study Day 1 if half-life is unknown)
14. Any previous or current exposure to ACE-083
15. Significant change in physical activity or exercise (e.g., significant increase or decrease in intensity or frequency) within 8 weeks before Study Day 1 or inability to maintain the baseline level of physical activity throughout the study
16. Any condition that would prevent MRI scanning or compromise the ability to obtain a clear and interpretable scan of the lower leg, as applicable (e.g., knee/hip replacement metallic implants)
17. Known active substance abuse, including alcohol
18. History of sensitivity to protein pharmaceuticals
19. Female that is lactating/breast-feeding