A Phase 1b/2a Clinical Trial to Evaluate the Safety and Efficacy of EN001 in Patients with Charcot-Marie-Tooth Disease type 1A(CMT1A) (Phase 1b: Open-label, Dose-escalation, Single-center; Phase 2a: Randomized, Double-blind, Placebo-controlled, Multicenter)

This clinical trial consists of two stages (Phase 1b and Phase 2a). Phase 1b is designed with a 3+3 dose escalation design to evaluate the safety, including tolerability, of EN001 and explore efficacy. Phase 2a will evaluate the efficacy and safety of EN001 in comparison with placebo.

-Phase 1b The study was designed using the traditional 3+3 dose escalation method to confirm the maximum tolerated dose (MTD) and determine the recommended phase 2 dose (RP2D).

Dose increase is carried out until the maximum tolerated dose (MTD) is confirmed at the high dose (Cohort 2), which is the maximum planned dose (MPD), or at a lower dose. The maximum tolerated dose (MTD) is defined as the highest dose at which the incidence of dose limiting toxicity (DLT) is lower than 33%. To determine the maximum tolerated dose (MTD), 3-6 test subjects from each dose cohort are enrolled and EN001 is administered twice at 4-week intervals, and dose-limiting toxicity (DLT) is evaluated until 4 weeks (visit 6).

The safety review committee (SRC) is comprised of the principal investigator, sponsor, etc. as members, and EN001 confirmed by the end of each cohort (end of dose-limiting toxicity (DLT) evaluation of the last dosed subject in the cohort). Safety data are comprehensively reviewed to determine all matters related to dose, such as increase or decrease in dose, and finally the recommended phase 2 dose (RP2D) is determined.

-Phase 2a The Phase 2a is a randomized, double-blind, placebo-controlled clinical trial. Eligible subjects will be randomly assigned in a 1:1:1 ratio to Study Group 1 (EN001 Low dose), Study Group 2 (EN001 High dose), or the placebo control group. The efficacy and safety of EN001 will be evaluated in comparison with placebo.

In addition, test subjects participating in phase 1b/2a will be followed up for safety and effectiveness for 5 years from the time of last EN001 administration according to the long-term follow-up protocol.

Inclusion Criteria:

1. Individuals who have voluntarily agreed to participate in this clinical trial.

2. Men and women aged 19 years or older at the time of providing written consent.

3. Individuals who meet all of the following genetic and clinical diagnostic criteria:

   1. Genetic diagnosis: CMT1A type

   2. Clinical diagnosis:

      • Those with a CMT Neuropathy Score version 2 (CMTNSv2) between 2 or more and 20 or less.
      • Those experiencing muscle weakness due to foot dorsiflexion impairment.

4. Women and men of childbearing potential who have agreed to use the appropriate contraceptive method(s) outlined in the protocol during the clinical trial period.

   • Appropriate contraception is defined as follows and is achieved by applying one or more methods of contraception.

     • Hormonal contraceptives
     • Implantation of an intrauterine device or intrauterine system
     • Sterilization procedures (vasectomy, tubal ligation, etc.)
     • Double contraceptive method: male condom along with other contraceptive methods [hormonal contraceptives (oral contraceptives, subcutaneous contraceptives (Implanon, etc.), long-acting contraceptive injections, emergency contraceptive pills), implantation of an intrauterine device or intrauterine system (Loop, Mirena), Infertility procedures (vasectomy, tubal ligation, etc.)]
     • Abstinence: Absolute abstinence. If, in the examiner's judgment, the subject's age, occupation, lifestyle, or sexual orientation warrants contraception, strict abstinence from sexual intercourse is also acceptable. However, periodic abstinence (e.g. Karenda method, ovulation method, symptomatic temperature method), abstinence, and external vaginal ejaculation are not recognized as appropriate contraceptive methods.

Exclusion Criteria:

1. Those with the following comorbidities confirmed at the time of screening

   1. Subjects with neuromuscular diseases other than CMT1A or neuropathy- inducing factors (uremia) that may affect the safety and efficacy evaluation of this clinical trial, according to the judgment of the investigator.

   2. Individuals diagnosed with type 1 or type 2 diabetes

   3. Individuals diagnosed with active pulmonary tuberculosis

   4. Patients with uncontrolled hypertension (systolic blood pressure over 180 mmHg or diastolic blood pressure over 110 mmHg)

   5. Subjects with other clinically significant diseases, including significant heart, lung, liver, kidney, hematological, immunological or behavioral diseases or malignant tumors, according to the investigator's judgment

   6. Individuals who display the specified test abnormalities in laboratory tests at the time of screening:

      • AST or ALT > 3 x ULN
      • Total bilirubin> 1.5 x ULN
      • Serum creatinine > 1.5 x ULN
      • Any one of the serum virus tests (HBsAg, anti-HBc, anti-HCV, HIV Ag/Ab) is positive (If anti-HBc positive) However, registration is possible if the HBV DNA test result is negative. (If anti-HCV positive) However, registration is possible if the HCV RNA test result is negative.

   7. Those who have ankle contracture or have undergone surgery that may affect muscle strength measurement tests

2. Medical history and surgical history

   1. Those who have undergone orthopedic surgery (bone or ligament correction, artificial joint implantation, osteotomy, arthroscopic surgery) on the lower extremities within 24 weeks before screening
   2. Those with a history of stroke or cerebral ischemic attack within 48 weeks before screening
   3. Those with a history of coronary artery disease, such as myocardial infarction or incomplete angina, within 48 weeks before screening
   4. Those with a history of malignant tumor within 240 weeks before screening (excluding basal cell carcinoma or squamous cell carcinoma that occurs on the skin)

3. Drugs and therapies prohibited from concurrent use

   1. Those who participated in another clinical trial and administered/applied clinical trial drugs/medical devices within 4 weeks before screening

   2. Those who administered/applied immunosuppressants, chemotherapy, radiation therapy, etc. within 12 weeks before screening

   3. Persons who have administered cell therapy or gene therapy throughout their lives

   4. Persons who have administered neurotoxic drugs that can accelerate peripheral nerve damage ① Within 1 week of Screening

      • Anti-inflammatory agents or antibiotics: Colchicine, Nitrofurantoin

      • Antiretroviral agents: Zalcitabine, Stavudine

      • Dichloroacetate

        ② Within 55 weeks of Screening

      • Antiarrhythmic agent: Amiodarone

      • Antiparasitic agent: Suramin

4. Persons with hypersensitivity to the components of clinical investigational products

5. Those who have had metal substances (heart pacemaker, nerve stimulator, cochlear implant, etc.) implanted in their body

6. Pregnant, lactating, or planning to become pregnant during the clinical trial period

7. Subjects with a psychiatric disorder (anxiety disorder, claustrophobia, or other significant mental disorder) or a history of drug and alcohol abuse that may affect the clinical trial, according to the judgment of the investigator.

8. Those who are deemed inappropriate to participate in clinical trials according to the judgment of the investigator