The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)

There are no therapeutic agents for CMT to date. Attempts were made to develop therapeutic agents, but efficacy could not be demonstrated in clinical studies. Most of the attempted developments for therapeutic agents targeted alleviating the symptoms of CMT1A by regulating the expression of PMP22. This study will use Engensis (VM202), which is a DNA plasmid that contains novel genomic cDNA hybrid human HGF coding sequence (HGF-X7) expressing two isoforms of HGF, HGF 728 and HGF 723. HGF has been thought of as an angiogenic factor, but it has been recently identified as serving the role of a neurotrophic factor. Moreover, it has been reported that it can contribute to muscle tissue regeneration by targeting on muscles. Considering the pathologic mechanism of CMT, the biological activity of HGF helps peripheral nerve regeneration, relieves muscle atrophy, and reduces pain, so it is highly likely to show a therapeutic effect for CMT.

Inclusion criteria

• Males or females ≥ 19 years of age and ≤ 65 years of age
• Patients with confirmed diagnosis of CMT1A by genetic testing
• Patients with mild to moderate severity assessed by Charcot Marie Tooth Neuropathy Score version 2 (CMTNS v2) with a score > 2 and ≤ 20
• Individuals with lower limb muscle weakness with minimum dorsiflexion or more
• Individuals who voluntarily consented to participate in this study and signed the IRB approved informed consent form after listening to a description on the characteristics of this clinical study prior to all screening tests
• Individuals who can comply with the requirements in the clinical study
• In case of females of child bearing potential, those who test negative in a urine or serum pregnancy test at screening
• Individuals who practice medically approved contraceptive methods throughout the clinical study

Exclusion criteria

• Patients with significant respiratory, circulatory, renal, gastrointestinal, hepatic, endocrine, hematologic, psychiatric disorders or other severe diseases, or alcohol or drug addiction who may develop safety issues or cause confusion in the interpretation of the clinical study results as determined by the principal investigator
• Patients with other neuromuscular diseases or neuropathy-inducing factors: Patients with chronic alcohol addiction, undergoing anticancer chemotherapy, or taking neurotoxic drugs
• Patients diagnosed with diabetes
• Patients diagnosed with inflammatory bowel disease
• Patients with a history of stroke or cerebral ischemic attack within 12 months prior to the screening date
• Patients with a history of coronary artery disease, such as myocardial infarction and unstable angina pectoris, within 12 months prior to the screening date
• Morbidly obese patients with body mass index (BMI) ≥ 37
• Patients who underwent orthopedic surgery (corrective surgery for bone and ligament, artificial joint implantation, osteosynthesis, osteotomy, arthroscopic surgery) in the lower limbs within 6 months prior to the screening date
• Patients who may be affected by the muscle strength measurement test due to ankle contracture or surgery
• Patients with uncontrolled hypertension (if systolic blood pressure is ≥ 160 mmHg or diastolic blood pressure is ≥ 100 mmHg at screening)
• Patients or patient's immediate family members (parents, siblings, offspring) with a history of malignant tumors within the last 5 years prior to the screening date, excluding basal cell carcinoma or squamous cell carcinoma that occurs on the skin (if it is determined that there is no possibility of relapse after resection), or with a family history of familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC)
• Patients who have not completed a national cancer screening program applicable to their sex and age (if it cannot be confirmed that the relevant test was received at a national cancer screening center or a recognized screening center)

However, if it is confirmed that the relevant test was received at a national cancer screening center or a recognized screening center during the screening period, and that the results were within normal range, the patients may participate in the clinical study.

Common to males and females: If a patient is ≥ 50 years of age, the results of a colonoscopy within 5 years prior to the screening must be determined as being within normal range, and if adenomatous polyps are evident, the results of a colonoscopy within 1 year must be determined as being within normal range (inflammatory polyps or hyperplastic polyps are included in the normal range). If a patient is ≥ 40 years of age, the results of a gastroscopy within 2 years prior to the screening must be within normal range. If a patient is ≥ 54 years of age and has a 30 pack-year history of smoking or more, the results of a low-dose chest CT within 2 years prior to the screening must be within normal range. In case of liver cancer, carriers of hepatitis B or hepatitis C virus and patients with hepatic cirrhosis fall under the exclusion criteria.

Females: For females ≥ 40 years of age, normal range findings must be confirmed in a mammogram within 2 years. For females ≥ 20 years of age, normal range findings must be confirmed in a Pap smear within 2 years.

• Patients diagnosed with active pulmonary tuberculosis
• Patients with HBV or HCV
• Patients who test positive in human immunodeficiency virus (HIV) antibody test
• Patients in an immunosuppressive state due to treatments such as immunosuppressants, chemotherapy, and radiotherapy
• Patients with a history of mental disease within 6 months prior to the screening date, which may interfere with participation in the study
• Patients who must take medications, that are known to have significant drug interactions within 14 days after the first administration of the investigational product or deemed unsuitable by the investigator's judgment
• Individuals who participated in another clinical study within 6 months before the time of screening
• Individuals who have shown significant adverse events such as hypersensitivity reactions to the investigational product
• Pregnant or breastfeeding females
• Other individuals determined ineligible by the principal investigator to participate in the clinical study due to other reasons including clinical laboratory test results