Evaluate the Safety of Neuronata-R® Inj. Suspended With HypoTHermosol® FRS (HTS-FRS) in Patients With ALS

Neuronata-R is produced by mixing the patient's own cerebrospinal fluid with cultured mesenchymal stem cells the day before administration. Therefore, as autologous cerebrospinal fluid is collected from the patient for drug production at each administration, the patient must endure the occurrence of adverse events (headache, pain, etc.) and pain caused by collection, and problems such as fatigue and time consumption of the medical staff's procedure have continuously emerged.

Therefore, a comparative equivalence tests and stability tests were conducted with HypoThermosol® FRS (HTS-FRS) as a suspension agent for Neuronata-R, and it was confirmed that there was no difference in the quality of the finished product depending on the type of additive and Neuronata-R using autologous cerebrospinal fluid as a suspension agent, and it was confirmed that it was safe as an additive through non-clinical trials.

The dose determination for the safety evaluation of HypoThermosol® FRS (HTS-FRS), which will be used as a suspension, was determined in consultation with the MFDS to use a 1:1 mixture of autologous CSF and HypoThermosol® FRS (HTS-FRS) as a suspension in the first stage dose, and only HypoThermosol® FRS (HTS-FRS) was used as a suspension in the second stage dose without cerebrospinal fluid. And, the administration period is follow-up for 4 weeks after administration twice every 26 days.

Inclusion criteria

• Among subjects diagnosed with familial or sporadic amyotrophic lateral sclerosis
• Subjects whose ALSFRS-R scores are in the range of 25~46 at the time of screening (Visit 1).
• Subjects who are able to visit the site by themselves or with other's support.
• When subjects and/or their legal guardians consent to participating in this clinical study.
• Subjects deemed, by the investigator, capable of complying with the clinical study protocol
• For child-bearing aged female subjects: Subjects who consent to sexual abstinence (refraining from sexual intercourse) or use of contraception method with annual failure rate of < 1% during the study period.

A female subject who has experienced the menarche, does not reach the menopause (or 12-month or longer amenorrhea for unknown reasons except menopause) and does not receive surgical sterilization (ovariectomy and/or hysterectomy) is regarded as the child-bearing aged woman.

Examples of contraception methods with annual failure rate of < 1% include bilateral tubal ligation, vasectomy, appropriate use of hormonal contraceptives that inhibit ovulation (supplemented by barrier method and spermicide), hormone-releasing intrauterine device and copper intrauterine device.

Based on clinical study period and subject's preferred lifestyle, the reliability of sexual abstinence should be evaluated. Periodic abstinence (e.g., calendar method, ovulation and post-ovulation symptothermal method) and extravaginal ejaculation are not acceptable contraception methods.

For male subjects: Subjects who, as described below, consent to sexual abstinence (refraining from sexual intercourse) or use of contraception method and consent to refrain from donation of sperm.

When a male subject has his child-bearing aged female partner or pregnant female partner, he should maintain sexual abstinence or use condom to avoid exposure to embryo. Such male subject should not donate sperm during this period.

Based on clinical study period and subject's preferred lifestyle, the reliability of sexual abstinence should be evaluated. Periodic abstinence and extravaginal ejaculation are not acceptable contraception methods.

Exclusion criteria

• Subjects who fail to satisfy ALS diagnosis criteria according to the revised World Federation of Neurology El Escorial Criteria [Rix Brooks, 2000].
• Subjects expected to have side effects on administration of cell therapy (such as subjects suspected to have malignant tumor, high-risk subjects vulnerable to psychogenic shock and severe hypertension subjects).
• ALSFRS-R score of less than 25 and 47 or higher during screening (visit 1)
• Subjects who fall into above Class II according to the New York Heart Association's functional classification (see the attachment), who have showed myocardial infarction, unstable arrhythmia and/or other significant cardiovascular diseases such as unstable angina in the past 3 months, or who show electrocardiographic signs of myocardial infarction or angina at the time of screening (Visit 1) or who received stent insertion or coronary artery bypass grafting.
• Subjects who have experienced epileptic seizure.
• Subjects with severe renal disorder (serum creatinine: not less than 3.0 mg/dL).
• Subjects with severe hepatic disorder (ALT, AST, or bilirubin: over 2.0 times of the normal upper limit).
• Subjects who show hemorrhagic tendency at the time of screening (PT and aPTT > 1.5 x ULN)
• Subjects who are found to have active viral infections (such as HBsAg, HCV Ab, HIV Ab, CMV IgM, EBV IgM, HSV IgM and Treponema pallidum) at the time of screening.
• Subjects with hypersensitivity to antibiotics (penicillin or streptomycin).
• Subjects with any malignant tumor in the past 5 years before screening, except malignant tumors with very low risk of metastasis or death (such as appropriately treated cervical intraepithelial neoplasia, skin basal or squamous cell carcinoma, localized prostate cancer or ductal carcinoma in situ).
• Subjects who are receiving any medicinal products that may affect bone marrow functions.
• Subjects with severe mental disorders (such as schizophrenia and bipolar disorder. However, exception applies to mild ALS-related cognitive impairment and secondary emotional trauma).
• Subjects for whom administration of investigational product is prohibited, subjects with conditions that may affect interpretation of results or subjects with conditions that may result in high risk of complications, such as the rest diseases, metabolic disorders, physical examination results and/or laboratory test results as diseases or such conditions are reasonably suspected.