The Study of Safety and Preliminary Efficacy of Aleeto in Patients with MultIple System Atrophy

This is a single-center, prospective, randomized, open-label, blinded outcome assessment (PROBE) study. At the end of the PROBE study, patients who have completed the study may opt to enter the open-label extension (OLE) study. The objective of the study is to evaluate the safety, tolerability and potential preliminary efficacy of Aleeto in the treatment of patients with multiple system atrophy (MSA).

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by a blend of autonomic dysfunction, Parkinson's syndrome, and cerebellar syndrome. The incidence of MSA ranges from 1.9 to 4.9 per 100,000 individuals, with an average age of onset of 56.2 years. Among individuals aged 50 years and older, the prevalence stands at 3.0 per 100,000. The mean age of MSA onset is 56.2 years, and the median survival ranges from 6.2 to 7.5 years. Severe autonomic dysfunction manifests early in the disease course, impacting patient survival. The challenges in early diagnosis, rapid disease progression, and bleak prognosis of MSA lead to approximately half of patients needing a walker or assistance from family members for mobility within three years of motor symptom onset. By the fifth year, 60% of patients rely on a wheelchair, and the majority become bedridden within six to eight years. This progression significantly diminishes their quality of life and survival.

Treating MSA, a rare neurodegenerative condition, remains a significant challenge. Current symptomatic and supportive therapies fall short of meeting the treatment requirements of MSA patients. Furthermore, potential adverse effects and disease progression factors restrict the use of certain drugs, highlighting the critical need for the development of disease-modifying or neuroprotective agents to decelerate disease advancement.

"Aleeto, a nerve repair protein created by Darwin Origin (Beijing) Biopharmaceutical Co.LTD, is derived from cellular exosomes, a set of specific microenvironmental protein polymers secreted by stem cells under emergency conditions. It boasts selective assembly, targeted delivery, highly efficient tissue repair, exceptional safety, chemical stability, and convenient storage. Previous basic research has indicated Aleeto's potential for promoting endogenous neural tissue repair, exhibiting significant neuroprotective and neurorestorative effects in animal models. Consequently, this project initiates a single-center, prospective, randomized, open-label, blinded outcome assessment (PROBE) study, followed by an open-label extension (OLE) study. The objectives are to evaluate the safety, tolerability, and potential preliminary efficacy of Aleeto in treating MSA patients and to explore effective MSA treatments.

This study aims to recruit 20 MSA-parkinsonian type (MSA-P) patients aged between 30 and 75 years. The visit content at each stage of this study includes vital signs, neurological examination, laboratory tests (such as routine blood test, blood biochemical examination, coagulation test, etc.), imaging examinations (such as MRI, bladder ultrasound), neurological assessments (such as unified multiple system atrophy rating scale \[UMSARS\], composite autonomic symptom score \[COMPASS\], EuroQol Five Dimensions Questionnaire \[EQ-5D\], Mini-Mental State Examination \[MMSE\]), and cerebrospinal fluid collection. Different stages of the study focus on monitoring patients' concomitant medications, adverse events, and serious adverse events. Detailed follow-up is conducted at the end of each treatment period, with face-to-face visits at specific time points. Additionally, researchers are required to promptly report and manage events when patients develop new neurological symptoms or suspicious events. The follow-up content of the study includes treatment and follow-up assessments at multiple stages. Initially, comprehensive physical examinations, laboratory tests (including blood, urine, pregnancy tests, etc.), multidimensional scoring assessments (such as UMSARS, COMPASS, EQ-5D, MMSE), and brain examinations through imaging techniques such as 3T MRI are performed on subjects at baseline. Subsequently, subjects enter three treatment periods and follow-up stages lasting a total of 90 days, with daily monitoring of vital signs, cerebrospinal fluid collection, laboratory tests, and adverse event documentation in each stage. Follow-up during the Open-Label Extension (OLE) phase (from day 90 to day 158 post-randomization) continues monitoring of vital signs, laboratory tests, and adverse event recording. At the follow-up visits on day 90, day 180, and day 360, comprehensive physical examinations, laboratory tests, gait analysis, bladder ultrasound, MRI, and repeat UMSARS, COMPASS, EQ-5D scoring are conducted. Additionally, if patients experience new neurological symptoms or suspicious events, additional visits will be carried out, and researchers are required to submit and interpret relevant data within 72 hours of the event occurrence.

The protocol of this study has been approved by the Ethics Committee of Beijing Tiantan Hospital. All participants will provide written informed consents before entering the study.

Eligibility Criteria:
Inclusion Criteria:

1.30 years ≤ 75 years of age, regardless of sex; 2.Clinically confirmed or clinically probable MSA-P; 3.Poor response to levodopa; 4.Symptom onset ≤3 years at first visit; 5.Walking ≥10 meters independently or with a walking aid; 6.Expected survival of ≥1 year, as determined by the investigator; 7.Signed informed consent.

Exclusion Criteria:

1. Head MRI at screening showing evidence of other CNS lesions consistent with a diagnosis of neurodegenerative disease other than MSA;
2. Patients with MMSE \<24 points prior to enrolment or with a previous definitive diagnosis of dementia;
3. Head MRI at screening showing other significant pathological findings including but not limited to: cerebral hemorrhage, acute phase of cerebral infarction, aneurysm, vascular malformation, infectious lesion, brain tumor or other space-occupying lesion (meningiomas or arachnoid cysts with a maximum diameter of \<1 cm need not be excluded);
4. Presence of immune disorders that are inadequately controlled or require treatment with biological agents;
5. Known history of allergy to biological agents such as proteins and cell products;
6. Patients who have received any vaccination within 1 month;
7. Patients with pre-existing, clearly diagnosed malignant tumor or being treated with anti-tumor drugs;
8. Patients with a history of clearly diagnosed epilepsy or taking antiepileptic drugs;
9. Presence of lumbar spine disease and deformity or other contraindications to lumbar puncture;
10. Patients with abnormal coagulation function prior to enrolment (e.g., platelet count \<100 × 10E9/L; prothrombin time \[PT\] \>3 s), previous diagnosis of coagulation disorders such as hemophilia, and patients currently receiving more than two types of antiplatelet medication;
11. Contraindications to MRI (e.g. claustrophobia, internal placement of pacemakers or paramagnetic metals, etc.);
12. With severe hepatic insufficiency, renal insufficiency or severe cardiac insufficiency (severe hepatic insufficiency refers to ALT value≥2.0 times the upper limit of normal value or AST value≥2.0 times the upper limit of normal value; severe renal insufficiency refers to CRE≥1.5 times the upper limit of normal value or eGFR\<40mL/min/1.73m2; severe cardiac insufficiency refers to NYHA class 3-4);
13. Hepatitis B active infection (hepatitis B surface antigen positive and/or serum HBV DNA positive or serum HBV DNA \> 2 × 10E8 IU/ml;
14. Hepatitis C virus antibody positive or history of positive test;
15. Positive HIV test or history of positive test;
16. Patients with a combined history of alcohol or drug abuse or alcohol or drug dependence within 2 years;
17. Other psychiatric disorders diagnosed according to DSM-V diagnostic criteria, or significant suicide intent;
18. Patients who are pregnant, breast-feeding, or who are likely to become pregnant and plan to become pregnant;
19. Patients who are participating in other interventional studies or using other investigational biological agents, drugs, or devices, and patients who have used other experimental drugs within 1 month or within 5 drug half-lives;
20. Unable to be cooperative and complete the follow-up due to other reasons.
21. Patients who, in the opinion of the investigator, are not suitable for participation in this trial.