Phase 1/2a Clinical Trial of PR001A in Patients With Parkinson's Disease With at Least One GBA1 Mutation (PROPEL) (PROPEL)

Inclusion Criteria:

• Body weight range of ≥40 kg (88 lbs) to ≤110 kg (242 lbs) and a BMI of 18 to 34 kg/m2.
• Diagnosis of Parkinson's Disease (PD) per UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria.
• Hoehn and Yahr Stage III-IV (as determined in OFF state).
• Stable use of background medications at least 8 weeks prior to investigational product (IP) administration, including but not limited to those used for treatment of PD. Gaucher Disease-PD patients receiving GD treatments should be on a stable regimen of their ERT or substrate replacement therapy (SRT) medication for at least 3 months prior to screening.
• At least 1 pathogenic GBA1 mutation confirmed by the central laboratory
• Negative screening test for Mycobacterium tuberculosis (MTB) or documented negative MTB test within 1 year prior to Screening.
• Patient and/or patient's legally authorized representative (LAR) has the ability to understand the purpose and risks of the study and provide written informed consent and authorization to use protected health information in accordance with national and local privacy regulations.
• Patient has a reliable study partner/informant (e.g., family member, friend) willing and able to participate in the study as a source of information on the patient's health status and cognitive and functional abilities (including providing input into the rating scales). The study partner should have regular contact with the patient (in person or via phone/video communication). The study partner must sign a separate partner informed consent form (ICF) indicating that she/he understands the study requirements and is willing to participate and attend study visits requiring study partner input.
• Women of nonchildbearing potential must be either surgically sterile or postmenopausal. Men and women of childbearing potential must use a highly effective method of contraception consistently and correctly for the duration of the study including the long-term follow-up.
• Men must agree to abstain from sperm donation for the duration of the study, including long-term follow-up.
• Women must agree to abstain from egg donation for the duration of the study, including long-term follow-up.
• Women of childbearing potential cannot be pregnant or lactating/breastfeeding and must have a negative result for serum pregnancy test at Screening.
• Patient is generally ambulatory, not dependent on walker or wheelchair
• Patient is living in the community (i.e., not in nursing home); some levels of assisted living may be permitted at the discretion of the Investigator.
• Pneumococcal and shingles vaccines are required within 10 years of screening (allowed to be performed during screening but must be given at least 4 weeks prior to start of the immunosuppressant treatment).
• Patient is up to date with age and gender-appropriate cancer screening as per local standard of care.

Exclusion Criteria:

• Diagnosis of a significant CNS disease other than Parkinson's Disease (PD) that may be a cause for the patient's PD symptoms or may confound study objectives.
• MoCA (Montreal Cognitive Assessment) score of <14
• Brain magnetic resonance image (MRI) / magnetic resonance angiography (MRA) indicating clinically significant abnormality, including evidence of prior hemorrhage, infarct >1 cm3 or >3 lacunar infarcts, or a structural abnormality deemed a contraindication to intracisternal injection.
• Hypersensitivity or contraindications to corticosteroid and/or sirolimus use (including but not limited to osteoporosis with vertebral fractures within 1 year prior to Screening, uncontrolled hypertension, poorly controlled diabetes, uncontrolled hyperlipidemia/hypercholesterolemia, uncontrolled renal insufficiency, or uncontrolled interstitial lung disease).

• Concomitant disease or condition within 6 months of Screening that could interfere with, or treatment of which might interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable safety risk to the patient or interfere with the patient's ability to comply with study procedures; including, but not limited to the following:

  1. Evidence of clinically significant liver pathology;
  2. Unstable autoimmune disease; autoimmune disease requiring chronic immunosuppression;
  3. Poorly controlled/not adequately managed diabetes (Screening glycosylated hemoglobin [HbA1C] ≥ 7%);
  4. History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class III or IV), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year prior to Screening;
  5. Clinically significant 12-lead ECG abnormalities at Screening, as determined by the Investigator;
  6. Uncontrolled hypertension;
  7. History of cancer within 5 years of Screening with the exception of fully excised non-melanoma skin cancers, non-metastatic prostate cancer, and full treated ductal carcinoma in situ, provided it has been stable for at least 6 months;
  8. History or current alcohol or drug abuse within 2 years of Screening;
  9. Any current psychiatric diagnosis that may interfere with patient's ability to perform study procedures and all assessments;
  10. At imminent risk of self-harm;
  11. Any medical disorders that, in the opinion of the Investigator, could interfere with study-related procedures (including safe performance of lumbar puncture [LP] or intracisternal injection), such as prohibitive spinal diseases, bleeding diathesis, clinically significant coagulopathy,, thrombocytopenia, or increased intracranial pressure;
  12. Documented stroke or transient ischemic attack within 1 year prior to Screening;
  13. History of seizure or unexplained blackouts within 10 years prior to Screening;
  14. Currently active infection or a severe infection (e.g., pneumonia, septicemia, central nervous system infections [e.g. meningitis, encephalitis]) within 12 weeks prior to Screening;
  15. History of severe allergic or anaphylactic reactions. History of hypersensitivity to any inactive ingredient of the IP or protocol-required immunosuppressant medications.
• Clinically significant abnormalities in laboratory test results at Screening.
• Participation within 3 months prior to Screening in another therapeutic investigational drug or device study with purported disease-modifying effects on PD, unless it can be documented that the patient received placebo.
• History of deep brain stimulator placement, focused ultrasound, or surgery for PD
• Any type of prior gene or cell therapy.
• Immunizations (live vaccines) in the 4 weeks prior to Screening. Note: Pneumococcal and shingles vaccine administrations are allowed during the screening period (patients not previously vaccinated should receive pneumococcal and/or shingles vaccine administration at least 4 weeks prior to sirolimus loading dose).
• Use of ambroxol within 8 weeks of dosing.
• Use of blood thinners in the 2 weeks prior to Screening, or the anticipated need to initiate blood thinners during the study. Antiplatelet therapies (prophylactic aspirin, clopidogrel) are acceptable if the patient is medically able to temporarily stop from at least 7 days prior to and at least 48 hours after intracisternal injection and LP.
• Contraindications or intolerance to imaging methods.
• Contraindications to general anesthesia or deep sedation.
• Positive urine test for drugs of abuse (including opiates, benzodiazepines, amphetamines, cocaine, barbiturates, and phencyclidine) without prescription, at Screening and Day -1. Note: Use of medical marijuana is permitted provided the patient is on a stable regimen. It is also permitted if the patient resides in a state in which the recreational use of marijuana is legalized, so long as the patient does not meet drug abuse criteria (as defined in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition).
• Patient is generally frail or has any medical condition, for which, in view of the Investigator, participation in the study would not be in the best interest of the patient or is likely to prohibit further participation during the study.

Other protocol-defined inclusion/exclusion criteria may apply.