Phase 1/2a Clinical Trial of PR001 (LY3884961) in Patients With Parkinson's Disease With at Least One GBA1 Mutation (PROPEL)

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
• •Spinal, cervical, or brain 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 or hypercholesterolemia as per Investigator assessment.
• •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 electrocardiogram (ECG) abnormalities at Screening, as determined by the Investigator;
• •6. Uncontrolled hypertension;
• •7. History of cancer, including B-cell cancers, 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.
• •16. Acute or chronic: hepatitis B (HBV); hepatitis C (HCV) infection must have completed curative antiviral treatment with HCV viral load below the limit of quantification or be HCV RNA negative due to prior treatment or natural resolution to be eligible for enrollment.
• •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 initiation of Immunosuppression regimen).
• •Use of ambroxol within 8 weeks of dosing.
• •Use of blood thinners in the 2 weeks prior to Screening lumbar puncture (LP) or intra-cisterna magna (ICM) procedure, or the anticipated need to initiate blood thinners during the study. Antiplatelet therapies (e.g., prophylactic aspirin, clopidogrel) are acceptable if the patient is medically able to temporarily stop 48 hours to 7 days (depending on the antiplatelet medication used) prior to and at least 48 hours after intracisternal injection and lumbar puncture.
• •Contraindications or intolerance to imaging methods (MRI, MRA, CT, DaT-SPECT) inducing claustrophobia and/or intolerance to contrast agents used for MRI, MRA or CT.
• •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.