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

NCT04127578 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: J3Z-MC-OJAA formerly PRV-PD101
• Study Type: interventional
• Target: 32
• Locations: 2 countries
• Sites: 15

Brief Summary

Study J3Z-MC-OJAA is a Phase 1/2a, multicenter, open-label, ascending dose, first in-human study that will evaluate the safety of intracisternal LY3884961 administration in patients with moderate to severe Parkinson's disease with at least 1 pathogenic GBA1 mutation. Two dose level cohorts of LY3884961 are planned (Dose Level 1 and Dose Level 2). The duration of the study is 5 years. During the first year, patients will be evaluated for the effect of LY3884961 on safety, tolerability, immunogenicity, biomarkers, and clinical efficacy measures. Patients will continue to be followed for an additional 4 years to continue to monitor safety as well as selected biomarker and efficacy measures.

Conditions

Parkinson Disease

Keywords

Parkinson's Disease; GBA1 mutation; Glucocerebrosidase; PD-GBA; Parkinson's Disease Gene Therapy; AAV9; Gene Therapy; GBA; Gaucher Disease

Outcome Measures

Primary Outcomes (12)

• Cumulative number of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

  5 years

• Incidence of procedure or treatment-emergent AEs measured by brain MRI, spine MRI and nerve conduction study (NCS)

  5 years

• Treatment emergent immunogenicity of AAV9 in blood

  Thru month 24

• Change from baseline in immunogenicity of AAV9 in blood

  Baseline and Month 24

• Treatment emergent immunogenicity of GCase in blood

  GCase (glucocerebrosidase)

  Thru Month 24

• Change from baseline in immunogenicity of GCase in blood

  GCase (glucocerebrosidase)

  Baseline and Months 24

• Treatment emergent immunogenicity of Nfl in blood

  GCase (glucocerebrosidase)

  Thru Month 24

• Change from baseline in immunogenicity of Nfl in blood

  GCase (glucocerebrosidase)

  Baseline and Month 24

• Treatment emergent immunogenicity of AAV9 in CSF

  Thru Month 24

• Change in immunogenicity of AAV9 in CSF

  Baseline and Month 12

• Treatment emergent immunogenicity of GCase in CSF

  Thru Month 24

• Change in immunogenicity of GCase in CSF

  Baseline, and Months 12

Secondary Outcomes (6)

• Change in glycolipid levels in blood

  Baseline, Days 7, 14, and 21, and Months 1, 1.5, 2, 3, 6, 9 and 12

• Change in GCase levels

  Baseline, Days 7, 14, and 21, and Months 1, 1.5, 2, 3, 6, 9 and 12

• GCase enzyme activity levels in blood

  Days 7, 14, and 21, and Months 1, 1.5, 2, 3, 6, 9 and 12

• Change in glycolipid levels in CSF

  Baseline, and Months 2, 6, and 12

• Change in GCase levels in CSF

  Baseline, and Months 2, 6, and 12

Study Arms (2)

Dose Level 1

EXPERIMENTAL

Biological: LY3884961; Drug: Methylprednisolone; Drug: Sirolimus

Dose Level 2

EXPERIMENTAL

Biological: LY3884961; Drug: Methylprednisolone; Drug: Sirolimus

Interventions

LY3884961 BIOLOGICAL

Participants will receive a single dose of LY3884961, administered intra-cisterna magna

Dose Level 1; Dose Level 2

Methylprednisolone DRUG

6 IV pulses administered as concomitant medication over 3 months

Dose Level 1; Dose Level 2

Sirolimus DRUG

Back-up treatment if corticosteroid is not well tolerated. Loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication

Dose Level 1; Dose Level 2

Eligibility Criteria

• Age: 35 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Body weight range of ≥40 kg (88 lbs) to ≤110 kg (242 lbs) and a body mass index (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 Practically Defined 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), documented negative MTB test within 1 year prior to Screening, or clearance by an infectious disease specialist.
• 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. Individuals in an exclusively same sex relationship (as their preferred and usual lifestyle) are not required to use contraception.
• 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).

You may not qualify if:

• 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:
• Evidence of clinically significant liver pathology;
• Unstable autoimmune disease; autoimmune disease requiring chronic immunosuppression;
• Poorly controlled/not adequately managed diabetes (Screening glycosylated hemoglobin \[HbA1C\] ≥ 7%);
• 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;
• Clinically significant 12-lead electrocardiogram (ECG) abnormalities at Screening, as determined by the Investigator;
• Uncontrolled hypertension;
• 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;
• History or current alcohol or drug abuse within 2 years of Screening;
• Any current psychiatric diagnosis that may interfere with patient's ability to perform study procedures and all assessments;
• At imminent risk of self-harm;

Sponsors & Collaborators

• Prevail Therapeutics: lead
• Eli Lilly and Company: collaborator

Study Sites (15)

Mayo Clinic, 13400 E. Shea Boulevard

Scottsdale, Arizona, 85259, United States

Location

Esperanza Clinical, 25220 Hancock Avenue

Murrieta, California, 92562, United States

Location

Rocky Mountain Clinical Research - CenExel - PPDS, 701 East Hampden Avenue Suite 510

Englewood, Colorado, 80113-2776, United States

Location

K2 Medical Research, 101 Southhall Lane, Suite 150

Maitland, Florida, 32751-5669, United States

Location

PPD, 100 West Gore Street, Suite 202

Orlando, Florida, 32806, United States

Location

Northwestern University Feinberg School of Medicine, Dept. of Neurology, Parkinson's Disease & Movement Disorders Center, 710 N. Lake Shore Drive, 11th Floor

Chicago, Illinois, 60611, United States

Location

Mayo Clinic, 200 First Street SW

Rochester, Minnesota, 55905, United States

Location

Mount Sinai Beth Israel, 10 Union Square East, Suite 5H

New York, New York, 10003, United States

Location

Joan and Sanford I. Weill Department of Medicine, 525 E 68th Street

New York, New York, 10065, United States

Location

Hospital of the University of Pennsylvania, 330 S. 9th Street

Philadelphia, Pennsylvania, 19107-6103, United States

Location

Vanderbilt University Medical Center, 1500 21st Avenue South Suite 2600

Nashville, Tennessee, 37212, United States

Location

Shaare Zedek Medical Center, 12 Shmuel Biet Street

Jerusalem, 91031, Israel

Location

Hadassah Medical Center, Hadassah Ein Kerem, Dept. of Neurology, P.O. Box 12000

Jerusalem, 91120, Israel

Location

Sheba Medical Center, Tel Hashomer

Ramat Gan, 52621, Israel

Location

Tel Aviv Sourasky Medical Center, 6 Weizmann St.

Tel Aviv, 64239, Israel

Location

Related Publications (1)

• De BP, Rosenberg JB, Selvan N, Wilson I, Yusufzai N, Greco A, Kaminsky SM, Heier LA, Ricart Arbona RJ, Miranda IC, Monette S, Nair A, Khanna R, Crystal RG, Sondhi D. Assessment of Safety and Biodistribution of AAVrh.10hCLN2 Following Intracisternal Administration in Nonhuman Primates for the Treatment of CLN2 Batten Disease. Hum Gene Ther. 2023 Sep;34(17-18):905-916. doi: 10.1089/hum.2023.067.

  PMID: 37624739 DERIVED

MeSH Terms

Conditions

Parkinson Disease; Gaucher Disease

Interventions

Methylprednisolone; Sirolimus

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Intervention Hierarchy (Ancestors)

Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Macrolides; Lactones; Organic Chemicals

Study Officials

• Travis B. Lewis, MD, PhD

  Prevail Therapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 14, 2019
• First Posted: October 15, 2019
• Study Start: January 3, 2020
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030
• Last Updated: March 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

IL (4); US (11)