A Clinical Trial of PR001 (LY3884961) in Patients With Peripheral Manifestations of Gaucher Disease (PROCEED)

• ClinicalTrials.gov Identifier: NCT05487599
• Recruitment Status: Recruiting
• First Posted: August 4, 2022
• Last Update Posted: January 13, 2023
• Sponsor: Prevail Therapeutics
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): Prevail Therapeutics

Study Description

Brief Summary:

Study J3Z-MC-OJAE is a Phase 1/2, multicenter, open-label, dose-finding study of LY3884961 evaluating the safety and tolerability in adults with peripheral manifestations of GD.

Up to 3 dose levels of LY3884961 will be assessed in 3 dose-finding cohorts of 3 patients. Following this, up to 6 patients may be enrolled into an expansion cohort.

For each enrolled patient, the study will be approximately 5 years in duration, including up to a 45-day screening period. During the first 18 months after dosing, subjects will be evaluated for the effects of LY3884961 on safety, tolerability, immunogenicity, biomarkers, and efficacy. Patients will be followed up for an additional 42 months to monitor safety, immunogenicity, and selected biomarker and efficacy parameters.

Condition or disease	Intervention/treatment	Phase
Gaucher Disease	Biological: LY3884961; Drug: Methylprednisolone; Drug: Sirolimus; Drug: Prednisone	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Dose-Finding, Phase 1/2 Study to Evaluate the Safety and Tolerability of a Single Intravenous Dose of LY3884961 in Patients With Peripheral Manifestations of Gaucher Disease (PROCEED)
• Actual Study Start Date: December 20, 2022
• Estimated Primary Completion Date: September 11, 2030
• Estimated Study Completion Date: September 11, 2030

Arms and Interventions

Arm	Intervention/treatment
Experimental: Low Dose LY3884961	Biological: LY3884961; Participants will receive a single dose of LY3884961, administered via IV infusion; Drug: Methylprednisolone; 1 IV pulse administered as concomitant medication; Drug: Sirolimus; Loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication; Drug: Prednisone; Administered orally as concomitant medication, followed by dose tapering
Experimental: Medium Dose LY3884961	Biological: LY3884961; Participants will receive a single dose of LY3884961, administered via IV infusion; Drug: Methylprednisolone; 1 IV pulse administered as concomitant medication; Drug: Sirolimus; Loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication; Drug: Prednisone; Administered orally as concomitant medication, followed by dose tapering
Experimental: High Dose LY3884961	Biological: LY3884961; Participants will receive a single dose of LY3884961, administered via IV infusion; Drug: Methylprednisolone; 1 IV pulse administered as concomitant medication; Drug: Sirolimus; Loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication; Drug: Prednisone; Administered orally as concomitant medication, followed by dose tapering
Experimental: Expansion cohort; LY3884961 dose to be determined	Biological: LY3884961; Participants will receive a single dose of LY3884961, administered via IV infusion; Drug: Methylprednisolone; 1 IV pulse administered as concomitant medication; Drug: Sirolimus; Loading dose, followed by maintenance dose, followed by dose tapering; administered as concomitant medication; Drug: Prednisone; Administered orally as concomitant medication, followed by dose tapering

Outcome Measures

Primary Outcome Measures :

1. Incidence and severity of Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: 5 years ]
2. Incidence and severity of clinically significant changes in heart rate as measured by 12-lead electrocardiogram (ECG) [ Time Frame: 5 years ]
3. Incidence and severity of clinically significant changes PR intervals as measured by 12-lead ECG [ Time Frame: 5 years ]
4. Incidence and severity of clinically significant changes RR intervals as measured by 12-lead ECG [ Time Frame: 5 years ]
5. Incidence and severity of clinically significant changes QRS intervals as measured by 12-lead ECG [ Time Frame: 5 years ]
6. Incidence and severity of clinically significant changes QT intervals as measured by 12-lead ECG [ Time Frame: 5 years ]
7. Incidence and severity of clinically significant changes in results of abdominal MRI (liver volume) [ Time Frame: 5 years ]
8. Incidence and severity of clinically significant changes in results of abdominal MRI (spleen volume) [ Time Frame: 5 years ]
9. Incidence and severity of clinically significant changes in the bone marrow burden (BMB) score results of bone MRI [ Time Frame: 5 years ]
10. Incidence and severity of clinically significant changes in physical examinations [ Time Frame: 5 years ]
11. Incidence and severity of clinically significant changes in GD1 Patient-Reported Outcome Measures (GD1-PROM) [ Time Frame: 5 years ]
12. Incidence and severity of clinically significant changes in EuroQol Group 5 dimension, 5 level (EQ-5D-5L) questionnaire responses [ Time Frame: 5 years ]
13. Incidence and severity of clinically significant changes in Fatigue Severity Scale (FSS) questionnaire responses [ Time Frame: 5 years ]
14. Incidence and severity of clinically significant changes in waist circumference [ Time Frame: 5 years ]
15. Incidence and severity of clinically significant changes in weight over time [ Time Frame: 5 years ]
16. Change in anti-AAV9 antibody titers in blood [ Time Frame: Up to 24 months ]
17. Change in anti-GCase antibody titers in blood [ Time Frame: Up to 24 months ]
18. Change in ELISPOT GCase or rAAV9 [ Time Frame: Up to 24 months ]
19. Viral shedding in saliva, urine or stool, as measured by qPCR [ Time Frame: Up to Month 3 ]

Secondary Outcome Measures :

1. Change and percent change from baseline in spleen volume (MN) as determined by centrally read MRI (magnetic resonance imaging) [ Time Frame: Up to 60 months ]
2. Change from baseline in platelet count [ Time Frame: Up to 60 months ]
3. Change from baseline in GCase enzyme activity levels in blood [ Time Frame: Up to 60 months ]
4. Change from baseline in GCase protein levels in blood [ Time Frame: Up to 60 months ]
5. Change from baseline in GluSph levels in blood [ Time Frame: Up to 60 months ]
6. Time from LY3884961 to enzyme replacement therapy (ERT)/substrate reduction therapy (SRT) discontinuation, if applicable [ Time Frame: 5 years ]
7. Time from discontinuation of ERT/SRT to re-initiation of ERT/SRT [ Time Frame: 5 years ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age 18-50 years inclusive at the time of informed consent.
2. Bi-allelic GBA1 mutations confirmed by the central laboratory.
3. On ERT or SRT for at least 2 years and on a stable, maximum tolerated dose, for at least 3 months prior to screening.

4. Evidence of suboptimal response to ERT or SRT as defined by at least one of the following parameters:

   1. splenomegaly with spleen volume ≥ 3 MN as evaluated by centrally read abdominal MRI
   2. hepatomegaly with liver volume ≥ 1.2 MN as evaluated by centrally read abdominal MRI
   3. thrombocytopenia, with platelet count < 100 × 103 per μL

   4. Bone manifestations of GD of at least moderate severity as defined by at least one of the following:

      • bone crisis within 1 year prior to screening
      • bone marrow infiltration as defined by total BMB score ≥ 7 on MRI
      • severe osteopenia or osteoporosis (Z score < -2.0)
5. Patient 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.
6. Women of nonchildbearing potential must be either surgically sterile (hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before Screening) or postmenopausal, defined as spontaneous amenorrhea for at least 2 years, with follicle stimulating hormone level in the postmenopausal range.
7. Men and women of childbearing potential (i.e., ovulating, premenopausal, and not surgically sterile) must use a highly effective method of contraception consistently and correctly for the duration of the study, including the long-term follow-up.
8. Men must agree to use a condom during any sexual intercourse (including those who have had a vasectomy) and abstain from sperm donation for the duration of the study, including long-term follow-up.
9. Women must agree to abstain from egg donation for the duration of the study, including long-term follow-up.
10. Patients must agree to abstain from blood donations for at least the first year of the study.

Exclusion Criteria:

1. Clinically significant neurological signs and symptoms and/or behavioral disturbances.
2. Active and progressive bone disease expected to require surgical treatment in the next 6 months.
3. History of total splenectomy or planned total splenectomy during the first 18 months of the study.
4. Splenomegaly > 10 MN.

5. Evidence of clinically significant liver disease, fragile liver, or history of exposure to hepatotoxins including:

   1. Recipient of a liver transplant or planned liver transplantation during the first 18 months of the study.
   2. Progressive hepatomegaly > 3MN
   3. History of Stage 2 or higher liver fibrosis
   4. History of alcohol or drug abuse within 2 years of Screening
   5. History of hepatitis B (HBV) infection, or currently active HBV infection; patients with a history of hepatitis C virus (HCV) infection must have completed curative antiviral treatment with HCV viral load below the limit of quantification or be HCV RNA negative
6. Thrombocytopenia with platelet count < 40 × 103 per μL.
7. Severe hyperlipidemia (triglycerides > 1,000 mg/dL).
8. Current diagnosis of unstable or clinically significant cardiovascular conditions based on Investigator assessment.
9. History of cancer within 5 years of Screening with the exception of fully excised non-melanoma skin cancers, non-metastatic prostate cancer, and fully treated ductal carcinoma in situ.
10. Concomitant disease, condition or treatment which, in the opinion of the Investigator, would pose an unacceptable risk to the patient or interfere with the patient's ability to comply with study procedures or interfere with the conduct of the study.
11. Women of childbearing potential, pregnant (i.e., positive serum pregnancy result at Screening and Day 1) or breastfeeding or intending to become pregnant during the course of the trial.
12. Use of any GD-related chaperone therapy within 4 weeks prior to Screening or expected need to initiate chaperone therapy during at least the first 18 months of the study.
13. Any type of prior gene or cell therapy.
14. Use of systemic immunosuppressant or steroid therapy other than protocol-specified immunosuppression.
15. Participation in another therapeutic investigational drug or device study within 3 months or 5 half-lives of the study agent, whichever is longer.
16. Clinically significant abnormalities in laboratory test results at Screening.

Contacts and Locations

Contacts

Contact: Prevail Therapeutics; (917) 336-9310; prevail_patients@lilly.com

Locations

United States, North Carolina

Duke University Health System; Not yet recruiting

Durham, North Carolina, United States, 27710-3017

Contact: Gretchen Clinical Research Coordinator 919-660-0757 Gretchen.nichting@duke.edu

United States, Virginia

Lysosomal Rare Disorders Research and Treatment Center; Recruiting

Fairfax, Virginia, United States, 22030-6066

Contact: Lauren Noll 571-732-4655 lnoll@ldrtc.org

Sponsors and Collaborators

Prevail Therapeutics

Eli Lilly and Company

Investigators

• Study Director: Sarah Neuhaus, DO; Prevail Therapeutics, a wholly owned subsidiary of Eli Lilly and Company

More Information

• Responsible Party: Prevail Therapeutics
• ClinicalTrials.gov Identifier: NCT05487599
• Other Study ID Numbers: J3Z-MC-OJAE
• First Posted: August 4, 2022
• Last Update Posted: January 13, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Prevail Therapeutics:

bi-allelic glucocerebrosidase-1; GBA; glucocerebrosidase; GBA1 mutation; Gaucher Disease; Gaucher; GD; Type 1 Gaucher; AAV9; Gene Therapy

Additional relevant MeSH terms:

Gaucher Disease; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Lipid Metabolism Disorders; Sirolimus; Prednisone; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal