Background

PR001 is a gene-replacement therapy that uses adeno-associated virus 9 (AAV9) to deliver a functional copy of the GBA1 gene to the brain. GBA1 encodes the enzyme glucocerebrosidase (GCase), a lysosomal enzyme involved in the breakdown of glycosphingolipids. PR001 is being developed for Parkinson’s disease associated with GBA1 mutations, and for Gaucher disease. The therapy comprises a one-time injection into the cerebrospinal fluid in the cisterna magna at the base of the brain.

Up to 10 percent of people with Parkinson’s disease carry a mutation in one copy of GBA1 that reduces enzyme activity and affects lysosomal function. Homozygous GBA1 mutations cause Gaucher disease, a lysosomal storage disease, which can begin in infancy or childhood and affects multiple organ systems, sometimes including the nervous system.

PR001 has been tested in mouse models of GCase deficiency. In mice treated chronically with a GCase inhibitor, intraventricular injection of PR001 increased enzyme activity and reduced glycolipid accumulation for at least six months. In a genetic model of Gaucher disease, PR001 restored GCase activity and improved the mobility of the mice on a balance beam. PR001 lowered the accumulation of insoluble α-synuclein, the major component of Lewy bodies in PD and other synucleinopathies, in two different mouse models (Nov 2019 conference news, see also Abeliovich et al., 2021). 

The gene therapy was tested in non-human primates, where injection of virus into the cisterna magna resulted in broad distribution of the virus in the brain and significant elevation of GCase protein in brain tissue. No toxicity was reported.

Findings

In July 2019, the FDA granted fast-track status to PR001 for PD.

In January 2020, Prevail Therapeutics began PROPEL, a Phase 1/2 sham-controlled trial in people with moderate to severe PD symptoms and a GBA mutation. Run at four academic medical centers and one clinical research organization in the U.S., the trial planned to enroll 16 participants, randomized to a one-time injection of high-dose virus, low-dose virus, or sham. The main study would last one year, with a four-year follow-up. The primary objective is safety and tolerability. Secondary and exploratory endpoints include blood and CSF measures of GCase, glycolipid metabolism, α-synuclein and neurofilament light chain, PR001 immunogenicity, measures of clinical and daily function, and MRI and dopamine imaging. One-year safety and biomarker data were expected in late 2020. The trial was planned to end in August 2026.

In August 2020, Prevail announced that serious adverse events had occurred three months after injection in the first treated PD-GBA patient, which the company attributed to an immune response to the AAV9 vector. The unspecified events reportedly resolved with immunosuppressive treatment. The study protocol was changed to an open-label design with no sham injection arm, and with concomitant administration of the immunosuppressants prednisone and sirolimus. Primary objectives were modified to include immunogenicity of AAV9 and GCase in blood and CSF, along with adverse events. In the patient, CSF GCase reportedly increased from undetectable to normal levels at three months. Subsequently, the company added rituximab to the immunosuppression protocol, and increased trial enrollment to 24. Recruitment was finished by July 2022, and the trial completion date is now June 2029.

In 2020, PR001 received orphan drug, rare pediatric drug, and fast-track designations for neuronopathic Gaucher disease, a form that affects the brain and spinal cord. Enrollment for an open-label Phase 1/2 trial in 15 infants and children with Gaucher disease started in June 2021; a dose-finding trial in adults began in December 2022. The studies are set to run until 2028 and 2030, respectively.

In January 2021, Prevail was acquired by Eli Lilly & Company (press release), and PR001 was renamed LY3884961.

In an April 30, 2024, investor’s call, Lilly said they had stopped the study in children with Gaucher disease. The trials in adults, and in people with PD, are continuing.

For details on LY3884961 trials, see clinicaltrials.gov.