Prevail Therapeutics Seeking to Bring Gene Therapy PR001 to Parkinson Disease With Phase 1/2a PROPEL Clinical Trial
CGTLive took a closer look at the design of the Eli Lilly subsidiary’s trial in PD for the AAV vector-based gene therapy.
Eli Lilly and Company subsidiary Prevail Therapeutics’ PR001 (also known as LY3884961), an investigational adeno-associated virus serotype 9 (AAV9) vector-based gene therapy, is currently being evaluated for the treatment of patients with Parkinson disease (PD) with at least 1 mutation in the GBA1 gene in the phase 1/2a PROPEL clinical trial (NCT04127578; J3Z-MC-OJAA).1
The multicenter, open-label PROPEL trial, which was initiated on January 3, 2020, takes the form of an ascending dose study. Travis B. Lewis, MD, PhD, the executive medical director at Prevail Therapeutics, is serving as an investigator for the study. PROPEL is evaluating a lower dose and a higher dose of PR001 in 2 separate cohorts. In both cohorts, patients will be treated with PR001 as a one-time treatment, along with 6 intravenous pulses of concomitant methylprednisolone over 3 months. Sirolimus may also be used as a concomitant medication if methylprednisolone is not well-tolerated.
The trial has an estimated completion date of June 2029 and is estimated to enroll 20 patients in total. According to the clinicaltrials.gov page, which was most recently updated on June 21, 2024, the study is currently recruiting at centers in Colorado, Florida, New York, Pennslyvania. A center in Chicago, Illinois is listed as active, but not recruiting and several centers in Israel are listed as completed.
PROPEL’s primary end points include the cumulative number of treatment-emergent adverse events (TEAEs) and serious AEs during a 5 year timeframe and the incidence of procedure AEs or TEAEs as measured via brain MRI, spine MRI, and nerve conduction study during a 5 year timeframe. Additional primary end points include the TE immunogenicity of AAV9, glucocerebrosidase (GCase), and Nfl in the blood and of AAV9 and GCase in the cerebrospinal fluid (CSF) through 24 months posttreatment; the change from baseline of immunogenicity of AAV9, GCase, and Nfl in the blood through 24 months posttreatment; and the change from baseline of immunogenicity of AAV9 and GCase through 12 months posttreatment. The study’s secondary end points include the change in glycolipid, GCase, and enzyme activity levels in the blood from baseline to 7 days, 14 days, 21 days, 1 month, 1.5 months, 2 months, 3 months, 6 months, 9 months, and 12 months posttreatment, as well as the change in glycolipid, GCase, and enzyme activity levels in the CSF from baseline to 2 months, 6 months, and 12 months posttreatment.
PROPEL is open to patients who have diagnosed with PD via the UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria and who are aged from 35 to 80 years. Participants are required to weigh from 88 to 242 lbs, to have a BMI of 18 to 34 kg/m2, to have at least 1 pathogenic mutation in GBA1, and to be Hoehn and Yahr Stage III-IV in the Practically Defined OFF state. In addition, patients are required to have a negative test for Mycobacterium tuberculosis at or within 1 year of screening; to be generally ambulatory; on stable use for background medications for at least 8 weeks before treatment with PR001; to have a reliable study partner/informant; to be up to date for appropriate cancer screenings; to not be living in a nursing home; and to have had pneumococcal and shingles vaccines within 10 years of screening. Patients with Gaucher disease-PD are allowed to participate but must be on a stable regimen of their enzyme/substrate replacement therapy for at least 3 months before screening. Additional inclusion criteria relate to contraceptive use/practices.
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Patients with a significant central nervous system (CNS) disease besides PD that could confound the study, those with a Montreal Cognitive Assessment score of less than 14; and those with a contraindication to intracisternal injection will be excluded from participation. Additional criteria for exclusion are clinically significant laboratory test abnormalities at screening; hypersensitivity or contraindications to corticosteroids or sirolimus; prior treatment with deep brain stimulator placement, focused ultrasound, or surgery for PD; prior treatment with any cell therapy or gene therapy; receipt of live vaccines in the 4 weeks before screening; receipt of ambroxol in the 8 weeks before screening; contraindications or intolerance to imaging methods; contraindications to general anesthesia or deep sedation; participation in another clinical trial for a drug or device intended to provide disease-modifying treatment for PD during the 3 months prior to screening, excepting cases where the patient only received a placebo; and history of any disease or condition during the 6 months before screening that could interfere with study conduct or procedures or constitute and unacceptable safety risk.
CGTLive® has previously interviewed Deborah Phippard, PhD, the chief scientific officer of Precision for Medicine, about the challenges of designing clinical trials for gene therapy products in PD. Phippard spoke about the topic generally, but pointed out several of the companies that are currently evaluating gene therapies in the disease.
“If you look at the companies that are currently working on gene therapy modalities for PD—there's a number of them—Capsida Biotherapeutics, Voyager Therapeutics, Prevail Therapeutics, AskBio—obviously, this is a rich area where research is certainly working,” Phippard told CGTLive in mid-2024. “But I think they're all taking different approaches to how to target the CNS—whether you would take the gene therapy and surgically insert it into the CNS or if you're taking an approach where you're designing a capsid to really get that into the CNS. It's exciting that there's many different approaches, more than one might work, but I'm sure they're all going to have different pros and cons.”
Notably, Prevail is also evaluating PR001 for the treatment of type 2 Gaucher disease (G2D), which is also linked to the GBA1 gene, in the phase 1/2 PROVIDE clinical trial (NCT04411654).2 The multicenter, open-label study initiated dosing in 2020 and its primary completion date is estimated to be in September 2028. CGTLive has previously covered the design of the trial.
