PR001 Hopes to Address Underlying Mutations in Neuronopathic Type 2 Gaucher Disease


CGTLive highlights the PROVIDE trial of PR001 for Gaucher Awareness Month.

Type 2 Gaucher disease (G2D) is the most severe, neuronopathic form of Gaucher disease in which infants and toddlers experience not only the spleen and liver enlargement and blood abnormalities of the other types of Gaucher disease but also progressive, irreversible brain damage beginning around the age of 6 months until death usually by the age of 2 years.

PR001, being developed by Prevail Therapeutics, is a single dose, potentially disease-modifying gene therapy that aims to address the mutations in the GBA1 gene responsible for Gaucher disease that disrupt the production of beta-glucocerebrosidase and therefore the metabolism of glycolipids, which aggregate α-Synuclein and lead to inflammation and neurodegeneration.

PR001 is being evaluated for the potential treatment of infants with GD2 in the phase 1/2 PROVIDE clinical trial (NCT04411654). The multicenter, open-label study initiated dosing in 2020 and is continuing to enroll up to its target enrollment of 15 participants. Its primary completion date is September 2028.

“This is a horrible disease; it’s a neurodegenerative condition that is very difficult to diagnose and we struggle to diagnose it early. Children really progress very quickly. Like all Gaucher disease, it's incredibly heterogeneous in terms of the phenotype that we see,” primary investigator Aimee Donald, MBChB, PhD, pediatrician, Royal Manchester Children’s Hospital, and professor at the University of Manchester, told CGTLive.

WATCH NOW: Aimee Donald, MBChB, PhD, on Assessing PR001 in Children With Type 2 Gaucher Disease

PR001 is an adeno-associated virus (AAV9) gene therapy administered via intracisternal magna injection. The therapy has been granted fast track, orphan drug, and rare pediatric disease designations by the FDAfor treating GD2.

"Intracisternal magna administration allows us to use this minimally invasive, very well-controlled, and very well-tolerated procedure which offers the potential to address the neurodegenerative manifestations of this disease because we are delivering the drug directly into cerebral spinal fluid,” Olga Uspenskaya, MD, PhD, vice president, clinical development, Prevail Therapeutics, told CGTLive.“ In GD2, we need to target the brain cells, which is why we are delivering to the cerebral spinal fluid which is in the closest contact with the brain.”

PROVIDE is enrolling up to 15 participants with a max age of 24 months with GD2 in low- and high-dose cohorts (FIGURE). Participants must have bi-allelic GBA1 mutations consistent with a clinical GD2 diagnosis and a reliable and informed parent or guardian able to provide updates on health status and cognitive and functional abilities. Exclusion criteria include significant central nervous system disease other than GD2, independent gait, severe peripheral symptoms of GD or concomitant disease deemed to interfere with the study, use of any substrate reduction therapy or strong inhibitors or inducers of cytochrome P450 3A4 or P-glycoprotein medications, herbals, or over-the-counter agents, prior cell or gene therapy treatment, too-recent vaccinations, need for continuous blood thinners, systemic immunosuppressant or corticosteroid therapy, recent participation in another investigational study, brain imaging revealing contraindications to intracisternal injections, other contraindications to radiography, contrast, anesthesia, or sedation, or clinically significant lab test abnormalities.

The study will follow each patient for 5 years, with the first year focused on evaluating primary outcomes of safety and tolerability as measured by incidence and severity of adverse events as well asimmunogenicity of AAV9 and GCase in blood and cerebrospinal fluid (CSF). Secondary outcomes include time to death, time to clinical event, changes in clinical function as measured by Bayley Scales of Infant and Toddler Development andWechsler Preschool and Primary Scale of Intelligence, change in motor skills as measured by Gross Motor Function Measure and BSID-III, change in clinical global impression, adaptive behavior and functioning, most troubling symptoms, and behavioral symptoms, and change in GCase and glycolipid levels in blood and CSF. In addition to PR001, participants will also receive a single IV dose of methylprednisolone as concomitant medication, a loading dose of sirolimus, followed by maintenance doses and dose taperingas concomitant medication, and oral prednisone as concomitant medication followed by dose tapering. Prevail has not yet provided preliminary data from the PROVIDE trial.

“I think we're all kind of waiting desperately to see the outcome of this trial, because I can't think of another trial that has approached GD2 specifically. There's nothing else out there at the moment for this patient population, so, it's a really important study, and not just important for GD2 or Gaucher disease, but across lysosomal storage disorders,” Donald said. “We have lots of infantile, very rapidly progressive forms of disease that affect the brain and we really need these studies to help us think about how we are going to get to the point that we can offer early diagnosis and early treatment that's effective.”

Prevail is also assessing IV infusion of PR001 for the treatment of GD1 in the phase 1/2 PROCEED clinical trial (NCT05487599) and for the treatment of Parkinson disease with GBA1 mutations in the phase 1/2 PROPEL clinical trial (NCT04127578). It has also received orphan drug designation for GD1.

"We're now moving into this area where we're starting to see actual gene therapies reaching patients. This is happening within lysosomal storage disorders, and also within Gaucher disease. I think this really will change things for patients quite significantly, because gene therapies give you the opportunity to affect the whole disease. These are really curative treatments that we're pursuing,” Donald added.

In light of October being Gaucher Awareness Month, Donald shared a last message to encourages clinicians to have their patients with Gaucher to self-register for the International Gaucher Alliance’s GARDIAN registry to aid clinical trial recruitment and bolsternatural history information for the disease.

Prevail Therapeutics provides PR001 program update. News release. Prevail Therapeutics. January 9, 2020.
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