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Early Trial for Prevail’s One-time Gene Therapy PR001 to Start Soon

PR001 GBA1 trial

Prevail Therapeutics will soon start its Phase 1/2 clinical trial evaluating the safety, tolerability, and early efficacy of its one-time gene therapy — called PR001 — for Parkinson’s disease associated with mutations in the GBA1 gene.

The trial is expected to enroll up to 16 people with confirmed GBA1 mutations. Participants will be randomly assigned to receive two escalating doses of PR001, or placebo, administered as a single injection.

The company expects that dosing will start during 2019.

“We are excited to begin dosing patients in our Phase 1/2 clinical trial for PD-GBA this year,” Asa Abeliovich, MD, PhD, founder and CEO of Prevail, said in a press release. “We believe PR001 has tremendous potential to slow or stop disease progression in patients with PD-GBA … who currently have no disease-modifying therapeutic options.”

People with GBA1 mutations have up to a five-fold higher risk of developing Parkinson’s disease. Indeed, estimates point to a link to GBA1 mutations in 7 to 10% of all Parkinson’s cases.

The GBA1 gene contains all the information necessary to produce the enzyme beta-glucocerebrosidase (GCase) — an important component of cells’ recycling factories, called lysosomes. Lack of this enzyme, or its faulty activity, will make cells accumulate toxic substances inside them, which may contribute to the neurodegeneration seen in Parkinson’s disease.

PR001 was designed as a single-dose gene therapy that will provide nerve cells with a fully working copy of the GBA1 gene. This new method uses a modified and harmless version of an adeno-associated virus (AAV9) to deliver the gene to cells, which will then be able to recover GCase function.

This gene therapy is expected to ease Parkinson’s disease symptoms triggered by the mutated gene.

Studies in mice and primates with Parkinson’s disease demonstrated that PR001 was well-tolerated. The gene therapy also was found to promote an increase in GCase enzyme activity, which resulted in reduced accumulation of toxic fatty molecules, and improvements in motor function.

The U.S. Food and Drug Administration (FDA) granted fast track designation to PR001 in July 2019 for the treatment of people with Parkinson’s disease associated with GBA1 gene mutations. The designation accelerates the therapy’s development and may help expedite its approval by providing more frequent meetings with the FDA and discussions about the therapy’s development plan.

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Prevail’s Gene Therapy Candidate PR001 Granted FDA Fast Track Status

PR001 Fast Track

The U.S. Food and Drug Administration (FDA) has granted Fast Track designation to Prevail Therapeutics’ lead gene therapy candidate, PR001, for the treatment of people with Parkinson’s disease associated with GBA1 gene mutations.

Fast Track status will support and expedite the clinical development, regulatory review, and potential marketing approval of PR001.

The FDA’s decision follows its acceptance of Prevail’s Investigational New Drug application in June. That IND acceptance will allow the company to initiate a Phase 1/2 clinical trial to assess PR001’s safety and tolerability.

Prevail expects to launch the trial, and start dosing patients, during the second half of 2019.

“We are pleased that the FDA has granted Fast Track Designation for PR001, which underscores the unmet need of patients with Parkinson’s disease with a GBA1 mutation,” Asa Abeliovich, MD, PhD, founder and CEO of Prevail, said in a press release.

People who carry a mutated GBA1 gene can have up to 5 times higher risk of developing Parkinson’s disease. Even though it remains unclear what links the two conditions, it is estimated that 7 to 10% of all Parkinson’s cases are related to GBA1 mutations.

The GBA1 gene holds the instructions to produce the enzyme beta-glucocerebrosidase (GCase). That enzyme is essential for the digestion and recycling of different types of molecules and cellular debris in tiny vesicles called lysosomes. If GCase activity is impaired in any way, toxic substances accumulate inside cells, particularly as people age, leading to excessive inflammation and —probably, scientists say — the neurodegeneration seen in Parkinson’s disease.

PR001 is intended to be a disease-modifying and single-dose gene therapy for individuals with mutations in the GBA1 gene. It uses a modified and harmless version of an adeno-associated virus (AAV9) to deliver a fully working copy of the defective gene to nerve cells. This should allow for long-lasting expression of working beta-glucocerebrosidase, easing disease symptoms caused by the mutated gene.

Studies in mice and primates with Parkinson’s disease demonstrated that PR001 was well-tolerated. The gene therapy was found to promote an increase in GCase enzyme activity in mice. That resulted in reduced accumulation of fatty molecules, and improvements in motor function.

“With no treatments available that modify the progressive course or the underlying disease process of Parkinson’s disease, a potential disease-modifying therapy like PR001 could significantly transform the lives of patients with this disease,” Abeliovich said.

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Potential One-time Gene Therapy for Parkinson’s Linked to GBA Mutations to Enter Clinical Trial

Parkinson's gene therapy trial

A potential gene therapy for Parkinson’s disease associated with mutations in the GBA1 gene, PR001, will move into clinical testing in patients after the U.S. Food and Drug Administration (FDA) accepted an application for the therapy, Prevail Therapeutics announced.

FDA acceptance of the company’s Investigational New Drug (IND) application allows Prevail to initiate a Phase 1/2 clinical trial assessing PR001’s safety and tolerability in Parkinson’s patients with disease-causing GBA1 mutations. Prevail expects to open the trial and begin dosing this year.

People with mutations in the GBA1 gene have a higher risk — possibly as high as five-fold — of developing Parkinson’s disease. Even though the exact relationship between both conditions is not clear, it is estimated that 7%–10% of all Parkinson’s cases are related to GBA1 mutations.

The GBA1 gene holds the instructions to produce the enzyme beta-glucocerebrosidase (GCase) that is active in lysosomesspecial compartments within cells that digest and recycle different types of molecules. If beta-glucocerebrosidase does not work as intended, toxic substances accumulate inside cells, particularly as people age, leading to excessive inflammation and —probably — the neurodegeneration seen in Parkinson’s disease.

PR001 is intended to be a disease-modifying and single-dose gene therapy for patients with mutations in this gene. It uses a modified and harmless version of an adeno-associated virus (AAV9) to deliver a fully working copy of the GBA1 gene to nerve cells. This should allow for long-lasting expression of functional beta-glucocerebrosidase, easing disease symptoms caused by the mutated gene.

AAV-9 has been widely used in various gene therapies both approved and in clinical testing, including Zolgensma, a recently approved gene therapy to treat spinal muscular atrophy. The viral construct appears to be safe and can effectively cross the blood-brain barrier, a semipermeable membrane that separates blood from cerebrospinal fluid and protects the brain from viruses and other “invaders” entering via the bloodstream.  

“We are pleased that the FDA has accepted the IND for our first program, which we believe has the potential to transform the lives of patients with Parkinson’s disease with a GBA1 mutation,” Asa Abeliovich, MD, PhD, founder and CEO of Prevail, said in a press release.

“At Prevail, our goal is to halt the progression of serious neurodegenerative diseases by applying precision medicine to the development of gene therapies. Our active IND brings us a step closer to achieving that goal, and we look forward to entering this new phase as a clinical-stage company,” he added.

Prevail, based in New York City, was founded in 2017 through a collaboration between Abeliovich,  OrbiMed and The Silverstein Foundation for Parkinson’s with GBA.

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