What side effects are associated with this type of intervention?

Common treatments for Parkinson's Disease include levodopa, dopamine agonists, and cholinesterase inhibitors. Levodopa, often combined with carbidopa, can cause nausea, somnolence, dizziness, headache, confusion, hallucinations, and orthostatic hypotension. Dopamine agonists may lead to compulsive behaviors and similar side effects as levodopa. Cholinesterase inhibitors, used for cognitive impairment, can worsen tremor and cause nausea and vomiting. Gene therapy targeting GBA1 mutations, like LY3884961, is still under investigation, but general gene therapy risks include immune reactions and off-target effects.

What prior FDA approvals exist?

Currently, there are no FDA-approved gene therapies specifically targeting GBA1 mutations for the treatment of Parkinson's Disease. However, traditional treatments for Parkinson's Disease include medications such as levodopa, dopamine agonists, and MAO-B inhibitors, which aim to manage symptoms rather than modify the disease course. The investigational therapy LY3884961 is a novel approach being studied for its potential to address the underlying genetic causes of Parkinson's Disease in patients with GBA1 mutations.

What other types of research exist?

Promising novel alternatives to LY3884961 for Parkinson's Disease patients include: 1) Antisense oligonucleotide therapy targeting SOD1 mutations, such as Tofersen, which has shown efficacy in clinical trials for ALS and may have potential applications in PD. 2) AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme, such as NBIb-1817 (VY-AADC01), which has demonstrated safety and clinical benefits in PD patients. 3) Small molecule inhibitors targeting LRRK2 mutations, which are currently in clinical trials and have shown promise in reducing neurodegeneration in PD models.

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Enzyme Replacement Therapy

PR001 for Parkinson's Disease

Q: What is the mechanism of action of this treatment?

Common treatments for Parkinson's Disease (PD) primarily focus on dopaminergic therapies, which aim to replenish or mimic dopamine, a neurotransmitter deficient in PD. Levodopa, often combined with carbidopa, is converted to dopamine in the brain, alleviating motor symptoms. Dopamine agonists (e.g., pramipexole, ropinirole) directly stimulate dopamine receptors, while MAO-B inhibitors (e.g., rasagiline, selegiline) prevent dopamine breakdown. These treatments are crucial as they address the core dopaminergic deficit in PD, improving patients' motor function and quality of life. Gene therapy, such as LY3884961 targeting GBA1 mutations, represents an emerging approach aiming to correct underlying genetic defects, potentially offering more sustained and disease-modifying benefits compared to traditional symptomatic treatments.

Phase 1 & 2

Recruiting

Research Sponsored by Prevail Therapeutics

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Body weight range of ≥40 kg (88 lbs) to ≤110 kg (242 lbs) and a body mass index (BMI) of 18 to 34 kg/m2.

Body weight range of ≥40 kg (88 lbs) to ≤110 kg (242 lbs) and a body mass index (BMI) of 18 to 34 kg/m2

Must not have

Diagnosis of a significant CNS disease other than Parkinson's Disease (PD) that may be a cause for the patient's PD symptoms or may confound study objectives

MoCA (Montreal Cognitive Assessment) score of <14

Timeline

Screening 3 weeks

Treatment Varies

Follow Up thru month 24

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a new treatment called LY3884961 for people with moderate to severe Parkinson's disease who have a specific genetic mutation. The treatment is given directly into the brain to see if it can help improve their symptoms. The study will last for several years to monitor safety and effectiveness.

Who is the study for?

This trial is for adults with Parkinson's Disease who have a specific GBA1 mutation, weigh between 88-242 lbs with a BMI of 18-34, and are in moderate to severe stages (Hoehn and Yahr Stage III-IV). They must be on stable medications for Parkinson's or Gaucher Disease treatments if applicable. Participants need a reliable informant, updated vaccinations, and agree to use effective contraception if necessary. Exclusions include other significant CNS diseases, certain MRI findings, hypersensitivity to study drugs, uncontrolled health conditions like hypertension or diabetes.

What is being tested?

The PROPEL trial tests the safety of PR001 (LY3884961), an investigational drug administered into the spinal fluid for those with Parkinson's linked to GBA1 mutations. It includes two dosage levels over five years—initially focusing on safety and efficacy within the first year followed by long-term effects monitoring.

What are the potential side effects?

Potential side effects may include reactions related to LY3884961 administration such as inflammation at injection site or immune response issues due to its novel nature; sirolimus could cause mouth sores or increase infection risk; methylprednisolone might lead to weight gain, mood swings or increased blood sugar.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My weight is between 88 and 242 lbs, and my BMI is between 18 and 34.

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My weight is between 88 and 242 lbs, and my BMI is between 18 and 34.

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I, or my legal representative, can understand and consent to the study.

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I agree not to donate sperm during and after the study.

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I have a confirmed GBA1 mutation.

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I have been diagnosed with Parkinson's Disease.

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My Parkinson's is in the moderate to severe stage.

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My Parkinson's is in the moderate to severe stage.

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I can walk without the help of a walker or wheelchair.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have a brain condition that is not Parkinson's but could be causing my symptoms.

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My cognitive test score is below 14.

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My MRI shows a significant issue in my spine, neck, or brain that could interfere with certain treatments.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ thru month 24

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~thru month 24

This trial's timeline: 3 weeks for screening, Varies for treatment, and thru month 24 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Change from baseline in immunogenicity of GCase in blood

Change from baseline in immunogenicity of Nfl in blood

Treatment emergent immunogenicity of GCase in blood

+1 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

2Treatment groups

Experimental Treatment

Group I: Dose Level 2Experimental Treatment3 Interventions

Group II: Dose Level 1Experimental Treatment3 Interventions

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Methylprednisolone

2015

Completed Phase 4

~2280

Sirolimus

2013

Completed Phase 4

~2750

0 / 12Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Parkinson's Disease (PD) primarily focus on dopaminergic therapies, which aim to replenish or mimic dopamine, a neurotransmitter deficient in PD. Levodopa, often combined with carbidopa, is converted to dopamine in the brain, alleviating motor symptoms. Dopamine agonists (e.g., pramipexole, ropinirole) directly stimulate dopamine receptors, while MAO-B inhibitors (e.g., rasagiline, selegiline) prevent dopamine breakdown. These treatments are crucial as they address the core dopaminergic deficit in PD, improving patients' motor function and quality of life. Gene therapy, such as LY3884961 targeting GBA1 mutations, represents an emerging approach aiming to correct underlying genetic defects, potentially offering more sustained and disease-modifying benefits compared to traditional symptomatic treatments.

A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson's disease.L-DOPA-induced dyskinesia in Parkinson's disease: a drug discovery perspective.