LY3962681 for Parkinson's Disease

(PROSPECT-PD Trial)

Recruiting at 2 trial locations

Overseen By Prevail Therapeutics

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Prevail Therapeutics

Must be taking: Parkinson's medications

Must not be taking: Continuous intestinal delivery

Disqualifiers: Neurological disease, Cardiovascular, Hepatic, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

108 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, LY3962681, designed for people with Parkinson's disease. Researchers aim to determine the drug's safety and behavior in the body, both in healthy volunteers and those with Parkinson's. Healthy volunteers will receive a single dose, while participants with Parkinson's will receive two doses, spaced over several months. Ideal candidates for the Parkinson's part of the trial have a confirmed diagnosis and stable symptoms, without other major neurological conditions. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but it mentions that you should have stable use of your medications for at least 8 weeks before starting the trial and be able to go 6 months without changing the dose. This suggests you may continue your current medications if they are stable.

Is there any evidence suggesting that LY3962681 is likely to be safe for humans?

Research shows that LY3962681 remains in the early stages of testing for safety in humans. Although no data from other studies confirm its safety yet, the current trial phase offers some insight. In Phase 1 trials, the main goal is to assess how well people tolerate the treatment. Researchers remain vigilant for any side effects. Since testing is still in its early stages, the exact safety profile of LY3962681 is not yet known. Gathering more data from this trial will enhance understanding of its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Parkinson's disease?

Unlike the standard treatments for Parkinson's disease, which often include medications like levodopa and dopamine agonists, LY3962681 offers a novel approach by being administered intrathecally, directly into the spinal fluid. This delivery method is unique because it allows the drug to bypass the blood-brain barrier more effectively, potentially enhancing its impact on the brain. Additionally, LY3962681 is being tested in both single and multiple ascending doses, which helps researchers understand its safety and optimal dosing. Researchers are excited about LY3962681 because it represents a potential new class of treatment that could offer more targeted relief with possibly fewer side effects.

What evidence suggests that LY3962681 might be an effective treatment for Parkinson's disease?

Research has shown that LY3962681 is a type of treatment called siRNA, designed to reduce the production of a protein called alpha-synuclein, which is linked to Parkinson's disease. By lowering alpha-synuclein levels, this treatment might help manage symptoms or slow the disease's progression. In this trial, participants will receive either a single ascending dose (SAD), multiple ascending doses (MAD) of LY3962681, or a placebo. Although LY3962681 remains in the early testing stages, its approach shows promise in addressing key aspects of Parkinson's disease. Initial studies focus on safety and understanding how the drug works in the body, crucial steps before evaluating its full effectiveness. Future results will provide more insights into its potential benefits. ^{1 4 5 6 7}

Who Is on the Research Team?

Travis Lewis

Principal Investigator

Prevail Therapeutics, a Wholly Owned Subsidiary of Eli Lilly and Company

Are You a Good Fit for This Trial?

This trial is for healthy volunteers and people with Parkinson's Disease. Participants will receive either the experimental drug LY3962681 or a placebo directly into their spinal fluid. The study has two parts: one where healthy individuals get a single dose, and another where Parkinson's patients get two doses.

Inclusion Criteria

UPSIT score of 10 percentile or less, corrected for age and sex (EU and UK only)

I am not on Parkinson's medication and don't plan to start in the next 6 months.

My brain scan shows signs of Parkinson's disease.

Exclusion Criteria

I do not have major brain disorders other than Parkinson's.

I am on a continuous intestinal Parkinson's medication like Duodopa.

Current concomitant disease or serious or unstable illnesses, including central nervous system (SAD study only), cardiovascular, hepatic, renal, gastroenterology, respiratory, endocrinologic, neurologic (MAD study only: other than Parkinson's disease), psychiatric, immunologic, or hematologic disease and other conditions that, in the investigator's opinion, could interfere with the conduct of the study or that would, in the opinion of the investigator, pose an unacceptable safety risk to the participant

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Single Ascending Dose (SAD) Treatment

Healthy volunteers receive a single dose of LY3962681 or placebo administered intrathecally

1 day

Multiple Ascending Dose (MAD) Treatment

Patients with Parkinson's disease receive two doses of LY3962681 or placebo administered intrathecally, 12 to 24 weeks apart

2 days

Follow-up (SAD)

Participants in the SAD study are monitored for safety and effectiveness after treatment

up to 52 weeks

Follow-up (MAD)

Participants in the MAD study are monitored for safety and effectiveness after the second dose

up to 52 weeks post Dose 2

What Are the Treatments Tested in This Trial?

Interventions

• LY3962681

Trial Overview The trial tests the safety and effects of LY3962681 on the body (PK/PD) when given in increasing amounts. Healthy participants are in the Single Ascending Dose part, while those with Parkinson's are in Multiple Ascending Doses part, receiving treatments weeks apart.

How Is the Trial Designed?

Group I: LY3962681 (SAD) Experimental Treatment 2 Interventions

Single ascending dose of LY3962681 or placebo (aCSF) administered intrathecally (IT) to healthy volunteers.

Group II: LY3962681 (MAD) Experimental Treatment 2 Interventions

Multiple ascending doses of LY3962681 or placebo (aCSF) administered IT to participants with Parkinson's disease.

Who Is Running the Clinical Trial?

Prevail Therapeutics

Lead Sponsor

Trials

5

Recruited

190+

Published Research Related to This Trial

The selective Group II mGlu receptor agonist LY379268 showed a dose-dependent increase in locomotor activity in rodent models of Parkinson's disease, indicating potential functional relief.

LY379268 provided neuroprotection against damage caused by 6-hydroxydopamine in both the striatum and substantia nigra, suggesting it may help protect dopamine-producing neurons, although its effectiveness in improving overall motor function remains uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the mGluR2/3 agonist LY379268 in rodent models of Parkinson's disease. Murray, TK., Messenger, MJ., Ward, MA., et al.[2019]

In a nonhuman primate model of Parkinson's disease, the partial D1 receptor agonist CVL-751 was found to be as effective as L-DOPA in improving movement and reducing disability.

CVL-751 treatment resulted in fewer dyskinesia side effects compared to L-DOPA, suggesting it could be a safer alternative for managing Parkinson's symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

D1 Agonist Improved Movement of Parkinsonian Nonhuman Primates with Limited Dyskinesia Side Effects. Young, D., Popiolek, M., Trapa, P., et al.[2021]

Levodopa-carbidopa intestinal gel (LCIG) treatment significantly improves functional status in advanced Parkinson's disease (APD) patients, reducing difficulties in daily activities like walking, dressing, and bathing by up to 76%, 42%, and 39%, respectively.

The improvements in functional status due to LCIG treatment translate to a substantial economic benefit, generating $2.6 billion in value for patients and offsetting 15% of the overall cost of LCIG treatment, which is significant given the $17.7 billion burden of disability associated with APD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Social Value of Improvement in Activities of Daily Living among the Advanced Parkinson's Disease Population. Sullivan, J., Shih, TM., van Eijndhoven, E., et al.[2021]

Levodopa-induced motor complications are common in Parkinson's disease, and while new formulations like intrajejunal l-dopa-carbidopa infusion and bilayered extended-release l-dopa-carbidopa have shown promise in improving motor fluctuations, many patients still experience significant disability.

Recent trials have explored various treatments for dyskinesia, including new amantadine formulations and serotonin agents, but challenges remain in translating these findings into effective clinical practices, as seen with the failed trials of mavoglurant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New treatments for levodopa-induced motor complications. Rascol, O., Perez-Lloret, S., Ferreira, JJ.[2022]

AV-101, a pro-drug that effectively targets NMDA receptors, significantly reduced L-Dopa-induced dyskinesias (LID) in MPTP-lesioned monkeys while preserving the antiparkinsonian effects of L-Dopa.

Unlike amantadine, which has known side effects, AV-101 showed no non-motor adverse effects, suggesting it may be a safer alternative for managing LID in Parkinson's disease patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AV-101, a Pro-Drug Antagonist at the NMDA Receptor Glycine Site, Reduces L-Dopa Induced Dyskinesias in MPTP Monkeys. Bourque, M., Grégoire, L., Patel, W., et al.[2023]

LY503430, a novel AMPA receptor potentiator, enhances glutamate signaling and shows promise for neuroprotection in rodent models of Parkinson's disease, demonstrating both functional and histological protection after neurotoxic injury.

The compound not only improved outcomes when administered after the onset of lesions but also increased levels of brain-derived neurotrophic factor (BDNF) and growth-associated protein-43 (GAP-43), suggesting potential for disease modification in Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LY503430: pharmacology, pharmacokinetics, and effects in rodent models of Parkinson's disease. O'Neill, MJ., Murray, TK., Clay, MP., et al.[2023]

In a study involving 16 patients with moderate Parkinson's disease, the NR2B-selective NMDA receptor antagonist MK-0657 did not show significant improvement in motor function compared to placebo, despite achieving the target plasma concentration.

While MK-0657 was generally well tolerated, it did lead to increases in blood pressure, indicating potential safety concerns that may limit its use in treating Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose administration of MK-0657, an NR2B-selective NMDA antagonist, does not result in clinically meaningful improvement in motor function in patients with moderate Parkinson's disease. Addy, C., Assaid, C., Hreniuk, D., et al.[2013]

The NMDA receptor antagonist LY235959 significantly reduced oral dyskinesias by 68% and diminished choreic dyskinesias in a study involving six monkeys with Parkinson's disease, indicating its potential to alleviate side effects of long-term levodopa therapy.

Importantly, LY235959 did not impair the antiparkinsonian effects of levodopa, suggesting that NMDA receptor blockade could be a safe and effective strategy to manage dyskinesias without compromising the treatment of Parkinson's symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levodopa-induced dyskinesias improved by a glutamate antagonist in Parkinsonian monkeys. Papa, SM., Chase, TN.[2017]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06565195

NCT06565195 | A Clinical Trial of LY3962681 in Healthy ... The purpose of this study is to evaluate the safety, tolerability, and PK/PD of LY3962681 in healthy volunteers and patients with Parkinson's disease. The study ...

2. movementdisorders.onlinelibrary.wiley.com movementdisorders.onlinelibrary.wiley.com/doi/full/10.1002/mds.29951

Clinical Trials - 2024 - Wiley Online Library Treatment with carvedilol resulted in improved RBDQ questionnaire (10.1±1.5 vs 7.4±3.4; p<0.05) and depression average scores (4.4±2.3 vs 2.6± ...

3. apdaparkinson.org apdaparkinson.org/article/vaccines-and-parkinsons-disease/

Vaccines & Medications Targeting Alpha-Synuclein A recent trial for Parkinson's disease dementia however, was stopped early without results. LY3962681 is a small interfering RNA (siRNA) that ...

4. mdsabstracts.org mdsabstracts.org/abstract/first-in-human-single-and-multiple-ascending-dose-trial-design-of-ly3962681-a-novel-intrathecally-delivered-sirna-targeting-%CE%B1-synuclein-mrna-for-the-treatment-of-patients-with-parkinson/

First-In-Human Single and Multiple Ascending Dose Trial ... A Phase 1 clinical trial evaluating LY3962681, a novel, intrathecally delivered siRNA directly targeting α-synucleinmRNA (SNCA) to reduce α-synuclein protein ( ...

5. withpower.com withpower.com/clinical-trials/for-parkinsons-disease-near-austin-tx

49 Parkinson's Disease Trials near Austin, TX LY3962681 for Parkinson's Disease. Austin, Texas. The purpose of this study is ... The drug already has data showing both safety and effectiveness. As a ...

6. delta.larvol.com delta.larvol.com/Products/?ProductId=4bc4fd5f-0099-4878-83ae-27621999047c

LY3962681 / Eli Lilly P1 data • CNS Disorders • Movement Disorders • Parkinson's Disease • SNCA ... Parkinson's Disease to Evaluate the Safety, Tolerability, and PK/PD of LY3962681 ...

7. synapse.patsnap.com synapse.patsnap.com/drug/30213188059d4613b07871a5cb0a2a26

LY-3962681 - Drug Targets, Indications, Patents ... Patients With Parkinson's Disease to Evaluate the Safety, Tolerability, and PK/PD of LY3962681. 100 Clinical Results associated with LY-3962681. Login to view ...