LY3962681 for Parkinson's Disease

(PROSPECT Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

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

Trial Summary

What is the purpose of this trial?

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 will be comprised of two parts, the Single Ascending Dose (SAD) study and the Multiple Ascending Doses (MAD) study. During the SAD portion of the study, healthy volunteers will receive a single dose of LY3962681 or placebo (artificial cerebrospinal fluid (aCSF), no active drug) given into the spinal fluid. During the MAD portion of the study, patients with Parkinson's disease will receive two doses of either LY3962681 or placebo (aCSF) administered into the spinal fluid. * The treatment period in the SAD study will be 1 day. The treatment period in the MAD study will be 2 days, 12 to 24 weeks apart. * The follow-up period in the SAD study will be up to 52 weeks. The follow-up period in the MAD study will be up to 52 weeks post Dose 2.

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.

What data supports the effectiveness of the drug LY3962681 for Parkinson's Disease?

Research on a similar drug, LY379268, which targets the same receptors, showed some protection in animal models of Parkinson's Disease, suggesting potential benefits. However, its ability to improve movement was less clear, indicating that while there might be some protective effects, the impact on symptoms needs further investigation. ^{1 2 3 4 5}

How does the drug LY3962681 differ from other Parkinson's disease treatments?

LY3962681 is unique because it targets Group II mGlu receptors, which may offer some neuroprotection in Parkinson's disease models, although its role in improving motor function is less clear. This mechanism is different from traditional treatments like levodopa, which primarily focus on dopamine replacement. ^{1 3 6 7 8}

Research Team

Travis Lewis

Principal Investigator

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

Eligibility Criteria

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

Trial Timeline

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

Treatment Details

Interventions

• LY3962681 (Other)

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Evaluation of the mGluR2/3 agonist LY379268 in rodent models of Parkinson's disease. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

D1 Agonist Improved Movement of Parkinsonian Nonhuman Primates with Limited Dyskinesia Side Effects. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Levodopa-induced dyskinesias improved by a glutamate antagonist in Parkinsonian monkeys. [2017]

4. Germany pubmed.ncbi.nlm.nih.gov

The Social Value of Improvement in Activities of Daily Living among the Advanced Parkinson's Disease Population. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

New treatments for levodopa-induced motor complications. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

LY503430: pharmacology, pharmacokinetics, and effects in rodent models of Parkinson's disease. [2023]

7. England 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. [2013]

8. Switzerland 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. [2023]