LY4006896 for Parkinson's Disease

Recruiting at 11 trial locations

Overseen By Steven Reynolds

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Eli Lilly and Company

Must be taking: Dopaminergic therapy

Disqualifiers: Neurological disease, Unstable illnesses, Allergies, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 61 weeks for Parkinson's disease, 48 weeks for healthy participants

127 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop taking your current medications. However, if you are being treated for Parkinson's disease, you must be on a stable dose of your current medication for at least 90 days before starting the trial and not expect to change it for 52 weeks.

What data supports the effectiveness of the drug LY4006896 for Parkinson's Disease?

Research on similar drugs, like LY-404,039, shows that they can reduce symptoms like dyskinesia (involuntary movements) and parkinsonism (symptoms similar to Parkinson's) in animal models. This suggests that LY4006896 might also help with these symptoms in Parkinson's Disease. ^{1 2 3 4 5}

What safety data exists for LY4006896 or similar treatments in humans?

In studies of a similar treatment, LY2140023, in healthy people, most side effects were mild and temporary, mainly affecting the stomach and nervous system. No serious side effects were reported, and the treatment was generally well tolerated. ^{2 4 6 7 8}

How does the drug LY4006896 differ from other Parkinson's disease treatments?

LY4006896 is unique because it acts as an agonist (activator) of metabotropic glutamate receptors 2 and 3 (mGluR2/3) and may also stimulate dopamine D2 receptors, potentially offering broader therapeutic effects for Parkinson's disease by reducing dyskinesia and psychosis-like behaviors. ^{1 2 5 7 9}

What is the purpose of this trial?

The purpose of this study is to generate evidence of the safety, tolerability, and pharmacokinetics/pharmacodynamics of IV LY4006896 compared with placebo in healthy participants and participants with Parkinson's disease.

Research Team

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Principal Investigator

Eli Lilly and Company

Eligibility Criteria

This trial is for healthy individuals and those with Parkinson's Disease who meet specific health criteria. The full eligibility requirements are not provided, but typically include factors like age range, disease severity, and absence of certain medical conditions.

Inclusion Criteria

My BMI is between 18 and 34.

I have good veins for blood tests or IV treatments.

Part A Single Ascending Dose (SAD) Only: Are overtly healthy

Exclusion Criteria

I am allergic to certain compounds.

I have a significant brain or nerve condition.

Part A Single Ascending Dose (SAD) Only: Have abnormal blood pressure or pulse rate

Timeline

Screening

Participants are screened for eligibility to participate in the trial

35-120 days

Treatment

Healthy participants receive a single escalating dose of LY4006896 and matching placebo; participants with Parkinson's disease receive multiple escalating doses

61 weeks for Parkinson's disease, 48 weeks for healthy participants

Follow-up

Participants are monitored for safety and effectiveness after treatment

17 weeks for Parkinson's disease, 5 weeks for healthy participants

Treatment Details

Interventions

• LY4006896

Trial Overview The study is testing the safety and effects of LY4006896 when given intravenously compared to a placebo. It aims to understand how the drug behaves in the body (pharmacokinetics) and its impact on Parkinson's symptoms (pharmacodynamics).

Participant Groups

Group I: Part B LY4006896 + Placebo Experimental Treatment 1 Intervention

Participants with Parkinson's disease will receive multiple escalating doses of LY4006896 and matching placebo.

Group II: Part A LY4006896 + Placebo Experimental Treatment 1 Intervention

Healthy participants will receive a single escalating dose of LY4006896 and matching placebo.

Who Is Running the Clinical Trial?

Eli Lilly and Company

Lead Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Findings from Research

LY-404,039 significantly reduced dyskinesia by 55% and psychosis-like behaviors by 50% in MPTP-lesioned marmosets when combined with L-DOPA, indicating its potential efficacy in treating Parkinson's disease symptoms.

The study suggests that LY-404,039, which also acts on dopamine D2 receptors, may offer broader therapeutic benefits compared to other mGluR2/3 agonists, supporting its potential repurposing for Parkinson's disease treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The mGluR2/3 orthosteric agonist LY-404,039 reduces dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset. Kang, W., Nuara, SG., Bédard, D., et al.[2023]

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]

The Phase I clinical trial of PF-06669571, a novel dopamine D1 receptor partial agonist, demonstrated that the drug was safe and well tolerated in 20 subjects with Parkinson's disease, with no serious safety concerns reported.

Although the primary endpoint for significant improvement in motor symptoms did not meet pre-specified criteria, a sensitivity analysis suggested potential efficacy, particularly when excluding an outlier with a very high L-DOPA dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Dopamine D1 Receptor Partial Agonist, PF-06669571, in Subjects with Idiopathic Parkinson's Disease. Gurrell, R., Duvvuri, S., Sun, P., et al.[2018]

The PD-1101 trial demonstrated that the gene therapy VY-AADC01 is well-tolerated in participants with moderately advanced Parkinson's disease, with no serious adverse events linked to the treatment reported over 36 months.

Participants in the higher dose cohorts experienced a significant reduction in their Parkinson's medication requirements (21%-30%) and showed stable or improved motor function and quality of life measures compared to baseline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial. Christine, CW., Richardson, RM., Van Laar, AD., et al.[2022]

In a 15-week phase II clinical trial involving 57 participants with early-stage Parkinson's disease, PF-06649751 demonstrated significant improvement in motor symptoms, as measured by the MDS-UPDRS Part III score, compared to placebo.

The safety profile of PF-06649751 was generally favorable, with most adverse events being mild to moderate, including nausea and headache, indicating it is well tolerated in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PF-06649751 efficacy and safety in early Parkinson's disease: a randomized, placebo-controlled trial. Riesenberg, R., Werth, J., Zhang, Y., et al.[2022]

LY2140023, an mGlu2/3 receptor agonist, was generally well tolerated in healthy subjects across 10 phase 1 studies, with no serious adverse events reported and most treatment-emergent adverse events (TEAEs) being mild and transient.

The most common TEAEs were gastrointestinal and nervous system-related, but there were no clear trends indicating increased incidence of these events with higher doses, suggesting a favorable safety profile for LY2140023.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events in healthy subjects exposed to single and multiple doses of LY2140023 monohydrate: pooled results from 10 phase 1 studies. Ayan-Oshodi, M., Wondmagegnehu, ET., Lowe, SL., et al.[2013]

The selective mGlu2 positive allosteric modulator LY-487,379 significantly reduced the severity of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats by approximately 54% when administered acutely, indicating its potential as an effective treatment to manage this side effect of Parkinson's disease therapy.

Long-term treatment with LY-487,379 during the induction of dyskinesia resulted in a reduction of dyskinesia severity by about 74% and 61% at different doses, without impairing the anti-parkinsonian effects of l-DOPA, suggesting that mGlu2 activation could be a promising strategy for both alleviating and preventing dyskinesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The highly selective mGlu2 receptor positive allosteric modulator LY-487,379 alleviates l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease. Hamadjida, A., Sid-Otmane, L., Kwan, C., et al.[2021]

LY354740, a selective agonist of group II metabotropic glutamate receptors, was found to reduce muscle rigidity in a rat model of Parkinson's disease, indicating potential antiparkinsonian properties.

The study demonstrated that LY354740 effectively diminished muscle rigidity induced by haloperidol in a dose-dependent manner, suggesting its efficacy in counteracting parkinsonian symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LY354740, a group II metabotropic glutamate receptor agonist with potential antiparkinsonian properties in rats. Konieczny, J., Ossowska, K., Wolfarth, S., et al.[2019]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

The mGluR2/3 orthosteric agonist LY-404,039 reduces dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset. [2023]

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

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

3. New Zealand pubmed.ncbi.nlm.nih.gov

A Phase I Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Dopamine D1 Receptor Partial Agonist, PF-06669571, in Subjects with Idiopathic Parkinson's Disease. [2018]

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

Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial. [2022]

5. England pubmed.ncbi.nlm.nih.gov

PF-06649751 efficacy and safety in early Parkinson's disease: a randomized, placebo-controlled trial. [2022]

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

Adverse events in healthy subjects exposed to single and multiple doses of LY2140023 monohydrate: pooled results from 10 phase 1 studies. [2013]

7. France pubmed.ncbi.nlm.nih.gov

The highly selective mGlu2 receptor positive allosteric modulator LY-487,379 alleviates l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease. [2021]

8. Germany pubmed.ncbi.nlm.nih.gov

LY354740, a group II metabotropic glutamate receptor agonist with potential antiparkinsonian properties in rats. [2019]

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

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