LY4060874 for Healthy Volunteers

Recruiting at 1 trial location

Overseen By There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Eli Lilly and Company

Must not be taking: GLP-1 agonists

Disqualifiers: Diabetes, Obesity surgery, Weight loss meds, others

Compensation: Varies

Number of Visits: 16

Duration: 13-18 weeks

132 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate safety and tolerability of LY4060874 in healthy participants. Study participation may last up to 22 weeks and up to approximately 16 study visits.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have taken any weight loss medications, including over-the-counter or prescribed ones, in the 3 months before the study.

What safety data exists for LY4060874 in humans?

There is no specific safety data available for LY4060874, but a similar compound, LY2140023, was generally well tolerated in healthy subjects with no serious adverse events reported in 10 studies. Most side effects were mild and temporary, mainly affecting the stomach and nervous system. ^{1 2 3 4 5}

Research Team

1-877-CTLILLY (1-877-285-4559) or 3176154559 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 who are interested in participating in a study to assess the safety of a new medication, LY4060874. Specific eligibility criteria details are not provided, but typically participants must meet certain health standards and be willing to commit to the study duration and visits.

Inclusion Criteria

To qualify as a participant of first-generation Japanese origin, the participant, the participant's biological parents, and all the participants' biological grandparents must be of exclusive Japanese descent and born in Japan

Are overtly healthy as determined by medical evaluation, including medical history and physical examination

Have a body mass index in the range of 20 to 29.9 kilogram per meter squared (kg/m²), inclusive, at screening

Exclusion Criteria

Have hemoglobin A1c (HbA1c) ≥ 5.7% or 39 millimoles/mole (mmol/mol) at screening

Are actively participating in a weight loss program or intend to initiate an intensive diet and/or exercise program during the study

I have used weight loss medication, including GLP-1 receptor agonists, in the last 3 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive single or multiple ascending doses of LY4060874 or placebo

13-18 weeks

Up to 16 visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• LY4060874

Trial Overview The trial is testing LY4060874 against a placebo (a substance with no therapeutic effect) to evaluate its safety when taken by healthy people. Participants will likely receive either the drug or placebo without knowing which one they're getting.

Participant Groups

Group I: LY4060874 (Part C Japanese) Experimental Treatment 1 Intervention

Multiple ascending doses of LY4060874 administered SC in Japanese participants.

Group II: LY4060874 (Part B) Experimental Treatment 1 Intervention

Multiple ascending doses of LY4060874 administered SC.

Group III: LY4060874 (Part B Chinese) Experimental Treatment 1 Intervention

Multiple ascending doses of LY4060874 administered SC in Chinese participants.

Group IV: LY4060874 (Part A Subcutaneous) Experimental Treatment 1 Intervention

Single ascending dose of LY4060874 administered subcutaneously (SC).

Group V: LY4060874 (Part A Intravenous) Experimental Treatment 1 Intervention

Single ascending dose of LY4060874 administered intravenously (IV).

Group VI: Placebo (SC) Placebo Group 1 Intervention

Placebo administered SC in Part A, B, and C.

Group VII: Placebo (IV) Placebo Group 1 Intervention

Placebo administered IV in Part A.

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

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]

A new method was developed to accurately measure the concentration of LY-404,039 in rat plasma, which involved a butylation step to enhance detection sensitivity and chromatographic performance, validated over a range of 2.0-1,000 ng/ml.

Pharmacokinetic studies showed that LY-404,039 has a very short terminal half-life of 0.27 hours and high clearance rate, indicating it is rapidly eliminated from the body, with dose-dependent effects observed after subcutaneous administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative determination of LY-404,039, a metabotropic glutamate 2/3 receptor agonist, in rat plasma using chemical derivatization and HPLC-MRM/MS. Kang, W., Gaudette, F., Bédard, D., et al.[2022]

In vitro studies showed that LY377604 can form 4-hydroxycarbazole, a compound previously linked to mutagenicity, but in vivo studies indicated that this compound was primarily excreted as a non-toxic glucuronide conjugate, with very low levels of free 4-hydroxycarbazole detected.

A 6-month carcinogenicity study in RasH2+/- mice found no tumors associated with LY377604, suggesting that the low levels of 4-hydroxycarbazole do not pose a significant carcinogenic risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The fate of 4-hydroxycarbazole metabolite: metabolism and carcinogenicity assessment of a β-adrenergic receptor modulator containing carbazole structure. He, MM., Ji, T., Barbuch, RJ., et al.[2012]

In a study involving halothane-anesthetized cats, the AMPA receptor antagonist LY-293558 significantly reduced ischemic brain damage by decreasing the volume of damage from 3,423 mm³ to 2,822 mm³ when administered before a middle cerebral artery occlusion.

The results suggest that AMPA receptor antagonists like LY-293558 could be a promising treatment for reducing focal ischemic damage in humans, as the study controlled key physiological variables during the post-ischemic period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroprotective effect of the AMPA receptor antagonist LY-293558 in focal cerebral ischemia in the cat. Bullock, R., Graham, DI., Swanson, S., et al.[2012]

The prodrug form of LY354740, specifically an N dipeptide derivative, significantly enhances intestinal absorption, achieving up to an 8-fold increase compared to the original compound.

This new derivative also demonstrates a remarkable 300-fold increase in potency for blocking anxiety in the fear-potentiated startle model in rats, suggesting it could be a more effective treatment for anxiety disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist. Bueno, AB., Collado, I., de Dios, A., et al.[2017]

References

1. 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]

2. England pubmed.ncbi.nlm.nih.gov

Quantitative determination of LY-404,039, a metabotropic glutamate 2/3 receptor agonist, in rat plasma using chemical derivatization and HPLC-MRM/MS. [2022]

3. England pubmed.ncbi.nlm.nih.gov

The fate of 4-hydroxycarbazole metabolite: metabolism and carcinogenicity assessment of a β-adrenergic receptor modulator containing carbazole structure. [2012]

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

Neuroprotective effect of the AMPA receptor antagonist LY-293558 in focal cerebral ischemia in the cat. [2012]

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

Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist. [2017]