A First-In-Human Study of LY3954068 in Participants With Early Symptomatic Alzheimer's Disease

A Single- and Multiple-Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LY3954068 in Patients With Early Symptomatic Alzheimer's Disease

The main purpose of this study is to evaluate the safety of LY3954068 in participants with early symptomatic Alzheimer's Disease (AD). The study will also investigate how much LY3954068 gets into the bloodstream and will test the effects of LY3954068 on markers of AD.

The study will be comprised of two parts, A and B. Each enrolled participant in Part A will receive a single dose of LY3954068 or placebo (no active drug) given into the spinal fluid. Each participant in Part B will receive 2 doses of either LY3954068 or placebo administered into the spinal fluid. Participants will have the opportunity to join an optional bridging period to a separate potential study where participants would receive LY3954068.

The study will last up to approximately 45 weeks for Part A, and 100 weeks for Part B, including the screening period.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: LY3954068; Drug: Flortaucipir F18; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Trial questions or participation questions: 1-877-CTLILLY (1-877-285-4559) or; Phone Number: 1-317-615-4559; Email: LillyTrials@Lilly.com
• Study Contact Backup: Name: Physicians interested in becoming principal investigators please contact; Email: clinical_inquiry_hub@lilly.com

Study Locations

• Japan
  • Bunkyō City, Japan, 113-8655
    • Recruiting
    • The University of Tokyo Hospital
    • Contact: Phone Number: 81120023812
    • Principal Investigator: Yoshiki Niimi
• United Kingdom
  • London, United Kingdom, WC1N 3BG
    • Recruiting
    • National Hospital for Neurology and Neurosurgery (UCLH)
    • Principal Investigator: Catherine Mummery
    • Contact: Phone Number: 0203 448 3011
  • Sheffield, United Kingdom, S10 2JF
    • Recruiting
    • Royal Hallamshire Hospital
    • Principal Investigator: Daniel Blackburn
    • Contact: Phone Number: 0114 2713339
  • Southampton, United Kingdom, SO16 6YD
    • Recruiting
    • University Hospital Southampton
    • Principal Investigator: Christopher Kipps
    • Contact: Phone Number: 2381204989
• United States
  • Florida
    • Maitland, Florida, United States, 32751
      • Recruiting
      • K2 Medical Research, LLC
      • Contact: Phone Number: 407-500-5252
      • Principal Investigator: Brandon Lenox
    • The Villages, Florida, United States, 32162
      • Recruiting
      • Charter Research, LLC
      • Contact: Phone Number: 352-775-1000
      • Principal Investigator: Jeffrey Norton
  • Georgia
    • Decatur, Georgia, United States, 30030
      • Recruiting
      • CenExel iResearch, LLC (CenExel iRA)
      • Contact: Phone Number: 404-537-1281
      • Principal Investigator: Kimball Johnson
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • Not yet recruiting
      • Massachusetts General Hospital (MGH)
      • Principal Investigator: Steven Arnold
      • Contact: Phone Number: 617-643-5607
  • New Jersey
    • Toms River, New Jersey, United States, 08755
      • Recruiting
      • CenExel AMRI
      • Principal Investigator: Arun Singh
      • Contact: Phone Number: 732-341-9500
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Duke University
      • Principal Investigator: Shruti Raja
      • Contact: Phone Number: 919-684-5196

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Have a body mass index (BMI) within the range 18 to 40 kilograms per square meter (kg/m²), inclusive, at screening.
• Have gradual and progressive change in memory function for greater than or equal to (≥) 6 months as reported by the participant or informant.
• Have a mini mental state examination (MMSE) score of 18 to 30 at screening.
• Have a clinical dementia rating (CDR) global score of 0.5 to 1.0, with a memory box score ≥ 0.5 at screening.
• Meet flortaucipir F18 positron emission tomography (PET) criteria, as defined in the TAUVID™ FDA label (TAUVID™ prescribing information, 2024), demonstrating evidence of tau pathology.
• Males who agree to follow contraceptive requirements, or women not of childbearing potential (WNOCBP).
• Participants must have up to 2 study partners who are with contact with the participant at least 10 hours per week and one of whom can attend study appointments.

Exclusion Criteria:

• Has current serious or unstable illnesses including cardiovascular, hepatic, renal, gastroenterological, respiratory, endocrinologic, neurologic (other than Alzheimer's Disease), psychiatric, immunologic, or hematologic disease and other conditions that, in the investigator's opinion, could interfere with the analyses in this study; or has a life expectancy of less than (<)24 months.
• Have a sensitivity to flortaucipir F18.
• Have contraindication to magnetic resonance imaging (MRI), including claustrophobia or the presence of contraindicated metal (ferromagnetic) implants/cardiac pacemaker.
• Have a current exposure to an amyloid targeted therapy (ATT). Prior exposure to ATTs greater than 1 year from the last dose may be permitted at the discretion of the investigator and in consultation with the sponsor.
• Have previous exposure to any Investigational Medicinal Product administered intrathecal (IT) or previous exposure to any anti-tau therapy.
• Have a history of clinically significant back pain, back pathology and/or back injury (for example, degenerative disease, spinal deformity or spinal surgery) that may predispose to complications or technical difficulty with lumbar puncture.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LY3954068 (Part A); Single ascending dose of LY3954068 administered intrathecally (IT)	Drug: LY3954068; Administered IT; Drug: Flortaucipir F18; Administered intravenously (IV) prior to Positron Emission Tomography (PET) scan
Placebo Comparator: Placebo (Part A); Single ascending dose of placebo administered IT	Drug: Flortaucipir F18; Administered intravenously (IV) prior to Positron Emission Tomography (PET) scan; Drug: Placebo; Administered IT
Experimental: LY3954068 (Part B); Multiple ascending dose of LY3954068 administered IT	Drug: LY3954068; Administered IT; Drug: Flortaucipir F18; Administered intravenously (IV) prior to Positron Emission Tomography (PET) scan
Placebo Comparator: Placebo (Part B); Multiple ascending dose of placebo administered IT	Drug: Flortaucipir F18; Administered intravenously (IV) prior to Positron Emission Tomography (PET) scan; Drug: Placebo; Administered IT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part B: Number of participants with one or more Adverse Event (s) (AEs), Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Event(s) (SAEs) considered by the investigator to be related to study drug administration	A summary of AEs, TEAEs, SAEs and other non-serious adverse events (AEs), regardless of causality, will be reported in the reported adverse events module	Baseline up to Week 52
Part A: Number of participants with one or more Adverse Event (s) (AEs), Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Event(s) (SAEs) considered by the investigator to be related to study drug administration	A summary of AEs, TEAEs, SAEs and other non-serious adverse events (AEs), regardless of causality, will be reported in the reported adverse events module	Baseline up to Week 24 and Week 72 (for optional bridging period participants)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Pharmacokinetics (PK): Maximum Observed Concentration (Cmax)	To evaluate plasma concentration of LY3954068	Day 1 up to Week 24
Part A: PK: Area Under the Concentration Versus Time Curve (AUC)	To evaluate plasma concentration of LY3954068	Day 1 up to Week 24
Part A: PK: Cerebrospinal Fluid (CSF) concentration of LY3954068	To evaluate CSF concentration of LY3954068	Day 3 up to Week 24
Part A: Pharmacodynamics (PD): Change from Baseline of CSF tau	To evaluate the effect of LY3954068 on CSF tau	Baseline up to Week 24
Part B: PK: Cmax	To evaluate plasma concentration of LY3954068	Day -1 up to Week 52
Part B: PK: AUC	To evaluate plasma concentration of LY3954068	Day -1 up to Week 52
Part B: PK: CSF concentration of LY3954068	To evaluate CSF concentration of LY3954068	Day 3 up to Week 52
Part B: PD: Change from Baseline of CSF tau	To evaluate the effect of LY3954068 on CSF tau	Baseline up to Week 52

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Investigators: Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 8 AM - 8 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Publications and helpful links

Helpful Links

• A First-In-Human Study of LY3954068 in Participants With Early Symptomatic Alzheimer's Disease

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2024
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: March 1, 2024
• First Submitted That Met QC Criteria: March 1, 2024
• First Posted (Actual): March 7, 2024

Study Record Updates

• Last Update Posted (Actual): August 24, 2026
• Last Update Submitted That Met QC Criteria: August 21, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Nervous System Diseases; Mild Cognitive Impairment; Dementia; Central Nervous System Diseases; Neurodegenerative Diseases; Mental Disorders; Brain Diseases; Tau; Neurocognitive Disorders; Tauopathies
• Additional Relevant MeSH Terms: Cognition Disorders; Frontotemporal Lobar Degeneration; Frontotemporal Dementia; Cognitive Dysfunction; Alzheimer Disease; Mental Disorders; Dementia; Brain Diseases; Nervous System Diseases; Neurodegenerative Diseases; Central Nervous System Diseases; Pick Disease of the Brain; Neurocognitive Disorders; Tauopathies; Substandard Drugs; Pharmaceutical Preparations; 7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole
• Other Study ID Numbers: 18795; J4T-MC-OLAA (Other Identifier: Eli Lilly and Company); 2024-510604-37-00 (Other Identifier: EU Trial Number); U1111-1302-6222 (Other Identifier: Universal Trial Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No