A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL628 in Participants With Early Alzheimer's Disease

A Phase 1b, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL628 in Participants With Early Alzheimer's Disease

This is a Phase 1b, multicenter, randomized, placebo-controlled, double-blind, multiple ascending dose (MAD) study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DNL628 in participants with early Alzheimer's disease (AD), defined as mild cognitive impairment, or mild AD with biomarker evidence of amyloid positivity.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease, Early Onset
• Intervention / Treatment: Drug: DNL628; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 68
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Clinical Trials at Denali Therapeutics; Phone Number: Email:; Email: clinical-trials@dnli.com

Study Locations

• United Kingdom
  • London, United Kingdom, WC1N 3BG
    • Recruiting
    • Clinical Site(s)

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

• BMI of ≥18 to < 32 kg/m2 and body weight of ≥45 kg
• Have a diagnosis of probable AD dementia based on NIA AA 2011 criteria, including amnestic or nonamnestic presentation at screening
• Have supportive evidence of AD pathology via historical records or laboratory testing at screening for amyloid positivity

• Have AD severity defined as the following at screening:

  • A Clinical Dementia Rating global score of 0.5 or 1
  • A Mini-Mental State Examination score of 20 to 30 (inclusive)

Key Exclusion Criteria:

• Have clinically significant neurological or cognitive disorders affecting the CNS other than AD, as determined by the investigator
• Have clinically significant psychiatric conditions
• Have any history of unstable or poorly controlled endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, hematological, or other significant medical condition that, in the opinion of the investigator, may interfere with the completion or interpretation of study assessment
• Have had a malignancy within 5 years before screening, except fully resected basal cell carcinoma or other malignancies (such as prostate cancer) at low risk of recurrence, depending on investigator and medical monitor agreement

• Have had previous anti amyloid or anti tau immunotherapy (including active immunization)

  • Note: ADAD participants who have participated in previous passive anti-amyloid immunotherapy > 6 months previously will be allowed, contingent on investigator and Sponsor agreement
• Have had previous exposure to gene therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm	Drug: DNL628; Multiple ascending doses
Placebo Comparator: Placebo Arm	Drug: Placebo; Multiple ascending doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence and severity of treatment-emergent adverse events (TEAEs) throughout the double-blind period	37 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
PK parameter: Maximum concentration (Cmax) of DNL628 in plasma	37 weeks
PK Parameter: Time to reach maximum concentration (tmax) of DNL628 in plasma	37 weeks
PK Parameter: Minimum concentration (Cmin) of DNL628 in plasma	37 weeks
PK Parameter: Area under the concentration-time curve (AUC) from time zero to time of last measurable concentration (AUClast) of DNL628 in plasma	37 weeks
PK Parameter: AUC from time 0 to the end of the dosing interval (AUCτ) of DNL628 in plasma	37 weeks
PK Parameter: terminal elimination half-life (t1/2) of DNL628 in plasma	37 weeks
PK Parameter: Accumulation ratio of DNL628 in plasma	37 weeks
Change from baseline in total tau and ptau181 as measured in CSF	25 weeks

Collaborators and Investigators

• Sponsor: Denali Therapeutics Inc.
• Investigators: Study Director: Medical Monitor, Denali Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2026
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: December 24, 2025
• First Submitted That Met QC Criteria: December 24, 2025
• First Posted (Actual): January 9, 2026

Study Record Updates

• Last Update Posted (Actual): February 23, 2026
• Last Update Submitted That Met QC Criteria: February 20, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Alzheimer's Disease
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease
• Other Study ID Numbers: DNLI-K-0001; 2025-523515-11-00 (Ctis)

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