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

Plain English Summary

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL628 in Participants With Early Alzheimer's Disease is a Phase 1 clinical trial sponsored by Denali Therapeutics Inc. studying Alzheimer Disease, Early Onset. This study tests a new drug called DNL628 for early Alzheimer's disease. It is for individuals with mild cognitive impairment or mild Alzheimer's disease who have signs of amyloid in their brain. Participants will receive either DNL628 or a placebo (inactive substance) and will be closely monitored for safety. There are no approved treatments that directly target the underlying pathology in this specific early stage of Alzheimer's disease. The trial aims to enroll 68 participants.

Official Summary

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.

Who Can Participate

Here is what you need to know about eligibility for this trial. You may be eligible if you have been diagnosed with early Alzheimer's disease (mild cognitive impairment or mild dementia) and have evidence of amyloid in your brain. You must be between 18 and 32 on a cognitive test (MMSE) and have a global cognitive score of 0.5 or 1. You cannot join if you have other significant brain or psychiatric conditions, serious uncontrolled medical issues, or have had certain cancer treatments within the last 5 years. Previous treatments for Alzheimer's that target amyloid or tau, or gene therapy, may exclude you. This trial is studying Alzheimer Disease, Early Onset, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The main goal is to see how safe and well-tolerated DNL628 is, meaning researchers will carefully track any side effects or problems that arise during the study. The specific primary outcome measures are: Incidence and severity of treatment-emergent adverse events (TEAEs) throughout the double-blind period (37 weeks). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 1, the first major stage of clinical testing. Phase 1 trials typically involve 20-100 participants and focus on safety, dosage levels, and side effects. The primary goal is not to test whether the treatment works but to establish that it is safe enough for further testing. About 70% of Phase 1 drugs advance to Phase 2. If successful, the treatment will proceed to Phase 2 efficacy testing.

Why This Trial Matters

This trial is important because it investigates a potential new treatment for early-stage Alzheimer's, addressing a critical need for therapies that can intervene before significant cognitive decline. This research targets Alzheimer Disease, Early Onset, where improved treatment options are needed.

Investor Insight

This Phase 1 study is an early step in drug development, focusing on safety and how the drug is processed by the body, with potential for future larger trials if successful. Phase 1 trials have approximately a 10% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the potential benefits and risks of DNL628 and if this trial is right for you. Participation involves regular clinic visits for assessments, blood draws, and receiving either the study drug or placebo. The study lasts about 37 weeks, and you will be monitored closely throughout. This trial is currently recruiting participants. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: SEQUENTIAL
• Masking: DOUBLE
• Enrollment: 68 participants

Interventions

• DRUG: DNL628 — Multiple ascending doses
• DRUG: Placebo — Multiple ascending doses

Primary Outcomes

• Incidence and severity of treatment-emergent adverse events (TEAEs) throughout the double-blind period (37 weeks)

Secondary Outcomes

• 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)

Full Eligibility Criteria

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

Trial Locations

• Clinical Site(s), London, United Kingdom

Frequently Asked Questions

Related Conditions

• Alzheimer Disease
• Mild Cognitive Impairment
• Dementia
• Neurodegenerative Diseases
• Amyloidosis
• Cognitive Disorders
• Neurology
• Geriatrics
• Pharmacology
• Clinical Trials

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