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Frontotemporal DementiaPhase 1/2NCT05262023

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia (FTD-GRN)

A Phase 1/2 study testing DNL593 in people with Frontotemporal Dementia, run by Denali Therapeutics Inc. at 26 sites in 12 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

This is a Phase 1/2, multicenter, randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of DNL593 in two parts followed by an optional open-label extension (OLE) period. Read more about this study

Who is it for?
Ages 18 to 80 yearsHealthy volunteers can take part
Conditions the study is for
Frontotemporal Dementia
What is being tested?
DNL593
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
85 participants
Where
26 sitesin 12 countries
Study dates
1 Feb 2022to Nov 2028
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • Part A:
  • Women of non-childbearing potential (surgically sterilized or post menopausal) or men, aged ≥18 to ≤ 55 years
  • BMI of ≥ 18 to ≤ 32 kg/m²
  • When engaging in sex with a woman of child bearing potential, two forms of birth control are required
  • Part B:
  • Women of non-childbearing potential (surgically sterilized or post menopausal) or men, aged ≥18 to ≤ 80 years. Women who are of childbearing potential but on highly effective, low user dependent contraceptive methods will be allowed.
Show all 12Show fewer
  • BMI of ≥ 18 to ≤ 32 kg/m²
  • Have a Clinical Dementia Rating® plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration global score ≥ 0.5
  • Have confirmed granulin (GRN) mutation via genetic testing or historical records available for review by investigator
  • When engaging in sex with a woman of child bearing potential, both the male participant and his female partner must use highly effective contraception
  • Part C:
  • All participants who completed Part B of this trial are eligible for an 18-month OLE if the participant has no unresolved clinically significant TEAEs, where continued dosing may represent a risk to participant safety.

Who cannot join

  • Have any history of clinically significant neurologic, psychiatric, endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic, renal, metabolic, hematologic, immunologic, or allergic disease, or other major disorders
  • Have a history of malignancy, except fully resected basal cell carcinoma or other malignancies at low risk of recurrence
  • Have a clinically significant history of stroke, cognitive impairment due to causes other than FTD, seizure within 5 years of screening, or head trauma with loss of consciousness within 2 years of screening
  • Have a positive serum pregnancy test or are currently lactating or breastfeeding

Trial locations and contacts

26 sites in 12 countries.

26 sites in 12 countries

Italy4 sites

  • ASST degli Spedali Civili di Brescia

    Brescia

  • Azienda Ospedaliera Universitaria Careggi

    Florence

  • IRCCS Istituto Auxologico Italiano

    Milan

  • Azienda Ospedaliera Cardinale G Panico

    Tricase

Other trials in Italy

United States3 sites

  • John Hopkins University

    Baltimore, Maryland, 21218

  • Hospital of the University of Pennsylvania

    Philadelphia, Pennsylvania, 19104

  • University of California San Francisco

    San Francisco, California, 94143

Other trials in United States

France3 sites

  • CHU de Nantes

    Nantes

  • CHU Rouen

    Rouen

  • CHU Toulouse

    Toulouse

Other trials in France

Spain3 sites

  • Hospital Clinic de Barcelona

    Barcelona, Barcelona, 8036

  • Hospital Universitario de Donostia

    Donostia / San Sebastian, Guipúzcoa, 20014

  • Hospital Universitario Virgen del Rocio

    Seville, Sevilla, 41013

Other trials in Spain

Belgium2 sites

  • University of Antwerp

    Antwerp

  • UZ Leuven

    Leuven

Other trials in Belgium

Brazil2 sites

  • L2IP - Instituto de Pesquisas Clinicas LTDA

    Brasília

  • Faculdade de Medicina Da Universidade de São Paulo

    São Paulo

Other trials in Brazil

Colombia2 sites

  • Hospital Universitario San Ignacio

    Bogotá

  • Grupo de Neurosicencias de la Universidad de Antioquia

    Medellín

Other trials in Colombia

Portugal2 sites

  • Hospital de Braga

    Braga

  • Campus Neurológico Sénior

    Torres Vedras

Other trials in Portugal

Turkey (Türkiye)2 sites

  • Istanbul University Istanbul Medical Faculty

    Istanbul

  • Ondokuz Mayis University Hospital

    Samsun

Other trials in Turkey (Türkiye)

Czechia1 site

  • Fakultni nemocnice v Motole

    Prague

Other trials in Czechia

Netherlands1 site

  • Erasmus University Medical Center

    Rotterdam

Other trials in Netherlands

United Kingdom1 site

  • Simbec Orion

    Merthyr Tydfil, Wales, CF48 4DR

Other trials in United Kingdom

About this study

Official title: A Phase 1/2, Multicenter, Randomized, Placebo-Controlled, Double Blind Single Dose and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia Followed by an Open-Label Extension

This is a Phase 1/2, multicenter, randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of DNL593 in two parts followed by an optional open-label extension (OLE) period.

Part A will evaluate the safety, tolerability, PK, and PD of single doses of DNL593 in healthy male and healthy female participants of nonchildbearing potential. Part B will evaluate the safety, tolerability, PK, and PD of multiple doses of DNL593 in participants with frontotemporal dementia (FTD) over 25 weeks. Part B will be followed by Part C, an optional 18-month OLE period available for all participants who complete Part B.

Being tested
DNL593, Placebo
Keywords
FTD, FTD-GRN, granulin
Medical subject headings
Frontotemporal Dementia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DNL593Drug

    Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

  • PlaceboDrug

    Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

Study groups in NCT05262023
Study groupRoleWhat they receive
DNL593 (Healthy Participant)ExperimentalNot described
Receives: Drug: DNL593
Placebo (Healthy Participant)Placebo comparatorNot described
Receives: Drug: Placebo
DNL593 (Participants with FTD)ExperimentalNot described
Receives: Drug: DNL593
Placebo (Participants with FTD)Placebo comparatorNot described
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs)

    Measured: up to 18 months

  2. Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values

    Measured: up to 18 months

  3. Change from baseline in vital sign measurements: systolic and diastolic blood pressure

    Measured: up to 18 months

  4. Change from baseline in vital sign measurements: heart rate

    Measured: up to 18 months

  5. Change from baseline in vital sign measurements: respiratory rate

    Measured: up to 18 months

  6. Change from baseline in vital sign measurements: body temperature

    Measured: up to 18 months

  7. Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals

    Measured: up to 18 months

  8. Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings

    Measured: up to 18 months

  9. Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS; Parts B and C only)

    Measured: up to 18 months

Secondary outcomes (11)

  1. PK Parameter: Maximum concentration (Cmax) of DNL593 in serum

    Measured: up to 18 months

  2. PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum

    Measured: up to 18 months

  3. PK Parameter: Area under the concentration-time curve (AUC) from time zero to time of last measurable concentration (AUClast) of DNL593 in serum

    Measured: up to 18 months

  4. PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum

    Measured: up to 18 months

  5. PK Parameter: AUC from time zero to infinity (AUC∞) of DNL593 in serum (Part A only)

    Measured: up to 84 days

  6. PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only)

    Measured: up to 18 months

  7. PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only)

    Measured: up to 18 months

  8. PK Parameter: AUC from time 0 to the end of the dosing interval (AUCτ) of DNL593 in serum (Parts B and C only)

    Measured: up to 18 months

  9. Concentration of DNL593 in cerebrospinal fluid (CSF)

    Measured: up to 18 months

  10. DNL593 CSF:serum concentration ratio

    Measured: up to 18 months

  11. Percentage change from baseline in plasma NfL

    Measured: up to 18 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Mar 2022
  2. Study start1 Feb 2022
  3. Primary completionDec 2026 (estimated)
  4. Study completionNov 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
85 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05262023
Sponsor's protocol ID
DNLI-H-0001
Other IDs
2023-508697-28-00, 2021-005733-16, 2023
Status last verified
Jan 2026
First submitted
1 Feb 2022
Last updated
15 Jan 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing DNL593 in people with Frontotemporal Dementia, run by Denali Therapeutics Inc. at 26 sites in 12 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 15 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 26 sites in Italy, United States, France, Spain, Belgium and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs) (time frame: up to 18 months). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05262023.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jan 2026.

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