Clinical trial • Phase I/II • Neurology
DNL593 for Frontotemporal dementia | Frontotemporal dementia (GRN mutation)
Phase I/II trial of DNL593 for Frontotemporal dementia | Frontotemporal dementia (GRN mutation).
Overview
- Trial Therapeutic Area
- Neurology
- Trial Disease
- Frontotemporal dementia | Frontotemporal dementia (GRN mutation)
- Trial Stage
- Phase I/II
- Drug Modality
- Peptide/protein/enzyme
Key dates
- Initial CTIS Submission Date
- 08-04-2024
- First CTIS Authorization Date
- 15-05-2024
Trial design
Randomised, open-label, placebo (dnl593 placebo, sterile lyophilisate in single-dose glass vials). no dose or schedule for placebo specified in provided data.-controlled, adaptive Phase I/II trial in Belgium, Spain, Portugal and others.
- Randomised
- Yes
- Open Label
- Yes
- Comparator
- Placebo (DNL593 Placebo, Sterile lyophilisate in single-dose glass vials). No dose or schedule for placebo specified in provided data.
- Adaptive
- True, includes dose-escalation design (Part A Dose Escalation) and protocol-specified cohort dose-stopping criteria (e.g. per Protocol Section 4.1.5 cohort stopping criteria: halt dosing if two participants experience severe (Grade 3 or higher) or serious AEs related to infusion-related reactions). Dose Escalation Committee (DEC-B) reviews and can pause dosing/screening/enrolment.
- Single Multiple Or Escalation Dose Combined
- Yes
- Target Sample Size
- 55
- Trial Duration For Participant
- 540
Eligibility
Recruits 55 Participants with cognitive impairment (frontotemporal dementia) are identified as a vulnerable population. The trial includes study-partner / caregiver informed consent documents and a Study-Partner authorization form indicating that study partners/caregivers are involved in consent/authorization processes where appropriate. Multiple participant-facing ICFs (including Pregnancy-and-Newborn, Pre-Screening Genetic Test, Study-Partner/caregiver ICFs) are provided in several languages..
- Pregnancy Exclusion
- • Have a positive serum pregnancy test or are currently lactating or breastfeeding
- Vulnerable Population
- Participants with cognitive impairment (frontotemporal dementia) are identified as a vulnerable population. The trial includes study-partner / caregiver informed consent documents and a Study-Partner authorization form indicating that study partners/caregivers are involved in consent/authorization processes where appropriate. Multiple participant-facing ICFs (including Pregnancy-and-Newborn, Pre-Screening Genetic Test, Study-Partner/caregiver ICFs) are provided in several languages.
Inclusion criteria
- {"criterion_text":"- Part A: - Women of non-childbearing potential (surgically sterilized or post menopausal) or men, aged ≥18 to ≤ 55 years\n- BMI of ≥ 18 to ≤ 32 kg/m²\n- When engaging in sex with a woman of child bearing potential, both the male participant and his female partner must use highly effective contraception\n- 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. \n- BMI of ≥ 18 to ≤ 32 kg/m²\n- Have a Clinical Dementia Rating® plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration global score ≥ 0.5 \n- Have confirmed granulin (GRN) mutation via genetic testing or historical records available for review by investigator\n- When engaging in sex with a woman of child bearing potential, both the male participant and his female partner must use highly effective contraception\n- 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."}
Exclusion criteria
- {"criterion_text":"- • 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\n- • Have a history of malignancy, except fully resected basal cell carcinoma or other malignancies at low risk of recurrence \n- • 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 \n- • Have a positive serum pregnancy test or are currently lactating or breastfeeding"}
Endpoints
Primary endpoints
- {"endpoint_text":"- Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs) [Timeframe: Up to 18 months]","definition_or_measurement_approach":"Assessment of incidence, severity and seriousness of TEAEs recorded during study participation; Timeframe stated as Up to 18 months."}
- {"endpoint_text":"- Change from baseline in safety laboratory values, vital sign measurements, ECG results, and physical/neurological examination findings [Timeframe: Up to 18 months]","definition_or_measurement_approach":"Change from baseline measured in laboratory safety tests, vital signs, ECGs and physical/neurological examinations; Timeframe stated as Up to 18 months."}
Secondary endpoints
- {"endpoint_text":"- DNL593 serum PK parameters (when feasible): Cmax, tmax, Ctrough, AUClast, AUCt , t 1/2, Accumulation ratio [Timeframe: Up to 18 months]","definition_or_measurement_approach":"Standard PK parameter measurement in serum (Cmax, tmax, Ctrough, AUClast, AUCt, t1/2, accumulation ratio); Timeframe Up to 18 months."}
- {"endpoint_text":"- Concentration of DNL593 in cerebrospinal fluid (CSF) [Timeframe: Up to 18 months]","definition_or_measurement_approach":"Measurement of DNL593 concentration in CSF samples; Timeframe Up to 18 months."}
- {"endpoint_text":"- DNL593 CSF:serum concentration ratio [Timeframe: Up to 18 months]","definition_or_measurement_approach":"Ratio of measured DNL593 concentration in CSF relative to serum; Timeframe Up to 18 months."}
- {"endpoint_text":"- Percentage change from baseline in plasma Nfl at Week 25","definition_or_measurement_approach":"Percent change from baseline in plasma neurofilament light (NfL) measured at Week 25."}
Recruitment
- Digital Remote Recruitment
- True, recruitment materials indicate use of digital or remote methods including email communications, telephone pre-screening and consent procedures, and vendor tools such as ScoutPass reloadable cards and electronic communications referenced in recruitment documents.
- Planned Sample Size
- 55
- Recruitment Window Months
- 69
- Consent Approach
- Informed consent obtained from adult participants (all participants aged ≥18). Study includes dedicated participant ICFs (Main ICF Part B/C), Pre-Screening Genetic Test ICF, Pregnancy-and-Newborn ICF, Travel Reimbursement ICF and Study-Partner/caregiver ICFs. For vulnerable participants with FTD, study-partner / caregiver ICFs and a Study-Partner authorization form are provided to handle consent/authorization as appropriate. Participant-facing documents are available in multiple languages (examples in English, Dutch, French, Spanish, Portuguese, Italian, Czech).
Methods
- Referral letters to clinicians / GPs (documented: Referral-Letter and GP letter documents listed per country).
- Recruitment arrangements documents/K1 templates per country (e.g., K1_Recruitment-Arrangements for BE, ES, IT, NL, PT, CZ) describing site-based recruitment procedures.
- Site-based recruitment via participating neurology clinics and hospitals (site lists and contact persons provided).
- Vendor-supported recruitment materials and incentives (ScoutPass reloadable, ScoutPass materials and Study Brochure referenced in country documents).
- Telephone contact and pre-ICF telephone consent/data-consent procedures (Pre-ICF Telephone-Data-Consent documents present).
- Email communication (S495-SC-PFD-Email Communication document referenced).
Geography
- Total Number Of Sites
- 18
- Total Number Of Participants
- 55
Belgium
- Earliest CTIS Part Ii Submission Date
- 29-04-2024
- Latest Decision Or Authorization Date
- 24-02-2026
- Processing Time Days
- 666
- Number Of Sites
- 2
- Number Of Participants
- 5
Sites
- Site Name
- Antwerp University Hospital
- Department Name
- Neurology
- Principal Investigator Name
- Rose Bruffaerts
- Principal Investigator Email
- rose.bruffaerts@uantwerpen.be
- Contact Person Name
- Rose Bruffaerts
- Contact Person Email
- rose.bruffaerts@uantwerpen.be
- Site Name
- UZ Leuven
- Department Name
- Neurology
- Principal Investigator Name
- Rik Vandenberghe
- Principal Investigator Email
- rik.vandenberghe@uzleuven.be
- Contact Person Name
- Rik Vandenberghe
- Contact Person Email
- rik.vandenberghe@uzleuven.be
Spain
- Earliest CTIS Part Ii Submission Date
- 29-04-2024
- Latest Decision Or Authorization Date
- 27-02-2026
- Processing Time Days
- 669
- Number Of Sites
- 3
- Number Of Participants
- 15
Sites
- Site Name
- University Hospital Virgen Del Rocio S.L.
- Department Name
- Neurology Department
- Principal Investigator Name
- Emilio Franco Macías
- Principal Investigator Email
- efranco17@gmail.com
- Contact Person Name
- Emilio Franco Macías
- Contact Person Email
- efranco17@gmail.com
- Site Name
- Hospital Universitario Donostia
- Department Name
- Neurology Department
- Principal Investigator Name
- Fermín Moreno Izco
- Principal Investigator Email
- fermin.morenoizco@osakidetza.eus
- Contact Person Name
- Fermín Moreno Izco
- Contact Person Email
- fermin.morenoizco@osakidetza.eus
- Site Name
- Hospital Clinic De Barcelona
- Department Name
- Neurology Department
- Principal Investigator Name
- Raquel Sánchez del Valle Díaz
- Principal Investigator Email
- rsanchez@clinic.cat
- Contact Person Name
- Raquel Sánchez del Valle Díaz
- Contact Person Email
- rsanchez@clinic.cat
Portugal
- Earliest CTIS Part Ii Submission Date
- 29-04-2024
- Latest Decision Or Authorization Date
- 24-02-2026
- Processing Time Days
- 666
- Number Of Sites
- 3
- Number Of Participants
- 7
Sites
- Site Name
- Hospital Pedro Hispano
- Department Name
- Departamento de Neurologia
- Principal Investigator Name
- Vítor Cruz
- Principal Investigator Email
- vitor.tedimcruz@ulsm.min-saude.com
- Contact Person Name
- Vítor Cruz
- Contact Person Email
- vitor.tedimcruz@ulsm.min-saude.com
- Site Name
- CNS Saude Lda.
- Department Name
- Unidade de Demências
- Principal Investigator Name
- Joana Morgado
- Principal Investigator Email
- joanacmorgado@gmail.com
- Contact Person Name
- Joana Morgado
- Contact Person Email
- joanacmorgado@gmail.com
- Site Name
- CCAB Centro Clinico Academico Braga Associacao
- Department Name
- Serviço de Neurologia
- Principal Investigator Name
- Álvaro Machado
- Principal Investigator Email
- alvmac@gmail.com
- Contact Person Name
- Álvaro Machado
- Contact Person Email
- alvmac@gmail.com
Netherlands
- Earliest CTIS Part Ii Submission Date
- 29-04-2024
- Latest Decision Or Authorization Date
- 25-02-2026
- Processing Time Days
- 667
- Number Of Sites
- 1
- Number Of Participants
- 3
Sites
- Site Name
- Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
- Department Name
- Neurology
- Principal Investigator Name
- Harro Seelaar
- Principal Investigator Email
- h.seelaar@erasmusmc.nl
- Contact Person Name
- Harro Seelaar
- Contact Person Email
- h.seelaar@erasmusmc.nl
Czechia
- Earliest CTIS Part Ii Submission Date
- 30-07-2025
- Latest Decision Or Authorization Date
- 19-09-2025
- Processing Time Days
- 51
- Number Of Sites
- 1
- Number Of Participants
- 5
Sites
- Site Name
- Fakultni Nemocnice V Motole
- Department Name
- Neurologická klinika
- Principal Investigator Name
- Jakub Hort
- Principal Investigator Email
- jakub.hort@gmail.com
- Contact Person Name
- Jakub Hort
- Contact Person Email
- jakub.hort@gmail.com
Italy
- Earliest CTIS Part Ii Submission Date
- 29-04-2024
- Latest Decision Or Authorization Date
- 27-02-2026
- Processing Time Days
- 669
- Number Of Sites
- 4
- Number Of Participants
- 12
Sites
- Site Name
- Istituto Auxologico Italiano IRCCS
- Department Name
- U.O. Neurologia e Laboratorio di Neuroscienze
- Principal Investigator Name
- Vincenzo Silani
- Principal Investigator Email
- vincenzo.silani@unimi.it
- Contact Person Name
- Vincenzo Silani
- Contact Person Email
- vincenzo.silani@unimi.it
- Site Name
- Azienda Socio Sanitaria Territoriale Degli Spedali Civili Di Brescia
- Department Name
- Unità Operativa di Neurologia
- Principal Investigator Name
- Salvatore Caratozzolo
- Principal Investigator Email
- salvatore.caratozzolo@asst-spedalicivili.it
- Contact Person Name
- Salvatore Caratozzolo
- Contact Person Email
- salvatore.caratozzolo@asst-spedalicivili.it
- Site Name
- Pia Fondazione Di Culto E Religione Card G Panico
- Department Name
- U.O.C. Malattie Neurodegenerative
- Principal Investigator Name
- Daniele Urso
- Principal Investigator Email
- d.ursoo@piafondazionepanico.it
- Contact Person Name
- Daniele Urso
- Contact Person Email
- d.ursoo@piafondazionepanico.it
- Site Name
- Careggi University Hospital
- Department Name
- Dipartimento Neuromuscoloscheletrico e degli organi di senso - (Padiglione 25 CTO-Neuromotorio)
- Principal Investigator Name
- Valentina Bessi
- Principal Investigator Email
- valentina.bessi@unifi.it
- Contact Person Name
- Valentina Bessi
- Contact Person Email
- valentina.bessi@unifi.it
France
- Earliest CTIS Part Ii Submission Date
- 29-04-2024
- Latest Decision Or Authorization Date
- 02-03-2026
- Processing Time Days
- 673
- Number Of Sites
- 4
- Number Of Participants
- 8
Sites
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Institut de la mémoire et de la maladie d’Alzheimer
- Principal Investigator Name
- Isabelle LE BER
- Principal Investigator Email
- isabelle.leber@upmc.fr
- Contact Person Name
- Isabelle LE BER
- Contact Person Email
- isabelle.leber@upmc.fr
- Site Name
- Centre Hospitalier Universitaire De Nantes
- Department Name
- CentreMémoire Ressources et Recherche
- Principal Investigator Name
- Claire Boutoleau-Bretonnière
- Principal Investigator Email
- claire.boutoleaubretonniere@chu-nantes.fr
- Contact Person Name
- Claire Boutoleau-Bretonnière
- Contact Person Email
- claire.boutoleaubretonniere@chu-nantes.fr
- Site Name
- Centre Hospitalier Universitaire De Toulouse
- Department Name
- Department of Neurology
- Principal Investigator Name
- Jérémie Pariente
- Principal Investigator Email
- jeremie.pariente@inserm.fr
- Contact Person Name
- Jérémie Pariente
- Contact Person Email
- jeremie.pariente@inserm.fr
- Site Name
- Centre Hospitalier Universitaire Rouen
- Department Name
- Department of Neurology
- Principal Investigator Name
- David Wallon
- Principal Investigator Email
- david.wallon@chu-rouen.fr
- Contact Person Name
- David Wallon
- Contact Person Email
- david.wallon@chu-rouen.fr
Sponsor
Primary sponsor
- Full Name
- Denali Therapeutics Inc.
- Organisation Type
- Pharmaceutical company
- Country Of Registered Address
- United States
Contract research organisations
- Name
- PPD Development L.P.
- Name
- Icon Clinical Research Limited
- Name
- IQVIA Limited
- Name
- Fisher Clinical Services GmbH
Third parties
- {"country":"United States","full_name":"PPD Development L.P.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"Australia","full_name":"Cogstate Limited","duties_or_roles":"Patient Material (Raters)","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Preventiongenetics LLC","duties_or_roles":"Genetic Screening","organisation_type":"Laboratory/Research/Testing facility"}
- {"country":"United States","full_name":"Kcas LLC","duties_or_roles":"Exploratory Endpoint Analysis","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Thermo Fisher Scientific Inc.","duties_or_roles":"Clinical supply","organisation_type":"Pharmaceutical company"}
- {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"United Kingdom","full_name":"Primevigilance Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Aperio Clinical Outcomes LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Scout Clinical","duties_or_roles":"Patient Reimbursement","organisation_type":"Hospital/Clinic/Other health care facility"}
- {"country":"Australia","full_name":"Redenlab Pty Limited","duties_or_roles":"Language assessments","organisation_type":"Pharmaceutical company"}
- {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"Primary / Surrogate endopoints test; Bioanalysis","organisation_type":"Pharmaceutical company"}
Investigational products
- Investigational Product Name
- DNL593
- Active Substance
- DNL593
- Modality
- Peptide/protein/enzyme
- Routes Of Administration
- Intravenous
- Route
- Intravenous
- Authorisation Status
- Investigational; MIA DE_BW_01_MIA_2021_0139 (as provided in product information)
- Investigational Product Name
- DNL593 Placebo, Sterile lyophilisate in single-dose glass vials
- Modality
- Other
- Authorisation Status
- Placebo (not applicable)
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