Clinical Trials Register

Summary
EudraCT Number:	2021-005733-16
Sponsor's Protocol Code Number:	DNLI-H-0001
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2022-06-22
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2021-005733-16

A.3

Full title of the trial

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

Multicentrické, randomizované, placebem kontrolované, dvojitě zaslepené klinické hodnocení fáze 1/2, s jednou dávkou a opakovanými dávkami, hodnotící bezpečnost, snášenlivost, farmakokinetiku a farmakodynamiku přípravku DNL593 u zdravých účastníků a účastníků s frontotemporální demencí s navazující odslepenou fází

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A 3 Part first-in-human study of DNL593 in healthy volunteers and patients with frontotemporal dementia (FTD)

První klinické hodnocení přípravku DNL593 s účastí lidí u zdravých dobrovolníků a pacientů s frontotemporální demencí (FTD)

A.3.2

Name or abbreviated title of the trial where available

Part B, C of first in human study of DNL593 in healthy volunteers & FTD patients

A.4.1

Sponsor's protocol code number

DNLI-H-0001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Denali Therapeutics Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Denali Therapeutics Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Denali Therapeutics Inc.
B.5.2	Functional name of contact point	Denali Therapeutics Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	161 Oyster Point Blvd.
B.5.3.2	Town/ city	South San Francisco
B.5.3.3	Post code	CA 94080
B.5.3.4	Country	United States
B.5.6	E-mail	clinical-trials@dnli.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	DNL593 Sterile Lyophilisate
D.3.2	Product code	DNL593
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	N/A
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	DNL593
D.3.9.3	Other descriptive name	DNL593
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	37.00 to 43.00
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Frontotemporal Dementia (FTD)

E.1.1.1

Medical condition in easily understood language

FTD - condition of the brain associated with loss of brain cells, affecting behaviour, judgement, language, memory
and motor skills

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10068968
E.1.2	Term	Frontotemporal dementia
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part B
- To investigate the safety and tolerability of multiple doses of DNL593 in participants with FTD-GRN.
Part C
- To investigate the safety and tolerability of multiple doses of DNL593 in participants with FTD-GRN up to 18 months.

E.2.2

Secondary objectives of the trial

Part B
- To characterize the serum PK of DNL593 following multiple doses of DNL593 in participants with FTD-GRN.
- To characterize the concentration of DNL593 in CSF following multiple doses in participants with FTD-GRN.
Part C
- To characterize the serum PK of DNL593 following multiple doses of DNL593 in participants with FTD-GRN.
- To characterize the concentration of DNL593 in CSF following multiple doses of DNL593 in participants with FTDGRN.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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.
• 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 118-month OLE if the participant has no unresolved clinically significant TEAEs, where continued dosing may represent a risk to participant safety.

E.4

Principal exclusion criteria

Part B
• 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

For full exclusion criterion for Part B, please refer to Section 5.1.2.2 of the protocol.

E.5 End points

E.5.1

Primary end point(s)

1. Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs)
2. Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values
3. Change from baseline in vital sign measurements: systolic and diastolic blood pressure
4. Change from baseline in vital sign measurements: heart rate
5. Change from baseline in vital sign measurements: respiratory rate
6. Change from baseline in vital sign measurements: body temperature
7. Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals
8. Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings
9. Change from baseline in Columbia-Suicide Severity Rating Scale (CSSRS; Parts B and C only)

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to 18 months

E.5.2

Secondary end point(s)

1. PK Parameter: Maximum concentration (Cmax) of DNL593 in serum
2. PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum
3. PK Parameter: Area under the concentration-time curve (AUC) from time zero to time of last measurable concentration (AUClast) of DNL593
in serum
4. PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum
5. PK Parameter: AUC from time zero to infinity (AUC∞) of DNL593 in serum (Part A only)
6. PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only)
7. PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only)
8. PK Parameter: AUC from time 0 to the end of the dosing interval (AUCτ) of DNL593 in serum (Parts B and C only)
9. Concentration of DNL593 in cerebrospinal fluid (CSF)
10. DNL593 CSF: serum concentration ratio

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to 18 months

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Brazil

Colombia

United States

France

Netherlands

Spain

Czechia

Italy

Belgium

Portugal

Turkey

United Kingdom

Serbia

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients with FTD with appointed study partner as an authorized representative to provide consent

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Not applicable as this is an experimental therapy - following completion of the post-study follow up visit, all participants
will be discharged from the study provided that the Investigator deems it appropriate to do so.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2023-03-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-07-13

P. End of Trial
P.	End of Trial Status	Completed

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials