Clinical Trials Register

Summary
EudraCT Number:	2021-005200-35
Sponsor's Protocol Code Number:	DNLI-E-0007
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-05-12
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

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2021-005200-35

A.3

Full title of the trial

A Phase 2/3, Multicenter, Double-Blind, Randomized Study to
Determine the Efficacy and Safety of DNL310 vs Idursulfase in
Pediatric Participants With Neuronopathic or Non-Neuronopathic
Mucopolysaccharidosis Type II

Estudio de fase 2/3, multicéntrico, doble ciego y aleatorizado para determinar la eficacia y la seguridad de DNL310 frente a idursulfasa en participantes pediátricos con mucopolisacaridosis neuronopática o no neuronopática de tipo II.

A.3.1

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

Study to determine effectiveness and safety of DNL310 vs Idursulfase in
Pediatric Participants With Neuronopathic or Non-Neuronopathic Hunter Syndrome

Estudio para determinar la efectividad y seguridad de DNL310 frente a Idursulfasa en participantes pediátricos con síndrome de Hunter neuronopático o no neuronopático.

A.4.1

Sponsor's protocol code number

DNLI-E-0007

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	Angela Kay
B.5.3	Address:
B.5.3.1	Street Address	161 Oyster Point Boulevard
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.5.4	Telephone number	900834223
B.5.6	E-mail	RegistroEspanolDeEstudiosClinicos@druginfo.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	DNL310
D.3.2	Product code	DNL310
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DNL310
D.3.9.2	Current sponsor code	DNL310 Drug Substance. Also referred to as: ETV:IDS Drug Substance or ETV-IDS Drug Substance
D.3.9.3	Other descriptive name	IDURONATE-2-SULFATASE FUSED TO A FC POLYPEPTIDE THAT BINDS TO THE HUMAN TRANSFERRIN RECEPTOR
D.3.9.4	EV Substance Code	SUB195572
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
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	No
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	Idursulfase (Elaprase)
D.2.1.1.2	Name of the Marketing Authorisation holder	Shire Human Genetic Therapies AB
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	idursulfase (ELAPRASE)
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Idursulfase
D.3.9.1	CAS number	50936-59-9
D.3.9.3	Other descriptive name	Purified form of the lysosomal enzyme iduronate-2-sulfatase
D.3.9.4	EV Substance Code	SUB22927
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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	No
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Mucopolysaccharidosis Type II [MPS II]

Mucopolisacaridosis de tipo II [MPS II]

E.1.1.1

Medical condition in easily understood language

Hunter Syndrome

Síndrome de Hunter

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

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

1. To evaluate the CNS activity of DNL310 vs idursulfase as measured by the cerebrospinal fluid (CSF) concentration of heparan sulfate
(HS) in participants with the neuronopathic form of mucopolysaccharidosis type II (nMPS II)

2. To evaluate the clinical CNS efficacy of DNL310 vs idursulfase on adaptive behavior as assessed by the Vineland Adaptive Behavior Scale, Third Edition (Vineland-3), in nMPS II participants

1.Evaluar la actividad en el SNC de DNL310 en comparación con la idursulfasa determinada mediante la concentración de heparán sulfato (HS) en el líquido cefalorraquídeo (LCR) en participantes con la forma neuronopática de la mucopolisacaridosis de tipo II (MPS II-n).
2.Evaluar la eficacia clínica en el SNC de DNL310 en comparación con la idursulfasa en la conducta adaptativa evaluada mediante las Escalas de conducta adaptativa de Vineland, tercera edición (Vineland-3), en participantes con MPS II-n.

E.2.2

Secondary objectives of the trial

1. To evaluate the clinical CNS efficacy of DNL310 vs idursulfase on neurocognitive development, as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), in nMPS II participants

2. To evaluate the clinical efficacy of DNL310 vs idursulfase on physical endurance as measured by the Six-Minute Walk Test (6MWT) in participants with the nnMPS II

3. To evaluate the onset and durability of peripheral efficacy of DNL310 vs idursulfase as measured by the urine concentration of total glycosaminoglycans (GAGs) by a massspectrometry–based detection method in nMPS II and nnMPS II participants

4.To evaluate the efficacy of DNL310 vs idursulfase on liver volume and spleen volume as measured by MRI in nMPS II and nnMPS II participants

5. To evaluate the parent’s/caregiver’s assessment of efficacy of DNL310 vs idursulfase as measured by the Parent/Caregiver Global
Impression of Change (CaGI-C) in nMPS II and nnMPS II participants

1.Evaluar eficacia clínica en el SNC de DNL310 vs la idursulfasa en el desarrollo neurocognitivo, con las Escalas de Bayley de desarrollo en lactantes y niños pequeños,(BSID-III), en pacientes con MPS II-n.
2.Eficacia clínica de DNL310 vs la idursulfasa en la resistencia física medida con la prueba de marcha de seis minutos en pacientes con la forma no neuronopática de mucopolisacaridosis de tipo II.
3.Evaluar el inicio y la duración de la eficacia periférica de DNL310 vs la idursulfasa medida por la concentración urinaria de GAGs totales por un método basado en espectrometría de masas en pacientes con MPS II-n y MPS II-nn.
4.Evaluar la eficacia de DNL310 vs la idursulfasa en los volúmenes hepático y esplénico medidos por RM en participantes con MPS II-n y MPS II-nn.
5.Evaluar la evaluación de los progenitores/cuidadores de la eficacia de DNL310 vs la idursulfasa con la escala de impresión global del cambio por el progenitor/cuidador (CaGI-C) en pacientes con MPS II-n y MPS II-nn.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Participants aged ≥2 to <6 years (Cohort A) or ≥6 to <17 years (Cohort B)

2. Confirmed diagnosis of MPS II (for Cohort A, nMPS II; for Cohort B, nnMPS II)

3. Be on maintenance enzyme replacement therapy (ERT) and have tolerated idursulfase for a minimum of 4 months prior to screening

1. Participantes con edad entre ≥2 y <6 años en (Cohorte A) o entre ≥6 y <17 (Cohorte B).
2. Diagnóstico confirmado MPS II (Cohorte A, MPS II-n; Cohorte B, MPS II-nn)
3. Estar en tratamiento de reemplazo enzimático de mantenimiento y haber tolerado la idursulfasa durante al menos 4 meses antes del período de selección.

E.4

Principal exclusion criteria

1. Have a documented mutation of other genes or genetic diagnosis accounting for developmental delay

2. Previously received an IDS gene therapy or stem cell therapy

3. Received any CNS-targeted MPS ERT within 6 months prior to screening

4. Have a contraindication for lumbar punctures and/or magnetic resonance imaging (MRIs)

5. Participated in any other investigational drug study or used an investigational drug within 60 days prior to screening or intend to receive another investigational drug during the study

1.Presentar una mutación documentada de otros genes o diagnóstico genético que explique el retraso del desarrollo.
2.Recepción previa de terapia génica de IDS o tratamiento con células madre.
3.Recepción de cualquier TRE para la MPS II dirigido al SNC en los 6 meses previos a la selección.
4.Contraindicación para la realización de punciones lumbares (PL) y/o resonancias magnéticas (RM).
5.Participación en cualquier otro estudio con un fármaco en investigación o uso de un fármaco en investigación en los 60 días previos a la selección o intención de recibir otro fármaco en investigación durante el estudio.

E.5 End points

E.5.1

Primary end point(s)

1. Percent change from baseline in CSF HS concentration at Week 24 (Cohort A only)

2. Change from baseline in the Vineland-3 at Week 96 (Cohort A only)

1. Variación porcentual de la concentración de HS en el LCR basal y la semana 24 (solo en la cohorte A).

2. Variación de la puntuación ABC del instrumento Vineland-3 basal l y la semana 96 (únicamente en la cohorte A).

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Week 24
2. Week 96

1. Semana 24
2. Semana 96

E.5.2

Secondary end point(s)

1. Change from baseline in the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at Week 96 (Cohort A only)

2. Change from baseline in distance walked in
the 6MWT at Week 48 (Cohort B only)

3. Percent change from baseline in the sum of urine HS and DS concentrations at Week 48 (Cohorts A and B)

4. a) Liver volume within the normal range (normal vs abnormal) as measured by MRI at Week 48 (Cohorts A and B)
b) Spleen volume within the normal range (normal vs abnormal) as measured by MRI at Week 48 (Cohorts A and B)

5. Improvement in CaGI-C Overall MPS II at Week 48 (Cohorts A and B)

1. Variación de las Escalas de Bayley de desarrollo en lactantes y niños pequeños,(BSID-III) en la semana 96 (solo en la cohorte A).

2. Variación de la distancia recorrida en la PM6M basal y la semana 48 (únicamente en la cohorte B).

3. Variación porcentual de la suma de las concentraciones de HS y DS en la orina basal y la semana 48 (cohortes A y B).

4a. Volumen hepático dentro del intervalo normal (normal frente a anormal) determinado mediante RM en la semana 48 (cohortes A y B).
4b. Volumen esplénico dentro del intervalo normal (normal frente a anormal) determinado mediante RM en la semana 48 (cohortes A y B).

5. Mejoría en la puntuación global de la CaGI-C en la MPS II en la semana 48 (cohortes A y B).

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Week 96
2. Week 48
3. Week 48
4. a) Week 48 b) Week 48
5. Week 48

1. Semana 96
2. Semana 48
3. Semana 48
4. a) Semana 48
4. b) Semana 48
5. Semana 48

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity

Inmunogenicidad

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

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)

Yes

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

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)

Yes

E.8.2.2

Placebo

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

Argentina

Australia

Brazil

Canada

Colombia

Mexico

United States

France

Sweden

Netherlands

Spain

Czechia

Germany

Italy

Belgium

Turkey

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

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

The end of this study is defined as the date on which LPLV occurs. LPLV is expected to occur approximately 2 years after the last participant is enrolled if the last participant is in Cohort A, or approximately 1 year after the last participant is enrolled if the last participant is in Cohort B, whichever has the later last study visit assessment.

El fin de estudio se define como la fecha en la que tiene lugar la última visita del último paciente participante. La última visita del último paciente participante se espera que tenga lugar aproximadamente 2 años después de que el último pacinente se haya reclutado, si el paciente pertenece a la Cohorte A, o aproximadamente 1 año después de que el último paciente participante sea reclutado si pertenece a la Cohorte B, o el que tenga la última visita de estudio.

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

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

The parent(s) or legally authorized representative (LAR) for each participant must provide written informed consent prior to performing any study procedures

Consentimiento informado por escrito otorgado por los progenitores o por el representante legal del participante previamente a la realización de cualquier procedimiento de estudio.

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)

This study will be followed by a separate optional Open Label Extension (OLE). All participants who complete this study
(without discontinuing study intervention), provide consent, and meet the OLE eligibility criteria will be given the option to enter the OLE and receive DNL310 until it becomes commercially available or the OLE is ended by the Sponsor, as long as the investigator agrees that there are no safety or compliance concerns with ongoing access.

Este estudio será seguido por una fase opcional y separada de Extensión Abierta (OLE).Todos los participantes que completen este estudio
(sin discontinuar), y que brinden su consentimiento y cumplan con los criterios de elegibilidad, se les ofrecerá entrar en la fase OLE y recibir DNL310 hasta que esté disponible comercialmente o que el promotor finalice la fase OLE, siempre que el investigador esté de acuerdo en que no hay preocupaciones de seguridad o cumplimiento con el acceso continuo.

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

2022-08-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-07-04

P. End of Trial
P.	End of Trial Status	Ongoing

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