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    Summary
    EudraCT Number:2021-005200-35
    Sponsor's Protocol Code Number:DNLI-E-0007
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2022-05-16
    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.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2021-005200-35
    A.3Full 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
    A.3.1Title 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
    A.4.1Sponsor's protocol code numberDNLI-E-0007
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorDenali Therapeutics Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDenali Therapeutics Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDenali Therapeutics Inc.
    B.5.2Functional name of contact pointClinical Trials Group at Denali
    B.5.3 Address:
    B.5.3.1Street Address161 Oyster Point Boulevard
    B.5.3.2Town/ citySouth San Francisco
    B.5.3.3Post codeCA 94080
    B.5.3.4CountryUnited States
    B.5.6E-mailclinical-trials@dnli.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDNL310
    D.3.2Product code DNL310
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDLN310
    D.3.9.2Current sponsor codeDNL310 Drug Substance. Also referred to as: ETV:IDS Drug Substance or ETV-IDS Drug Substance
    D.3.9.3Other descriptive nameIDURONATE-2-SULFATASE FUSED TO A FC POLYPEPTIDE THAT BINDS TO THE HUMAN TRANSFERRIN RECEPTOR
    D.3.9.4EV Substance CodeSUB195572
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Idursulfase (Elaprase)
    D.2.1.1.2Name of the Marketing Authorisation holderShire Human Genetic Therapies AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameidursulfase (ELAPRASE)
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIdursulfase
    D.3.9.1CAS number 50936-59-9
    D.3.9.3Other descriptive namePurified form of the lysosomal enzyme iduronate-2-sulfatase
    D.3.9.4EV Substance CodeSUB22927
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    Mucopolysaccharidosis Type II [MPS II]
    E.1.1.1Medical condition in easily understood language
    Hunter Syndrome
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary 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
    E.2.3Trial contains a sub-study No
    E.3Principal 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. For non-run-in Cohort A and Cohort B only: be on maintenance enzyme replacement therapy (ERT) and have tolerated idursulfase for a minimum of 4 months (ie, 16 weeks) of idursulfase therapy during the period immediately prior to screening.
    E.4Principal exclusion criteria
    1. Have a documented pathogenic or likely pathogenic variants that are known to cause developmental delay or decline, cognitive dysfunction, seizures, or other significant CNS disorders.

    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
    E.5 End points
    E.5.1Primary 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
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Week 24
    2. Week 96
    E.5.2Secondary 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)
    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    Turkey
    Belgium
    Czechia
    France
    Germany
    Italy
    Netherlands
    Spain
    Sweden
    United Kingdom
    E.8.7Trial 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 or 2.5 years (for run-in participants) after the last participant is enrolled if the last participant is in Cohort A, or approximately 1 year or 1.5 years (for run-in participants) after the last participant is enrolled if the last participant is in Cohort B, whichever has the later last study visit assessment.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 54
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 43
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 11
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details 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
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 22
    F.4.2.2In the whole clinical trial 54
    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)(Study DNLI-E-0008). 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.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-06-10
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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