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    Summary
    EudraCT Number:2019-004909-27
    Sponsor's Protocol Code Number:DNLI-E-0002
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-05-01
    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 ConcernedUK - MHRA
    A.2EudraCT number2019-004909-27
    A.3Full title of the trial
    A PHASE 1/2, MULTICENTER, OPEN-LABEL STUDY TO DETERMINE THE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF DNL310 IN PEDIATRIC SUBJECTS WITH HUNTER SYNDROME
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    STUDY TO EVALUATE THE SAFETY AND ESTABLISH A SAFE DOSE OF DNL310 IN PEDIATRIC SUBJECTS WITH HUNTER SYNDROME
    A.4.1Sponsor's protocol code numberDNLI-E-0002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04251026
    A.5.4Other Identifiers
    Name:139904Number:IND Number
    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 pointDNLI 310 Clinical Operations Group
    B.5.3 Address:
    B.5.3.1Street Address161 Oyster Point Blvd
    B.5.3.2Town/ citySouth San Francisco,
    B.5.3.3Post codeCA 94080
    B.5.3.4CountryUnited States
    B.5.6E-mailDNL310Inquiries-team@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 Drug Substance
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Yes
    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 INNNot applicable
    D.3.9.2Current sponsor codeAlso 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 Yes
    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
    Hunter Syndrome (Mucopolysaccharidosis Type II [MPS II])
    E.1.1.1Medical condition in easily understood language
    Hunter Syndrome
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10056917
    E.1.2Term Hunter's syndrome
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the safety and tolerability of DNL310 in paediatric subjects with MPS II
    E.2.2Secondary objectives of the trial
    To characterize the effects of DNL310 on Hunter Syndrome (HS) concentrations in CSF
    • To characterize the PK of once-weekly IV infusions of DNL310 in serum
    • To characterize immunogenicity of DNL310 in serum
    • To characterize the effects of DNL310 on HS concentrations in urine
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Informed consent signed by the subject, if able to legally provide consent, or signed by the parent(s) or LAR and subject assent if required based on local regulations, Ethics Committee (EC), and subject age
    2) Body weight at screening as follows:
    • Cohort A: ≥ 19 kg
    • Cohort B: ≥ 10 kg
    3) Age at study entry as follows:
    • Cohort A (first 4 subjects): nMPS II subjects aged 5 to 10 years, inclusive, at screening
    • Cohort B: subjects aged 2 to 18 years, inclusive, at screening, after DMC recommendation and MHRA approval to expand both the age range and include all phenotypes of MPSII (e.g., nMPS II, non-neuronopathic, or unknown).
    Cohort B will have 3 subcohorts (B1, B2, B3) based on starting dose. Subjects will be assigned sequentially to subcohort B1, B2, and B3, but stratified by age, with the first 2 subjects aged 2 to < 5 years enrolled to B1 and a minimum of one subject aged 10 to 18 years in each group.
    4) Subject and parent(s) or LAR are willing and have the ability to comply with protocol requirements, according to the investigator’s judgment
    5) Male subjects with a confirmed diagnosis of MPS II based on the following:
    • Reduced IDS activity in plasma, white blood cells, and/or skin fibroblasts consistent with MPS II (≤ 10% of the lower limit of the normal range, based on the testing laboratory’s range), and
    • A documented mutation in the IDS gene
    6) Subjects enrolled prior to DMC and MHRA approval of enrolling non-neuronopathic subjects must have nMPS II based on at least one of the following:
    • Cognitive ability standard score ≤ 85 at the screening assessment and/or a documented decline of at least 7.5 points in the standard score in the previous 6 to 18 months based on any one of the following tests, all performed without clinically significant hearing loss or with hearing aids present:
    o BSID (BSID-III preferred; BSID-II is acceptable if BSID-III unavailable)
    o NVI of the KABC-II
    o DAS-II
    o Mullen Scales of Early Learning
    o Wechsler Preschool and Primary Scale of Intelligence IV
    • The subject has the same genetic mutation as a blood relative with confirmed nMPS II. Confirmed nMPS II requires a genetic diagnosis of MPS II and clinically established cognitive delay or regression based on a standard score of cognitive ability ≤ 85, and/or a documented decline of at least 7.5 points in the standard score in the previous 6 to 18 months based on any one of the following tests, all performed without clinically significant hearing loss or with hearing aids present:
    o BSID (BSID-III preferred; BSID-II is acceptable if BSID-III unavailable)
    o NVI of the KABC-II
    o DAS-II
    o Mullen Scales of Early Learning
    o Wechsler Preschool and Primary Scale of Intelligence IV
    • The subject has a large deletion(s) or rearrangement(s) in the IDS gene or other definitive mutation indicative of nMPS II as determined by an independent external review panel
    7) For subjects receiving IV IDS ERT (e.g., Elaprase): tolerated a minimum of 4 months of therapy during the period immediately prior to screening
    8) For subjects with hearing impairment requiring hearing aids, every effort has been made to encourage compliance with the use of functioning hearing aid(s) before baseline neurocognitive assessments, and parent/LAR or subject agrees to encourage wearing them during the study and on neurocognitive testing days.
    9) When engaging in sex with a woman of childbearing potential, both the male subject and his female partner must use highly effective contraception consisting of two forms of birth control, one of which must be a male barrier method such as a latex or polyurethane condom) from start of dosing throughout the clinical study period, and for 90 days after the final study drug administration.
    E.4Principal exclusion criteria
    1) Unstable or poorly controlled medical condition(s) or significant medical or psychological comorbidity or comorbidities) based on medical history, screening laboratory values, ECGs, or other screening procedures that, in the opinion of the investigator, would interfere with safe participation in the trial or interpretation of study assessments
    2) Use of any CNS-targeted MPS II ERT (e.g., IT IDS, transferrin- or insulin receptor–mediated IDS delivery to CNS) within 3 months before Study Day 1 for subjects aged ≥ 5 years, and within 6 months before Study Day 1 for subjects aged < 5 years. Subjects may be rescreened for this study after the appropriate washout has been completed.
    3) Use of an IDS gene therapy or stem cell therapy, including hematopoietic stem cell transplantation, at any time
    4) Use of genistein within 30 days of screening, or intended use of genistein during the study. Subjects who discontinue genistein may be rescreened after a 30-day washout has been completed.
    5) Participation in any other investigational drug trial or use of an investigational drug within 60 days prior to screening and thereafter. Subjects may rescreen for this study after the 60-day washout has been completed.
    6) Documented mutation of other genes, including loci adjacent to the IDS gene (e.g., fragile X mental retardation 1 [FMR1] or AF4/FMR2 family member 2 [i.e., AFF2 or FMR2]), that are known to be associated with developmental delay, seizures, or other significant CNS disorders
    7) Documented loss of activity of sulfatases other than IDS, indicating multiple sulfatase deficiency
    8) Clinically significant thrombocytopenia (< 100 GI/L [100,000/mm3]), other clinically significant coagulation abnormality, or significant active bleeding, or require treatment with an anticoagulant or more than two antiplatelet agents. Subjects excluded for this reason may be rescreened for this study at least 30 days after the coagulopathy, anticoagulant, or antiplatelet treatments have stopped.
    9) Contraindication for LPs, for any reason
    10) Have a clinically significant history of stroke, status epilepticus, head trauma with loss of consciousness, or any CNS disease that is not Hunter syndrome–related within 1 year of screening
    11) Have had a ventriculoperitoneal (VP) shunt placed or any other brain surgery, or have a clinically significant VP shunt malfunction within 30 days of screening. Subjects may be rescreened after the 30-day waiting period has elapsed.
    Note: subjects who have newly diagnosed intracranial hypertension (e.g., CSF opening pressure > 30 cm H2O) requiring placement of a VP shunt may rescreen 30 days after shunt placement.
    12) Have any clinically significant CNS trauma or disorder, including severe untreated intracranial hypertension, that, in the opinion of the investigator, may interfere with assessment of study endpoints or make participation in the study unsafe
    13) History of serious adverse reaction to IDS enzyme or any component of the IMP, e.g., hypersensitivity or anaphylaxis requiring hospitalization, that cannot be managed with SOC treatment for infusion reactions
    14) Have had a donation or loss of more than 10% total blood volume over 8 weeks preceding entry into the treatment period. Subjects excluded for this reason may be rescreened after the 8 weeks have elapsed.
    E.5 End points
    E.5.1Primary end point(s)
    Safety endpoints:
    • Frequency and severity of AEs, including IRRs (which include allergic reactions and anaphylaxis)
    • Vital sign measurements
    • 12-lead ECGs
    • Physical examinations, including neurological examinations
    • Safety laboratory assessments (including hematology, serum clinical chemistry, urinalysis, and coagulation)
    • Urine total GAG concentrations (normalized to creatinine)
    • Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of ADAs during the study relative to baseline
    • Use of concomitant medications
    • Liver and spleen volumes as assessed by ultrasound
    • Change from baseline in CGI-S
    • CGI-I
    • Change from baseline in PGI-S
    • PGI-I
    • Change from baseline in the total score on the ADL-HS scale
    • Change from baseline in stool consistency, per the Bristol Stool Scale
    • Change from baseline in 6MWT for subjects ≥ 6 years old who are able to follow instructions at baseline
    E.5.1.1Timepoint(s) of evaluation of this end point
    A DMC will be established to provide an ongoing review and assessment of the safety data, and to safeguard the interests and safety of the participating subjects in the study. An interim analysis for futility will be conducted to determine whether the dose should be increased or the trial should be terminated early based on lack of potential for benefit or unacceptable benefit-to-risk ratio. The analysis is planned for when at least 10 subjects have completed the study (i.e., 6 months of treatment with DNL310 or premature discontinuation from the trial).
    E.5.2Secondary end point(s)
    Pharmacodynamics and Exploratory Measures:
    • Change from baseline in CSF concentration of HS and DS
    • Change from baseline in urine concentration (normalized to creatinine) of HS and DS
    • Change from baseline in serum concentration of HS and DS
    • Change from baseline in levels of CSF biomarkers of lysosomal function (including sphingolipids, gangliosides and/or bis(monoacylglycerol)phosphate [BMP]), inflammation (including soluble triggering receptor expressed on myeloid cells 2 [sTREM2] and cytokines), and neuronal injury (including neurofilament light chain [Nf-L])
    • Change from baseline in levels of serum biomarkers of neuronal injury (including Nf-L)
    • Change from baseline in the toileting abilities percentage (TAP), defined as a percentage of the maximum score that could be achieved on the TAS
    • Change from baseline in the cognitive-domain and the language- and motor-domain age-equivalent score (AES) and standard scores on either the BSID-III or the nonverbal index (NVI) of the KABC-II
    • Change from baseline in the composite AES and standard scores on the VABS-II
    • Change from baseline in ABR parameters
    • Change from baseline in ITQOL for subjects < 5 years of age
    • Change from baseline in CHQ-PF28 for subjects ≥ 5 years of age
    • Change from baseline in PedsQL-FIM

    Pharmacokinetics endpoints may include but will not be limited to the following parameters:
    • Cmax
    • Trough concentration (Cmin)
    • Tmax
    • Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUC0–last)
    • Area under the concentration-time curve from time zero extrapolated to infinity (AUC0–∞)
    • Area under the concentration-time curve over a dosing interval (AUC0–τ)
    • Apparent terminal elimination rate constant (λz)
    • Apparent terminal elimination t1/2
    • Accumulation ratio
    E.5.2.1Timepoint(s) of evaluation of this end point
    PD and exploratory endpoints will be evaluated at the end of study (6-months of treatment) as the analysis is described as change from baseline.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    staggered cohorts design
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 EEA5
    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
    Germany
    Italy
    Netherlands
    United Kingdom
    United States
    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
    LSLV
    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 months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    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: 15
    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: 4
    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) Yes
    F.1.2.1Number of subjects for this age range: 1
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    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 No
    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
    Mentally handicaped patients age 2 to 18 at screening, may be enrolled into the study, if they satisfy all protocol eligibility criteria and their parent(s)/legal representative(s) give consent in accordance with national requirements.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 6
    F.4.2.2In the whole clinical trial 16
    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)
    Patients who complete the main and safety extension part of the study may be eligible to enrol into the long term extension trial planned by study sponsor. Patients who do not consent or are not eligible to take part in the long term safety extension study will return to their standard of care treatment under the discretion of the study doctor or patient's primary physician.
    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 Decision2020-06-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-22
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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