Clinical trial • Phase II/III • Neurology|Rare Disease
Iduronate-2-sulfatase fused to a Fc polypeptide that binds to the human transferrin receptor for Mucopolysaccharidosis Type II | Hunter syndrome
Phase II/III trial of Iduronate-2-sulfatase fused to a Fc polypeptide that binds to the human transferrin receptor for Mucopolysaccharidosis Type II | Hun…
Overview
- Trial Therapeutic Area
- Neurology|Rare Disease
- Trial Disease
- Mucopolysaccharidosis Type II | Hunter syndrome
- Trial Stage
- Phase II/III
- Drug Modality
- Peptide/protein/enzyme
- Paediatric Trial
- Yes
Key dates
- Initial CTIS Submission Date
- 15-10-2024
- First CTIS Authorization Date
- 15-11-2024
Trial design
Randomised, comparator arms: idursulfase (elaprase) 0.5 mg/kg weekly (iv) — cohort a: 0.5 mg/kg weekly for 96 weeks; cohort b: 0.5 mg/kg weekly for 48 weeks. investigational arm: dnl310 (iduronate-2-sulfatase fused to an fc polypeptide that binds to the human transferrin receptor) 15 mg/kg weekly (iv) — cohort a: 15 mg/kg weekly for 96 weeks; cohort b: 15 mg/kg weekly for 48 weeks.-controlled Phase II/III trial in Netherlands, Germany, France and others.
- Randomised
- Yes
- Comparator
- Comparator arms: Idursulfase (Elaprase) 0.5 mg/kg weekly (IV) — Cohort A: 0.5 mg/kg weekly for 96 weeks; Cohort B: 0.5 mg/kg weekly for 48 weeks. Investigational arm: DNL310 (iduronate-2-sulfatase fused to an Fc polypeptide that binds to the human transferrin receptor) 15 mg/kg weekly (IV) — Cohort A: 15 mg/kg weekly for 96 weeks; Cohort B: 15 mg/kg weekly for 48 weeks.
- Target Sample Size
- 32
- Trial Duration For Participant
- 672 (Cohort A); 336 (Cohort B)
Eligibility
Recruits 32 paediatric patients.
- Vulnerable Population
- The trial includes vulnerable pediatric participants (age cohorts include participants aged ≥2 to <6 years and ≥6 to <26 years). Age-specific assent and consent procedures are provided: multiple pediatric assent forms and parental/guardian consent (parental ICFs) are listed for different age ranges (e.g. 2-6 years, 7-10 years, 11-13 years, 14-16 years, 12-17 years, 15-17 years). Subject information and informed consent forms and caregiver/parental documents are available in multiple country/language-specific versions (documents present for Dutch, German, French, Italian, Czech, Swedish, Spanish, English). Guardians/legal representatives provide consent for minors; assent is obtained from children per the age-specific assent documents.
Inclusion criteria
- {"criterion_text":"- Participants aged ≥2 to <6 years (Cohort A) or ≥6 to <26 years (Cohort B)"}
- {"criterion_text":"- Confirmed diagnosis of MPS II (for Cohort A, nMPS II; for Cohort B, nnMPS II)"}
- {"criterion_text":"- For non-run-in Cohort A and Cohort B only: Be on maintenance ERT and have tolerated a minimum of 4 months (ie, 16 weeks) of idursulfase therapy during the period immediately prior to screening."}
Exclusion criteria
- {"criterion_text":"- Have documented pathogenic or likely pathogenic variants that are known to cause developmental delay or decline, cognitive dysfunction, seizures, or other significant CNS disorders."}
- {"criterion_text":"- Previously received an IDS gene therapy or stem cell therapy"}
- {"criterion_text":"- Received any CNS-targeted MPS ERT within 6 months prior to screening"}
- {"criterion_text":"- Have a contraindication for lumbar punctures and/or magnetic resonance imaging (MRIs)"}
- {"criterion_text":"- 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"}
Endpoints
Primary endpoints
- {"endpoint_text":"- Ratio to baseline in CSF HS concentration at Week 24 (Cohort A)","definition_or_measurement_approach":"CSF concentration of heparan sulfate (HS) measured and reported as ratio to baseline at Week 24 to evaluate CNS activity of DNL310 vs idursulfase in nMPS II participants."}
- {"endpoint_text":"- Change from baseline in the Vineland-3 at Week 96 (Cohort A)","definition_or_measurement_approach":"Change from baseline in adaptive behaviour assessed by the Vineland-3 instrument at Week 96 to evaluate clinical CNS efficacy."}
Secondary endpoints
- {"endpoint_text":"- Change from baseline in the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at Week 96 (Cohort A only)","definition_or_measurement_approach":"Change from baseline in BSID-III cognitive domain at Week 96 (Cohort A only) to evaluate neurocognitive development."}
- {"endpoint_text":"- Change from baseline in the Vineland-3 ABC score at Week 96 (Cohort A only)","definition_or_measurement_approach":"Change from baseline in Vineland-3 ABC score at Week 96 (Cohort A only)."}
- {"endpoint_text":"- Ratio to baseline in serum NfL at Week 96 (Cohort A only)","definition_or_measurement_approach":"Serum neurofilament light (NfL) level reported as ratio to baseline at Week 96 (Cohort A only)."}
- {"endpoint_text":"- Change from baseline in distance walked (meters) in the 6MWT at Week 48 (Cohort B only)","definition_or_measurement_approach":"Change from baseline in distance walked (meters) in the 6-minute walk test at Week 48 (Cohort B only)."}
- {"endpoint_text":"- Ratio to baseline in the sum of urine HS and DS concentrations (normalized to creatinine) at Week 24 (Cohorts A and B)","definition_or_measurement_approach":"Urine HS plus DS concentrations normalized to creatinine, reported as ratio to baseline at Week 24 (Cohorts A and B)."}
- {"endpoint_text":"- Ratio to baseline in the sum of urine HS and DS concentrations (normalized to creatinine) at Week 48 (Cohorts A and B)","definition_or_measurement_approach":"Urine HS plus DS concentrations normalized to creatinine, reported as ratio to baseline at Week 48 (Cohorts A and B)."}
- {"endpoint_text":"- Liver volume within the normal range (normal vs abnormal) as measured by magnetic resonance imaging (MRI) at Week 48 (Cohorts A and B)","definition_or_measurement_approach":"Liver volume assessed by MRI at Week 48 and categorised as within normal range vs abnormal (Cohorts A and B)."}
- {"endpoint_text":"- Spleen volume within the normal range (normal vs abnormal) as measured by MRI at Week 48 (Cohorts A and B)","definition_or_measurement_approach":"Spleen volume assessed by MRI at Week 48 and categorised as within normal range vs abnormal (Cohorts A and B)."}
- {"endpoint_text":"- Improvement in Parent/Caregiver Global Impression of Change (CaGI-C) Overall MPS II at Week 48 (Cohorts A and B)","definition_or_measurement_approach":"Parent/Caregiver Global Impression of Change (CaGI-C) overall assessment of MPS II at Week 48 (Cohorts A and B)."}
Recruitment
- Planned Sample Size
- 32
- Recruitment Window Months
- 70
- Consent Approach
- Informed consent is obtained from parents/legal representatives for minors; age-appropriate assent is obtained from pediatric participants according to age-specific assent documents. Multiple country/language-specific Subject Information Sheets and Informed Consent Forms (ICFs) and assent forms are provided (documents listed for Dutch, German, French, Italian, Czech, Swedish, Spanish, English). Caregiver/parental ICFs and separate pediatric assent forms are provided per documented age bands.
Methods
- Clinic posters displayed at participating sites (country-specific clinic posters listed in recruitment documents).
- Caregiver letters and caregiver brochures provided to parents/guardians (country-specific caregiver brochures/letters present).
- Clinical trial posting information and local recruitment arrangements documents provided at site level (country-specific Clinical Trial Posting Information documents).
- Informed-consent flip-charts and site informational materials for caregivers and participants made available at sites.
Geography
- Total Number Of Sites
- 12
- Total Number Of Participants
- 32
Netherlands
- Latest Decision Or Authorization Date
- 03-12-2024
- Number Of Sites
- 1
- Number Of Participants
- 3
Sites
- Site Name
- Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
- Department Name
- Centre for lysosomal and metabolic disease, Paediatrics
- Principal Investigator Name
- Hannerieke van den Hout
- Principal Investigator Email
- j.vandenhout@erasmusmc.nl
- Contact Person Name
- Hannerieke van den Hout
- Contact Person Email
- j.vandenhout@erasmusmc.nl
Germany
- Latest Decision Or Authorization Date
- 19-11-2024
- Number Of Sites
- 3
- Number Of Participants
- 10
Sites
- Site Name
- University Medical Center Hamburg-Eppendorf
- Department Name
- Klinik und Poliklinik für Kinder- und Jugendmedizin
- Principal Investigator Name
- Nicole Maria Muschol
- Principal Investigator Email
- muschol@uke.de
- Contact Person Name
- Nicole Maria Muschol
- Contact Person Email
- muschol@uke.de
- Site Name
- SphinCS GmbH
- Principal Investigator Name
- Eugen Mengel
- Principal Investigator Email
- eugen.mengel@sphincs.de
- Contact Person Name
- Eugen Mengel
- Contact Person Email
- eugen.mengel@sphincs.de
- Site Name
- Kommunale Traegergesellschaft Cottbus mbH
- Department Name
- Klinik für Kinder- und Jugendmedizin
- Principal Investigator Name
- Simone Stolz
- Principal Investigator Email
- S.Stolz@mul-ct.de
- Contact Person Name
- Simone Stolz
- Contact Person Email
- S.Stolz@mul-ct.de
France
- Latest Decision Or Authorization Date
- 19-11-2024
- Number Of Sites
- 1
- Number Of Participants
- 3
Sites
- Site Name
- Centre Hospitalier Universitaire De Lille
- Department Name
- Centre de référence - Maladies Héréditaires du Métabolisme de l'enfant et de l'adulte
- Principal Investigator Name
- Anne-Sophie GUEMANN
- Principal Investigator Email
- annesophie.guemann@chru-lille.fr
- Contact Person Name
- Anne-Sophie GUEMANN
- Contact Person Email
- annesophie.guemann@chru-lille.fr
Italy
- Latest Decision Or Authorization Date
- 25-11-2024
- Number Of Sites
- 1
- Number Of Participants
- 3
Sites
- Site Name
- Azienda Sanitaria Universitaria Friuli Centrale
- Department Name
- Centro di Coordinamento Regionale per le Malattie Rare
- Principal Investigator Name
- Maurizio Scarpa
- Principal Investigator Email
- Maurizio.scarpa@asufc.sanita.fvg.it
- Contact Person Name
- Maurizio Scarpa
- Contact Person Email
- Maurizio.scarpa@asufc.sanita.fvg.it
Czechia
- Latest Decision Or Authorization Date
- 15-11-2024
- Number Of Sites
- 1
- Number Of Participants
- 4
Sites
- Site Name
- Vseobecna Fakultni Nemocnice V Praze
- Department Name
- Klinika dětského a dorostového lékařství
- Principal Investigator Name
- Martin Magner
- Principal Investigator Email
- martin.magner@vfn.cz
- Contact Person Name
- Martin Magner
- Contact Person Email
- martin.magner@vfn.cz
Belgium
- Latest Decision Or Authorization Date
- 25-11-2024
- Number Of Sites
- 2
- Number Of Participants
- 3
Sites
- Site Name
- UZ Brussel
- Department Name
- Kinderneurologie
- Principal Investigator Name
- Luc Régal
- Principal Investigator Email
- luc.regal@uzbrussel.be
- Contact Person Name
- Luc Régal
- Contact Person Email
- luc.regal@uzbrussel.be
- Site Name
- Antwerp University Hospital
- Department Name
- Kinderneurologie
- Principal Investigator Name
- François Eyskens
- Principal Investigator Email
- francois.eyskens@uza.be
- Contact Person Name
- François Eyskens
- Contact Person Email
- francois.eyskens@uza.be
Spain
- Latest Decision Or Authorization Date
- 15-11-2024
- Number Of Sites
- 2
- Number Of Participants
- 4
Sites
- Site Name
- Hospital Universitari Vall D Hebron
- Department Name
- Pediatric
- Principal Investigator Name
- Mireia Del Toro Riera
- Principal Investigator Email
- mireia.deltoro@vallhebron.cat
- Contact Person Name
- Mireia Del Toro Riera
- Contact Person Email
- mireia.deltoro@vallhebron.cat
- Site Name
- Hospital Infantil Universitario Nino Jesus
- Department Name
- Pediatric
- Principal Investigator Name
- Laura López Marin
- Principal Investigator Email
- llopezm@salud.madrid.org
- Contact Person Name
- Laura López Marin
- Contact Person Email
- llopezm@salud.madrid.org
Sweden
- Latest Decision Or Authorization Date
- 15-11-2024
- Number Of Sites
- 1
- Number Of Participants
- 2
Sites
- Site Name
- Queen Silvia Childrens Hospital - Sahlgrenska University Hospital - Vaestra Goetalandsregionen
- Department Name
- Prövningsenhet barn, Vitaminvägen 21 416 50 Gothenburg, Sweden
- Principal Investigator Name
- Niklas Darin
- Principal Investigator Email
- niklas.darin@vgregion.se
- Contact Person Name
- Niklas Darin
- Contact Person Email
- niklas.darin@vgregion.se
Sponsor
Primary sponsor
- Full Name
- Denali Therapeutics Inc.
- Organisation Type
- Pharmaceutical company
- Country Of Registered Address
- United States
Contract research organisations
- Name
- PPD Development LP
- Responsibilities
- Operational and clinical trial support (duties codes: 1,11,12,13,5,8,9)
- Name
- Clario
- Responsibilities
- Site scales management certification and central patient questionnaires evaluation
- Name
- IQVIA Limited
- Responsibilities
- Interactive Response Technology (IRT) support / global helpdesk
Third parties
- {"country":"United States","full_name":"Evidera Inc.","duties_or_roles":"patients interviews after patient is enrolled","organisation_type":"Pharmaceutical company"}
- {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"code:14","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Clario","duties_or_roles":"site scales management certification and central patient questionnaires evaluation","organisation_type":"Industry"}
- {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"codes:1,11,12,13,5,8,9","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Trulab","duties_or_roles":"code:7","organisation_type":"Industry"}
- {"country":"United Kingdom","full_name":"Primevigilance Limited","duties_or_roles":"code:8","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"The Tova Co.","duties_or_roles":"Site ToVA certification and central patient ToVA evaluation","organisation_type":"Non-Pharmaceutical company"}
- {"country":"United States","full_name":"IQVIA Limited","duties_or_roles":"code:3 (IRT support)","organisation_type":"Industry"}
- {"country":"United States","full_name":"Aperio Clinical Outcomes LLC","duties_or_roles":"code:7","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"PK/ADA testing; code:4","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Greenwood Genetic Center Inc.","duties_or_roles":"uGAG, IDS Testing; code:4","organisation_type":"Laboratory/Research/Testing facility"}
- {"country":"United States","full_name":"Frontage Laboratories Inc.","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Medical image analysis/ review - ECG, spirometry, MRI, Echo","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"AGMedNet","duties_or_roles":"code:6","organisation_type":"Industry"}
- {"country":"United States","full_name":"TruTechnologies","duties_or_roles":"code:7","organisation_type":"Industry"}
- {"country":"United States","full_name":"Preventiongenetics LLC","duties_or_roles":"Genotyping","organisation_type":"Laboratory/Research/Testing facility"}
- {"country":"United States","full_name":"Labconnect LLC","duties_or_roles":"code:4","organisation_type":"Laboratory/Research/Testing facility"}
Investigational products
- Investigational Product Name
- DNL310 (sponsor code DNL310)
- Active Substance
- Iduronate-2-sulfatase fused to a Fc polypeptide that binds to the human transferrin receptor
- Modality
- Peptide/protein/enzyme
- Routes Of Administration
- Intravenous use
- Route
- Intravenous
- Authorisation Status
- Investigational (not marketed)
- Starting Dose
- 15 mg/kg
- Dose Levels
- 15 mg/kg (weekly)
- Frequency
- Weekly
- Maximum Dose
- Max daily dose amount field: 15 mg/kg; maxTotalDoseAmount: 1440 (as reported in product data)
- Investigational Product Name
- Elaprase (idursulfase)
- Active Substance
- Idursulfase
- Modality
- Peptide/protein/enzyme
- Routes Of Administration
- Intravenous use
- Route
- Intravenous
- Authorisation Status
- Marketing authorisation (EU) - Elaprase (EU marketing authorisation listed)
- Starting Dose
- 0.5 mg/kg
- Dose Levels
- 0.5 mg/kg (weekly)
- Frequency
- Weekly
- Maximum Dose
- Max daily dose amount field: 0.5 mg/kg; maxTotalDoseAmount: 48 (as reported in product data)
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