A Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of DNL310 in Pediatric Participants with Hunter Syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Denali Therapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

22 Jun 2021 → 13 May 2026

Decision date (initial)

2024-06-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Denali Therapeutics Inc.

External identifiers

EU CT number

2023-508619-22-00

EudraCT number

2019-004909-27

ClinicalTrials.gov

NCT04251026

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Pharmacokinetic, Pharmacodynamic, Safety

To characterize the safety and tolerability of DNL310 in pediatric participants with MPS II (all cohorts)

Secondary objectives 6

1. To characterize the CNS effects of DNL310 on heparan sulfate (HS) concentrations in cerebrospinal fluid (CSF) (all cohorts)
2. To characterize the CNS effects of DNL310 on adaptive behaviors as assessed by the Vineland Adaptive Behavior Scale (all cohorts)
3. To characterize the PK of once-weekly intravenous (IV) infusions of DNL310 in serum (all cohorts)
4. To characterize immunogenicity of DNL310 in serum (all cohorts)
5. To characterize the peripheral effects of DNL310 on HS concentrations in urine (all cohorts)
6. To characterize the peripheral effects of DNL310 on liver volume as measured by magnetic resonance imaging (MRI)

Conditions and MedDRA coding

Hunter Syndrome (Mucopolysaccharidosis Type II [MPS II])

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002845-PIP01-20

Plan to share IPD

No

IPD plan description

Is stated in ClinicalTrial.gov.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Confirmed diagnosis of MPS II
2. Cohort A: Participants aged ≥5 to ≤10 years with neuronopathic MPS II
3. Cohort B: Participants aged ≥ 1 to ≤ 18 years with non-neuronopathic, neuronopathic MPSII or unknown phenotype
4. Cohort C:Participants aged < 4 years with neuronopathic MPS II (this cohort can include participants ≥4 to ≤18 years of age if the participant is a blood relative with the same genetic mutation as a participant aged < 4 years who will be enrolled in the study)
5. Cohort D: Participants aged ≤ 18 years, with nMPS II and nnMPS II and preexisting hepatomegaly, who have never taken standard-of-care ERT
6. Cohort E: neuronopathic MPS II participants aged ≥6 years at screening, non-neuronopathic MPS II participants <6 or ≥17 years at screening, and neuronopathic MPS II participants ≥1 to ≤18 years at screening with a history of prior haematopoietic stem cell transplantation or gene therapy who have completed at least 48 weeks in Study DNLI-E-0001
7. For participants receiving intravenous iduronate 2-sulfatase (IDS) ERT, tolerated a minimum of 4 months of therapy during the period immediately prior to screening.

Exclusion criteria 9

1. Unstable or poorly controlled medical condition(s) or significant medical or psychological comorbidity or comorbidities 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 within 3 months before study start for participants aged ≥5 years, and within 6 months before study start for participants aged <5 years.
3. Use of IDS gene therapy or stem cell therapy at any time (except for participants in Cohort E)
4. Clinically significant thrombocytopenia, other clinically significant coagulation abnormality, or significant active bleeding, or required treatment with an anticoagulant or more than two antiplatelet agents
5. Contraindication for lumbar punctures
6. Have a clinically significant history of stroke, status epilepticus, head trauma with loss of consciousness, or any CNS disease that is not MPS II-related within 1 year of screening
7. 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
8. Have any clinically significant CNS trauma or disorder that, in the opinion of the investigator, may interfere with assessment of study endpoints or make participation in the study unsafe
9. Have clinically significant anemia

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Incidence and severity of treatment-emergent adverse events (TEAEs) throughout the 24-week study period, the safety extension (Week 104), the open-label extension (Week 261), and across the study
2. Incidence and severity of infusion-related reactions (IRRs) throughout the 24-week study period, the safety extension (Week 104), the open-label extension (Week 261), and across the study
3. Change from baseline in urine total glycosaminoglycan (GAG) concentration throughout the 24-week study period, the safety extension (Week 104), the open-label extension (Week 261), and across the study
4. Change from baseline in concomitant medication throughout the 24-week study period, the safety extension (Week 104), the open-label extension (Week 261), and across the study

Secondary endpoints 14

1. Percent change from baseline in cerebrospinal fluid (CSF) of heparan sulfate [Time Frame:24 weeks]
2. Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale Adaptive Behavior Composite (ABC) score [Time Frame: 49 weeks]
3. Participants with improvement in individual disease progression in the Vineland Adaptive Behavior Scale subdomain scores [Time Frame: 49 weeks]
4. PK parameter: Maximum observed concentration (Cmax) of DNL310 in serum [Time Frame: 24 weeks]
5. PK parameter: Trough concentration (Cmin) of DNL310 in serum [Time Frame: 24 weeks]
6. PK parameter: Time to maximum observed concentration (tmax) of DNL310 in serum [Time Frame: 24 weeks]
7. PK parameter: Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of DNL310 in serum [Time Frame: 24 weeks]
8. PK parameter: Area under the concentration-time curve from time zero to infinity (AUC∞) of DNL310 in serum [Time Frame: 24 weeks]
9. PK parameter: Area under the concentration-time curve over a dosing interval (AUCτ) of DNL310 in serum [Time Frame: 24 weeks]
10. PK parameter: Apparent terminal elimination half-life (t½) of DNL310 in serum [Time Frame: 24 weeks]
11. Characterization of immunogenicity of DNL310 in serum, as measured by the incidence of anti-drug antibodies (ADAs) relative to baseline [Time Frame: 24 weeks]
12. Percent change from baseline in urine concentration of heparan sulfate (HS) [Time Frame: 24 weeks]
13. Participants with liver volume in the normal range [Time Frame: 24 weeks and 49 weeks]
14. Percentage change form baseline in liver volume [Time Frame: 24 weeks and 49 weeks]

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Denali Therapeutics Inc.

Sponsor organisation

Denali Therapeutics Inc.

Address

161 Oyster Point Boulevard

City

South San Francisco

Postcode

94080-2042

Country

United States

Scientific contact point

Organisation

Denali Therapeutics Inc.

Contact name

Clinical Trials Group at Denali

Public contact point

Organisation

Denali Therapeutics Inc.

Contact name

Clinical Trials Group at Denali

Third parties 11

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 28 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications