A Study to Determine the Efficacy and Safety of Tividenofusp Alfa (DNL310) vs Idursulfase in Pediatric and Young Adult Participants With Neuronopathic or Non Neuronopathic Mucopolysaccharidosis Type II

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 and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

11 Nov 2022 → ongoing

Decision date (initial)

2024-11-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Denali Therapeutics Inc. - Commercial

External identifiers

EU CT number

2024-510990-21-00

EudraCT number

2021-005200-35

ClinicalTrials.gov

NCT05371613

ISRCTN

ISRCTN11652897

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Pharmacokinetic, Others, Pharmacodynamic

1. To evaluate the CNS activity of DNL310 vs idursulfase as measured by the CSF concentration of HS in nMPS II participants
2. To evaluate the clinical CNS efficacy of DNL310 vs idursulfase on adaptive behavior as assessed by the Vineland-3 in nMPS II participants

Secondary objectives 6

1. To evaluate the clinical CNS efficacy of DNL310 vs idursulfase on neurocognitive development, as assessed by the BSID-III cognitive domain in nMPS II participant
2. To evaluate the clinical CNS efficacy of DNL310 vs idursulfase on adaptive behavior as assessed by the Vineland-3 ABC in nMPS II participants
3. To evaluate the efficacy of DNL310 vs idursulfase on neuronal injury in nMPS II participants
4. To evaluate the clinical efficacy of DNL310 vs idursulfase on physical endurance as measured by the 6MWT in participants with the nnMPS II
5. 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
6. 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

Conditions and MedDRA coding

Mucopolysaccharidosis Type II [MPS II]

Study design 4 periods

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, Food And Drug Administration, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002845-PIP01-20

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. Participants aged ≥2 to <6 years (Cohort A) or ≥6 to <26 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 ERT and have tolerated a minimum of 4 months (ie, 16 weeks) of idursulfase therapy during the period immediately prior to screening.

Exclusion criteria 5

1. Have 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Ratio to baseline in CSF HS concentration at Week 24 (Cohort A)
2. Change from baseline in the Vineland-3 at Week 96 (Cohort A)

Secondary endpoints 9

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 the Vineland-3 ABC score at Week 96 (Cohort A only)
3. Ratio to baseline in serum NfL at Week 96 (Cohort A only)
4. Change from baseline in distance walked (meters) in the 6MWT at Week 48 (Cohort B only)
5. Ratio to baseline in the sum of urine HS and DS concentrations (normalized to creatinine) at Week 24 (Cohorts A and B)
6. Ratio to baseline in the sum of urine HS and DS concentrations (normalized to creatinine) at Week 48 (Cohorts A and B)
7. Liver volume within the normal range (normal vs abnormal) as measured by magnetic resonance imaging (MRI) at Week 48 (Cohorts A and B)
8. Spleen volume within the normal range (normal vs abnormal) as measured by MRI at Week 48 (Cohorts A and B)
9. Improvement in Parent/Caregiver Global Impression of Change (CaGI-C) Overall MPS II at Week 48 (Cohorts A and B)

Investigational products

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

Test 1

Comparator 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

Jose Alcantara Rodriguez

Public contact point

Organisation

Denali Therapeutics Inc.

Contact name

Clinical Trials Group

Third parties 19

Locations

8 EU/EEA countries · 12 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 153 files

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

Application history

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