Tividenofusp Alfa for Hunter Syndrome

(COMPASS Trial)

Recruiting at 47 trial locations

Overseen By Clinical Trials at Denali Therapeutics

Age: < 65

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Denali Therapeutics Inc.

Must be taking: Enzyme replacement

Must not be taking: Investigational drugs

Disqualifiers: Genetic mutation, Gene therapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Phase 2/3 duration not specified

63 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called tividenofusp alfa (DNL310) for individuals with Hunter syndrome (mucopolysaccharidosis type II, or MPS II), a rare genetic disorder affecting many body parts, including the brain. The study compares DNL310's effects with standard treatments to assess its efficacy and safety. Two groups participate: one for individuals with neurological symptoms and another for those without. Participants with MPS II who haven't recently received certain treatments or have maintained a stable treatment plan might be suitable candidates. As a Phase 2, Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking advancements in MPS II treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on enzyme replacement therapy (ERT), you must have either not received it continuously for 4 months before screening or be on maintenance ERT and have tolerated idursulfase for at least 4 months before screening.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that tividenofusp alfa, also known as DNL310, appears safe for treating Hunter Syndrome (MPS II). In long-term studies, patients tolerated the treatment well, with no serious side effects reported. Early results also indicated that tividenofusp alfa significantly lowered disease markers in the brain and other parts of the body.

While the FDA takes more time to review this treatment, ongoing studies continue to provide important safety information. Since tividenofusp alfa is used in clinical trials for a serious condition like Hunter Syndrome, researchers closely monitor it for any possible risks, ensuring patient safety remains a top priority. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about DNL310 for Hunter Syndrome because it offers a new approach by targeting the underlying cause of the disease. Unlike current treatments like idursulfase, which primarily replace the missing enzyme, DNL310 is engineered to cross the blood-brain barrier and potentially address neurological symptoms. This innovative mechanism could significantly improve the quality of life for patients by reaching areas of the body that existing therapies can't effectively target.

What evidence suggests that this trial's treatments could be effective for Hunter Syndrome?

Research has shown that tividenofusp alfa, also known as DNL310, may help treat Hunter syndrome (MPS II). Early results indicate it significantly lowers disease markers in the brain and body, suggesting it could address the disease's root cause. This treatment replaces the missing or faulty enzyme in people with MPS II, potentially improving their condition. Participants in this trial may receive either DNL310 or idursulfase, another treatment option. These initial findings offer promise for those considering participation in clinical trials. ^{3 5 6 7 8}

Who Is on the Research Team?

Jose Alcantara Rodriguez, PharmD

Principal Investigator

Denali Therapeutics Inc.

Are You a Good Fit for This Trial?

This trial is for kids with Hunter Syndrome (MPS II), aged 2-6 or 6-17, depending on the group. They must have been treated with idursulfase for at least 4 months. Kids can't join if they've had gene or stem cell therapy for MPS, are unable to undergo lumbar punctures/MRIs, received CNS-targeted ERT recently, or participated in other drug trials within the last 60 days.

Inclusion Criteria

I have been diagnosed with MPS II.

I am between 2 and 17 years old.

I have been on enzyme replacement therapy and tolerated idursulfase for at least 4 months.

Exclusion Criteria

I haven't had CNS-targeted enzyme replacement therapy in the last 6 months.

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

I have had gene or stem cell therapy for my condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either tividenofusp alfa (DNL310) or idursulfase in a double-blind, randomized manner

Phase 2/3 duration not specified

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants may opt into continuation of treatment with DNL310 or idursulfase based on pre-specified criteria

What Are the Treatments Tested in This Trial?

Interventions

• DNL310
• Idursulfase

Trial Overview The study compares Tividenofusp Alfa (DNL310), a new treatment that reaches the brain better than current therapies, against Idursulfase, which is standard care. It's randomized and double-blind meaning neither participants nor researchers know who gets which treatment until after results are collected.

How Is the Trial Designed?

Group I: Open-label Treatment Phase Experimental Treatment 2 Interventions

Participants who meet pre-specified criteria may receive DNL310 or idursulfase

Group II: Cohort B: Participants with nnMPS II Experimental Treatment 2 Interventions

Group III: Cohort A: Participants with nMPS II Experimental Treatment 2 Interventions

Who Is Running the Clinical Trial?

Denali Therapeutics Inc.

Lead Sponsor

Trials

24

Recruited

1,900+

Published Research Related to This Trial

Pabinafusp alfa, a novel treatment for Hunter syndrome, successfully crosses the blood-brain barrier and has shown a significant reduction in glycosaminoglycan (GAG) accumulation in cerebrospinal fluid, indicating its potential effectiveness in treating central nervous system symptoms associated with the disease.

In a 26-week phase 2 study involving MPS-II patients in Brazil, the 2.0 mg/kg dosage of pabinafusp alfa demonstrated the best safety and efficacy profile, with positive neurocognitive signals observed despite the short duration of the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil. Giugliani, R., Martins, AM., So, S., et al.[2022]

Intrathecal administration of iduronate-2-sulfatase in cynomolgus monkeys showed significantly better penetration into the cerebrospinal fluid compared to intravenous delivery, indicating it may effectively target the central nervous system manifestations of Hunter syndrome.

The study demonstrated a proportional dose/exposure relationship for intrathecal iduronate-2-sulfatase, with systemic bioavailability ranging from 40-83%, suggesting that this method could enhance treatment efficacy for neurological symptoms associated with the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and bioavailability of a therapeutic enzyme (idursulfase) in cynomolgus monkeys after intrathecal and intravenous administration. Xie, H., Chung, JK., Mascelli, MA., et al.[2018]

Idursulfase (Elaprase) is the first approved enzyme replacement therapy for Hunter syndrome, showing significant benefits in a phase II/III clinical trial, including increased walking distance, improved pulmonary function, and reduced organ size and urinary glycosaminoglycans (GAGs) excretion in patients.

The treatment is generally well tolerated, although some patients may experience infusion reactions, marking idursulfase as a promising symptomatic therapy that addresses the underlying enzymatic deficiency in Hunter syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Idursulfase in Hunter syndrome treatment. Zareba, G.[2017]

In a phase I/II trial involving 31 patients with MPS II, treatment with idursulfase beta resulted in a significant reduction of urinary glycosaminoglycan (GAG) levels, indicating effective clearance of the accumulated substance associated with the disorder.

Idursulfase beta also improved endurance as shown by the 6-minute walk test, and it was generally safe with manageable side effects, primarily mild skin reactions that were easily treated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter syndrome). Sohn, YB., Cho, SY., Park, SW., et al.[2021]

Long-term enzyme replacement therapy with idursulfase for Hunter syndrome showed sustained clinical improvements over 3 years, including a 25.1% increase in absolute forced vital capacity and significant enhancements in walking distance.

While 53% of patients experienced infusion-related adverse events, these decreased over time, and the presence of neutralizing antibodies in 23% of patients was associated with reduced pulmonary function improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome. Muenzer, J., Beck, M., Eng, CM., et al.[2022]

Transplanted fibroblasts provided a long-lasting source of lysosomal enzymes for three patients with Hunter's syndrome, showing significant increases in enzyme activity over 2.5 to 3.75 years.

The therapy led to improved catabolism of heparan and dermatan sulfates, evidenced by changes in urinary oligosaccharide profiles, and these benefits persisted even with changes in immunosuppressive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzyme replacement therapy by fibroblast transplantation: long-term biochemical study in three cases of Hunter's syndrome. Dean, MF., Stevens, RL., Muir, H., et al.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05371613

NCT05371613 | A Study to Determine the Efficacy and ... A Study to Determine the Efficacy and Safety of Tividenofusp Alfa (DNL310) vs Idursulfase in Pediatric and Young Adult Participants With Neuronopathic (nMPS II) ...

2. neurologylive.com neurologylive.com/view/fda-delays-review-deadline-hunter-syndrome-agent-tividenofusp-alfa

FDA Delays Review Deadline for Hunter Syndrome Agent ... The FDA extended the review period for tividenofusp alfa, a potential Hunter syndrome treatment, to April 5, 2026, after additional pharmacology ...

3. empr.com empr.com/news/fda-extends-review-for-tividenofusp-alfa-for-hunter-syndrome/

FDA Extends Review for Tividenofusp Alfa for Hunter ... Interim findings showed treatment with tividenofusp alfa significantly reduced central nervous system and peripheral biomarkers of disease, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04251026

NCT04251026 | A Study of Tividenofusp Alfa (DNL310) in ... This is a multicenter, multiregional, open-label study to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of tividenofusp alfa (DNL310), ...

5. drug-dev.com drug-dev.com/denali-therapeutics-announces-fda-review-extension-of-bla-for-tividenofusp-alfa-for-the-treatment-of-mps-ii-hunter-syndrome/

Denali Therapeutics Announces FDA Review Extension of ... Hunter syndrome, also known as MPS II, is a rare genetic lysosomal storage disease caused by mutations in the iduronate-2-sulfatase (IDS) gene.

6. denalitherapeutics.com denalitherapeutics.com/patient-community/hunter-syndrome-mps-ii

Hunter Syndrome (MPS II) - Denali Therapeutics The objective of the COMPASS study is to determine the efficacy and safety of DNL310 vs idursulfase, an enzyme replacement therapy (ERT). To learn more about ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05371613

NCT05371613 | A Study to Determine the Efficacy and ... A Study to Determine the Efficacy and Safety of Tividenofusp Alfa (DNL310) vs Idursulfase in Pediatric and Young Adult Participants With Neuronopathic (nMPS II) ...

8. nasdaq.com nasdaq.com/articles/denali-therapeutics-reports-promising-long-term-data-tividenofusp-alfa-hunter-syndrome

Denali Therapeutics Reports Promising Long-Term Data ... Denali Therapeutics reports long-term benefits and safety data for tividenofusp alfa in treating Hunter syndrome (MPS II).