DNL126 for Sanfilippo Syndrome

Not currently recruiting at 4 trial locations

Overseen By Clinical Trials at Denali Therapeutics

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Denali Therapeutics Inc.

Must not be taking: CNS-targeted ERT, Genistein, Anakinra

Disqualifiers: Unstable conditions, Non-ambulatory, Others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called DNL126, an enzyme replacement therapy, for individuals with Sanfilippo Syndrome Type A (MPS IIIA), a rare condition affecting brain function. The main goal is to determine if DNL126 is safe and effective for those with this condition. The study divides participants into different groups to examine various aspects of the treatment's effects. Individuals diagnosed with MPS IIIA who exhibit noticeable symptoms might be suitable candidates for this trial. As a Phase 1/Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Do I need to stop my current medications to join the trial?

The trial requires that you stop using genistein or anakinra at least 7 days before screening and during the study. Additionally, you must not have used any CNS-targeted MPS IIIA enzyme replacement therapy within 3 months before the trial starts.

Is there any evidence suggesting that DNL126 is likely to be safe for humans?

Research shows that DNL126, a type of enzyme replacement therapy, is being tested to help treat Sanfilippo syndrome Type A. Earlier studies have demonstrated that DNL126 works by replacing the missing enzyme in people with this condition. The treatment is currently in an early trial phase, focusing on safety and tolerability.

Researchers closely monitor participants for any side effects or problems during this phase. Although detailed safety information isn't available yet, approval for this phase indicates that DNL126 has passed some initial safety tests in humans. Researchers consider it safe enough to try in more people.

Overall, DNL126 remains under study, with safety as a top priority. Participants are carefully monitored to address any potential issues quickly. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Sanfilippo syndrome?

Unlike the standard treatments for Sanfilippo Syndrome, which focus on managing symptoms, DNL126 offers a novel approach by directly targeting the underlying cause of the disease. Researchers are excited because DNL126 uses a unique mechanism of action to potentially halt or slow down the progression of the disease, rather than just alleviating symptoms. This breakthrough could mean a significant step forward in improving the quality of life and long-term outcomes for patients with Sanfilippo Syndrome.

What evidence suggests that DNL126 might be an effective treatment for Sanfilippo syndrome?

Research has shown that DNL126, which participants in this trial will receive, offers promising results for treating Sanfilippo Syndrome Type A (MPS IIIA). In a recent study, patients experienced a significant drop in heparan sulfate levels in their spinal fluid. High levels of heparan sulfate are linked to the symptoms of Sanfilippo Syndrome. Although no treatments for MPS IIIA have been approved yet, these early findings suggest DNL126 could help manage the condition. Further research is needed to confirm these results and ensure the treatment's safety and effectiveness. ^{1 3 4 6 7}

Who Is on the Research Team?

Ana-Claire Meyer, MD

Principal Investigator

Denali Therapeutics

Are You a Good Fit for This Trial?

This trial is for children with Sanfilippo Syndrome Type A (MPS IIIA), specifically those who have a confirmed diagnosis. If they have an older sibling with the same severe condition, they may also qualify to participate in this study.

Inclusion Criteria

My sibling has severe MPS IIIA and I have the same severe condition.

I have been diagnosed with MPS IIIA.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Core Study Period

Participants receive DNL126 to assess safety, tolerability, PK, PD, and exploratory clinical efficacy

25 weeks

Open-label Extension

Participants may continue to receive DNL126 to further assess long-term safety and efficacy

72 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• DNL126

Trial Overview The trial is testing DNL126, which is being studied for safety, how well it's tolerated by patients, its movement and actions within the body (PK/PD), and potential benefits on symptoms of MPS IIIA over a core period of 6 months followed by an extension of approximately 18 months.

How Is the Trial Designed?

Group I: Cohort B2 Experimental Treatment 1 Intervention

Participants with MPS IIIA

Group II: Cohort B1 Experimental Treatment 1 Intervention

Participants with MPS IIIA

Group III: Cohort A3 Experimental Treatment 1 Intervention

Participants with MPS IIIA

Group IV: Cohort A2 Experimental Treatment 1 Intervention

Participants with MPS IIIA

Group V: Cohort A1 Experimental Treatment 1 Intervention

Participants with MPS IIIA

Who Is Running the Clinical Trial?

Denali Therapeutics Inc.

Lead Sponsor

Trials

24

Recruited

1,900+

Published Research Related to This Trial

In a phase IIb trial involving 21 patients with Sanfilippo syndrome type A, intrathecal administration of recombinant human heparan-N-sulfatase (rhHNS) successfully reduced levels of heparan sulfate and glycosaminoglycans in the cerebrospinal fluid and urine, indicating a biochemical response to treatment.

Although the primary goal of preventing neurocognitive decline was not achieved, the treatment was generally safe with mostly mild adverse events, and no serious complications or deaths occurred, suggesting that rhHNS IT may be a tolerable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial. Wijburg, FA., Whitley, CB., Muenzer, J., et al.[2019]

Enzyme replacement therapy is the only treatment for infantile-onset Pompe disease, which significantly improves health outcomes, but some patients experience severe infusion-related reactions that can limit treatment access.

A new individualized desensitization protocol using microdilution and premedication with antihistamines, corticosteroids, and tranexamic acid was successfully implemented in two infants, allowing them to continue therapy safely and effectively, potentially reducing morbidity and mortality associated with the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Desensitization of two young patients with infantile-onset Pompe disease and severe reactions to alglucosidase alfa. Gragnaniello, V., Fecarotta, S., Pecoraro, A., et al.[2020]

A successful desensitization protocol for alglucosidase alfa enzyme replacement therapy was implemented for a 9-year-old girl with infantile onset Pompe disease, demonstrating that desensitization is feasible for patients with hypersensitivity reactions.

The tailored multi-step, three-fold dose escalation approach highlights the importance of individualized treatment plans involving a multidisciplinary team to ensure safety and efficacy in managing hypersensitivity during enzyme replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzyme replacement therapy desensitization in a child with infantile onset Pompe disease. Toh, TSW., Chong, KW., Goh, AEN., et al.[2023]

Sanfilippo syndrome (MPS III) is a neurodegenerative disorder caused by enzyme deficiencies that lead to heparan sulfate accumulation, resulting in severe neurological symptoms starting in childhood, but currently, there is no effective therapy available.

Research using animal models has advanced the understanding of MPS III and is paving the way for potential treatments, including planned clinical trials for enzyme replacement and gene therapy specifically targeting MPS IIIA and MPS IIIB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sanfilippo syndrome: causes, consequences, and treatments. Fedele, AO.[2022]

Gene therapy for Sanfilippo A syndrome is feasible, as demonstrated by the successful use of a retroviral vector to deliver the sulfamidase gene, resulting in complete correction of the enzymatic defect in fibroblasts.

The study achieved phenotypic correction even at low levels of viral transduction, indicating that effective gene therapy may not require high viral loads, but careful selection of target cells is crucial for optimal outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction of Sanfilippo A skin fibroblasts by retroviral vector-mediated gene transfer. Bielicki, J., Hopwood, JJ., Anson, DS.[2008]

Cerliponase alfa, an enzyme replacement therapy, has been shown to effectively slow the decline of motor and language functions in patients with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), based on a phase 1/2 trial.

While cerliponase alfa is the first treatment targeting the underlying cause of CLN2, it is associated with common adverse events such as convulsions and upper respiratory infections, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of Cerliponase Alfa: Recombinant Human Enzyme Replacement Therapy for Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2. Lewis, G., Morrill, AM., Conway-Allen, SL., et al.[2021]

Sanfilippo syndrome type D is caused by a deficiency of the enzyme N-acetylglucosamine-6-sulphatase, leading to lysosomal storage issues, and only 15 patients have been documented in the literature.

This study identified two novel mutations in affected Italian families: a large intragenic deletion and a nonsense mutation, with the deletion being the first of its kind reported in any Sanfilippo subtype, highlighting the genetic diversity of this rare disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification and characterisation of an 8.7 kb deletion and a novel nonsense mutation in two Italian families with Sanfilippo syndrome type D (mucopolysaccharidosis IIID). Beesley, CE., Concolino, D., Filocamo, M., et al.[2022]

Sanfilippo disease, a type of mucopolysaccharidosis (MPS III), is caused by genetic defects leading to the accumulation of heparan sulfate, resulting in severe neurodegenerative changes and cognitive disabilities.

While there are currently no approved therapies for Sanfilippo disease, recent advancements in clinical trials are exploring enzyme replacement therapy, gene therapy, and substrate reduction therapy as potential treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How close are we to therapies for Sanfilippo disease? Gaffke, L., Pierzynowska, K., Piotrowska, E., et al.[2019]

Sanfilippo Syndrome (MPS III) is caused by a deficiency in one of four lysosomal enzymes, leading to neurodegenerative symptoms and developmental regression, typically resulting in death by the second decade of life, although some individuals may live into their 30s to 60s.

Current treatments are limited to supportive care, but experimental therapies such as enzyme replacement, gene therapy, stem cell therapy, and substrate reduction are being explored to potentially improve outcomes for affected individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mucopolysaccharidosis III (Sanfilippo Syndrome)- disease presentation and experimental therapies. Gilkes, JA., Heldermon, CD.[2014]

Caregivers of patients with Sanfilippo syndrome type B experience significant and ongoing burden due to the disease's impact on family life, including challenges like sleep disturbances and communication difficulties.

There is a need for a specific quality of life questionnaire for caregivers of Sanfilippo B patients to better address their unique challenges and improve management practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the caregiver burden associated with Sanfilippo syndrome type B: panel recommendations based on qualitative and quantitative data. Shapiro, E., Lourenço, CM., Mungan, NO., et al.[2020]

A 68-month-old boy with CLN1 disease was treated for 26 months with a novel enzyme replacement therapy (AGT-194) that penetrates the blood-brain barrier, showing no side effects during the treatment.

The treatment led to a decrease in seizure frequency and an improvement in the boy's quality of life, suggesting that this approach could be a feasible option for managing CLN1 disease and warrants further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of CLN1 disease with a blood-brain barrier penetrating lysosomal enzyme. Hahn, A., Sato, Y., Ikeda, T., et al.[2022]

Intracerebroventricular enzyme replacement therapy (ICV-ERT) using cerliponase alfa is the first approved treatment for CLN2 disease, effectively slowing neurological decline in affected children.

Data from over 3000 ICV-ERT procedures in 48 patients showed low rates of device-related adverse events (0.27%) and infections (0.33%), indicating that following established procedural guidelines enhances patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of the "Hamburg Best Practice Guidelines for ICV-Enzyme Replacement therapy (ERT) in CLN2 Disease" Based on 6 Years Treatment Experience in 48 Patients. Schwering, C., Kammler, G., Wibbeler, E., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06181136

NCT06181136 | Study of DNL126 in Pediatric Participants ... This is a multicenter, open-label, Phase 1/2 study to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical efficacy of ...

2. curesanfilippofoundation.org curesanfilippofoundation.org/2024/11/denali-announces-dnl126-demonstrate-robust-reduction-from-baseline-in-csf-heparan-sulfate-levels-including-normalization/

Denali announces DNL126 demonstrates "robust reduction ... Preliminary data from our Phase 1/2 study of DNL126 in MPS IIIA demonstrate a robust reduction from baseline in CSF heparan sulfate levels, including ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34600820/

Long-term safety and clinical outcomes of intrathecal ... Introduction: Currently, there is no effective therapy for mucopolysaccharidosis IIIA (MPS IIIA). · Methods: Patients aged ≥3 years with MPS IIIA ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7391468/

A Cure for Sanfilippo Syndrome? A Summary of Current ... There are currently no approved treatments for MPS III, but a number of therapeutic approaches are under development.

5. ir.ultragenyx.com ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-fda-acceptance-and-priority-review

Ultragenyx Announces FDA Acceptance and Priority ... The most frequently reported treatment-related adverse events to date were elevations in liver enzymes, and the majority of these events were ...

6. curesanfilippofoundation.org curesanfilippofoundation.org/2023/12/dnl126-enzyme-replacement-type-a-phase-i-ii-denali/

DNL126 Enzyme Replacement | MPS IIIA | Phase I-II | Denali DNL-126 is an investigational enzyme replacement therapy for patients with Sanfilippo syndrome type A. The enzyme deficient in Sanfilippo type ...

7. denalitherapeutics.com denalitherapeutics.com/patient-community/sanfilippo-syndrome-mps-iii-a

sanfilippo syndrome (mps iii a) - Denali Therapeutics DNL126 is being studied in a Phase 1/2 study of children with MPS IIIA to evaluate the appropriate dose of DNL126 in addition to gathering important safety data ...