DNL126 for Sanfilippo Syndrome

Recruiting at 3 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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a multicenter, open-label, Phase 1/2 study to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and exploratory clinical efficacy of DNL126 in participants with Sanfilippo syndrome Type A (MPS IIIA). The core study period is 25 weeks (approximately 6 months) and is followed by a 72-week (approximately 18 month) open-label extension (OLE). Participants with MPS IIIA will be enrolled in two planned cohorts, and additional participants with MPS IIIA may be enrolled in three optional cohorts.

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.

What data supports the effectiveness of the treatment DNL126 for Sanfilippo Syndrome?

While there is no direct evidence for DNL126, enzyme replacement therapy has shown promise in treating other types of mucopolysaccharidoses (MPS), and clinical trials are exploring its potential for Sanfilippo Syndrome. Additionally, a phase IIb trial of intrathecal heparan-N-sulfatase, a similar enzyme replacement, showed some effectiveness in Sanfilippo Syndrome type A. ^{1 2 3 4 5}

What safety data exists for DNL126 or similar enzyme replacement therapies?

The safety of enzyme replacement therapies like cerliponase alfa has been studied in conditions such as CLN2 disease, showing common side effects like convulsions and infections, but with low rates of serious device-related issues. Another enzyme therapy for CLN1 disease showed no unacceptable side effects in a case study, suggesting these treatments can be generally safe with proper monitoring. ^{6 7 8 9 10}

How is the drug DNL126 different from other treatments for Sanfilippo Syndrome?

DNL126 is an enzyme replacement therapy specifically targeting Sanfilippo Syndrome Type A, which is unique because there are currently no standard treatments available for this condition. This therapy aims to replace the missing enzyme needed to break down heparan sulfate, potentially addressing the root cause of the disease. ^{2 3 5 11 12}

Research Team

Ana-Claire Meyer, MD

Principal Investigator

Denali Therapeutics

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

How close are we to therapies for Sanfilippo disease? [2019]

3. Israel pubmed.ncbi.nlm.nih.gov

Mucopolysaccharidosis III (Sanfilippo Syndrome)- disease presentation and experimental therapies. [2014]

4. New Zealand pubmed.ncbi.nlm.nih.gov

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

5. United States 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). [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Review of Cerliponase Alfa: Recombinant Human Enzyme Replacement Therapy for Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Treatment of CLN1 disease with a blood-brain barrier penetrating lysosomal enzyme. [2022]

8. United States 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. [2022]

9. Italy pubmed.ncbi.nlm.nih.gov

Desensitization of two young patients with infantile-onset Pompe disease and severe reactions to alglucosidase alfa. [2020]

10. Thailand pubmed.ncbi.nlm.nih.gov

Enzyme replacement therapy desensitization in a child with infantile onset Pompe disease. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Correction of Sanfilippo A skin fibroblasts by retroviral vector-mediated gene transfer. [2008]

12. England pubmed.ncbi.nlm.nih.gov

Analysis of the caregiver burden associated with Sanfilippo syndrome type B: panel recommendations based on qualitative and quantitative data. [2020]