Gene Therapy vs Stem Cell Treatment for Hurler Syndrome

(HURCULES Trial)

Not currently recruiting at 9 trial locations

Overseen By Orchard Medical Information

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Orchard Therapeutics

Must not be taking: Prohibited medications

Disqualifiers: HIV, Hepatitis, Cancer, Seizures, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: Varies depending on treatment arm

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial compares two treatments for Hurler syndrome, a genetic disorder affecting metabolism. Researchers are testing a new gene therapy, OTL-203, against the standard stem cell transplant (Allo-HSCT) to determine which is more effective. The goal is to identify which approach better improves symptoms and quality of life for patients with Hurler syndrome. Individuals with a confirmed diagnosis of Hurler syndrome and normal cognitive scores might be suitable candidates for this study. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants a chance to contribute to a treatment that could soon become widely available.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking any medications that are prohibited by the trial, you may need to stop them. It's best to discuss your current medications with the trial team.

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

Research has shown that OTL-203, a gene therapy being tested for Hurler syndrome, is generally well-tolerated. Early results from previous studies indicated that the safety of OTL-203 is similar to earlier treatments, meaning patients did not experience unexpected side effects from the gene therapy itself.

The other treatment in the trial, allo-HSCT (a type of stem cell transplant), is a standard treatment for Hurler syndrome. Preparation for both treatments includes medications called busulfan and fludarabine, which are known to have some side effects. However, these side effects are expected and can be managed as part of the treatment process.

Overall, past studies have shown both treatments to be safe, with OTL-203 being a newer option that shows promise in managing side effects well. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about OTL-203 because it represents a cutting-edge approach to treating Hurler syndrome through gene therapy. Unlike traditional treatments, which often involve enzyme replacement therapy or hematopoietic stem cell transplantation, OTL-203 works by delivering a functioning copy of the faulty gene directly into the patient's cells. This could potentially correct the underlying genetic defect, offering a more permanent solution. On the other hand, Allo-HSCT, another treatment being explored, involves transplanting healthy donor stem cells to replace the patient's defective cells, aiming to give the body a fresh start with cells that can produce the missing enzyme. Both treatments offer promising new avenues compared to current methods, which primarily focus on managing symptoms and slowing disease progression.

What evidence suggests that this trial's treatments could be effective for Hurler syndrome?

Research has shown that OTL-203, a type of gene therapy, may help treat Hurler syndrome. Earlier studies suggest it could improve physical symptoms of the condition. In this trial, participants in one arm will receive OTL-203. Those who received it in previous studies showed positive changes in specific health indicators related to Hurler syndrome. This therapy works by adding healthy genes to correct the genetic issue causing the disease. While more information is needed for a complete understanding, early results are promising and indicate that OTL-203 could be an effective treatment option. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

This trial is for patients with Hurler syndrome (MPS-IH) who have a cognitive score of ≥70 and confirmed MPS-IH diagnosis. They must not have uncontrolled seizures, active infections resistant to treatment, severe organ damage, or other conditions that risk safety or data quality. Those previously treated with stem cell transplants or gene therapy, enrolled in another interventional study, unable to follow the protocol, or positive for certain infectious diseases are excluded.

Inclusion Criteria

Your cognitive test score should be at least 70, as measured by specific tests for your age group.

I have been diagnosed with MPS-IH through genetic testing.

A special group of doctors needs to confirm that you have MPS-IH.

Exclusion Criteria

Subjects with an active infection not responsive to treatment, end-organ damage, or any other disease that contraindicates performance of any of the procedures detailed in the protocol, or medical conditions or extenuating circumstances that, in the opinion of the Investigator, might compromise the subject's well-being or safety, or the interpretability of the subject's clinical data

I have been diagnosed with MDS or AML.

I have cancer, but it's not just skin cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline

Baseline assessments are conducted prior to randomization and treatment initiation

1 week

Treatment

Participants receive either OTL-203 gene therapy or allo-HSCT with conditioning regimen

Varies depending on treatment arm

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Allo-HSCT
• OTL-203

Trial Overview The trial compares OTL-203 (a new gene therapy) against the standard allogeneic hematopoietic stem cell transplant (HSCT). It's designed to see which one is more effective and safer for treating Hurler syndrome. Patients will be randomly assigned to receive either the experimental gene therapy or the standard HSCT treatment.

How Is the Trial Designed?

Group I: OTL-203 Experimental Treatment 1 Intervention

Eligible subjects randomized to Arm 1 will receive an intravenous (IV) infusion of OTL-203 gene therapy. Subjects will receive conditioning regimen with busulfan and fludarabine prior to OTL-203 infusion.

Group II: Allo-HSCT Active Control 1 Intervention

Eligible subjects randomized to Arm 2 will receive allogeneic hematopoietic stem cell transplantation. Subjects will receive conditioning regimen with busulfan and fludarabine prior to allo-HSCT.

Allo-HSCT is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Allo-HSCT for:

• Acute Leukemias
• Myelodysplastic Syndromes
• Myeloproliferative Neoplasms
• Chronic Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Chronic Lymphocytic Leukemia
• Severe Aplastic Anemia
• Fanconi Anemia
• Hurler Syndrome

Approved in United States as Allo-HSCT for:

• Acute Myeloid Leukemia
• Myelodysplastic Syndromes
• Myeloproliferative Neoplasms
• Chronic Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Chronic Lymphocytic Leukemia
• Severe Aplastic Anemia
• Fanconi Anemia
• Hurler Syndrome

Approved in Canada as Allo-HSCT for:

• Acute Leukemias
• Myelodysplastic Syndromes
• Myeloproliferative Neoplasms
• Chronic Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Chronic Lymphocytic Leukemia
• Severe Aplastic Anemia
• Fanconi Anemia
• Hurler Syndrome

Approved in Japan as Allo-HSCT for:

• Acute Leukemias
• Myelodysplastic Syndromes
• Myeloproliferative Neoplasms
• Chronic Myeloid Leukemia
• Acute Lymphoblastic Leukemia
• Chronic Lymphocytic Leukemia
• Severe Aplastic Anemia
• Fanconi Anemia
• Hurler Syndrome

Who Is Running the Clinical Trial?

Orchard Therapeutics

Lead Sponsor

Trials

23

Recruited

106,000+

Published Research Related to This Trial

In a study of 18 Hurler syndrome patients undergoing allogenic transplantation of hemopoietic stem cells (allo-THSC), significant improvements were observed in nasal cavity and paranasal sinus conditions post-transplant, indicating effective correction of symptoms related to the disease.

After the transplantation, 64.2% of patients experienced a decrease in rhinitis symptoms, and 66.6% showed improved aeration of the sinuses, suggesting that allo-THSC not only addresses the genetic disorder but also alleviates associated respiratory complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Rhinosinusitis in Hurler syndrome patients requiring hematopoietic stem cells transplantation]. Karpishchenko, SA., Dolgov, OI., Bykova, TA., et al.[2020]

A fludarabine-based conditioning regimen for hematopoietic cell transplantation in five children with Hurler syndrome showed low toxicity, with no severe regimen-related toxicity observed, indicating a safer approach for these patients.

All five patients survived at a median follow-up of 32 months, demonstrating sustained donor engraftment, with three achieving full donor chimerism, suggesting that this treatment can effectively stabilize the condition and improve long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transplantation of allogeneic CD34-selected stem cells after fludarabine-based conditioning regimen for children with mucopolysaccharidosis 1H (M. Hurler). Grigull, L., Beilken, A., Schrappe, M., et al.[2013]

In a study of 27 children with Hurler's syndrome who underwent hematopoietic stem cell transplants, 78% had a favorable long-term outcome with functional grafts after a median follow-up of 4.7 years, despite some experiencing disease progression.

The transplantation approach, using either HLA-matched or mismatched donors without T cell depletion, resulted in a low incidence of graft-versus-host disease (GvHD) and improved cognitive function, although effects on corneal and skeletal issues were limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Souillet, G., Guffon, N., Maire, I., et al.[2004]

The combination of enzyme replacement therapy (ERT) with hematopoietic stem cell transplantation (HSCT) in 12 children with Hurler syndrome was found to be feasible and well tolerated, with most patients showing a decrease in urinary GAG excretion during ERT.

Despite some complications, such as graft failure and acute graft-versus-host disease (GVHD), 11 out of 12 patients survived after a median follow-up of 3 months, indicating that this combined approach may improve outcomes in Hurler syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome. Grewal, SS., Wynn, R., Abdenur, JE., et al.[2019]

In an ongoing study of eight children with Hurler syndrome, autologous hematopoietic stem and progenitor cell gene therapy showed a safety profile similar to standard stem-cell transplantation, with all patients achieving sustained engraftment and supraphysiologic levels of IDUA activity within a month.

The therapy led to significant metabolic corrections, including decreased urinary glycosaminoglycan levels and detectable IDUA activity in cerebrospinal fluid, along with stable cognitive and motor skills, improved MRI findings, and normal growth patterns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome. Gentner, B., Tucci, F., Galimberti, S., et al.[2021]

Stem cell transplantation (SCT) is currently the only treatment available for Hurler syndrome (HS) that can prevent the progression of central nervous system disease, but its effectiveness varies among patients.

The review highlights the long-term outcomes and complications associated with SCT in HS patients, indicating that while SCT can improve clinical parameters, there are significant limitations and factors influencing the variability in patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical outcome of Hurler syndrome after stem cell transplantation. Aldenhoven, M., Boelens, JJ., de Koning, TJ.[2008]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06149403

A Study to Investigate the Efficacy and Safety of OTL-203 in ... The study is a multi-center, randomized, active controlled clinical trial designed to evaluate the efficacy and safety of OTL-203 in patients with ...

2. ir.orchard-tx.com ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-last-patient-treated

Orchard Therapeutics Announces Last Patient Treated in ... Orchard Therapeutics Announces Last Patient Treated in Registrational Trial of OTL-203 for MPS-I Hurler Syndrome ... The trial (NCT06149403), ...

3. ucsf.edu ucsf.edu/news/2024/10/428651/advancing-care-devastating-disease-through-gene-therapy

Advancing Care of a Devastating Disease Through Gene ... A new international trial is investigating the efficacy and safety of gene therapy in patients with Hurler syndrome and will compare results of gene therapy ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1525001625008147

Non-neurological, non-skeletal outcomes after ... Non-neurological, non-skeletal outcomes after hematopoietic stem and progenitor cell-gene therapy (OTL-203) for Hurler syndrome. Author links ...

5. ir.orchard-tx.com ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-first-patient-randomized

Orchard Therapeutics Announces First Patient ... The trial, referred to as HURCULES, compares treatment with OTL-203 to standard of care with allogeneic hematopoietic stem cell transplant (HSCT), and is ...

6. ir.orchard-tx.com ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-interim-data-otl-203-showing

Orchard Therapeutics Announces Interim Data for OTL-203 ... Safety: Treatment with OTL-203 has been generally well-tolerated with a safety profile consistent with the selected conditioning regimen.

7. ir.orchard-tx.com ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-presents-new-interim-data-otl-203-proof

Orchard Therapeutics Presents New Interim Data from OTL ... As of April 2020 , all eight patients with the severe Hurler subtype of MPS-I have been treated with OTL-203. Patients have been followed for a ...