Gene Therapy vs Stem Cell Treatment for Hurler Syndrome

(HURCULES Trial)

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

41 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial compares a new gene therapy called OTL-203 with traditional stem cell transplants in patients with a severe genetic disorder called MPS-IH. The goal is to see if gene therapy can better correct the genetic defect causing the disease compared to replacing damaged cells with healthy ones from a donor.

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.

What data supports the effectiveness of the treatment for Hurler Syndrome?

Stem cell transplantation (SCT) is currently the only treatment that can prevent the progression of central nervous system disease in Hurler Syndrome patients, and it has been shown to improve survival and mitigate disease symptoms. However, the success of SCT can vary, and it is associated with some risks and complications. ^{1 2 3 4 5}

Is gene therapy or stem cell treatment safe for Hurler Syndrome?

Stem cell transplantation for Hurler Syndrome has been studied and can be effective, but it comes with risks such as infection and graft failure. Some studies show that using certain conditioning regimens can reduce toxicity, and most patients have survived with stable donor engraftment. ^{1 2 3 5 6}

How is the treatment Allo-HSCT, OTL-203 different from other treatments for Hurler Syndrome?

Allo-HSCT (Allogeneic Hematopoietic Stem Cell Transplantation) is unique because it involves transplanting stem cells from a donor to help correct the genetic disorder in Hurler Syndrome, aiming to prevent disease progression in the central nervous system. While it is the standard treatment, it is only partially curative and can have complications, unlike enzyme replacement therapy which is often used in combination to improve outcomes. ^{1 2 3 4 5}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

References

1. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Rhinosinusitis in Hurler syndrome patients requiring hematopoietic stem cells transplantation]. [2020]

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

Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome. [2021]

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

The clinical outcome of Hurler syndrome after stem cell transplantation. [2008]

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

Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources. [2004]

6. England pubmed.ncbi.nlm.nih.gov

Transplantation of allogeneic CD34-selected stem cells after fludarabine-based conditioning regimen for children with mucopolysaccharidosis 1H (M. Hurler). [2013]