Gene Therapy vs Stem Cell Treatment for Hurler Syndrome

(HURCULES Trial)

Recruiting in Palo Alto (17 mi)

+9 other locations

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Waitlist Available

Sponsor: Orchard Therapeutics

Must not be taking: Prohibited medications

Disqualifiers: HIV, Hepatitis, Cancer, Seizures, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

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.

Trial 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 (Stem Cell Transplant)
• OTL-203 (Gene Therapy)

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, Australia 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

🇦🇺 Approved in Australia 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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

UCSF Benioff Children's Hospital Oakland Oakland, CA

University of California, San Francisco (UCSF) Benioff Children's Hospital San Francisco, CA

The Children's Hospital of Philadelphia Philadelphia, PA

UCSF Benioff Children's Hospital San Francisco, CA

More Trial Locations

Who Is Running the Clinical Trial?

Orchard Therapeutics Lead Sponsor

References

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

[Rhinosinusitis in Hurler syndrome patients requiring hematopoietic stem cells transplantation]. [2020] Allogenic transplantation of hemopoetic stem cells (allo-THSC) is one of the most effective treatment methods for Hurler syndrome, aimed at maximal correction of complications related to the genetic disorder. Presence of infection in the recipient is an adverse risk factor, affecting the possibility of starting the conditioning regimen and THSC peforming in general.

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

Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome. [2021] Allogeneic hematopoietic stem-cell transplantation is the standard of care for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). However, this treatment is only partially curative and is associated with complications.

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

The clinical outcome of Hurler syndrome after stem cell transplantation. [2008] Hurler syndrome (HS) is a severe inborn error of metabolism causing progressive multi-system morbidity and death in early childhood. At present, stem cell transplantation (SCT) is the only available treatment that can prevent central nervous system disease progression in HS patients. Although SCT has been shown to be effective for several important clinical outcome parameters, the reported clinical outcome after successful SCT is variable among HS patients and there are still some major limitations. This review will focus on the clinical outcome of HS patients after successful SCT, with particular emphasis on the long-term outcome and complications. In addition, factors that are suggested to contribute to the variable outcome are outlined, as well as the limitations of SCT in HS patients.

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] Hurler syndrome is a debilitating genetic disease with a typical life span of 5 to 8 years. Early hematopoietic stem cell transplantation (HSCT) mitigates disease symptoms and improves survival. However, morbidity and mortality associated with HSCT can limit its success. We describe the initial experience with combined use of enzyme replacement therapy (ERT, laronidase) and HSCT in Hurler syndrome.

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] Over the last 15 years, we have performed a total of 30 haematopoietic stem cell transplants on 27 children suffering from Hurler's syndrome. These children were of median age 11 months at the time of diagnosis and 25 months at the time of transplantation. The phenotype was severe in 21 cases (78%). The donor was familial in 13 cases: nine genotypically identical, one phenotypically identical father and three HLA-mismatched donors. Unrelated donors were selected in 17 cases: four phenotypically identical and 13 with 1-4 HLA mismatches. The conditioning regimen generally consisted of busulphan 600 mg/m(2) plus cyclophosphamide (Endoxan) 260 mg/kg and cyclosporin with methotrexate for GvHD prophylaxis. Rabbit anti-thymocyte globulin (Thymoglobuline) was given for all unrelated or familial mismatched transplantations. The median nucleated cell dose infused was 6.00 x 10(8) TNC/kg. No bone marrow (apart from one) was T cell depleted. For first transplants, engraftment was observed in 23/27 patients (pts) (85%). Primary graft failure was observed in 4/27 patients (16%), two were retransplanted from an unrelated donor, one with success. Four patients have died. The primary cause of death was infection in three cases (TRM : 11%) and disease progression in one case, after primary graft failure. Of the 23 living patients, two have disease progression after graft failure and 21 (78%) have functional grafts with a favourable long-term outcome after a median follow-up of 4.7 years, having either full or mixed chimaerism. Among surviving patients with functional grafts, 13 (62%) were transplanted from unrelated donors of whom 10 (77 %) had HLA disparities. There was a remarkably low incidence of GvHD. In our experience, haematopoietic stem cell transplantation using an HLA-matched familial donor or an HLA-matched or -mismatched unrelated donor without T cell depletion or irradiation can achieve a favourable outcome in Hurler's syndrome, with improved cognitive function, but with a limited effect on the corneas and skeleton.

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] Hurler syndrome (MPS1H) is a progressive inborn error of mucopolysaccharide metabolism leading to premature death. Allogeneic hematopoietic cell transplantation (HCT) can achieve stabilization and improve long-term survival. However, large studies have shown that preparative regimen-related toxicity (RRT) and graft failure rates have been relatively high. We transplanted five Hurler children with a fludarabine-based conditioning regimen, consisting of fludarabine/busulphan/ATG for matched family donor (MFD), with the addition of melphalan for mismatched family donor and matched unrelated donor (MUD) transplantations. Median age at HCT was 27 months (range 10-36). The source of stem cells was bone marrow in one MFD and CD34-selected PBSC in four patients. Median CD34+ cell dose was 25 x 10(6)/kg (range 11.5-54). No RRT > grade II was observed. All patients are surviving at a median of 32 months (range 14-41) and show sustained donor engraftment with 3/5 having full donor chimerism, and 2/5 mixed chimerism (> 85%). We conclude that this regimen is feasible and has low toxicity in Hurler children. In combination with high doses of CD34+ selected cells (> 10 x 10(6)/kg) and donor lymphocyte infusions, stable engraftment could be achieved in unrelated and mismatched related transplantations.