In Utero Enzyme Replacement Therapy for Lysosomal Storage Diseases

(PEARL Trial)

Overseen By Emma Canepa, MS, CCRP

Age: 18 - 65

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: University of California, San Francisco

Must not be taking: Anticoagulants

Disqualifiers: Severe anomaly, Cardiopulmonary disease, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

For detailed information, please view our study website: https://pearltrial.ucsf.edu/ The investigators aims to determine the the maternal and fetal safety and feasibility of in utero fetal enzyme replacement therapy in fetuses with Lysosomal Storage Diseases.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you require therapeutic dosing of anticoagulation (blood thinners) within 24 hours before or after the intervention, you may not be eligible to participate.

What data supports the effectiveness of the drug Aldurazyme (laronidase) for treating lysosomal storage diseases?

Laronidase (Aldurazyme) is effective as an enzyme replacement therapy for mucopolysaccharidosis type I (MPS I), a type of lysosomal storage disease, by reducing glycosaminoglycan storage and improving symptoms like joint movement and respiratory function. It has been shown to have a good safety profile with manageable side effects. ^{1 2 3 4 5}

Is laronidase (Aldurazyme) safe for humans?

Laronidase (Aldurazyme) has been shown to have an acceptable safety profile in humans, with common side effects including fever, vomiting, rash, and hives. In a study, the approved dose had the lowest incidence of side effects, and long-term use showed it could stabilize or improve many symptoms of the condition it treats. ^{1 2 3 5 6}

How is the drug Aldurazyme (laronidase) unique for treating lysosomal storage diseases?

Aldurazyme (laronidase) is unique because it is an enzyme replacement therapy specifically designed to replace the deficient enzyme in mucopolysaccharidosis type I (MPS I), and it is administered through intravenous infusions. This approach directly addresses the underlying enzyme deficiency, which is different from other treatments that may only manage symptoms. ^{1 2 3 7 8}

Research Team

Tippi Mackenzie, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for pregnant women aged 18-50 with fetuses diagnosed with certain Lysosomal Storage Diseases (LSDs) between 18 to nearly 35 weeks of gestation. Candidates must be able to consent and follow study requirements. Exclusions include mothers needing anticoagulation around the time of treatment, additional fetal genetic risks, or significant maternal health issues.

Inclusion Criteria

I am a pregnant woman aged 18-50, between 18 to 34 weeks of pregnancy.

I am pregnant with a living fetus between 18 to 34 weeks.

My unborn baby has been diagnosed with a lysosomal storage disorder.

Exclusion Criteria

I have health issues that make it unsafe for me to undergo fetal surgery.

I will need blood-thinning medication around the time of my procedure.

My unborn child has a genetic condition posing a high health risk.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

In utero enzyme replacement therapy (ERT) is administered to fetuses with Lysosomal Storage Disorders every 2-4 weeks via the umbilical vein.

Throughout pregnancy

Every 2-4 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and antibody levels.

6 years

Treatment Details

Interventions

• Aldurazyme (laronidase) (Enzyme Replacement Therapy)

Trial Overview The trial tests the safety and feasibility of administering Aldurazyme (laronidase), an enzyme replacement therapy, directly to a fetus in utero when diagnosed with LSDs like Gaucher Disease or Pompe Disease.

Participant Groups

Group I: Experimental: in utero enzyme replacement therapy Experimental Treatment 1 Intervention

ERT will be delivered in utero. Typically, the target of the procedure to administer in utero ERT will be the umbilical vein near the insertion of the umbilical cord into the placenta. The dose of the ERT will be dependent on the specific disease process and enzyme being replaced, and the estimated weight of the fetus. The dosage will be the same as the recommended weight-based postnatal dosing, adjusted for estimated fetal weight. IUERT will be repeated every 2-4 weeks, which is an interval consistent with the standard of care for IUTs (every 2-4 weeks) to avoid excessive access through the umbilical vein. This interval is also consistent with the half-life of each relevant enzyme.

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Duke University

Collaborator

Trials

2,495

Recruited

5,912,000+

Findings from Research

Laronidase (Aldurazyme) is a safe and effective treatment for stabilizing or improving pulmonary function and physical endurance in patients with mucopolysaccharidosis type I (MPS-I).

While laronidase cannot correct central nervous system issues related to MPS-I, ongoing research is exploring intrathecal administration for specific complications, highlighting the need for long-term studies to better understand its overall impact on disease progression and survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Laronidase (Aldurazyme): enzyme replacement therapy for mucopolysaccharidosis type I. Pastores, GM.[2019]

A retrospective study of 20 patients with mucopolysaccharidosis type I (MPS I) showed that switching from weekly laronidase infusions (0.58 mg/kg) to every other week (1.2 mg/kg) was well tolerated and did not lead to any deterioration in clinical outcomes.

Patients reported higher compliance and satisfaction with the every other week dosing regimen, suggesting it may be a viable alternative for those struggling with the standard weekly infusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alternative laronidase dose regimen for patients with mucopolysaccharidosis I: a multinational, retrospective, chart review case series. Horovitz, DD., Acosta, AX., Giugliani, R., et al.[2018]

In a 26-week study involving 33 patients with mucopolysaccharidosis type I, the approved dose of laronidase (0.58 mg/kg weekly) was found to provide the best reduction in lysosomal storage and had the lowest incidence of adverse events compared to alternative dosing regimens.

All dosing regimens had an acceptable safety profile, but the approved regimen had fewer infusion-related reactions, making it the preferred option for maximizing treatment benefits while minimizing risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A dose-optimization trial of laronidase (Aldurazyme) in patients with mucopolysaccharidosis I. Giugliani, R., Rojas, VM., Martins, AM., et al.[2008]

In a study of 45 patients with mucopolysaccharidosis I (MPS I), laronidase significantly improved respiratory function, with a mean increase of 5.6 percentage points in forced vital capacity compared to placebo after 26 weeks.

Laronidase was well-tolerated and also led to improvements in physical capacity, reduced liver enlargement, and decreased urinary glycosaminoglycans, indicating its efficacy and safety in treating MPS I.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). Wraith, JE., Clarke, LA., Beck, M., et al.[2022]

Laronidase, a treatment for mucopolysaccharidosis I, showed long-term efficacy with significant improvements in physical function, such as increased walking distance and better shoulder flexibility, over a 3.5-year period involving 45 patients.

The treatment was generally safe, with most infusion reactions being mild and manageable, although 93% of patients developed antibodies to laronidase, and one patient experienced a serious allergic reaction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Clarke, LA., Wraith, JE., Beck, M., et al.[2009]

Long-term treatment with laronidase (Aldurazyme) for 6 years in 5 out of 10 patients with mucopolysaccharidosis I (MPS I) showed significant improvements, including a 76% reduction in urinary glycosaminoglycans and increased range of motion in shoulder flexion and extension.

Patients experienced substantial growth, with pre-pubertal individuals gaining an average of 33 cm in height and 31 kg in weight, alongside improved daily functioning and decreased sleep apnea, indicating that early intervention may lead to better health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 years. Sifuentes, M., Doroshow, R., Hoft, R., et al.[2007]

Early enzyme replacement therapy (ERT) with laronidase in younger siblings diagnosed with Hurler-Scheie syndrome led to significant improvements or stabilization of symptoms compared to older siblings who started treatment after symptoms developed.

Younger siblings who received ERT before significant symptoms appeared showed better overall health outcomes, including less progression of cardiac, musculoskeletal, and cognitive issues, suggesting that starting treatment early can prevent severe clinical manifestations of mucopolysaccharidosis type I.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early treatment with laronidase improves clinical outcomes in patients with attenuated MPS I: a retrospective case series analysis of nine sibships. Al-Sannaa, NA., Bay, L., Barbouth, DS., et al.[2018]

Laronidase (Aldurazyme) has been shown to be a well-tolerated and effective enzyme replacement therapy for treating mucopolysaccharidosis type I (MPS I) in patients without neuronal involvement, based on pre-clinical studies and clinical trials.

Current challenges in treating MPS I include the need for early screening to identify patients before irreversible damage occurs, predicting disease severity, addressing neurological complications, and establishing effective patient monitoring protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Laronidase treatment of mucopolysaccharidosis I. Wraith, EJ., Hopwood, JJ., Fuller, M., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Laronidase (Aldurazyme): enzyme replacement therapy for mucopolysaccharidosis type I. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Alternative laronidase dose regimen for patients with mucopolysaccharidosis I: a multinational, retrospective, chart review case series. [2018]

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

A dose-optimization trial of laronidase (Aldurazyme) in patients with mucopolysaccharidosis I. [2008]

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

Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). [2022]

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

Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. [2009]

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

A follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 years. [2007]

7. England pubmed.ncbi.nlm.nih.gov

Early treatment with laronidase improves clinical outcomes in patients with attenuated MPS I: a retrospective case series analysis of nine sibships. [2018]

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

Laronidase treatment of mucopolysaccharidosis I. [2018]