In Utero Enzyme Replacement Therapy for Lysosomal Storage Diseases

(PEARL Trial)

Overseen By Emma Canepa, MS, CCRP

Age: 18 - 65

Sex: Female

Trial Phase: Phase 1

Sponsor: University of California, San Francisco

Must not be taking: Anticoagulants

Disqualifiers: Severe anomaly, Cardiopulmonary disease, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: Throughout pregnancy

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method of administering enzyme replacement therapy (Aldurazyme, or laronidase) to unborn babies diagnosed with Lysosomal Storage Diseases (LSDs). Researchers aim to determine the safety and feasibility of treating these conditions before birth by delivering the treatment through the umbilical vein. This trial targets pregnant women whose fetuses have been diagnosed with specific LSDs. The goal is to improve the health of babies by initiating treatment earlier than usual. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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 prior data suggests that in utero enzyme replacement therapy is safe for fetuses with Lysosomal Storage Diseases?

Research has shown that Aldurazyme, also known as laronidase, is generally safe for humans. Common side effects are usually mild, such as a rash or fever. However, some individuals have experienced allergic reactions, which can be serious and may occur during or shortly after treatment.

Aldurazyme is already approved for treating another condition, indicating it is usually well-tolerated. Although this trial involves administering the treatment before birth, existing safety data is promising. As this is an early phase trial, the primary goal is to study safety and practicality, so researchers will closely monitor safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about in utero enzyme replacement therapy (ERT) for lysosomal storage diseases because it represents a groundbreaking approach to treating these conditions before birth. Unlike traditional treatments, which typically begin after the baby is born, this therapy involves administering enzymes directly to the fetus through the umbilical vein. This early intervention could potentially prevent or significantly reduce the damage caused by enzyme deficiencies, offering hope for better health outcomes. By delivering the treatment in utero, there's a unique opportunity to address the disease at its earliest stages, potentially altering its course before it can impact the newborn's development.

What evidence suggests that in utero enzyme replacement therapy is effective for Lysosomal Storage Diseases?

Studies have shown that Aldurazyme (laronidase) effectively treats mucopolysaccharidosis type I (MPS I), a condition characterized by the buildup of certain substances in the body. Research indicates that enzyme replacement therapy (ERT), such as Aldurazyme, can help reduce this buildup. In this trial, participants will receive in utero enzyme replacement therapy with Aldurazyme. Early findings suggest that starting ERT before birth may enhance brain development, particularly if the enzyme influences brain function. In children with similar conditions, ERT has effectively managed symptoms and improved quality of life. This offers hope that using Aldurazyme before birth might provide similar benefits. ^{1 3 4 6 7}

Who Is on the Research Team?

Tippi Mackenzie, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Aldurazyme (laronidase)

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.

How Is the Trial Designed?

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.

Aldurazyme (laronidase) is already approved in European Union, United States for the following indications:

Approved in European Union as Aldurazyme for:

• Mucopolysaccharidosis I (MPS I); non-neurological symptoms

Approved in United States as Aldurazyme for:

• Hurler syndrome (MPS I); Hurler-Scheie forms of MPS I; Scheie form with moderate to severe symptoms

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04532047

Study Details | NCT04532047 | PEARL (PrEnAtal Enzyme ... It is also probable that in some cases, initiation of ERT in utero leads to improved neurodevelopmental outcomes if the replaced enzyme impacts the neurologic ...

2. withpower.com withpower.com/trial/phase-1-glycogen-storage-disease-type-ii-3-2021-63fbc

In Utero Enzyme Replacement Therapy for Lysosomal ... Laronidase (Aldurazyme) is effective as an enzyme replacement therapy for mucopolysaccharidosis type I (MPS I), a type of lysosomal storage disease, by reducing ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8800365/

Fetal therapies and trials for lysosomal storage diseases Enzyme replacement therapies (ERT) are effective therapies for children with various types of LSDs, including mucopolysaccharide diseases (MPS), ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6581069/

Enzyme replacement therapy with laronidase (Aldurazyme ... To evaluate the effectiveness and safety of treating mucopolysaccharidosis type I with laronidase enzyme replacement therapy as compared to placebo. Search ...

5. mdpi.com mdpi.com/1422-0067/21/8/2975

Intravenous Enzyme Replacement Therapy in ... The aim of this review is to summarize the evidence on efficacy, effectiveness and safety of intravenous enzyme replacement therapy (ERT) available for ...

6. ema.europa.eu ema.europa.eu/en/documents/product-information/aldurazyme-epar-product-information_en.pdf

Aldurazyme, INN-laronidase - EMA Aldurazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed ... 5.3 Preclinical safety data. Non-clinical data reveal no ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2023/125058s246lbl.pdf

Aldurazyme - accessdata.fda.gov Hypersensitivity reactions including anaphylaxis have been reported in patients during or up to. 3 hours after ALDURAZYME infusions. Some of these reactions ...