Antibody Levels and Biomarkers for Pompe Disease

Recruiting at 53 trial locations

Overseen By Astellas Gene Therapies

Age: Any Age

Sex: Any

Trial Phase: Academic

Sponsor: Astellas Gene Therapies

Must be taking: Enzyme replacement

Disqualifiers: AAV therapy, Gene therapy, Ventilation support, others

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

Compensation: Varies

Number of Visits: 6

100 Participants Needed

Trial Summary

What is the purpose of this trial?

Pompe disease is a genetic condition which causes muscle weakness over time. People with Pompe disease have a faulty gene that makes an enzyme called acid alpha-glucosidase (or GAA). This enzyme breaks down a type of sugar called glycogen. Without this enzyme, there is a build-up of glycogen in the cells of the body. This causes muscle weakness and other symptoms. Pompe disease can happen at any age, but in late-onset Pompe disease, symptoms generally start from 12 months old onwards. The standard treatment for people with Pompe disease is to receive regular infusions of the GAA enzyme. This is known as enzyme replacement therapy. However, people can build up antibodies against the GAA enzyme over time. Gene therapy is used to treat conditions caused by a faulty gene. It works by replacing the faulty gene with a working gene inside the cells of the body. The working gene is delivered into the cells using certain viruses as carriers (vectors). Viruses are often used as carriers as they can easily get inside cells. The genetic material of the original virus is replaced with the working gene, so only the working gene gets inside the cells. A common virus used as a carrier in gene therapy is the adeno-associated virus (or AAV). This is like an adenovirus, which causes the common cold. The original type of AAV does not cause any harm to humans. However, people that have previously been infected with the original type of AAV may have built up antibodies against AAV. These antibodies may stop the AAV carrier with the working gene getting inside the cells. Researchers want to learn more about antibody levels against AAV and the GAA enzyme in people with late-onset Pompe disease. They also want to learn about other substances in the blood that provide more information about late-onset Pompe disease. These are known as biomarkers. In this study, older teenagers and adults with late-onset Pompe disease will take part. They will not have had gene therapy using AAV. There will be 2 groups - those who have never had enzyme replacement therapy, and those who have had enzyme replacement therapy for 6 months or more. No study treatment will be given during the study, but blood and urine samples will be taken for testing. The main aims of the study are to check antibody levels against AAV8 (a type of AAV) in people with late-onset Pompe disease who had not received any treatment using AAV, to check antibody levels against the GAA enzyme in people previously treated with GAA as part of enzyme replacement therapy, to check levels of biomarkers for Pompe disease, and to check for medical problems. In the study, people will visit the study clinic several times. Some visits may be in the person's home. The first visit is to check if they can take part. Those who can take part will have a medical examination, and have their vital signs checked. Vital signs include blood pressure, heart rate, breathing rate and temperature. Blood samples will be taken to check antibody levels against the GAA enzyme and against AAV8. Blood and urine samples will also be taken to check for biomarkers for Pompe disease. Blood and urine samples will be taken about every 4 months for up to 2 years.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on enzyme replacement therapy (ERT), you must have been on it for at least 6 months to participate.

What data supports the effectiveness of the treatment for Pompe Disease?

The research shows that enzyme replacement therapy (ERT) is effective in treating Pompe disease, as it has been shown to prolong survival in infantile-onset Pompe disease and is effective for adults with late-onset Pompe disease. ^{1 2 3 4 5}

Is the treatment for Pompe disease safe for humans?

The treatment, enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA), has been studied for safety in both infantile-onset and late-onset Pompe disease. While it has shown to prolong survival, it can cause immune responses and central nervous system changes, indicating some safety concerns. ^{3 5 6 7 8}

How does this drug differ from other treatments for Pompe disease?

This drug, enzyme replacement therapy (ERT) with alglucosidase alpha (rhGAA), is unique because it involves replacing the missing enzyme in Pompe disease patients, which helps improve muscle function and prolong survival. However, many patients develop antibodies against the drug, which can affect its effectiveness, although low to intermediate antibody levels may not significantly impact clinical outcomes. ^{1 2 5 9 10}

Research Team

Medical Director

Principal Investigator

Astellas Gene Therapies

Eligibility Criteria

This study is for older teens and adults with late-onset Pompe disease, a condition causing muscle weakness. Participants either have never had enzyme replacement therapy or have been on it for at least 6 months. They must be able to attend study visits and agree not to join other clinical trials during this one.

Inclusion Criteria

I have never had enzyme replacement therapy or have been on it for 6+ months.

I have been diagnosed with Late-Onset Pompe Disease (LOPD).

You promise not to join any other research studies with new treatments while you are in this study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Baseline Assessment

Participants undergo a medical examination and have their vital signs checked. Blood and urine samples are taken to check antibody levels and biomarkers.

1 visit

1 visit (in-person)

Monitoring

Blood and urine samples are collected approximately every 4 months to monitor antibody levels and biomarkers.

Up to 2 years

Visits every 4 months (in-person or at home)

Follow-up

Participants are monitored for any medical problems and changes in antibody levels and biomarkers.

Up to 2 years

Treatment Details

Interventions

• No Intervention

Trial Overview The study isn't testing a new treatment but is looking at antibody levels against AAV8 (a harmless virus used in gene therapy) and the GAA enzyme involved in standard Pompe disease treatment. It also measures biomarkers related to the disease through regular blood and urine tests over two years.

Participant Groups

Group I: Participants with Late-Onset Pompe Disease Experimental Treatment 1 Intervention

Adolescent or adult participants with LOPD.

Who Is Running the Clinical Trial?

Astellas Gene Therapies

Lead Sponsor

Trials

7

Recruited

400+

Findings from Research

Out of 344,056 newborns screened since 2005, 13 were identified with later-onset Pompe disease, demonstrating that newborn screening effectively facilitates early detection of this condition.

Early treatment was initiated for four patients based on symptoms like hypotonia and muscle weakness, highlighting the importance of monitoring motor development and serum creatine kinase levels for timely intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. Chien, YH., Lee, NC., Huang, HJ., et al.[2022]

In a study of 168 patients with infantile-onset Pompe disease, the median age for symptom onset was 2 months, with a high mortality rate; only 25.7% survived past 12 months and 12.3% were ventilator-free.

Key symptoms such as cardiomegaly, hypotonia, and respiratory distress typically appeared around 4 months of age, and early symptom onset was linked to a higher risk of early death, highlighting the severe nature of this condition despite treatment efforts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. Kishnani, PS., Hwu, WL., Mandel, H., et al.[2022]

Enzyme replacement therapy (ERT) for adults with late-onset Pompe disease showed significant improvements in walking distance and muscle strength over the first two years of treatment, based on a study of 62 patients.

However, ERT did not demonstrate a statistically significant impact on respiratory function or body mass index, indicating that while ERT is effective for certain outcomes, it may not address all aspects of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of enzyme replacement therapy in adults with late-onset Pompe disease: results from the NCS-LSD cohort study. Anderson, LJ., Henley, W., Wyatt, KM., et al.[2022]

Newborn screening for classic infantile-onset Pompe disease (IOPD) allows for early treatment with recombinant human acid α-glucosidase (rhGAA), leading to positive long-term outcomes such as independent walking and no need for mechanical ventilation in all patients studied.

After a median treatment duration of 63 months, while patients showed good motor function and daily activity participation, some experienced gradual muscle weakness and common speech disorders, indicating that while rhGAA is effective, there are still limitations and ongoing challenges in managing the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth. Chien, YH., Lee, NC., Chen, CA., et al.[2022]

In a study of 23 infants with infantile Pompe disease (IPD), 70% showed neuroimaging abnormalities at baseline, but many of these issues, such as ventricular enlargement and cerebrospinal fluid accumulation, improved significantly with enzyme replacement therapy (ERT) over time.

Follow-up imaging revealed emerging white matter changes in some older patients, highlighting the need for ongoing neuroimaging to monitor potential complications like cerebral aneurysms in patients receiving ERT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroimaging findings in infantile Pompe patients treated with enzyme replacement therapy. McIntosh, PT., Hobson-Webb, LD., Kazi, ZB., et al.[2022]

In a study involving 8 infants with infantile-onset Pompe disease, treatment with recombinant human acid alpha-glucosidase (rhGAA) for 52 weeks resulted in improved survival rates, with 6 out of 8 patients alive and 5 free from invasive ventilator support by the end of the study.

The treatment was found to be safe and well tolerated, leading to significant clinical improvements in cardiomyopathy, growth, and motor function, with patients achieving new motor milestones and a median age at death or treatment withdrawal of 21.7 months, which is significantly later than expected for untreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chinese hamster ovary cell-derived recombinant human acid alpha-glucosidase in infantile-onset Pompe disease. Kishnani, PS., Nicolino, M., Voit, T., et al.[2022]

In a study of 6 Hungarian patients with Pompe disease receiving enzyme replacement therapy (ERT), it was found that treatment led to increased activation of T cells, indicating a pro-inflammatory immune response.

The therapy also resulted in a dose-dependent increase in interferon-gamma (IFN-γ) production from T cells, suggesting that while ERT is effective, it may provoke immune responses that could interfere with its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzyme replacement therapy induces T-cell responses in late-onset Pompe disease. Banati, M., Hosszu, Z., Trauninger, A., et al.[2011]

Avalglucosidase alfa demonstrated a positive clinical effect in individuals with infantile-onset Pompe disease who had previously shown clinical decline on alglucosidase alfa, with trends indicating improved motor function, especially at the 40 mg/kg dose.

The study, involving 22 participants over a 25-week period, reported high treatment compliance (100%) and no serious treatment-related adverse events, suggesting that avalglucosidase alfa is safe and well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of avalglucosidase alfa in individuals with infantile-onset Pompe disease enrolled in the phase 2, open-label Mini-COMET study: The 6-month primary analysis report. Kishnani, PS., Kronn, D., Brassier, A., et al.[2023]

In a study of 25 patients with late onset Pompe disease treated with enzyme replacement therapy (ERT), 72% developed antibodies against the treatment, but these antibodies did not significantly affect clinical outcomes over one year.

Patients with low to intermediate antibody titers showed no differences in muscle function, respiratory performance, or muscle imaging results compared to those without antibodies, suggesting that these antibody levels may not impact the efficacy of ERT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study of the effect of anti-rhGAA antibodies at low and intermediate titers in late onset Pompe patients treated with ERT. Fernández-Simón, E., Carrasco-Rozas, A., Gallardo, E., et al.[2020]

In a study of 243 patients with infantile Pompe disease, 25.1% were identified as CRIM-negative, which is associated with poor response to enzyme replacement therapy (ERT) due to high antibody levels against the treatment.

Understanding a patient's CRIM status, which can often be predicted from GAA gene mutations, is crucial before starting ERT, as it can guide immunomodulation strategies to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience. Bali, DS., Goldstein, JL., Banugaria, S., et al.[2022]

References

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

Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. [2022]

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

A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. [2022]

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

Effectiveness of enzyme replacement therapy in adults with late-onset Pompe disease: results from the NCS-LSD cohort study. [2022]

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

Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth. [2022]

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

Neuroimaging findings in infantile Pompe patients treated with enzyme replacement therapy. [2022]

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

Chinese hamster ovary cell-derived recombinant human acid alpha-glucosidase in infantile-onset Pompe disease. [2022]

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

Enzyme replacement therapy induces T-cell responses in late-onset Pompe disease. [2011]

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

Safety and efficacy of avalglucosidase alfa in individuals with infantile-onset Pompe disease enrolled in the phase 2, open-label Mini-COMET study: The 6-month primary analysis report. [2023]

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

Study of the effect of anti-rhGAA antibodies at low and intermediate titers in late onset Pompe patients treated with ERT. [2020]

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

Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience. [2022]