Gene Therapy (AT845) for Pompe Disease

(FORTIS Trial)

Not currently recruiting at 8 trial locations

Overseen By Astellas Pharma Global Development, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Audentes Therapeutics

Must be taking: Enzyme replacement therapy

Must not be taking: Immunosuppressive therapy, Antiviral therapy

Disqualifiers: HIV, Hepatitis B/C, Cardiomyopathy, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy called AT845 for individuals with Late Onset Pompe Disease (LOPD). The goal is to determine if AT845 is safe and effective for those who have received enzyme replacement therapy (ERT) for at least two years. The trial includes different groups receiving varying doses of AT845 through an IV infusion. Suitable candidates for this trial are those diagnosed with Pompe disease who have been on a stable dose of ERT and can walk at least 40 meters without stopping. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I have to stop taking my current medications for the trial?

The trial requires that you have been on a stable dose of enzyme replacement therapy (ERT) with rhGAA for at least 6 months before starting. Other medications for chronic conditions must be stable for at least 30 days before dosing. If you are on immune-modulating agents, you must stop them 90 days before dosing. If you are on drugs for myopathy or neuropathy with immunosuppressive therapy, you must stop them 3 months before starting the study.

Will I have to stop taking my current medications?

The trial requires that participants have been on a stable dose of enzyme replacement therapy (ERT) for at least 6 months before joining. Other medications for chronic conditions must be stable for at least 30 days before starting the trial. If you are taking immune-modulating agents or drugs for myopathy or neuropathy, you may need to stop them before participating.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that AT845, a gene therapy for Late Onset Pompe Disease (LOPD), has been safe so far. In studies, most participants handled the treatment well without serious side effects. The therapy involves an infusion that delivers genes to help the body produce an enzyme necessary for healthy muscles.

Reports from the FORTIS study, which focuses on AT845, indicate that the therapy appears safe for adults with LOPD. Although some minor side effects, such as temporary discomfort, have occurred, no major safety issues have been identified. Researchers continue to monitor participants to ensure the treatment remains safe and effective.

Overall, while more information is still being gathered, current evidence suggests that AT845 is well-tolerated by individuals with this condition. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard enzyme replacement therapies for Pompe disease, AT845 is a gene therapy that aims to provide a more lasting solution by delivering a functional copy of the GAA gene directly to the patient's cells. This allows the body to produce the enzyme acid alpha-glucosidase (GAA) internally, potentially reducing the need for frequent treatments. Researchers are excited about AT845 because it targets the root cause of the disease rather than just managing symptoms, offering the promise of more sustained improvements and better quality of life for patients.

What evidence suggests that this trial's treatments could be effective for Pompe Disease?

Research has shown that AT845, a gene therapy for Pompe disease, holds promise in treating this condition. Pompe disease occurs when the body lacks sufficient acid α-glucosidase (GAA), leading to muscle weakness. Studies in mice demonstrated that restoring GAA can alleviate muscle and breathing issues. Early human results suggest that AT845 might help by delivering a functional version of the GAA gene to the body, potentially improving muscle function and reducing symptoms for those with Late Onset Pompe Disease (LOPD). Although further research is necessary, the results so far are encouraging. Participants in this trial will receive varying doses of AT845 to assess its effectiveness and safety. ^{1 2 6 7 8}

Who Is on the Research Team?

Medical Director

Principal Investigator

Astellas Pharma Global Development, Inc.

Are You a Good Fit for This Trial?

Adults over 18 with Late Onset Pompe Disease (LOPD) who have been on enzyme replacement therapy for at least 2 years are eligible. They must not have certain allergies, be part of another study, or have conditions that could affect safety or results. Participants must agree to not donate blood or reproductive cells for a period after receiving the trial treatment.

Inclusion Criteria

Subject or legally authorized representative(s) (LAR) (if applicable) provides written informed consent.

Subject and LAR(s) are willing and able to comply with study visits and study procedures.

My lung function is at least 30% of what is expected for someone healthy.

Exclusion Criteria

You have high levels of GAA antibodies in your blood.

I am allergic or cannot take the study drug or corticosteroids due to health reasons.

I haven't taken immune-modulating drugs in the last 90 days, except for inhaled corticosteroids.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of AT845 via intravenous infusion

1 day

1 visit (in-person)

Core Observation

Participants are monitored for safety and efficacy with scheduled visits and assessments

48 weeks

Regular visits (in-person)

Long-term Follow-up

Participants are seen every 6 months for safety follow-up visits

Up to 5 years postdose

Biannual visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• AT845

Trial Overview

The clinical trial is testing AT845, a gene transfer therapy, in adults with LOPD to assess its safety and effectiveness. This phase 1/2 trial involves multiple centers where participants receive increasing doses of AT845 while their health outcomes are monitored.

How Is the Trial Designed?

Group I: Third Dose Cohort Experimental Treatment 1 Intervention

1x10\^14 vg/kg of AT845 administered via intravenous infusion

Group II: Second Dose Cohort Experimental Treatment 1 Intervention

6x10\^13 vg/kg of AT845 administered via intravenous infusion

Group III: Initial Dose Cohort Experimental Treatment 1 Intervention

3x10\^13 vg/kg of AT845 administered via intravenous infusion

Who Is Running the Clinical Trial?

Audentes Therapeutics

Lead Sponsor

Trials

8

Recruited

270+

Astellas Gene Therapies

Lead Sponsor

Trials

7

Recruited

400+

Published Research Related to This Trial

In a screening for a Phase I clinical trial of AAV gene therapy for late-onset Pompe disease (LOPD), 74% of the 19 participants had minimal or no neutralizing antibodies against the AAV8 vector, which is important for the therapy's effectiveness.

Participants showed significant variability in muscle function and lung capacity, with the average six-minute walk test distance at 60% of the expected range, indicating the need for careful patient selection in gene therapy trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Screening data from 19 patients with late-onset Pompe disease for a phase I clinical trial of AAV8 vector-mediated gene therapy. Hannah, WB., Case, LE., Smith, EC., et al.[2023]

In a 52-week study involving 3 patients with late-onset Pompe disease, gene therapy using the AAV8 vector showed promising safety and bioactivity, allowing subjects to discontinue enzyme replacement therapy (ERT) after 26 weeks without serious adverse events.

All participants exhibited sustained increases in serum GAA activity and significant improvements in muscle GAA activity by week 52, indicating that AAV8-LSPhGAA could effectively replace ERT and warrants further clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of liver depot gene therapy in late-onset Pompe disease. Smith, EC., Hopkins, S., Case, LE., et al.[2023]

Gene therapy using a recombinant adeno-associated virus (AAV8) vector to deliver human acid alpha-glucosidase (GAA) effectively corrected glycogen storage issues in muscles of presymptomatic Pompe mice, highlighting its potential as a treatment for Pompe disease.

Early administration of the AAV8/GAA therapy is crucial, as older mice with established symptoms showed only marginal improvements in motor function and no increase in muscle strength, indicating that timely intervention is key for preserving muscle health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ability of adeno-associated virus serotype 8-mediated hepatic expression of acid alpha-glucosidase to correct the biochemical and motor function deficits of presymptomatic and symptomatic Pompe mice. Ziegler, RJ., Bercury, SD., Fidler, J., et al.[2008]

Gene therapy for Pompe disease, using an adeno-associated virus (AAV) vector, has shown promise in early clinical trials by providing a single infusion that allows the liver to continuously produce the enzyme GAA, potentially surpassing the need for frequent enzyme replacement therapy (ERT).

This gene therapy not only corrects GAA deficiency and reduces glycogen accumulation in the heart and skeletal muscle but also induces immune tolerance to GAA, which may enhance its effectiveness compared to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver depot gene therapy for Pompe disease. Kishnani, PS., Koeberl, DD.[2020]

The recombinant adeno-associated virus serotype 8 (AAV2/8) vector showed no significant short- or long-term toxicity in a preclinical study, indicating it is safe for use as an adjunctive therapy for Pompe disease.

The AAV2/8 vector effectively increased enzyme activity and reduced glycogen accumulation in tissues, with better efficacy observed in male subjects compared to females, suggesting potential for improved treatment outcomes when combined with enzyme replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease. Wang, G., Young, SP., Bali, D., et al.[2020]

Higher doses of recombinant human acid-α glucosidase (rhGAA), up to 40 mg/kg weekly, are safe and lead to significant improvements in gross motor function, lingual strength, and pulmonary function in patients with infantile-onset and late-onset Pompe disease.

In a study of 11 patients who had been on standard enzyme replacement therapy for at least 12 months, those receiving higher doses showed better biochemical markers and no safety concerns, suggesting that dose escalation should be considered for patients experiencing clinical decline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature. Khan, AA., Case, LE., Herbert, M., et al.[2022]

In a phase 3 trial involving 100 participants with late-onset Pompe disease, avalglucosidase alfa demonstrated a significant improvement in respiratory function (measured by forced vital capacity) compared to the standard treatment, alglucosidase alfa, with a mean difference of 2.43%.

Avalglucosidase alfa also showed better outcomes in functional endurance (measured by the 6-minute walk test), indicating its potential as a more effective treatment option without new safety concerns compared to the existing therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial. Diaz-Manera, J., Kishnani, PS., Kushlaf, H., 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]

AT845, an adeno-associated viral vector designed to deliver human GAA to skeletal muscle and heart, showed effective glycogen clearance and functional improvement in a mouse model of Pompe disease, indicating its potential as a treatment.

While AT845 was tolerated at low doses in cynomolgus macaques, high doses triggered an immune response against the human GAA, leading to inflammation and cardiac issues, highlighting the challenges of using human proteins in animal models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity. Eggers, M., Vannoy, CH., Huang, J., et al.[2022]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04174105

NCT04174105 | Gene Transfer Study in Patients With Late ...

This study (FORTIS) will evaluate the safety and efficacy of an investigational gene replacement therapy, AT845, in adult subjects with LOPD.

2.

ncbi.nlm.nih.gov

ncbi.nlm.nih.gov/books/NBK470558/

Glycogen Storage Disease Type II - StatPearls - NCBI Bookshelf

Glycogen storage disease type II, or Pompe disease, is a rare inherited disorder caused by a deficiency of the enzyme acid α-glucosidase (GAA).

3.

sciencedirect.com

sciencedirect.com/science/article/pii/S1878747923004634

Therapeutic Approaches in Glycogen Storage Disease ...

Conclusion. ERT has been a major advance in the treatment of Pompe disease. The therapy results in a remarkable reversal of pathology in cardiac muscle in ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6642941/

Progress and challenges of gene therapy for Pompe disease

Experiments in Gaa−/− mice show that the expression of secretable GAA results in the rescue of muscle and cardiorespiratory impairment with reduced GAA ...

5.

mdaconference.org

mdaconference.org/abstract-library/two-year-safety-and-exploratory-efficacy-of-at845-gene-replacement-therapy-for-late-onset-pompe-disease-fortis-a-phase-1-2-open-label-clinical-study/

Two-year safety and exploratory efficacy of AT845 gene ...

Analysis of functional outcomes through 2-years post-treatment is ongoing and will be presented as available. This study is funded by Astellas Gene Therapies.

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6642935/

Liver depot gene therapy for Pompe disease - PMC

Overall, currently available data indicate that clinical trials evaluating the safety and efficacy of liver depot gene therapy are warranted in patients with ...

7.

newsroom.astellas.com

newsroom.astellas.com/2022-02-07-Astellas-Announces-Positive-Safety-Data-from-the-FORTIS-Study-of-AT845-in-Adults-with-Late-Onset-Pompe-Disease

Press release

Astellas Announces Positive Safety Data from the FORTIS Study of AT845 in Adults with Late-Onset Pompe Disease. Feb 7, 2022. - Data presented at the 18th ...

8.

checkrare.com

checkrare.com/gene-therapy-and-pompe-disease-preliminary-results-from-phase-i-ii-study-with-at845-2/

Gene Therapy and Pompe Disease: Preliminary Results ...

All participants showed evidence of AT845 vector transduction and an increase in GAA activity in the muscle compared to baseline.Three ...