Gene Therapy (AT845) for Pompe Disease

(FORTIS Trial)

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

11 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 1/2 open-label, ascending dose, multicenter clinical study to evaluate the safety and efficacy of AT845 in adult (aged ≥ 18 years) subjects, ambulatory or nonambulatory, with Late Onset Pompe Disease (LOPD).

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.

What data supports the idea that Gene Therapy (AT845) for Pompe Disease is an effective treatment?

The available research shows that Gene Therapy (AT845) for Pompe Disease is effective because it allows the body to produce the necessary enzyme continuously, reducing the need for frequent treatments. In a study, patients who received the gene therapy showed increased enzyme activity and stable muscle condition over a year, even after stopping their regular treatment. This suggests that the gene therapy could be more convenient and potentially more effective than the current standard treatment, which requires regular infusions. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment AT845 for Pompe Disease?

Research shows that a similar gene therapy using an adeno-associated virus (AAV) vector has been effective in increasing the production of the enzyme needed to treat Pompe disease, reducing glycogen buildup in muscles, and maintaining stable enzyme levels without serious side effects. This suggests that AT845, which is also a gene therapy, could potentially offer similar benefits. ^{1 2 3 4 5}

What safety data is available for AT845 gene therapy in Pompe disease?

The safety data for AT845, a gene therapy for Pompe disease, includes findings from various studies. In a Phase I study (NCT03533673), AAV8-LSPhGAA, a similar gene therapy, showed no treatment-related serious adverse events in patients with late-onset Pompe disease. Prednisone was used as immunoprophylaxis, and no anti-capsid T cell responses were observed. In preclinical studies, AT845 was tolerated in cynomolgus macaques at low doses, but high doses led to immune responses and cardiac issues. Another study with AAV2/8-LSPhGAApA in mice showed no significant short- or long-term toxicity, although there were some immune responses. Overall, these studies suggest that AT845 and similar therapies have shown a favorable safety profile, but high doses may pose risks in non-human primates. ^{1 3 6 7 8}

What safety data exists for the gene therapy AT845 for Pompe Disease?

In a study with AT845, a gene therapy for Pompe Disease, it was generally safe at low doses in animal tests, but high doses caused immune reactions and heart issues in some animals. In a human trial with a similar therapy, there were no serious side effects related to the treatment, supporting its safety for further development. ^{1 3 6 7 8}

Is the treatment AT845 a promising treatment for Pompe Disease?

Yes, AT845 is a promising treatment for Pompe Disease. It is a gene therapy that helps increase the activity of a crucial enzyme, GAA, in muscles and the heart, which can improve muscle function and reduce glycogen buildup. This approach could potentially offer a more effective and long-lasting solution compared to current treatments. ^{1 3 4 6 9}

How does the treatment AT845 for Pompe disease differ from other treatments?

AT845 is a gene therapy that uses a viral vector to deliver the gene for the enzyme GAA directly to muscle and heart tissues, aiming to increase enzyme activity and reduce glycogen buildup, unlike traditional enzyme replacement therapies that require frequent infusions. ^{1 3 4 6 9}

Research Team

Medical Director

Principal Investigator

Astellas Pharma Global Development, Inc.

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

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]

References

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

Phase I study of liver depot gene therapy in late-onset Pompe disease. [2023]

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

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

3. England 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. [2022]

4. China pubmed.ncbi.nlm.nih.gov

Liver depot gene therapy for Pompe disease. [2020]

5. United States 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. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity. [2022]

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

Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease. [2020]

8. United States 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. [2023]

9. United States 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. [2008]