ASP2016 + Prednisolone for Friedreich Ataxia

Recruiting at 4 trial locations

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Waitlist Available

Sponsor: Astellas Gene Therapies

No Placebo Group

Trial Summary

What is the purpose of this trial?

Friedreich Ataxia is a rare condition that causes damage to the nervous system and muscles. People with Friedreich Ataxia have difficulty walking, lose sensation in their arms and legs, and have slurred speech. It can also affect the heart and many people with Friedrich Ataxia develop serious heart problems. Friedreich Ataxia is a genetic condition which means a faulty gene is passed down through families. This type of gene therapy treats a genetic condition by providing a healthy copy of the gene. At the time this study started, there was no approved treatment for heart problems in people with Friedreich Ataxia. In this study, ASP2016 is being tested in humans for the first time. The people taking part are adults with Friedreich Ataxia who have heart problems. The main aims of the study are to check the safety of ASP2016 and how people cope with (tolerate) ASP2016. ASP2016 is given as a slow injection into a vein. This is called an infusion. People will also take tablets of a medicine called prednisolone. This is taken to stop the immune system interfering with ASP2016. Each person in the study will be given 1 single infusion of ASP2016. Different small groups will receive lower or higher doses of ASP2016. Each person will stay overnight in the clinic for at least 1 night after their infusion. For the first few months, people will visit the clinic regularly. There may be the option of home visits by a study nurse at some visits. At the 6-month and 12-month visits extra tests, procedures, and scans will be done. One of these is an ECHO (echocardiogram) scan. This is like an ultrasound scan for the heart. Another is an endomyocardial biopsy. A tiny piece of their heart tissue is removed (biopsy). A flexible hollow tube (catheter) goes into the blood vessels up to the heart. Then, a small device on the end of the catheter takes a tiny piece of heart tissue (about the size of a pencil tip). Another is a cardiac MRI. This takes pictures of the inside of the heart using a powerful magnet. Another is a cardiopulmonary exercise test (CPET). This involves moving a specially designed set of bicycle pedals using hands and arms. This will check how the lungs, heart and muscles are affected during exercise. After the 12-month visit, people will visit the clinic every few months for up to a few years.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop all current medications. However, if you are taking omaveloxolone, you may need to stop it for 3 weeks before enrolling or agree not to start it during the 52-week period after receiving the study intervention. Participants on omaveloxolone must also discontinue strong or moderate CYP3A4 inducers and inhibitors.

What data supports the idea that ASP2016 + Prednisolone for Friedreich Ataxia is an effective treatment?

The available research does not provide specific data on the effectiveness of ASP2016 + Prednisolone for Friedreich Ataxia. However, studies on similar treatments using adeno-associated viruses (AAV) to deliver the frataxin gene show promising results. For example, one study found that an AAV9 coding for frataxin improved symptoms and extended the lifespan of mouse models with Friedreich Ataxia. Another study demonstrated that an AAVrh.10hFXN treatment improved heart function and reduced mortality in mice. These findings suggest that gene therapy approaches, like ASP2016, could potentially be effective for treating Friedreich Ataxia. ^{1 2 3 4 5}

What safety data is available for ASP2016 + Prednisolone treatment in Friedreich Ataxia?

The provided research does not directly address the safety data for ASP2016 (also known as rAAV8-hPGK-hFXNco) combined with Prednisolone in Friedreich Ataxia. However, it discusses related gene therapy approaches using different adeno-associated virus (AAV) vectors for frataxin expression, such as AAV9 and AAVrh.10, which have shown potential in improving symptoms and cardiac function in mouse models. These studies highlight the importance of determining effective and safe dosing to avoid toxicity. Prednisolone, under various brand names, is a well-known corticosteroid with established safety profiles in other conditions, but specific safety data for its use in combination with ASP2016 for Friedreich Ataxia is not provided in the research. ^{2 3 4 6 7}

Is the treatment ASP2016 a promising treatment for Friedreich Ataxia?

Yes, ASP2016 is a promising treatment for Friedreich Ataxia. It uses a virus to deliver a healthy version of the frataxin gene, which is important because people with this condition have a faulty version of this gene. Studies in mice have shown that similar treatments can improve symptoms and extend life. This suggests that ASP2016 could help people with Friedreich Ataxia by increasing the levels of the frataxin protein in their bodies. ^{1 2 3 5 8}

Research Team

Global Medical Lead

Principal Investigator

Astellas Pharma Global Development, Inc.

Eligibility Criteria

Adults with Friedreich Ataxia and associated heart disease can join this trial. They must be able to tolerate the treatment and agree to overnight clinic stays, regular visits, or home nurse visits. The study excludes those who might have complications from gene therapy or cannot undergo necessary tests like biopsies.

Inclusion Criteria

My heart's pumping ability is moderately reduced.

I am not taking strong or moderate drugs that affect liver enzyme CYP3A4 while on omaveloxolone.

I stopped taking omaveloxolone 3 weeks ago and passed the liver function tests.

Exclusion Criteria

My heart scan shows significant scarring.

I cannot undergo certain heart tissue tests due to health risks.

Participant has a contraindication to cardiac magnetic resonance imaging (CMRI) with contrast, including hypersensitivity to gadolinium contrast agent, cardiac pacemaker or implantable cardiac defibrillator

Treatment Details

Interventions

• ASP2016 (Gene Therapy)
• Prednisolone (Corticosteroid)

Trial Overview The trial is testing ASP2016, a new gene therapy given as an infusion for treating heart problems in Friedreich Ataxia patients. It's being tested alongside prednisolone tablets to check safety and tolerance at different doses.

Participant Groups

Group I: ASP2016 Experimental Treatment 2 Interventions

Participants will receive a single dose of ASP2016. Participants will also receive daily prednisolone beginning 1 day prior to ASP2016 dose and for at least 16 weeks after ASP2016 dose, in order to suppress the immune response to ASP2016.

Who Is Running the Clinical Trial?

Astellas Gene Therapies

Lead Sponsor

Trials

7

Recruited

400+

Findings from Research

A new cellular assay was developed to measure frataxin expression from the FRDA gene, which is crucial for identifying potential treatments for Friedreich ataxia, a neurodegenerative disease affecting motor function.

The study successfully created fusion proteins of frataxin and enhanced green fluorescent protein (EGFP), allowing researchers to visualize and enhance FRDA gene expression, which could lead to the discovery of pharmacological agents that improve frataxin levels in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Upregulation of expression from the FRDA genomic locus for the therapy of Friedreich ataxia. Sarsero, JP., Li, L., Wardan, H., et al.[2023]

Gene therapy using an adeno-associated virus (AAV9) to deliver human frataxin significantly increased the lifespan of genetically modified mice with Friedreich ataxia, with the highest dose (6×10^11 v.p.) more than doubling their life expectancy.

The treatment also improved cardiac function, as shown by echocardiography, and successfully delivered the human frataxin protein to multiple organs, indicating its potential as a therapeutic approach for Friedreich ataxia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models. Gérard, C., Xiao, X., Filali, M., et al.[2020]

AAVrh.10hFXN, an adeno-associated virus vector delivering the human frataxin gene, shows promise in treating cardiac issues in Friedreich's ataxia, with a significant improvement in heart function and mortality observed at a dose of 1.8 × 10^12 gc/kg in a mouse model.

The study identified effective dosing levels that can achieve frataxin levels comparable to healthy human heterozygotes, suggesting potential for safe and effective treatment in larger animal models, paving the way for future clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia. Munoz-Zuluaga, C., Gertz, M., Yost-Bido, M., et al.[2023]

The YG8-800 mouse model, which has a human frataxin transgene with 800 GAA repeats, exhibits a phenotype that closely resembles the symptoms of Friedreich ataxia in humans, making it a more suitable model for studying the disease.

Injecting YG8sR mice with an AAV-PHP.B that delivers shRNA targeting the frataxin gene enhances their disease phenotype, indicating that this approach could be useful for testing potential therapies in a model that better reflects the severity of human FRDA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype. Bouchard, C., Gérard, C., Yanyabé, SG., et al.[2023]

Researchers identified key DNA sequences that regulate the expression of the frataxin (FXN) gene, which is crucial for treating Friedreich's ataxia (FRDA), by testing 19 different DNA constructs in human cells.

The study demonstrated that FXN expression could be successfully achieved in both human-induced pluripotent stem cells and in vivo in mice, suggesting that these regulatory sequences could be used in future gene therapy approaches for FRDA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defining Transcription Regulatory Elements in the Human Frataxin Gene: Implications for Gene Therapy. Li, J., Li, Y., Wang, J., et al.[2023]

A novel therapeutic approach using TALEs (Transcription Activator-Like Effectors) fused with a transcription activation domain successfully increased frataxin expression in fibroblasts from Friedreich ataxia patients, showing a twofold increase in frataxin mRNA and protein levels.

The specific TALEFrat#8-VP64 construct was effective in both patient-derived fibroblasts and a mouse model, suggesting its potential as a treatment for alleviating symptoms of Friedreich ataxia, although other tested TADs did not enhance frataxin expression significantly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins. Chapdelaine, P., Coulombe, Z., Chikh, A., et al.[2022]

Dimethyl fumarate (DMF) has been identified as a potential therapy for Friedreich's Ataxia (FA) by significantly increasing the expression of the frataxin gene (FXN) in both cell and mouse models, as well as in humans, suggesting its efficacy in addressing the underlying cause of the disease.

The mechanism by which DMF enhances FXN expression involves reducing harmful R-loop formations that inhibit transcription, leading to improved mitochondrial function and a notable 85% increase in FXN expression in patients with Multiple Sclerosis treated with DMF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich's Ataxia. Jasoliya, M., Sacca, F., Sahdeo, S., et al.[2023]

The study demonstrates that the high-capacity herpes simplex virus type 1 (HSV-1) amplicon vector can effectively deliver the entire FXN genomic locus, leading to the production of three frataxin isoforms in both cultured neuronal cells and in vivo, which is crucial for treating Friedreich's ataxia.

Delivery of the iBAC-FXN vector resulted in correct expression of frataxin isoforms in patient-derived cells, highlighting the potential of this gene therapy approach for long-term treatment of hereditary ataxia caused by FXN mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delivery of the 135 kb human frataxin genomic DNA locus gives rise to different frataxin isoforms. Pérez-Luz, S., Gimenez-Cassina, A., Fernández-Frías, I., et al.[2023]

References

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

Upregulation of expression from the FRDA genomic locus for the therapy of Friedreich ataxia. [2023]

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

An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models. [2020]

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

Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype. [2023]

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

Defining Transcription Regulatory Elements in the Human Frataxin Gene: Implications for Gene Therapy. [2023]

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

A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins. [2022]

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

Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich's Ataxia. [2023]

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

Delivery of the 135 kb human frataxin genomic DNA locus gives rise to different frataxin isoforms. [2023]