ASP2016 + Prednisolone for Friedreich Ataxia

Recruiting at 4 trial locations

Overseen By Astellas Pharma Global Development Inc.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Astellas Gene Therapies

Must be taking: Prednisolone

Disqualifiers: Late-onset FA, CPET inability, others

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

Compensation: Varies

Number of Visits: 6

Duration: 16 weeks

14 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new treatment, ASP2016 (a gene therapy), for individuals with Friedreich Ataxia, a rare genetic condition affecting the nervous system and heart. Participants will receive an infusion of ASP2016 along with prednisolone tablets to aid in treatment acceptance. The trial will focus on assessing the safety and tolerance of ASP2016. It is open to adults diagnosed with Friedreich Ataxia who are experiencing heart problems. As a Phase 1 trial, participants will be among the first to receive this new treatment, assisting researchers in understanding its effects in people.

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.

Is there any evidence suggesting that ASP2016 is likely to be safe for humans?

Research shows that ASP2016 is a gene therapy using a virus to deliver a healthy version of a gene. This therapy targets heart problems related to Friedreich Ataxia. In animal studies, similar therapies have shown promise in reversing heart issues without major side effects.

ASP2016 is in the early stages of human testing, marking its first trial in people. As a result, limited safety information exists for humans. However, similar gene therapies have been studied and are generally well-tolerated in other conditions. The trial will closely monitor participants to assess their response to the treatment.

Participants will also take prednisolone, a medicine that helps prevent the immune system from reacting to the gene therapy. Prednisolone is commonly used and generally considered safe, though it can cause side effects like increased appetite or mood changes.

Overall, while ASP2016 is new in humans, existing research on similar treatments and the careful monitoring in this trial aim to ensure safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Friedreich Ataxia?

ASP2016 is unique because it introduces a novel approach to treating Friedreich Ataxia by using a single-dose format combined with prednisolone to manage the immune response. Unlike current treatments that primarily focus on symptom management, ASP2016 targets the underlying causes of the disease, offering a potential breakthrough in how Friedreich Ataxia is treated. Researchers are particularly excited about its ability to work on a molecular level, which could pave the way for more effective long-term management of this condition.

What evidence suggests that ASP2016 might be an effective treatment for Friedreich Ataxia?

Research shows that ASP2016, which participants in this trial will receive, might help treat heart issues in people with Friedreich Ataxia. This gene therapy uses a virus to deliver a healthy version of the frataxin gene, defective in those with the condition. Animal studies have demonstrated that this method can repair heart damage associated with Friedreich Ataxia. Although limited information exists from human studies, the mechanism suggests potential benefits. In this trial, Prednisolone accompanies ASP2016 to help the body accept the treatment. ^{1 2 3 4 5}

Who Is on the Research Team?

Global Medical Lead

Principal Investigator

Astellas Pharma Global Development, Inc.

Are You a Good Fit for This Trial?

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.

Participant agrees not to begin omaveloxolone treatment during the 52-week period after receiving study intervention

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single infusion of ASP2016 and daily prednisolone for at least 16 weeks

16 weeks

Regular clinic visits, with potential home visits by a study nurse

Follow-up

Participants are monitored for safety and effectiveness after treatment, with additional tests at 6-month and 12-month visits

12 months

Clinic visits every few months, with extra tests at 6 and 12 months

Long-term follow-up

Participants continue to visit the clinic every few months for up to a few years to monitor long-term safety and efficacy

Up to 60 months

What Are the Treatments Tested in This Trial?

Interventions

• ASP2016
• Prednisolone

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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]

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]

Citations

1. orpha.net orpha.net/en/drug/substance/688356

Knowledge on rare diseases and orphan drugs Recombinant adeno-associated virus serotype 8 expressing codon optimized human frataxin gene cDNA under the control of a ubiquitous hPGK promoter (rAAV8-hPGK ...

2. synapse.patsnap.com synapse.patsnap.com/drug/67ecf726dbad42c891b3400664230850

ASP-2016 - Drug Targets, Indications, Patents rAAV8-hPGK-hFXNco, recombinant adeno-associated virus serotype 8 expressing codon optimized human frataxin gene cDNA under the control of a ubiquitous hPGK ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10862410/

AAV8 gene therapy reverses cardiac pathology and prevents ... These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy. Keywords: Friedreich's ataxia, frataxin, cardiomyopathy, adeno-associated ...

4. cell.com cell.com/molecular-therapy-family/methods/pdf/S2329-0501(24)00009-3.pdf

AAV8 gene therapy reverses cardiac pathology and ... Development of frataxin gene expression measures for the evaluation of experimental treatments in Friedreich's ataxia. PLoS One 8, e63958.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06483802

A Study of ASP2016 in Adults Who Have Heart Disease ... A Study of ASP2016 in Adults Who Have Heart Disease Associated With Friedreich Ataxia. ClinicalTrials.gov ID NCT06483802. Sponsor Astellas Gene Therapies.