A Study of ASP2016 in Adults Who Have Heart Disease Associated With Friedreich Ataxia

A Multicenter, Open-Label, Dose Escalation, Phase 1b Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of ASP2016 for Friedreich Ataxia Cardiomyopathy

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.

Inclusion Criteria:

• Participant has both a clinical diagnosis of Friedreich ataxia (FA) and a documented history of genetic diagnosis of FA with either a guanine-adenine-adenine (GAA) trinucleotide repeat (TNR) expansion in intron 1 of both gene for frataxin (FXN) alleles or a GAA TNR expansion of intron 1 of one FXN allele and a pathogenic variant in the other FXN allele.
• Participant has a resting LVEF ≥ 40% and < 55% as measured at screening by ECHO.
• Participant has a body mass index range of 17.0 to 30.0 kg/m2.
• Participant agrees not to begin omaveloxolone treatment during the 52-week period after receiving study intervention.
• Participants on omaveloxolone, who opt to discontinue omaveloxolone, may enroll if they stop omaveloxolone for 3 weeks and pass study screening, including LFTs.
• Participants on omaveloxolone, who opt to stay on omaveloxolone will need to have been on it for a minimum of 3 months, with LFTs that pass diagnostic assessments exclusion criteria at screening and prior to dosing with ASP2016. Prior elevation(s) in AST/ALT associated with omaveloxolone use must be discussed with the sponsor medical monitor. If there is a liver function test (LFT) elevation after treatment, participant agrees to stop omaveloxolone treatment until 52 weeks.
• Participants on omaveloxolone will need to discontinue strong or moderate cytochrome P450 3A4 (CYP3A4) inducers and inhibitors.
• Woman of Child Bearing Potential (WOCBP) on omaveloxolone must use a nonhormonal, highly effective methods of contraception (e.g., nonhormonal intrauterine device system), as omaveloxolone may interfere with hormonal methods of contraception.

Exclusion Criteria:

• Participant has late-onset FA, defined as symptom onset after the age of 25 years.
• Participant is unable to complete cardiopulmonary exercise testing (CPET) procedure.
• Participant has a contraindication to endomyocardial biopsy or cardiac catheterization.
• Participant has a contraindication to cardiac magnetic resonance imaging (CMRI) with contrast, including hypersensitivity to gadolinium contrast agent, cardiac pacemaker or implantable cardiac defibrillator.
• Participant has an elevated titer of anti-AAV8 total antibodies, as determined by central testing.
• Participant has significant fibrosis on CMRI, defined as late gadolinium enhancement of > 15% left ventricular myocardial mass.