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Friedreich’s ataxia (FA) is a rare, inherited progressive genetic neuromuscular disease with high unmet medical need

FA affects the nerves and spinal cord, causing loss of control of body movements (ataxia)

A person with FA

Will usually need a wheelchair within 10 to 20 years of symptoms beginning

May be completely incapacitated in later stages of the disease

May have a shortened life span


Mortality in FA is most commonly due to cardiac complications

59% of FA deaths are from cardiac dysfunction

Only symptomatic treatment options are available, with none addressing the underlying cause of the disease—the defective frataxin gene

FA is the
most common hereditary ataxia

Males and females
are equally affected

One in every 40,000 to
50,000 people have FA

Approximately 9,000 patients
in the United States and ~26,000 patients in the European Union are affected

FA is a multisystem disease

Cardiac
Hypertrophic and dilated cardiomyopathy, arrhythmia, and mortality

Skeletal abnormalities
Scoliosis and pes cavus

Hearing loss
Auditory neuropathy/dyssynchrony and vestibular dysfunction

Endocrine
Diabetes, impaired fasting glucose, and impaired glucose tolerance

Vision
Nystagmus and oculomotor disturbances

Fatigue
Nearly all patients experience significant fatigue that impacts quality of life


FA also shows progressive neurological symptoms

LOSS of balance and coordination

• Progressive gait and balance instability
• Impaired coordination affecting mobility
• Loss of reflexes
• Dysarthria (slurred speech)

LOSS of sensation in the arms and legs

LOSS of vision and hearing

Living with FA

Frataxin

The primary cause of FA is a triplet repeat mutation in the FXN gene, which codes for the frataxin protein

Frataxin is a mitochondrial iron-binding protein involved in iron homeostasis

Iron is critical for many essential cellular processes, including energy production. However, too little or too much iron can be harmful

The frataxin deficiency associated with FA disrupts iron regulation and mitochondrial function

As a result, cells in the heart and brain accumulate iron, which promotes the production of reactive oxygen species and leads to mitochondrial damage

Genetics of FA

An increased number of GAA repeats between exon 1 and 2 of the FXN gene are implicated with the cause and severity of the disease

The FXN gene is located
on chromosome
9q13-q21.1

Normal FXN has GAA repeat levels ranging from 1 to 43

Mutated FXN has GAA repeat levels ranging from 44 to 1,700

FA is a natural candidate for gene transfer therapy

These factors contribute to making FA a natural candidate for gene therapy treatment

Recessive disease is caused by a single gene

Phenotype is directly related to the amount of frataxin

Carriers are clinically unaffected even with reduced frataxin levels

All patients express some frataxin and no aberrant protein, so the immune system recognizes frataxin as self

Targeting of one or more affected organs will be clinically meaningful

Proof of concept in animal models suggests viability of therapy

AavantiBio’s distinctive approach is to specifically target both the neurological and the cardiac impairments caused by FA

AVB-202 for the treatment of FA

We optimized our gene transfer therapy construct to target the genetic root cause of FA in the tissues most impacted

AVB-202 is being developed with a transgene to encode full-length frataxin protein (210 amino acids) packaged into an AAV9 capsid under the control of a promoter specifically designed to drive expression in neurons and cardiac cells and target the neurological and cardiac manifestations of FA

The AVB-202 construct combined with a dual route of administration and our novel immunomodulatory strategy optimizes the safety, efficacy, and potential for AVB-202 to be best in class in FA

References

1. Cnop M, et al. J Neurochem. 2013;126(Suppl 1):94-102. 2. Cook A, Giunti P. Br Med Bull. 2017;124(1):19-30. 3. Dürr A, et al. N Engl J Med. 1996;335(16):1169-1175. 4. European Medicines Agency. EU/3/18/2037: Public summary of opinion on orphan designation: Omaveloxolone for treatment of Friedreich’s ataxia. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3182037. Accessed December 16, 2020. 5. Koeppen AH. J Neurol Sci. 2011;303(1-2):1-12. 6. Llorens JV, et al. Front Neurosci. 2019;13:75. 7. National Institute of Neurological Disorders and Stroke. Friedreich’s Ataxia Fact Sheet. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Friedreichs-Ataxia-Fact-Sheet. Accessed December 14, 2020. 8. National Organization for Rare Disorders. Friedreich’s Ataxia. https://rarediseases.org/rare-diseases/friedreichs-ataxia/. Accessed November 4, 2020. 9. Parkinson MH, et al. J Neurochem. 2013;126(Suppl 1):103-117. 10. Ruano L, et al. Neuroepidemiology. 2014;42(3):174-183. 11. Sandi C, et al. Front Genet. 2014;5:165. 12. Santos R, et al. Antioxid Redox Signal. 2010;13(5):651-690. 13. Schmucker S, Puccio H. Hum Mol Genet. 2010;19(R1):R103-R110. 14. Tsou AY, et al. J Neurol Sci. 2011;307(1-2):46-49.