Methylprednisolone Treatment of Friedreich Ataxia

Context:

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease of children and adults
for which there is presently no therapy. One of the hallmarks of FRDA is a deficiency of
frataxin protein, causing dysregulation of iron metabolism, lack of detoxification, and
increased iron bioavailability. The accumulation of iron in mitochondria leads to increased
sensitivity to oxidative stress. A secondary inflammatory response has also been proposed to
be present in FRDA, as revealed in autopsy studies and in the alteration of immune pathways
in microarray analysis. Inflammation in FRDA raises the possibility of a therapeutic benefit
from anti-inflammatory steroid treatment, as inflammation may directly underlie multiple
complications of FRDA including cardiomyopathy. In support of this theory are clinical
observations and patient self-reports of improvement of ataxia symptoms following the
prescription of steroids for indications other than the primary FRDA diagnosis.

Objectives:

Primary: To assess the effect of oral administration of methylprednisolone on the functional
performance scores of patients with FRDA using the Timed 25-Foot Walk (T25FW).

Secondary: To assess the effect of methylprednisolone on neurological performance measures
(Friedreich Ataxia Rating Scale, 9-Hole Peg Test, 1-minute walk, home-based measures of gait,
hand function and speech assessed through smartphone application) and to assess the safety
and tolerability of methylprednisolone in the FRDA population.

Study Design:

This study is an open-label clinical trial of methylprednisolone in patients with FRDA.

Setting/Participants:

This study will take place at the Children's Hospital of Philadelphia as an outpatient trial
in 5 children who are at least 5 years and less than 10 years of age, and in 5 adults ages 45
years and older, with genetically confirmed FRDA.

See below for description of study intervention and measures.

Inclusion Criteria:

- Subjects with FRDA confirmed by genetic testing who are able to walk 25 feet
(assistive devices allowed).

- Children between ages 5 and less than 10 years or adults ages 45 years and older at
screening.

- Stable doses of all medications, vitamins and supplements for 30 days prior to study
entry and for the duration of the study. Throughout the study, all possible efforts
will be made to maintain stable doses of concomitant medications.

- Females who are not pregnant or breast feeding, and who do not intend to become
pregnant. Females of child-bearing potential must use a reliable method of
contraception and must provide a negative urine pregnancy test at screening.

- Informed consent for adult participants, parent/guardian permission (informed consent)
and child assent for pediatric participants.

Exclusion Criteria:

- Patients unable to walk 25 feet.

- Treatment with methylprednisolone or cyclic methylprednisolone during the 3 previous
months before inclusion.

- Treatment with gamma interferon, immunoglobulin G or other immunomodulating treatment
the 3 previous month before inclusion

- Immunosuppressive treatment within 6 month of inclusion

- Prior history of a disease associated with immune dysfunction

- Poorly controlled Diabetes Mellitus (HbA1C > 9.0)

- History of untreated or uncontrolled hypertension

- Presence of infectious disease or other active infections which the treating physician
finds relevant

- Active or previous history of liver or renal failure

- Known history of renal insufficiency or creatinine > 2 x upper limit of normal (ULN)

- Active infection at time of screening

- History of known osteoporosis