 It’s an autosomal recessive inherited disease that

causes progressive damage to the nervous system. It is

the most common inherited ataxia, affecting
approximately 1 in 29,000 individuals.[1] FRDA
manifests in initial symptoms of poor coordination
such as gait disturbance; it can also lead
to scoliosis, heart diseaseand diabetes, but does not
affect cognitive function. The disease is progressive,
and in most cases a wheelchair is required for
mobility.
 The ataxia of Friedreich's ataxia results from
the degeneration of nervous tissue in the spinal cord, in
particular sensory neurons essential (through connections with
the cerebellum) for directing muscle movement of the arms and
legs. The spinal cord becomes thinner and nerve cells lose some
of their myelin sheath (the insulating covering on some nerve
cells that helps conduct nerve impulses).
 The condition is named after the German physician Nikolaus
Friedreich, who first described it in the 1860s
 Friedreich's ataxia is an autosomal recessive disorder that
occurs when the FXN gene on chromosome 9 contains
amplified intronic GAA repeats (an example
of Trinucleotide repeat expansion). The FXN gene encodes
the protein frataxin.[5] GAA repeat expansion causes
frataxin levels to be reduced and long tracts of GAA
repeats induce chromosome breaks in (in vivo yeast
studies). Frataxin is an iron-binding protein responsible
for forming iron–sulphur clusters. One result of frataxin
deficiency is mitochondrial iron overload which can cause
damage to many proteins.[5] The exact role of frataxin in
normal physiology remains unclear.[6]
 Muscle weakness in the arms and legs
 Loss of coordination
 Vision impairment
 Hearing impairment
 Slurred speech
 Curvature of the spine (scoliosis)
 High plantar arches (pes cavus deformity of the foot)
 Diabetes (about 20% of people with Friedreich's ataxia develop carbohydrate
intolerance and 10% develop diabetes mellitus)[3]
 Heart disorders (e.g., atrial fibrillation, and resultant tachycardia (fast heart rate)
and hypertrophic cardiomyopathy)
 Nicotinamide (vitamin B3) represents was found effective in preclinical FA models
and well-tolerated by FA patients. An open-label, dose-escalation study
demonstrated that higher doses boosted frataxin expression and attenuated
abnormal heterochromatin, but failed to establish any clinical benefit in a study of
12 months. The trial is being extended.
 A Cochrane review on treatment of patients with Friedreich ataxia
with antioxidants concluded that there is limited but not persuasive evidence of
efficacy.An antioxidant Idebenone was removed from the Canadian market in 2013
due to lack of effectiveness.
 Horizon Pharma's development plan of interferon gamma-1B for treatment of FA
was given fast track designation by the Food and Drug Administration in
2015.However, in the Phase 3 trial released in December 2016, the results did not
meet primary endpoints. The trial is to be repeated with new endpoints
 Interferon gamma, or IFN-gamma, is a naturally occurring protein that plays an
important role in immune response.
 The U.S. Food and Drug Administration has approved the protein under the brand
name Actimmune to treat two rare diseases, one that affects immune cells and
another that affects bone formation. Those conditions are chronic granulomatous
disease and severe malignant osteoporosis.
 Horizon Pharma, which makes IFN-gamma, is now investigating the drug as a
potential treatment for people with Friedreich’s ataxia, or FA.

 IFN-gamma was first recognized as a potential therapy when scientists discovered
that it increased frataxin levels in mice with FA and in cells obtained from people
with the disease. The scientists thought IFN-gamma might increase the
transcription of the gene that codes for frataxin. Transcription is the process under
which a DNA code is transferred to messenger RNA, which then oversees the
formation of a protein. Increasing the transcription of the frataxin gene increases
the amount of frataxin protein that cells produce
 The positive results from the animal and laboratory studies, published in the scientific
journal Human Molecular Genetics in 2012, led to multiple clinical trials on whether Acimmune
could increase frataxin levels in humans.
 One trial (NCT01965327) was sponsored by the Children’s Hospital of Philadelphia in
collaboration with the Friedreich’s Ataxia Research Alliance and Vidara Therapeutics, Horizon
Pharma has since acquired.
 The results of the trial, published in Acta Neurologica Scandinavica in 2015, were mixed:
Researchers found increases in frataxin levels in some types of cells, but not in others.
 A decided plus was that scores on a measure of FA function — the Friedreich’s Ataxia Rating Scale,
or FARS — improved significantly, although the trial was not placebo-controlled.
 After the study’s encouraging results, Horizon Pharma committed to continue exploring
Actimmune as an FA treatment. It obtained FDA fast-track status for Actimmune as an FA therapy.
This will accelerate the approval process if clinical trials continue to show positive results.

 In June 2015 Horizon Pharma announced to conduct a phase 3 randomized, multi-
center, double-blind, placebo-controlled study to evaluate the efficacy and safety
of ACTIMMUNE® (interferon-γ 1b) in the treatment of Friedreich's Ataxia (FA)
and to evaluate the pharmacokinetic (PK) characteristics of the drug
(NCT02415127) in FA patients.
Condition or disease Intervention/treatment Phase

Friedreich's Ataxia Drug: Interferon γ-1b Phase 3

Drug: Placebo

Study Type : Interventional

Actual Enrollment : 92 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Randomized, Multicenter, Double-Blind, Placebo-Controlled,
Efficacy, Safety, and Pharmacokinetic Study
of ACTIMMUNE® (Interferon γ-1b) in Children and Young Adults
With Friedreich's Ataxia
Study Start Date : June 2015
Actual Primary Completion November 2016
Date :
Actual Study Completion Date : November 2016
Arm
Experimental: Interferon γ-1bApproximately
45 participants will receive subcutaneous (SC)
doses of ACTIMMUNE® 3 times a week (TIW)
for a total of 26 weeks.
Placebo Comparator: PlaceboApproximately
45 participants will receive SC doses of
placebo TIW for a total of 26 weeks.
Intervention/treatment
Drug: Interferon γ-1bThe study drug dose is
planned to be escalated on a weekly basis
over the first 4 weeks of treatment (from 10
µg/m² to 25, 50, and 100 µg/m²). The dose
may be reduced, interrupted, or held based on
tolerability. By Week 13, all participants are to
be on a stable tolerated dose of study drug in
order to continue study participation; the dose
may not be further increased after week 13,
however, it may be reduced on a case-by-case
basis to manage drug-related adverse events
(AEs).
Other Name: ACTIMMUNE®
Drug: PlaceboThe volume of placebo is
planned to correspond with volume of study
drug that would be given to the participant if
the participant was randomized to the study
drug arm.
 Primary Outcome Measures :
 Change From Baseline to Week 26 in the Friedreich's Ataxia Rating Scale (FARS)-
mNeuro Score [ Time Frame: Baseline, Week 26 ]The FARS assessment includes
neurological signs that specifically reflect neural substrates affected in FA. Based
on a neurological examination, bulbar, upper limb, lower limb, peripheral nerve,
and upright stability/gait functions were assessed. The FARS-mNeuro score
excludes the peripheral nervous system subscale score and the facial and tongue
atrophy and fasciculations from the bulbar subscale score. Scores range from 0
(normal) to 93 (most impairment). A negative change from baseline is an
improvement.
 Change From Baseline to Week 26 in Activities of Daily Living (ADL) Score [ Time Frame: Baseline, Week 26 ]Participants and/or
their caregivers rated 9 areas of daily living skills (speech, swallowing, cutting food and handling utensils, dressing, personal
hygiene, falling, walking, quality of sitting position, and bladder function) on a 5-point scale (0=normal, 4=greatest loss of
function) with allowable increments of 0.5 if the participant or caregiver strongly felt that a task falls between 2 scores. ADL
scores can range from 0 (normal) to 36 (greatest loss of function). A negative change from baseline indicates improvement.

 Change From Baseline at Week 26 in Timed 25-Foot Walk (T25FW) [ Time Frame: Baseline, Week 26 ]The T25FW is a quantitative
measure of lower extremity function. Participants are directed to 1 end of a clearly marked 25-foot course and instructed to walk
25 feet as quickly as possible, but safely. The task is immediately administered again by having the participant walk back the
same distance, and the score for the test is the average of the 2 walks (after reciprocal transformation). Participants may use
assistive devices when performing this task, with the same assistive device used at each assessment. A negative change from
Baseline indicates improvement.
 Number of FARS-mNeuro Responders and Non-Responders at Week 26 [ Time Frame:Week 26 ]A participant was considered a
responder if they had an improvement (decrease) of at least 3 points from Baseline at Week 26 for the FARS-mNeuro score. The
FARS assessment includes neurological signs that specifically reflect neural substrates affected in FA. Based on a neurological
examination, bulbar, upper limb, lower limb, peripheral nerve, and upright stability/gait functions were assessed. The FARS-
mNeuro score excludes the peripheral nervous system subscale score and the facial and tongue atrophy and fasciculations from
the bulbar subscale score. Scores range from 0 (normal) to 93 (most impairment).
 Change From Baseline to Week 26 in Total Friedreich Ataxia Rating Scale Score (FARStot) [ Time Frame: Baseline, Week 26 ]The
FARS assessment includes neurological signs that specifically reflect neural substrates affected in FA. Based on a neurological
examination, bulbar, upper limb, lower limb, peripheral nerve, and upright stability/gait functions are assessed. FARStot scores
range from 0 (normal) to 125 (most impairment). A negative change from baseline indicates improvement.
 FARS-mNeuro

ADL

T25FW

FARS-mNeuro responder rate

FARStot
 Arm/Group Title Interferon γ-1b Placebo
Arm/Group Description Subcutaneous (SC) doses of ACTIMMUNE® 3 SC doses of placebo TIW for a total of 26
times a week (TIW) for a total of 26 weeks. weeks.
Period Title: Overall Study
Started 47 45
Completed 46 45
Not Completed 1 0
Reason Not Completed
Adverse Event 1 0
 https://friedreichsataxianews.com/friedreichs-ataxia-experimental-
treatments/actimmune-interferon-gamma/