An Open-Label Extension Study to Evaluate the Long-Term Safety, Tolerability, Biological Activity, and Systemic Exposure of ATYR1940 in Adult Patients with Facioscapulohumeral Muscular Dystrophy (FSHD)

FSHD is a rare, debilitating genetic myopathy. The primary clinical phenotype
of FSHD patients is progressive skeletal muscle weakness which usually starts
with muscles in the face and neck, and moves to the shoulder girdle, upper
arms, trunk, and legs. As weakness progresses, musculoskeletal deformities
(e.g., scapular winging, hyper-lordosis, and kyphoscoliosis) develop, and
mobility becomes severely compromised. There are currently no pharmacological
interventions for this disease worldwide.

ATYR1940 is a protein therapeutic candidate administered intravenously. This
protein is identical to amino acids 2-506 of the human histidyl tRNA synthetase
(HARS). HARS is a physiologically relevant modifier of muscle cell biology, and
the ATYR1940 nonclinical data suggest that it may have therapeutic effect in
patients with inflammatory muscle diseases, including FSHD, by modulating both
immune and muscle cell responses.

The objectives of this study are to:
• Evaluate the safety, tolerability, and immunogenicity of long-term treatment
with intravenous (IV) ATYR1940 in adult patients with facioscapulohumeral
muscular dystrophy (FSHD) previously enrolled in clinical study ATYR1940-C-002.
• Evaluate the effects of long-term ATYR1940 treatment on clinically relevant
measures of muscle strength and function, including:
• Quantitative Muscle Testing (QMT); and
• Manual muscle testing (MMT), as determined by the Investigator
• Evaluate the effects of long-term ATYR1940 treatment on patient-reported
quality of life (QoL).
• Evaluate the effects of long-term ATYR1940 treatment on muscle disease
burden, based on skeletal muscle magnetic resonance imaging (MRI).
• Explore biological and pharmacodynamic (PD) changes in the inflammatory
immune state in peripheral blood.
• Determine the long-term systemic exposure to ATYR1940 through pharmacokinetic
(PK) sampling.

Study ATYR1940-C-005 is a multi-national, multi-center, open-label extension
study designed to evaluate the long-term safety, effects on muscle, PD, and
systemic exposure of ATYR1940 in adult patients with FSHD previously treated in
the Protocol ATYR1940-C-002 (i.e., the parent study). This study will be
conducted at the same study centers at which patients were enrolled in the
parent study.

Patients who participated in >=Cohort 2 in the parent study, completed the
double-blind treatment period in the parent study; in the Investigator*s
opinion, demonstrated acceptable tolerability of study drug; are considered by
the Investigator to be compliant with study drug and the study procedures; and
do not meet any criterion for study drug discontinuation are eligible for
participation in the current study, contingent upon Investigator and patient
agreement to continue study drug treatment.

Patients may be treated with ATYR1940 under this protocol until ATYR1940 is
approved or its development is discontinued, the study is closed by the
Sponsor, or a criterion for study drug discontinuation is met.

In the current study, all patients will receive ATYR1940 3.0 mg/kg administered
via IV infusion over 90 minutes once weekly, unless it is determined by the
Investigator in consultation with the Medical Monitor and Sponsor that a
patient should receive a lower dose level from the Parent study and/or the
infusion volume and dosing duration (e.g., infusion over 30 minutes) should be
adjusted, as medically indicated. The treatment assignment in the parent study
will remain blinded.

Foreseeable Benefits

The current study represents a long term extension study to the parent study,
ATYR1940-C-002, a second clinical investigation of ATYR1940 in patients with
facioscapulohumeral muscular dystrophy (FSHD). FSHD is a chronic condition that
severely weakens skeletal muscles, significantly impairs mobility and
interferes greatly with patients* daily functioning.

There are currently no specific treatments available for any form of FSHD
disease; supportive therapy is the primary treatment, aimed at palliating the
physical dysfunction, pain and fatigue. Considering the debilitating nature of
the disease and the absence of specific therapy, there remains a pressing unmet
medical need for an efficacious, safe and disease-specific treatment for FSHD.

Although there is no pharmacologic treatment for muscle disease in FSHD, both
the dystrophic changes and the inflammatory process have been considered
rational disease targets. Recent data in FSHD suggest that focusing on the
inflammatory status of muscles in patients a priori in a clinical study could
increase the likelihood of seeing an impact of an immune modulator on the
disease.

ATYR 1940 is a recombinant protein having 100% identity to the first 506 amino
acids of human cystolic histadyl-tRNA synthetase and is being developed as a
treatment for rare myopathies with an immune component including genetic
dystrophies.

Non-clinical studies in animals have shown that IV administered ATYR1940
attenuates immune disorder effectively in the dose range to be studied in
humans. Non-clinical studies in immune cells isolated from the blood of healthy
subjects have shown direct immune modulatory effects of ATYR1940. Taken
together, ATYR1940 nonclinical data suggest that it may have therapeutic effect
in patients with inflammatory muscle diseases, including FSHD, by modulating
both immune and muscle cell responses.

The first in human clinical trial in healthy volunteers demonstrated the safety
and tolerability of single ascending doses of ATYR1940, and additional multiple
dosing in patients supports the proposed multiple-dose study of ATYR1940 in
patients.

However, as with any clinical trial of an investigational agent, it is unsure
whether the study drug will improve the symptoms of the subjects or alter the
disease state of those participating in the trial. The results of this trial
will benefit future research in FSHD.

Possible Risks Based on Experience in Clinical Studies

To date, more than 40 subjects (24 healthy subjects and approximately 16
subjects with FSHD) have received at least one dose of ATYR1940 via infusion
ranging from 0.1 to 3.0 mg/kg. Overall, ATYR1940 has been well-tolerated.

In a study completed with healthy volunteers, subjects were given a single dose
of ATYR1940 up to 3.0 mg/kg. The most common adverse events reported were
dizziness and headache in 13% of subjects and abdominal distension (feeling
bloated), fatigue, nasopharyngitis (common cold), and sore throat in 8% of
subjects.

In ongoing studies, patients with FSHD were treated with ATYR1940 at weekly
doses via infusion of 0.3 and 1.0 mg/kg for 4 weeks and 3.0 mg/kg for 12 weeks.
The most common adverse events reported were back pain in 27% of subjects,
joint pain, cough, and headache in 20% of subjects, and muscle pain, nausea,
and presyncope (feeling faint, lightheaded) in 13% of subjects. All events were
mild or moderate in intensity and all were considered non-serious except for
one event described below. Some patients showed abnormalities in their blood
and urine results, however, these were all considered mild in intensity, not
clinically significant, and unrelated to ATYR1940.

Generalized infusion related reactions have been reported in patients treated
weekly with 3.0 mg/kg of ATYR1940 (via 30-minute infusion) for 6 or more
weeks. One generalized infusion related reaction was considered to be
serious. In all cases, symptoms resolved after stopping the infusion and in
some instances, treating with medication and IV fluids. ATYR1940 dosing was
permanently discontinued in all patients who experienced an IRR.

Signs and symptoms of the observed generalized infusion related reactions
occurred during or after the infusion and included: flushing (temporary redness
of the skin, sometimes accompanied by feeling hot), sweating, itchiness, a
tingling sensation on the lips, lightheadedness, fainting, shortness of breath,
chills, low heart rate and/or blood pressure, and/or headache. These patients
also had increases in their Jo-1 antibody levels while participating in the
clinical studies, but the relationship between the Jo-1 Ab increases and the
generalized infusion related reaction is unknown at this time.

Patients will be monitored for these and other symptoms that may indicate a
generalized IRR during study drug infusions. There have been stopping rules
added to the study to ensure patient safety: patients will have study drug
discontinued and will not receive further drug if an infusion reaction occurs
or if their Jo-1 antibody level rises above 1.5 U/L.

In animal studies, some animals given ATYR1940 twice weekly, at doses
significantly higher than will be used in this trial, had anti-drug antibodies
detected and showed symptoms including skin changes, difficulty breathing and
decreased physical activity levels, minutes after ATYR1940 IV administration.
The symptoms were temporary in the majority of animals and there was no
evidence of the chronic lung or muscle damage. In a small percentage of
animals treated at the highest dose levels, death or severe illness requiring
euthanasia occurred acutely in the setting of these symptoms.

There is a small risk that a patient could develop very high levels of
anti-drug antibodies during the course of the study that could alter how the
protein works in the body and/or could cause an illness called anti-synthetase
syndrome. ATYR1940 may increase the risk of developing this illness.

Patients will be monitored regularly for lung function and for anti-drug
antibody levels, and as stated above, will be discontinued if the Jo-1 Ab level
rises above a threshold that is much less than what is considered positive for
anti-synthetase syndrome (7 U/L is considered equivocal, >=10 U/L positive).

ATYR1940 has not yet been tested to see if it affects pregnancy. Therefore,
patients should not become pregnant, or father a baby, while on this study.
Women should not breastfeed a baby while in this study. Men should not donate
sperm while in this study.

Possible risks and adverse effects related to the study procedures

• Blood sample collection: It may be painful when blood is drawn from the vein.
Some people get dizzy or faint from a blood draw. The patient could also get an
infection (rare), or have bleeding, redness, or bruising at the skin puncture.
• ECG: The sticky pads used for these tests may cause skin irritation.
• Spirometry: The patient may feel the need to cough or you may feel short of
breath during or after the test.
• MRI: There are no known harmful side-effects associated with temporary
exposure to the strong magnetic field used by MRI scanners. However, there are
important safety concerns to consider before performing or undergoing an MRI
scan (for example patients cannot wear anything with metal and precautions are
needed if they have artificial limbs or a pacemaker). The patient may also feel
some discomfort or anxiety when lying inside of the MRI scanner.

For further information about risks and side effects, please refer to the
patient information leaflet.

Patients will be monitored for safety, including respiratory events and immune
responses, throughout the study. A Data Monitoring Board will review all safety
data on an ongoing basis. Unforeseen/unwanted events will be taken care of by
the study staff at all sites, which are experienced in handling patients with
FSHD and in conducting similar clinical trials.

Based on the data available to date and the planned safety monitoring, as well
as the high unmet need for treatments in FSHD, the overall risk-benefit balance
for this trial is considered to be acceptable.