An Open-Label Extension Study to Evaluate the Long-Term Safety, Tolerability, and Biological Activity of ATYR1940 in Patients With Limb Girdle and Facioscapulohumeral Muscular Dystrophy
Phase: PHASE1
Conditions: Facioscapulohumeral Muscular Dystrophy, Limb Girdle Muscular Dystrophy
Sponsor: aTyr Pharma, Inc.

aTyr Pharma, Inc. 
Clinical Study Protocol Number ATYR1940-C-006 
22 March 2016 
CONFIDENTIAL 
1 
Version 1.0 (Original) 
aTyr Pharma, Inc. 
An Open-Label Extension Study to Evaluate the Long-Term Safety, 
Tolerability, and Biological Activity of ATYR1940 in Patients with Limb 
Girdle and Fascioscapulohumeral Muscular Dystrophy 
Protocol Number:  ATYR1940-C-006 
This study will be conducted according to the protocol and in compliance with  
Good Clinical Practice, the ethical principles stated in the Declaration of Helsinki, 
and other applicable regulatory requirements. 
Study Sponsor:
aTyr Pharma, Inc. 
3545 John Hopkins Court, Suite #250 
San Diego, CA 92121 
USA 
 
aTyr Pharma, Inc. 
Telephone:  
 
E-mail:  
Sponsor Signatory 
 
 
 
aTyr Pharma, Inc. 
Mobile Telephone: 
 
IND Number: 
122045 
EudraCT Number: 
2016-000624-25 
Document Date (Version):
22 March 2016 (Version 1.0; Original) 
NCT #: NCT02836418

aTyr Pharma, Inc. 
Clinical Study Protocol Number ATYR1940-C-006 
22 March 2016 
CONFIDENTIAL 
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Version 1.0 (Original) 
INVESTIGATOR STATEMENT 
I understand that all documentation provided to me by aTyr Pharma, Inc. (aTyr), or its 
designated representative(s) concerning this study that has not been published previously 
will be kept in the strictest confidence.  This documentation includes the study protocol, 
investigator brochure, case report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board (IRB)/Ethics Committee (EC).  No changes will be made to the 
study protocol without the prior written approval of aTyr and the IRB/EC, except where 
necessary to eliminate an immediate hazard to a patient. 
I have read, understood, and agree to abide by all the conditions and instructions contained 
in this protocol. 
Investigator Signature 
Date 
Printed Name 

aTyr Pharma, Inc. 
Clinical Study Protocol Number ATYR1940-C-006 
22 March 2016 
CONFIDENTIAL 
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Version 1.0 (Original) 
CLINICAL STUDY SYNOPSIS 
Protocol Title:  
An Open-Label Extension Study to Evaluate the Long-Term Safety, 
Tolerability, and Biological Activity of ATYR1940 in Patients with Limb 
Girdle and Fascioscapulohumeral Muscular Dystrophy
Protocol Number: 
ATYR1940-C-006 
Study Phase: 
1b/2a 
Investigators / Study 
Centers: 
This is a multi-national, multi-center study being conducted at 
centers in the United States (US) and Europe who participated in the 
Study ATYR1940-C-003 (Stage 1 only) or ATYR1940-C-004 (i.e., 
the parent studies). 
Study Objectives: 
The objectives of this study are to: 

Evaluate the safety, tolerability, and immunogenicity of long-
term treatment with intravenous (IV) ATYR1940 in patients
with limb girdle muscular dystrophy 2B (LGMD2B) or
fascioscapulohumeral muscular dystrophy (FSHD) previously
enrolled in clinical study ATYR1940-C-003 (Stage 1 only) or
ATYR-1940-C-004.

Explore the biological and pharmacodynamic (PD) activity of
ATYR1940 in patients with LGMD2B and FSHD, based on
changes in:

Serum-based muscle biomarkers.

Inflammatory immune state in peripheral blood.

Muscle disease and muscle disease burden, based on skeletal
muscle magnetic resonance imaging (MRI).

Skeletal muscle strength.

Upper and lower extremity muscle function.

Quality of life measures.
Study Design: 
Study ATYR1940-C-006 is a multi-national, multi-center, open-
label extension study designed to evaluate the long-term safety, 
effects on muscle, and PD of ATYR1940 in patients with LGMD2B 
or FSHD previously treated in the Protocol ATYR1940-C-003 
(Stage 1 only) or ATYR1940-C-004 (i.e., the parent studies).  This 
study will be conducted at the same study centers at which patients 
were enrolled in the parent studies. 
Patients who completed the treatment period in the parent study; in 
the Investigator’s opinion, demonstrated acceptable tolerability of 
ATYR1940, are considered by the Investigator to be compliant with 
ATYR1940 and the study procedures, and do not meet any criterion 

aTyr Pharma, Inc. 
Clinical Study Protocol Number ATYR1940-C-006 
22 March 2016 
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for ATYR1940 discontinuation are eligible for participation in the 
current study, contingent upon Investigator and patient agreement to 
continue ATYR1940 treatment.  
Ideally, when a patient transfers from the parent study to this 
extension study, the duration between the last ATYR1940 dose in 
the parent study and first ATYR1940 dose in this extension study is 
1 week; however, a maximum duration of 3 weeks is permissible.  
(A window >3 weeks may be permissible on a case-by-case basis, if 
required due to administrative reasons, after consultation with the 
Medical Monitor.) 
For the first 12 weeks in this extension study, patients will receive 
ATYR1940 at the highest tolerated dose received in the parent 
study; no dose adjustments are allowed during this 12-week period.  
After 12 weeks, if the patient is demonstrating good tolerability, the 
ATYR1940 dose may be increased on a patient-specific basis at the 
Investigator’s discretion, in consultation with the Sponsor and 
Medical Monitor.  ATYR1940 dose increases to >3.0 mg/kg are not 
permissible.   
All patients will receive ATYR1940 on a weekly basis in this study, 
regardless of the frequency of dosing in the parent study.   
ATYR1940 will be administered via IV infusion over 90 minutes.  If 
medically indicated, the infusion duration and volume may be 
adjusted at the Investigator’s discretion in consultation with the 
Medical Monitor and Sponsor. 
Number of Patients 
Planned: 
Based on the design of the parent studies, it is estimated that up to 
24 patients will be enrolled in this study. 
Diagnosis and Main 
Criteria for Inclusion: 
Patients must meet all of the following criteria to be considered 
eligible for study entry: 

Enrolled in and completed the treatment period in the parent
study.

Demonstrated, in the Investigator’s opinion, acceptable
tolerability of ATYR1940.

In the Investigator’s opinion, patient has shown acceptable
compliance with ATYR1940 and the study procedures in the
parent study and is willing and able to comply with all
procedures in the current study.

Is, in the Investigator’s and Sponsor’s opinion, a suitable
candidate for continued ATYR1940 treatment.

Provide written informed consent or assent (as appropriate,
based on age of majority) after the nature of the study has
been explained and prior to the performance of any
research-related procedures.

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22 March 2016 
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Exclusion Criteria: 
Patients meeting any of the following criteria are not eligible for 
study entry: 

At any time during participation in the parent study, met a
ATYR1940 discontinuation criterion, including, but not limited
to:
-
Jo-1 antibody (Ab) levels ≥1.5 U/mL.
-
Clinical evidence of a generalized infusion-related reaction
(IRR) (see Section 7.5.5.1).
-
Clinical evidence of a National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events
(CTCAE) (version 4.03) ≥Grade 2, study-drug-related
serious adverse event (SAE).
-
Pregnancy.
-
Progression of disease that, in the opinion of the
Investigator, precluded further participation in the study.
-
Withdrawal of consent or assent.
-
Other findings that, at the discretion of the Investigator
and/or Sponsor, indicated that study drug administration
should be discontinued.

Is expected to require treatment with curcumin or systemic
albuterol (intermittent inhaled albuterol is permissible) during
study participation; or use of a product that putatively enhances
muscle growth (e.g., insulin-like growth factor, growth
hormone) or activity (e.g., Coenzyme Q, Coenzyme A, creatine,
L-carnitine) on a chronic basis; or statin treatment initiation or
significant adjustment to statin regimen (stable, chronic statin
use is permissible).

Planned to receive any vaccination during study participation.

Abnormal baseline findings, medical condition(s), or laboratory
findings that, in the Investigator’s opinion, might jeopardize the
patient's safety or decrease the chance of obtaining satisfactory
data needed to achieve the objectives of the study.

Evidence of clinically significant cardiovascular, pulmonary,
hepatic, renal, hematological, metabolic, dermatological, or
gastrointestinal disease, or has a condition that requires
immediate surgical intervention or other treatment or may not
allow safe participation.

If female and of childbearing potential (premenopausal and not
surgically sterile), has a positive pregnancy test at entry or is
unwilling to use contraception from the time of entry through
the 3-month Follow-up visit.  Acceptable methods of birth
control include abstinence, barrier methods, hormones, or intra-

aTyr Pharma, Inc. 
Clinical Study Protocol Number ATYR1940-C-006 
22 March 2016 
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uterine device.  

If male, is unwilling to use a condom plus spermicide during
sexual intercourse from the time of entry through the 1-month
Follow-up visit.
Test Products, Doses, 
and Mode of 
Administration: 
ATYR1940 is a 505 amino acid protein identical to the wild-type 
amino acids 2-506 of human histidyl tRNA synthetase (HARS).  
ATYR1940 is formulated at a target concentration of 25 mg/mL as a 
sterile, nonpyrogenic solution in a formulation buffer containing 
histidine, sodium chloride, and polysorbate 20 at pH 7.3 and filled 
into type 1 borosilicate glass vials (5 mL) with butyl rubber stoppers 
and aluminum seals.  The fill volume of the clinical trial material is 
4 mL.  The product is non-preserved and is suitable for a single-dose 
use by IV administration.   
ATYR1940 will be administered via IV infusion. 
For the first 12 weeks in this extension study, patients will receive 
ATYR1940 at the highest tolerated dose received in the parent 
study; no dose adjustments are allowed during this 12-week period.  
After 12 weeks, if the patient is demonstrating good tolerability, the 
ATYR1940 dose may be increased on a patient-specific basis at the 
Investigator’s discretion, in consultation with the Sponsor and 
Medical Monitor.  ATYR1940 dose increases to >3.0 mg/kg are not 
permissible.   
The Sponsor has the discretion to delay dosing or decrease a 
patient's dose, based on relevant data reviewed concurrently in an 
individual patient (e.g., Jo-1 Ab levels) and/or additional clinical 
information provided by the Investigator. 
All patients will receive ATYR1940 on a weekly basis in this study, 
regardless of the frequency of dosing in the parent study.   
ATYR1940 will be administered IV as a 90-minute infusion.  
The ATYR1940 dose will be prepared for infusion in 100 mL 
(0.3 and 1.0 mg/kg) or 250 mL (3.0 mg/kg) saline as long as 
clinically indicated; refer to the Pharmacy Manual for details.  
During the course of the study, the Investigator may confer with the 
Medical Monitor and Sponsor if medically indicated or if there does 
not appear to be an increased risk to the patient, to decrease the 
study drug infusion time and/or volume of study drug administration 
on an individual patient basis. 
Duration of 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, as follows: 

Jo-1 Ab levels ≥1.5 U/mL.

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Clinical Study Protocol Number ATYR1940-C-006 
22 March 2016 
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
Clinical evidence of a generalized IRR (see Section 7.5.5.1).

Clinical evidence of an NCI CTCAE (version 4.03) ≥Grade 2,
study-drug-related SAE.

Pregnancy.

Progression of disease that, in the opinion of the Investigator,
precludes further participation in the study.

Withdrawal of consent or assent.

Other findings that, at the discretion of the Investigator and/or
Sponsor, indicate that study drug administration should be
discontinued.
Duration of Study: 
See above. 
Study Endpoints: 
Safety: 
Safety and tolerability will be evaluated by the following in all 
patients: 

Incidence of treatment-emergent adverse events (TEAEs) and
SAEs overall and by intensity.

Changes from baseline in:
-
Safety laboratory test results.
-
Electrocardiogram (ECG) findings.
-
Vital signs measurements.
-
Pulmonary evaluations (pulmonary function tests [PFTs]
and pulse oximetry).
-
Incidence and level of anti-drug antibodies (ADA) titers
and Jo-1 Ab levels.

Exploratory characterization of immune response to
ATYR1940.
Muscle Effects: 

Changes from baseline in the following clinical parameters:

Muscle disease burden on lower extremity skeletal muscle
MRI.

Muscle strength, based on manual muscle testing (MMT).

Upper and lower extremity muscle function, based on the
Brooke and Vignos scales, respectively.
Pharmacodynamics 
(Exploratory): 
The PD activity of ATYR1940 will be evaluated based on the 
following endpoints: 

Changes in muscular-dystrophy-related inflammatory immune
state in peripheral blood, as assessed by:

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Clinical Study Protocol Number ATYR1940-C-006 
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
Circulating immune proteins, such as cytokines.

Ex vivo inflammatory immune protein (including cytokines)
release from peripheral blood mononuclear cells (PBMCs).

Immunophenotyping of circulating PBMCs.

Changes in serum- and/or plasma-based muscle biomarkers
Quality of Life 
(Exploratory): 
Quality of life will be assessed, based on the Individualized 
Neuromuscular Quality of Life (INQoL) questionnaire and, for 
patients with FSHD, the FSHD-specific Health Inventory (FSHD-
HI) questionnaire. 
Systemic Exposure: 
Systemic exposure will be determined through sparse 
pharmacokinetic (PK) sampling.  As the data allow, PK parameters 
will be calculated from the drug concentration data using 
WinNonlin. 
Sample Size 
Considerations: 
No formal sample size calculation was performed for this extension 
study. 
Statistical Methods: 
Statistical analyses of safety, PK, and PD data will be primarily 
descriptive in nature.  Continuous variables will be summarized 
using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum).  Categorical variables will be 
summarized showing the number and percentage (n, %) of patients 
within each classification. 
Schedule of Events: 
The Schedule of Events is presented in Table 1.  

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Clinical Study Protocol Number ATYR1940-C-006 
22 March 2016 
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Table 1: 
Schedule of Events 
Assessment 
Study Period / Frequency of Assessments 
Treatment Period 
Follow-up 
Week 14 in 
Parent 
Study/ 
Week 1 in 
Current 
Study1,2,3 
Weekly 
(W2, W3, 
etc) 
Monthly 
(Q4W) 
(Week 4, 8, 
etc) 
Every 6 
weeks 
(Q6W) 
(Week 6, 
12, etc) 
Every 3 
Months 
(Q12W) 
(Week 12, 
24, etc) 
Every 6 
Months 
(Q24W) 
Week 24, 
48, etc. 
1-week 
F/U 
4-week F/U 
12-week 
F/U 
Visit Window (days) 
- 
±3D4 
±3D4 
±3D4 
±5D4 
±5D4 
±3D 
±3D 
±5D 
Informed consent/assent 
X1 
Confirm inclusion/exclusion criteria 
X1 
Weight5 
X 
X 
X 
X 
Vital signs6 
X3 
X 
X 
X 
X 
Complete physical examination 
X 
X 
X 
Surveillance skeletal muscle MRI 
X 
X7 
X 
ATYR1940 administration8 
X1 
X 
12-lead ECG9
X3 
X 
X 
X 
Pulse oximetry10 
X1 
X 
X 
X 
X 
Pulmonary function tests11 
FEV1, FVC, and FEV1/FVC ratio 
X1 
X 
X 
Total lung capacity and DLCO 
X1 
X 
X 
Adverse events 
X3 
X 
X 
X 
X 
Prior/concomitant medications 
X3 
X 
X 
X 
X 
Manual muscle testing 
X 
X 
X 

aTyr Pharma, Inc. 
Clinical Study Protocol Number ATYR1940-C-006 
22 March 2016 
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Version 1.0 (Original) 
Assessment 
Study Period / Frequency of Assessments 
Treatment Period 
Follow-up 
Week 14 in 
Parent 
Study/ 
Week 1 in 
Current 
Study1,2,3 
Weekly 
(W2, W3, 
etc) 
Monthly 
(Q4W) 
(Week 4, 8, 
etc) 
Every 6 
weeks 
(Q6W) 
(Week 6, 
12, etc) 
Every 3 
Months 
(Q12W) 
(Week 12, 
24, etc) 
Every 6 
Months 
(Q24W) 
Week 24, 
48, etc. 
1-week 
F/U 
4-week F/U 
12-week 
F/U 
Visit Window (days) 
- 
±3D4 
±3D4 
±3D4 
±5D4 
±5D4 
±3D 
±3D 
±5D 
Upper and lower extremity function12 
X 
X 
X 
INQoL 
X 
X 
X 
X 
FSHD-HI13 
X1 
X 
X 
X 
Laboratory Assessments
Pregnancy test14 
X3 
X 
X 
Hematology, serum chemistries, and 
urine analysis with microscopy15 
X 
X 
X 
X 
X 
Plasma complement factors16 
X1 
X 
X 
Serum complement and tryptase 
levels17 
X1 
X 
X 
Jo-1 antibodies18 
X 
X 
X 
X 
X 
ADA19 
X 
X 
X 
X 
X 
HARS (human histidyl-tRNA 
synthetase; serum) 
X 
X 
Serum ATYR1940 concentrations20 
X 
X 
X 
Muscle biomarkers 
X1 
X 
X 
X 
Biomarkers in blood 
X 
X 
X 
X 

aTyr Pharma, Inc. 
Clinical Study Protocol Number ATYR1940-C-006 
22 March 2016 
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Version 1.0 (Original) 
Assessment 
Study Period / Frequency of Assessments 
Treatment Period 
Follow-up 
Week 14 in 
Parent 
Study/ 
Week 1 in 
Current 
Study1,2,3 
Weekly 
(W2, W3, 
etc) 
Monthly 
(Q4W) 
(Week 4, 8, 
etc) 
Every 6 
weeks 
(Q6W) 
(Week 6, 
12, etc) 
Every 3 
Months 
(Q12W) 
(Week 12, 
24, etc) 
Every 6 
Months 
(Q24W) 
Week 24, 
48, etc. 
1-week 
F/U 
4-week F/U 
12-week 
F/U 
Visit Window (days) 
- 
±3D4 
±3D4 
±3D4 
±5D4 
±5D4 
±3D 
±3D 
±5D 
PBMCs for immunophenotyping 
(general and disease-related) and 
culture for immune protein release 
X 
X 
X 
X 
Assessments for Patients in Parent 
Study ATYR1940-C-003 Only 
Visual acuity 
X1 
X 
X 
X 
Pure Tone Audiometry 
X1 
X 
X 
X 
Note:  On ATYR1940 administration days, laboratory samples are to be collected and assessments performed pre-infusion, unless otherwise specified. 
1 
Week 1 in the current study (ESW1) is equivalent to Week 14 in the parent study (PSW14).  The Week 1 column in this table reflects assessments that are to be performed at 
ESW1 (cells with heavy weight borders) in addition to those performed at PSW14 (cells with regular weight borders), as indicated in the parent study protocol.  All PSWeek 
14/ESWeek 1 assessments are to be completed and eligibility is to be confirmed before the first ATYR1940 dose in the current study at ESW1.  
2 
A maximum duration of 3 weeks is permissible between the last ATYR1940 dose in the parent study (i.e., at Week 13) and the first ATYR1940 dose in the current study (at 
ESW1).  A window >3 weeks may be permissible on a case-by-case basis, if required due to administrative reasons, after consultation with the Medical Monitor.  
3 
If there is >1 week (+3 days) between the last ATYR1940 dose in the parent study and the first ATYR1940 dose in the current study, the assessments indicated are to be 
repeated within 7 days before ESW1. 
4 
For scheduling purposes, a ±3-day window is permissible around ATYR1940 infusion; however, each ATYR1940 dose must be separated by at least 5 days and no more 
than 9 days and only 1 dose may be administered within a given study week; if a patient’s scheduled visit day is changed in a given week (e.g., changed from Tuesday to 
Thursday), then subsequent weekly visits may be accordingly adjusted (e.g., Thursdays) or may revert back to the original schedule (e.g., Tuesdays), provided ATYR1940 is 
administered according to the timeframes specified. For the every 12-week and 6-month visits, a ±5-day window is permissible. 
5 
Weight is to be re-measured any time the Investigator suspects the patient has experienced a notable change in weight (±10%) and the ATYR1940 dose recalculated.   

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Vital signs are to be measured on weekly dosing days pre-infusion; every 30 minutes (±5 minutes) during the infusion; at the end of the infusion (±5 minutes); at 30 minutes 
(±5 minutes) after the end of infusion; and at additional time points as clinically indicated.  Vital signs also must be measured within 7 days before ATYR1940 
administration at ESW1.  (On weekly dosing days, post-infusion vital sign measurements also will be collected before blood sample collection.)  In addition, vital signs are to 
be measured in the event of a generalized IRR (see Section 8.5.9.4).   
7 
To be performed every 3 months (±1 week). 
8 
ATYR1940 will be administered via IV infusion over 90 minutes (-5 minutes, +15 minutes), unless it is determined by the Investigator in consultation with the Medical 
Monitor and Sponsor that a patient should receive a different dosing duration, as medically indicated. 
9 
A 12-lead ECG is to be performed on the designated dosing days prior to and 30 minutes (±15 minutes) following the end of infusion and once at the additional designated 
follow-up visits.  A 12-lead ECG must be performed within 7 days before ATYR1940 administration at ESW1.  In addition, ECGs are to be performed in the event of a 
generalized IRR (see Section 8.5.9.4). 
10 
Pulse oximetry is to be performed on weekly dosing days from 5 minutes prior to the start of infusion through 30 minutes (-5 minutes, +15 minutes) after the end of infusion; 
at the additional designated follow-up visits; and as clinically indicated if the patient experiences pulmonary signs or symptoms (e.g., chest tightness, increased respiratory 
rate).  In addition, pulse oximetry is to be performed in the event of a generalized IRR (see Section 8.5.9.4) 
11 
Pulmonary function tests, including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio are to be measured prior to infusion at 
Week 1; then on the designated dosing days (every 6 weeks) at 2.5 hours (±30 minutes) after the end of infusion; and at the designated follow-up visit.  Total lung capacity 
and diffusion capacity of the lung for carbon monoxide (DLCO), are to be measured at Week 1; then on the designated dosing days (every 12 weeks); and at the designated 
follow-up visit.  In addition, pulmonary function tests are to be conducted in the event of a generalized IRR (see Section 8.5.9.4). 
12 
Upper extremity function to be measured using the Brooke scale; lower extremity function to be measured using the Vignos scale. 
13 
The FSHD HI should be completed at the same time of day and before other assessments scheduled for that day, including the InQoL.  The order of assessments should 
remain consistent throughout the study. 
14 
Urine pregnancy testing is required for females of childbearing potential (i.e., premenopausal and not surgically sterile) only.  Pregnancy testing must be performed within 7 
days before ATYR1940 administration at ESW1.  Testing is to be performed using the local laboratory and before study drug infusion.   
15 
Clinical safety laboratory tests include clinical chemistry, hematology, and urine analysis with microscopy.  On the designated dosing days, blood samples for safety 
laboratory tests are to be collected pre-infusion.  Patients with evidence of a generalized IRR are to have additional safety laboratory tests performed, as described in Section 
8.5.9.4. 
16 
Blood samples for complement factors in plasma (including C3a, C4a, C5a, Bb, and SC5b-9) will be collected on the designated dosing days prior to and 1.5 hours 
(±15 minutes) after the end of infusion and at the designated follow-up visit.  In addition, samples for complement factors in plasma are to be collected in the event of a 
generalized IRR (see Section 8.5.9.4). 

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Blood samples for tryptase, C3, C4, and CH50 will be collected on the designated dosing days prior to and 1.5 hours (±15 minutes) after the end of infusion on the 
designated dosing days and at the designated follow-up visit.  In addition, samples for assessment of tryptase, C3, C4, and CH50 are to be collected in the event of a 
generalized IRR (see Section 8.5.9.4). 
18 
Blood samples for assessment of Jo-1 Ab are to be collected on dosing days prior to initiation of infusion, and at the additional time points indicated.  The Week 1 Jo-1 Ab 
sample must be obtained and result reviewed within 2 weeks prior to the first ATYR1940 dose.  In addition, samples for assessment of Jo-1 Ab are to be collected in the 
event of a generalized IRR (see Section 8.5.9.4). 
19 
Blood samples for analysis of antidrug antibodies (ADA) are to be collected on the designated dosing days prior to initiation of infusion and at the additional time points 
indicated.  Blood samples for assessment of ADA are to be collected in the event of a generalized IRR (see Section 8.5.9.4).  For patients with elevated ADA at the 12-week 
F/U visit, additional ADA testing should be performed every 1 to 3 months until level returns to baseline. 
20 
Blood samples for assessment of ATYR1940 concentrations are to be collected on the designated dosing days at end of infusion and 4 hours after the start of infusion.  
ATYR1940 serum concentrations also are to be collected in the event of a generalized IRR (see Section 8.5.9.4).  

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
Ab 
Antibody 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CA 
Competent Authority 
CK 
Creatine kinase 
Cmax 
Maximum serum concentration 
CRA 
Clinical Research Associate 
CSS 
Clinical Severity Score 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLCO 
Diffusion capacity of the lung for carbon monoxide 
DMB 
Data Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End-of-Study 
ESW1 
Week 1 in the extension study 
EU 
European Union 

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Abbreviation 
Definition 
FEV1 
Forced expiratory volume in 1 second 
FSHD 
Facioscapulohumeral muscular dystrophy 
FSHD-HI 
Facioscapulohumeral Muscular Dystrophy-Health Inventory 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HARS 
Human histidyl tRNA synthetase 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IND 
Investigational New Drug Application 
INQoL 
Individualized Neuromuscular Quality of Life 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IV 
Intravenous 
LGMD 
Limb Girdle Muscular Dystrophy 
LGMD2B 
Limb Girdle Muscular Dystrophy 2B 
MCP-1 
Monocyte chemoattractant protein-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP-9 
Matrix metallopeptidase 9 

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Abbreviation 
Definition 
MMT 
Manual muscle testing 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
NCI 
National Cancer Institute 
NSAID 
Non-steroidal anti-inflammatory drug 
PBMCs 
Peripheral blood mononuclear cells
PD 
Pharmacodynamic(s) 
PFT 
Pulmonary function test 
PK 
Pharmacokinetic(s) 
PSW14 
Week 14 in the parent study 
Q12W 
Every 12 weeks 
Q4W 
Every 4 weeks 
Q6W 
Every 6 weeks 
RBC 
Red blood cell (count) 
RMIC 
Rare muscle diseases with an immune component 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
STIR 
Short tau inversion recovery 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 

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Abbreviation 
Definition 
tmax 
Time to maximum serum concentration 
TNF 
Tumor necrosis factor 
US 
United States 
WBC 
White blood cell (count) 

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TABLE OF CONTENTS 
INVESTIGATOR STATEMENT .............................................................................................. 2 
CLINICAL STUDY SYNOPSIS ................................................................................................ 3 
LIST OF ABBREVIATIONS ................................................................................................... 14 
TABLE OF CONTENTS .......................................................................................................... 18 
LIST OF TABLES IN THE TEXT .......................................................................................... 22 
1.
Study Personnel and Administrative Structure .......................................................... 23 
2.
Introduction .................................................................................................................... 24 
2.1. 
Limb Girdle Muscular Dystrophy .................................................................... 24 
2.2. 
Facioscapulohumeral Muscular Dystrophy .................................................... 26 
2.3. 
ATYR1940 .......................................................................................................... 29 
2.4. 
Rationale for Current Study ............................................................................. 31 
3.
Study Objectives and Endpoints................................................................................... 33 
3.1. 
Objectives............................................................................................................ 33 
3.2. 
Study Endpoints ................................................................................................. 33 
3.2.1.
Safety and Tolerability Endpoints ........................................................ 33
3.2.2.
Muscle Effects ...................................................................................... 33
3.2.3.
Pharmacodynamics (Exploratory) ........................................................ 34
3.2.4.
Quality of Life (Exploratory) ................................................................ 34
3.2.5.
Systemic Exposure ................................................................................ 34
4.
Investigational Plan ....................................................................................................... 35 
4.1. 
Overall Study Design and Plan ......................................................................... 35 
4.2. 
Justification for the Study Design .................................................................... 35 
5.
Study Population ............................................................................................................ 37 
5.1. 
Inclusion Criteria ............................................................................................... 37 
5.2. 
Exclusion Criteria .............................................................................................. 37 
5.3. 
Source of Patients ............................................................................................... 38 
6.
Study Conduct ................................................................................................................ 39 
6.1. 
Patient Identification, Enrollment, and Randomization ................................ 39 
6.2. 
Patient Management .......................................................................................... 39 
6.3. 
Patient Adherence .............................................................................................. 39 

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6.4. 
Withdrawal and Replacement of Patients ....................................................... 39 
6.4.1. 
Study Drug Discontinuation Criteria .................................................... 39
6.4.2. 
Study Withdrawal Criteria .................................................................... 40
6.5. 
Study Completion............................................................................................... 41 
6.6. 
Study Termination ............................................................................................. 41 
6.7. 
Investigator Compliance ................................................................................... 41 
7.
Study Drug ...................................................................................................................... 42 
7.1. 
Study Drug Supply ............................................................................................. 42 
7.2. 
Study Drug Packaging and Labeling ............................................................... 42 
7.2.1. 
Procedures for Breaking the Blind........................................................ 42
7.3. 
Study Drug Storage............................................................................................ 42 
7.4. 
Study Drug Accountability................................................................................ 42 
7.5. 
Study Drug Dose and Administration .............................................................. 43 
7.5.1.
Dose and Route of Administration ....................................................... 43
7.5.2.
Infusion Rate and Volume .................................................................... 43
7.5.3.
Dosing Frequency and Treatment Intervals .......................................... 44
7.5.4.
Dose Reduction ..................................................................................... 44
7.5.5.
Clinical Management Plan for Potential Immunogenicity ................... 44
7.5.6.
Data Monitoring Board ......................................................................... 48
7.6. 
Rationale for the Dose(s) Selected .................................................................... 48 
7.7. 
Prior and Concomitant Medications and Procedures .................................... 49 
8.
Study Visits and Assessments ....................................................................................... 50 
8.1. 
Informed Consent and, if applicable, Assent................................................... 50 
8.2. 
Pregnancy Testing .............................................................................................. 50 
8.3. 
Concomitant Medications ................................................................................. 50 
8.4. 
Pharmacodynamic and Pharmacokinetic Measurements .............................. 50 
8.4.1. 
Pharmacodynamics ............................................................................... 50
8.4.2. 
Pharmacokinetics .................................................................................. 57
8.5. 
Safety Measurements ......................................................................................... 57 
8.5.1. 
Physical Examination, including Neurological Examinations ............. 57

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8.5.2.
Weight ................................................................................................... 58
8.5.3.
Visual Acuity (Patients who Participated in Parent Study 
ATYR1940-C-003 Only) ...................................................................... 58
8.5.4.
Pure Tone Audiometry (Patients who Participated in Parent 
Study ATYR1940-C-003 Only)............................................................ 58
8.5.5.
Vital Signs............................................................................................. 58
8.5.6.
Pulse Oximetry ..................................................................................... 58
8.5.7.
Pulmonary Function Tests .................................................................... 59
8.5.8.
12-Lead Electrocardiogram .................................................................. 59
8.5.9.
Safety Laboratory Tests ........................................................................ 59
8.5.10.
Adverse Events ..................................................................................... 62
9.
Statistical Analyses......................................................................................................... 68 
9.1. 
Statistical Basis for Sample Size ....................................................................... 68 
9.2. 
Statistical and Analytical Plan .......................................................................... 68 
9.2.1.
General Methods ................................................................................... 68
9.2.2.
Analysis Populations............................................................................. 68
9.2.3.
Missing, Unused, and Spurious Data .................................................... 68
9.2.4.
Disposition of Patients .......................................................................... 69
9.2.5.
Demographics and Baseline Characteristics ......................................... 69
9.2.6.
Extent of Exposure................................................................................ 69
9.2.7.
Prior and Concomitant Medications ..................................................... 69
9.2.8.
Safety Analysis ..................................................................................... 69
9.2.9.
Safety and Immunogenicity Analyses .................................................. 69
9.2.10.
Pharmacodynamic Analyses ................................................................. 70
9.2.11.
ATYR1940 Serum Concentrations ....................................................... 71
9.2.12.
Interim Analyses ................................................................................... 71
9.3. 
Changes to the Planned Statistical Methods ................................................... 71 
10.
Ethical, Legal, and Administrative Considerations .................................................... 72 
10.1. Good Clinical Practice ....................................................................................... 72 
10.2. Informed Consent .............................................................................................. 72 
10.3. Institutional Review Board/Ethics Committee ................................................ 72 

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10.4. Amending the Protocol ...................................................................................... 73 
10.5. Confidentiality .................................................................................................... 73 
10.6. Publication Policy............................................................................................... 73 
11.
Study Management ........................................................................................................ 75 
11.1. Data Quality Assurance ..................................................................................... 75 
11.2. Case Report Forms and Source Documentation ............................................. 75 
11.3. Monitoring .......................................................................................................... 75 
11.4. Inspections .......................................................................................................... 76 
11.5. Financial Disclosure Reporting Obligations .................................................... 76 
11.6. Archiving Study Records .................................................................................. 76 
12.
REFERENCES ............................................................................................................... 77 

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LIST OF TABLES IN THE TEXT 
Table 1:
Schedule of Events ............................................................................................................ 9
Table 2:
Manual Muscle Testing Order ......................................................................................... 51
Table 3:
Manual Muscle Testing Positions ................................................................................... 53
Table 4:
Manual Muscle Testing Grading Scale ........................................................................... 54
Table 5:
Grading System for the Brooke Scale ............................................................................. 55
Table 6:
Grading System for the Vignos Scale ............................................................................. 55
Table 7:
Biomarkers to be Measured in Blood .............................................................................. 56
Table 8:
Criteria for Determination of Adverse Event Relationship to Study Drug ..................... 65

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1.
STUDY PERSONNEL AND ADMINISTRATIVE
STRUCTURE
Study Sponsor:
aTyr Pharma, Inc. 
3545 John Hopkins Court, Suite #250 
San Diego, CA 92121 
USA 
Primary Sponsor Contact: 
 
aTyr Pharma, Inc. 
Telephone:  
 
E-mail:  
Sponsor Signatory:
Sponsor Signatory 
 
 
aTyr Pharma, Inc. 
Mobile Telephone: 
 
Medical Monitor: 
 
 
aTyr Pharma, Inc. 
Telephone: 
 
E-mail: 

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2.
INTRODUCTION
The rare muscle diseases with an immune component (RMIC) represent a group of rare 
autoimmune and genetic muscle conditions characterized by inflammatory cell 
infiltration into muscle tissue.  RMIC encompass the more severe and grave forms of 
diseases, such as polymyositis, dermatomyositis, sporadic inclusion body myositis, 
immune necrotizing myopathy, Duchenne’s muscular dystrophy, limb girdle muscular 
dystrophy (LGMD), and facioscapulohumeral muscular dystrophy (FSHD).  Many of the 
RMIC disorders are genetically-based and thus are defined and diagnosed by a 
combination of clinical signs and genetic analysis.  Patients with RMIC suffer from 
debilitating muscle weakness and experience significant morbidity and, in some diseases, 
an increased mortality compared to the general population.  As a group, RMIC are 
associated with tremendous patient suffering and constitute a high unmet medical need.1,2  
2.1. 
Limb Girdle Muscular Dystrophy 
Limb girdle muscular dystrophies are a group of uniformly progressive muscular 
dystrophies that share a common, but highly variable clinical presentation characterized 
predominantly by proximal weakness affecting the pelvic and shoulder girdles, and 
usually sparing the face.  This group of disorders is currently being re-classified based on 
profound advances in the molecular genetics underlying these diseases.  The various 
LGMD diseases are categorized by inheritance pattern, including those with dominantly 
inherited forms (i.e., LGMD1) and those with recessively-inherited forms (i.e., LGMD2).  
Within these categories, the diseases are further characterized by the causative genetic 
defect.  Currently, LGMD is a collection of ~30 genetic muscle diseases caused by 
mutations at more than 50 genetic loci.3  Because of the heterogeneity of LGMD and the 
lack of diagnostic specificity, there are few reports on the prevalence of LGMD; 
however, it is estimated to range from 1:14,500 to 1:123,000, depending on the 
genetically defined form (Genetics Home Reference 2015).  The age of onset, severity, 
and features of LGMD vary among the subtypes.  Overall, LGMD affects men and 
women equally.   
LGMD2B is a recessively inherited dystrophy, often termed dysferlinopathy, since the 
causative mutations reside within the dysferlin gene (DYSF).4  LGMD2B is characterized 
mainly by two distinct clinical phenotypes:  LGMD syndrome, with early weakness and 
atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood and 
with slow progression, and Miyoshi myopathy, with muscle weakness and atrophy in 
young adults, most marked in the distal parts of the legs, especially the gastrocnemius 
and soleus muscles.  Over a period of years, the weakness and atrophy spread to the 
thighs and gluteal muscles.  The forearms may become mildly atrophic, with decrease in 
grip strength, but the small muscles of the hands are spared.  Two other phenotypes of 
LGMD2B that have been identified are less commonly seen, distal anterior compartment 
myopathy, a rapidly progressing form that presents in the third decade, with weakness of 

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the anterior tibialis muscles followed by severe weakness in the lower limbs followed by 
the upper limbs, and dysferlinopathy with rigid spine, which presents with lower limb 
weakness and atrophy in addition to contractures of the neck, chest, hip, and knee.3  
Although cardiomyopathy occurs in some forms of LGMD, this feature is not commonly 
seen in LGMD2B.  LGMD2B, representing ~5% of patients with autosomal recessive 
LGMD, is one of the most common forms in the United States (US).5,6 
There are multiple lines of evidence supporting a prominent role of inflammation in the 
pathophysiology of LGMD2B.  The genetic mutations in dysferlin appear to create a 
defect in muscle membrane repair.7  Alterations in this process likely create a 
pathophysiological environment in muscle that triggers an immune response.  LGMD2B 
has been demonstrated to have a predominant immune cell-mediated pathology.8,9  
Patients with LGMD2B possess a dysregulated immune response, including cellular 
infiltration into affected muscle, increased expression of pro-inflammatory cytokines and 
altered cellular responses, including effects on myeloid cells.10,11 Analysis of muscle 
biopsies from LGMD2B patients (including Myoshi myopathy, distal anterior 
compartment myopathy, and LGMD12,13), has revealed that the most prominent cellular 
immunophenotype in LGMD muscle is infiltration with CD4 > CD8 positive T-cells, and 
macrophages, cell types that are modulated by ATYR1940 (see Section 2.3).  Cytokine 
patterns typically reflect Th1 and M1 differentiation processes, including interleukin 
(IL)-1, interferon-, and tumor necrosis factor (TNF)-.  These characteristics are also 
reflected in mouse models of LGMD2B in which the dysferlin gene is mutated, including 
the requirement for T and B cells in disease8, as well as the expression of pro-
inflammatory cytokines.14  Further, inhibition of inflammatory cytokines results in 
reduction in disease in dysferlin-deficient mice.15,16  The muscle in patients with 
dysferlinopathy is characterized by massive immune cell infiltrates, and dysferlin-
negative monocytes were shown to be aggressive and phagocytose more particles, 
suggesting that dysferlin deregulation in monocytes might contribute to disease 
progression.10,13  
There currently is no pharmacologic treatment for the muscle disease in LGMD, 
including corticosteroids.17  Thus, symptomatic patients are managed with palliative and 
supportive care, typically including physical, occupational, and exercise therapy and with 
physical support (e.g., canes, walkers) as needed.  Investigation of gene therapies and cell 
transfer therapies for the treatment of this condition is ongoing; however, the efficacy and 
long-term safety of such therapies have not yet been established.18  Furthermore, such 
therapies have immunologic complications as well as issues regarding mechanism of 
delivery to muscles throughout the body.19   
The predominant role of the immune system in LGMD2B suggests 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 non-corticosteroid immunomodulator.   

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2.2. 
Facioscapulohumeral Muscular Dystrophy 
FSHD is a rare, debilitating genetic myopathy.  The primary clinical phenotype of FSHD 
patients is progressive skeletal muscle weakness that develops in a descending, 
asynchronous pattern.20,21  Weakness 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, hyperlordosis, and kyphoscoliosis) 
develop, and mobility becomes severely compromised.   
Inflammation as an early event and single muscle involvement has been proposed to play 
a role in FSHD pathophysiology.22  The infiltrative inflammatory process includes 
invasion of CD4 and CD8 T cells, B lymphocytes and monocytes, particularly into 
skeletal muscles that are in the early stages of disease.22  Once disease progresses in a 
particular muscle, weakness ensues and dystrophic changes, including necrosis, 
phagocytosis, regeneration, variation in fiber size, and proliferation of connective tissues 
with fatty infiltration/replacement, can eventually be seen.23 
There are currently no pharmacological interventions for this disease worldwide. 
Although it is the most common genetic muscular dystrophy, FSHD is a rare disease, 
with an estimated prevalence of 1 in 15,000 to 20,000.21,24  FSHD typically presents in 
adolescence to early adulthood, and up to 20% of patients become wheelchair dependent 
after age 50.21  Less frequently, clinical signs and symptoms of FSHD are evident earlier 
in childhood, including during the first decade of life.  Classification of FSHD by age of 
onset into early and late presentation is noted in the literature, although the nomenclature 
is variable.  Infantile onset FSHD, which comprises less than 5% of all cases of FSHD, 
has been classified as early onset FSHD, and a commonly cited definition for it – facial 
weakness prior to 5 years of age and shoulder girdle weakness prior to 10 years of age – 
was applied in a study by Brouwer and colleagues25 and has been adopted by others.  
This early onset FSHD phenotype is characterized by more severe, rapidly progressive 
muscle involvement, often resulting in wheelchair dependence by the end of the first 
decade.26  Although subclinical extramuscular manifestations of FSHD involving the eye 
(retinal vasculopathy, characterized by telangiectatic blood vessels and microaneurysms 
on fluorescein angiography, but without loss of vision) and ear (high frequency hearing 
loss) occur relatively frequently in patients with FSHD,27 patients with infantile onset 
FSHD appear to be more commonly susceptible to severe extramuscular involvement at a 
young age.25,26  For example, sensorineural hearing loss in infantile onset FSHD is 
progressive and may affect language and social development in these patients.  In some 
patients, an exudative retinopathy, described as Coats syndrome,28 presents the potential 
for retinal detachment and vision loss, if uncorrected.  Therefore, auditory and 
ophthalmic screening and/or monitoring, and intervention, where feasible, are 
recommended in pediatric patients with infantile onset FSHD.  

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There is limited published literature describing other early onset patients with FSHD who 
do not meet criteria for the phenotype described by Brouwer et al.25, but who have 
symptom onset within approximately the first decade of life.  This group of patients may 
also be considered to have early onset FSHD, distinguished by age at presentation; 
however, it is unclear if this group of early onset FSHD patients follows a clinical course 
similar to that classically reported in adults, or if there may be distinct phenotypes within 
this population.  
FSHD became a genetically defined muscular dystrophy with the discovery of the 
molecular genetics of FSHD129 and FSHD2.30  Over 90% of FSHD patients are 
considered to have FSHD1, a dominantly inherited disease that maps to variable sized 
deletions of a repeated microsatellite array (D4Z4) in the sub-telomeric region of 
chromosome 4q35.  Normal, unaffected individuals have from 11 to 100 of these array 
repeats, while those with FSHD1 have only 1 to 10 repeats.29  Individuals with the fewest 
array repeats within this range (1-3) tend to have earlier-onset disease and more rapid 
disease progression.31,32 
FSHD2, a second form that affects approximately 5% of patients, results from a mutation 
in the chromatin modulator gene, SMCHD1 on chromosome 18.  The inheritance pattern 
of FHSD2 can be considered “di-genic”, because as in FSHD1, a permissive 4q35 
haplotype that generates a novel polyadenylation signal distal to the D4Z4 repeat array is 
required for disease penetrance.30 
There is considerable variability in onset and disease progression in individuals with 
FSHD1 and 2.  An epigenetic basis (interindividual differences in CpG methylation at 
D4Z4) for this basis has been recently uncovered.33 
Since the identification of these genetic etiologies of FSHD, a primary focus on the 
pathogenesis of FSHD has been on the D4Z4 repeat.  This deoxyribonucleic acid 
sequence contains a copy of DUX4, a transcription factor gene normally expressed in 
germ line development, but repressed in somatic tissue such as skeletal muscle.34  It has 
been hypothesized that contracted D4Z4 repeat arrays in FSHD1, or specific SMCHD1 
mutations in FSHD2 set the stage for the FSHD phenotype by establishing a “relaxed 
chromatin state” that results in somatic cell de-repression of DUX4 expression, 
particularly in skeletal muscle.21,29,35  Mis-regulated, ectopic expression of numerous 
DUX4 regulated genes then occurs, leading to transcriptional profiles associated with 
abnormal muscle regenerative, vascular and immune responses.  Aspects of these profiles 
have been linked to the immunopathology observed in patients with FSHD.36 
Although the genetic basis for the disease has been defined, and the pattern of muscle 
involvement in FSHD generally is predictable, the particular muscles involved are not.  
For example, a single muscle in a limb or the trunk may be severely affected while for 
reasons that are unclear, an adjacent muscle will be either affected later in the disease 
course or spared completely.   

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Inflammatory and dystrophic disease processes can be followed in individual muscles 
using magnetic resonance imaging (MRI), a methodology of increasing utility for 
monitoring the progression of muscular dystrophies.22,37,38,39  The T1-weighted signal 
intensity by MRI is believed to represent fatty infiltration, while the short tau inversion 
recovery (STIR) signal intensity suggests the presence of inflammation.  This increase in 
signal intensity is due to an increase in the T2 relaxation time, which can be measured 
using quantitative MRI.38,40  A recent study with FSHD patients and controls found 
inflammation (CD8+ and CD4+ T cells), specifically in muscle biopsies taken from STIR 
hyperintense muscles.22  Longitudinal MRI studies have recently shown that 
inflammatory changes in FSHD skeletal muscle directly precede fatty infiltration.41  In 
addition, the degree of fatty infiltration as determined by the number of T1-positive 
muscles has been correlated with a commonly used measure of functional status, the 
FSHD clinical severity score (CSS).22  These data suggest that MRI findings could be 
highly informative in clinical studies in FSHD patients.21,22 
The inflammatory immune response in FSHD is also reflected in the peripheral 
circulation of individuals with FSHD through several lines of evidence.  First, in FSHD 
patients with muscle inflammation detected by STIR positive MRI, activated immune 
cells (CD8+ T cells [pSTAT1+, T-bet+] and CD14+pSTAT1+ cells) are present in the 
circulation.  Peripheral blood mononuclear cells (PBMCs) from individuals with STIR 
positive muscle also show evidence of activation in cell culture by spontaneously 
releasing high amounts of immune proteins such as IL-10, IL-6, TNF-α and IL-12p40 
into the culture medium compared to controls.22 
In other studies of the inflammatory immune state of FSHD patients, elevated levels of 
circulating immune proteins, including monocyte chemoattractant protein-1 (MCP-1), 
epidermal growth factor, matrix metallopeptidase 9 (MMP-9), creatine kinase-myocardial 
band, and tissue plasminogen activator, are seen in FSHD patients compared to control, 
unaffected individuals.42 
There currently are no pharmacologic treatments for the muscle disease in FSHD.  
Furthermore, there are no validated animal models in this disease for use in drug 
development.43  However, both the dystrophic changes and the inflammatory process 
have been considered rational disease targets.22  To date, a small number of drugs with 
potential impact either on the inflammatory response or the muscle itself have been 
evaluated in FSHD in clinical studies, albeit without positive results.  These included the 
non-specific immunosuppressant, prednisone,44 and molecules that are thought to 
enhance muscle mass:  beta adrenergic agonists,45 creatine monohydrate 
supplementation, and myostatin inhibitors.46  In these clinical studies, no clinically 
meaningful benefit was observed.  However, no effort was made to stratify the patients 
based on the degree of inflammation or specific muscle involvement.   

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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.22  
2.3. 
ATYR1940 
ATYR1940 is a protein therapeutic candidate identical to amino acids 2-506 of wild-type 
human histidyl tRNA synthetase (HARS).  ATYR1940 does not belong to any 
established therapeutic class.  ATYR1940 is a preservative-free liquid concentrate 
(4.0 mL) supplied at a concentration of approximately 25 mg/mL in a 5 mL single-use 
type 1 glass vial that is further diluted with 0.9% normal saline for intravenous (IV) 
administration.   
Non-clinical studies in animals have shown that IV administered ATYR1940 is 
efficacious in various immune driven disease models in an active dose range of 1.0 to 
3.0 mg/kg, including normalization or reduction of severe statin-induced skeletal 
myopathy, as indicated by improved muscle histology (decreased inflammatory cell 
infiltration, necrotic fibers and fibrotic changes compared to control); decreased muscle 
protein levels in serum (e.g., decreased skeletal troponin I); decreased cellular infiltration 
(decreased CD68+ cells by immunohistochemistry [IHC], decreased CD11b and CD14 
messenger ribonucleic acid [mRNA; macrophage lineage]; decreased CD3+ cells by IHC, 
CD8a and CD8b mRNAs [T cells] and increased myeloperoxidasehigh by IHC [neutrophil 
marker]); and decreased inflammatory marker levels in skeletal muscle tissues (e.g., 
decreased IL-6, MCP-1, and MMP-9).  These data support the role of HARS in 
modulating immune responses in skeletal muscle, and the potential of ATYR1940 to 
therapeutically suppress inflammatory cell infiltration (such as CD8+ cells) into skeletal 
muscles, thereby attenuating skeletal muscle fiber atrophy and circulating evidence of 
muscle disease, including pathologic serum levels of creatine kinase (CK) and other 
muscle proteins in patients with FSHD and other RMIC disorders.   
Nonclinical studies in immune cells isolated from the blood of healthy subjects have 
shown direct immune modulatory effects of ATYR1940, including attenuation of 
cytokines released from stimulated T cells and decreased spontaneous release of 
cytokines from M1 macrophages differentiated in the presence of ATYR1940. 
Clinical data with ATYR1940 are available from one completed study in healthy 
volunteers; limited clinical data are available from ongoing studies in patients with 
muscular dystrophies.   
The completed healthy volunteer study included 24 healthy subjects who tested negative 
for antibodies against HARS (i.e., Jo-1 antibody [Ab]) exposed to a single IV dose of 
ATYR1940 in a Phase 1, first-in-human, randomized, double blind, placebo-controlled, 
single ascending dose study (ATYR1940-C-001).  In this study, ATYR1940 was 
investigated at doses of 0.1, 0.3, 1.0, and 3.0 mg/kg.  Within each dose cohort, 6 subjects 
received ATYR1940 and 2 subjects received placebo.  A single, 30-minute IV infusion of 

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ATYR1940 0.1 to 3.0 mg/kg was safe and well tolerated by healthy subjects.  All adverse 
events (AEs) were mild in severity, non-serious, and transient.  Overall, treatment-
emergent AEs (TEAEs) reported for more than 1 ATYR1940-treated subject included 
dizziness, headache, abdominal distension, fatigue, nasopharyngitis, nausea, and 
oropharyngeal pain.  No dose relationship was apparent with regard to the occurrence of 
these AEs.  Furthermore, no clinically relevant changes from baseline in safety laboratory 
tests, vital signs, electrocardiograms (ECGs), pulmonary function tests (PFTs), or arterial 
oxygen saturation (based on pulse oximetry) were observed.  Six ATYR1940-treated 
subjects were determined to be anti-drug-antibody (ADA) positive at at least one post-
dose time point; one of these subjects also was ADA positive at baseline.  ADA positivity 
was not associated with any temporal adverse systemic symptoms, safety laboratory 
abnormalities, or abnormal spirometry or pulse oximetry findings in any of these 
subjects.  Furthermore, the pharmacokinetics (PK) of ATYR1940 was not altered in these 
subjects. 
Results of PK analyses from Study ATYR1940-C-001 revealed evidence of systemic 
exposure to ATYR1940 in all treated subjects at all dose levels.  Following an 
approximate 30-minute IV infusion of ATYR1940, peak serum concentrations generally 
occurred at or shortly after the end of infusion, with a mean time to attain maximum 
serum concentration (tmax) of approximately 0.5 hours, followed by a mono-phasic 
decline.  Mean ATYR1940 exposure increased with increasing dose in a dose 
proportional manner.  Mean maximum serum concentration (Cmax) values increased 
approximately 24-fold over a 30-fold dose range, with mean Cmax values of 603, 1470, 
5480, and 14,700 ng/mL at doses of 0.1, 0.3, 1.0, and 3.0 mg/kg, respectively.  Mean 
AUC0-inf was 3050, 7090, 28,800, and 77,500 ng*h/mL at doses of 0.1, 0.3, 1.0, and 
3.0 mg/kg, respectively.  Mean total systemic clearance was low (ranging from 
approximately 0.6-0.8 mL/min/kg) and the volume of distribution was small 
(approximately 0.2 L/kg), resulting in a terminal half-life (t1/2) of approximately 3-
6 hours across all dose levels.  No pharmacodynamic (PD) effects of ATYR1940 were 
observed in this single-dose healthy subject study.   
Limited data are available from the first clinical investigation of ATYR1940 in patients 
with FSHD, Study ATYR1940-C-002, “A Placebo-Controlled, Randomized, Multiple 
Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Biological Activity of ATYR1940 in Adult Patients with Molecularly Defined Genetic 
Muscular Dystrophies”.  This study is being conducted in adult patients with FSHD at 
multiple sites in Europe (EU) and the US.  In this study, patients are randomized (3:1) to 
receive ATYR1940 or placebo at doses of 0.3 or 1.0 for 4 weeks or 3.0 mg/kg for 
12 weeks in sequential dose cohorts; qualified patients have the option to continue or 
initiate (i.e., in the case of patients randomized to the placebo group) ATYR1940 
treatment in an ongoing extension study (ATYR1940-C-005). 

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Generalized infusion-related reactions (IRRs) have been reported for 3 patients treated in 
studies of ATYR1940, including one event that was considered serious.  These events 
were observed following more than 4 weeks of dosing with 3.0 mg/kg ATYR1940 as a 
30-minute, 50-mL IV infusion once weekly, and resolved after stopping the infusion and,
in some instances, administering medications and IV fluids.  Patients who experienced
generalized IRRs were permanently discontinued from dosing.
The Sponsor has initiated the “parent” studies (Study ATYR1940-C-003 and ATYR-C-
004) to this extension study.  Study ATYR1940-C-003 is entitled “An Open-Label,
Intrapatient Dose-Escalation Study to Evaluate the Safety, Tolerability, Immunogenicity,
and Biological Activity of ATYR1940 in Patients With Early Onset and Other Pediatric
Onset Facioscapulohumeral Muscular Dystrophy” and is being conducted in the US and
EU.  Study ATYR1940-C-004 is entitled “An Open-Label, Intrapatient Dose Escalation
Study to Evaluate the Safety, Tolerability, Immunogenicity, and Biological Activity of
ATYR1940 in Patients with Limb Girdle and Facioscapulohumeral Muscular
Dystrophies”.  In both studies, which are being conducted in the US and EU, patients
receive ATYR1940 for 12 weeks.  Patients who were enrolled in Study ATYR1940-C-
004 or in Stage 1 of Study ATYR1940-C-003 and meet the entry criteria may participate
in this extension study and continue treatment with weekly ATYR1940.  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 (see Section 6.4.1).
2.4. 
Rationale for Current Study 
aTyr has shown that: 1) HARS is detected in blood samples from healthy individuals and 
patients (preclinical work) and in the ATYR1940-C-001 study in blood samples from 
healthy subjects participating in the study and 2) human skeletal muscle cells release 
HARS during differentiation, a process that can be regulated by molecules already known 
to modulate muscle mass and blocked by antibodies to HARS.  Furthermore, 
pharmacological application of ATYR1940 1) alters cytokine and other immune protein 
release from human primary immune cells, and 2) has immune modulatory activity in 
rodent models, including a rat model of myopathy.  Taken together, 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. 
LGMD2B and FSHD are chronic diseases that will likely require lifelong therapy.  In the 
parent studies, ATYR1940 is administered over a relatively short period of up to 
12 weeks (including weekly dosing in the ATYR1940-C-003 study and weekly and twice 
weekly dosing in the ATYR1940-C004 study).  No maximum duration of therapy has 
been set in the current study, and patients will be allowed to receive treatment with 
ATYR1940 until ATYR1940 is approved or its development is discontinued, the study is 

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closed by the Sponsor, or a criterion for study drug discontinuation is met (see Section 
6.4.1).  The safety and efficacy of longer term exposure to ATYR1940 will be 
continuously assessed over the course of this extension study. 

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3.
STUDY OBJECTIVES AND ENDPOINTS
3.1. 
Objectives
The objectives of the study are to: 

Evaluate the safety, tolerability, and immunogenicity of long-term treatment with
IV ATYR1940 in patients with LGMD2B or FSHD previously enrolled in clinical
study ATYR1940-C-003 (Stage 1 only) or ATYR-1940-C-004.

Explore the biological and PD activity of ATYR1940 in patients with LGMD2B
and FSHD, based on changes in:
-
Serum-based muscle biomarkers.
-
Inflammatory immune state in peripheral blood.
-
Muscle disease and muscle disease burden, based on skeletal muscle MRI.
-
Skeletal muscle strength.
-
Upper and lower extremity muscle function.
-
Quality of life measures.
3.2. 
Study Endpoints
3.2.1. 
Safety and Tolerability Endpoints
The safety and tolerability endpoints of this study are: 

Incidence of TEAEs and serious adverse events (SAEs) overall and by intensity.

Changes from baseline in:

Safety laboratory test results.

ECG findings.

Vital signs measurements.

Pulmonary evaluations (PFTs and pulse oximetry).

Incidence and level of ADA titers and Jo-1 Ab levels.

Exploratory characterization of immune response to ATYR1940.
3.2.2. 
Muscle Effects 
Muscle strength and function will be evaluated by the following: 

Muscle disease burden on lower extremity skeletal muscle MRI.

Muscle strength, based on manual muscle testing (MMT).

Upper and lower extremity muscle function, based on the Brooke and Vignos
scales, respectively.

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3.2.3. 
Pharmacodynamics (Exploratory) 
The PD effects of ATYR1940 will be evaluated by the following: 

Changes in muscular-dystrophy-related inflammatory immune state in peripheral
blood, as assessed by:
-
Circulating immune proteins, such as cytokines.
-
Ex vivo inflammatory immune protein (including cytokines) release from
PBMCs.
-
Immunophenotyping of circulating PBMCs.

Changes in serum- and/or plasma-based muscle biomarkers.
3.2.4. 
Quality of Life (Exploratory) 
Quality of life will be assessed based on the following: 

Individualized Neuromuscular Quality of Life (INQoL) questionnaire.

For patients with FSHD, the FSHD-specific Health Inventory (FSHD-HI)
questionnaire.
Specific endpoints based on quality of life data have not been defined. 
3.2.5. 
Systemic Exposure 
Systemic exposure will be determined through sparse PK sampling.  As the data allow, 
PK parameters will be calculated from the drug concentration data using WinNonlin. 

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4.
INVESTIGATIONAL PLAN
4.1. 
Overall Study Design and Plan
Study ATYR1940-C-006 is a multi-national, multi-center, open-label extension study 
designed to evaluate the long-term safety, effects on muscle, and PD of ATYR1940 in 
patients with LGMD2B and FSHD previously treated in the parent studies.  This study 
will be conducted at the same study centers at which patients were enrolled in the parent 
studies. 
Patients who participated in and completed the treatment period in the parent study; in the 
Investigator’s opinion, demonstrated acceptable tolerability of ATYR1940, are 
considered by the Investigator to be compliant with ATYR1940 and the study 
procedures, and do not meet any criterion for ATYR1940 discontinuation are eligible for 
participation in the current study, contingent upon Investigator and patient agreement to 
continue ATYR1940 treatment.  
Ideally, when a patient transfers from the parent study to this extension study, the 
duration between the last ATYR1940 dose in the parent study and first ATYR1940 dose 
in this extension study is 1 week; however, a maximum duration of 3 weeks is 
permissible.  (A window >3 weeks may be permissible on a case-by-case basis, if 
required due to administrative reasons, after consultation with the Medical Monitor.) 
For the first 12 weeks in this extension study, patients will receive ATYR1940 at the 
highest tolerated dose received in the parent study; no dose adjustments are allowed 
during this 12-week period.  After 12 weeks, if the patient is demonstrating good 
tolerability, the ATYR1940 dose may be increased on a patient-specific basis at the 
Investigator’s discretion, in consultation with the Sponsor and Medical Monitor.  
ATYR1940 dose increases to >3.0 mg/kg are not permissible.   
All patients will receive ATYR1940 on a weekly basis in this study, regardless of the 
frequency of dosing in the parent study.   
ATYR1940 will be administered via IV infusion over 90 minutes.  If medically indicated, 
the infusion duration and volume may be adjusted at the Investigator’s discretion in 
consultation with the Medical Monitor and Sponsor. 
4.2. 
Justification for the Study Design 
ATYR1940 is being developed for rare, severe, muscle diseases with an immune 
component (i.e., RMIC), for which few, if any, efficacious treatment options exist, and no 
efficacious pharmacological therapies are approved.  Given the significant unmet medical 
need in these disorders, and in LGMD2B and FSHD, in particular, advancing safe and 
efficacious therapies into patients as rapidly as possible is warranted.   
The current study allows for patients who have demonstrated acceptable tolerability of 
ATYR1940 and who are candidates for continued treatment, in the Investigator’s 

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opinion, to start or continue ATYR1940 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.  As all patients will receive ATYR1940, it will be given in an 
open-label fashion. 
The study includes ADA and Jo-1 Ab testing, detailed clinical monitoring for potential 
generalized IRRs, extended safety follow-up, and a specific plan to assist investigators in 
the clinical management of patients in whom clinical signs of generalized IRRs occur 
(see Section 7.5.5). 

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5.
STUDY POPULATION
Based on the design of the parent studies, it is estimated that up to 24 patients will be 
enrolled in this study. 
5.1. 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible for study entry: 
1. Enrolled in and completed the treatment period in the parent study.
2. Demonstrated, in the Investigator’s opinion, acceptable tolerability of
ATYR1940.
3. In the Investigator’s opinion, patient has shown acceptable compliance with
ATYR1940 and the study procedures in the parent study and is willing and able to
comply with all procedures in the current study.
4. Is, in the Investigator’s and Sponsor’s opinion, a suitable candidate for continued
ATYR1940 treatment.
5. Provide written informed consent or assent (as appropriate, based on age of
majority) after the nature of the study has been explained and prior to the
performance of any research-related procedures.
5.2. 
Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for study entry: 
1. At any time during participation in the parent study, met a ATYR1940
discontinuation criterion, including, but not limited to:
a.
Jo-1 Ab levels ≥1.5 U/mL.
b. Clinical evidence of a generalized IRR (see Section 7.5.5.1).
c.
Clinical evidence of a National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) (version 4.03) ≥Grade 2, study-drug-
related SAE.
d. Pregnancy.
e.
Progression of disease that, in the opinion of the Investigator, precluded
further participation in the study.
f.
Withdrawal of consent or assent.
g. Other findings that, at the discretion of the Investigator and/or Sponsor,
indicated that study drug administration should be discontinued.
2. Is expected to require treatment with curcumin or systemic albuterol (intermittent
inhaled albuterol is permissible) during study participation; or use of a product

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that putatively enhances muscle growth (e.g., insulin-like growth factor, growth 
hormone) or activity (e.g., Coenzyme Q, Coenzyme A, creatine, L-carnitine) on a 
chronic basis; or statin treatment initiation or significant adjustment to statin 
regimen (stable, chronic statin use is permissible). 
3. Planned to receive any vaccination during study participation.
4. Abnormal baseline findings, medical condition(s), or laboratory findings that, in
the Investigator’s opinion, might jeopardize the patient's safety or decrease the
chance of obtaining satisfactory data needed to achieve the objectives of the
study.
5. Evidence of clinically significant cardiovascular, pulmonary, hepatic, renal,
hematological, metabolic, dermatological, or gastrointestinal disease, or has a
condition that requires immediate surgical intervention or other treatment or may
not allow safe participation.
6. If female and of childbearing potential (premenopausal and not surgically sterile),
has a positive pregnancy test at entry or is unwilling to use contraception from the
time of entry through the 3-month Follow-up visit.  Acceptable methods of birth
control include abstinence, barrier methods, hormones, or intra-uterine device.
7. If male, is unwilling to use a condom plus spermicide during sexual intercourse
from the time of entry through the 1-month Follow-up visit.
5.3. 
Source of Patients 
This will be a multinational, multi-center study.  Each study center is required to obtain 
local Institutional Review Board (IRB)/Ethics Committee (EC) and national regulatory 
approval to conduct the study before enrollment of patients may commence.  Patients 
who previously participated in Study ATYR1940-C-003 (Stage 1 only) or 
ATYR1940-C-004 and who meet the entry criteria of the current study will be eligible for 
enrollment.  

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6.
STUDY CONDUCT
6.1. 
Patient Identification, Enrollment, and Randomization
Patients will be identified by a unique, 5-digit identification (ID) number consisting of 
the parent study number (i.e., “3” or “4”), a 1-digit site number, and the 3-digit patient 
numbers assigned in the parent study.  For example, Patient 
 in parent study 
ATYR1940-C-003 would be renumbered as Patient 
in this extension study. 
Consented patients who satisfy all entry criteria will be enrolled into the study. 
Randomization is not applicable to this study.  Patients who qualify for the study will be 
enrolled in the study at Week 1 and study drug will be dispensed to the patient. 
6.2. 
Patient Management 
All patients must provide written informed consent or assent, as appropriate, based on 
local age of majority, before the performance of any study-related procedures.  Patients 
who are determined to be eligible for the study will be enrolled into the study at the 
baseline visit (Week 1) and will receive IV infusions of ATYR1940 weekly.  Patients 
will attend posttreatment follow-up visits 1, 4, and 12 weeks following completion of 
dosing.  The 12-week follow-up visit is the End-of-Study (EOS) visit.  
6.3. 
Patient Adherence 
All patients are required to adhere to the protocol-specified dosing and visit schedules.  If 
a patient misses a scheduled visit, attempts should be made to reschedule the visit within 
the visit windows specified in Table 1.  Failure to attend scheduled study visits may result 
in discontinuation from the study. 
6.4. 
Withdrawal and Replacement of Patients 
6.4.1. 
Study Drug Discontinuation Criteria 
Study drug must be discontinued if any of the following events occur: 

Jo-1 Ab levels ≥1.5 U/mL.  Refer to Section 7.5.5 for complete details regarding the
management of potential immunogenicity.

Clinical evidence of a generalized IRR (see Section 7.5.5.1).  Refer to Section 7.5.5
for complete details regarding the management of potential immunogenicity.

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
Clinical evidence of an NCI CTCAE (version 4.03) ≥ Grade 2, study-drug-related
SAE.

Pregnancy.

Progression of disease that, in the opinion of the Investigator, precludes further
participation in the study.

Withdrawal of consent or assent.

Other findings that, at the discretion of the Investigator and/or Sponsor, indicate that
study drug administration should be discontinued.
All patients who have been dosed with any amount of ATYR1940 will continue to be 
followed for safety.  Patients who discontinue ATYR1940 dosing at any time during the 
treatment period should return to the study center for the 1-, 4-, and 12-week 
posttreatment follow-up visits and as clinically indicated. 
Patients who discontinue ATYR1940 due to a generalized IRR or Jo-1 Ab levels 
≥1.5 U/mL are to return to the study center for weekly visits as clinically indicated for 
safety follow up.  At a minimum, such patients must attend the 1-, 4-, and 12-week 
posttreatment follow-up visits (see Section 7.5.5).   
Patients who withdraw their consent or assent will not receive any further study drug, but 
will be offered all follow-up safety assessments.   
If a patient fails to attend scheduled study assessments, the Investigator must determine 
and document the reasons and the circumstances as completely and accurately as 
possible. 
6.4.2. 
Study Withdrawal Criteria 
Patients will be informed that they have the right to withdraw from the study at any time 
for any reason, without prejudice to their medical care.  The Investigator also has the 
right to withdraw patients from the study for any of the following reasons: 

Patient non-adherence to ATYR1940 or protocol requirements.

Patient unwillingness to continue in the study.

Any other reason, based upon the medical judgment of the Investigator.
The reason for study withdrawal is to be documented in the patient’s source documents 
and electronic case report form (eCRF). 
At the time of discontinuation from the study, patients are to have all the assessments 
planned for the 1- and 4-week posttreatment follow-up visits performed within 7-days 
after the last study drug dose, if feasible.  (Note that some assessments are listed in both 
the 1- and 4-week follow-up visit; such assessments need only to be performed once at 
the time of discontinuation.) 

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Patients who are withdrawn from the study for any reason will not be replaced. 
6.5. 
Study Completion 
A patient is considered to have completed the study if they complete the EOS visit. 
6.6. 
Study Termination 
If the Sponsor or Investigator discovers conditions arising during the study that suggest 
the study should be halted, then this can happen only after appropriate consultation 
between the Sponsor and Investigator.  Conditions that may warrant study termination 
include, but are not limited to: 

The discovery of any unexpected, significant, or unacceptable risk to the patients
enrolled in the study.

Insufficient adherence to the protocol requirements.

A decision on the part of the Sponsor to suspend or discontinue development of
ATYR1940.
6.7. 
Investigator Compliance 
Study centers that deviate significantly from the protocol without prior approval from the 
Sponsor and regulatory authorities may be discontinued from the study.  The Investigator 
at each study center is responsible for ensuring the accuracy and completeness of all 
research records, the accountability of ATYR1940, and the conduct of clinical and 
laboratory evaluations as outlined in the protocol.  The Investigator is responsible for 
ensuring that the clinical study is performed in accordance with the Declaration of 
Helsinki and the International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) guidance documents. 

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7.
STUDY DRUG
aTyr or designee will supply ATYR1940 to the pharmacies at all participating study 
centers.   
7.1. 
Study Drug Supply 
ATYR1940 is a 505 amino acid protein identical to the wild-type amino acids 2-506 of 
human HARS.  ATYR1940 is formulated at a target concentration of 25 mg/mL as a 
sterile, non-pyrogenic solution in a formulation buffer containing histidine, sodium 
chloride, and polysorbate 20 at pH 7.3 and filled into type 1 borosilicate glass vials 
(5 mL) with butyl rubber stoppers and aluminum seals.  The fill volume of the clinical 
trial material is 4 mL.  The product is non-preserved and is suitable for a single-dose use 
by IV administration. 
7.2. 
Study Drug Packaging and Labeling 
ATYR1940 will be packaged in boxes containing vials of ATYR1940.  The pharmacist 
will dilute ATYR1940 in saline, based on each patient’s body weight, and transfer the 
dose to be administered to an infusion set. 
Study drug labels will not bear any statement that is false or misleading in any manner or 
represents that the ATYR1940 is safe or effective for the purposes for which it is being 
investigated.  The content of the labeling will be in accordance with local regulatory 
specifications and requirements.  
7.2.1. 
Procedures for Breaking the Blind 
This is an open-label study. 
7.3. 
Study Drug Storage 
ATYR1940 is to be stored in a locked area, accessible only to appropriate study 
personnel. 
ATYR1940 is to be stored in a freezer at -20C ± 5C.  Prior to preparation for 
administration, ATYR1940 is to be thawed in the refrigerator for 3 to 72 hours.  The 
infusion set containing ATYR1940 is to be prepared just before use and should not be 
placed at room temperature for more than 6 hours.   
ATYR1940 is for single-use administration and does not contain any preservatives or 
anti-microbial or bacteriostatic agents.   
7.4. 
Study Drug Accountability 
The Investigator or delegate will maintain accurate records of receipt and condition of 
ATYR1940, including dates of receipt.  In addition, accurate records will be kept of the 
date administered, quantity administered, and the patient to whom ATYR1940 was 

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administered.  Any reasons for departure from the protocol-specified dispensing regimen 
must also be recorded.   
The Investigator is responsible for the accountability of all used and unused ATYR1940 
vials.  The site ID number and patient initials are to be recorded on each ATYR1940 
accountability log.  Each time study personnel dispense ATYR1940 for a patient, they are 
to record the date dispensed, amount dispensed, and their initials.  Study personnel are to 
monitor the inventory of clinical supplies and maintain a count of all used and unused 
supplies. 
A Clinical Research Associate (CRA) will review ATYR1940 accountability records 
during routine monitoring visits.  At the completion of the study, there will be a final 
reconciliation of all ATYR1940 vials. 
7.5. 
Study Drug Dose and Administration 
7.5.1. 
Dose and Route of Administration 
ATYR1940 will be administered via IV infusion. 
For the first 12 weeks in this extension study, patients will receive ATYR1940 at the 
highest tolerated dose received in the parent study; no dose adjustments are allowed 
during this 12-week period.  After 12 weeks, if the patient is demonstrating good 
tolerability, the ATYR1940 dose may be increased on a patient-specific basis at the 
Investigator’s discretion, in consultation with the Sponsor and Medical Monitor.  
ATYR1940 dose increases to >3.0 mg/kg are not permissible.   
All patients will receive ATYR1940 on a weekly basis in this study, regardless of the 
frequency of dosing in the parent study.   
7.5.2. 
Infusion Rate and Volume 
ATYR1940 will be administered IV as a 90-minute infusion.   
The ATYR1940 dose will be prepared for infusion in 100 mL (0.3 and 1.0 mg/kg) or 
250 mL (3.0 mg/kg) saline, as long as clinically indicated; refer to the Pharmacy Manual 
for details.   
During the course of the study, the Investigator may confer with the Medical Monitor and 
Sponsor if medically indicated or if there does not appear to be an increased risk to the 
patient, to decrease the study drug infusion time and/or volume of study drug 
administration on an individual patient basis.  In such cases, the change(s) should be 
clearly documented in drug accountability records. 
Body weight obtained at Week 1 will be used for preparation of each patient’s mg/kg 
ATYR1940 dose.  If the patient has a notable change in body weight (±10%) during the 
study, the Medical Monitor is to be notified regarding recalculation of ATYR1940 dose.  

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7.5.3. 
Dosing Frequency and Treatment Intervals 
All patients will receive ATYR1940 weekly. 
Samples for determination of Jo-1 Ab levels will be collected before each ATYR1940 
dose; the Jo-1 Ab level from the previous dose will be used for the acceptability of dosing 
on each dosing day.  ATYR1940 is to be permanently discontinued for any patient with a 
Jo-1 Ab level ≥1.5 U/mL. 
7.5.4. 
Dose Reduction 
If, in the Investigator’s judgment, the patient is not tolerating a dose level, the Medical 
Monitor is to be contacted regarding the potential for dose reduction to a lower 
ATYR1940 dose level, or discontinuation of treatment (e.g., as would be the case for a 
generalized IRR), as appropriate. 
The Sponsor has the discretion to delay dosing, change infusion duration, or decrease a 
patient's dose, based on relevant data reviewed concurrently in an individual patient (e.g., 
Jo-1 Ab levels) and/or additional clinical information provided by the Investigator. 
7.5.5. 
Clinical Management Plan for Potential Immunogenicity 
7.5.5.1. 
Infusion-Related Reactions 
Generalized IRRs have been reported for 3 patients treated in studies of ATYR1940, 
including one event that was considered serious.  The constellation of symptoms in these 
patients has varied, but the overarching diagnosis is IRR of a generalized nature (i.e., not 
at the site of injection), which occurred during the infusion of ATYR1940, but only after 
the patient had received multiple doses of ATYR1940. The IRRs occurred in the setting 
of infusing ATYR1940 over 30-minutes in 50 mL of normal saline.  These reactions 
resolved after stopping the infusion and, in some instances, administering medications 
and/or IV fluids. 
Thus, generalized IRR is a risk following the repeated administration of ATYR1940.  In 
an effort to mitigate this risk, the infusion duration and volume of infusion have been 
increased.  These changes are intended to decrease the concentration of ATYR1940 being 
infused at any given time and allow for medical assessment earlier in the course of an 
IRR by providing a wider window to stop the infusion before the entire dose has been 
administered. 
In addition, patients are to be closely monitored for a generalized IRR throughout the 
study drug infusion.  Signs and symptoms of a generalized IRR may vary among patients, 
and may include, but are not limited to, one or more of the following:   

Fever

Chills, rigors, myalgia

Facial or systemic erythema, pallor, facial swelling

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
Chest tightness, difficulty breathing, wheezing, stridor, tachypnea, bronchospasm,
cough

Tachycardia or significant pulse rate increase from baseline without other obvious
cause

Bradycardia or significant pulse rate decrease from baseline

Pre-syncope or syncope

Hypotension, orthostatic hypotension, or blood pressure swings, including
hypertension

Skin rash, urticaria, angioedema, or pruritus

Swelling of the throat, tongue, mouth, or lip

Difficulty speaking; hoarse or raspy voice

Excessive salivation; difficulty swallowing

Nausea, vomiting, cramps, or diarrhea

Development of a headache, especially moderate or greater, after start of infusion
A generalized IRR could be occurring when any symptoms suggestive of such a reaction 
begin during the study drug infusion or during the post-infusion observation period.  
While these symptoms may be self-limiting, such symptoms may signal the possibility of 
a severe reaction that could escalate into a life-threatening situation.   
In the event of a generalized IRR, study drug infusion must be stopped immediately (and 
not re-administered) and appropriate medical care must be given.  If necessary, the 
patient should be transferred to an acute care facility.  Once the patient is stabilized, 
additional blood samples are to be collected and procedures performed, as per Section 
8.5.9.4. 
7.5.5.2. 
Jo-1 Antibody Testing, Stopping Rules, and Anti-Synthetase Syndrome 
In patients treated with ATYR1940 who experienced a generalized IRR, low levels of an 
antibody known as Jo-1 Ab have been detected.  These antibodies are directed against 
ATYR1940 (and the parent protein, HARS).  The nature of the relationship of these 
antibodies to the generalized IRRs is not yet clear, but the development of either Jo-1 Ab 
levels and generalized IRRs or both has been identified as a risk following the repeated 
administration of ATYR1940.  These risks, however, can be monitored closely, including 
by assessment of Jo-1 Ab levels using a commercial assay and monitoring for signs of 
generalized IRRs.  Because generalized IRRs have occurred in association with low 
levels of Jo-1 Abs, a low threshold of Jo-1 Abs has been set:  patients who develop Jo-1 
Ab levels of ≥1.5 U/mL will discontinue ATYR1940, but continue to be followed as 

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described in this section, and patients with Jo-1 Ab levels ≥1.5 U/mL will be excluded 
from study participation. 
A very rare autoimmune disorder known as anti-synthetase syndrome, characterized 
clinically by an inflammatory myopathy, skin manifestations, arthritis, and often 
associated with interstitial lung disease,47,48 is associated with Jo-1 Ab as well, albeit at 
higher Jo-1 Ab levels than observed during ATYR1940 dosing.  The pathophysiological 
processes that lead to the development of this rare syndrome, and to auto-immune 
responses to HARS, are not known.  Clinical and genetic factors, including human 
leukocyte antigen haplotype, that confer increased risk for the development of anti-
synthetase syndrome have been identified, but how these factors confer risk is poorly 
understood.49 
The diagnosis of an anti-synthetase syndrome is made based on a combination of clinical 
findings and Jo-1 Ab levels through commercially available serological assessments.50 
Anti-synthetase syndrome, once diagnosed, is usually treated by immunosuppression, 
often by the use of systemic corticosteroids.48
The development of an anti-synthetase syndrome is a theoretical, albeit unlikely risk 
following the repeated administration of ATYR1940.  This risk, however, can be 
monitored closely, by assessment of clinical signs and symptoms and by following Jo-1 
Ab levels.  With the commercial Jo-Ab assay used in this study, a level of 7 U/mL is 
thought to be the lower limit for an equivocal finding of Jo-1 Ab-associated anti-
synthetase syndrome and a level of 10 U/mL is considered positive.  The risk of a patient 
developing Jo-1 Ab levels diagnostic for anti-synthetase syndrome is mitigated by the 
fact that ATYR1940 dosing will be discontinued if a Jo-1 Ab level of ≥1.5 U/mL is 
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The actions listed below are to be taken by the Investigator to manage patients with a Jo-
1 Ab result that reaches the threshold of ≥1.5 U/mL during the study.   
1)
The patient will no longer receive ATYR1940, and
2) The patient will return to the study center for visits as per protocol, if feasible, and
be required to return to the clinical site for the 1-, 4-, and 12-week posttreatment
follow-up visits, at a minimum.
In addition, any patient who develops clinical manifestations of an anti-synthetase 
syndrome (with or without reaching a Jo-1 Ab threshold of ≥1.5 U/mL) will: 
1) No longer receive ATYR1940, if the clinical manifestations occur before
administration of any planned dose, and
2) Receive appropriate, acute medical treatment as warranted clinically, including
immunosuppressive interventions, and
3) Be referred to an appropriate medical professional (e.g., rheumatologist or
equivalent) who is experienced with anti-synthetase syndrome, and
4) Return to the study center for visits as per the protocol schedule, if feasible, but
must attend the 1-, 4-, and 12-week posttreatment follow-up visits, at a minimum.
The Medical Monitor will monitor patients’ Jo-1 Ab levels concurrently with the 
Investigator during the conduct of the study, and will confer regarding any patient(s) with 
rising Jo-1 Ab titers.  The Medical Monitor and Investigator will discontinue ATYR1940 
for patients whose Jo-1 Ab level reaches ≥1.5 U/mL.  The Investigator must inform the 
study Medical Monitor promptly regarding any patient who develops clinical 
manifestations of an anti-synthetase syndrome. 
Patients in whom sufficiently high Jo-1 Ab levels develop will have samples tested for 
Ab isotyping (immunoglobulin G/immunoglobulin M).  The neutralizing capacity of the 
Ab may be tested as well. 
7.5.5.3. 
Anti-Drug Antibodies 
The development of humoral immune responses characterized by the formation of Ab to 
exogenously administered proteins occurs commonly.  ATYR1940 is a protein-based 
therapeutic, a truncated version of the human protein, HARS, which is 100% identical to 
the wild-type human sequence.  ADAs were observed following single-dose 
administration of ATYR1940 in nonclinical studies and when administered to healthy 
subjects.  The ADAs in humans occurred infrequently, titers were low, and the 
development of an ADA response was neither associated with any safety laboratory 
abnormalities nor temporal adverse systemic clinical symptoms.  These clinical data 
suggest that ADAs may be observed in the current clinical study.  The Sponsor has 
developed a sensitive assay to detect ADAs to ATYR1940, which will be utilized in this 
study.  Specifically, all patients will have repeated ADA assessments during the study 

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(see Table 1), to monitor the presence or absence of ADAs, and measure titers, where 
present.  
For patients with elevated ADA at the 12-week F/U visit, additional ADA testing should 
be performed every 1 to 3 months until the level returns to the pre-infusion baseline.  
Patients in whom sufficiently high titer ADAs develop will have samples tested for 
immunoglobulin G and M against ATYR1940 as well as ADA neutralizing capacity. 
7.5.5.4. 
Clinical Monitoring 
The development of clinically significant immunogenicity, including immediate 
hypersensitivity reactions, delayed hypersensitivity reactions, and immune complex 
deposition, is a potential safety concern for any biological drug candidate.  This study 
includes specific safety measures to monitor for this risk, and prospectively manage any 
potential adverse effects.  Clinical monitoring includes close observation for generalized 
IRRs during, or shortly after, IV infusions of ATYR1940, including vital signs, ECGs, 
pulse oximetry, and PFTs.  Frequent physical examinations with vital signs will be 
conducted during the course of the study to monitor for symptoms of potential 
generalized IRRs (see Section 7.5.5.1).  Safety laboratory examinations will be 
performed at each visit, including serum chemistry evaluations and complete blood 
counts.  Blood samples to assess for signs of immunogenicity will be taken periodically 
(Table 1). 
Infusion of ATYR1940 will be discontinued in any patient who has symptoms of a 
generalized IRR (see Section 7.5.5.1).  Patients with evidence of a generalized IRR 
should have additional procedures and tests performed as outlined in Section 8.5.9.4. 
7.5.6. 
Data Monitoring Board 
A Data Monitoring Board (DMB), consisting of at least 4 independent physicians and a 
statistician with expertise in clinical research, clinical immunology, and the clinical 
management of muscular dystrophies, has been assembled to review safety data and other 
pertinent data from all ongoing clinical studies of ATYR1940.  The ATYR1940 DMB 
will meet on a quarterly basis to review available, interim clinical safety and other 
pertinent data as defined for each protocol, from all patients enrolled in studies of 
ATYR1940, including this study. 
7.6. 
Rationale for the Dose(s) Selected 
For the first 12 weeks in this extension study, patients will receive ATYR1940 at the 
highest tolerated dose received in the parent study; no dose adjustments are allowed 
during this 12-week period.  After 12 weeks, if the patient is demonstrating good 
tolerability, the ATYR1940 dose may be increased on a patient-specific basis at the 
Investigator’s discretion, in consultation with the Sponsor and Medical Monitor.  
ATYR1940 dose increases to >3.0 mg/kg are not permissible.  
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7.7. 
Prior and Concomitant Medications and Procedures 
The following treatments and procedures are prohibited prior to and/or during study 
participation, as indicated below: 

Immunomodulatory agents, as follows:

Targeted biological therapies (e.g., etanercept, omalizumab) are prohibited during
study participation.

Corticosteroids are prohibited during study participation.

Non-steroidal anti-inflammatory drugs (NSAIDS):  High-dose NSAIDs (either
stable or intermittent dosing) are prohibited during study participation.  Contact
the Medical Monitor if questions arise regarding the definition of high-dose.

Low-dose NSAIDs (stable daily dosing) are acceptable during the study and
should be maintained through the last scheduled MRI.

Low-dose NSAIDs (intermittent dosing in patients not on stable dose) are
permitted to treat pain during the study, with the exception of within 48 hours
before each MRI.

Vaccination during study participation is prohibited.

All investigational agents or devices (other than ATYR1940 and mobility devices)
are prohibited during study participation.

Products that putatively enhance muscle growth (e.g., insulin-like growth factor,
growth hormone) or activity (e.g., Coenzyme Q, Coenzyme A, creatine, L-carnitine)
are prohibited during study participation.

Curcumin is prohibited during study participation.

Systemic albuterol is prohibited during study participation.  (Intermittent inhaled
albuterol is permissible.)

Initiation of statins (as a new drug to a patient) or significant adjustment to statin
regimen is prohibited during the study.  Stable, chronic statin use is permissible.

Major surgeries are prohibited during study participation.

Muscle biopsies involving muscles being followed in the current study are prohibited
during study participation.
The Investigator should contact the Medical Monitor with any questions or clarifications 
regarding concomitant medications. 
All other concomitant medications and procedures are allowed.  
All medications, including vitamin and anti-oxidant supplements, are to be recorded in 
the source documents and in the eCRF. 

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8.
STUDY VISITS AND ASSESSMENTS
8.1. 
Informed Consent and, if applicable, Assent
All patients must provide written informed consent or assent, as appropriate, based on 
local age of majority, before any samples are collected or evaluations performed in this 
study that are not part of standard patient care.  Assent to participate, along with 
parental/guardian written informed consent, is required for patients who are not age of 
majority at the time of screening and/or enrollment, according to IEC/EC requirements.  
Patients who become of majority age during the course of the study are required to 
provide written informed consent to continue participation. 
8.2. 
Pregnancy Testing 
Urine -human chorionic gonadotropin pregnancy testing is to be performed for female 
patients of childbearing potential (i.e., premenopausal or not surgically sterile) before 
ATYR1940 infusion at Week 1.  Any patient with a positive result is not eligible for 
study participation.  Urine pregnancy testing also is to be performed during the study at 
the time points indicated in Table 1.  All samples will be analyzed by the local laboratory.  
Study drug is to be discontinued for any patient determined to be pregnant during study 
participation (see Section 6.4.1 and 8.5.10.8). 
8.3. 
Concomitant Medications 
All medications and supplements the patient received after completion of the last visit in 
the parent study and all medications and supplements the patient receives during the 
course of the study are to be documented in the source documents and in the eCRF. 
8.4. 
Pharmacodynamic and Pharmacokinetic Measurements 
8.4.1. 
Pharmacodynamics 
8.4.1.1. 
Muscle Biomarker Panel 
Blood samples for the assessment of serum-based muscle biomarkers will be collected 
from all patients at the time points indicated in Table 1.   
8.4.1.2. 
Muscle Surveillance Magnetic Resonance Imaging 
MRI is a non-invasive method that can be applied to the study of skeletal muscle tissue, 
not only for assessment of anatomy and structure, but also to assess aspects of muscle 
pathophysiology, including inflammation and fatty infiltration41,51,52 in muscular 
dystrophy patients.  MRI will be performed in this study to evaluate changes in lower 
extremity muscle disease burden following treatment with ATYR1940, based on changes 
in inflammation within skeletal muscle tissue.   
Patients without contraindications for MRI (e.g., metal prosthesis or pacemaker, per site 
MRI protocol, as well as those with disease features precluding ability to perform MRI) 
will undergo a lower extremity skeletal muscle Surveillance MRI examination at the time 

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points designated in Table 1.  Imaging will be performed locally at each site, using either 
1.5 or 3.0 Tesla Siemens or Philips scanner, based on a protocol provided in the Imaging 
Acquisition Protocol.  The MRI scans will be formatted to acquire multiple acquisition 
sequences, including T1 and STIR.  
Images will be reviewed and interpreted by a central reader with expertise in muscle 
MRI, as outlined in the Imaging Acquisition Protocol.  For each time point, muscle 
inflammation will be assessed based on the presence or absence of STIR hyperintensity, 
and fat infiltration on T1-weighted sequences will be graded using the Fischer 
score.Wattjes, Kley, Fischer 53  
8.4.1.3. 
Manual Muscle Testing 
Muscle strength is to be formally assessed at the time points designated in Table 1 by the 
Investigator or designee using consistent methodology and by the same individual at the 
study center at all scheduled visits, if feasible.  
Muscles are to be tested in the order defined in Table 2.  Generally, for bilateral muscle 
testing, each muscle group is first tested on the right and then the left, prior to proceeding 
to the next muscle group.  Some muscle groups are listed with anti-gravity testing, but for 
a weaker patient, these are to be tested in a side-lying or supine position, per Table 3; the 
re-test for a weaker patient is indicated in italics.  The ankle plantar flexors are first tested 
in prone, and then retested in standing for scoring purposes.  Results will be graded using 
a modified Medical Research Council scale54 (see Table 4). 
Table 2: 
Manual Muscle Testing Order 
Position / Muscle Group 
Order of 
Testing 
Sitting 
Trapezius (shoulder elevators) 
1 
Deltoid middle (shoulder abductors) 
2 
Biceps brachii (elbow flexors) 
3 
Wrist extensors (extensor carpi ulnaris/radialis) 
4 
Wrist flexors (flexor carpi radialis/ulnaris) 
5 
Iliopsoas (hip flexors) 
6 
Quadriceps femoris (knee extensors) 
7 
Ankle dorsiflexors (tibialis anterior) 
8 
Supine 
Neck flexors (scalenes, sternocleidomastoid) 
9 
Trapezius (gravity eliminated test if needed) -  
Deltoid middle (gravity eliminated test if needed) -  
Gluteus medius (gravity eliminated test if needed) - 

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Sidelying (lying on left side-right muscles tested) 
Gluteus medius (hip abductors) 
10 
Iliopsoas (gravity eliminated test if needed) -  
Gluteus maximus (gravity eliminated test if needed) - 
Hamstrings (gravity eliminated test if needed) -  
Biceps brachii (gravity eliminated test if needed) -  
Neck flexors (gravity eliminated test if needed) -  
Neck extensors (gravity eliminated test if needed) -  
Prone 
Neck extensors (longissimus, semispinalis, iliocostalis, splenius cervicis) 
11 
Gluteus maximus (hip extensors)  
12 
Hamstrings (knee flexors)  
13 
Ankle plantar flexors (initial test; gastrocnemius)  
14 
Sidelying (lying on right side-left muscles tested) 
Gluteus medius (hip abductors) 
15 
Iliopsoas (gravity eliminated test if needed) -  
Quadriceps (gravity eliminated test if needed) -  
Gluteus maximus (gravity eliminated test if needed) -  
Hamstrings (gravity eliminated test if needed) -  
Biceps brachii (gravity eliminated test if needed) -  
Ankle dorsiflexors (gravity eliminated test if needed) - 
Standing 
Ankle plantar flexors (second test if needed) 
16 

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Table 3: 
Manual Muscle Testing Positions 
Muscle Group 
Testing Positions 
Anti-gravity 
Gravity Eliminated 
Trapezius (shoulder elevators) 
Sitting 
Supine 
Deltoid middle (shoulder abductors) 
Sitting 
Supine 
Biceps brachii (elbow flexors) 
Sitting 
Sidelying 
Wrist extensors Sitting (pronation) 
Sitting (pronation) 
Sitting (neutral) 
Wrist flexors Sitting (supination) 
Sitting (supination) 
Sitting (neutral) 
Iliopsoas (hip flexors) 
Sitting 
Sidelying 
Quadriceps femoris (knee extensors) 
Sitting 
Sidelying 
Ankle dorsiflexors 
Sitting 
Sidelying 
Neck flexors 
Supine 
Sidelying 
Gluteus medius (hip abductors) 
Sidelying 
Supine 
Neck extensors 
Prone 
Sidelying 
Gluteus maximus (hip extensors) 
Prone 
Sidelying 
Hamstrings (knee flexors) 
Prone 
Sidelying 
Ankle plantar flexors 
Prone/Standing 
Sidelying 

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Table 4: 
Manual Muscle Testing Grading Scale 
Description 
Grade 
Normal strength 
5 
Uncertain muscle weakness 
 5- 
Inability to resist against maximal pressure throughout range of motion 
  4+ 
Ability to resist against moderate pressure throughout range of motion 
4 
Ability to resist against minimal pressure throughout range of motion 
 4- 
Ability to move through full range of motion against gravity and to resist against minimal 
pressure through partial range of motion, then contraction breaks abruptly 
  3+ 
Ability to move through full range of motion against gravity 
3 
Ability to move through greater than one half range of motion against gravity 
 3- 
Ability to move through less than one half range of motion against gravity 
  2+ 
Ability to move through full range of motion with gravity eliminated 
2 
Ability to move in any arc of motion with gravity eliminated 
 2- 
A flicker of movement is seen or felt in the muscle 
1 
No contraction palpable 
0 
Extracted from Personius KE et al. Physical Therapy. 1994;74:253-263.  Available from 
http://ptjournal.apta.org/content/74/3/253.full.pdf. 
8.4.1.4. 
Functional Assessment of Upper and Lower Limbs 
Upper extremity muscle function will be measured using the Brooke scale (see Table 5).  
Lower extremity muscle function will be measured using the Vignos scale (see Table 6).  
These scales are commonly used in studies of neuromuscular disorders.55  Lower scores 
on each of these scales are associated with better muscle function.  
Grades of both upper and lower extremity muscle function will be based on the 
Investigator’s (or designee’s) commands and/or direct observation of patient ability to 
perform the movements or activities specified.  

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Table 5: 
Grading System for the Brooke Scale 
Grade 
Description 
1 
Starting with arms at the sides, the patient can abduct the arms in a full circle until they 
touch above the head 
2 
Can raise arms above head only by flexing the elbow (shortening the circumference of 
the movement) or using accessory muscles 
3 
Cannot raise hands above head, but can raise an 8-oz glass of water to the mouth 
4 
Can raise hands to the mouth, but cannot raise an 8-oz glass of water to the mouth 
5 
Cannot raise hands to the mouth, but can use hands to hold a pen or pick up pennies 
from the table 
6 
Cannot raise hands to the mouth and has no useful function of hands 
Extracted from:  Lu Y-M, Lue Y-J. Strength and Functional Measurement for Patients with Muscular Dystrophy.  In:  
Hegde M, ed.  Muscular Dystrophy, 2012.  ISBN: 978-953-51-0603-6, InTech.  Available from: 
http://www.intechopen.com/books/muscular-dystrophy/strength-decrease-pattern-and-functional-measurement-for-
patients-with-muscular-dystrophy. 
Table 6: 
Grading System for the Vignos Scale 
Grade 
Description 
1 
Walks and climbs stairs without assistance 
2 
Walks and climbs stair with aid of railing 
3 
Walks and climbs stairs slowly with aid of railing (over 25 seconds for eight standard 
steps) 
4 
Walks unassisted and rises from chair but cannot climb stairs 
5 
Walks unassisted but cannot rise from chair or climb stairs 
6 
Walks only with assistance or walks independently with long leg braces 
7 
Walks in long leg braces but requires assistance for balance 
8 
Stands in long leg braces but unable to walk even with assistance 
9 
Is in a wheelchair 
10 
Is confined to a bed 
Extracted from:  Lu Y-M, Lue Y-J. Strength and Functional Measurement for Patients with Muscular Dystrophy.  In:  
Hegde M, ed.  Muscular Dystrophy, 2012.  ISBN: 978-953-51-0603-6, InTech.  Available from: 
http://www.intechopen.com/books/muscular-dystrophy/strength-decrease-pattern-and-functional-measurement-for-
patients-with-muscular-dystrophy. 
8.4.1.5. 
INQoL 
The INQoL is a validated, muscle-disease-specific measure of quality of life.  The self-
administered questionnaire consists of 45 questions within 10 sections.  Four sections 
focus on the impact of key muscle disease symptoms (weakness, locking [i.e., myotonia], 
pain, and fatigue); 5 sections focus on the impact (degree and importance of impact) 
muscle disease has on particular areas of life; and the remaining section focuses on the 

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positive and negative effects of treatment.56  Patients will complete the InQoL at the time 
points designated in Table 1. 
8.4.1.6. 
FSHD-specific Health Inventory 
The FSHD-HI is a validated, disease-specific patient outcome measure for FSHD that 
measures a patient’s perception of their total disease burden and 14 additional areas of 
FSHD symptomatic health.57  The FSHD-HI consists of 116 questions and takes 
approximately 15 minutes to complete. 
Patients will complete the FSHD-HI at the time points designated in Table 1.  The 
FSHD-HI should be completed at the same time of day and before other assessments 
scheduled for that day, including the InQoL.  The order of assessments should remain 
consistent throughout the study.  
8.4.1.7. 
Biomarkers 
Nonclinical studies suggest ATYR1940 may have an immunomodulatory impact on 
myopathies with an immune component, such as LGMD2B and FSHD.  Such activity 
will be examined in this study by measuring circulating biomarkers, immunophenotyping 
of PBMCs, and measuring the release of cytokines from PBMCs ex vivo, all of which 
have been reported previously to be dysregulated in patients with FSHD.  Blood samples 
for assessment of biomarkers, immunophenotyping in PBMCs, and ex vivo culturing for 
disease-related immune protein release in PBMCs will be collected before, during, and 
following treatment with ATYR1940, at time points specified in Table 1. 
All biomarkers will be analyzed by designated central laboratories.  Biomarkers to be 
measured may include, but are not limited to, those listed in Table 7.  
Table 7: 
Biomarkers to be Measured in Blood 
Biomarkers 
GM-CSF, IFN-, IL-10, IL-18, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, MIP-1-α, MIP-1-, MCP-1, TNF-α, 
TNF- 
BDNF, Eotaxin-1, Factor VII, ICAM-1, IL-1-α, IL-1-, IL-1ra, IL-12p40, IL-12p70, IL-15, IL-17, IL-23, 
MMP-3, MMP-9, SCF, VEGF 
AAT, C3, Fibrinogen, Haptoglobin, IgA, IgM, VDBP 
CD40, CD40-L, G-CSF 
E-Selectin, IP-10, IL-6r, MIP-3 alpha, MCP-2, MCP-4, MIG, MPIF-1
ENA-78, IL-13, IL-16, MDC, CK-MB, IgE, PSA-f 
Amphiregulin, Epiregulin, FGFb, HB-EGF, PLGF, PDGF-BB, Tenscin C, TGFa, EGF, EGFr 
B2M, Lp(a), CRP, SAP, SHBG, TBG, vWF, Vitronectin 
EPO, MPO 
Note:  Biomarkers are defined in the Laboratory Manual. 

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For all analytes, the date and actual time of sample collection will be recorded in the 
source documents and the eCRF.  Refer to the Laboratory Manual for details regarding 
sample processing, storage, and shipment. 
8.4.2. 
Pharmacokinetics 
Formal PK will not be determined as a part of this study; however, systemic exposure to 
ATYR1940 will be confirmed.  Serum concentrations of ATYR1940 will be determined 
from samples collected at end of infusion and 4 hours after the start of infusion at the 
time points designated in Table 1.  
The date and actual time of sample collection will be recorded in the source documents 
and the eCRF. 
Samples will be analyzed by a central laboratory.  Refer to the Laboratory Manual for 
details regarding sample processing, storage, and shipment. 
8.5. 
Safety Measurements 
8.5.1. 
Physical Examination, including Neurological Examinations 
Complete physical examinations are to be performed at the time points indicated in 
Table 1.  The complete physical examination includes assessment of the following: 

General appearance

Head, eyes, ears, nose, and throat

Cardiovascular system

Respiratory system

Gastrointestinal system (abdomen)

Lymphatic system

Musculoskeletal system

Skin

Psychiatric

Neurological - A complete neurologic examination, including assessment of
mental status, memory, cranial nerves, motor function, reflexes, and sensory
testing, is to be performed as part of the complete physical examination.
Physical examinations may also be performed at any time during the study, as clinically 
indicated. 
Abnormal, clinically significant examination findings are to be reported as an AE, if the 
finding represents a change from baseline. 

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8.5.2. 
Weight 
Body weight is to be measured at the time points designated in Table 1, as well as prior to 
dosing any time the Investigator suspects the patient has experienced a notable change in 
weight (± 10%). 
The patient’s Week 1 weight (from the current study) is to be used to calculate the 
ATYR1940 dose.  If the patient has experienced a notable change in weight, as defined 
above, the Medical Monitor is to be notified regarding recalculation of ATYR1940 dose.  
Any change in total ATYR1940 dose resulting from a change in body weight is to be 
documented in the source documents and in the eCRF. 
8.5.3. 
Visual Acuity (Patients who Participated in Parent Study ATYR1940-C-
003 Only) 
Standardized best corrected visual acuity for the right and left eyes will be documented 
and recorded in the eCRF at the time points indicated in Table 1.  The method used to 
evaluate visual acuity in the parent study should be continued for each patient for 
consistency. 
8.5.4. 
Pure Tone Audiometry (Patients who Participated in Parent Study 
ATYR1940-C-003 Only) 
Pure tone audiometry will be performed for right and left ears by an audiometrist and will 
be documented and recorded in the eCRF at the time points indicated in Table 1.   
8.5.5. 
Vital Signs 
Vital signs are to be measured prior to any scheduled blood sample collection.  On dosing 
days, vital signs are to be measured pre-infusion; every 30 minutes (±5 minutes) during 
the infusion; and at the end of the infusion (±5 minutes); at 30 minutes (±5 minutes) after 
the end of infusion; and at additional time points as clinically indicated.  Both preinfusion 
and postinfusion vital signs will be measured before any scheduled blood sample 
collection. 
Abnormal, clinically significant vital signs results are to be reported as AEs, if the finding 
represents a change from baseline. 
Additional vital signs are required for patients with evidence of a generalized IRR, as 
described in Section 8.5.9.4. 
8.5.6. 
Pulse Oximetry 
Pulse oximetry is to be performed from 5 minutes prior to infusion until 30 minutes 
(-5 minutes, +15 minutes) after the end of infusion at the time points indicated in Table 1 
and as clinically indicated if the patient experiences pulmonary signs or symptoms (e.g., 
chest tightness, increased respiratory rate).  Readings below 95% are to be noted.   

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Additional pulse oximetry is required for patients with evidence of a generalized IRR, as 
described in Section 8.5.9.4. 
8.5.7. 
Pulmonary Function Tests 
The following PFTs are to be measured at the time points indicated in Table 1.  On study 
drug administration days, these PFTs are to be measured 2.5 hours (±30 minutes) after 
the end of infusion. 

Forced expiratory volume in 1 second (FEV1)

Forced vital capacity (FVC)

FEV1/FVC ratio
The following PFTs also are to be measured at the time points indicated in Table 1: 

Total lung capacity

Diffusion capacity of the lung for carbon monoxide (DLCO)
Patients for whom a facial mask was used for PFT assessments in the parent study should 
continue to use a facial mask for all PFT assessments in this study. 
Additional PFTs are required for patients with evidence of a generalized IRR, as 
described in Section 8.5.9.4. 
8.5.8. 
12-Lead Electrocardiogram
A 12-lead ECG is to be performed at the time points indicated in Table 1.  On study drug 
administration days, 12-lead ECGs are to be performed prior to and 30 minutes 
(±15 minutes) following the end of infusion and reviewed by the Investigator.  
Heart rate; PR, QR, and QT (uncorrected) intervals will be recorded on the eCRF.  
Abnormal, clinically significant ECG results are to be reported as AEs, if the finding 
represents a change from baseline. 
Additional ECGs are required for patients with evidence of a generalized IRR, as 
described in Section 8.5.9.4.  
8.5.9. 
Safety Laboratory Tests 
8.5.9.1. 
Hematology, Serum Chemistries, and Urine Analysis with Microscopy 
Blood samples are to be collected for assessment of hematology and serum chemistry 
parameters and urine samples for urine analysis with microscopy, at the time points 
indicated in Table 1.  Laboratory samples are to be collected after vital signs are 
measured. 
Samples will be analyzed by the central laboratory. 

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The following safety laboratory parameters will be measured: 
Hematology 

Hematocrit

Neutrophils

Hemoglobin

Lymphocytes

Red blood cell (RBC) count

Monocytes

White blood cell (WBC) count

Eosinophils

Platelet count

Basophils
Serum Chemistries 

Aspartate aminotransferase (AST)

Myoglobin

Alanine aminotransferase (ALT)

C-reactive protein

Total bilirubin

Total protein

Insulin-like growth factor 1

Cholesterol (non-fasting)

Gamma-glutamyl transferase

Sodium

Alkaline phosphatase

Potassium

Blood urea nitrogen

Chloride

Creatinine

Bicarbonate

Lactate dehydrogenase

Magnesium

Creatine kinase (CK)*

Calcium

Troponin

Inorganic phosphate
Urine Analysis and Microscopy 

Color

pH

Specific gravity

Protein

Glucose

Ketones

Blood

Microscopy (including RBCs, WBCs,
RBC casts, WBC casts, bacteria, and
crystals)
*Elevated CK values will be fractionated. 
Safety laboratory tests may be repeated as necessary during treatment at a schedule 
determined by the Investigator, based on the patient’s clinical status.   
Abnormal, clinically significant laboratory findings observed are to be reported as AEs, if 
the finding represents a change from baseline. 
Additional safety laboratory tests are required for patients with evidence generalized IRR, 
as described in Section 8.5.9.4. 

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8.5.9.2. 
Complement and Tryptase 
Blood samples for measurement of C3a, C4a, C5a, Bb, and SC5b-9 in plasma and CH50, 
C3, C4 and tryptase in serum are to be collected according to the schedule defined in 
Table 1.  A central laboratory will be used for sample analysis.  Other products of 
complement may be tested as appropriate. 
8.5.9.3. 
Antibody and HARS Measurements 
Blood samples for measurement of Jo-1 Ab, ADA, and serum HARS levels are to be 
collected according to the schedule defined in Table 1.  Samples will be analyzed by a 
central laboratory.  The Week 1 Jo-1 Ab sample must be obtained and result reviewed 
within 2 weeks prior to the first ATYR1940 dose. 
For patients with elevated ADA at the 12-week F/U visit, additional ADA testing should 
be performed every 1 to 3 months until the level returns to the pre-infusion baseline. 
8.5.9.4. 
Additional Laboratory Testing and Procedures in Patients with 
Generalized Infusion-Related Reactions 
Patients who experience generalized IRRs (see Section 7.5.5.1) must have their infusion 
stopped and be treated as medically indicated.  Vital signs, pulse oximetry, and ECGs are 
to be performed to gather clinical information as soon as possible after the onset of 
clinical symptoms of a generalized IRR (for instance, immediately after cessation of the 
study drug infusion if such a reaction is seen).  Vital signs are to be monitored as 
medically indicated and pulse oximetry is to be monitored continuously for at least 
2 hours after the end of infusion or until the patient has recovered, whichever is longer.  
ECGs should be repeated as medically indicated. 
Once medical treatment of the IRR has begun, blood samples are to be obtained for 
assessment of: 

Plasma complement factors (C3a, C4a, C5a, Bb, and SC5b-9)

Serum complement (CH50, C3, and C4) and tryptase
Additionally, the following tests and procedures are to be performed 1.5 to 2 hours after 
the onset of symptoms: 

Samples for assessment of:
-
Complete safety laboratory panel, including urine analysis and microscopy
(Section 8.5.9.1)
-
Plasma complement factors (C3a, C4a, C5a, Bb, and SC5b-9)
-
Serum complement (CH50, C3, and C4) and tryptase
-
Biomarkers and ATYR concentrations

PFTs – FEV1, FVC, FEV1/FVC ratio, total lung capacity, DLCO

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The Investigator must inform the study Medical Monitor promptly regarding any patient 
who experiences a generalized IRR for additional instruction. 
Patients who experience generalized IRRs will continue to be monitored / have repeat 
assessments performed at a schedule determined by the Investigator in consultation with 
the Medical Monitor and Sponsor.  Appropriate follow up for the patient must occur to 
ensure that there are no late-occurring sequelae. 
8.5.10. 
Adverse Events 
8.5.10.1. 
Definitions 
8.5.10.1.1. Adverse Event 
An AE is defined in the ICH Guideline for Good Clinical Practice as “any untoward 
medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment” (ICH E6:1.2). 
Worsening of a pre-existing medical condition, (i.e., diabetes, migraine headaches, gout) 
is to be considered an AE if there is either an increase in severity, frequency, or duration 
of the condition or an association with significantly worse outcomes. 
Interventions for pretreatment conditions (i.e., elective cosmetic surgery) or medical 
procedures that were planned before study enrollment are not considered AEs. 
In the case of death, only record “Fatal” for the event causing death.  AEs that are 
ongoing at the end of the study or time of death are to be noted as “continuing.”  
Classification of AEs is to be done by the Investigator is according to the NCI CTCAE, 
version 4.03. 
The Investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual patient represents a significant change from 
baseline.  In general, abnormal laboratory findings without clinical significance (based on 
the Investigator’s judgment) should not be recorded as AEs; however, laboratory value 
changes requiring therapy or adjustment in prior therapy are considered AEs. 
8.5.10.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE.  For the purposes of Investigational New Drug Application (IND) 
safety reporting, “reasonable possibility” and/or at least possibly related means there is 
evidence to suggest a causal relationship between the drug and the AE.  A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any AE caused by a drug. 

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8.5.10.1.3. Serious Adverse Event 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  

is fatal

is life-threatening (i.e., places the patient at immediate risk of death)

requires in-patient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect

Is an important medical event.  An important medical event is an event that may not
result in death, be life-threatening, or require hospitalization but may be considered
an SAE when, based upon appropriate medical judgment, it may jeopardize the
patient and may require medical or surgical intervention to prevent one of the
outcomes listed in the definitions for SAEs.  Examples of such medical events include
allergic bronchospasm requiring intensive treatment in an emergency room or at
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization,
or the development of drug dependency or drug abuse.
A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital 
admission that includes a minimum of an overnight stay in a health care facility.  Any AE 
that does not meet one of the definitions of serious (i.e., emergency room visit, out-
patient surgery, or requires urgent investigation) may be considered by the Investigator to 
meet the “important medical event” criterion for classification as an SAE. 
8.5.10.1.4. Unexpected Adverse Event 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed; or, if an Investigator’s Brochure is not required or available, is not consistent 
with the risk information described in the General Investigational Plan or elsewhere in 
the current application, as amended.   
8.5.10.1.5. Serious and Unexpected Suspected Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is any event that meets all 
3 of the following definitions: 
1) suspected adverse reaction (Section 8.5.10.1.2);
2) serious (Section 8.5.10.1.3); and
3) unexpected (Section 8.5.10.1.4).

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8.5.10.2. 
Adverse Event Assessment 
All AEs will be collected and recorded in this study from the time of the first ATYR1940 
dose in this study through the EOS visit, or after the end of the study, if thought to be 
related to study drug.  (AEs occurring through 30 days after the last study drug dose in 
the parent study and those occurring >30 days after the last study drug dose in the parent 
study that are considered by the Investigator to be study drug-related are to be reported in 
the parent study.)  This includes AEs the patient reports spontaneously, those observed by 
the Investigator, and those elicited by the Investigator in response to open-ended 
questions during scheduled study center visits.  Furthermore, all AEs that presented in the 
parent study that are ongoing at Week 1 in the current study will be recorded as such. 
Each AE is to be assessed by the Investigator with regard to the following categories. 
Serious/Non-Serious 
AEs that meet the criteria specified in Section 8.5.10.1.3 are to be considered serious. 
Relationship to Study Drug 
The relationship of each AE to ATYR1940 is to be assessed by the Investigator according 
to categories in Table 8. 

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Table 8: 
Criteria for Determination of Adverse Event Relationship to Study 
Drug 
Relationship between ATYR1940 and AE: 
AE (is): 
Category 
None 
Unlikely 
Possibly 
Likely 
Definitely 
Clearly the result of an external factor 
Yes 
No 
No 
No 
No 
Probably/possibly the result of another 
factor 
No 
Yes 
Yes 
No 
No 
Has a chronological relationship with 
the time of administration and/or 
represents a known reaction to Study 
Drug 
No 
No 
Yes 
Yes 
Yes 
Disappears or decreases after 
discontinuation of the Study Drug 
NA 
NA 
NA 
Yes 
Yes 
Recurs on renewed administration 
(re-challenge) 
No 
No 
NA 
NA 
Yes or 
NA** 
** 
A re-challenge is not required; if done, re-challenge would be expected to be positive. 
NA Not applicable 
Intensity 
The intensity of each AE is to be assessed by the Investigator according to the NCI 
CTCAE, version 4.03.  If the AE is not included in the NCI CTCAE, version 4.03, then 
the Investigator is to determine the intensity of the AE according to the following criteria: 

Mild (Grade 1): Asymptomatic or mild symptoms: clinical or diagnostic observations
only; intervention not indicated.

Moderate (Grade 2): Minimal, local, or non-invasive intervention indicated; limiting
age-appropriate instrumental activities of daily living.

Severe (Grade 3): Severe or medically significant but not immediately life
threatening: hospitalization or prolongation of hospitalization indicated; disabling;
limiting self-care activities of daily living; incapacitating with inability to work or
perform normal daily activity.

Life-threatening (Grade 4): consequences: urgent intervention indicated.

Death (Grade 5) related to an AE.
8.5.10.3. 
Recording Adverse Events 
All AEs occurring from the time written informed consent is obtained through the EOS 
visit are to be recorded in the source documents and in the eCRF.  All AE reports are to 
contain the following details regarding the AE:  a brief description, onset date and time, 

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resolution date and time, intensity, treatment required, relationship to ATYR1940, 
ATYR1940 action taken, outcome, and whether the event is classified as serious. 
8.5.10.4. 
Reporting Serious Adverse Events 
SAEs will be collected and recorded throughout the study period, beginning with the 
signing of the ICF through the EOS visit, or after the end of the study if thought to be 
related to ATYR1940. 
The Investigator must report all SAEs within 24 hours of discovery to: 
 
Email: 
  
Telephone number: 
 
A completed SAE report is to be sent to the Medical Monitor’s attention within 24 hours 
of discovering the event.  The initial report should include at least the following 
information: 

Patient’s ID number;

Description and date of the event;

Criterion for serious; and

Preliminary assignment of causality to ATYR1940.
The Medical Monitor will contact the Investigator via telephone for follow-up 
information regarding the SAE, as appropriate. 
The Investigator, or designated party, should notify the appropriate IRB/EC of SAEs 
occurring at the study center and other AE reports received from aTyr, in accordance 
with local procedures and statutes. 
SAEs that are considered as possible or probably related to the investigational product, 
and as unexpected (i.e., SUSARs), will be reported to the concerned Competent 
Authorities (CAs) and IRBs/ECs by the Sponsor or Sponsor’s designee as required by 
applicable local regulations.  Per regulation, any fatal or life-threatening SUSAR will be 
reported to the CAs/IRBs/ECs within 7 calendar days, and additional information within 
an additional 8 calendar days.  The Sponsor or Sponsor¹s designee is required to submit 
any other SUSAR to the CAs/IRBs/ECs within 15 calendar days of notification.  The 
Sponsor or its designee is also responsible for notifying the investigational sites of all 
expedited SAEs.  The Investigator must keep copies of all expedited SAE information 
including correspondence with the Sponsor on file.   

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8.5.10.5. 
Follow-Up of Adverse Events 
The Investigator must continue to follow all SAEs and non-serious AEs considered to be 
at least possibly related to ATYR1940 either until resolution or the Investigator assesses 
them as chronic or stable.  This follow-up may extend after the end of the study. 
8.5.10.6. 
Reporting Safety Information 
The Investigator must promptly report to his or her IRB/EC all unanticipated problems 
involving risks to patients.  This includes death from any cause and all SAEs reasonably 
or possibly associated with the use of ATYR1940 according to the IRB/EC’s procedures.  
The Sponsor will assess the severity and frequency of adverse drug reactions in adults 
versus pediatric patients, and will submit findings annually in the Development Safety 
Update Report/Annual Report. 
8.5.10.7. 
Protocol Deviations Due to an Emergency or Adverse Event 
Departures from the protocol will be determined as allowable on a case-by-case basis and 
only in the event of an emergency.  The Investigator or other physician in attendance in 
such an emergency must contact the Medical Monitor as soon as possible to discuss the 
circumstances of the emergency. 
The Medical Monitor, in conjunction with the Investigator, will decide whether the 
patient should continue to participate in the study.  All protocol deviations and reasons 
for such deviations must be noted in the eCRF. 
8.5.10.8. 
Pregnancy 
Pregnancies occurring while the patient is receiving ATYR1940 or within 30 days after 
the patient’s last dose of ATYR1940 will not be considered serious, but are to be reported 
using the same procedures as for SAEs described in Section 8.5.10.4. 
ATYR1940 must be discontinued immediately in the event of a pregnancy.  The patient 
should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for 
further evaluation and counseling. 
The Investigator will follow the patient until completion of the pregnancy, and must 
notify the Medical Monitor of the outcome within 5 days.  The Investigator will provide 
this information as a follow-up to the initial report. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(i.e., spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly), then the Investigator 
should report it as such.  Furthermore, all neonatal deaths that occur within 30 days of 
birth are to be reported, without regard to causality, as SAEs.  In addition, any infant 
death after 30 days that the Investigator suspects is related to the in utero exposure to the 
ATYR1940 should also be reported. 

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9.
STATISTICAL ANALYSES
9.1. 
Statistical Basis for Sample Size
No formal sample size calculation was performed; patients that participated in the parent 
study and meet the entry criteria for the current study may be enrolled.  Based on the 
design of the parent studies, it is estimated that up to 24 patients will be enrolled in this 
study. 
9.2. 
Statistical and Analytical Plan 
An overview of the statistical methodology to be employed is provided in the following 
subsections.  Details regarding the statistical methodology will be documented in a 
formal Statistical Analysis Plan (SAP) prior to database lock.  The methodology for 
serum ATYR1940 concentrations and PD analyses will be documented in separate SAPs. 
9.2.1. 
General Methods 
Statistical analyses will be primarily descriptive in nature, since the goal of the study is to 
determine the safety, tolerability, and immunogenicity of ATYR1940.  This goal will be 
achieved by the results of a deterministic algorithm; thus, statistical hypothesis testing is 
neither intended nor appropriate within this context.   
Continuous variables will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum).  Categorical variables will be summarized 
showing the number and percentage (n, %) of patients within each classification. 
Data obtained from the parent study will be combined with data from the current study.  
For patients assigned to ATYR1940 in the parent study, data obtained from the parent 
study will be combined with data from the current study.   
For patients who received ATYR1940 ≤4 weeks previously in the parent study, baseline 
refers to the baseline in the parent study (i.e., the most recent assessment obtained before 
the first study drug dose.)  For patients who received ATYR1940 >4 weeks previously in 
the parent study, baseline refers to assessment obtained before the first ATYR1940 dose 
at Week 1 in the current study.   
9.2.2. 
Analysis Populations 
All patients who have received at least 1 dose (partial or full) of ATYR1940 and have a 
postinfusion safety observation will be included in safety analyses.  Additional analysis 
populations will be defined in the SAP.   
9.2.3. 
Missing, Unused, and Spurious Data 
Analyses will be based on observed data only; no data will be imputed. 

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9.2.4. 
Disposition of Patients 
The numbers and proportions of patients who are enrolled in and complete the study and 
who are early terminations will be summarized.  Reasons for study discontinuation after 
the start of study treatment will be tabulated. 
9.2.5. 
Demographics and Baseline Characteristics 
A summarization of demographic and baseline disease characteristic data, as documented 
in each parent study, will be presented for patients in this extension study.  Data to be 
tabulated will include at least demographic and baseline characteristics such as sex, age, 
race, height, weight, and body mass index, and disease-specific diagnostic and historical 
information.  Medical history also will be similarly summarized. 
9.2.6. 
Extent of Exposure 
Descriptive statistics will be presented overall and, if applicable, each dose level, for the 
number of doses received, percent of expected dose received, and actual dose received 
overall (i.e., across the parent and extension study), and in each the parent and extension 
study.  Furthermore, descriptive statistics for the number of doses missed or held will be 
presented, if warranted by the data.  A tabular summary and listing of drug administration 
and dose intensity and a by-patient listing of the date and time of each ATYR1940 dose 
and the dose administered also will be presented.   
9.2.7. 
Prior and Concomitant Medications 
Tabulations of prior and concomitant medications, coded using the World Health 
Organization drug dictionary, will be produced.  All prior and concomitant medications 
administered will be presented in a data listing.  
9.2.8. 
Safety Analysis 
9.2.9. 
Safety and Immunogenicity Analyses 
Safety evaluations will be based on the incidence, type, and intensity of AEs, and 
changes from baseline in safety laboratory tests, ECG findings, vital signs measurements, 
PFTs, and pulse oximetry.  Immunogenicity will be assessed based on the incidence of 
infusion site reactions, ADA titers, changes in Jo-1 and ADA titers over time, as 
appropriate, as well as changes from baseline over time in immune-based laboratory tests, 
including, for example, tryptase, complement factors, and cytokines.  Safety variables 
will be tabulated and presented for all patients who receive any amount of study drug and 
have follow-up safety data.  Tabulations will be presented for safety data overall and 
separately for the parent and extension studies. 
AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA) for purposes of summarization.  The overall incidence of AEs 
occurring during the study will be summarized by MedDRA system organ class and 
preferred term.  The incidence of TEAEs also will be summarized by system organ class 

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and preferred term.  For the purpose of analysis, a TEAE is defined as any AE that occurs 
after administration of the first dose of ATYR1940 through the 12-week posttreatment 
follow-up visit, or any event that is present at baseline, but worsens in intensity or is 
subsequently considered drug-related by the Investigator.  Severe TEAEs, SAEs, and 
discontinuation rates of study therapy due to TEAEs also will be summarized.   
Events that are considered related to treatment (possibly, likely, or definitely drug-
related) will also be tabulated.  A tabulation will also be provided that enumerates TEAEs 
by maximum severity.  Deaths, SAEs, and TEAEs resulting in study discontinuation will 
be tabulated, if warranted by the data.   
All AEs occurring on study will be listed in by-patient data listings.  
Clinical laboratory parameters will be summarized across time points and changes from 
baseline will be summarized.  The frequency of clinically significant abnormal laboratory 
values will be tabulated.  Shift tables will be produced for selected laboratory parameters, 
including at least hemoglobin, WBC count, absolute neutrophil count, absolute 
lymphocyte count, platelet count, AST, ALT, total bilirubin, alkaline phosphatase, 
creatinine, and electrolytes.  These tables will summarize the number of patients with 
each baseline CTCAE grade and changes to the maximum CTCAE grade on study. 
Changes in vital signs parameters (i.e., systolic and diastolic blood pressures, pulse rate, 
respiration rate, and body temperature) will be summarized across time points, and 
changes from baseline will be summarized.  Changes in ECG findings, PFTs, and pulse 
oximetry will be summarized, as appropriate, and by-patient listings will be provided.  
Serological findings, including Jo-1 and ADA Ab titers will be tabulated, and by-patient 
listings provided.  
Additional safety analyses may be determined at any time without prejudice, in order to 
enumerate rates of toxicities most clearly, and to define further the safety profile of 
ATYR1940. 
9.2.10. 
Pharmacodynamic Analyses 
9.2.10.1. 
Lower Extremity Skeletal Muscle MRI 
Surveillance MRI of both of muscles in both of the lower extremities will be performed 
to assess muscle disease burden.  At each time point, muscle inflammation will be 
assessed based on the presence or absence of STIR hyperintensity, and fat infiltration on 
T1-weighted sequences will be graded using the Fischer score.53 
9.2.10.2. 
Biomarkers 
Details regarding analyses of biomarkers will be the patient of a separate PK/PD analysis 
plan. 

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9.2.11. 
ATYR1940 Serum Concentrations 
Details regarding serum concentrations of ATYR1940 and HARS levels will be covered 
under a separate PK/PD analysis plan. 
9.2.12. 
Interim Analyses 
Clinical data from this open-label study will be assessed at regular intervals during the 
conduct of the study.  Safety data and other pertinent data will be summarized quarterly 
for review by the DMB (see Section 7.5.6). 
9.3. 
Changes to the Planned Statistical Methods 
Changes to the planned statistical methods will be documented in the clinical study 
report. 

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10.
ETHICAL, LEGAL, AND ADMINISTRATIVE
CONSIDERATIONS
10.1. 
Good Clinical Practice
This study will be conducted according to the protocol and in compliance with ICH GCP, 
the ethical principles stated in the Declaration of Helsinki, and other applicable 
regulatory requirements. 
The Investigator confirms this by signing the protocol. 
10.2. 
Informed Consent 
Written informed consent and assent, as appropriate, based on age of majority, in 
compliance with 21 Code of Federal Regulations § 50 and/or ICH and European 
regulations will be obtained from each patient prior to undergoing any protocol-specific 
tests or procedures that are not part of routine care. 
aTyr or designee will provide informed consent form (ICF) and assent templates to the 
Investigator for use in developing a study center-specific consent documents.  Prior to 
submission of the study center-specific ICF/assent form to the IRB/EC, these documents 
must be reviewed and approved by aTyr or designee.  Any changes requested by the 
IRB/EC must also be approved by aTyr or designee.  The final IRB/EC-approved ICF/ 
assent form must be provided to aTyr or designee.  Revisions to the ICF/assent form 
required during the study must be approved by aTyr or designee, and a copy of the 
revised ICF/assent form provided to aTyr or designee. 
Before recruitment and enrollment, each prospective patient (or legal guardian) will be 
given a full explanation of the study and be allowed to read the ICF/assent form in a 
language they understand.  After the Investigator or designee is assured that the 
patient/legal guardian understands the commitments of participating in the study, the 
patient/legal guardian will be asked to sign and date the ICF and assent form, as 
appropriate.   
A copy of the fully signed and dated ICF/assent form will be given to the patient.  The 
original will be maintained in the patient’s medical record at the study center.  All active 
patients will sign an updated ICF if revisions are made to the ICF during the course of the 
study. 
10.3. 
Institutional Review Board/Ethics Committee 
Federal and European regulations and ICH require that approval be obtained from an 
IRB/EC prior to participation of patients in research studies.  Approval by the Competent 
Authority, if applicable, or as required by local laws and regulations is also required in 
the EU.  Prior to the study onset, the protocol, any protocol amendments, ICFs, 
advertisements to be used for patient recruitment and any other written information 
regarding this study to be provided to a patient must be approved by the IRB/EC. 

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All IRB/EC approvals must be dated and signed by the IRB/EC Chairperson or designee 
and must identify the IRB/EC by name and address, the clinical protocol by title and/or 
protocol number, and the date approval or favorable opinion was granted for the clinical 
research. 
No drug will be released to the site to dose a patient until written IRB/EC authorization 
has been received by aTyr or designee.
The Investigator is responsible for obtaining continuing review of the clinical research at 
least annually or more often if specified by the IRB/EC.  The Investigator must supply 
aTyr or designee with written documentation of the approval of the continued clinical 
research. 
The Investigator, sponsor, or designee as applicable, will make all attempts to ensure that 
the IRB/EC is constituted and operates in accordance with Federal and ICH GCP and any 
local regulations. 
10.4. 
Amending the Protocol 
Any changes in this research activity, except those to remove an apparent immediate 
hazard to the patient, must be reviewed and approved by aTyr or designee and the 
IRB/EC that approved the study.  Amendments to the protocol must be submitted in 
writing to the Investigator’s IRB/EC for approval prior to patients being enrolled into the 
amended protocol. 
aTyr may make administrative changes (i.e., changes that do not significantly affect 
patient safety or the study’s scope or scientific quality) without any further approvals.  
All amendments will be distributed to all protocol recipients. 
10.5. 
Confidentiality 
All study findings and documents will be regarded as confidential.  The Investigator and 
other study personnel must not disclose such information without prior written approval 
from aTyr. 
Patient confidentiality will be strictly maintained to the extent possible under the law.  
Patient names must not be disclosed.  Patients will be identified in the eCRFs and other 
documents submitted to aTyr or its designated representative, by their initials, birth date, 
and/or assigned patient number.  Documents that identify the patient (e.g., the signed 
ICF) should not to be submitted to aTyr or its designated representative, and must be 
maintained in confidence by the Investigator. 
10.6. 
Publication Policy 
It is anticipated that the results of this study will be presented at scientific meetings 
and/or published in a peer reviewed scientific or medical journal.  The initial planned 
publication will be a multi-center report of the study outcome.  Additional publications 

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from a given center can only occur after the publication of the multi-center results.  A 
prepublication manuscript is to be provided to aTyr at least 30 days prior to the 
submission of the manuscript to a publisher.  Similarly, aTyr will provide any company-
prepared manuscript to the Investigators for review at least 30 days prior to submission to 
a publisher. 

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11.
STUDY MANAGEMENT
11.1. 
Data Quality Assurance
aTyr or its designated representative will conduct a study center visit to verify the 
qualifications of each Investigator, inspect study center facilities, and inform the 
Investigator of responsibilities and procedures for ensuring adequate and correct study 
documentation. 
11.2. 
Case Report Forms and Source Documentation 
The Investigator and designees agree to maintain accurate eCRFs and source 
documentation as part of case histories.  Source documents are the originals of any 
documents used by the Investigator or subinvestigator or hospital/institution that allow 
verification of the existence of the patient and substantiate the integrity of the data 
collected during the study. 
aTyr or designee will provide eCRFs to the study center.  eCRFs will be completed for 
each patient.  It is the Investigator’s responsibility to ensure the accuracy, completeness, 
and timeliness of the data reported in the patient’s eCRF.  Source documentation 
supporting the eCRF data should indicate the patient’s participation in the study and 
should document the dates and details of informed consent, study procedures, AEs, and 
patient status.   
The Investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected / data are available, preferably on the same day that 
a patient is seen for an examination, treatment, or any other study procedure.  Any 
outstanding entries must be completed immediately after the final examination.  An 
explanation should be given for all missing data. 
The Investigator must sign and date the Investigator’s Statement at the end of the eCRF 
to endorse the recorded data.   
11.3. 
Monitoring 
A CRA or other representative of the Sponsor will conduct a study center visit to verify 
the qualifications of each Investigator, inspect study center facilities, and inform the 
Investigator of responsibilities and procedures for ensuring adequate and correct study 
documentation  
During the course of the study, the CRA will make study center visits to review protocol 
compliance, compare eCRFs and individual patient medical records, assess drug 
accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements in respect to GCP.  eCRFs will be verified with source 
documentation.  The review of medical records will be performed in a manner to ensure 
that patient confidentiality is maintained. 

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11.4. 
Inspections 
Regulatory authorities and/or quality assurance personnel from aTyr or its designated 
representative may wish to carry out such source data checks and/or in-center audit 
inspections.  The Investigator assures aTyr of the necessary support at all times.  In the 
event of an audit, the Investigator agrees to allow the Sponsor’s representatives and any 
regulatory agencies access to all study records. 
11.5. 
Financial Disclosure Reporting Obligations 
Investigators and subinvestigators are required to provide financial disclosure 
information to the sponsor to permit the sponsor to fulfill its regulatory obligation.  
Investigators and subinvestigators must commit to promptly updating the information if 
any relevant changes occur during the study and for a period of one year after the 
completion of the study. 
11.6. 
Archiving Study Records 
Essential documents should be retained for a minimum of 2 years after the last approval 
of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
However, these documents should be retained for a longer period if required by the 
applicable local requirements. 
ICH requires that patient identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 

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12.
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