Safety, Tolerability, Pharmacokinetics, and Biological Activity of ATYR1940 in Adult Participants With Muscular Dystrophy

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and tolerability profile of ATYR1940 in the treatment of adult participants with molecularly defined genetic muscular dystrophies

Detailed Description
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Study ATYR1940-C-002 is a multi-national, multi-center, double-blind, randomized, placebo-controlled, ascending dose study designed to evaluate the safety, tolerability, PK, immunogenicity, and pharmacodynamic effects of ATYR1940 in participants with FSHD. Up to 44 participants are planned to be enrolled at multiple study centers in the United States and Europe; the actual number of participants enrolled will depend on the number of cohorts initiated. Participants will be screened for study eligibility during the Screening period within 3 weeks before Baseline (that is, Day 1, the first day of Study Drug administration). Eligible participants, based on Screening assessments, will be randomly assigned to treatment with ATYR1940 or placebo. Participants who are randomized will be considered enrolled in the study.

Official Title
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A Placebo-Controlled, Randomized, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), and Biological Activity of ATYR1940 in Adult Patients With Molecularly Defined Genetic Muscular Dystrophies

Conditions
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Facioscapulohumeral Muscular Dystrophy (FSHD)

Intervention / Treatment
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* Biological: Placebo
* Biological: ATYR1940


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is a male or female aged 18 to 65 years, inclusive. Participant has an established, genetically-confirmed, diagnosis of FSHD with clinical findings meeting existing criteria. Participant has provided written informed consent after the nature of the study has been explained and prior to the performance of any research-related procedures. Participant is, in the Investigator's opinion, willing and able to comply with all study procedures. Cohorts ≥2 only: Participant has imaging findings meeting defined criteria for muscle inflammation in at least 1 skeletal muscle. Exclusion Criteria: Participant is currently receiving treatment with an immunomodulatory agent or has a history of such treatment, including targeted biological therapies (for example, etanercept, omalizumab) within the 3 months before Baseline; corticosteroids within 4 weeks before Baseline; or high-dose non-steroidal anti-inflammatory agents (NSAIDs) within 2 weeks before Baseline. Participant is currently receiving curcumin or albuterol or requires such treatment during study participation. Participant has evidence of an alternative diagnosis other than FSHD, based on prior muscle biopsy or genetic test findings. Participant has a presumptive diagnosis of FSHD, based on clinical assessment, but does not yet have genetic confirmation of the diagnosis. Participant has a severe retinopathy. Participant has a history of obstructive or restrictive lung disease (including interstitial lung disease, pulmonary fibrosis, or asthma), or evidence for interstitial lung disease on Screening chest radiograph. Participant has a history of anti-synthetase syndrome, prior Jo-1 antibody (Ab)-positivity, or has a positive or equivocally positive Jo-1 Ab test result during Screening. Participant has acute or clinically relevant Epstein-Barr virus or cytomegalovirus infection or re-activation. Participant has a chronic infection such as hepatitis B virus, hepatitis C virus, or human immunodeficiency virus or a history of tuberculosis. Participant has received a vaccination within 8 weeks before Baseline or vaccination is planned during study participation. Participant has symptomatic cardiomyopathy or severe cardiac arrhythmia that may, in the Investigator's opinion, limit the participant's ability to complete the study protocol. Participant has anemia (as defined for participant's age and gender by local laboratory range). Participant has gamma-glutamyl transferase (GGT) or serum creatinine levels >2 × the upper limit of normal (ULN). Participant has abnormal baseline findings, medical condition(s), or laboratory findings that, in the Investigator's opinion, might jeopardize participant's safety or decrease the chance of obtaining satisfactory data needed to achieve the objectives of the study. Participant has 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. Participant has used any investigational product or device (other than a mobility assistance device) within 30 days before Baseline. Participant has received a product intended to enhance muscle growth within 30 days before Baseline. Participant underwent muscle biopsy within 30 days before Baseline. Participant initiated treatment with a statin or had a significant adjustment to their statin regimen within 3 months before Baseline. (Stable, chronic statin use is permissible.) Participant has received a product that putatively enhances muscle growth (for example, insulin-like growth factor, growth hormone) or activity (for example, Coenzyme A) on a chronic basis within 4 weeks before Baseline. Participant is unwilling to abstain from strenuous physical activity for 24 hours prior to each study center visit. Participant previously received ATYR1940. If female and of childbearing potential (premenopausal and not surgically sterile), participant has a positive pregnancy test at Screening or is unwilling to use contraception from the time of Screening through 1 month after the last Study Drug dose. Acceptable methods of birth control include abstinence, barrier methods, hormones, or intra-uterine device. If male, participant is unwilling to use a condom plus spermicide during sexual intercourse from the time of Screening through 1 month after the last Study Drug dose. Cohorts ≥2 only: Participant has a known contraindication for magnetic resonance imaging (MRI) assessments (for example metal prosthesis or pacemaker) as per local site MRI protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: ATYR1940 0.3 mg/kg<br>Participants will receive ATYR1940 0.3 milligrams/kilograms (mg/kg) intravenous (IV) infusion once weekly for 4 weeks. | Biological: ATYR1940<br>* Concentrate for solution for infusion<br>|
| Experimental: Cohort 2: ATYR1940 1.0 mg/kg<br>Participants will receive ATYR1940 1.0 mg/kg IV infusion once weekly for 4 weeks. | Biological: ATYR1940<br>* Concentrate for solution for infusion<br>|
| Experimental: Cohort 3: ATYR1940 3.0 mg/kg<br>Participants will receive ATYR1940 3.0 mg/kg IV infusion once weekly for 12 weeks. | Biological: ATYR1940<br>* Concentrate for solution for infusion<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo matched to ATYR1940 IV infusion once weekly for 4 weeks in Cohorts 1 and 2 and for 12 weeks in Cohort 3. | Biological: Placebo<br>* Concentrate for solution for infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAEs were defined as adverse events (AEs) with an onset following administration of the first dose of study drug. An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with study drug. Worsening of a pre-existing medical condition, (that is, diabetes, migraine headaches, gout) should have been considered an AE if there was either an increase in severity, frequency, or duration of the condition or an association with significantly worse outcomes. Classification of AEs was to be done by the Investigator according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. | Up to End of Study (up to Week 25) | 
| Number of Participants With Positive Anti-Drug Antibodies (ADA) | Titers through Week 14 are summarized. For Cohorts 1 and 2, samples that screened positive but did not confirm on confirmatory assay were not titered. | Baseline up to Week 14 | 
| Number of Participants With a Positive or Equivocal Jo-1 Antibody (Ab) Test Result | Criterion for a positive Jo-1 Ab test result: >10.0 units/milliliter (U/mL), a cut-point associated with anti-synthetase syndrome. Criterion for an equivocal Jo-1 Ab test result: 7.0 to 10.0 U/mL. Participants were required to have a negative Jo-1 Ab test result (defined as <7 U/mL) for inclusion in the study as well as to continue dosing with study drug during the study. | Baseline up to Week 14 | 
| Number of Participants With a Clinically Significant Laboratory Abnormality | Laboratory parameters included hematology (hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell count, neutrophils, lymphocytes, monocytes, eosinophils, basophils); serum chemistries (blood urea nitrogen, creatinine, total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase (GGT), alkaline phosphatase, sodium, total protein, bicarbonate, potassium, calcium, chloride, magnesium, inorganic phosphate, creatine phosphokinase [will be fractionated if elevated], lactic dehydrogenase, erythrocyte sedimentation rate, C-reactive protein, troponin, myoglobin, insulin-like growth factor 1, cholesterol [non-fasting]); Urinalysis (Color, pH, specific gravity, protein, glucose, ketones, blood). Clinically significant laboratory abnormalities were based upon Investigator's discretion. A summary of all Serious AEs and Other AEs (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. | Baseline up to Week 14 | 
| Number of Participants With a Physical Examination Abnormality | Body systems that were evaluated during the physical examination included general appearance, head, eyes, ears, nose, throat (HEENT), cardiovascular system, respiratory system, chest (breasts), gastrointestinal system (abdomen), lymphatic system, musculoskeletal system, skin, psychiatric, and neurologic. Neurologic examination included assessment of mental status, memory, cranial nerves, motor function, and reflexes, and sensory testing. The body systems with at least 1 physical abnormality is presented. One participant could be represented in more than 1 body system category. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. | Up to End of Study (up to Week 25) | 
| Number of Participants With a Vital Sign-Related Event Resulting in a TEAE | The vital sign parameters that were evaluated included heart rate, systolic and diastolic blood pressure, and respiration rate as well as temperature. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. | Up to End of Study (Up to Week 25) | 
| Number of Participants With a Pulmonary Function Event Resulting in a TEAE | Pulmonary function testing included measurements of forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. | Up to End of Study (Up to Week 25) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Manual Muscle Testing (MMT) Score at Week 6 and Week 14 | MMT was graded on a scale from 0 (no movement) to 10 (normal movement). Each side of the body and the position in which each muscle was tested were recorded for each participant. The total MMT score were calculated by averaging a converted MMT scores across all tested muscle groups. Decreased motor function was indicated by decreased individual muscle or composite MMT score. | Baseline, Week 6 and Week 14 | 
| Change From Baseline in Individualized Neuromuscular Quality of Life (INQoL) - Overall QoL at Week 6 and Week 14 | The INQoL is a validated muscle disease-specific measure of quality of life. The self-administered questionnaire consisted of 45 questions with 4 domains measuring the impact of common muscle disease symptoms (weakness, locking [or myotonia], pain, and fatigue); 5 domains measuring the influence of the muscle disease on particular areas of life (activities, independence, relationships, emotions, and body image); and the last domain focused on the positive and negative effects of treatment and was divided into 2 scores. All responses were given in a 7-point Likert scale, with improved QoL indicated by decreased scores. Overall QoL score was calculated from preselected 5 domains (activities, independence, relationships, emotions, and body image) by adding the scores from each domain. In summary, INQoL yielded 11 scores and 1 QoL score. The Overall scoring used a scale of 0-100, with improved QoL indicated by decreased scores. | Baseline, Week 6 and Week 14 | 
| Maximum Observed Plasma Concentration (Cmax) of ATYR1940 |  | Cohort 1: Predose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, and 8.0 hours after the start of infusion at Weeks 2 and 5; Cohorts 2 and 3: Predose, 0.5, 1.0, 2.0, 4.0, and 6.0 hours after the start of infusion at Weeks 2, 5, and 13 (Cohort 3 only) | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of ATYR1940 |  | Cohort 1: Predose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, and 8.0 hours after the start of infusion at Weeks 2 and 5; Cohorts 2 and 3: Predose, 0.5, 1.0, 2.0, 4.0, and 6.0 hours after the start of infusion at Weeks 2, 5, and 13 (Cohort 3 only) | 
| Area Under the Plasma Concentration Time Curve From Time 0 to Time t (AUC 0-t) of ATYR1940 |  | Cohort 1: Predose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, and 8.0 hours after the start of infusion at Weeks 2 and 5; Cohorts 2 and 3: Predose, 0.5, 1.0, 2.0, 4.0, and 6.0 hours after the start of infusion at Weeks 2, 5, and 13 (Cohort 3 only) | 
| Average of Half-life (T1/2) of ATYR1940 |  | Cohort 1: Predose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, and 8.0 hours after the start of infusion at Weeks 2 and 5; Cohorts 2 and 3: Predose, 0.5, 1.0, 2.0, 4.0, and 6.0 hours after the start of infusion at Weeks 2, 5, and 13 (Cohort 3 only) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FSHD