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

NCT02239224 | Completed Phase 1 Results DMC

• 2 other identifiers: ATYR1940-C-0022014-001753-17
• Study Type: interventional
• Target: 20
• Locations: 4 countries
• Sites: 5

Brief Summary

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

Conditions

Facioscapulohumeral Muscular Dystrophy (FSHD)

Keywords

FSHD

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (6)

• Percent Change From Baseline in Manual Muscle Testing (MMT) Score at Week 6 and Week 14

  Baseline, Week 6 and Week 14

• Change From Baseline in Individualized Neuromuscular Quality of Life (INQoL) - Overall QoL at Week 6 and Week 14

  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)

Study Arms (4)

Cohort 1: ATYR1940 0.3 mg/kg

EXPERIMENTAL

Participants will receive ATYR1940 0.3 milligrams/kilograms (mg/kg) intravenous (IV) infusion once weekly for 4 weeks.

Biological: ATYR1940

Cohort 2: ATYR1940 1.0 mg/kg

EXPERIMENTAL

Participants will receive ATYR1940 1.0 mg/kg IV infusion once weekly for 4 weeks.

Biological: ATYR1940

Cohort 3: ATYR1940 3.0 mg/kg

EXPERIMENTAL

Participants will receive ATYR1940 3.0 mg/kg IV infusion once weekly for 12 weeks.

Biological: ATYR1940

Placebo

PLACEBO COMPARATOR

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

Interventions

Placebo BIOLOGICAL

Concentrate for solution for infusion

Placebo

ATYR1940 BIOLOGICAL

Concentrate for solution for infusion

Cohort 1: ATYR1940 0.3 mg/kg; Cohort 2: ATYR1940 1.0 mg/kg; Cohort 3: ATYR1940 3.0 mg/kg

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• aTyr Pharma, Inc.: lead

Study Sites (5)

aTyr Pharma Investigative Site

Rochester, New York, 14642, United States

Location

aTyr Pharma Investigative Site

Columbus, Ohio, 43210, United States

Location

aTyr Pharma Investigative Site

Marseille, France

Location

aTyr Pharma Investigative Site

Rome, Italy

Location

aTyr Pharma Investigative Site

Nijmegen, Netherlands

Location

MeSH Terms

Conditions

Muscular Dystrophy, Facioscapulohumeral

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Gennyne Walker
• Organization: aTyR Pharma

clinicaltrials@atyrpharma.com

858 731 8389

Study Officials

• Sanjay Shukla, MD

  aTyr Pharma

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 7, 2014
• First Posted: September 12, 2014
• Study Start: September 4, 2014
• Primary Completion: December 14, 2015
• Study Completion: December 14, 2015
• Last Updated: August 11, 2021
• Results First Posted: August 11, 2021

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1); NL (1); US (2); IT (1)