Pulmonary Sarcoidosis
Conditions
Keywords
Pulmonary Sarcoidosis, Resokine, Sarcoidosis, Granulomas, Inflammation, Lymphoproliferative Disorders, Interstitial Lung Disease, Neuropilin-2, Steroids, Oral corticosteroids, Immunomodulatory, tRNA Synthetase, ATYR1923 (efzofitimod)
Brief summary
This randomized, double-blind, placebo matched to efzofitimod-controlled, study will evaluate the safety, tolerability, immunogenicity, pharmacokinetic (PK), and preliminary efficacy of multiple ascending doses of IV efzofitimod in participants with pulmonary sarcoidosis undergoing a protocol-guided oral corticosteroid (OCS) tapering regimen.This study will consist of 3 staggered multiple dose cohorts. Each eligible participant will participate in only one cohort during the study. Within each cohort, 12 participants will be randomized 2:1 to efzofitimod (N=8) or placebo matched to efzofitimod (N=4).
Interventions
BIOLOGICALEfzofitimod 1.0 mg/kg or Placebo
Participants to receive efzofitimod 1.0 mg/kg IV every 4 weeks or placebo matched to efzofitimod every 4 weeks
BIOLOGICALEfzofitimod 3.0 mg/kg or Placebo
Participants to receive efzofitimod 3.0 mg/kg IV every 4 weeks or placebo matched to efzofitimod every 4 weeks
BIOLOGICALEfzofitimod 5.0 mg/kg or Placebo
Participants to receive efzofitimod 5.0 mg/kg IV every 4 weeks or placebo matched to efzofitimod every 4 weeks
Sponsors
Foundation for Sarcoidosis Research
aTyr Pharma, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
36 participants with pulmonary sarcoidosis will be randomized into one of 3 sequential cohorts, each comprising 12 participants allocated 2:1 to efzofitimod:placebo matched to efzofitimod
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosis of pulmonary sarcoidosis for ≥6 months (cutaneous and ocular involvement allowed), defined as: * Histologically proven diagnosis of sarcoidosis by bronchoscopy, biopsy (any organ) or bronchioalveolar lavage * Parenchymal lung involvement by historical radiological evidence * Must have symptomatic and/or active pulmonary sarcoidosis as evidenced by: * Modified Medical Research Council Dyspnea Scale grade of \>= 1; and * Forced vital capacity ≥50%; and * Receiving treatment with 10 to 25 mg/day of oral prednisone (or equivalent), at a stable dose for ≥4 weeks prior to Day 1, and capable of undergoing the protocol-specified steroid taper regimen. * Body weight ≥45 kg and \<160 kg. Key
Exclusion criteria
* Current disease presentation consistent with Lofgren's syndrome. * History of severe allergic or anaphylactic reactions to therapeutic proteins or known sensitivity to efzofitimod or to its inactive components (L-histidine, sodium chloride, sucrose, L-methionine, and polysorbate-20). * Treatment with biological immunomodulators such as tumor necrosis factor-alpha inhibitors. * Current evidence of clinically significant cardiovascular, hepatic, renal, hematological, metabolic, or gastrointestinal disease, or has a condition that requires other treatment. * Clinically significant pulmonary hypertension requiring vasodilator treatment. * Any history of tuberculosis or evidence of active systemic non-tuberculosis fungal or mycobacterial infection within 1 year of Screening. * History of clinically significant cardiac, neurological, gastrointestinal, and/or renal manifestations of sarcoidosis. * Any condition that necessitated hospitalization within the 3 months prior to Day 1 or is likely to require so during the study. * Participation in another clinical study of an investigational agent or device within 3 months (small molecules) / 6 months (biologics) or 5 half-lives (if known) of the agent, whichever is longer. * History of or positive results of screening for hepatitis B, hepatitis C or human immunodeficiency virus. * Is an active, heavy smoker of tobacco/nicotine-containing products (defined as \>20 cigarettes/day or e-cigarette equivalent). * Active substance abuse or history of substance abuse within the 12 months prior to Screening. * Participant has received a live vaccination within 8 weeks before Day 1 or inoculation with a live vaccine is planned during study participation. * Positive for Jo-1 antibodies (Ab) at Screening, or past history of Jo-1 Ab positivity. * Significant and/or acute illness within 5 days prior to drug administration that may impact safety assessments, in the opinion of the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Baseline up to Week 24 | An AE was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. TEAEs were defined as any adverse event or worsening of an existing condition after initiation of the investigational product and through 30 days after the participant's last study visit (study completion or early termination). SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-adjusted Area Under the Curve (AUC) of Background Oral Corticosteroid (OCS) Usage Over Study Period | Baseline up to Week 24 (Day 1 to End of Dosing Period) | Time adjusted AUC is a measure of steroid burden and approximates the average daily OCS dose (mg/day) post-baseline for each participant. Time adjusted AUC was calculated by AUC divided by the number of days between first and last day of time interval of interest. |
| Number of Participants Who Achieved and Maintained The Targeted Tapered Dose of Prednisone 5 mg/Day (or Equivalent) | Baseline up to Week 24 | — |
| Number of Participants With Positive Anti-Drug Antibodies (Anti-Efzofitimod) | Baseline up to Week 24 | The number of all participants having drug reactive antibodies at any point in time (efzofitimod and placebo matched to efzofitimod) have been reported. |
| Number of Participants With at Least One Positive Anti-Jo-1 Antibodies Titers | Baseline up to Week 24 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo matched to efzofitimod via IV infusion every 4 weeks until Week 20. | 12 |
| Efzofitimod 1.0 mg/kg Participants received efzofitimod 1.0 mg/kg via IV infusion every 4 weeks until Week 20. | 8 |
| Efzofitimod 3.0 mg/kg Participants received efzofitimod 3.0 mg/kg via IV infusion every 4 weeks until Week 20. | 8 |
| Efzofitimod 5.0 mg/kg Participants received efzofitimod 5.0 mg/kg via IV infusion every 4 weeks until Week 20. | 9 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Investigator Decision | 0 | 1 | 0 | 0 |
| Overall Study | Participant Unable to Participate Due to COVID-19 Quarantine Restrictions | 2 | 1 | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Efzofitimod 1.0 mg/kg | Efzofitimod 3.0 mg/kg | Efzofitimod 5.0 mg/kg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 52.5 years STANDARD_DEVIATION 10.2 | 54.5 years STANDARD_DEVIATION 11.3 | 51.8 years STANDARD_DEVIATION 11.4 | 50.8 years STANDARD_DEVIATION 9.2 | 52.4 years STANDARD_DEVIATION 10.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 7 Participants | 8 Participants | 9 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 2 Participants | 6 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 5 Participants | 6 Participants | 3 Participants | 23 Participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 4 Participants | 5 Participants | 20 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 4 Participants | 4 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 8 | 0 / 8 | 0 / 9 |
| other Total, other adverse events | 10 / 12 | 8 / 8 | 7 / 8 | 8 / 9 |
| serious Total, serious adverse events | 1 / 12 | 1 / 8 | 0 / 8 | 0 / 9 |
Outcome results
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. TEAEs were defined as any adverse event or worsening of an existing condition after initiation of the investigational product and through 30 days after the participant's last study visit (study completion or early termination). SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'.
Time frame: Baseline up to Week 24
Population: The Safety Set included all participants who received any amount of study drug and were based on the actual treatment received, if this differs from that to which the participant was randomized.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 10 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Efzofitimod 1.0 mg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Efzofitimod 1.0 mg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 8 Participants |
| Efzofitimod 3.0 mg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 7 Participants |
| Efzofitimod 3.0 mg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Efzofitimod 5.0 mg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 8 Participants |
| Efzofitimod 5.0 mg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
Secondary
Number of Participants Who Achieved and Maintained The Targeted Tapered Dose of Prednisone 5 mg/Day (or Equivalent)
Time frame: Baseline up to Week 24
Population: The mITT Set included all participants who had received any amount of study drug and were based on the randomized treatment, regardless of which treatment the participant actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Achieved and Maintained The Targeted Tapered Dose of Prednisone 5 mg/Day (or Equivalent) | 7 Participants |
| Efzofitimod 1.0 mg/kg | Number of Participants Who Achieved and Maintained The Targeted Tapered Dose of Prednisone 5 mg/Day (or Equivalent) | 1 Participants |
| Efzofitimod 3.0 mg/kg | Number of Participants Who Achieved and Maintained The Targeted Tapered Dose of Prednisone 5 mg/Day (or Equivalent) | 4 Participants |
| Efzofitimod 5.0 mg/kg | Number of Participants Who Achieved and Maintained The Targeted Tapered Dose of Prednisone 5 mg/Day (or Equivalent) | 5 Participants |
Secondary
Number of Participants With at Least One Positive Anti-Jo-1 Antibodies Titers
Time frame: Baseline up to Week 24
Population: The mITT Set included all participants who had received any amount of study drug and were based on the randomized treatment, regardless of which treatment the participant actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With at Least One Positive Anti-Jo-1 Antibodies Titers | 0 Participants |
| Efzofitimod 1.0 mg/kg | Number of Participants With at Least One Positive Anti-Jo-1 Antibodies Titers | 0 Participants |
| Efzofitimod 3.0 mg/kg | Number of Participants With at Least One Positive Anti-Jo-1 Antibodies Titers | 0 Participants |
| Efzofitimod 5.0 mg/kg | Number of Participants With at Least One Positive Anti-Jo-1 Antibodies Titers | 0 Participants |
Secondary
Number of Participants With Positive Anti-Drug Antibodies (Anti-Efzofitimod)
The number of all participants having drug reactive antibodies at any point in time (efzofitimod and placebo matched to efzofitimod) have been reported.
Time frame: Baseline up to Week 24
Population: The mITT Set included all participants who had received any amount of study drug and were based on the randomized treatment, regardless of which treatment the participant actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Positive Anti-Drug Antibodies (Anti-Efzofitimod) | 1 Participants |
| Efzofitimod 1.0 mg/kg | Number of Participants With Positive Anti-Drug Antibodies (Anti-Efzofitimod) | 0 Participants |
| Efzofitimod 3.0 mg/kg | Number of Participants With Positive Anti-Drug Antibodies (Anti-Efzofitimod) | 1 Participants |
| Efzofitimod 5.0 mg/kg | Number of Participants With Positive Anti-Drug Antibodies (Anti-Efzofitimod) | 0 Participants |
Secondary
Time-adjusted Area Under the Curve (AUC) of Background Oral Corticosteroid (OCS) Usage Over Study Period
Time adjusted AUC is a measure of steroid burden and approximates the average daily OCS dose (mg/day) post-baseline for each participant. Time adjusted AUC was calculated by AUC divided by the number of days between first and last day of time interval of interest.
Time frame: Baseline up to Week 24 (Day 1 to End of Dosing Period)
Population: The modified intent-to-treat (mITT) Set included all participants who had received any amount of study drug and were based on the randomized treatment, regardless of which treatment the participant actually received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time-adjusted Area Under the Curve (AUC) of Background Oral Corticosteroid (OCS) Usage Over Study Period | 8.64 mg/day | Standard Deviation 4.2 |
| Efzofitimod 1.0 mg/kg | Time-adjusted Area Under the Curve (AUC) of Background Oral Corticosteroid (OCS) Usage Over Study Period | 6.83 mg/day | Standard Deviation 1.41 |
| Efzofitimod 3.0 mg/kg | Time-adjusted Area Under the Curve (AUC) of Background Oral Corticosteroid (OCS) Usage Over Study Period | 8.36 mg/day | Standard Deviation 3.68 |
| Efzofitimod 5.0 mg/kg | Time-adjusted Area Under the Curve (AUC) of Background Oral Corticosteroid (OCS) Usage Over Study Period | 7.43 mg/day | Standard Deviation 3.3 |