A Phase 1 Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GS-5745 in Subjects With Chronic Obstructive Pulmonary Disease
The primary objective of the study is to assess the safety and tolerability of multiple infusions of andecaliximab (formerly GS-5745) in participants with chronic obstructive pulmonary disease (COPD) as assessed by adverse events (AEs) and laboratory abnormalities.
Sex: All, ages: 40 Years to 75 Years
Key Inclusion Criteria:
* Weight: ≥ 45 kg to < 120 kg at screening
* Males or non-pregnant, non-lactating females
* Male individuals and female individuals of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception. Male individuals must refrain from sperm donation for 90 days post last infusion of the study drug
* Diagnosis of COPD per Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for at least 6 months prior to screening and anticipated to remain on stable therapy for the duration of the study
* Post-bronchodilator forced expiratory volume in one second (FEV1) ≥ 40% predicted
* No changes in COPD medications within 30 days prior to randomization
* Hepatic panel \[aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, direct bilirubin, alkaline phosphatase, lactate dehydrogenase (LDH)\] ≤ 2 times the upper limit of the normal range (ULN)
* Serum creatinine ≤ 2.0
* Hemoglobin ≥ 8.5 g/dL (both males and females)
* Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L (1,500 mm\^3)
* Platelets ≥ 100 x 10\^9/L
Key Exclusion Criteria:
* Clinically significant active infection as judged by the investigator during screening
* Known history of HIV, hepatitis B or C during screening. Individuals who are hepatitis B surface antigen positive, but who received a successful series of hepatitis B vaccinations and never had the disease remain eligible
* A positive QuantiFERON-TB GOLD test during screening
* History of malignancy within the last 5 years except for patients who have been treated locally for non-melanoma skin cancer or cervical carcinoma in situ
* Any serious cardiac event such as myocardial infarction, unstable or life-threatening arrhythmia, hospitalization for cardiac failure within 6 months prior to randomization or any significant or new electrocardiogram (ECG) finding at Visit 1 as judged by the Investigator
* A hospitalization for a respiratory event such as, but not limited to, COPD, pneumonia, bronchiolitis, within the previous 6 months prior to randomization
* Chronic lung disease other than COPD such as: asthma, cystic fibrosis or fibrotic disease, α-1-antitrypsin deficiency, interstitial lung disease, pulmonary thromboembolic disease, or bronchiectasis
* Chronic use of systemic corticosteroids and/or treatment with systemic corticosteroids for an acute exacerbation of COPD (AECOPD) event, or other medical condition not requiring hospitalization, within 90 days of randomization.
* Treatment with antibiotics for an AECOPD event, or other medical condition not requiring hospitalization within 90 days of randomization, or any minor medical event not requiring hospitalization within 14 days of randomization.
* Treatment with any marketed or investigational biologic within 5 half-lives of the molecule or if unknown within 90 days of screening
* Individuals currently on nonbiologic immune modulator medications such as: azathioprine, cyclosporine, hydroxychloroquine, leflunomide, methotrexate, mycophenolate mofetil, sulfasalazine, tofacitinib, within 90 days of randomization
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Participant flow
| Milestone | Andecaliximab | Placebo |
|---|
| Started | 8 | 3 |
| Completed | 7 | 2 |
| Not completed | 1 | 1 |
Outcome results
- Percentage of Participants Experiencing Treatment-Emergent Adverse Events (Primary), Number, percentage of participants: Andecaliximab 75.0; Placebo 33.3
- Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities (Primary), Number, percentage of participants: Andecaliximab 87.5; Placebo 100.0
- Percentage of Participants Who Developed Anti-andecaliximab Antibodies (Primary), Number, percentage of participants: Andecaliximab 12.5
- Pharmacokinetic (PK) Parameter of Andecaliximab: AUClast for Days 1, 15 and 29 (Secondary), Mean, day*ug/mL: Andecaliximab 1206.7 +/- 357.75
- PK Parameter of Andecaliximab: AUCinf for Day 1 (Secondary), Mean, day*ug/mL: Andecaliximab 1398.1 +/- 265.26
- PK Parameter of Andecaliximab: %AUCexp for Day 1 (Secondary), Mean, percentage of AUC: Andecaliximab 19.97 +/- 12.781
- PK Parameter of Andecaliximab: Cmax for Days 1, 15 and 29 (Secondary), Mean, ug/mL: Andecaliximab 236.7 +/- 62.70
- PK Parameter of Andecaliximab: Tmax for Days 1, 15 and 29 (Secondary), Mean, day: Andecaliximab 0.08 +/- 0.076
- PK Parameter of Andecaliximab: Clast for Days 1, 15 and 29 (Secondary), Mean, ug/mL: Andecaliximab 37.07 +/- 18.740
- PK Parameter of Andecaliximab: Tlast for Days 1, 15 and 29 (Secondary), Mean, day: Andecaliximab 12.96 +/- 2.582
- PK Parameter of Andecaliximab: λz for Day 1 (Secondary), Mean, 1/day: Andecaliximab 0.137 +/- 0.0263
- PK Parameter of Andecaliximab: CL for Day 1 (Secondary), Mean, mL/day: Andecaliximab 296.5 +/- 64.67
- PK Parameter of Andecaliximab: Vz for Day 1 (Secondary), Mean, mL: Andecaliximab 2200.9 +/- 442.03
- PK Parameter of Andecaliximab: Vss for Day 1 (Secondary), Mean, mL: Andecaliximab 2178.7 +/- 450.66
- PK Parameter of Andecaliximab: t1/2 for Day 1 (Secondary), Mean, day: Andecaliximab 5.24 +/- 1.102
Adverse events
Time frame: First dose date up to Day 29 plus 30 days
| Arm | Deaths | Serious adverse events | Other adverse events |
|---|
| Andecaliximab | 0/8 (0.0%) | 0/8 (0.0%) | 6/8 (75.0%) |
| Placebo | 0/3 (0.0%) | 0/3 (0.0%) | 1/3 (33.3%) |
Other adverse events by term
| Term | Organ system | Andecaliximab | Placebo |
|---|
| Anaemia | Blood and lymphatic system disorders | 1/8 | 0/3 |
| Nausea | Gastrointestinal disorders | 1/8 | 0/3 |
| Vomiting | Gastrointestinal disorders | 1/8 | 0/3 |
| Pain | General disorders | 1/8 | 0/3 |
| Upper respiratory tract infection | Infections and infestations | 0/8 | 1/3 |
| Urinary tract infection | Infections and infestations | 1/8 | 0/3 |
| Ligament sprain | Injury, poisoning and procedural complications | 1/8 | 0/3 |
| Periorbital contusion | Injury, poisoning and procedural complications | 1/8 | 0/3 |
| Blood creatine phosphokinase increased | Investigations | 1/8 | 0/3 |
| Electrocardiogram QT prolonged | Investigations | 1/8 | 0/3 |
| Lymphocyte count decreased | Investigations | 1/8 | 0/3 |
| Neutrophil count increased | Investigations | 1/8 | 0/3 |
| Platelet count increased | Investigations | 1/8 | 0/3 |
| White blood cell count increased | Investigations | 1/8 | 0/3 |
| Proteinuria | Renal and urinary disorders | 1/8 | 0/3 |
| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | 1/8 | 0/3 |
| Productive cough | Respiratory, thoracic and mediastinal disorders | 1/8 | 0/3 |
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | 1/8 | 0/3 |