Asthma
Conditions
Brief summary
The goals of this clinical study were to assess the safety, tolerability, blood levels, and disease impact of UPB-101 when given to adults with mild asthma. Eligible participant were consecutively assigned to 1 of 3 to 5 planned treatment groups. Each treatment group consisted of 8 individuals, six of whom will received active drug (UPB-101) and 2 who received placebo. Neither the study doctors nor the participants knew which participants were assigned to active study drug and which were assigned to placebo. The study was performed at 4 experienced research sites in the United Kingdom.
Detailed description
This was a two-part phase 1b, multi-center randomized, double-blind (Investigator and Subject blinded; Sponsor unblinded), placebo-controlled, multiple ascending-dose study to assess the safety, tolerability, immunogenicity, pharmacokinetics (PK), and pharmacodynamics (PD) of UPB-101 administered subcutaneously (SC) to adult subjects with asthma. The study consists of Part A and Part B. Part A included 3 cohorts with pre-set dosing regimens. Part B (optional) included up to 2 additional cohorts whose doses and dosing intervals decided based upon the safety, PK, and PD results from Part A (i.e., an adaptive design), as applicable. The regimens selected for Part B did not exceed the exposures (i.e., doses and/or dosing intervals) included in Part A. Eight subjects were randomized per cohort (6 active, 2 placebo). Thus, a total of 32 subjects were enrolled in the study with 24 subjects in Part A and 8 in Part B.
Interventions
DRUGUPB-101
Subcutaneous injection
DRUGPlacebo
Subcutaneous injection
Sponsors
Upstream Bio Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, aged 18 to 60, and has physician-diagnosed asthma 2. Body mass index (BMI) between 18 and 35 kg/m2 3. Blood eosinophil cell count ≥200 (OR ≥150 combined with fractional exhaled nitric oxide \[a measure of lung airway inflammation\] \>25) at one screening visit and ≥150 at the other screening 4. Agrees to follow the required contraceptive techniques 5. Female or male participant agrees not to donate eggs or sperm, respectively, for a period of 120 days after the last dose of the study drug 6. Able to perform spirometry (breathing tests) 7. Asthma and non-biologic asthma medication have been stable for the past 2 months
Exclusion criteria
1. Employee, consultant, and/or immediate family member of any person involved in the conduct of the study 2. Previous exposure to the study drug or known allergy/sensitivity to any of its ingredients 3. Pregnant or breastfeeding female 4. Unable to fast and avoid strenuous exercise for 9 hours prior to each site visit 5. Serious allergic reaction to any injected drug 6. Significantly abnormal clinical laboratory test results or a significant medical condition 7. Recently donated blood (including blood products) or experienced significant loss of blood 8. Has pacemaker or a significantly abnormal electrocardiogram 9. An active or a serious infection in the past 8 weeks 10. Poorly-controlled diabetes or abnormal kidney function 11. Tests positive to illicit drugs or nicotine and cannot limit alcohol consumption 12. Tests positive for human immunodeficiency virus antibodies (HIV), hepatitis B, hepatitis C antibodies, or tuberculosis 13. Received any vaccine within the past month 14. Received any immunosuppressant therapies in the past 15. Received an antibody or therapeutic biologic product in the last 6 months 16. Received steroids (other than inhaled) in the past 2 months 17. Participated recently in a clinical study 18. Current tobacco smokers or has smoked within the last year 19. Tested positive for COVID-19 in the past month
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment-emergent Adverse Events and Serious Adverse Events | Baseline through 24 weeks | Overall Summary of Treatment-emergent Adverse Events (TEAEs) and Adverse Events (AEs) up to Week 24 (Safety Population) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Anti-drug Antibodies | Baseline through Week 32 | Blood samples were analyzed for the presence of ADAs using validated assays. Low titer ADA responses were detected toward the end of the concentration vs time profile. There was no evident effect of ADAs on drug exposure and no immune-related adverse events |
| Maximum Observed Concentration of UPB-101 | First Dose = Day 1. Last Dose = Baseline through 32 weeks. | Blood samples were collected and analyzed using a validated assay to determine the Cmax (ug/mL) of UPB-101. The pharmacokinetic (PK) parameters were estimated using non-compartmental analysis. |
| Time to Maximum Observed Concentration of UPB-101 | Baseline through 32 weeks | Blood samples were collected and analyzed using a validated assay to determine the Tmax (days) of UPB-101. The pharmacokinetic (PK) parameters were estimated using non-compartmental analysis. |
| Area Under the Concentration-time Curve Under One Dosing Interval of UPB-101 | Baseline through 32 weeks | Blood samples were collected and analyzed using a validated assay to determine the AUClast (d.ug/mL) of UPB-101. The pharmacokinetic (PK) parameters were estimated using non-compartmental analysis. |
Countries
United Kingdom
Participant flow
Recruitment details
The study was conducted in 4 sites in the United Kingdom (UK).
Participants by arm
| Arm | Count |
|---|---|
| Active Substance 1 UPB-101 Cohort 1 (100 mg) | 6 |
| Active Substance 2 UPB-101 Cohort 2 (200 mg) | 6 |
| Active Substance 3 UPB-101 Cohort 3 (300 mg) | 6 |
| Active Substance 4 UPB-101 Cohort 4 (25 mg) | 6 |
| Placebo Placebo: Subcutaneous injection | 8 |
| Total | 32 |
Baseline characteristics
| Characteristic | Active Substance 1 | Active Substance 2 | Active Substance 3 | Active Substance 4 | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 35.7 years STANDARD_DEVIATION 10.31 | 37.7 years STANDARD_DEVIATION 8.82 | 32.7 years STANDARD_DEVIATION 9.54 | 48.0 years STANDARD_DEVIATION 5.25 | 37.0 years STANDARD_DEVIATION 11.41 | 38.1 years STANDARD_DEVIATION 10.22 |
| BMI at Screening (kg/m2) | 26.57 kg/m^2 STANDARD_DEVIATION 3.025 | 25.18 kg/m^2 STANDARD_DEVIATION 2.074 | 25.22 kg/m^2 STANDARD_DEVIATION 2.848 | 27.65 kg/m^2 STANDARD_DEVIATION 2.518 | 25.56 kg/m^2 STANDARD_DEVIATION 3.11 | 26.01 kg/m^2 STANDARD_DEVIATION 2.784 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 7 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 2 Participants | 6 Participants | 7 Participants | 23 Participants |
| Region of Enrollment United Kingdom | 6 participants | 6 participants | 6 participants | 6 participants | 8 participants | 32 participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 2 Participants | 2 Participants | 3 Participants | 16 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 4 Participants | 4 Participants | 5 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 8 |
| other Total, other adverse events | 5 / 6 | 6 / 6 | 5 / 6 | 3 / 6 | 6 / 8 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 8 |
Outcome results
Primary
Number of Treatment-emergent Adverse Events and Serious Adverse Events
Overall Summary of Treatment-emergent Adverse Events (TEAEs) and Adverse Events (AEs) up to Week 24 (Safety Population)
Time frame: Baseline through 24 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active Substance 1 | Number of Treatment-emergent Adverse Events and Serious Adverse Events | any TEAEs | 19 adverse events |
| Active Substance 1 | Number of Treatment-emergent Adverse Events and Serious Adverse Events | SAEs | 0 adverse events |
| Active Substance 2 | Number of Treatment-emergent Adverse Events and Serious Adverse Events | any TEAEs | 17 adverse events |
| Active Substance 2 | Number of Treatment-emergent Adverse Events and Serious Adverse Events | SAEs | 0 adverse events |
| Active Substance 3 | Number of Treatment-emergent Adverse Events and Serious Adverse Events | any TEAEs | 12 adverse events |
| Active Substance 3 | Number of Treatment-emergent Adverse Events and Serious Adverse Events | SAEs | 0 adverse events |
| Active Substance 4 | Number of Treatment-emergent Adverse Events and Serious Adverse Events | SAEs | 0 adverse events |
| Active Substance 4 | Number of Treatment-emergent Adverse Events and Serious Adverse Events | any TEAEs | 9 adverse events |
| Placebo | Number of Treatment-emergent Adverse Events and Serious Adverse Events | any TEAEs | 25 adverse events |
| Placebo | Number of Treatment-emergent Adverse Events and Serious Adverse Events | SAEs | 0 adverse events |
Secondary
Area Under the Concentration-time Curve Under One Dosing Interval of UPB-101
Blood samples were collected and analyzed using a validated assay to determine the AUClast (d.ug/mL) of UPB-101. The pharmacokinetic (PK) parameters were estimated using non-compartmental analysis.
Time frame: Baseline through 32 weeks
Population: The PK Population included all subjects who received at least 1 complete dose of active study drug (UPB-101) and for whom at least 1 PK parameter was estimated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Substance 1 | Area Under the Concentration-time Curve Under One Dosing Interval of UPB-101 | AUClast after the first dose | 187 day*μg/mL | Standard Deviation 40.8 |
| Active Substance 1 | Area Under the Concentration-time Curve Under One Dosing Interval of UPB-101 | AUClast after the last dose | 613 day*μg/mL | Standard Deviation 115 |
| Active Substance 2 | Area Under the Concentration-time Curve Under One Dosing Interval of UPB-101 | AUClast after the first dose | 449 day*μg/mL | Standard Deviation 101 |
| Active Substance 2 | Area Under the Concentration-time Curve Under One Dosing Interval of UPB-101 | AUClast after the last dose | 1740 day*μg/mL | Standard Deviation 496 |
| Active Substance 3 | Area Under the Concentration-time Curve Under One Dosing Interval of UPB-101 | AUClast after the last dose | 1420 day*μg/mL | Standard Deviation 453 |
| Active Substance 3 | Area Under the Concentration-time Curve Under One Dosing Interval of UPB-101 | AUClast after the first dose | 1220 day*μg/mL | Standard Deviation 236 |
| Active Substance 4 | Area Under the Concentration-time Curve Under One Dosing Interval of UPB-101 | AUClast after the first dose | 73.4 day*μg/mL | Standard Deviation 26.6 |
Secondary
Incidence of Anti-drug Antibodies
Blood samples were analyzed for the presence of ADAs using validated assays. Low titer ADA responses were detected toward the end of the concentration vs time profile. There was no evident effect of ADAs on drug exposure and no immune-related adverse events
Time frame: Baseline through Week 32
Population: Subjects who received any kind of study intervention, and had at least one blood sample measured for ADAs.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Substance 1 | Incidence of Anti-drug Antibodies | 4 Participants |
| Active Substance 2 | Incidence of Anti-drug Antibodies | 5 Participants |
| Active Substance 3 | Incidence of Anti-drug Antibodies | 1 Participants |
| Active Substance 4 | Incidence of Anti-drug Antibodies | 2 Participants |
| Placebo | Incidence of Anti-drug Antibodies | 0 Participants |
Secondary
Maximum Observed Concentration of UPB-101
Blood samples were collected and analyzed using a validated assay to determine the Cmax (ug/mL) of UPB-101. The pharmacokinetic (PK) parameters were estimated using non-compartmental analysis.
Time frame: First Dose = Day 1. Last Dose = Baseline through 32 weeks.
Population: The PK Population included all subjects who received at least 1 complete dose of active study drug (UPB-101) and for whom at least 1 PK parameter was estimated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Substance 1 | Maximum Observed Concentration of UPB-101 | Cmax after first dose | 8.82 ug/mL | Standard Deviation 2.25 |
| Active Substance 1 | Maximum Observed Concentration of UPB-101 | Cmax after last dose | 16.3 ug/mL | Standard Deviation 5.03 |
| Active Substance 2 | Maximum Observed Concentration of UPB-101 | Cmax after first dose | 21.8 ug/mL | Standard Deviation 3.78 |
| Active Substance 2 | Maximum Observed Concentration of UPB-101 | Cmax after last dose | 41.8 ug/mL | Standard Deviation 5.69 |
| Active Substance 3 | Maximum Observed Concentration of UPB-101 | Cmax after last dose | 33.8 ug/mL | Standard Deviation 8.39 |
| Active Substance 3 | Maximum Observed Concentration of UPB-101 | Cmax after first dose | 32.4 ug/mL | Standard Deviation 6.23 |
| Active Substance 4 | Maximum Observed Concentration of UPB-101 | Cmax after first dose | 1.85 ug/mL | Standard Deviation 0.602 |
Secondary
Time to Maximum Observed Concentration of UPB-101
Blood samples were collected and analyzed using a validated assay to determine the Tmax (days) of UPB-101. The pharmacokinetic (PK) parameters were estimated using non-compartmental analysis.
Time frame: Baseline through 32 weeks
Population: The PK Population included all subjects who received at least 1 complete dose of active study drug (UPB-101) and for whom at least 1 PK parameter was estimated.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Active Substance 1 | Time to Maximum Observed Concentration of UPB-101 | Tmax after first dose | 6.98 days |
| Active Substance 1 | Time to Maximum Observed Concentration of UPB-101 | Tmax after last dose | 5.00 days |
| Active Substance 2 | Time to Maximum Observed Concentration of UPB-101 | Tmax after first dose | 5.95 days |
| Active Substance 2 | Time to Maximum Observed Concentration of UPB-101 | Tmax after last dose | 3.94 days |
| Active Substance 3 | Time to Maximum Observed Concentration of UPB-101 | Tmax after last dose | 4.98 days |
| Active Substance 3 | Time to Maximum Observed Concentration of UPB-101 | Tmax after first dose | 6.93 days |
| Active Substance 4 | Time to Maximum Observed Concentration of UPB-101 | Tmax after first dose | 9.94 days |