Alpha1-Antitrypsin Deficiency
Conditions
Brief summary
This study will evaluate the efficacy, safety and pharmacokinetics (PK) of VX-864 in PiZZ subjects.
Interventions
DRUGVX-864
Tablets for oral administration.
DRUGPlacebo
Placebo matched to VX-864 for oral administration.
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Subjects must have a PiZZ genotype confirmed at screening * Plasma AAT levels indicating severe deficiency at screening Key
Exclusion criteria
* History of a medical condition that could negatively impact the ability to complete the study * Solid organ, or hematological transplantation or is currently on a transplant list * History of use of gene therapy or RNAi therapy at any time previously Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | From Baseline at Day 28 |
| Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 up to Week 8 |
Secondary
| Measure | Time frame |
|---|---|
| Change in Plasma Antigenic AAT Levels | From Baseline at Day 28 |
| Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Pre-dose at Day 7, Day 14, Day 21 and Day 28 |
Countries
Canada, Germany, Ireland, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
This study was conducted in participants 18 through 80 of years of age, inclusive with the PiZZ genotype.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo matched to VX-864 in the treatment period for 28 days. | 7 |
| VX-864 100 mg Participants received VX-864 100 mg q12h in the treatment period for 28 days. | 10 |
| VX-864 300 mg Participants received VX-864 300 mg q12h in the treatment period for 28 days. | 9 |
| VX-864 500 mg Participants received VX-864 500 mg q12h in the treatment period for 28 days. | 18 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal of consent (not due to adverse event) | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | VX-864 100 mg | VX-864 300 mg | VX-864 500 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 63.4 years STANDARD_DEVIATION 10.5 | 55.1 years STANDARD_DEVIATION 5.3 | 53.2 years STANDARD_DEVIATION 16.2 | 57.4 years STANDARD_DEVIATION 9.9 | 57.0 years STANDARD_DEVIATION 10.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 8 Participants | 8 Participants | 15 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | 4.7 micromole per liter STANDARD_DEVIATION 1.3 | 4.0 micromole per liter STANDARD_DEVIATION 0.7 | 3.8 micromole per liter STANDARD_DEVIATION 0.9 | 4.1 micromole per liter STANDARD_DEVIATION 0.6 | 4.1 micromole per liter STANDARD_DEVIATION 0.9 |
| 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 | 7 Participants | 10 Participants | 9 Participants | 18 Participants | 44 Participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 6 Participants | 14 Participants | 31 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 3 Participants | 4 Participants | 13 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 / 7 | 0 / 10 | 0 / 9 | 0 / 18 |
| other Total, other adverse events | 4 / 7 | 7 / 10 | 7 / 9 | 17 / 18 |
| serious Total, serious adverse events | 0 / 7 | 0 / 10 | 0 / 9 | 2 / 18 |
Outcome results
Primary
Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels
Time frame: From Baseline at Day 28
Population: Full analysis set (FAS) included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | -0.1 micromole per liter | Standard Error 0.3 |
| VX-864 100 mg | Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | 2.3 micromole per liter | Standard Error 0.3 |
| VX-864 300 mg | Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | 2.3 micromole per liter | Standard Error 0.2 |
| VX-864 500 mg | Change in Plasma Functional Alpha-1 Antitrypsin (AAT) Levels | 2.1 micromole per liter | Standard Error 0.2 |
p-value: <0.000195% CI: [1.5, 3.1]Mixed-effects Model for Repeated Measure
p-value: <0.000195% CI: [1.6, 3.1]Mixed-effects Model for Repeated Measure
p-value: <0.000195% CI: [1.5, 2.9]Mixed-effects Model for Repeated Measure
Primary
Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Day 1 up to Week 8
Population: The safety set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With AEs | 4 participants |
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 0 participants |
| VX-864 100 mg | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 0 participants |
| VX-864 100 mg | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With AEs | 7 participants |
| VX-864 300 mg | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With AEs | 7 participants |
| VX-864 300 mg | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 0 participants |
| VX-864 500 mg | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With AEs | 17 participants |
| VX-864 500 mg | Safety and Tolerability as Assessed by Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 2 participants |
Secondary
Change in Plasma Antigenic AAT Levels
Time frame: From Baseline at Day 28
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Plasma Antigenic AAT Levels | -0.1 micromole per liter | Standard Error 0.4 |
| VX-864 100 mg | Change in Plasma Antigenic AAT Levels | 3.4 micromole per liter | Standard Error 0.4 |
| VX-864 300 mg | Change in Plasma Antigenic AAT Levels | 2.9 micromole per liter | Standard Error 0.4 |
| VX-864 500 mg | Change in Plasma Antigenic AAT Levels | 2.6 micromole per liter | Standard Error 0.2 |
p-value: <0.000195% CI: [2.4, 4.6]Mixed-effects Model for Repeated Measure
p-value: <0.000195% CI: [1.9, 4]Mixed-effects Model for Repeated Measure
p-value: <0.000195% CI: [1.8, 3.7]Mixed-effects Model for Repeated Measure
Secondary
Observed Pre-dose Plasma Concentration (Ctrough) of VX-864
Time frame: Pre-dose at Day 7, Day 14, Day 21 and Day 28
Population: Pharmacokinetic (PK) set included participants who received at least 1 dose of study drug. Here Number analyzed signifies those participants who were evaluable for this endpoint at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Day 7 | 1.13 microgram per milliliter | Standard Deviation 0.743 |
| Placebo | Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Day 14 | 0.852 microgram per milliliter | Standard Deviation 0.34 |
| Placebo | Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Day 21 | 0.868 microgram per milliliter | Standard Deviation 0.503 |
| Placebo | Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Day 28 | 0.797 microgram per milliliter | Standard Deviation 0.327 |
| VX-864 100 mg | Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Day 28 | 1.29 microgram per milliliter | Standard Deviation 0.646 |
| VX-864 100 mg | Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Day 7 | 1.62 microgram per milliliter | Standard Deviation 0.665 |
| VX-864 100 mg | Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Day 21 | 1.21 microgram per milliliter | Standard Deviation 0.77 |
| VX-864 100 mg | Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Day 14 | 1.47 microgram per milliliter | Standard Deviation 0.847 |
| VX-864 300 mg | Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Day 28 | 2.55 microgram per milliliter | Standard Deviation 2.4 |
| VX-864 300 mg | Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Day 14 | 4.35 microgram per milliliter | Standard Deviation 5.36 |
| VX-864 300 mg | Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Day 21 | 1.79 microgram per milliliter | Standard Deviation 0.922 |
| VX-864 300 mg | Observed Pre-dose Plasma Concentration (Ctrough) of VX-864 | Day 7 | 2.74 microgram per milliliter | Standard Deviation 2.89 |