A Phase 2, Open-label Study Evaluating Efficacy and Safety of VX-864 in Subjects With Alpha-1 Antitrypsin Deficiency Who Have the PiZZ Genotype, Over 48 Weeks
Phase: PHASE2
Conditions: Alpha-1 Antitrypsin Deficiency
Sponsor: Vertex Pharmaceuticals Incorporated



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2 
PROTOCOL SYNOPSIS 
Title 
A Phase 2, Open-label Study Evaluating Efficacy and Safety of VX-864 in 
Subjects With Alpha-1 Antitrypsin Deficiency Who Have the PiZZ Genotype, 
Over 48 Weeks 
  
Brief Title 
A Study to Evaluate Efficacy and Safety of VX-864 in Subjects With the PiZZ 
Genotype  
 
 
Clinical Phase and 
Clinical Study Type  
Phase 2 efficacy and safety 
 
 
Objectives 
Primary Objective 
• 
To evaluate the efficacy of VX-864 on blood levels of functional alpha-1 
antitrypsin (AAT) in individuals with the PiZZ genotype 
Secondary Objectives 
• 
To evaluate the efficacy of VX-864 on blood levels of antigenic AAT in 
individuals with the PiZZ genotype 
• 
To evaluate the efficacy of VX-864 on blood levels of Z-polymer in 
individuals with PiZZ genotype 
• 
To evaluate the efficacy of VX-864 on liver Z-polymer in individuals with 
the PiZZ genotype (in Group B only) 
• 
To evaluate the safety and tolerability of VX-864 in individuals with the PiZZ 
genotype  
Endpoints 
Primary Endpoint 
• 
Change from baseline in blood levels of functional AAT at Week 48 
Secondary Endpoints 
• 
Change from baseline in blood levels of functional AAT over time 
• 
Change from baseline in blood levels of antigenic AAT over time 
• 
Change from baseline in blood levels of Z-polymer over time 
• 
Change from baseline in Z-polymer accumulation in the liver over time (in 
Group B only) 
• 
Safety and tolerability assessments based on adverse events (AEs), clinical 
laboratory values, standard 12-lead ECGs, and vital signs  

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Number of Subjects 
Approximately 20 subjects with the PiZZ genotype will be enrolled: Groups A 
and B will enroll approximately 10 subjects each. 
 
 
Study Population 
Group A: Male and female subjects 18 through 80 years of age, inclusive, with the 
PiZZ genotype 
Group B: Male and female subjects 18 through 70 years of age, inclusive, with the 
PiZZ genotype 
 
 
Investigational Drug 
Active substance: VX‑864 
 
Activity: AAT modulator 
 
Strength and route of administration: 100-mg or 250-mg tablets for oral 
administration 
 
 
Study Duration 
Excluding the Screening Period, each subject will participate in the study for 
approximately 52 weeks (48-week Treatment Period and 28-day Safety Follow-up 
Period). In subjects who consent to the posttreatment Telemedicine Visit(s), the 
total duration for study participation will increase by approximately 24 weeks 
(i.e., approximately 76 weeks total, from Screening Period through posttreatment 
Telemedicine Visit). 
 
 
Study Design 
This is a Phase 2, open-label, multicenter study. Approximately 20 subjects with 
the PiZZ genotype will be enrolled. Groups A and B will enroll approximately 
10 subjects each. All subjects will receive VX-864 500 mg every 12 hours (q12h) 
for 48 weeks. Figure 2-1 displays the study design. 
Group A subjects will not have a liver biopsy. 
Subjects in Group B will have 2 liver biopsies performed over the course of the 
study. All liver biopsies will be performed percutaneously. All subjects in 
Group B (approximately 10 subjects) will have a liver biopsy during the 
Pretreatment Interval (Figure 2-1). Approximately 5 subjects (Cohort B1) will 
have a second liver biopsy at Week 24. Approximately 5 subjects (Cohort B2) will 
have a second liver biopsy at Week 48.  
The pretreatment liver biopsy must be performed at least 7 days before Day 1 
dosing, after all eligibility criteria have been met. Local laboratory hematology 
and coagulation results must be collected and reviewed by investigator within 
approximately 48 hours prior to the liver biopsy being performed. The Week 24 
and Week 48 liver biopsies will be performed 3 hours (±30 minutes) postdose 
relative to the morning dose. 
The Safety Follow-up Visits are required for all subjects. In subjects who 
terminate their participation early, the ETT visit, which may be conducted at the 
site or by telephone or video interview, replaces the Safety Follow-up Visit, if the 

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ETT Visit occurs 3 weeks or later following the last dose of study drug. All 
subjects may also consent to the posttreatment Telemedicine Visit(s) following 
final dose of study drug, to monitor for development of AEs of rash (for up to 
6 months) and to monitor any ongoing AEs of rash (for up to 6 months following 
resolution of AEs of rash; see Section 9.1.6). 
Figure 2-1 
VX22-864-108 Study Design 
 
n: size of subsample; N: number of subjects 
Note: Figure is not drawn to scale.  
a 
In subjects not requiring augmentation therapy washout, the Screening Period will be up to 
28 days. In subjects requiring augmentation therapy washout, the Screening Period will be up 
to 70 days. 
b 
Day -14 to Day -7; pretreatment liver biopsy must be performed at least 7 days before Day 1 
dosing. 
c 
There will be no further dosing in this study as of 25 September 2023. All subjects may 
consent to the posttreatment Telemedicine Visit(s) following final dose of study drug, to 
monitor for development of AEs of rash (for up to 6 months) and monitor any ongoing AEs of 
rash (for up to 6 months following resolution of AEs of rash; see Section 9.1.6). 
Figure 2-2 displays the general recommended order of key screening assessments 
for subjects who have received augmentation therapy within 42 days before the 
initial screening visit. 
Figure 2-2 
Recommended Order of Key Screening Assessments for 
Subjects Who Have Received Augmentation Therapy 
Within 42 Days Before the Initial Screening Visit 
 
AAT: alpha-1 antitrypsin; LFT: liver function test 
Note: Figure is not drawn to scale. 
a 
If serum chemistry was completed more than 28 (+7) days before Day 1 dosing, the LFT 
panel must be completed within 28 (+7) days before Day 1 dosing. 
b 
Pretreatment liver biopsy must be performed at least 7 days before Day 1 dosing. 
Figure 2-3 displays the general recommended order of key screening assessments 
for subjects who have not received augmentation therapy within 42 days before 
the initial screening visit. 

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Figure 2-3 
Recommended Order of Key Screening Assessments for 
Subjects Who Have Not Received Augmentation Therapy 
Within 42 Days Before the Initial Screening Visit 
 
AAT: alpha-1 antitrypsin; LFT: liver function test  
Note: Figure is not drawn to scale. 
a 
If serum chemistry was completed more than 28 (+7) days before Day 1 dosing, the LFT 
panel must be completed within 28 (+7) days before Day 1 dosing. 
b 
Pretreatment liver biopsy must be performed at least 7 days before Day 1 dosing. 
 
Assessments 
Efficacy: Blood samples for levels of functional AAT, antigenic AAT, and 
Z-polymer, and liver biopsy (to evaluate Z-polymer accumulation in the liver) 
Safety: AEs, clinical laboratory assessments, standard 12-lead ECGs, clinical 
evaluation of vital signs, and physical examinations 
 
 
Statistical Analyses 
The primary efficacy endpoint is the change from baseline in blood levels of 
functional AAT at Week 48.  
Assuming (1) the mean of blood levels of functional AAT at baseline is 4.1 µM 
(SD of 0.6 µM); (2) post-baseline blood levels of functional AAT have a constant 
coefficient of variation of 0.25; and (3) an intra-subject correlation of 0.8 between 
baseline and post-baseline measurements, the 95% CI for the change from 
baseline in blood levels of functional AAT at Week 48 has a half-width between 
0.59 and 1.24 if the observed change from baseline is between 2 and 7 µM with a 
sample size of 16 evaluable subjects (combining Groups A and B). To account for 
up to a 20% dropout rate, 20 subjects will be enrolled. 
The primary analysis will be based on a mixed-effects model for repeated 
measures (MMRM) with change from baseline in blood levels of functional AAT 
as the dependent variable. The model will include visit as a fixed effect. 
Interim analyses may be conducted at the discretion of the sponsor. 
 

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3 
SCHEDULE OF ASSESSMENTS 
Please note, as of 25 September 2023 this study is no longer screening or enrolling subjects. 
Schedules of assessments are in Table 3-1 (Screening for subjects who have received 
augmentation therapy within 42 days before the initial screening visit), Table 3-2 (Screening for 
subjects who have not received augmentation therapy within 42 days before the initial screening 
visit), Table 3-3 (Treatment Period, Day 1 through Week 24), and Table 3-4 (Treatment Period, 
Week 25 through Safety Follow-up). All visits will be scheduled relative to the Day 1 Visit in 
this study. 
Except where specified otherwise, assessments may be performed in any order when more than 
1 assessment is required at a particular time point. All assessments will be performed before 
study drug dosing (Section 9.6), unless noted otherwise. 
Table 3-1 
Study VX22-864-108: Screening for Subjects Who Have Received 
Augmentation Therapy Within 42 Days Before the Initial Screening Visit 
Event/Assessment 
Screening Perioda 
Day -70 through Day -1 
Comments 
Informed consent  
X 
 
Demographics 
X 
Section 11.2 
Medical history 
X 
Medications review 
X 
Section 9.5 
Prior augmentation therapy 
review 
X 
Subjects must discontinue augmentation therapy 
>42 days before the levels of antigenic AAT are 
obtained to determine eligibility.  
Section 9.1.1.1 and Figure 9-2 
Height and weight 
X 
Height and weight will be measured with shoes 
off. Section 11.6.6  
Vital signs 
X 
Complete before blood draws after subject has 
rested for ≥5 minutes.  
Sections 11.6.3 and 11.6.4 
Pulse oximetry 
X 
Physical examination 
X 
Section 11.6.3 
Standard 12-lead ECG 
X 
Performed in triplicate, with subject in supine 
position after resting for ≥5 minutes. Performed 
prior to blood draws. Section 11.6.5 
Spirometry 
X 
To be performed according to ATS/ERS 
guidelines. A historical ppFEV1 result within 
1 year prior to the first Screening Visit can be used 
to establish eligibility. Section 11.6.7 
Urine β-hCG  
X 
All female subjects; Section 11.6.2 
 
a  The Screening Period may require multiple visits to complete assessments and to enable scheduling and 
completion of the pretreatment liver biopsy before Day 1 dosing (Table 3-3). Screening Period may be extended 
as described in Section 9.1.1.6. 

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Table 3-1 
Study VX22-864-108: Screening for Subjects Who Have Received 
Augmentation Therapy Within 42 Days Before the Initial Screening Visit 
Event/Assessment 
Screening Perioda 
Day -70 through Day -1 
Comments 
Serum FSH  
X 
Obtained to confirm postmenopausal status in 
female subjects who have spontaneous 
amenorrhea for ≥12 months without an alternative 
cause and do not have a history of bilateral 
oophorectomy or hysterectomy. If a subject has a 
previous documented FSH result within the 
performing laboratory’s range for postmenopausal 
females, this assessment does not need to be 
repeated. Section 11.6.2 
Serum chemistry 
X 
All subjects must complete a safety laboratory test 
panel (Table 11-2) at the first screening visit to 
establish eligibility.  
If serum chemistry (Table 11-2) was completed 
more than 28 (+7) days before Day 1 dosing, the 
LFT panel (Table 11-3) must be completed within 
28 (+7) days before Day 1 dosing 
(Section 9.1.1.3). 
Section 11.6.2 
Hematology 
X 
Coagulation 
 
X 
 
Drug test (urine or blood), 
including cotinine 
X 
Section 11.6.2 
Alcohol test (urine, blood, or 
breath) 
X 
Serology (HbsAg, HCV RNA, 
and HIV-1/HIV-2 Abs) 
X 
Urinalysis 
X 
PiZZ genotyping 
X 
• 
Sample must be collected and tested at the 
central laboratory for all subjects, except 
subjects with historical evidence provided 
from another Vertex study.  
• 
A historical genotype (not from another 
Vertex study) may be used to establish 
eligibility with medical monitor approval. 
Subjects who have been enrolled, and whose 
screening genotype from the central 
laboratory does not confirm study eligibility, 
must be discontinued from the study.  
• 
PiZZ genotype must be confirmed in all 
subjects. In Group A subjects, it must be 
confirmed before Day 1 dosing. In Group B 
subjects, it must be confirmed prior to the 
pretreatment liver biopsy. 
See Section 8.1, Inclusion Criterion #4 
Sites should allow at least 14 days for sample 
processing and results reporting. 
Blood sample for antigenic 
AAT  
X 
Samples for antigenic and functional AAT will be 
obtained at the same time.  

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Table 3-1 
Study VX22-864-108: Screening for Subjects Who Have Received 
Augmentation Therapy Within 42 Days Before the Initial Screening Visit 
Event/Assessment 
Screening Perioda 
Day -70 through Day -1 
Comments 
Blood sample for functional 
AAT  
X 
Blood samples will be obtained for antigenic AAT 
and sent to the central laboratory at the initial 
screening visit. If this sample is obtained ≤42 days 
after the last dose of augmentation therapy, 
another sample must be drawn >42 days after the 
last dose of augmentation therapy to confirm 
eligibility in all subjects. In Group A subjects, it 
must be confirmed before Day 1 dosing. In 
Group B subjects, it must be confirmed prior to the 
pretreatment liver biopsy.  
Sites should allow at least 14 days for sample 
processing and results reporting. 
See Figure 9-2 and Sections 11.1 and 11.4.1 for 
details. 
Blood sample for Z-polymer  
X 
Section 11.4.1 
Adverse events 
Continuous from signing 
of ICF through 
completion of study 
participation 
Section 11.6.1 
AAT: alpha-1 antitrypsin; ATS: American Thoracic Society; β-hCG: beta-human chorionic gonadotropin; 
ERS: European Respiratory Society; FSH: follicle-stimulating hormone; HbsAg: hepatitis B surface antigen; 
HCV RNA: hepatitis C virus ribonucleic acid; HIV-1/HIV-2 Abs: antibodies against human immunodeficiency 
viruses 1 and 2; ICF: informed consent form; LFT: liver function test; ppFEV1: percent predicted forced 
expiratory volume in 1 second 
 

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Table 3-2 
Study VX22-864-108: Screening for Subjects Who Have Not Received 
Augmentation Therapy Within 42 Days Before the Initial Screening Visit 
Event/Assessment 
Screening Perioda 
Day -28 through Day -1 
Comments 
Informed consent  
X 
 
Demographics 
X 
Section 11.2 
Medical history 
X 
Medications review 
X 
Section 9.5 
Prior augmentation therapy 
review 
X 
Section 9.1.1.2 and Figure 9-3 
Height and weight 
X 
Height and weight will be measured with shoes 
off. Section 11.6.6  
Vital signs 
X 
Complete before blood draws after subject has 
rested for ≥5 minutes.  
Sections 11.6.3 and 11.6.4 
Pulse oximetry 
X 
Physical examination 
X 
Section 11.6.3 
Standard 12-lead ECG 
X 
Performed in triplicate, with subject in supine 
position after resting for ≥5 minutes. Performed 
prior to blood draws. Section 11.6.5 
Spirometry 
X 
To be performed according to ATS/ERS 
guidelines. A historical ppFEV1 result within 
1 year prior to the first Screening Visit can be used 
to establish eligibility. Section 11.6.7 
Urine β-hCG  
X 
All female subjects; Section 11.6.2 
Serum FSH  
X 
Obtained to confirm postmenopausal status in 
female subjects who have spontaneous 
amenorrhea for ≥12 months without an alternative 
cause and do not have a history of bilateral 
oophorectomy or hysterectomy. If a subject has a 
previous documented FSH result within the 
performing laboratory’s range for postmenopausal 
females, this assessment does not need to be 
repeated. Section 11.6.2 
Serum chemistry 
X 
All subjects must complete a safety laboratory test 
panel (Table 11-2) at the first screening visit to 
establish eligibility.  
If serum chemistry (Table 11-2) was completed 
more than 28 (+7) days before Day 1 dosing, the 
LFT panel (Table 11-3) must be completed within 
28 (+7) days before Day 1 dosing 
(Section 9.1.1.3). 
Section 11.6.2 
Hematology 
X 
Coagulation 
 
X 
 
Drug test (urine or blood), 
including cotinine 
X 
Section 11.6.2 
Alcohol test (urine, blood, or 
breath) 
X 
Serology (HbsAg, HCV RNA, 
and HIV-1/HIV-2 Abs) 
X 
 
a  The Screening Period may require multiple visits to complete assessments, and to enable scheduling and 
completion of the pretreatment liver biopsy before Day 1 dosing (Table 3-3). Screening Period may be extended 
as described in Section 9.1.1.6. 

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Table 3-2 
Study VX22-864-108: Screening for Subjects Who Have Not Received 
Augmentation Therapy Within 42 Days Before the Initial Screening Visit 
Event/Assessment 
Screening Perioda 
Day -28 through Day -1 
Comments 
Urinalysis 
X 
PiZZ genotyping 
X 
• 
Sample must be collected and tested at the 
central laboratory for all subjects, except 
subjects with historical evidence provided 
from another Vertex study.  
• 
A historical genotype (not from another 
Vertex study) may be used to establish 
eligibility with medical monitor approval.  
Subjects who have been enrolled, and whose 
screening genotype from the central 
laboratory does not confirm study eligibility, 
must be discontinued from the study.  
• 
PiZZ genotype must be confirmed in all 
subjects. In Group A subjects, it must be 
confirmed before Day 1 dosing. In Group B 
subjects, it must be confirmed prior to the 
pretreatment liver biopsy. 
See Section 8.1, Inclusion Criterion #4 
Sites should allow at least 14 days for sample 
processing and results reporting. 
Blood sample for antigenic 
AAT  
X 
Samples for antigenic and functional AAT will be 
obtained at the same time.  
Blood sample(s) for level of antigenic AAT will 
be obtained to determine eligibility in all subjects. 
In Group A subjects, it must be confirmed before 
Day 1 dosing. In Group B subjects, it must be 
confirmed prior to the pretreatment liver biopsy.  
Sites should allow at least 14 days for sample 
processing and results reporting. 
See Figure 9-3 and Sections 11.1 and 11.4.1 for 
details. 
Blood sample for functional 
AAT  
X 
Blood sample for Z-polymer  
X 
Section 11.4.1 
Adverse events 
Continuous from signing 
of ICF through 
completion of study 
participation 
Section 11.6.1 
AAT: alpha-1 antitrypsin; ATS: American Thoracic Society; β-hCG: beta-human chorionic gonadotropin; 
ERS: European Respiratory Society; FSH: follicle-stimulating hormone; HbsAg: hepatitis B surface antigen; 
HCV RNA: hepatitis C virus ribonucleic acid; HIV-1/HIV-2 Abs: antibodies against human immunodeficiency 
viruses 1 and 2; ICF: informed consent form; LFT: liver function test; ppFEV1: percent predicted forced 
expiratory volume in 1 second 
 

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4 
TABLE OF CONTENTS 
1 
Title Page ................................................................................................................................ 1 
2 
Protocol Synopsis ................................................................................................................... 4 
3 
Schedule of Assessments........................................................................................................ 8 
4 
Table of Contents ................................................................................................................. 23 
List of Tables............................................................................................................................ 26 
List of Figures .......................................................................................................................... 26 
List of Abbreviations................................................................................................................ 27 
5 
Introduction.......................................................................................................................... 30 
5.1 
Background ..................................................................................................................... 30 
5.2 
Study Rationale .............................................................................................................. 30 
6 
Study Objectives .................................................................................................................. 31 
6.1 
Primary Objective ........................................................................................................... 31 
6.2 
Secondary Objectives ..................................................................................................... 31 
7 
Study Endpoints ................................................................................................................... 31 
7.1 
Primary Endpoint ............................................................................................................ 31 
7.2 
Secondary Endpoints ...................................................................................................... 31 
8 
Study Population .................................................................................................................. 32 
8.1 
Inclusion Criteria ............................................................................................................ 32 
8.2 
Exclusion Criteria ........................................................................................................... 33 
9 
Study Implementation ......................................................................................................... 35 
9.1 
Study Design .................................................................................................................. 35 
9.1.1 
Screening ................................................................................................................ 36 
9.1.1.1 
Screening for Subjects Who Have Received Augmentation Therapy Within 
42 Days Before the Initial Screening Visit ...................................................... 36 
9.1.1.2 
Screening for Subjects Who Have Not Received Augmentation Therapy 
Within 42 Days Before the Initial Screening Visit .......................................... 37 
9.1.1.3 
LFT Panel Before Day 1 Dosing ...................................................................... 38 
9.1.1.4 
Repetition of Screening Assessment(s) ............................................................ 38 
9.1.1.5 
Rescreening ...................................................................................................... 39 
9.1.1.6 
Extension of the Screening Period ................................................................... 39 
9.1.2 
Treatment Period .................................................................................................... 39 
9.1.2.1 
Telephone Visits............................................................................................... 39 
9.1.3 
Use of Remote Measures ........................................................................................ 40 
9.1.3.1 
Home Health Follow-up Consultation With the Investigator .......................... 40 
9.1.4 
Safety Follow-up .................................................................................................... 40 
9.1.5 
Early Termination of Treatment ............................................................................. 40 
9.1.6 
Posttreatment Telemedicine Visit(s) ...................................................................... 41 
9.1.7 
Timing Under Extenuating Circumstances............................................................. 41 
9.1.8 
Lost to Follow-up ................................................................................................... 41 
9.1.9 
Completion of Study Participation ......................................................................... 41 
9.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 42 

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9.3 
Rationale for Study Elements ......................................................................................... 42 
9.3.1 
Study Population..................................................................................................... 42 
9.3.2 
Study Drug Dose and Duration .............................................................................. 42 
9.3.3 
Rationale for Study Assessments ........................................................................... 42 
9.4 
Study Restrictions ........................................................................................................... 42 
9.4.1 
Exposure to Sunlight .............................................................................................. 44 
9.5 
Prior and Concomitant Medications ............................................................................... 44 
9.6 
Administration ................................................................................................................ 44 
9.6.1 
Dosing ..................................................................................................................... 44 
9.7 
Dose Modification for Toxicity ...................................................................................... 44 
9.8 
Study Drug Interruption and Stopping Rules ................................................................. 44 
9.9 
Removal of Subjects ....................................................................................................... 46 
9.10 Replacement of Subjects ................................................................................................ 46 
10 Study Drug Information and Management ....................................................................... 47 
10.1 Preparation and Dispensing ............................................................................................ 47 
10.2 Packaging and Labeling ................................................................................................. 47 
10.3 Study Drug Supply, Storage, and Handling ................................................................... 47 
10.4 Drug Accountability ....................................................................................................... 47 
10.5 Disposal, Return, or Retention of Unused Drug ............................................................. 47 
10.6 Compliance ..................................................................................................................... 47 
10.7 Blinding and Unblinding ................................................................................................ 48 
11 Assessments .......................................................................................................................... 48 
11.1 Timing of Assessments ................................................................................................... 48 
11.2 Subject and Disease Characteristics ............................................................................... 49 
11.4 Efficacy ........................................................................................................................... 49 
11.4.1 
Blood Samples for Levels of Functional and Antigenic AAT and Z-polymer ...... 50 
11.4.2 
Percutaneous Liver Biopsy in Group B Only ......................................................... 50 
11.6 Safety .............................................................................................................................. 52 
11.6.1 
Adverse Events ....................................................................................................... 52 
11.6.2 
Clinical Laboratory Assessments ........................................................................... 52 
11.6.3 
Physical Examinations and Vital Signs .................................................................. 55 
11.6.4 
Pulse Oximetry ....................................................................................................... 55 
11.6.5 
Electrocardiograms ................................................................................................. 55 

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11.6.6 
Height and Weight .................................................................................................. 56 
11.6.7 
Spirometry .............................................................................................................. 56 
11.6.8 
Contraception and Pregnancy ................................................................................. 56 
11.6.8.1 Contraception ................................................................................................... 56 
11.6.8.2 Pregnancy ......................................................................................................... 58 
12 Statistical Analysis ............................................................................................................... 59 
12.2 Analysis Sets .................................................................................................................. 59 
12.3 Statistical Analysis ......................................................................................................... 60 
12.3.1 
General Considerations ........................................................................................... 60 
12.3.2 
Background Characteristics .................................................................................... 60 
12.3.3 
Efficacy Analysis .................................................................................................... 60 
12.3.3.1 Analysis of Primary Endpoint .......................................................................... 60 
12.3.3.2 Analysis of Secondary Efficacy Endpoints ...................................................... 61 
12.3.3.3 Multiplicity Adjustment ................................................................................... 61 
12.3.3.4 Missing Data Handling .................................................................................... 61 
12.3.4 
Safety Analysis ....................................................................................................... 61 
12.4 Interim Analysis ............................................................................................................. 61 
12.5 Data Monitoring Committee Analysis ............................................................................ 61 
13 Procedural, Ethical, Regulatory, and Administrative Considerations ........................... 62 
13.1 Adverse Event and Serious Adverse Event Documentation, Severity Grading, and 
Reporting ........................................................................................................................ 62 
13.1.1 
Adverse Events ....................................................................................................... 62 
13.1.1.1 Definition of an Adverse Event........................................................................ 62 
13.1.1.2 Clinically Significant Assessments .................................................................. 62 
13.1.1.3 Documentation of Adverse Events................................................................... 63 
13.1.1.4 Adverse Event Severity .................................................................................... 63 
13.1.1.5 Adverse Event Causality .................................................................................. 64 
13.1.1.6 Study Drug Action Taken ................................................................................ 64 
13.1.1.7 Adverse Event Outcome .................................................................................. 65 
13.1.1.8 Treatment Given............................................................................................... 65 
13.1.2 
Serious Adverse Events .......................................................................................... 65 
13.1.2.1 Definition of a Serious Adverse Event............................................................. 65 
13.1.2.2 Reporting and Documentation of Serious Adverse Events .............................. 66 
13.1.2.3 Expedited Reporting and Investigator Safety Letters ...................................... 67 
13.2 Administrative Requirements ......................................................................................... 67 
13.2.1 
Product Complaints ................................................................................................ 67 
13.2.2 
Ethical Considerations ............................................................................................ 67 
13.2.3 
Subject Information and Informed Consent ........................................................... 67 
13.2.4 
Investigator Compliance ......................................................................................... 68 
13.2.5 
Access to Records ................................................................................................... 68 
13.2.6 
Subject Privacy ....................................................................................................... 68 
13.2.7 
Record Retention .................................................................................................... 68 
13.2.8 
Study Termination .................................................................................................. 69 
13.2.9 
End of Study ........................................................................................................... 69 

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13.3 Data Quality Assurance .................................................................................................. 69 
13.4 Monitoring ...................................................................................................................... 69 
13.5 Electronic Data Capture ................................................................................................. 70 
13.6 Confidentiality and Disclosure ....................................................................................... 70 
13.7 Publications and Clinical Study Report .......................................................................... 70 
13.7.2 
Clinical Study Report ............................................................................................. 71 
14 References ............................................................................................................................. 72 
15 Protocol Signature Pages .................................................................................................... 73 
15.1 Sponsor Signature Page .................................................................................................. 73 
15.2 Investigator Signature Page ............................................................................................ 74 
 
List of Tables 
Table 3-1 
Study VX22-864-108: Screening for Subjects Who Have Received Augmentation 
Therapy Within 42 Days Before the Initial Screening Visit ................................... 8 
Table 3-2 
Study VX22-864-108: Screening for Subjects Who Have Not Received 
Augmentation Therapy Within 42 Days Before the Initial Screening Visit ......... 11 
Table 3-3 
Study VX22-864-108: Treatment Period, Day 1 through Week 24 ..................... 13 
Table 3-4 
Study VX22-864-108: Treatment Period, Week 25 through Safety Follow-Up .. 19 
Table 9-1 
Study Restrictions ................................................................................................. 42 
Table 11-1 
Acceptable Pharmacokinetic Sampling Windows ................................................ 49 
Table 11-2 
Safety Laboratory Test Panels .............................................................................. 53 
Table 11-3 
Liver Function Test Panel ..................................................................................... 53 
Table 11-4 
Safety Laboratory Tests to Investigate Transaminases Elevations ....................... 55 
Table 11-5 
Acceptable Methods of Contraception.................................................................. 57 
Table 13-1 
Grading of AE Severity ........................................................................................ 63 
Table 13-2 
Classifications for AE Causality ........................................................................... 64 
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE .................. 64 
Table 13-4 
Classifications for Outcome of an AE .................................................................. 65 
List of Figures 
Figure 2-1 
VX22-864-108 Study Design ................................................................................. 6 
Figure 2-2 
Recommended Order of Key Screening Assessments for Subjects Who Have 
Received Augmentation Therapy Within 42 Days Before the Initial Screening 
Visit ......................................................................................................................... 6 
Figure 2-3 
Recommended Order of Key Screening Assessments for Subjects Who Have Not 
Received Augmentation Therapy Within 42 Days Before the Initial Screening 
Visit ......................................................................................................................... 7 
Figure 9-1 
VX22-864-108 Study Design ............................................................................... 36 
Figure 9-2 
Recommended Order of Key Screening Assessments for Subjects Who Have 
Received Augmentation Therapy Within 42 Days Before the Initial Screening 
Visit ....................................................................................................................... 37 
Figure 9-3 
Recommended Order of Screening Assessments for Subjects Who Have Not 
Received Augmentation Therapy Within 42 Days Before the Initial Screening 
Visit ....................................................................................................................... 38 
 

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List of Abbreviations 
Abbreviation 
Definition 
AAT 
alpha-1 antitrypsin 
AATD 
alpha-1 antitrypsin deficiency 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ASMA 
anti-smooth muscle antibody 
AST 
aspartate transaminase 
ATS 
American Thoracic Society 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
CCP 
cyclic citrullinated peptide 
CI 
confidence interval 
CMV 
cytomegalovirus 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus-19 pandemic 
CPAP 
clinical pharmacology analysis plan 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRP 
C-reactive protein 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A 
cytochrome P450 3A 
d 
Day 
DNA 
deoxyribonucleic acid 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EENT 
eyes, ears, nose, and throat 
eGFR 
estimated glomerular filtration rate 
ERS 
European Respiratory Society 
ETT 
Early Termination of Treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLI 
Global Lung Function Initiative 
GPS 
Global Patient Safety 
HbsAg 
hepatitis B surface antigen 
HCV  
hepatitis C virus 

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Abbreviation 
Definition 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV-1/HIV-2 Abs 
antibodies against human immunodeficiency viruses 1 and 2 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IgA/G/M 
immunoglobulin A/G/M 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) (US) 
INR 
international normalized ratio 
IRB 
institutional review board 
LFT 
liver function test 
LKM-1 
liver-kidney microsomal type 1 
max 
maximum value 
min 
minimum value 
MMRM 
mixed-effects model for repeated measures 
n 
size of subsample 
N 
total sample size (e.g., number of subjects treated) 
NSAIDs 
nonsteroidal anti-inflammatory drug 
OATP1B1 
organic anion transporting polypeptide 1B1 
P 
probability 
PD 
pharmacodynamic, pharmacodynamics 
PE 
physical examination 
Pex 
pulmonary exacerbation 
PI 
principal investigator 
PiZZ 
homozygous for the Z mutation of the SERPINA1 gene that encodes the AAT protein 
ppFEV1 
percent predicted forced expiratory volume in 1 second 
q12h 
every 12 hours 
QT 
QT interval 
QTc 
QT interval corrected 
QTcF 
QT interval corrected by Fridericia’s formula 
RNA 
ribonucleic acid 
RNAi 
ribonucleic acid interference 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV2 
severe acute respiratory syndrome coronavirus 2 
SD 
standard deviation 
SS 
Safety Set 
SUSAR 
suspected, unexpected, serious adverse reaction 
TE 
treatment-emergent 

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Abbreviation 
Definition 
TEAE 
treatment-emergent adverse event 
UGT1A1/A4 
uridine diphosphate glucuronosyltransferase family 1 member A1/A4 
ULN 
upper limit of normal 
wk 
Week 
 

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inform future development of potential new small molecules in AATD. Hence, this study will 
evaluate VX-864 over a longer period than prior studies, i.e., 48 weeks in subjects with the PiZZ 
genotype. 
6 
STUDY OBJECTIVES 
6.1 
Primary Objective 
• To evaluate the efficacy of VX-864 on blood levels of functional AAT in individuals with 
the PiZZ genotype 
6.2 
Secondary Objectives 
• To evaluate the efficacy of VX-864 on blood levels of antigenic AAT in individuals with the 
PiZZ genotype  
• To evaluate the efficacy of VX-864 on blood levels of Z-polymer in individuals with PiZZ 
genotype 
• To evaluate the efficacy of VX-864 on liver Z-polymer in individuals with the PiZZ 
genotype (in Group B only) 
• To evaluate the safety and tolerability of VX-864 in individuals with the PiZZ genotype 
7 
STUDY ENDPOINTS 
7.1 
Primary Endpoint 
• Change from baseline in blood levels of functional AAT at Week 48 
7.2 
Secondary Endpoints 
• Change from baseline in blood levels of functional AAT over time 
• Change from baseline in blood levels of antigenic AAT over time 
• Change from baseline in blood levels of Z-polymer over time 
• Change from baseline in Z-polymer accumulation in the liver over time (in Group B only) 
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, 
standard 12-lead ECGs, and vital signs 

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8 
STUDY POPULATION 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
investigator’s team before subjects are enrolled. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible. 
8.1 
Inclusion Criteria 
1. Subject will sign and date an informed consent form (ICF).  
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines (Section 11.6.8.1), and other study procedures. 
3. In subjects not undergoing liver biopsies (Group A):  
• Subjects between the ages of 18 and 80 years, inclusive, at the time of ICF signing. 
 
In subjects undergoing liver biopsies (Group B): 
• Subjects between the ages of 18 and 70 years, inclusive at the time of the ICF signing.  
4. Subjects must have a PiZZ genotype confirmed during screening.  
• All subjects must have PiZZ genotype tested at the central laboratory, except for subjects 
who have had historical genotype results obtained via the central laboratory as part of 
another Vertex study. 
• A historical genotype (not from another Vertex study) may be used to establish eligibility 
with medical monitor approval. Subjects who have been enrolled, and whose screening 
genotype from the central laboratory does not confirm study eligibility, must be 
discontinued from the study.  
• In Group A subjects, the PiZZ genotype must be confirmed before Day 1 dosing. In 
Group B subjects, the PiZZ genotype must be confirmed prior to the pretreatment liver 
biopsy. 

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5. In subjects not undergoing biopsies (Group A) 
• A forced expiratory volume in 1 second (FEV1) value ≥30% of predicted mean for age, 
sex, and height (equations of the Global Lung Function Initiative [GLI]) during screening 
or a historical result within 1 year before the initial Screening Visit. Post-bronchodilator 
spirometry measurements must meet American Thoracic Society (ATS)/European 
Respiratory Society (ERS) criteria for acceptability and repeatability.  
In subjects undergoing biopsies (Group B) 
• An FEV1 value ≥40% of predicted mean for age, sex, and height (equations of the GLI) 
during screening or a historical result within 1 year before the initial Screening Visit. 
Post-bronchodilator spirometry measurements must meet ATS/ ERS criteria for 
acceptability and repeatability. 
6. Body mass index (BMI) of 18.0 to 35 kg/m2, inclusive. 
7. Screening antigenic AAT <8 µM. For subjects who have received augmentation therapy 
within 42 days before the initial screening visit, results used to confirm eligibility must be 
drawn >42 days after the last dose of augmentation therapy. Levels of antigenic AAT must 
be obtained from the central laboratory and results confirmed in all subjects. In Group A 
subjects, it must be confirmed prior to Day 1. In Group B subjects, it must be confirmed prior 
to the pretreatment liver biopsy. 
8.2 
Exclusion Criteria 
1. History of any illness or any clinical condition that, in the opinion of the investigator or the 
subject’s general practitioner, might confound the results of the study or pose an additional 
risk in administering study drug to the subject. This may include, but is not limited to, history 
of relevant drug or food allergies; history of cardiovascular or central nervous system 
disease; history or presence of clinically significant pathology; history of mental disease; and 
history of cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 
cervical carcinoma in situ (all 3 with no recurrence for the last 5 years). 
2. Solid organ or hematological transplantation or is currently on a transplant list.  
3. Subjects who have undergone gastrectomy or major resection of the small bowel or proximal 
colon. 
4. All clinically important pulmonary disease as deemed by investigator, including but not 
limited to unstable AATD‑related chronic obstructive pulmonary disease (COPD), interstitial 
lung disease, cystic fibrosis, pulmonary hypertension with or without cor pulmonale, history 
of pulmonary embolism, or malignant lung cancer.  
5. Subjects for whom discontinuation of augmentation therapy is not considered to be in their 
best interest, based on the clinical judgement of the treating physician. 
6. Only in subjects undergoing liver biopsies (in Group B), any contraindication to a 
percutaneous liver biopsy including a bleeding diathesis, ascites, or chronic need for 
treatment with anti-coagulants or anti-platelet agents. 
7. Current diagnosis of active hepatitis and/or significant chronic liver disease of any etiology 
other than AATD-associated non-cirrhotic liver disease including, but not limited to hepatic 
cirrhosis, portal hypertension, or confirmed or suspected esophageal varices.  

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8. History of Gilbert’s Syndrome. 
9. History of use of gene therapy or RNAi therapy at any time previously. 
10. Hypersensitivity to any component of the investigational drug product. 
11. History of significant alcohol consumption within 3 months before screening, defined as 
more than 1 drink/day for females or 2 drinks/day for males (1 drink = 5 ounces [150 mL] of 
wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor), or alcohol 
consumption during the study that is not compliant with the protocol-defined restriction 
(Table 9-1). 
12. Use of oral corticosteroids (at any dose) for a duration of greater than 3 months at any time 
within the 3 months before screening. 
13. Use of inhaled cannabis within the 6 months before screening, or illegal drugs within 1 year 
before screening as deemed by the investigator (use of non-inhaled, ingestible forms of 
cannabis-containing products are not exclusionary if legal in the subject’s region).  
14. Risk factors for Torsade de Pointes (e.g., familial long QT syndrome, chronic hypokalemia, 
heart failure) or concomitant medications that prolong the QT/QTc interval or any history of 
unstable cardiac disorder that, in the opinion of the investigator, might put the subject at risk 
or may confound the results of the study.  
15. Any clinically significant ECG abnormality (as determined by the investigator) or median 
QTcF of triplicate standard 12-lead ECGs >450 msec at screening.  
16. Any of the following abnormal laboratory values at screening: 
• Platelet count <150 × 109/L 
• Albumin <3.5 g/dL 
• International normalized ratio (INR) ≥1.2 
• Hemoglobin <10 g/dL for women and <12 g/dL for men 
• Total bilirubin >upper limit of normal (ULN) 
• Aspartate transaminase (AST), alanine transaminase (ALT), or alkaline phosphatase 
(ALP) >2 × ULN 
• Gamma-glutamyl transferase (GGT) >2 × ULN 
• Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2 (calculated by the 
Modification of Diet in Renal Disease Study equation)  
17. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) RNA, or 
antibodies against human immunodeficiency viruses 1 and 2 (HIV-1/HIV-2 Abs) during 
screening.  
18. Cigarette smoking during the past 6 months or a positive cotinine test at screening that is due 
to smoking or an electronic nicotine delivery system. Positive cotinine test due to nicotine 
replacement therapy for the purposes of smoking cessation, as attested by the investigator, is 
permitted. 
19. Use of the substances, activities, or devices during the time periods indicated in Section 9.4. 

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20. Ongoing or prior participation in a study of an investigational treatment within 28 days or 
5 terminal half-lives (whichever is longer) before screening. The duration of the elapsed time 
may be longer if required by local regulations. For subjects who have participated in a prior 
Vertex study, approval of the medical monitor is required. 
21. All female subjects must have a negative pregnancy test at screening. Premenopausal female 
subjects of child-bearing potential must also have a negative pregnancy test (urine or serum 
test) on Day 1 and must not be breastfeeding or planning to become pregnant during the 
study or within 90 days after the last study drug dose. 
Male subjects who plan to donate sperm or who have a female partner who is pregnant, 
nursing, or planning to become pregnant during the study or within 90 days after the last 
study drug dose. 
22. Subject or close relative of the subject is the investigator or a sub-investigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of 
the study at that site. 
9 
STUDY IMPLEMENTATION 
9.1 
Study Design 
This is a Phase 2, open-label, multicenter study. A schematic of the study design is shown in 
Figure 9-1. Approximately 20 subjects with the PiZZ genotype will be enrolled. Groups A and B 
will enroll approximately 10 subjects each. All subjects will receive VX-864 500 mg every 
12 hours (q12h) for 48 weeks. Group A subjects will not have a liver biopsy. Subjects in 
Group B will have 2 liver biopsies performed over the course of the study. All liver biopsies will 
be performed percutaneously. All subjects in Group B (approximately 10 subjects) will have a 
liver biopsy during the Pretreatment Interval (Figure 9-1). Approximately 5 subjects (Cohort B1) 
will have a second liver biopsy at Week 24. Approximately 5 subjects (Cohort B2) will have a 
second liver biopsy at Week 48. The pretreatment liver biopsy must be performed at least 7 days 
before Day 1 dosing, after all eligibility criteria have been met. Local laboratory hematology and 
coagulation results must be collected and reviewed by investigator within approximately 
48 hours prior to the liver biopsy being performed. The Week 24 and Week 48 liver biopsies will 
be performed 3 hours (±30 minutes) postdose relative to the morning dose. The Safety Follow-up 
Visits are required for all subjects. In subjects who terminate their participation early, the ETT 
visit, which may be conducted at the site or by telephone or video interview, replaces the Safety 
Follow-up Visits, if the ETT Visit occurs 3 weeks or later following the last dose of study drug. 
All subjects may also consent to the posttreatment Telemedicine Visit(s) following final dose of 
study drug, to monitor for development of AEs of rash (for up to 6 months) and monitor any 
ongoing AEs of rash (for up to 6 months following resolution of AEs of rash; see Section 9.1.6). 

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Figure 9-1 
VX22-864-108 Study Design 
n: size of subsample; N: number of subjects 
Note: Figure is not drawn to scale. 
a 
In subjects not requiring augmentation therapy washout, the Screening Period will be up to 28 days. In 
subjects requiring augmentation therapy washout, the Screening Period will be up to 70 days. 
b 
Day -14 to Day -7; pretreatment liver biopsy must be performed at least 7 days before Day 1 dosing. 
c 
There will be no further dosing in this study as of 25 September 2023. All subjects may consent to the 
posttreatment Telemedicine Visit(s) following final dose of study drug, to monitor for development of AEs 
of rash (for up to 6 months) and monitor any ongoing AEs of rash (for up to 6 months following resolution of 
AEs of rash; see Section 9.1.6). 
9.1.1 
Screening 
The Screening Period may require multiple visits to complete assessments, and to enable 
evaluation of eligibility (Table 3-1 and Table 3-2). Please note, there will be no further 
enrollment of subjects in this study. 
9.1.1.1 
Screening for Subjects Who Have Received Augmentation Therapy 
Within 42 Days Before the Initial Screening Visit 
The Screening Period may be up to 70 days in duration (Day -70 through Day -1) for subjects 
who are discontinuing augmentation therapy. This is to accommodate an appropriate washout of 
augmentation therapy that is ≥42 days in duration, enable enough time to perform all required 
screening assessments which will require multiple visits during screening, and to enable 
scheduling of the pretreatment liver biopsy (Table 3-1). 
Figure 9-2 displays the general recommended order of key screening assessments for subjects 
who are discontinuing augmentation therapy for subjects screening for enrollment in Groups A 
or B. 
Blood samples will be obtained for antigenic AAT at the initial Screening Visit. If the subject 
received the last dose of augmentation therapy >42 days prior to sample collection, these results 
can be used to determine eligibility. If this sample is obtained ≤42 days after the last dose of 
augmentation therapy, another sample must be drawn >42 days after the last dose of 
augmentation therapy to confirm eligibility.  

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Figure 9-2 
Recommended Order of Key Screening Assessments for Subjects Who 
Have Received Augmentation Therapy Within 42 Days Before the Initial 
Screening Visit 
AAT: alpha-1 antitrypsin; β-hCG: beta-human chorionic gonadotropin; FSH: follicle-stimulating hormone; LFT: 
liver function test 
Note: Figure not drawn to scale. Sites should allow at least 14 days for sample processing and results 
reporting for level of antigenic AAT and the PiZZ genotype. 
a 
Safety assessments include height and weight, vital signs, pulse oximetry, physical examination, ECG, FSH, 
β-hCG, serology, serum chemistry, hematology, coagulation, and urinalysis. 
b 
If serum chemistry (Table 11-2) was completed more than 28 (+7) days before Day 1 dosing, the LFT panel 
(Table 11-3) must be completed within 28 (+7) days before Day 1 dosing (Section 9.1.1.3). 
c 
In Group B only, the pretreatment liver biopsy must be performed at least 7 days before Day 1 dosing, after 
all eligibility criteria have been met. Local laboratory hematology and coagulation results must be collected 
and reviewed by investigator within approximately 48 hours prior to the liver biopsy being performed.  
9.1.1.2 
Screening for Subjects Who Have Not Received Augmentation 
Therapy Within 42 Days Before the Initial Screening Visit 
For subjects who were not on augmentation therapy and hence do not require a washout period, 
the Screening Period will be up to 28 days in duration (Day -28 through Day -1). 
Figure 9-3 displays the general recommended order of screening assessments for subjects who 
are not discontinuing augmentation therapy for subjects screening for enrollment in Groups A or 
B.  

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Figure 9-3 
Recommended Order of Screening Assessments for Subjects Who Have 
Not Received Augmentation Therapy Within 42 Days Before the Initial 
Screening Visit 
 
AAT: alpha-1 antitrypsin; β-hCG: beta-human chorionic gonadotropin; FSH: follicle-stimulating hormone; LFT: 
liver function test 
Note: Figure not drawn to scale. Sites should allow at least 14 days for sample processing and results 
reporting for level of antigenic AAT and the PiZZ genotype. 
a 
Safety assessments include height and weight, vital signs, pulse oximetry, physical examination, ECG, FSH, 
β-hCG, serology, serum chemistry, hematology, coagulation, and urinalysis. 
b 
If serum chemistry (Table 11-2) was completed more than 28 (+7) days before Day 1 dosing, the LFT panel 
(Table 11-3) must be completed within 28 (+7) days before Day 1 dosing (Section 9.1.1.3). 
c 
In Group B only, the pretreatment liver biopsy must be performed at least 7 days before Day 1 dosing, after 
all eligibility criteria have been met. Local laboratory hematology and coagulation results must be collected 
and reviewed by investigator within approximately 48 hours prior to the liver biopsy being performed. 
9.1.1.3 
LFT Panel Before Day 1 Dosing 
If serum chemistry (Table 11-2) was completed more than 28 (+7) days before Day 1 dosing, the 
liver function test (LFT) panel (Table 11-3) must be completed within 28 (+7) days before Day 1 
dosing. If an LFT panel is completed, the following results must be met before the subject may 
proceed to dosing on Day 1: 
• ALT and AST ≤2 × ULN  
• Total bilirubin ≤ULN  
If the LFT panel results preclude the subject from proceeding to Day 1 dosing, the LFT panel 
may be repeated every 3 to 4 days until the above criteria are met.  
9.1.1.4 
Repetition of Screening Assessment(s) 
Repeating individual screening assessment(s) that did not meet eligibility criteria is not 
permitted, with the following exceptions: 
• If there is clear evidence of a damaged sample, laboratory error, equipment malfunction, or if 
the investigator believes the result is not consistent with the subject’s current medical 
condition or historic result, collection of a repeat sample for the appropriate laboratory test or 
assessment may be permitted. 
• Spirometry, which may be retested once. 
• Exclusionary ALT, AST, GGT, total bilirubin, ALP, INR, platelet, hemoglobin, albumin, or 
eGFR test results, which may be retested once. 

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• Exclusionary ECG test results, which may be retested once. 
• Screening levels of antigenic AAT performed to determine eligibility may be repeated.  
The repeat screening assessment or blood sample may be conducted or drawn, respectively, at 
the clinic or at home by a qualified visiting nurse, where permitted by local regulations. If repeat 
values of the individual assessment(s) are within the eligibility criteria and completed within the 
screening window, then the subject is eligible for the study. 
9.1.1.5 
Rescreening 
Subjects may be rescreened only once for non-safety assessments, except if subject experiences a 
pulmonary exacerbation (PEx) during the first rescreening, or in the event the clinical site closes 
or becomes not operational during the first rescreening due to unforeseen reasons (e.g., COVID-
19 associated shutdown of site) in which case the subjects may be rescreened more than once. If 
a subject is rescreened, all screening assessments will be repeated, except for:  
• PiZZ genotyping 
• Follicle-stimulating hormone (FSH) level (if serum FSH level was in the postmenopausal 
range as determined by the laboratory performing the test during prior screening) 
If a subject is rescreened, a new screening window will begin when the first rescreening 
assessment has been initiated. 
9.1.1.6 
Extension of the Screening Period 
A subject may have the Screening Period window extended by 2 weeks without medical monitor 
approval for the following reasons: 
• Repetition of Screening Period assessments (Section 9.1.1.4) 
• A PEx during the Screening Period 
• Unexpected operational or logistic delays, or to meet the eligibility criteria. 
Subjects who have not received augmentation therapy within 42 days before the initial Screening 
Visit may have the Screening Period window extended for an additional 2 weeks (total of 
4 weeks extension) with medical monitor approval. 
9.1.2 
Treatment Period 
Treatment Period assessments are listed in Table 3-3 and Table 3-4 (Day 1 through Week 48 
Visit).  
Completion of study participation is defined in Section 9.1.9. 
9.1.2.1 
Telephone Visits 
For female subjects of childbearing potential only, the result from the urine home pregnancy test 
kit will be reported by the subject to the study site at these telephone visits.  
In subjects who consent to the posttreatment Telemedicine Visit(s), this visit may be conducted 
as a telephone or video interview, as detailed in Section 9.1.6. Urine pregnancy tests will not be 
required for these visits. 

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9.1.3 
Use of Remote Measures 
The initial Screening Visit and study visits on Day -14 to Day -7 (in Group B only), Day 1, 
Weeks 24, 48, and Safety Follow-up must be performed in the clinic, even under extenuating 
circumstances. However, at Screening Visits (other than the initial visit) when the assessments 
are feasible to conduct in the home setting, and at other study visits as specified in Table 3-3 and 
Table 3-4 where permitted by local regulations, study assessments may be performed remotely 
(i.e., home visit). The decision to conduct study visits remotely or in clinic will be at the 
discretion of the investigator after consultation with the subject.  
Early Termination of Treatment (ETT) visit may be performed by telephone or video. 
If local regulations or site practice do not allow remote measures, all study visits will be 
performed in the clinic. 
9.1.3.1 
Home Health Follow-up Consultation With the Investigator 
Following all home visits, the investigator or qualified designee will review all source 
documentation associated with the assessments performed at the home visit. The investigator or 
qualified designee will then engage the subject in a telephone call, telemedicine video 
conference, or in person within 5 business days after the home visit. This consultation may occur 
outside the visit window. The home health follow-up consultation with the investigator or 
qualified designee may include, but is not limited to, verbal confirmation of safety assessments 
and study compliance information as appropriate. The investigator or qualified designee will 
follow up on any assessments that were not performed as scheduled. Additional details will be 
provided in the Study Reference Manual. 
9.1.4 
Safety Follow-up 
The Safety Follow-up Visits are scheduled to occur 14 and 28 (± 2) days after the last dose of 
study drug. The Safety Follow-up Visit assessments are listed in Table 3-4.  
The Safety Follow-up Visits are required for all subjects. 
9.1.5 
Early Termination of Treatment  
If a subject prematurely discontinues study treatment, an ETT Visit should be scheduled as soon 
as possible after the decision to discontinue study drug treatment. Subjects who prematurely 
discontinue study drug treatment will also be required to complete the Safety Follow-up Visits, 
approximately 14 and 28 (± 2) days after their last dose of study drug. 
If the ETT Visit occurs 3 weeks or later following the last dose of study drug, then the ETT Visit 
will replace the Safety Follow-up Visits, and a separate Safety Follow-up Visit will not be 
required. The ETT visit may be performed at the site or by telephone or video. 
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends, and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study (Section 9.9), the study data and samples collected will remain part of the study. 

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9.1.6 
Posttreatment Telemedicine Visit(s) 
In subjects who consent to the posttreatment Telemedicine Visit(s), current status of symptoms 
from resolved or ongoing AEs of rash will be discussed via a telephone or video interview, 
which may consist of multiple telemedicine visits, if necessary according to AE resolution status.  
This telemedicine visit will be 6 months after last dose or AE of rash resolution as follows: 
• subjects with no AEs of rash are to be followed for up to 6 months after the last dose of study 
drug 
• subjects with AEs of rash are to be followed for up to 6 months following resolution of their 
respective AE(s) of rash 
Recommended precautions for exposure to sunlight (Section 9.4.1) should be followed through 
the final posttreatment Telemedicine Visit. Subjects should also be instructed to contact the 
investigational site if they develop new or worsening rash. 
9.1.7 
Timing Under Extenuating Circumstances 
In the event that extenuating circumstances (e.g., events related to COVID-19) or unforeseen 
conditions (e.g., natural disasters or unforeseen external factors impacting clinical site) alter the 
timing of a scheduled visit being conducted, the investigator should notify the medical monitor, 
and the visit window specified in the Schedule of Assessments during the Treatment Period may 
be expanded by up to ± 7 days upon consultation with the investigator and medical monitor.  
For study visits requiring a liver biopsy, the visit will be rescheduled upon consultation with the 
investigator and medical monitor.  
9.1.8 
Lost to Follow-up 
A subject will be considered lost to follow-up if both of the following occur: 
• The subject misses 2 consecutive study visits (telephone contact, clinic, and/or home visit) 
and is subsequently unable to be contacted by telephone (3 documented attempts by 
telephone within 2 weeks following the second missed visit) 
• The subject does not respond within 2 weeks to a registered letter sent after the 3 attempted 
telephone contacts. 
9.1.9 
Completion of Study Participation 
Completion of study participation for each individual subject is defined as one of the following:  
• For subjects who complete the Treatment Period: the last Safety Follow‑up Visit. 
• For subjects who prematurely discontinue study drug treatment but do not withdraw consent, 
the latest of the following: the Week 48 Visit, ETT Visit, or the last Safety Follow‑up Visit 
(if required), or the last posttreatment Telemedicine Visit. 
• For subjects who withdraw consent: the date of withdrawal of consent (Section 9.9). 
If subjects are lost to follow-up (Section 9.1.8), the date of completion of study participation will 
be defined as the date of last contact.  
The end of study is defined in Section 13.2.9. 

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Table 9-1 
Study Restrictions 
Restricted Medication/Food/Activity a 
Timing of Restriction 
Start 
Stop 
UGT1A1/UGT1A4 moderate and strong 
inhibitors  
7 days or 5 half-lives (whichever is 
longer) before the first dose of study drug 
28 days after final 
dose of study drug 
UGT1A1/UGT1A4 moderate and strong 
inducers 
14 days before the first dose of study drug 
Prescription or nonprescription NSAIDs, 
anti-coagulants, or anti-platelet agents 
(e.g., warfarin, clopidogrel, aspirin, 
ibuprofen) 
10 days before liver biopsy e 
28 days after final 
dose of study drug 
Other investigational drugs or devices 
28 days before screening, 5 half-lives 
before screening, or time determined by 
local requirements (whichever is longer) 
28 days after final 
dose of study drug 
Augmentation therapy  
(human alpha-1 proteinase inhibitor) 
More than 42 days before level of 
antigenic AAT is obtained for eligibility 
28 days after final 
dose of study drug 
Tobacco products, including use of 
electronic tobacco devices, 
e.g., e-cigarettes d 
6 months before screening 
28 days after final 
dose of study drug 
Inhaled cannabis 
6 months before screening 
28 days after final 
dose of study drug 
Alcohol: no more than 1 drink/day for 
females or 2 drinks/day for males 
(1 drink = 5 ounces [150 mL] of wine or 
12 ounces [360 mL] of beer or 1.5 ounces 
[45 mL] of hard liquor) 
Signing of ICF 
28 days after final 
dose of study drug 
AAT: alpha-1 antitrypsin; ICF: informed consent form; NSAID: nonsteroidal anti-inflammatory drug; 
UGT1A1/A4: uridine diphosphate glucuronosyltransferase family 1 member A1/A4 
a 
See Section 9.5 for guidance on concomitant medications.  
b 
Chronic use of corticosteroids is prohibited with the exception that subjects may receive doses of prednisone 
or prednisolone of up to 5 mg/day chronically. Use of rosuvastatin at doses of up to 10 mg/day, and 
atorvastatin at doses of up to 20 mg/day is permitted. Also, an acute course of corticosteroids (as described in 
Section 9.5) as standard of care to treat a pulmonary exacerbation is permitted (dose and duration per 
investigator judgment in consultation with the Sponsor). In addition, use of inhaled fluticasone propionate 
and inhaled salmeterol are prohibited. 
c 
In Group B only, sedation and local anesthesia (e.g., midazolam, fentanyl, local lidocaine) used for the liver 
biopsy procedure are allowed. Low-dose non-NSAID pain medications (e.g., acetaminophen with codeine, 
oxycodone, acetaminophen with oxycodone) are allowed for post-procedure pain. VX-864 may cause 
increased exposure of sensitive CYP3A4 substrates. When utilizing sensitive CYP3A4 substrates for 
sedation, local anesthesia, or acute pain management, caution should be utilized and dose adjustments may 
be considered. 
d 
Nicotine replacement therapy under the direction of a physician is allowed. 
e 
During the Treatment Period, occasional, limited ibuprofen (≤1200 mg/day) use for pain is allowed in both 
Groups A and B. In Group B only, limited ibuprofen use for pain is allowed until 10 days before the liver 
biopsy, at which time all ibuprofen use is prohibited until 2 weeks after the liver biopsy.  
 

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9.4.1 
Exposure to Sunlight  
Subjects will take appropriate measures to minimize exposure to UVA/UVB radiation from 
Day 1 through the final posttreatment Telemedicine Visit. As a precaution, subjects should avoid 
being in strong direct sunlight and/or UVA/UVB exposure or use protective clothing, broad 
spectrum sunscreen (UVA + UVB coverage), and sunglasses from first dose until the final 
posttreatment Telemedicine Visit (Section 9.1.6).  
9.5 
Prior and Concomitant Medications 
Information regarding prior and concomitant medications, including any AATD medications or 
therapies, other medications, and herbal and naturopathic remedies, will be collected in each 
subject’s source documentation for medications taken within the 70 days before the first dose of 
study drug in this study through completion of study participation, as defined in Section 9.1.9. 
• Subjects should stop augmentation therapy regimen for at least 42 days prior to level of 
antigenic AAT sample collection used to determine eligibility, and refrain from restarting 
augmentation therapy until 28 days after final dose of study drug.  
• Subjects may receive doses of prednisone or prednisolone up to 5 mg/day chronically. 
• Subjects may receive an acute course of corticosteroids (prednisone, prednisolone, 
hydrocortisone, or triamcinolone only) as standard of care to treat a PEx (dose and duration 
per investigator judgement in consultation with the Sponsor).  
• Sedation and local anesthesia (e.g., midazolam, fentanyl, local lidocaine) used for the liver 
biopsy procedure (Group B only) are allowed. Low-dose non-nonsteroidal anti-inflammatory 
drug (NSAID) pain medications (e.g., acetaminophen with codeine, oxycodone, 
acetaminophen with oxycodone) are allowed for post-procedure pain. VX-864 may cause 
increased exposure of sensitive CYP3A4 substrates. When utilizing sensitive CYP3A4 
substrates for sedation, local anesthesia, or acute pain management, caution should be 
utilized and dose adjustments may be considered. 
Clinical experience suggests that VX-864 strongly inhibits CYP3A4 and may increase exposure 
of sensitive CYP3A4 substrates. Therefore, concomitant administration of sensitive CYP3A4 
substrates are prohibited (Table 9-1). VX-864 is a mild inhibitor of organic anion transporting 
polypeptide 1B1 (OATP1B1) and as such use of OATP1B1 substrates are permitted (except 
when also a substrate of CYP3A4). 
9.6 
Administration 
9.6.1 
Dosing 
There will be no further dosing in this study as of 25 September 2023. 
9.7 
Dose Modification for Toxicity 
No dose modifications for toxicity are allowed. Treatment may be interrupted as outlined in 
Section 9.8. If any unacceptable toxicity arises, individual subjects will discontinue dosing 
(Section 9.1.5). 
9.8 
Study Drug Interruption and Stopping Rules 
The medical monitor should be notified of an interruption of study drug for any reason and of the 
resumption of study drug after such interruption. 

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The investigator has the discretion to discontinue study drug treatment at any time if the 
investigator feels that the subject’s continued participation in the study jeopardizes the subject’s 
safety. 
Any subject with worsening of AATD or disease progression that, in the judgement of the 
treating physician, requires (re)initiation of standard of care treatment (per local guidelines) that 
is prohibited in this study (including AAT augmentation therapy) will discontinue study drug 
treatment, and will be discontinued from the study. 
Any subject with QTcF values above the threshold values as described in Section 11.6.5 will 
discontinue study drug treatment. 
On Day 1, urine and serum beta-human chorionic gonadotropin (β-hCG) tests will be performed 
and subsequently every 4 weeks, continuing through completion of study participation, a urine 
β-hCG test will be performed. If a urine pregnancy test is positive, all study drug dosing will 
stop, and the pregnancy will be confirmed with a serum β-hCG test. If pregnancy is confirmed, 
the procedures outlined in Section 11.6.8.2 will be followed.  
Study drug treatment may be interrupted for safety concerns at discretion of the investigator. 
Study drug administration must be interrupted immediately (before confirmatory testing), and the 
medical monitor must be notified, if any of the following criteria are met: 
• ALT or AST >5 × ULN  
• Total bilirubin >3 × ULN  
• ALT or AST >3 × ULN associated with total bilirubin >2 × ULN and/or clinical jaundice 
Subjects with new treatment-emergent ALT or AST elevations of >3 × ULN, or total bilirubin 
>2 × ULN, must be followed closely, including confirmatory testing performed within 2 to 
3 days of the initial finding and there must be close monitoring of ALT, AST, and bilirubin 
levels thereafter, as clinically indicated. 
If a subject cannot return to the site for confirmatory testing, a local laboratory may be used. 
Local laboratory results must be reported immediately to the medical monitor, and the subject 
must have the tests repeated and sent to the central laboratory as soon as possible (ideally within 
2 to 3 days).  
In subjects who met the interruption criteria listed above, transaminase and/or bilirubin levels 
must be assessed at a frequency of every 3 to 4 days until the elevations return to normal limits 
or the subject’s baseline levels, whichever is higher, and the subject must be followed closely for 
clinical progression. A thorough investigation of potential causes must be conducted. The 
investigation will include (but will not be limited to) the following: clinical chemistry, 
hematology and coagulation panels as described in Table 11-2 (including bilirubin measured 
with the BILT3 assay), additional clinical laboratory tests as described in Table 11-4, a liver 
ultrasound scan, and a consultation with a hepatologist. The liver ultrasound scan, consultation 
with a hepatologist, and/or other tests may be waived with approval from medical monitor.  
• If an alternative, reversible cause of transaminase elevation and/or increased bilirubin has not 
been identified, study drug must be permanently discontinued. 

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• If an alternative, reversible cause of transaminase elevation and/or increased bilirubin has 
been identified, study drug administration may be resumed after transaminases and/or 
bilirubin return to baseline or are <ULN, whichever is higher. Approval of the medical 
monitor is required before resumption of study drug. Upon resumption of study drug, for 
the following 2 weeks, transaminases and bilirubin should be monitored every 3 to 4 days, 
and then weekly for another 2 weeks.  
If a protocol-defined transaminase and/or bilirubin elevation interruption threshold recurs, then 
study drug must be permanently discontinued, regardless of the presumed etiology. 
. 
9.9 
Removal of Subjects  
Subjects may withdraw from the study at any time at their own request. Subjects may be 
withdrawn from study drug treatment at any time at the discretion of the investigator or Vertex 
for safety, behavior, noncompliance with study procedures, or administrative reasons. If a subject 
has been withdrawn from study drug treatment, the reason for withdrawal should be documented 
and every effort should be made to continue to follow the subject until the end of the study. 
In addition, a subject must be discontinued from study drug treatment if the subject meets any of 
the following criteria: 
• Has a screening PiZZ genotype from the central laboratory that does not confirm study 
eligibility after a historical PiZZ genotype or was used to establish eligibility. These subjects 
must be discontinued from the study (Section 8.1). 
• Meets any of the stopping (discontinuation) criteria (Section 9.8) 
• Becomes pregnant (the subject or the female partner of a male subject; Section 11.6.8.2) 
If a subject does not return for a scheduled visit, reasonable effort will be made to contact the 
subject. In any circumstance, reasonable effort will be made to document subject outcome. The 
investigator will inquire about the reason for withdrawal, request that the subject return all 
unused investigational product(s), request that the subject return for a Safety Follow-up Visit, if 
applicable (see Section 9.1.5), and follow up with the subject regarding any unresolved AEs. 
If a subject withdraws consent for the study, no further assessments will be performed. Vertex 
may retain and continue using the study data and samples after the study ends and may use the 
samples and information in the development of the study compound, for other drugs and 
diagnostics, in publications and presentations, and for education purposes. If a subject withdraws 
from the study, the study data and samples collected will remain part of the study. A subject will 
not be able to request the withdrawal of his/her information from the study data. A subject may 
request destruction of the samples collected from him/her during the study as long as those 
samples can be identified as his/her samples. 
9.10 
Replacement of Subjects 
Subjects who withdraw or are withdrawn for nonsafety reasons during the study drug treatment 
period may be replaced at Vertex’s discretion. 

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10 
STUDY DRUG INFORMATION AND MANAGEMENT 
10.1 
Preparation and Dispensing 
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects. 
10.2 
Packaging and Labeling 
Vertex will supply the 100-mg or 250-mg VX‑864 tablets. Study drug labeling will be in 
compliance with applicable local and national regulations. Additional details about packaging, 
labeling, and dispensing for VX‑864 will be in the Pharmacy Manual. 
10.3 
Study Drug Supply, Storage, and Handling 
The investigator, or an authorized designee (e.g., a licensed pharmacist), will ensure that all 
investigational product is stored in a secured area, under recommended storage conditions, and in 
accordance with applicable regulatory requirements. To ensure adequate records, all study drugs 
will be accounted for via the drug accountability forms as instructed by Vertex. 
Detailed instructions regarding the storage, handling, and dispensation of the study drug will be 
provided in the Pharmacy Manual. 
10.4 
Drug Accountability 
The pharmacist or designated study site staff will maintain information regarding the dates and 
amounts of (1) study drug received; (2) study drug dispensed to the subjects; and (3) study drug 
returned by the subjects. A central pharmacy will be used for subjects opting to have home 
health visits. Subjects will be instructed to return all used and unused materials associated with 
the study drug to the home health nurse or site. These materials will be retained at the site or 
central pharmacy according to instructions provided by Vertex or its designee. The study monitor 
will review study drug records and inventory throughout the study. If a site or central pharmacy 
uses a site-specific drug accountability system and/or process, including processes associated 
with the destruction of returned materials, the process must be documented and approved by 
Vertex. The study monitor must review the drug accountability documentation on a regular basis. 
The study monitor will promptly communicate to Vertex any discrepancies he/she is unable to 
resolve with the site. 
10.5 
Disposal, Return, or Retention of Unused Drug 
The study site staff or pharmacy personnel will retain all materials returned by the subjects until 
the study monitor has performed drug accountability. The investigator will ensure that the 
materials are destroyed in compliance with applicable environmental regulations, institutional 
policy, and any special instructions provided by Vertex. Destruction will be adequately 
documented. 
The principal investigator (PI), study site staff, including pharmacy personnel will assist Vertex 
with any recall activities (as applicable) and place impacted investigational medicinal product 
(IMP) in quarantine when requested. 
10.6 
Compliance  
To ensure treatment compliance, the investigator or designee will supervise all study drug dosing 
that occurs at the site or in the subject’s home at required study visits. At each visit, site 

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personnel/home healthcare nurses will review that the subject is compliant with study drug 
dosing and remind the subject of study drug dosing requirements. Compliance will also be 
assessed by ongoing study drug count. 
If a subject demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the investigator will contact the medical monitor to discuss discontinuing the subject 
from the study. 
10.7 
Blinding and Unblinding 
This is an open-label study; however, subjects should not be informed of their study-related 
levels of functional and antigenic AAT, levels of blood Z-polymer, liver biopsy results, or 
during the Treatment Period, regardless if the subject permanently 
discontinues.  
Levels of antigenic AAT obtained during screening will be provided to study sites in order to 
confirm the subject’s eligibility to enroll in the study. All subsequent antigenic AAT results will 
not be disclosed to the study sites. Levels of functional AAT, levels of blood Z-polymer, and 
liver biopsy results will not be disclosed to the study sites.  
Access to restricted data: 
Levels of functional and antigenic AAT, levels of blood Z-polymer, and liver biopsy results 
(excluding quality control) will be considered as restricted data. During the conduct of the study, 
the Vertex study team will not have access to restricted data until the final analysis, with the 
exception of the screening levels of antigenic AAT. Shortly before any planned efficacy analysis 
of restricted data is conducted, the data will be reviewed for data cleaning purposes by a 
biostatistician who is not part of the study team. 
A limited Vertex team not directly involved in the conduct of the study may have access to levels 
of functional and antigenic AAT, levels of blood Z-polymer, liver biopsy results, 
 
safety data (e.g., AEs, clinical laboratory assessments) for continuous monitoring purposes. No 
results of analyses of restricted data will be shared with the study sites or with the Vertex study 
team. 
11 
ASSESSMENTS 
The schedule of assessments are shown in Table 3-1 through Table 3-4. 
11.1 
Timing of Assessments  
The initial screening visit and study visits on Day -14 to Day -7 (Pretreatment Interval), Day 1, 
Weeks 24, 48, and Safety Follow-up, must be performed in the clinic, even under extenuating 
circumstances. At all other visits, remote measures may be used. Rescreening and screening 
assessments that were not conducted at the initial visit may be conducted remotely when the 
assessments are feasible to conduct in the home setting, if agreed upon after investigator and 
subject consultation (Section 9.1.3), and only where permitted by local regulations.  
Early Termination of Treatment (ETT) may be performed by telephone or video visit. 
Repetition of eligibility assessments during the Screening Period is permitted per conditions 
described in Section 9.1.1.4. 

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11.2 
Subject and Disease Characteristics 
Subject and disease characteristics include the following: demographics, medical history, height, 
and weight. Cigarette and or e-cigarette smoking history (current smoker; ever smoker; never 
smoker) will be collected for each subject including time since quitting and pack-years and 
cartridge-years of smoking history (packs/day × number of years; cartridges/day × number of 
years). 
11.4 
Efficacy 
Blood levels of functional AAT, antigenic AAT, and Z-polymer, and the liver biopsy (Group B) 
will be performed to evaluate efficacy. The purpose of the liver biopsy is to enable evaluation of 
the efficacy of VX-864 on Z-polymer in the liver, 
 
 Each of these assessments are detailed below. 

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11.4.1 
Blood Samples for Levels of Functional and Antigenic AAT and 
Z-polymer 
Detailed procedures for the collection, processing, handling, and storage of blood samples for 
functional AAT, antigenic AAT, and Z-polymer levels will be provided 
 
.  
11.4.2 
Percutaneous Liver Biopsy in Group B Only 
Liver biopsies will be performed percutaneously. All subjects in Group B will have 2 liver 
biopsies performed during the study, including the first biopsy during the Pretreatment Interval 
(Day -14 to Day -7), and the second biopsy at either Week 24 or Week 48 of the Treatment 
Period. Specifically, approximately 5 subjects (Cohort B1) will have their second liver biopsy at 
Week 24, and approximately 5 subjects (Cohort B2) will have their second liver biopsy at 
Week 48. 
Biopsies will be used to evaluate Z-polymer accumulation in the liver, 
 
. 
, 
The timing of the biopsy relative to the last dose of study drug will be recorded. The liver biopsy 
should be performed 3 (±30 minutes) hours postdose relative to the morning dose.  
Detailed procedures for the collection of liver biopsy and further procedures for processing and 
handling of liver samples will be described in the Liver Biopsy Manual and 
 
.  

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11.6 
Safety 
Safety evaluations will include AEs, clinical laboratory assessments, clinical evaluation of vital 
signs, standard 12-lead ECGs, physical examinations (PEs), and pulse oximetry. 
11.6.1 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with current ICH E6 GCP 
Guidelines. Section 13.1 outlines the definitions, collection periods, criteria, and procedures for 
documenting, grading, and reporting AEs. A separate document that details AE CRF completion 
guidelines for investigators as well as training will be provided. 
11.6.2 
Clinical Laboratory Assessments 
Blood and urine samples will be analyzed at a central laboratory, with the exception of the urine 
pregnancy tests in all subjects, and hematology and coagulation laboratory assessments as 
appropriate for liver biopsies in Group B subjects. As described below, urine pregnancy tests will 
either be analyzed by the site or at home using a home kit. On Day 1, blood samples will be 
collected before the first dose of the study drug. At all other scheduled visits, these samples will 
be collected at any time during the visit. 
For purposes of study conduct, only laboratory tests done in the central laboratory may be used. 
Local laboratories may be used at the discretion of the local investigator for management of 
urgent medical issues, safety concerns, or under extenuating circumstances. If a local laboratory 
test value is found to be abnormal and clinically significant, it will be verified by the central 
laboratory as soon as possible after the investigator becomes aware of the abnormal result. If it is 
not possible to send a timely specimen to the central laboratory (e.g., the subject was hospitalized 
elsewhere), the investigator may base the assessment of an AE on the local laboratory value. 
The investigator will have access to all laboratory results for subjects from their site through the 
central laboratory portal. The central laboratory will additionally provide laboratory alerts to 
notify the investigator by email in the event of a laboratory result of potential clinical 
significance.  
Laboratory test results that are abnormal and considered clinically significant will be reported as 
AEs (see Section 13.1.1.2). 
The safety laboratory test panels are shown in Table 11-2. 

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Table 11-2 
Safety Laboratory Test Panels 
Serum Chemistry 
Hematology 
Urinalysisa 
Glucose 
Blood urea nitrogenb 
Creatinine 
Sodium 
Potassium  
Calcium  
Chloride  
Magnesium  
Bicarbonate  
Phosphate  
Total bilirubin (direct bilirubin, 
indirect bilirubin) 
Alkaline phosphatase  
Aspartate transaminase 
Alanine transaminase 
Amylase 
Lipase 
Gamma-glutamyl transferase  
Protein  
Albumin  
Creatine kinase 
Urate 
Cholesterol  
Triglycerides 
Low-density lipoprotein  
High-density lipoprotein 
C-reactive protein 
Hemoglobin 
Erythrocytes 
Mean corpuscular volume 
Platelets 
Reticulocytes 
Leukocytes 
Differential (absolute and percent): 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes  
Monocytes 
Coagulation 
Activated partial thromboplastin time  
Prothrombin time 
Prothrombin time International 
Normalized Ratio  
Leukocyte esterase  
Nitrite  
Urine protein  
Urine blood 
a 
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, microscopic examination of 
urine will be done, and results will be provided for leukocytes, erythrocytes, crystals, bacteria, and casts. 
b 
If blood urea nitrogen cannot be collected, urea may be substituted. 
Additional Tests at Screening:  
If serum chemistry (Table 11-2) was completed more than 28 (+7) days before Day 1 dosing, the 
LFT panel (Table 11-3) must be completed within 28 (+7) days before Day 1 dosing 
(Section 9.1.1.3). 
Table 11-3 
Liver Function Test Panel 
Serum Chemistry 
Total bilirubin (direct bilirubin, indirect bilirubin) 
Alkaline phosphatase  
Aspartate transaminase 
Alanine transaminase 
Gamma-glutamyl transferase  
 

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The following additional tests will be performed during screening to assess eligibility:  
• Serology test for HBsAg, HCV RNA, and HIV-1/HIV-2 Abs 
• Urine β-hCG for all female subjects  
• FSH: Blood samples for FSH will be obtained to confirm postmenopausal status in female 
subjects who have spontaneous amenorrhea for ≥12 months without an alternative cause and 
do not have a history of bilateral oophorectomy or hysterectomy. Serum FSH levels within 
the laboratory’s range for postmenopausal women can be used to confirm whether female 
subjects are of non-childbearing potential. If a subject has a previous documented FSH result 
within the performing laboratory’s range for postmenopausal females, this assessment does 
not need to be repeated. 
Pregnancy Testing for Female Subjects of Childbearing Potential (as defined in Section 11.6.8):  
• On Day 1, urine and serum β-hCG tests will be performed and subsequently every 4 weeks, 
continuing through completion of study participation, a urine β-hCG test will be performed. 
Urine home pregnancy test kits will be provided by the study site.  
• If a urine pregnancy test is positive, all study drug dosing will stop and the pregnancy will be 
confirmed with a serum β-hCG test. If pregnancy is confirmed, the procedures outlined in 
Section 11.6.8.2 will be followed. 
Drug and Alcohol Screening: Opiates, methadone, cannabinoids, cocaine, 
amphetamines/methamphetamines, barbiturates, benzodiazepines, cotinine, and alcohol levels 
will be assessed by a blood or urine test; alcohol breath tests are acceptable alternatives for 
alcohol testing. Subjects may undergo random urine drug screen and alcohol testing if deemed 
appropriate by the investigator. Drug screen results must be negative for a subject to receive 
study drug. 
Additional Evaluations: Additional clinical laboratory evaluations will be performed at other 
times if judged to be clinically appropriate.  
Additional Tests to be Performed Following Transaminases Elevations: 
As outlined under conditions described in Study Drug Interruption and Stopping Rules in 
Section 9.8, additional tests to be performed in subjects with transaminases elevations are shown 
in Table 11-4. 

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Table 11-4 
Safety Laboratory Tests to Investigate Transaminases Elevations 
Auto-immunology 
Other Tests 
Urinalysis 
Anti-DNA (double-stranded) antibodies 
Antinuclear antibodies 
Complement C3 
ASMA 
LKM-1 antibody 
Rheumatoid factor 
anti-CCP 
Serum immunoglobulin 
   IgA, IgG (and IgG subclasses), and 
   IgM 
Blood CPK 
Blood alcohol levels 
SARS-CoV2a 
Serology for hepatitis A, B, C, Db, E 
Serology for EBV 
Serology for CMV 
Urine drug screen  
   (including acetaminophen or 
   paracetamol)  
ASMA: anti-smooth muscle antibody; CCP: cyclic citrullinated peptide; CMV: cytomegalovirus; CPK: creatine 
phosphokinase; EBV: Epstein-Barr virus; IgA/G/M: immunoglobulin A/G/M; LKM-1: liver-kidney 
microsomal type 1; SARS-CoV2: severe acute respiratory syndrome coronavirus 2 
a 
Where permitted by local regulations. 
b 
Hepatitis D testing will only be performed if hepatitis B test result is positive. 
11.6.3 
Physical Examinations and Vital Signs 
A complete PE of all body systems and vital signs assessment will be performed at screening and 
select study visits. At home visits, a qualified nurse will perform a review of symptoms. The 
review of symptoms will include a verbal review of symptoms by body system. If there are any 
findings from the verbal review that are considered abnormal by the investigator, the subject will 
be instructed to have a complete PE in the clinic. 
A complete PE includes a review of the following systems: head, neck, and thyroid; eyes, ears, 
nose, and throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; 
musculoskeletal; and neurological. Breast, anorectal, and genital examinations will be performed 
when medically indicated. After screening, any clinically significant abnormal findings in PEs 
will be reported as AEs (see Section 13.1.1.2). 
Vital signs include blood pressure (systolic and diastolic), temperature (oral), pulse rate, and 
respiration rate. The subject will be instructed to rest for at least 5 minutes before vital signs are 
assessed. After screening, any clinically significant abnormal findings in vital signs will be 
reported as AEs (see Section 13.1.1.2).  
11.6.4 
Pulse Oximetry 
Pulse oximetry is a noninvasive measure of oxygen delivery to the tissues and has been 
correlated with clinical status and lung function. Arterial oxygen saturation by pulse oximetry 
will be assessed following at least a 5-minute rest and before study drug dosing. At visits when 
study drug is taken at the site, pulse oximetry will be collected before study drug dosing.  
11.6.5 
Electrocardiograms 
Standard 12-lead ECGs will be performed in triplicate using a machine capable of capturing 
ECG traces. Additional standard 12-lead ECGs will be performed at any other time if clinically 
indicated. Detailed instructions are provided in the Study Reference Manual. The performance of 
all ECGs will adhere to the following guidelines: 

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• The ECG will be done before any other procedures that may affect heart rate, such as blood 
draws. 
• The subject will be instructed to rest for at least 5 minutes before having an ECG. 
• The test should be performed in the supine position. 
ECG traces will be made available for safety review by the investigator and maintained with 
source documentation. Clinically significant ECG abnormalities occurring during the study 
through completion of study participation will be recorded as AEs.  
To ensure safety of the subjects, a qualified individual at the study site or a qualified home nurse 
at home health visits (Section 9.1.3) will make comparisons of the QTcF value generated on the 
ECGs obtained at any time point after the first dose of drug administered in the Treatment Period 
to the predose baseline QTcF value taken on Day 1 in the Treatment Period. If the median QTcF 
(of the safety ECGs performed in triplicate) is increased by >60 msec from the baseline (as 
defined in Section 12.3.1) or an absolute median QTcF value is ≥500 msec for any scheduled 
ECG assessment, triplicate ECGs will be repeated within 10 minutes of the initial assessment to 
confirm the original measurement. A subject with a confirmatory ECG that demonstrates a 
median QTcF (of the safety ECGs performed in triplicate) that has increased by >60 msec from 
the baseline or an absolute median QTcF value ≥500 msec will discontinue dosing. If the median 
QTcF (from the confirmatory ECGs repeated within 10 minutes of the initial assessment) falls 
below the threshold, the subject may continue dosing. If the confirmatory ECG is above the 
threshold then for safety monitoring, triplicate ECGs will be repeated at least every hour until the 
median QTcF value from 2 successive time points falls below the threshold value that triggered 
the repeat measurement. 
11.6.6 
Height and Weight 
Height and weight will be measured and with shoes off.  
11.6.7 
Spirometry 
Spirometry will be performed according to the ATS/ERS guidelines.3, 4, 5 A historical percent 
predicted forced expiratory volume in 1 liter (ppFEV1) results within 1 year before the first 
Screening Visit can be used to determine eligibility. Further details are provided in the Study 
Reference Manual. 
11.6.8 
Contraception and Pregnancy  
The effects of VX-864 on pregnancy, and lactation in humans are not known. No new safety 
concerns were identified when female subjects received VX-864 in combination with the oral 
contraceptives levonorgestrel and ethinyl estradiol. VX-864 did not show genotoxic potential in 
a standard battery of in vitro and in vivo studies. Reproductive toxicology studies of VX-864 
have not shown teratogenicity in rats and rabbits. Refer to the VX-864 IB for additional details. 
11.6.8.1 
Contraception 
Study participation requires compliance with the contraception guidelines outlined below: 
Contraception for the couple is waived for the following: 
• True abstinence for the subject, when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, and post-ovulation 

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methods) and withdrawal are not acceptable methods of contraception. True abstinence must 
be practiced from the Screening Visit through 90 days after the dose of study drug. 
• If the male is infertile (e.g., bilateral orchiectomy). If a male subject is assumed to have 
complete bilateral absence of the vas deferens, infertility must be documented before the 
dose of study drug (e.g., examination of a semen specimen or by demonstration of the 
absence of the vas deferens by ultrasound). 
• If the female is of non-childbearing potential. To be considered of non-childbearing potential, 
the female must meet at least 1 of the following criteria: 
o Postmenopausal: Amenorrheic for at least 12 consecutive months and a serum FSH level 
within the laboratory’s reference range for postmenopausal females 
o Documented hysterectomy or bilateral oophorectomy/salpingo-oophorectomy 
Note: All other females (including females with tubal ligations and females who do not have 
a documented bilateral oophorectomy/salpingo-oophorectomy) will be considered to be of 
childbearing potential. 
• Exclusive same-sex relationships. 
For subjects for whom the contraception requirement is not waived, study participation 
requires a commitment from the subject that at least 1 acceptable method of contraception will 
be used as a couple. Methods of contraception must be in successful use from signing of consent, 
approximately 28 days before study drug administration (unless otherwise noted), and until 
90 days following study drug administration. Additional contraception requirements may need to 
be followed according to local regulations and/or requirements. Acceptable methods of 
contraception are listed in Table 11-5. 
Table 11-5 
Acceptable Methods of Contraception 
Method 
Male Subjects and Their 
Female (Non-study) Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Vasectomy 6 months or more previously, with a 
documented negative postvasectomy semen 
analysis for sperm 
Yes 
Yes 
Documented bilateral tubal ligation performed at 
least 6 months previously 
Yes 
Yes 
Male or female condom with or without 
spermicidea 
Yes 
Yes 
Female barrier contraception (such as 
diaphragm, cervical cap, or sponge) with 
spermicide 
Yes 
Yes 

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Table 11-5 
Acceptable Methods of Contraception 
Method 
Male Subjects and Their 
Female (Non-study) Partners 
Female Subjects and 
Their Male (Non-study) 
Partners 
Continuous use of a non-hormone releasing 
intrauterine device for at least 90 days before the 
dose of study drug 
Yes 
Yes 
Oral, patch, implanted, injected hormonal 
contraceptives, if used consistently and correctly 
for at least 60 days before the dose of study drug 
Yes 
No  
Note: At least 1 acceptable method of contraception must be used by couples not exempt from the contraception 
requirement.  
a 
A female condom cannot be used with a male condom due to risk of tearing. 
Additional notes: 
• Male and female subjects who are not sexually active at the time of screening must agree to 
follow the contraceptive requirements of this study if they become sexually active with a 
partner of the opposite sex. 
• Male subjects must not donate sperm during the period starting from the dose of study drug 
until 90 days after the dose of study drug. 
• Female subjects of childbearing potential should not plan to become pregnant during the 
study or within 90 days after the dose of study drug. For male subjects with a female partner 
of childbearing potential, the couple should not plan to become pregnant during the study or 
within 90 days after the dose of study drug, with the exception of couples who plan to 
become pregnant by artificial insemination using sperm banked by the male subject before 
the dose of study drug or sperm from another source. 
• Male subjects whose female partner becomes pregnant through well-documented in vitro 
fertilization (donated sperm) or banked sperm (collected before the subject received study 
drug), or is otherwise already pregnant before the male subject’s dose of study drug, must be 
compliant with the contraception requirements. In this scenario, the male subject and his 
female partner must commit to using a male condom (to ensure there is no exposure of the 
fetus to study drug) from signing consent through 90 days after the dose of study drug.  
• Female subjects should not nurse a child from signing consent through 90 days following the 
study drug administration. 
• Unique situations that may not fall within the above specifications may be discussed with the 
Vertex medical monitor or authorized designee on an individual basis. 
11.6.8.2 
Pregnancy 
Subjects will be counseled to inform the investigator of any pregnancy that occurs during study 
treatment and for 90 days after the last dose of study drug. 
If a subject or the female partner of a male subject becomes pregnant while participating in the 
study, study drug will be permanently discontinued immediately. The investigator will notify the 
medical monitor and Vertex Global Patient Safety (GPS) within 24 hours of the site's knowledge 
of the subject's (or partner's) pregnancy using the Pregnancy Information Collection Form. 

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12.3 
Statistical Analysis 
12.3.1 
General Considerations 
All individual subject data for subjects who were enrolled or received at least 1 dose of study 
drug will be presented in individual subject data listings. Data from Groups A and B will be 
pooled for the analysis of endpoints collected in both groups, unless specified otherwise. 
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, SD, median, minimum value (min), and maximum value 
(max). 
Categorical variables will be summarized using counts and percentages. 
Baseline value, unless specified otherwise, will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected before the first dose of study drug. For 
ECGs, the baseline value will be defined as the average of the non-missing pretreatment 
measurements (triplicate) on Day 1. 
Change (absolute change) from baseline will be calculated as Post-baseline value – Baseline 
value. 
Treatment-emergent (TE) Period will include the time from the first dose of study drug to 
28 days after the last dose of study drug or to the completion of study participation (as defined in 
Section 9.1.9), whichever occurs first. 
12.3.2 
Background Characteristics 
Subject disposition (e.g., enrolled, completed treatment, discontinued treatment) will be 
summarized based on the All Subjects Set. 
Demographics (e.g., age) and background characteristics (e.g., blood levels of antigenic AAT at 
screening, prior augmentation therapy, Z-polymer accumulation in the liver at baseline in Group 
B), will be summarized. Also, medical history and medication use will be summarized 
descriptively. 
Exposure to study drug (i.e., duration of treatment) will be summarized based on the SS. Study 
drug compliance (i.e., percentage of days without study drug interruption) will be summarized 
based on the FAS. 
Important protocol deviations will be provided in an individual subject data listing, and 
summarized, as appropriate. 
Additional details will be provided in the SAP. 
12.3.3 
Efficacy Analysis 
Only the principal features of the efficacy analysis will be presented in this section. For more 
details, refer to the SAP. 
12.3.3.1 
Analysis of Primary Endpoint 
The primary efficacy endpoint is the change from baseline in blood levels of functional AAT at 
Week 48.  
The primary analysis will be based on a mixed-effects model for repeated measures (MMRM) 
with change from baseline in blood levels of functional AAT as the dependent variable. The 

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model will include visit as a fixed effect. The model will be estimated using restricted maximum 
likelihood. Denominator degrees of freedom for the F-test for fixed effects will be estimated 
using the Kenward-Roger approximation. An unstructured covariance structure will be used to 
model the within-subject errors. If the model estimation does not converge, a compound 
symmetry covariance structure will be used instead. 
The primary result obtained from the model will be the estimated change from baseline in blood 
levels of functional AAT at Week 48 and the corresponding 95% CI and P value for the within-
group comparison. 
12.3.3.2 
Analysis of Secondary Efficacy Endpoints 
The change from baseline in blood levels of functional AAT at additional visits will be reported 
based on a similar model to that used for the analysis of the primary endpoint. The change from 
baseline in blood levels of antigenic AAT and blood levels of Z-polymer will be analyzed in a 
similar manner to the change from baseline in blood levels of functional AAT.  
The change from baseline in Z-polymer accumulation in the liver at Weeks 24 and 48 will be 
summarized descriptively. In addition, the change from baseline in Z-polymer accumulation in 
the liver combining both cohorts within Group B (i.e., Week 24 for Cohort B1 and Week 48 for 
Cohort B2) will be summarized descriptively. 
12.3.3.3 
Multiplicity Adjustment 
There will be no multiplicity adjustment performed in the analysis of this study. 
12.3.3.4 
Missing Data Handling 
For the primary analysis, missing data will be assumed to be missing at random conditional on 
the observed data; consequently, no imputation of missing data will be performed. 
12.3.4 
Safety Analysis 
The overall safety profile of VX-864 will be assessed in terms of the following safety and 
tolerability endpoints:  
• Incidence of treatment-emergent adverse events (TEAEs)  
• Clinical laboratory values (i.e., serum chemistry, hematology, coagulation, and urinalysis)  
• Standard 12-lead ECGs  
• Vital signs  
• Pulse oximetry  
For safety analyses, no statistical hypothesis testing will be conducted. All safety data will be 
presented in individual subject data listings. Additional details will be provided in the SAP. 
12.4 
Interim Analysis 
Interim analyses may be conducted at the discretion of the sponsor. 
12.5 
Data Monitoring Committee Analysis 
Not applicable. 

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13 
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
13.1 
Adverse Event and Serious Adverse Event Documentation, Severity 
Grading, and Reporting 
13.1.1 
Adverse Events 
13.1.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with the treatment. This includes any newly 
occurring event or worsening of a pre-existing condition (e.g., increase in its severity or 
frequency) after the ICF is signed.  
An AE is considered serious if it meets the definition in Section 13.1.2.1.  
13.1.1.2 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, PEs, and vital signs will be assessed and 
those deemed to have clinically significant worsening from baseline will be documented as an 
AE. When possible, a clinical diagnosis for the study assessment will be provided, rather than the 
abnormal test result alone (e.g., urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself will be listed as the AE (e.g., bacteria in urine or decreased 
hemoglobin). 
An abnormal study assessment is considered clinically significant if the subject has 1 or more of 
the following: 
• Concomitant signs or symptoms related to the abnormal study assessment 
• Further diagnostic testing or medical/surgical intervention 
• A change in the dose of study drug or discontinuation from the study 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether the 
study assessment results are clinically significant will be made by the investigator. 

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A laboratory value that is Grade 4 will not automatically be a serious adverse event (SAE). A 
Grade 4 laboratory value will be an SAE if the subject’s clinical status indicates a 
life-threatening AE. 
13.1.1.3 
Documentation of Adverse Events 
All AEs will be collected from the time the ICF is signed until the following times: 
• For subjects who do not enroll: time of screen failure (e.g., screen failure, withdrawal of 
consent) 
• For enrolled subjects: completion of study participation, as defined in Section 9.1.9  
All subjects will be queried, using nonleading questions, about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms will be identified as 
1 overall event or diagnosis. All AEs for enrolled subjects will be recorded in the CRF and 
source document. AEs for subjects who are screened but not subsequently enrolled will be 
recorded only in the subject’s source documents. The following data will be documented for 
each AE: 
• Description of the event 
• Classification of “serious” or “nonserious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity  
• Causal relationship to study drug(s)  
• Action taken  
• Outcome  
• Concomitant medication or other treatment given 
13.1.1.4 
Adverse Event Severity 
The investigator will determine and record the severity of all serious and nonserious AEs. The 
guidance available at the following website will be consulted: Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0, Cancer Therapy Evaluation Program, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed 
July 2022). The severity of an AE described by a term that does not appear in the CTCAE will be 
determined according to the definitions in Table 13-1.  
Table 13-1 
Grading of AE Severity  
Classification 
Description 
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 (Moderate) 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADLa 
Grade 3 (Severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADLb 

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Table 13-1 
Grading of AE Severity  
Classification 
Description 
Grade 4 (Life-
threatening) 
Life-threatening consequences; urgent intervention indicated  
Grade 5 (Death) 
Death related to adverse event 
Source: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm (Accessed July 2022) 
ADL: activities of daily living; AE: adverse event 
Note: A semi-colon indicates ‘or’ within the description of the grade. 
a 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
13.1.1.5 
Adverse Event Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug(s). Causality will be classified using the categories in Table 13-2. 
Table 13-2 
Classifications for AE Causality 
Classification 
Definition 
Related 
There is an association between the event and the administration of investigational 
study drug, a plausible mechanism for the event to be related to the investigational 
study drug and causes other than the investigational study drug have been ruled out, 
and/or the event reappeared on re-exposure to the investigational study drug. 
Possibly related 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to be 
related to investigational study drug, but there may also be alternative etiology, 
such as characteristics of the subject’s clinical status or underlying disease. 
Unlikely related 
The event is unlikely to be related to the investigational study drug and likely to be 
related to factors other than investigational study drug.  
Not related 
The event is related to an etiology other than the investigational study drug (the 
alternative etiology will be documented in the subject’s medical record). 
AE: adverse event 
13.1.1.6 
Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken 
will be classified according to the categories in Table 13-3.  
Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classificationa 
Definition 
Dose not changed 
Study drug dose not changed in response to an AE 
Dose reduced 
Study drug dose reduced in response to an AE 
Drug interrupted 
Study drug administration interrupted in response to an AE  
Drug withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not applicable 
Action taken regarding study drug administration does not apply.  
“Not applicable” will be used in circumstances such as when the investigational 
treatment had been completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is possible. 

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Table 13-3 
Classifications for Study Drug Action Taken With Regard to an AE 
Classificationa 
Definition 
AE: adverse event 
a 
Refer to Sections 9.7 and 9.8 for directions regarding what drug actions are permitted per protocol.  
13.1.1.7 
Adverse Event Outcome 
An AE will be followed until the investigator has determined and provided the final outcome. 
The outcome will be classified according to the categories in Table 13-4. 
Table 13-4 
Classifications for Outcome of an AE 
Classification 
Definition 
Recovered/resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/resolved with 
sequelae 
Resolution of an AE with residual signs or symptoms 
Not recovered/not 
resolved (continuing) 
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing 
Fatal 
Outcome of an AE is death. “Fatal” will be used when death is at least possibly 
related to the AE. 
Unknown 
Outcome of an AE is not known (e.g., a subject lost to follow-up) 
AE: adverse event 
13.1.1.8 
Treatment Given 
The investigator ensures adequate medical care is provided to subjects for any AEs, including 
clinically significant laboratory values related to study drug. In addition, the investigator will 
describe whether any treatment was given for the AE. “Yes” is used if any treatment was given 
in response to an AE, and may include treatments such as other medications, surgery, or physical 
therapy. “No” indicates the absence of any kind of treatment for an AE. 
13.1.2 
Serious Adverse Events 
13.1.2.1 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following outcomes: 
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after 
participation and is suspected of being a delayed toxicity due to administration of the study 
drug) 
• Life-threatening, such that the subject was at immediate risk of death from the reaction as it 
occurred  
• Inpatient hospitalization or prolongation of hospitalization 
• Persistent or significant disability/incapacity (disability is defined as a substantial disruption 
of a person’s ability to conduct normal life functions) 
• Congenital anomaly or birth defect 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
subject or may require medical or surgical intervention to prevent 1 of the outcomes listed 

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above (e.g., an allergic bronchospasm requiring intensive treatment in an emergency room or 
at home)  
If a subject has a hospitalization or procedure (e.g., surgery) for an event or condition that 
occurred before the subject signed the ICF, and the hospitalization or procedure was planned 
before the subject signed the ICF, the hospitalization or procedure will not be considered to 
indicate an SAE, unless an AE caused the hospitalization or procedure to be rescheduled sooner 
or to be prolonged relative to what was planned. In addition, hospitalizations clearly not 
associated with an AE (e.g., social hospitalization for purposes of respite care) will not be 
considered to indicate an SAE. 
Clarification will be made between the terms “serious” and “severe” because they are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may be 
of relatively minor medical significance, such as a severe headache. This is not the same as 
“serious”, which is based on subject/event outcome or action described above and is usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness, not 
severity, serves as a guide for defining expedited regulatory reporting obligations.  
13.1.2.2 
Reporting and Documentation of Serious Adverse Events 
All SAEs that occur after obtaining informed consent and assent (where applicable) through 
completion of study participation, regardless of causality, will be reported by the investigator to 
Vertex GPS within 24 hours of identification. In addition, all SAEs that occur after completion 
of study participation and are considered related to study drug(s) will be reported to Vertex GPS 
within 24 hours of identification.  
For SAEs that occur after obtaining informed consent and assent (where applicable) through 
completion of study participation, the SAE Form will be completed for new/initial events as well 
as to report follow-up information on previously reported events. Investigators are asked to 
report follow-up information as soon as it becomes available to ensure timely reporting to health 
authorities.  
Please send completed SAE Forms to Vertex GPS via: 
Email: globalpatientsafety@vrtx.com (preferred choice) 
Fax: +1-617-341-6159  
For technical issues related to submitting the form, contact telephone: +1-617-341-6677 
SAEs that occur after completion of study participation and are considered related to study 
drug(s) will be recorded on the Vertex Clinical Trial Safety Information Collection Form 
(hereafter referred to as the “SAE Form”) using a recognized medical term or diagnosis that 
accurately reflects the event. SAEs will be assessed by the investigator for relationship to the 
investigational study drug(s) and possible etiologies. On the SAE Form, relationship to study 
drug(s) will be assessed only as related (includes possibly related) or not related (includes 
unlikely related), and severity assessment will not be required. For the purposes of study 
analysis, if the event has not resolved at the end of the study reporting period, it will be 
documented as ongoing. For purposes of regulatory safety monitoring, the investigator is 
required to follow the event to resolution and report the outcome to Vertex using the SAE Form. 

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13.1.2.3 
Expedited Reporting and Investigator Safety Letters 
Vertex, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions (SUSARs) involving the study drug(s) to all regulatory authorities, IEC, and 
participating investigators in accordance with current ICH E2A Guidelines and/or local 
regulatory requirements, as applicable. In addition, Vertex, or authorized designee, will be 
responsible for the submission of safety letters to central IECs.  
It is the responsibility of the investigator or designee to promptly notify the local IRB/IEC of all 
unexpected serious adverse drug reactions involving risk to human subjects. 
13.2 
Administrative Requirements 
13.2.1 
Product Complaints 
A product complaint is defined as any verbal or written communication addressed to Vertex, or 
designee, of inquiry or dissatisfaction with the identity, strength, quality, or purity of a released 
drug product, IMP, or medical device. In addition, suspected counterfeit/falsified product is 
considered a product complaint.  
Product complaints are to be reported to Vertex. 
13.2.2 
Ethical Considerations 
The study will be conducted in accordance with the current ICH E6 GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the subjects. The study will be 
conducted only at sites where IRB/IEC approval has been obtained. The protocol, IB, sample 
ICF, advertisements (if applicable), written information given to the subjects (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the investigator or Vertex, as allowable by local applicable laws and 
regulations. 
13.2.3 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject or legal representative or guardian (if applicable), and assent will be obtained from the 
subject (if applicable), before study participation. The method of obtaining and documenting the 
informed consent and assent (if applicable) and the contents of the consent will comply with 
current ICH E6 GCP Guidelines and all applicable laws and regulations and will be subject to 
approval by Vertex or its designee. 
ICFs for reconsent may be provided electronically or by post mail to subjects or legal 
representatives or guardians (if applicable), where permitted by local regulations. The subject 
and/or legal representative or guardian will review the ICF with an appropriately qualified 
member of the investigator’s team via telephone contact or video call. After this review, the 
subject and/or legal representative or guardian will reconsent verbally and by signing and dating 
the ICF and returning it to the site via post mail. The signed and dated ICF will then be signed 
and dated by the investigator.  

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13.2.4 
Investigator Compliance 
No modifications to the protocol will be made without the approval of both the investigator and 
Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, 
or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification 
before implementation, except where the modification is necessary to eliminate an apparent 
immediate hazard to human subjects. Vertex will submit all protocol modifications to the 
required regulatory authorities. 
When circumstances require an immediate departure from procedures set forth in the protocol, 
the investigator will contact Vertex to discuss the planned course of action. If possible, contact 
will be made before the implementation of any changes. Any departures from the protocol will 
be fully documented in the source documentation and in a protocol deviation log.  
13.2.5 
Access to Records 
The investigator will make the office and/or hospital records of subjects enrolled in this study 
available for inspection by Vertex or its representative at the time of each monitoring visit and 
for audits. The records will also be available for direct inspection, verification, and copying, as 
required by applicable laws and regulations, by officials of the regulatory health authorities 
(FDA and others). The investigator will comply with applicable privacy and security laws for use 
and disclosure of information related to the research set forth in this protocol.  
13.2.6 
Subject Privacy 
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all data provided to Vertex, study reports, and communications relating to 
the study will identify subjects by assigned subject numbers, and access to subject names linked 
to such numbers will be limited to the site and the study physician and will not be disclosed to 
Vertex. As required by applicable laws and regulations in the countries in which the study is 
being conducted, the investigator will allow Vertex and/or its representatives access to all 
pertinent medical records to allow for the verification of data gathered and the review of the data 
collection process. The FDA and regulatory authorities in other jurisdictions, including the 
IRB/IEC, may also request access to all study records, including source documentation, for 
inspection. 
For sites participating in the US, and in accordance with the Health Insurance Portability and 
Accountability Act (HIPAA) and associated regulations, an executed HIPAA authorization will 
be obtained by the site from each subject (or the legal representative of the subject) before 
research activities may begin. Each HIPAA authorization will comply with all HIPAA 
requirements including authorization allowing the site access to and use of the subject’s 
personally identifiable health information, authorization for the site to disclose such information 
to Vertex, the FDA, and other parties requiring access under the protocol, and statements as to 
the purpose for which such information may be used and for how long. 
13.2.7 
Record Retention 
The investigator will maintain all study records according to current ICH E6 GCP Guidelines 
and/or applicable local regulatory requirement(s), whichever is longest, as described in the 
Clinical Trial Agreement. If the investigator withdraws from the responsibility of keeping the 
study records, custody will be transferred to a person willing to accept the responsibility and 
Vertex will be notified. 

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13.2.8 
Study Termination 
At any time, Vertex may terminate this study in its entirety or may terminate this study at any 
particular site. In addition, for reasonable cause, either the investigators or their IRBs/IECs may 
terminate the study at their center. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited 
to: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• Decision to modify drug development plan 
• Decision by the FDA or other regulatory authority 
Written notification that includes the reason for the clinical study termination is required. 
13.2.9 
End of Study 
The end of study is defined as the last scheduled visit (or scheduled contact) of the last subject. 
13.3 
Data Quality Assurance 
Vertex or its designated representative will conduct a study site visit on-site or remote (as 
applicable by local regulation) to verify the qualifications of each investigator, inspect clinical 
study site facilities, and inform the investigator of responsibilities and procedures for ensuring 
adequate and correct study documentation per current ICH E6 GCP Guidelines. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each subject. Study 
data for each enrolled subject will be entered into a CRF by study site personnel using a secure, 
validated, web-based electronic data capture (EDC) application. Vertex will have read-only 
access to site-entered clinical data in the EDC application.  
Instances of missing, discrepant, or uninterpretable data will be queried with the investigator for 
resolution. Any changes to study data will be made to the CRF and documented in an audit trail, 
which will be maintained within the clinical database. 
13.4 
Monitoring 
The study will be monitored by Vertex or its designee in accordance with written procedures. 
Monitoring and auditing procedures developed or approved by Vertex for these activities comply 
with GCP regulatory requirements and guidelines. The monitoring strategy may include onsite, 
remote, and central monitoring activities, in accordance with local regulations. The study site 
monitor will ensure that the investigation is conducted according to the protocol design and 
regulatory requirements. 

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13.5 
Electronic Data Capture 
Vertex will provide the study sites with secure access to and training on the EDC application 
sufficient to permit study site personnel to enter or correct information in the CRFs on the 
subjects for which they are responsible.  
A CRF will be completed for each enrolled study subject. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s 
CRF. Source documentation supporting the CRF data will indicate the subject’s participation in 
the study and will document the dates and details of study procedures, AEs, other observations, 
and subject status. 
The investigator, or designated representative, will complete the CRF as soon as possible after 
information is collected.  
The audit trail entry will show the user’s identification information and the date and time of any 
correction. The investigator will provide formal approval of all the information in the CRFs, 
including any changes made to them, to endorse the final submitted data for the subjects for 
whom the investigator is responsible.  
Vertex will retain the CRF data and corresponding audit trails. A copy of the final archival CRF 
in the form of a compact disc or other electronic media will be placed in the investigator’s 
study file. 
13.6 
Confidentiality and Disclosure 
Any and all scientific, commercial, and technical information disclosed by Vertex in this 
protocol or elsewhere will be considered the confidential and proprietary property of Vertex. The 
investigator shall hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator shall not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study. 
The investigator understands that the information developed from this clinical study will be used 
by Vertex in connection with the development of the study drug and other drugs and diagnostics, 
and therefore may be disclosed as required to other clinical investigators, business partners and 
associates, the FDA, and other government agencies. The investigator also understands that, to 
allow for the use of the information derived from the clinical study, the investigator has the 
obligation to provide Vertex with complete test results and all data developed in the study. 
13.7 
Publications and Clinical Study Report 

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13.7.2 
Clinical Study Report  
A CSR, written in accordance with the current ICH E3 Guideline, will be submitted in 
accordance with local regulations. 

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14 
REFERENCES 
1 
Bergin DA, Reeves EP, Hurley K, Wolfe R, Jameel R, Fitzgerald S, et al. The circulating 
proteinase inhibitor alpha-1 antitrypsin regulates neutrophil degranulation and 
autoimmunity. Sci Transl Med. 2014;6(217):217ra1. 
2 
Geraghty P, Eden E, Pillai M, Campos M, McElvaney NG, Foronjy RF. Alpha1-
Antitrypsin activates protein phosphatase 2A to counter lung inflammatory responses. 
Am J Respir Crit Care Med. 2014;190(11):1229-42. 
3 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
4 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
5 
Culver BH, Graham BL, Coates AL, Wanger J, Berry CE, Clarke PK, et al. 
Recommendations for a standardized pulmonary function report. An official American 
Thoracic Society technical statement. Am J Respir Crit Care Med. 2017;196(11):1463-
72. 
6 
Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good 
publication practice for communicating company-sponsored medical research: GPP3. 
Ann Intern Med. 2015;163(6):461-4. 
7 
International Committee of Medical Journal Editors (ICMJE). December 2017. 
Recommendations for conduct, reporting, editing, and publication of scholarly work in 
medical journals. Available at: http://www.icmje.org/recommendations/. Accessed 
22 July 2022. 
 

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15 
PROTOCOL SIGNATURE PAGES 
15.1 
Sponsor Signature Page 
Protocol #: 
VX22-864-108 
Version #: 
2.0 
Version Date: 
02 November 2023 
Study Title: A Phase 2, Open-label Study Evaluating Efficacy and Safety of VX-864 in 
Subjects With Alpha-1 Antitrypsin Deficiency Who Have the PiZZ Genotype, Over 48 Weeks 
 
This clinical study protocol has been reviewed and approved by the sponsor. 
Printed Name 
 
Title 
Signature 
 
Date 
 

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15.2 
Investigator Signature Page 
Protocol #:  
VX22-864-108 
Version #: 
2.0 
Version Date: 
02 November 2023 
Study Title: A Phase 2, Open-label Study Evaluating Efficacy and Safety of VX-864 in 
Subjects With Alpha-1 Antitrypsin Deficiency Who Have the PiZZ Genotype, Over 48 Weeks 
 
 
 
I have read Protocol VX22-864-108, Version 2.0, and agree to conduct the study according to its 
terms. I understand that all information concerning VX‑864 and this protocol supplied to me by 
Vertex Pharmaceuticals Incorporated (Vertex) is confidential. 
 
 
Printed Name 
 
 
Signature 
 
Date