-
Important Safety Information Trial 3MOA/Eligibility Trial 2
Safety ProfileTrial 1 Dosing/DDI
INDICATIONS AND USAGETRIKAFTA is indicated for the treatment of
CF in patients aged 6 years and older who have at least one F508del
mutation in the cystic fibrosis transmembrane conductance regulator
(CFTR) gene or a mutation in the CFTR gene that is responsive based
on in vitro data.
If the patient’s genotype is unknown, an FDA-cleared CF mutation
test should be used to confirm the presence of at least one F508del
mutation or a mutation that is responsive based on in vitro
data.
IMPORTANT SAFETY INFORMATIONLIVER FUNCTION TEST ELEVATIONS
• Elevated transaminases have been observed in patients with CF
treated with TRIKAFTA. Bilirubin elevations have also been observed
with TRIKAFTA treatment. Assessments of liver function tests (ALT,
AST, and bilirubin) are recommended prior to initiating TRIKAFTA,
every 3 months during the first year of treatment, and annually
thereafter
• In the event of significant elevations in liver function
tests, e.g. ALT or AST >5x the upper limit of normal (ULN) or
ALT or AST >3x ULN with bilirubin >2x ULN, dosing should be
interrupted and laboratory tests closely followed until the
abnormalities resolve. Following the resolution of liver function
test elevations, consider the benefits and risks of resuming
treatment
• For patients with a history of hepatobiliary disease or liver
function test elevations, more frequent monitoring should be
considered
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
®
TRIPLE COMBINATION THERAPY FOR PATIENTS WITHCYSTIC FIBROSIS (CF)
WITH AT LEAST ONE F508del MUTATION
OR AT LEAST ONE OTHER RESPONSIVE MUTATION2
A BREAKTHROUGH TREATMENT—
FOR PATIENTS AGED 6 YEARS AND OLDER1,2
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Important Safety Information Trial 3MOA/Eligibility Trial 2
Safety ProfileTrial 1 Dosing/DDI
2
TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor)
Clinical Brochure Table of Contents
IMPORTANT SAFETY INFORMATION
MECHANISM OF ACTION
ELIGIBILITY
IN PATIENTS AGED 12+ HETEROZYGOUS FOR THE F508del MUTATION/OTHER
SPECIFIC MUTATION
IN PATIENTS AGED 12+ HOMOZYGOUS FOR THE F508del MUTATION
SAFETY PROFILE
IN PATIENTS AGED 6 THROUGH 11 YEARS
DOSING AND ADMINISTRATION
DRUG INTERACTIONS
SUMMARY
3
4
5
6
13
19
25
33
36
39
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
3
LIVER FUNCTION TEST ELEVATIONS• Elevated transaminases have been
observed in patients with CF treated with TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor). Bilirubin
elevations have also been observed with TRIKAFTA treatment.
Assessments of liver function tests (ALT, AST, and bilirubin) are
recommended prior to initiating TRIKAFTA, every 3 months during the
first year of treatment, and annually thereafter
• In the event of significant elevations in liver function
tests, e.g. ALT or AST >5x ULN or ALT or AST >3x ULN with
bilirubin >2x ULN, dosing should be interrupted and laboratory
tests closely followed until the abnormalities resolve. Following
the resolution of liver function test elevations, consider the
benefits and risks of resuming treatment
• For patients with a history of hepatobiliary disease or liver
function test elevations, more frequent monitoring should be
considered
CONCOMITANT USE WITH CYP3A INDUCERS• Exposure to ivacaftor is
significantly decreased and exposure to elexacaftor and
tezacaftor
are expected to decrease by the concomitant use of strong CYP3A
inducers, which may reduce the therapeutic effectiveness of
TRIKAFTA. Co-administration with strong CYP3A inducers is not
recommended
CONCOMITANT USE WITH CYP3A INHIBITORS• Exposure to elexacaftor,
tezacaftor, and ivacaftor are increased when co-administered
with
strong or moderate CYP3A inhibitors. The dose of TRIKAFTA should
be reduced when used concomitantly with moderate or strong CYP3A
inhibitors
CATARACTS• Cases of non-congenital lens opacities have been
reported in pediatric patients treated with
ivacaftor-containing regimens. Baseline and follow up
ophthalmological examinations are recommended in pediatric patients
initiating treatment with TRIKAFTA
PEDIATRIC USE• The safety and effectiveness of TRIKAFTA in
patients with CF younger than 6 years of age
have not been established
SERIOUS ADVERSE REACTIONS• Serious adverse reactions that
occurred more frequently in patients treated with TRIKAFTA
compared to placebo were rash (1% vs
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.4
• Improved cellular processing and trafficking (elexacaftor and
tezacaftor) and potentiated channel-open probability
(ivacaftor)2,3
• Reduced channel-open probability3
and/or
DEFECTIVEF508del-CFTR PROTEIN
Defective CFTRprotein
Cell surface
Proteindegradation
Chloride ion
ELEXACAFTOR, TEZACAFTOR, and IVACAFTOR
• Impaired cellular processing and trafficking3
Overall CFTR activity is increased by
DEFECTIVEF508del-CFTR PROTEIN
Defective CFTRprotein
Cell surface
Proteindegradation
Chloride ion
ELEXACAFTOR, TEZACAFTOR, and IVACAFTOR
Targeting responsive CFTR mutations increases CFTR
activity2,3
DEFECTIVE CFTR PROTEINS
SPECIFIC RESPONSIVE PROTEINS
Overall CFTR activity may be decreased by
TRIKAFTA® (ELEXACAFTOR/TEZACAFTOR/IVACAFTOR AND IVACAFTOR) IS
APPROVED FOR PATIENTS WITH CF AGED 6 YEARS AND OLDER WHO HAVE AT
LEAST ONE F508del MUTATION IN THE CFTR GENE OR A MUTATION IN THE
CFTR GENE THAT IS RESPONSIVE BASED ON IN VITRO DATA2
CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane
conductance regulator.
MOA/Eligibility
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
5
or
For patients aged 6 years and older with at least 1 of 178
mutations2
VISIT WWW.TRIKAFTAHCP.COM OR REFER TO THE FULL PRESCRIBING
INFORMATION TO SEE WHICH MUTATIONS ARE ELIGIBLE
Mutations were considered responsive if CFTR activity resulted
in a net increase of ≥10% over baseline after adding
elexacaftor/tezacaftor/ivacaftor.2
Indicated based on clinical data
F508del
Other indicated mutations based on in vitro data4a
170 less common mutations are also eligible.
G551D R117H
R347P A455E
D1152H G85E
L206W
MOST COMMON RESPONSIVE MUTATIONS
aThese mutations are present in ≥0.6% of individuals with
CF.4
Important Safety InformationLIVER FUNCTION TEST ELEVATIONS•
Elevated transaminases have been observed in patients with CF
treated with TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor). Bilirubin
elevations have also been observed with TRIKAFTA treatment.
Assessments of liver function tests (ALT, AST, and bilirubin) are
recommended prior to initiating TRIKAFTA, every 3 months during the
first year of treatment, and annually thereafter
MOA/Eligibility
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
http://www.trikaftahcp.comhttps://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.6
Trial 1
PRIMARY ENDPOINT2
• Absolute change in ppFEV1 from baseline at Week 4- Preplanned
interim analysis was conducted after ≥140 patients completed the
Week 4 visit
and ≥100 patients completed the Week 12 visit- There were 403
patients included in the preplanned interim analysis at Week 4
• Absolute change in ppFEV1• Number of pulmonary
exacerbationsd
• Absolute change in sweat chloride• Absolute change in
CFQ-R
Respiratory Domain score
FROM BASELINE THROUGH WEEK 24:FROM BASELINE AT WEEK 24:
FROM BASELINE AT WEEK 4:
• Absolute change in BMI
• Absolute change in CFQ-R Respiratory Domain score
Trial 1: A placebo-controlled trial in patients heterozygous for
the F508del mutation and another specific mutation2,5
• Confirmed CF diagnosis, clinically stable, and at least 12
years of age• Heterozygous for the F508del mutation and one of ~200
other mutations in the CFTR gene that
resulted in either: - No CFTR protein - A CFTR protein that
lacks baseline activity and is not responsive to ivacaftor and
tezacaftor/ivacaftor• ppFEV1 between 40% to 90% at screening
BASELINE WEEK 24a
WEEK 4(primary endpoint)
RANDOMIZED
1:1 Placebo q12h with fat-containing food (N=203)
TRIKAFTA®(elexacaftor/tezacaftor/ivacaftor and ivacaftor)
200 mg/100 mg/150 mg qam and 150 mg qpm with fat-containing food
(N=200)
All patients remained on their other standard-of-care CF
therapies.2
TRIAL 1
DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 3 STUDY2,5
aAll patients who completed the study were eligible to roll over
into a 192-week, open-label Extension Study.2,6bKey exclusion
criteria included clinically significant cirrhosis with or without
portal hypertension, a history of colonization with organisms
associated with a more rapid decline in pulmonary status
(including, but not limited to, Burkholderia cenocepacia,
Burkholderia dolosa, and Mycobacterium abscessus), and solid organ
or hematologic transplantation.2,5
cA hierarchical testing procedure was performed for key
secondary endpoints. For an endpoint to be significant, both it and
all previous tests in the hierarchy had to achieve P
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.7
• To evaluate long-term safety and tolerability of TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor) in patients with
CF who are heterozygous for the F508del mutation and another
specific mutation or who are homozygous for the F508del
mutation
Extension Study limitations and disclosures• The study was not
placebo-controlled; therefore, causality cannot be attributed,
and
hypothesis testing cannot determine whether within-arm changes
were due to drug effect• Data in the final analysis may differ from
data reported in this interim analysis• The Extension Study may not
meet the FDA definition of an adequate and well-controlled
study due to its study design
Study design2,6,7
• Patients with CF who are heterozygous for the F508del mutation
and another specific mutation who completed Trial 1 were eligible
to roll over into an ongoing, 192-week, open-label Extension Study-
Results presented here are from an interim analysis of the
Extension Study, which occurred
when 100% of the patients from Trial 1 had completed 24 weeks of
the Extension Study• All patients who completed Trial 1 were
eligible to roll over into the Extension Study• Those already
receiving TRIKAFTA continued taking it, for a total of 48 weeks of
exposure (n=196).
Those previously taking placebo began taking TRIKAFTA, for a
total of 24 weeks of exposure (n=203)• The safety data were pooled
across all cohorts and include all data available at the time of
analysis
Interim analysis of the open-label Extension Study in patients
who completed Trial 17
PRIMARY ENDPOINT
aIn the trial, a pulmonary exacerbation was defined as a change
in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or
more of 12 prespecified sinopulmonary signs/symptoms.2
AT EXTENSION STUDY WEEK 24:
• Absolute change from baseline in ppFEV1• Absolute change in
sweat chloride• Number of pulmonary exacerbationsa
• Absolute change in BMI• Absolute change from baseline in
CFQ-R Respiratory Domain score
SECONDARY ENDPOINTS
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
HETEROZYGOUS F508del/OTHER SPECIFIC MUTATION
Trial 1
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.8
Lung function results with TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor)2,6,7
TRIAL 1 EXTENSION IA (24 WEEKS)
12
8
16
4
0
-4Baseline WK4
primary endpoint
TRIKAFTA initiated
DAY 15 WK8 WK12 WK16 WK20 WK24 EXT WK4 EXT WK8 EXT WK12 EXT WK16
EXT WK20 EXT WK24
Ab
solu
te c
han
ge
in p
pF
EV
1
(per
cen
tag
e p
oin
ts, L
S m
ean
wit
h S
E)
TRIKAFTA (N=200) Placebo (N=203) Placebo→TRIKAFTA
(N=189)TRIKAFTA→TRIKAFTA (N=180)
14.9
14.3
percentage points at EXT Week 24(95% CI: 13.5, 16.3)
percentage points at EXT Week 24(95% CI: 12.9, 15.7)
ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE AT EXTENSION STUDY WEEK
242,6,7a
EXTENSION STUDY
ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE2
TRIAL 1
SIGNIFICANT IMPROVEMENT in mean absolute change vs placebo from
baseline at Week 4 based on preplanned interim analysis (95% CI:
12.1, 15.4; P
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.9
Important Safety InformationLIVER FUNCTION TEST ELEVATIONS
(cont'd)• In the event of significant elevations in liver function
tests, e.g. ALT or AST >5x ULN or ALT or AST
>3x ULN with bilirubin >2x ULN, dosing should be
interrupted and laboratory tests closely followed until the
abnormalities resolve. Following the resolution of liver function
test elevations, consider the benefits and risks of resuming
treatment
0.8
Est
imat
ed e
vent
rat
e p
er y
ear
1.0
0.6
0.4
0.2
0TRIKAFTA
through Week 24
0.37
Placebo TRIKAFTAè TRIKAFTA at EXT Week 24
(95% CI: 0.24, 0.44)
Placeboè TRIKAFTA at EXT Week 24
(95% CI: 0.19, 0.39)
0.98
through Week 24 (RR: 0.37 [95% CI:
0.25, 0.55]; P
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
10
Results for sweat chloride with TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor)2,3,6,7
ABSOLUTE CHANGE IN SWEAT CHLORIDE FROM BASELINE AT EXTENSION
STUDY WEEK 242,3,6,7a
Important Safety InformationCONCOMITANT USE WITH CYP3A INDUCERS•
Exposure to ivacaftor is significantly decreased and exposure to
elexacaftor and tezacaftor
are expected to decrease by the concomitant use of strong CYP3A
inducers, which may reduce the therapeutic effectiveness of
TRIKAFTA. Co-administration with strong CYP3A inducers is not
recommended
EXTENSION IA (24 WEEKS)
0
-30
-20
-10
-40
-50
WK4 WK8 WK12 WK16 WK20 WK24 EXT WK4 EXT WK8 EXT WK12 EXT WK16
EXT WK20 EXT WK24
Ab
solu
te c
han
ge
in s
wea
t ch
lori
de
(mm
ol/
L, L
S m
ean
wit
h S
E)
Baseline
10TRIAL 1
TRIKAFTA initiated
TRIKAFTA (N=200) Placebo (N=203) Placebo→TRIKAFTA
(N=187)TRIKAFTA→TRIKAFTA (N=183)
41.8significant reduction for TRIKAFTA vs placebo through Week
24 (95% CI: -44.4, -39.3; P
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.11
12
8
16
4
0
-4Baseline WK4DAY 15 WK8 WK12 WK16 WK20 WK24 EXT WK24EXT WK20EXT
WK16EXT WK12EXT WK8EXT WK4
CF
Q-R
Res
pir
ato
ry D
om
ain
sco
re(p
oin
ts, L
S m
ean
wit
h S
E)
EXTENSION IA (24 WEEKS)TRIAL 1
MCID
TRIKAFTA initiated
20
TRIKAFTA (N=200) Placebo (N=203) Placebo→TRIKAFTA
(N=197)TRIKAFTA→TRIKAFTA (N=192)
MCID, minimal clinically important difference. The MCID
threshold for CFQ-R Respiratory Domain score is 4 points in
patients with CF with stable respiratory symptoms and represents
the minimal change a patient can detect.11
Results for CFQ-R Respiratory Domain score with TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor)2,3,6,7
ABSOLUTE CHANGE IN CFQ-R RESPIRATORY DOMAIN SCORE FROM BASELINE
AT EXTENSION STUDY WEEK 242,3,6,7a
improvement for TRIKAFTA vs placebo through Week 24 (95% CI:
17.5, 23.0; P
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.12
Body mass index (BMI) results with TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor)2,5-7
Important Safety InformationCATARACTS• Cases of non-congenital
lens opacities have been reported in pediatric patients treated
with ivacaftor-containing regimens. Baseline and follow up
ophthalmological examinations are recommended in pediatric patients
initiating treatment with TRIKAFTA
PEDIATRIC USE• The safety and effectiveness of TRIKAFTA in
patients with CF younger than 6 years
of age have not been established
TRIAL 1 EXTENSION IA (24 WEEKS)
Baseline WK4 WK8 WK12 WK16 EXT WK4 EXT WK8 EXT WK12 EXT WK16 EXT
WK20 EXT WK24DAY 15
Ab
solu
te c
han
ge
in B
MI (
kg/m
2 , L
S m
ean
wit
h S
E)
WK20
1.2
1.4
1.0
0.8
0.6
0.4
0.2
0.0
-0.2WK24
TRIKAFTA initiated
TRIKAFTA (N=200) Placebo (N=203) Placebo→TRIKAFTA
(N=196)TRIKAFTA→TRIKAFTA (N=190)
1.2at EXT Week 24 (95% CI: 1.03, 1.40)
TRIKAFTAPLACEBOkg/m2
1.3at EXT Week 24 (95% CI: 1.09, 1.46)
kg/m2
increase for TRIKAFTA vs placebo through Week 24 (95% CI: 0.85,
1.23; P
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.13
• Confirmed CF diagnosis, clinically stable, and at least 12
years of age
• Homozygous for the F508del mutation
• ppFEV1 between 40% to 90% at screening
Trial 2: A head-to-head trial in patients homozygous for the
F508del mutation2,12
DOUBLE-BLIND, ACTIVE-CONTROLLED, PHASE 3 STUDY2,12
HOMOZYGOUS F508del MUTATION
PRIMARY ENDPOINT2
• Absolute change in ppFEV1 from baseline at Week 4
FROM BASELINE AT WEEK 4:KEY SECONDARY ENDPOINTS2c
• Absolute change in sweat chloride
• Absolute change in CFQ-R Respiratory Domain score
aAll patients who completed the study were eligible to roll over
into a 192-week, open-label Extension Study.2,6bKey exclusion
criteria included clinically significant cirrhosis with or without
portal hypertension, a history of colonization with organisms
associated with a more rapid decline in pulmonary status
(including, but not limited to, Burkholderia cenocepacia,
Burkholderia dolosa, and Mycobacterium abscessus), and solid organ
or hematologic transplantation.2,13
cA hierarchical testing procedure was performed for key
secondary endpoints. For an endpoint to be significant, both it and
all previous tests in the hierarchy had to achieve a hierarchy of
P
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.14
Interim analysis of the open-label Extension Study in patients
who completed Trial 27
PRIMARY ENDPOINT
• To evaluate long-term safety and tolerability of TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor) in patients with
CF who are heterozygous for the F508del mutation and another
specific mutation or who are homozygous for the F508del
mutation
Study design6,7,12
• Patients who are homozygous for the F508del mutation who
completed Trial 2 were eligible to roll over into an ongoing,
192-week, open-label Extension Study- Results presented here are
from an interim analysis of the Extension Study, which occurred
when
100% of the patients ongoing from Trial 1 had completed 24 weeks
of the Extension Study. Concurrently, patients from Trial 2
completed 36 weeks, which is the length of the data represented
here
• All patients who completed Trial 2 were eligible to roll over
into the Extension Study• Patients in Trial 2 already receiving
TRIKAFTA continued taking it, for a total of 40 weeks of
exposure (n=55). Those previously taking tezacaftor/ivacaftor
and ivacaftor began taking TRIKAFTA, for a total of 36 weeks of
exposure (n=52)
• The safety data were pooled across all cohorts and include all
data available at the time of analysis
• Absolute change in sweat chloride• Absolute change from
baseline in
CFQ-R Respiratory Domain score
• Absolute change from baseline in ppFEV1• Absolute change in
BMI
SECONDARY ENDPOINTS
AT EXTENSION STUDY WEEK 24: AT EXTENSION STUDY WEEK 36:
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
Extension Study limitations and disclosures• The study was not
placebo-controlled; therefore, causality cannot be attributed,
and
hypothesis testing cannot determine whether within-arm changes
were due to drug effect• Data in the final analysis may differ from
data reported in this interim analysis• The Extension Study may not
meet the FDA definition of an adequate and well-controlled
study due to its design
HOMOZYGOUS F508del MUTATION
Trial 2
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.15
WK4 EXT WK4 EXT WK8 EXT WK12 EXT WK16 EXT WK20 EXT WK24 EXT WK28
EXT WK32 EXT WK36
8
4
0
Baseline
Ab
solu
te c
han
ge
in p
pF
EV
1 (p
erce
ntag
e p
oin
ts, L
S m
ean
wit
h S
E)
-4
12
16
DAY 15
EXTENSION IA (36 WEEKS)TRIAL 2
TRIKAFTA initiated
TRIKAFTA (N=55)
Tezacaftor/ivacaftor and ivacaftor (N=52)
Tezacaftor/ivacaftor and ivacaftor→TRIKAFTA (N=49)
TRIKAFTA→TRIKAFTA (N=51)
Lung function results with TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor)2,6,7,12
ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE2,12
ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE AT EXTENSION STUDY WEEK
366,7,12a
EXTENSION STUDY
SIGNIFICANT INCREASEin mean absolute change vs
tezacaftor/ivacaftor and ivacaftor at Week 4 (95% CI: 7.4, 12.6;
P
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.16
0
-30
-20
-10
-40
-50
DAY 15
Ab
solu
te c
han
ge
in s
wea
t ch
lori
de
(mm
ol/
L, L
S m
ean
wit
h S
E)
Baseline EXT WK24EXT WK20EXT WK16EXT WK12EXT WK8EXT WK4WK4
10 EXTENSION IA (24 WEEKS)TRIAL 2
TRIKAFTA initiated
TRIKAFTA (N=55)
Tezacaftor/ivacaftor and ivacaftor (N=52)
Tezacaftor/ivacaftor and ivacaftor→TRIKAFTA (N=48)
TRIKAFTA→TRIKAFTA (N=50)
Results for sweat chloride with TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor)2,6,7
HOMOZYGOUS F508del MUTATION
ABSOLUTE CHANGE IN SWEAT CHLORIDE FROM BASELINE AT EXTENSION
STUDY WEEK 242,6,7ab
ABSOLUTE CHANGE IN SWEAT CHLORIDE FROM BASELINE2
SIGNIFICANT REDUCTIONin mean absolute change vs
tezacaftor/ivacaftor and ivacaftor at Week 4 (95% CI: -50.1, -40.1;
P
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.17
8
-8
4
0
BaselineDAY 15 WK4
-4
12
16
20
CF
Q-R
Res
pir
ato
ry D
om
ain
sco
re
(po
ints
, LS
mea
n w
ith
SE
)
EXT WK24EXT WK20EXT WK16EXT WK12EXT WK8EXT WK4
EXTENSION IA (24 WEEKS)TRIAL 2
MCID
TRIKAFTA initiated
TRIKAFTA (N=55)
Tezacaftor/ivacaftor and ivacaftor (N=52)
Tezacaftor/ivacaftor and ivacaftor→TRIKAFTA (N=51)
TRIKAFTA→TRIKAFTA (N=54)
at EXT Week 24 (95% CI: 8.9, 18.8)
points13.8 TRIKAFTAACTIVE COMPARATOR
at EXT Week 24 (95% CI: 9.5, 19.2)
points14.3
The MCID threshold for the CFQ-R Respiratory Domain score is 4
points: In patients with CF with stable respiratory symptoms,
changes of ≥4 points reflect a clinically relevant change that a
patient can detect.11
aFor the TRIKAFTA-to-TRIKAFTA group, baseline from Trial 2 was
used. For the active comparator-to-TRIKAFTA group, baseline from
treatment initiation in the Extension Study was used.7
bCFQ-R Respiratory Domain scores were not collected at Extension
Study Week 36; the results shown include data at Extension Study
Week 24.6
In Trial 2, mean baseline CFQ-R Respiratory Domain score was
70.6 points for patients receiving TRIKAFTA and 72.6 points for
those receiving the active comparator.14
ABSOLUTE CHANGE IN CFQ-R RESPIRATORYDOMAIN SCORE FROM
BASELINE2,12
HOMOZYGOUS F508del MUTATION
CFQ-R Respiratory Domain score measured composite
patient-reported outcomes in the following respiratory symptoms:
waking up from coughing, coughing, difficulty breathing, wheezing,
congestion, and mucus production.10
Results for CFQ-R Respiratory Domain score with TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor)2,6,7,12
TRIAL 2 SECONDARY ENDPOINT
Important Safety InformationCONCOMITANT USE WITH CYP3A
INHIBITORS• Exposure to elexacaftor, tezacaftor, and ivacaftor are
increased when co-administered with
strong or moderate CYP3A inhibitors. The dose of TRIKAFTA should
be reduced when used concomitantly with moderate or strong CYP3A
inhibitors
SIGNIFICANT IMPROVEMENTin mean absolute change vs
tezacaftor/ivacaftor and ivacaftor at Week 4 (95% CI: 11.8, 23.0;
P
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.18
EXTENSION IA (36 WEEKS)TRIAL 2
WK4Baseline
Ab
solu
te c
han
ge
in B
MI (
kg/m
2 , L
S m
ean
wit
h S
E)
1.2
1.0
0.8
1.6
1.4
0.6
0.4
0.2
0.0
-0.2
EXT WK36EXT WK32EXT WK28EXT WK24EXT WK20EXT WK16EXT WK12EXT
WK8EXT WK4
TRIKAFTA initiated
TRIKAFTA (N=55)
Tezacaftor/ivacaftor and ivacaftor (N=52)
Tezacaftor/ivacaftor and ivacaftor→TRIKAFTA (N=51)
TRIKAFTA→TRIKAFTA (N=53)
1.2at EXT Week 36 (95% CI: 0.82, 1.54)
TRIKAFTAACTIVE COMPARATOR
1.3at EXT Week 36 (95% CI: 0.95, 1.65)
kg/m2
kg/m2
HOMOZYGOUS F508del MUTATION
Body mass index results with TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor)2,6,7
ABSOLUTE CHANGE IN BMI FROM BASELINE AT EXTENSION STUDY WEEK
362,6,7a
TRIAL 2/EXTENSION STUDY
Important Safety InformationCATARACTS• Cases of non-congenital
lens opacities have been reported in pediatric patients treated
with ivacaftor-containing regimens. Baseline and follow up
ophthalmological examinations are recommended in pediatric patients
initiating treatment with TRIKAFTA
PEDIATRIC USE• The safety and effectiveness of TRIKAFTA in
patients with CF younger than 6 years
of age have not been established
aFor the TRIKAFTA-to-TRIKAFTA group, baseline from Trial 2 was
used. For the active comparator-to-TRIKAFTA group, baseline from
treatment initiation in the Extension Study was used.7
For context, a person who weighed 132 lb and was 5’5” tall at
baseline and took TRIKAFTA for 36 to 40 weeks may have gained about
6 to 8 lb at the time of the interim analysis.
TRIKAFTATRIKAFTA
Results from this interim analysis are based on an uncontrolled,
open-label study. Click here for additional limitations and
disclosures.
• Patients taking TRIKAFTA in Trial 2 had a mean increase in BMI
of 0.6 kg/m2 at Week 4 (95% CI: 0.41, 0.79). BMI was not a
predefined endpoint; it was measured as part of the physical
assessment. Analyses were not corrected for multiplicity2,12
In Trial 2, mean baseline BMI was 21.8 kg/m2 (range: 16.0, 28.4)
for patients receiving TRIKAFTA and 21.9 kg/m2 (range: 15.6, 34.6)
for patients receiving the active comparator.14
Trial 2
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.19
Safety data from 510 patients with CF in 2 double-blind,
controlled, Phase 3 trials of 24 weeks (Trial 1) and 4 weeks (Trial
2) treatment duration2
• A total of 257 patients with CF aged 12 years and older
received at least one dose of
TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor)
• Except where otherwise noted, the safety data provided below
are from Trial 1, the placebo-
controlled 24-week trial with patients heterozygous for the
F508del mutation and another
specific mutation. The safety profiles for the patients with CF
enrolled in Trials 2 and 3 were
similar to that observed in Trial 1
• With the exception of sex differences in rash, the safety
profile of TRIKAFTA was generally similar
across all subgroups of patients regardless of age, sex,
baseline ppFEV1, and geographic region
Serious adverse reactions2
• In Trial 1, serious adverse reactions that occurred more
frequently in patients treated with TRIKAFTA compared to placebo
were rash (1% vs
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
20
Safety profile (cont’d)Most common adverse reactions in Trial
12
aIncludes upper respiratory tract infection and viral upper
respiratory tract infection.bIncludes abdominal pain, abdominal
pain upper, and abdominal pain lower.cIncludes rash, rash
generalized, rash erythematous, rash macular, and rash
pruritic.
ALT, alanine aminotransferase; AST, aspartate aminotransferase;
CPK, creatine phosphokinase.
• Additional adverse reactions reported in
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
21
Laboratory and vital sign abnormalities
Liver function test elevations2,16
Rash events2
• The overall incidence of rash events was 10% in patients
treated with TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and
ivacaftor) and 5% in placebo-treated patients
• The incidence of rash events was higher in female patients
treated with TRIKAFTA (16%) than in male patients treated with
TRIKAFTA (5%)
• Hormonal contraceptives may play a role in the occurrence of
rash. For patients taking hormonal contraceptives who develop rash,
consider interrupting TRIKAFTA and hormonal contraceptives.
Following the resolution of rash, consider resuming TRIKAFTA
without the hormonal contraceptives. If rash does not recur,
resumption of hormonal contraceptives can be considered
Additional information on rash15
• The median time to onset of first rash event was 12 days
(range 5-157 days) in patients treated with TRIKAFTA and 23 days
(range 1-157 days) in placebo-treated patients. The median duration
of rash events was 8 days (range 1-92 days) in patients treated
with TRIKAFTA and 9 days (range 3-61 days) in placebo-treated
patients
• The rash events were exanthematous—consistent with a typical
drug eruption
• The incidence of adverse reactions of transaminase elevations
(AST and/or ALT) was 11% in patients treated with TRIKAFTA and 4%
in placebo-treated patients2
• No patients treated with TRIKAFTA discontinued due to
transaminase elevations3
• Maximum indirect bilirubin elevations >1.5x ULN occurred in
11% of patients treated with TRIKAFTA. Maximum direct bilirubin
elevations >1.5x ULN occurred in 3% of patients treated with
TRIKAFTA2
• No patients treated with TRIKAFTA developed maximum direct
bilirubin elevation >2x ULN2
Safety profile (cont’d)
TRIKAFTA(N=202)
Placebo(N=201)
Elevated ALT or AST, n (%)
>3x ULN 16 (8) 11 (5)
>5x ULN 5 (2) 3 (1)
>8x ULN 3 (1) 2 (1)
Total bilirubin elevation >2x ULN, % 4
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.22
Safety profile (cont’d)Laboratory and vital sign abnormalities
(cont'd)
Increased CPK2
• The incidence of maximum CPK >5x ULN was 10% in patients
treated with TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and
ivacaftor) and 5% in placebo-treated patients
• Among the patients treated with TRIKAFTA with CPK elevation
>5x ULN, 14% (3/21) required treatment interruption and none
discontinued treatment
• The proportion of patients who had an increase in systolic
blood pressure of >140 mmHg and 10 mmHg from baseline on at
least 2 occasions:
- 4% of patients treated with TRIKAFTA
- 1% of placebo-treated patients
• The proportion of patients who had an increase in diastolic
blood pressure of >90 mmHg and 5 mmHg from baseline on at least
2 occasions:
- 1% of patients treated with TRIKAFTA
- 2% of placebo-treated patients
Increased blood pressure2
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
TRIKAFTA(N=202)
Placebo(N=201)
Mean systolic blood pressure, mmHgBaseline 113 114
Maximum increase from baseline 3.5 0.9
Mean diastolic blood pressure, mmHgBaseline 69 70
Maximum increase from baseline 1.9 0.5
Maximum increase from baseline in mean blood pressureMaximum
increase from baseline in mean blood pressure
Safety Profile
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.23
Safety results from the Extension Study Interim Analysis6,7
• The safety results at the time of the interim analysis
remained consistent with the safety
results observed in Trial 1. No new safety concerns were
identified
• Results presented are from an interim analysis. Data from
additional interim analyses and
the final analysis may differ from what are presented here
• Incidence of adverse events are expected to increase as the
mean exposure to study
drug increases
• 1.4% of patients (n=7) had adverse events leading to treatment
discontinuation
• Serious adverse reactions occurring in ≥1% of patients taking
TRIKAFTA were infective pulmonary exacerbation of CF (8.3%), distal
intestinal obstruction syndrome (1.0%), and
hemoptysis (1.0%)
• The majority of adverse events were considered mild or
moderate in severity
- Patients with adverse events by maximum severity: mild
(35.6%), moderate (47.0%),
severe (10.1%), and life-threatening (0.4%)
506 PATIENTS RECEIVED ≥1 DOSE OF TRIKAFTA
37.2 WEEKS MEAN EXPOSURE
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
Results from this interim analysis are based on an uncontrolled,
open-label study. Click here for additional limitations and
disclosures.
Safety results for TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor
and ivacaftor) from the interim analysis of the open-label
Extension Study
TRIKAFTA n (%)(N=506)
Infective pulmonary exacerbation of CF 127 (25.1%)
Cough 118 (23.3%)
Oropharyngeal pain 74 (14.6%)
Nasopharyngitis 69 (13.6%)
Headache 66 (13.0%)
Sputum increased 63 (12.5%)
Upper respiratory tract infection 60 (11.9%)
Fatigue 51 (10.1%)
Most common adverse reactions occurring in ≥10% of patients in
the interim analysis
Safety Profile
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.24
Safety results from the Extension Study Interim Analysis
(cont’d)6,7
Liver function test elevations
• 7.1% of patients experienced elevated transaminases, the
majority (89%) of which were
considered mild or moderate in severity and were associated with
ALT/AST elevations 5x ULN. Four patients required treatment
interruption, and
none discontinued treatment
Increased blood pressure
• Mean systolic and diastolic blood pressure in the Extension
Study were consistent with those
from Trial 1
- Patients who transitioned from placebo to TRIKAFTA experienced
an increase in mean
blood pressure that was similar to that observed in the TRIKAFTA
group in Trial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
aIncludes dermatitis, drug eruption, rash, rash erythematous,
rash maculopapular, rash papular, and rash pruritic.17
Results from this interim analysis are based on an uncontrolled,
open-label study. Click here for additional limitations and
disclosures.
Safety results for TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor
and ivacaftor) fromthe interim analysis of the open-label Extension
Study (cont’d)
Safety Profile
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
25
Trial 3: An open-label study in patients with CF aged 6 through
11 years18
aAll patients who completed the last treatment period visit and
did not permanently discontinue the study drug were enrolled in the
open-label Extension Study.
bKey exclusion criteria included clinically significant
cirrhosis with or without portal hypertension, lung infection with
organisms associated with a more rapid decline in pulmonary status
(including, but not limited to, Burkholderia cenocepacia,
Burkholderia dolosa, and Mycobacterium abscessus), and solid organ
or hematologic transplantation.
• Phase 3, 24-week, open-label, multicenter study evaluating the
safety and tolerability of TRIKAFTA
Trial 3 was an open-label study with no placebo-controlled arm;
therefore, causality cannot be attributed to TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor).
TRIAL DESIGNa
KEY INCLUSION CRITERIAb
66 patients received TRIKAFTA.
Dosage was based on weight:
•
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
26
Trial 3: An open-label study in patients with CF aged 6 through
11 years18 (cont’d)
Results from this trial are based on an uncontrolled, open-label
study. Click here for more trial design information.
Safety analyses (primary endpoint)
• All patients (N=66) in the study were included in the safety
analysis. If a patient was unable to complete an in-clinic visit,
safety information was collected remotely with site personnel
• If a patient was unable to complete laboratory tests at the
scheduled Week 24 time point, unscheduled visits were conducted
after Week 24
• The main safety analyses were based on data collected up to
Week 24. Additional analyses were conducted with data from
unscheduled visits, and those results were consistent with the main
analyses
Efficacy analyses (secondary endpoints)• N values declined over
time for each efficacy endpoint, as some patients
were unable to complete in-clinic visits due to the pandemic
• The N values differ across endpoints due to varying
restrictions placed on data collection during the pandemic
• The main efficacy analyses were based on data collected
in-clinic through Week 24. Additional analyses were performed to
evaluate the impact of missing data and to evaluate home-based
data. All analyses were consistent with the main analyses
Study disclosures and impact of COVID-19
• This 24-week safety study was conducted between August 2019
and August 2020, and overlapped with the COVID-19 pandemic
• Due to the onset of the pandemic, some patients were unable to
complete in-person evaluations at all time points. For patients who
were unable to complete in-person visits, data were collected
remotely and those patients remained in the study
• Additional analyses were performed to evaluate data collected
from unscheduled visits. The results of those analyses were
consistent with the main analyses
Trial 3
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor)
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
27
Trial 3: An open-label study in patients with CF aged 6 through
11 years18 (cont’d)
Results from this trial are based on an uncontrolled, open-label
study. Click here for more trial design information.
FROM BASELINE THROUGH WEEK 24:
SELECT SECONDARY ENDPOINTS
• Absolute change in ppFEV1• Absolute change in sweat chloride
concentration• Absolute change in CFQ-R Respiratory Domain score•
Absolute change in LCI2.5
FROM BASELINE AT WEEK 24:
• Absolute change in BMI and BMI-for-age z-score
PRIMARY ENDPOINT
• Safety and tolerability of TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor) from baseline as
determined by AEs and clinical and laboratory assessmentsa
aSafety and tolerability assessments were based on AEs, clinical
laboratory values, electrocardiograms, vital signs, pulse oximetry,
and ophthalmologic examinations.
AEs, adverse events; LCI, lung clearance index; SD, standard
deviation.
TRIKAFTA
Sex, female, % 59.1
Mean age, years (SD) 9.3 (1.9)
Mean ppFEV1 (SD) 88.8 (17.7)
Mean sweat chloride, mmol/L (SD) 102.2 (9.1)
Mean BMI, kg/m2 (SD) 16.39 (1.69)
Mean BMI-for-age z-score (SD) -0.16 (0.74)
Mean LCI2.5, units (SD) 9.77 (2.68)
Mean CFQ-R Respiratory Domain score, points (SD) 80.3 (15.2)
Baseline characteristics
Trial 3
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.28
Safety results from Trial 3 were similar to those observed in
Trials 1 and 2 in patients aged 12 years and older• A total of 66
patients with CF aged 6 through 11 years received at least 1 dose
of TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor)
Results from this trial are based on an uncontrolled, open-label
study. Click here for more trial design information.
Trial 3 safety profile18
Most common adverse reactions in Trial 3
TRIKAFTA n (%)(N=66)
Cough 28 (42.4)
Headache 16 (24.2)
Pyrexia 14 (21.2)
Oropharyngeal pain 12 (18.2)
Upper respiratory tract infection 11 (16.7)
Nasal congestion 10 (15.2)
Rasha 8 (12.1)
Abdominal pain 8 (12.1)
Rhinorrhea 8 (12.1)
Viral upper respiratory tract infection 8 (12.1)
ALT increased 7 (10.6)
Diarrhea 7 (10.6)
Influenza 7 (10.6)
Vomiting 7 (10.6)
Incidence of adverse reactions occurring in ≥10% of patients
Study disclosures and impact of COVID-19: safety analyses
(primary endpoint)
• All patients (N=66) in the study were included in the safety
analysis. If a patient was unable to complete an in-clinic visit,
safety information was collected remotely with site personnel
• If a patient was unable to complete laboratory tests at the
scheduled Week 24 time point, unscheduled visits were conducted
after Week 24
• The main safety analyses were based on data collected up to
Week 24. Additional analyses were conducted with data from
unscheduled visits, and those results were consistent with the main
analyses
Click here for more information about the impact of COVID-19 on
the study.
aIncludes preferred term of rash only.
Trial 3
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
29
TRIKAFTA (N=66)
Elevated ALT or AST, n (%)
>3x ULN 7 (10.6)
>5x ULN 1 (1.5)
>8x ULN 0
Total bilirubin elevation >2x ULN, % 0
Incidence of maximum transaminase and maximum total bilirubin
elevations
• The incidence of adverse reactions of transaminase elevations
(AST and/or ALT) was 10.6% in patients treated with TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor). No patients
discontinued due to transaminase elevations
• Maximum indirect bilirubin elevations >2x to ≤3x ULN
occurred in 4.6% of patients treated with TRIKAFTA. Maximum direct
bilirubin elevations >1.5x ULN occurred in 0%. No patients had
transaminase elevations >3x ULN and total bilirubin >2x
ULN
• No patients aged 6 through 11 years had creatine kinase levels
>5x ULN
Rash events18,19
• Rash events occurred in 15 (22.7%) patients. All rash events
were mild or moderate in severity as determined by the study
investigatora
• 1 patient (1.5%) discontinued due to rash erythematous; all
other rash events resolved without interruption of study drug
Serious adverse reactions
• 1 patient (1.5%) experienced serious adverse reactions. These
concurrent reactions were rhinovirus infection, metapneumovirus
infection, and pneumonia
Laboratory and vital sign abnormalities
Liver function test elevations
Trial 3 safety profile18 (cont’d)
Results from this trial are based on an uncontrolled, open-label
study. Click here for more trial design information.
aIncludes rash, rash erythematous, rash maculopapular, rash
papular, and skin exfoliation.
Trial 3
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.30
Trial 3 secondary endpoints
ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE THROUGH WEEK 2418
ABSOLUTE CHANGE IN SWEAT CHLORIDE FROM BASELINE THROUGH WEEK
2418
SECONDARY ENDPOINT
SECONDARY ENDPOINT
Important Safety InformationLIVER FUNCTION TEST ELEVATIONS•
Elevated transaminases have been observed in patients with CF
treated with TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor). Bilirubin
elevations have also been observed with TRIKAFTA treatment.
Assessments of liver function tests (ALT, AST, and bilirubin) are
recommended prior to initiating TRIKAFTA, every 3 months during the
first year of treatment, and annually thereafter
Results from this trial are based on an uncontrolled, open-label
study. Click here for more trial design information.
10.2 percentage pointsINCREASE IN ppFEV1(95% CI: 7.9, 12.6) |
Baseline percent, mean (SD): 88.8 (17.7)N at baseline: 62 | N at
Week 24: 15
-60.9 mmol/LDECREASE IN SWEAT CHLORIDE(95% CI: -63.7, -58.2) |
Baseline mmol/L, mean (SD): 102.2 (9.1)N at baseline: 62 | N at
Week 24: 28
Study disclosures and impact of COVID-19: efficacy analyses
(secondary endpoints)18
• N values declined over time for each efficacy endpoint, as
some patients were unable to complete in-office visits due to the
pandemic
• The N values differ across endpoints due to varying
restrictions placed on data collection during the pandemic
• The main efficacy analyses were based on data collected
in-clinic through Week 24. Additional analyses were performed to
evaluate the impact of missing data and to evaluate home-based
data. All analyses were consistent with the main analyses
Click here for more information about the impact of COVID-19 on
the study.
Trial 3
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
31
Results from this trial are based on an uncontrolled, open-label
study. Click here for more trial design information.
Important Safety InformationLIVER FUNCTION TEST ELEVATIONS
(cont’d)
• In the event of significant elevations in liver function
tests, e.g. ALT or AST >5x ULN or ALT or AST >3x ULN with
bilirubin >2x ULN, dosing should be interrupted and laboratory
tests closely followed until the abnormalities resolve. Following
the resolution of liver function test elevations, consider the
benefits and risks of resuming treatment
Trial 3 secondary endpoints (cont’d)
CFQ-R Respiratory Domain score measured composite
patient-/caregiver-reported outcomes in the following respiratory
symptoms: waking up from coughing, wheezing, coughing, congestion,
difficulty breathing, and mucus production.10
The MCID threshold for CFQ-R Respiratory Domain score is 4
points in patients with CF with stable respiratory symptoms and
represents the minimal change a patient can detect.11
ABSOLUTE CHANGE IN CFQ-R RESPIRATORY DOMAIN SCORE FROM BASELINE
THROUGH WEEK 2418
SECONDARY ENDPOINT
7.0 pointsINCREASE IN CFQ-R RESPIRATORY DOMAIN SCORE(95% CI:
4.7, 9.2) | Baseline score, mean (SD): 80.3 (15.2)N at baseline: 65
| N at Week 24: 36
ABSOLUTE CHANGE IN BMI AND BMI-FOR-AGE Z-SCORE FROM BASELINE AT
WEEK 2418
SECONDARY ENDPOINT
1.02 kg/m2INCREASE IN BMI(95% CI: 0.76, 1.28) | Baseline kg/m2,
mean (SD): 16.39 (1.69) N at baseline: 66 | N at Week 24: 33
0.37INCREASE IN BMI-FOR-AGE Z-SCORE(95% CI: 0.26, 0.48) |
Baseline score, mean (SD): -0.16 (0.74) N at baseline: 66 | N at
Week 24: 33
Body mass index z-scores, also called BMI SD scores, are
measures of relative weight adjusted for a child’s age and sex. For
example, a child age 9 starting with a BMI around the 60th
percentile would increase to around the 70th percentile.20,21
Trial 3
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor).
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
32
Important Safety InformationCONCOMITANT USE WITH CYP3A
INDUCERS
• Exposure to ivacaftor is significantly decreased and exposure
to elexacaftor and tezacaftor are expected to decrease by the
concomitant use of strong CYP3A inducers, which may reduce the
therapeutic effectiveness of TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor). Co-administration
with strong CYP3A inducers is not recommended
Trial 3 secondary endpoints (cont’d)
Results from this trial are based on an uncontrolled, open-label
study. Click here for more trial design information.
ABSOLUTE CHANGE IN LCI2.5 FROM BASELINE THROUGH WEEK 2418
SECONDARY ENDPOINT
-1.71 units DECREASE IN LCI2.5(95% CI: -2.11, -1.30) | Baseline
units, mean (SD): 9.77 (2.68)N at baseline: 53 | N at Week 24:
22
LCI is a measure of lung physiology derived from multiple breath
washout tests. LCI represents a measure of the number of times the
volume of gas in the lung at the start of the washout must be
turned over in order to wash out the tracer gas to the predefined
endpoint. With increasing disease severity, LCI increases.22
Reid, 11F508del/another CF gene mutation
People with CF pictured may or may not be taking TRIKAFTA.
Trial 3
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
33
Recommended dosage
Dosing and administration2
ivacaftor 75 mg
1 light blue tablet
elexacaftor 50 mg/ tezacaftor 25 mg/ ivacaftor 37.5 mg
2 light orange tablets
Tablets are not actual size.
MORNING EVENING~12 hours apart
• TRIKAFTA is a fixed-dose combination containing elexacaftor 50
mg, tezacaftor 25 mg, and ivacaftor 37.5 mg co-packaged with
ivacaftor 75 mg tablets
• The elexacaftor, tezacaftor, and ivacaftor tablets are light
orange, capsule-shaped, and debossed with “T50” on one side and
plain on the other
• The ivacaftor tablets are light blue, capsule-shaped, and
printed with “V 75” in black ink on one side and plain on the
other
For patients aged 6 through 11 years weighing
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
34
Not actual size.NDC: 51167-331-01
Recommended dosage
Dosing and administration2 (cont’d)
Tablets are not actual size.
For patients aged 6 through 11 years weighing ≥30 kg (≥66 lb)
and 12 years and older2,23
MORNING EVENING~12 hours apart
• TRIKAFTA is a fixed-dose combination containing elexacaftor
100 mg, tezacaftor 50 mg, and ivacaftor 75 mg co-packaged with
ivacaftor 150 mg tablets
• The elexacaftor, tezacaftor, and ivacaftor tablets are orange,
capsule-shaped, and debossed with “T100” on one side and plain on
the other
• The ivacaftor tablets are light blue, capsule-shaped, and
printed with “V 150” in black ink on one side and plain on the
other
For patients aged 6 through 11 years weighing ≥30 kg (≥66 lb)
and 12 years and older
Product packaging• TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor
and ivacaftor) is supplied in cartons containing 4 weekly wallets,
each with 21 tablets
ivacaftor 150 mg
1 light blue tablet
elexacaftor 100 mg/ tezacaftor 50 mg/
ivacaftor 75 mg
2 orange tablets
Dosing/DDI
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
35
Dosing and administration2 (cont’d)Dosage adjustments for
hepatic impairment
In patients with severe hepatic impairment (Child-Pugh Class
C)
In patients with moderate hepatic impairment (Child-Pugh Class
B)
SHOULD NOT BE USED
aLiver function tests should be closely monitored. b TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor) is not recommended
for patients with moderate hepatic impairment. If TRIKAFTA is used
in patients with moderate hepatic impairment, it should be with
caution and at a reduced dose, as follows:
• Day 1: Patients should take 2 elexacaftor/tezacaftor/ivacaftor
tablets in the morning • Day 2: Patients should take 1
elexacaftor/tezacaftor/ivacaftor tablet in the morning • Continue
alternating Day 1 and Day 2 dosing thereafter• No evening dose of
the ivacaftor tablet should be taken
• No dose adjustment is required for patients with mild hepatic
impairment. Liver function tests should be closely monitored
• TRIKAFTA has not been studied in patients with severe hepatic
impairment, but the exposure is expected to be higher than in
patients with moderate hepatic impairment. TRIKAFTA should not be
used in patients with severe hepatic impairment
• No dosage adjustment is recommended in patients with mild or
moderate renal impairment. TRIKAFTA has not been studied in
patients with severe renal impairment or end-stage renal disease
and should be used with caution in these patients
MISSED DOSE
MISSED MORNING DOSE
• If ≤6 hours have passed, take as soon as possible and take the
evening dose as scheduled
• If >6 hours have passed, take the missed morning dose as
soon as possible, but do not take evening dose and continue as
scheduled the following day
MISSED EVENING DOSE
• If ≤6 hours have passed, take as soon as possible and take
next morning dose as scheduled
• If >6 hours have passed, do not take missed dose and take
next morning dose as scheduled the following day
Morning and evening doses should not be taken at the same
time
USE SHOULD ONLY BE CONSIDERED WHEN THERE IS A CLEAR MEDICAL NEED
AND THE BENEFIT EXCEEDS THE RISKab
Dosing/DDI
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
36
TRIKAFTA interactionDose recommendation
## Increased exposure of TRIKAFTA expected with strong or
moderate CYP3A inhibitors
Moderate CYP3A inhibitors including: fluconazole,
erythromycin
ALTERNATE TABLETS EVERY MORNING
aContinue dosing with 2 elexacaftor/tezacaftor/ivacaftor tablets
twice a week, approximately 3 to 4 days apart.bContinue dosing with
2 elexacaftor/tezacaftor/ivacaftor tablets and 1 ivacaftor tablet
on alternate days.
Drug interactions2
Strong CYP3A inhibitors including: ketoconazole, itraconazole,
posaconazole, voriconazole, telithromycin, clarithromycin
NO TABLET IN THE EVENING
NO TABLET IN THE EVENING
IN THE MORNING (TWICE A WEEK)
DAY 1 elexacaftor 50 mg/tezacaftor 25 mg/ ivacaftor 37.5 mg
2 light orange tablets
DAY 1 elexacaftor 50 mg/tezacaftor 25 mg/ ivacaftor 37.5 mg
2 light orange tablets
DAY 4a
elexacaftor 50 mg/tezacaftor 25 mg/ ivacaftor 37.5 mg
2 light orange tablets
DAY 2b
ivacaftor 75 mg
1 light blue tablet
66 Reduced exposure of TRIKAFTA expected with strong CYP3A
inducers
• The concomitant use of CYP3A inducers may reduce TRIKAFTA
efficacy
Strong CYP3A inducers including:rifampin, rifabutin,
phenobarbital, carbamazepine, phenytoin, St. John’s wort (Hypericum
perforatum)
CONCOMITANT USE NOT RECOMMENDED
Drug interaction profiles and related dosing considerations2
Clinical considerations for TRIKAFTA®
(elexacaftor/tezacaftor/ivacaftor and ivacaftor) are based on drug
interaction studies, modeling, other clinical factors, and/or
predicted interactions due to elimination pathways. Dosage
adjustments are required for concomitant use with strong and
moderate CYP3A inhibitors.
For patients aged 6 through 11 years weighing
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
37
aContinue dosing with 2 elexacaftor/tezacaftor/ivacaftor tablets
twice a week, approximately 3 to 4 days apart.bContinue dosing with
2 elexacaftor/tezacaftor/ivacaftor tablets and 1 ivacaftor tablet
on alternate days.
## Increased exposure of substrates may occur with TRIKAFTA
• Ivacaftor may inhibit CYP2C9
• Ivacaftor or tezacaftor/ivacaftor increases digoxin exposure
and may increase exposure of other sensitive P-gp substrates
• Elexacaftor and M23-ELX inhibit OATP1B1 and OATP1B3 in
vitro
## Increased exposure of TRIKAFTA expected with strong or
moderate CYP3A inhibitors
CYP2C9 substrates including: warfarin, glimepiride,
glipizide
P-glycoprotein (P-gp) substrates including: digoxin,
cyclosporine, everolimus, sirolimus, tacrolimus
OATP1B1 and OATP1B3 substrates including2: statins, glyburide,
nateglinide, repaglinide
Caution and appropriate monitoring should be used with CYP2C9,
P-gp, and OATP1B1 and OATP1B3 substrates
Drug interaction profiles and related dosing considerations2
Drug interactions2 (cont’d)
Strong CYP3A inhibitors including: ketoconazole, itraconazole,
posaconazole, voriconazole, telithromycin, clarithromycin
Moderate CYP3A inhibitors including: fluconazole,
erythromycin
IN THE MORNING (TWICE A WEEK)
ALTERNATE TABLETS EVERY MORNING
66 Reduced exposure of TRIKAFTA expected with strong CYP3A
inducers
• The concomitant use of CYP3A inducers may reduce TRIKAFTA
efficacy
Strong CYP3A inducers including:rifampin, rifabutin,
phenobarbital, carbamazepine, phenytoin, St. John’s wort (Hypericum
perforatum)
CONCOMITANT USE NOT RECOMMENDED
TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor)
interaction
Dose recommendation
For patients aged 6 through 11 years weighing ≥30 kg (≥66 lb)
and 12 years and older2,23
NO TABLET IN THE EVENING
DAY 1 elexacaftor 100 mg/tezacaftor 50 mg/
ivacaftor 75 mg
2 orange tablets
DAY 4a elexacaftor 100 mg/tezacaftor 50 mg/
ivacaftor 75 mg
2 orange tablets
NO TABLET IN THE EVENING
DAY 1 elexacaftor 100 mg/tezacaftor 50 mg/
ivacaftor 75 mg
2 orange tablets
DAY 2b
ivacaftor 150 mg
1 light blue tablet
Dosing/DDI
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.38
References: 1. Data on file. Vertex Pharmaceuticals
Incorporated. Boston, MA. REF-4142 (v1.0); 2019. 2. TRIKAFTA
[prescribing information]. Boston, MA: Vertex Pharmaceuticals
Incorporated; June 2021.3. Middleton PG, Mall MA, Dřevínek P, et
al. Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a
singlePhe508del allele. N Engl J Med. 2019;381(19):1809-1819.
doi:10.1056/NEJMoa1908639 4. Cystic FibrosisFoundation Patient
Registry. 2019 Annual Data Report. Cystic Fibrosis Foundation;
2019. AccessedMay 12, 2021.
https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2019-Patient-Registry-Annual-Data-Report.pdf.
5. Middleton PG, Mall MA, Dřevínek P, et al.
Elexacaftor–tezacaftor–ivacaftorfor cystic fibrosis with a single
Phe508del allele. N Engl J Med. (suppl). 2019;381(19):1809-1819.
doi:10.1056/NEJMoa1908639 6. Data on file. Vertex Pharmaceuticals
Incorporated. Boston, MA. REF-6056 (v1.0); 2020.7. Griese M, Costa
A, Linnemann RW, et al. Safety and efficacy of
elexacaftor/tezacaftor/ivacaftor for 24 weeks orlonger in people
with cystic fibrosis and one or more F508del alleles: interim
results of an open-label phase 3 clinicaltrial. Am J Respir Crit
Care Med. 2021;203(3):381-385. doi:10.1164/rccm.202008-3176LE 8.
Data on file. VertexPharmaceuticals Incorporated. Boston, MA.
REF-3492 (v1.0); 2019. 9. Data on file. Vertex
PharmaceuticalsIncorporated. Boston, MA. REF-3898 (v1.0); 2019. 10.
CFQ-R Cystic Fibrosis Questionnaire-Revised. Cystic
FibrosisFoundation. Quittner, Modi, Watrous and Messer, 2000.
Revised 2002. English version 2.0. 11. Quittner AL, Modi
AC,Wainwright C, et al. Determination of the minimal clinically
important difference scores for the Cystic
FibrosisQuestionnaire-Revised respiratory symptom scale in two
populations of patients with cystic fibrosis and chronicPseudomonas
aeruginosa airway infection. Chest. 2009;135(6):1610-1618.
doi:10.1378/chest.08-1190 12. Heijerman HG,McKone EF, Downey DG, et
al. Efficacy and safety of the elexacaftor plus tezacaftor plus
ivacaftorcombination regimen in people with cystic fibrosis
homozygous for the F508del mutation: a double-blind,randomised,
phase 3 trial [published correction appears in Lancet.
2020;395(10238):1694]. Lancet.2019;394(10212):1940-1948.
doi:10.1016/S0140-6736(19)32597-8 13. Heijerman HG, McKone EF,
Downey DG,et al. Efficacy and safety of the elexacaftor plus
tezacaftor plus ivacaftor combination regimen in people with
cysticfibrosis homozygous for the F508del mutation: a double-blind,
randomised, phase 3 trial. Lancet
(suppl).2019;394(10212):1940-1948. 14. Data on file. Vertex
Pharmaceuticals Incorporated. Boston, MA. REF-3497 (v1.0);2019. 15.
Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA.
REF-3535 (v3.0); 2019. 16. Data on file.Vertex Pharmaceuticals
Incorporated. Boston, MA. REF-3493 (v1.0); 2019. 17. Data on file.
VertexPharmaceuticals Incorporated. Boston, MA. REF-6673 (v1.0);
2020. 18. Zemanick ET, Taylor-Cousar JL, DaviesJ, et al. A phase 3
open-label study of ELX/TEZ/IVA in children 6 through 11 years of
age with CF and at least oneF508del allele. Am J Respir Crit Care
Med. Published online March 18, 2021.
doi:10.1164/rccm.202102-0509OC 19.Data on file. Vertex
Pharmaceuticals Incorporated. Boston, MA. REF-9151 (v1.0); 2021.
20. Must A, Anderson SE.Body mass index in children and
adolescents: considerations for population-based applications. Int
J Obes (Lond).2006;30(4):590-594. doi:10.1038/sj.ijo.0803300 21.
Data on file. Vertex Pharmaceuticals Incorporated. Boston,MA.
REF-9234 (v1.0); 2021. 22. Horsley A. Lung clearance index in the
assessment of airways disease. Respir Med.2009;103(6):793-799.
doi:10.1016/j.rmed.2009.01.025 23. Data on file. Vertex
Pharmaceuticals Incorporated.Boston, MA. REF-6607 (v2.0); 2021.
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf
-
Dosing/DDIImportant Safety Information Trial 3MOA/Eligibility
Trial 2 Safety ProfileTrial 1
3939
TRIKAFTA is manufactured for Vertex Pharmaceuticals
Incorporated.TRIKAFTA, the TRIKAFTA logo, Vertex, and the Vertex
logo are registered trademarks of Vertex Pharmaceuticals
Incorporated.All other trademarks referenced herein are the
properties of their respective owners.© 2021 Vertex Pharmaceuticals
Incorporated | VXR-US-28-1900303 (v4.0) | 06/2021
Please click for Important Safety Information and full
Prescribing Information for TRIKAFTA.
PATIENTS 12 YEARS AND OLDER HETEROZYGOUS FOR THE F508del
MUTATION AND ANOTHER SPECIFIC MUTATIONa
A breakthrough treatment for patients with CF 6 years and older
with responsive mutations2
a These specific mutations in the CFTR gene resulted in either
no CFTR protein or a CFTR protein that is not responsive to
ivacaftor and tezacaftor/ivacaftor.2,5
vs active comparator at Week 4 (95% CI: 7.4, 12.6; P