Clinical Brochure | TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor … · 2020. 12. 22. · clinical brochure table of contents important safety information mechanism of action responsive

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



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


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



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®


MOA/Eligibility


http://www.trikaftahcp.comhttps://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf



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



• 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


HETEROZYGOUS F508del/OTHER SPECIFIC MUTATION

Trial 1




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



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


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


41.8significant reduction for TRIKAFTA vs placebo through Week 24 (95% CI: -44.4, -39.3; P



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


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



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


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



• 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



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:


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


Trial 2




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


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



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)




Results for sweat chloride with TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor)2,6,7


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



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


MCID

TRIKAFTA initiated

TRIKAFTA (N=55)




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


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




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)




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


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




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


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


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



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


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




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



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




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


aIncludes dermatitis, drug eruption, rash, rash erythematous, rash maculopapular, rash papular, and rash pruritic.17


Safety results for TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor) fromthe interim analysis of the open-label Extension Study (cont’d)

Safety Profile



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:

•


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)



27

Trial 3: An open-label study in patients with CF aged 6 through 11 years18 (cont’d)


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





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)


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



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)


aIncludes rash, rash erythematous, rash maculopapular, rash papular, and skin exfoliation.

Trial 3





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®



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



31


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).



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)


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




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


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




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




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


IN THE MORNING (TWICE A WEEK)

DAY 1 elexacaftor 50 mg/tezacaftor 25 mg/ ivacaftor 37.5 mg


DAY 1 elexacaftor 50 mg/tezacaftor 25 mg/ ivacaftor 37.5 mg


DAY 4a

elexacaftor 50 mg/tezacaftor 25 mg/ ivacaftor 37.5 mg


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


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


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


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





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.




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


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

Documents

Clinical Brochure | TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor … · 2020. 12. 22. · clinical brochure table of contents important safety information mechanism of action responsive