Clinical Trials for Age 12 Years and Older:
Patients with CF age 12 years and older who are homozygous for the F508del mutation in the CFTR gene
STUDY DESIGN
A Phase 3, 24-week, randomized, double-blind, placebo-controlled, two-arm study evaluating efficacy and safety of SYMDEKO1,2
24 weeks
SYMDEKO (n=248)
Placebo (n=256)
SYMDEKO (n=248)
Placebo (n=256)
- Patients (N=504) were randomized to receive either tezacaftor/ivacaftor 100 mg/150 mg qd and ivacaftor 150 mg qd 12 hours apart or placebo q12h with fat-containing food, in addition to their currently prescribed CF therapies
Study Population
- Selected inclusion criteria1,2
Confirmed CF diagnosis and clinically stable
Patients ≥12 years of age (mean age, 26.3 years) and homozygous for the F508del mutation
Percent predicted FEV1 (ppFEV1) ≥40% and ≤90% at screening (mean baseline ppFEV1, 60.0)
- Selected exclusion criteria1
History of colonization with organisms associated with a more rapid decline in pulmonary status, such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus
Two or more abnormal liver function tests at screening (ALT, AST, AP, GGT ≥3 x ULN or total bilirubin ≥2 x ULN), or AST or ALT ≥5 x ULN
Endpoints
- Primary endpoint1
-
Mean absolute change in ppFEV₁ from baseline through Week 24
-
- Key secondary endpoints1,2
-
Relative change in ppFEV₁ from baseline through Week 24
-
Number of pulmonary exacerbations from baseline through Week 24*
-
Absolute change in BMI from baseline at Week 24
-
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain score from baseline through Week 24
-
CFQ-R Respiratory Domain score evaluated respiratory symptoms, including cough, sputum production, and difficulty breathing3
-
-
- A hierarchical testing procedure was used for the primary and key secondary endpoints. For an endpoint to be significant, both it and all previous tests in the hierarchy had to achieve P≤0.051,4
*A pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre‑specified sino-pulmonary signs/symptoms.
SUMMARY OF RESULTS
PRIMARY ENDPOINT: MEAN ABSOLUTE CHANGE IN ppFEV11,2
4.0 PERCENTAGE POINTS SIGNIFICANT IMPROVEMENT VS PLACEBO
in LS mean absolute change in ppFEV₁ from baseline through Week 24 (95% CI: 3.1, 4.8; P<0.0001)1,2
Absolute Change in ppFEV1 in EVOLVE1,2
CHANGES IN ppFEV1 FROM BASELINE VS PLACEBO THROUGH WEEK 241,4,5,a
Subgroups by baseline ppFEV1
Absolute change in ppFEV1 from baseline
(percentage points)
<40%
(SYMDEKO n=23; placebo n=24; range 27.8% to <40%)
+3.5
(95% CI: 1.0, 6.1)
≥40 to <70%
(SYMDEKO n=156; placebo n=152)
+4.2
(95% CI: 3.1, 5.2)
≥70%
(SYMDEKO n=66; placebo n=80; range ≥70% to 96.2%)
+3.7
(95% CI: 2.2, 5.2)
ᵃIn EVOLVE, while ppFEV1 at screening was 40-90%, changes may have occurred before baseline.1,2
- Improvements in mean absolute change in ppFEV1 vs placebo across pre-specified subgroups were observed regardless of age, sex, baseline ppFEV1, colonization with Pseudomonas, and concomitant use of standard-of-care medications for CF1,2,4
KEY SECONDARY ENDPOINT: RELATIVE CHANGE IN ppFEV11
6.8 PERCENT SIGNIFICANT IMPROVEMENT VS PLACEBO
in LS mean relative change in ppFEV1 from baseline through Week 24 (95% CI: 5.3, 8.3; P<0.0001)1
KEY SECONDARY ENDPOINT: NUMBER OF PULMONARY EXACERBATIONS1,2
Annualized Rate of Pulmonary Exacerbations Through Week 241,2
Pulmonary exacerbations: Additional analyses
- 47% reduction in event rate leading to IV antibiotic use vs placebo (74 events for placebo vs 39 events for SYMDEKO [RR: 0.53, 95% CI: 0.34, 0.82]), not statistically significant2,6,b
- 22% reduction in event rate leading to hospitalization (33 events for placebo vs 26 for SYMDEKO [RR: 0.78, 95% CI: 0.44, 1.36]), not statistically significant6,b
bEstimated event rate per year calculated using 48 weeks per year.2
KEY SECONDARY ENDPOINT: LS MEAN ABSOLUTE CHANGE IN BODY MASS INDEX (BMI)1
+0.06 kg/m2 IN THE SYMDEKO GROUP VS PLACEBO
at Week 24 (95% CI: -0.08, 0.19) (not statistically significant)1,2,c
ᶜPlacebo baseline BMI: 21.12 kg/m²; SYMDEKO baseline BMI: 20.96 kg/m².²
KEY SECONDARY ENDPOINT: LS MEAN ABSOLUTE CHANGE IN CFQ-R RESPIRATORY DOMAIN SCORE1
5.1 POINT INCREASE VS PLACEBO
in absolute change from baseline through Week 24 (95% CI: 3.2, 7.0) (not statistically significant)1,2,d
dThe MCID threshold for CFQ-R Respiratory Domain scores is 4 points in patients with CF with stable respiratory symptoms, which is the minimal change a patient can detect.⁷
ALT, alanine transaminase; AST, aspartate transaminase; AP, alkaline phosphatase; BMI, body mass index; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CI, confidence interval; GGT, gamma-glutamyl transferase; IV, intravenous; LS, least squares; MCID, minimal clinically important difference; ppFEV₁, percent predicted forced expiratory volume in 1 second; q12h, every 12 hours; qd, once a day; RR, relative risk; ULN, upper limit of normal.
Patients age 12 years and older with CF heterozygous for F508del and a mutation predicted to be responsive to tezacaftor/ivacaftor
STUDY DESIGN
A Phase 3, randomized, double-blind, placebo-controlled, 2-period, 8-week crossover study evaluating efficacy and safety of SYMDEKO (N=244)1,2
Treatment period 1
(8 weeks)
SYMDEKO
Ivacaftor
Placebo
Washout period
(8 weeks)
Treatment period 2
(8 weeks)
Ivacaftor
Placebo
SYMDEKO
Placebo
SYMDEKO
Ivacaftor
- Patients were randomized to receive one treatment sequence taken with fat-containing food, in addition to their currently prescribed CF therapies: tezacaftor/ivacaftor 100 mg/150 mg qd and ivacaftor 150 mg qd 12 hours apart (n=161), ivacaftor 150 mg alone q12h (n=156), or placebo q12h (n=161); patients received 2 of 3 treatment options
Study Population
- Selected inclusion criteria1-3
-
Confirmed CF diagnosis and clinically stable
-
Patients ≥12 years of age (mean age 34.8 years)
-
One copy of the F508del mutation and one copy of a mutation predicted to be responsive to tezacaftor/ivacaftor. Indicated mutations that were eligible and enrolled included: 2789+5G→A, 3272-26A→G, 3849+10kbC→T, 711+3A→G, A455E, D110H, D1152H, D579G, E831X, L206W, P67L, R1070W, R117C, R347H, R352Q, S945L, and S977F
-
Percent predicted FEV1 (ppFEV1) ≥40% and ≤90% at screening (mean baseline ppFEV1, 62.3%)
-
- Selected exclusion criteria1
-
History of colonization with organisms associated with a more rapid decline in pulmonary status, such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus
-
Two or more abnormal liver function tests at screening (ALT, AST, AP, GGT ≥3 x ULN or total bilirubin ≥2 x ULN), or AST or ALT ≥5 x ULN
-
Endpoints
- Primary endpoint: Mean absolute change in ppFEV1 from baseline to the average of Week 4 and Week 81,2
- Key secondary endpoint: Absolute change in CFQ-R Respiratory Domain score from baseline to the average of Week 4 and Week 81,2
- CFQ-R Respiratory Domain score evaluated respiratory symptoms, including cough, sputum production, and difficulty breathing4
Additional mutations determined to be responsive to tezacaftor/ivacaftor based on in vitro data and were eligible but not enrolled in EXPAND were: A1067T, D110E, D1270N, E193K, E56K, F1052V, F1074L, K1060T, R74W1,3
SUMMARY OF RESULTS
PRIMARY ENDPOINT:
LS MEAN ABSOLUTE CHANGE IN ppFEV1 VS PLACEBO1,2
PRIMARY ENDPOINT: LS MEAN ABSOLUTE CHANGE IN ppFEV1 VS PLACEBO1,2
6.8 PERCENTAGE POINTS SIGNIFICANT IMPROVEMENT VS PLACEBO
in mean absolute change in ppFEV1 from baseline to the average of Weeks 4 and 8 (95% CI: 5.7, 7.8; P<0.0001)1,2
Absolute Change in ppFEV1 in EXPAND2
- Improvements in ppFEV1 compared to placebo in patients with splice and missense mutations were 7.4 percentage points (95% CI: 6.0, 8.7) and 5.9 percentage points (95% CI: 4.2, 7.5), respectively1
- For individual mutations, changes in ppFEV1 varied by genotype and ranged from -1.0 to 10.1. These were ad hoc analyses. Please see the Summary by Mutation section for additional information1
OTHER EFFICACY ANALYSIS
2.1 PERCENTAGE POINTS SIGNIFICANT IMPROVEMENT VS IVACAFTOR
in LS mean absolute change in ppFEV1 from baseline to the average of Weeks 4 and 8 (95% CI: 1.2, 2.9; P<0.0001)1
CHANGES IN ppFEV1 FROM BASELINE VS PLACEBO TO THE
AVERAGE OF WEEKS 4 AND 81-3,a
Subgroups by baseline ppFEV1
LS mean absolute change in ppFEV1 from baseline
(percentage points)
<40%
(SYMDEKO n=16; placebo n=15; range 34.6% to <40%)
+4.4
(95% CI: 1.1, 7.8)
≥40 to <70%
(SYMDEKO n=89; placebo n=95)
+6.4
(95% CI: 5.1, 7.8)
≥70%
(SYMDEKO n=54; placebo n=50; range ≥70% to 93.5%)
+8.2
(95% CI: 6.4, 10.1)
aIn EXPAND, while ppFEV1 at screening was 40-90%, changes may have occurred before baseline.1,2
- Improvements in mean absolute change in ppFEV1 vs placebo across pre-specified subgroups were observed regardless of age, sex, baseline ppFEV1, colonization with Pseudomonas, and concomitant use of standard-of-care medications for CF1-3
KEY SECONDARY ENDPOINT: LS MEAN ABSOLUTE CHANGE FROM BASELINE IN
CFQ-R RESPIRATORY DOMAIN SCORE1,2
KEY SECONDARY ENDPOINT: LS MEAN ABSOLUTE CHANGE FROM BASELINE IN CFQ-R RESPIRATORY DOMAIN SCORE1,2
VS PLACEBO
11.1 POINT SIGNIFICANT IMPROVEMENT
from baseline to the average of Weeks 4 and 8 (95% CI: 8.7, 13.6; P<0.0001)1
CFQ-R: Ad hoc analyses
- Improvements in CFQ-R Respiratory Domain score compared to placebo in patients with splice and missense mutations were 9.5 points (95% CI: 6.3, 12.7) and 13.4 points (95% CI: 9.6, 17.3), respectively1
- For individual mutations, changes in CFQ-R Respiratory Domain score varied by genotype and ranged from -11.1 to 29.2. Please see the Summary by Mutation page for additional information1
VS IVACAFTOR
1.4 POINT TREATMENT DIFFERENCE
from baseline to the average of Weeks 4 and 8 (95% CI: -1.0, 3.9; not statistically significant)2,b
bThe MCID threshold for CFQ-R Respiratory Domain scores is 4 points in patients with CF with stable respiratory symptoms, which is the minimal change a patient can detect.5
SUMMARY BY MUTATION
EXPAND (TRIAL 2): RESULTS FOR PATIENTS
WITH SPLICE MUTATIONS1
EXPAND (TRIAL 2): RESULTS FOR PATIENTS WITH SPLICE MUTATIONS1
Splice Mutations1
Results shown as difference in mean change (95% CI) from study baseline for patients treated with SYMDEKO vs placebo (n=93 for SYMDEKO, n=97 for placebo):
| Mutation |
Absolute Change in |
Absolute Change In |
Absolute Change in Sweat Chloride (mmol/L) (95% CI)a,c |
|---|---|---|---|
|
Splice Mutations |
7.4 (6.0, 8.7) |
9.5 (6.3, 12.7) | -5.4 (-8.0, -2.7) |
| Mutation |
Absolute Change in |
Absolute Change In |
Absolute Change in Sweat Chloride (mmol/L) (95% CI)a,c |
|---|---|---|---|
|
Splice Mutations |
7.4 (6.0, 8.7) |
9.5 (6.3, 12.7) | -5.4 (-8.0, -2.7) |
By Individual Splice Mutation1
Results shown as mean (minimum, maximum) for change from study baseline for patients treated with SYMDEKO:
| Mutation (n) |
Absolute Change in |
Absolute Change In |
Absolute Change in Sweat Chloride (mmol/L) (min, max)a,c |
|---|---|---|---|
| 2789+5G→A (25) |
8.6 (-1.5, 23.4) |
12.0 (-8.3, 38.9) | -3.2 (-16.5, 9.0) |
|
3272-26A→G (23) |
5.7 (-2.1, 25.9) |
5.7 (-22.2, 44.4) | -3.8 (-22.3, 16.5) |
| 3849+10kbC→T (43) | 5.8 (-7.2, 22.3) | 8.2 (-25.0, 47.2) | -5.6 (-27.0, 8.5) |
| 711+3A→G (2) | 4.3 (2.0, 6.7) |
-4.2 (-5.6, -2.8) |
-15.4 (-21.0, -9.8) |
| E831Xd (0) | N/A | N/A | N/A |
| Mutation (n) |
Absolute Change in |
Absolute Change In |
Absolute Change in Sweat Chloride (mmol/L) (min, max)a,c |
|---|---|---|---|
| 2789+5G→A (25) |
8.6 (-1.5, 23.4) |
12.0 (-8.3, 38.9) | -3.2 (-16.5, 9.0) |
|
3272-26A→G (23) |
5.7 (-2.1, 25.9) |
5.7 (-22.2, 44.4) | -3.8 (-22.3, 16.5) |
| 3849+10kbC→T (43) | 5.8 (-7.2, 22.3) | 8.2 (-25.0, 47.2) | -5.6 (-27.0, 8.5) |
| 711+3A→G (2) | 4.3 (2.0, 6.7) |
-4.2 (-5.6, -2.8) |
-15.4 (-21.0, -9.8) |
| E831Xd (0) | N/A | N/A | N/A |
aAverage of Week 4 and Week 8 values.
bAbsolute change in ppFEV1 by individual mutations is an ad hoc analysis.
cAbsolute change in CFQ-R Respiratory Domain score and absolute change in sweat chloride by mutation subgroups and by individual mutations are ad hoc analyses.
dPatients enrolled did not receive tezacaftor/ivacaftor treatment.
EXPAND (TRIAL 2): RESULTS FOR PATIENTS WITH MISSENSE MUTATIONS1
EXPAND (TRIAL 2): RESULTS FOR PATIENTS WITH
MISSENSE MUTATIONS1
Missense Mutations
Results shown as difference in mean (95% CI) change from study baseline for patients treated with SYMDEKO vs placebo-treated patients (n=66 for SYMDEKO, n=63 for placebo):
| Mutation |
Absolute Change in |
Absolute Change In |
Absolute Change in Sweat Chloride (mmol/L) (95% CI)a,c |
|---|---|---|---|
|
Missense Mutations |
5.9 (4.2, 7.5) |
13.4 (9.6, 17.3) | -16.3 (-19.7,-12.9) |
| Mutation |
Absolute Change in |
Absolute Change In |
Absolute Change in Sweat Chloride (mmol/L) (95% CI)a,c |
|---|---|---|---|
|
Missense Mutations |
5.9 (4.2, 7.5) |
13.4 (9.6, 17.3) | -16.3 (-19.7,-12.9) |
By Individual Missense Mutations1
Results shown as mean (minimum, maximum) for change from study baseline for patients treated with SYMDEKO:
| Mutation (n) |
Absolute Change in |
Absolute Change In |
Absolute Change in Sweat Chloride (mmol/L) (min, max)a,c |
|---|---|---|---|
| D579G (2) |
8.1 (-0.2, 16.4) |
11.1 (5.6, 16.7) | -23.1 (-24.8, -21.5) |
|
D110H (1) |
-1.0 (-1.0, -1.0) |
-11.1 (-11.1, -11.1) | -22.5 (-22.5, -22.5) |
| D1152H (21) | 3.8 (-2.5, 12.5) | 15.2 (-8.3, 55.6) | -4.1 (-15.0, 11.5) |
| A455E (11) | 8.5 (2.6, 16.1) |
11.6 (-11.1, 44.4) |
-0.3 (-8.8, 14.0) |
| L206W (4) | 3.0 (-4.5, 10.2) | 12.5 (-2.8, 38.9) | -36.1 (-44.5, -27.5) |
| P67L (11) |
9.4 (0.0, 31.9) |
11.7 (-12.5, 72.2) | -29.3 (-50.0, 0.8) |
|
R1070W (2) |
6.1 (2.0, 10.1) |
29.2 (16.7, 41.7) | -13.8 (-26.8, -0.8) |
| R117C (1) | 2.9 (2.9, 2.9) | 16.7 (16.7, 16.7) | -38.8 (-38.8, -38.8) |
| R347H (2) | -0.5 (-2.8, 1.7) |
5.6 (-5.6, 16.7) |
-13.8 (-19.0, -8.5) |
| R352Q (2) | 4.9 (2.6, 7.1) | 8.3 (8.3, 8.3) | -43.3 (-49.8, -36.8) |
| S945L (7) | 9.6 (0.7, 19.5) | 11.3 (-4.2, 25.0) | -29.0 (-42.5, -8.0) |
| S977F (2) | 10.1 (5.5, 14.7) | -1.4 (-8.3, 5.6) | -13.9 (-22.3, -5.5) |
| Mutation (n) |
Absolute Change in |
Absolute Change In |
Absolute Change in Sweat Chloride (mmol/L) (min, max)a,c |
|---|---|---|---|
| D579G (2) |
8.1 (-0.2, 16.4) |
11.1 (5.6, 16.7) | -23.1 (-24.8, -21.5) |
|
D110H (1) |
-1.0 (-1.0, -1.0) |
-11.1 (-11.1, -11.1) | -22.5 (-22.5, -22.5) |
| D1152H (21) | 3.8 (-2.5, 12.5) | 15.2 (-8.3, 55.6) | -4.1 (-15.0, 11.5) |
| A455E (11) | 8.5 (2.6, 16.1) |
11.6 (-11.1, 44.4) |
-0.3 (-8.8, 14.0) |
| L206W (4) | 3.0 (-4.5, 10.2) | 12.5 (-2.8, 38.9) | -36.1 (-44.5, -27.5) |
| P67L (11) |
9.4 (0.0, 31.9) |
11.7 (-12.5, 72.2) | -29.3 (-50.0, 0.8) |
|
R1070W (2) |
6.1 (2.0, 10.1) |
29.2 (16.7, 41.7) | -13.8 (-26.8, -0.8) |
| R117C (1) | 2.9 (2.9, 2.9) | 16.7 (16.7, 16.7) | -38.8 (-38.8, -38.8) |
| R347H (2) | -0.5 (-2.8, 1.7) |
5.6 (-5.6, 16.7) |
-13.8 (-19.0, -8.5) |
| R352Q (2) | 4.9 (2.6, 7.1) | 8.3 (8.3, 8.3) | -43.3 (-49.8, -36.8) |
| S945L (7) | 9.6 (0.7, 19.5) | 11.3 (-4.2, 25.0) | -29.0 (-42.5, -8.0) |
| S977F (2) | 10.1 (5.5, 14.7) | -1.4 (-8.3, 5.6) | -13.9 (-22.3, -5.5) |
aAverage of Week 4 and Week 8 values.
bAbsolute change in ppFEV1 by individual mutations is an ad hoc analysis.
cAbsolute change in CFQ-R Respiratory Domain score and absolute change in sweat chloride by mutation subgroups and by individual mutations are ad hoc analyses.
ALT, alanine transaminase; AST, aspartate transaminase; AP, alkaline phosphatase; BMI, body mass index; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CI, confidence interval; FEV1, forced expiratory volume in 1 second; GGT, gamma-glutamyl transferase; LS, least squares; MCID, minimal clinically important difference; N/A, not applicable; n, patient numbers analyzed; ppFEV1, percent predicted forced expiratory volume in 1 second; q12h, every 12 hours; qd, once a day; ULN, upper limit of normal.
INDICATIONS AND USAGE
SYMDEKO is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.
INDICATIONS AND USAGE
SYMDEKO is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Transaminase (ALT or AST) Elevations
- Elevated transaminases have been observed in patients with CF receiving SYMDEKO, as well as with ivacaftor monotherapy. Assessments of transaminases (ALT and AST) are recommended prior to initiating SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring should be considered
- Dosing should be interrupted in patients with significant elevations of transaminases (e.g., ALT or AST >5x upper limit of normal [ULN], or ALT or AST >3x ULN with bilirubin >2x ULN) and laboratory tests should be closely followed until abnormalities resolve. Following resolution of transaminase elevations, consider the benefits and risks of resuming treatment
Hypersensitivity Reactions, Including Anaphylaxis
- Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue SYMDEKO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with SYMDEKO
Concomitant Use With CYP3A Inducers
- Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by concomitant use of CYP3A inducers, which may reduce the therapeutic effectiveness of SYMDEKO. Co-administration of SYMDEKO with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort, is not recommended
Cataracts
- Cases of non-congenital lens opacities have been reported in pediatric patients treated with SYMDEKO, as well as with ivacaftor monotherapy. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with SYMDEKO
ADVERSE REACTIONS
Serious Adverse Reactions
- Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with SYMDEKO compared to placebo included distal intestinal obstruction syndrome, 3 (0.6%) patients treated with SYMDEKO vs. 0 placebo patients
Most Common Adverse Reactions
- The most common adverse reactions in Trials 1 and 3 occurring in ≥3% of patients treated with SYMDEKO (N=334) and at a higher rate than for placebo (N=343) were headache, nausea, sinus congestion, and dizziness
- The safety profile in patients age 6 to less than 12 years from an open-label Phase 3 trial (N=70) was similar to that observed in Trials 1 and 3
USE IN SPECIFIC POPULATION
Pediatric Use
- The safety and effectiveness of SYMDEKO in patients with CF younger than 6 years of age have not been studied
Click here to access full Prescribing Information.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del. N Engl J Med. 2017;377(21):2013-2023. 3. Cystic Fibrosis Foundation. Patient Registry Annual Data Report 2015. Bethesda, MD. Cystic Fibrosis Foundation; 2016. 4. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del. NEngl J Med. 2017;377(21)(suppl1-29):2013-2023. 5. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0258 (v2.0); 2019. 6. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0551 (v2.0); 2019. 7. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21):2024-2035. 3. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21)(suppl1-25):2024-2035. 4. CFQ-R Cystic Fibrosis Questionnaire-REVISED. Cystic Fibrosis Foundation. Quittner, Modi, Watrous and Messer, 2000. Revised 2002. CFQ-R—Parent, English Version 2.0. 5. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618.
INDICATIONS AND USAGE
SYMDEKO is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Transaminase (ALT or AST) Elevations
- Elevated transaminases have been observed in patients with CF receiving SYMDEKO, as well as with ivacaftor monotherapy. Assessments of transaminases (ALT and AST) are recommended prior to initiating SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring should be considered
- Dosing should be interrupted in patients with significant elevations of transaminases (e.g., ALT or AST >5x upper limit of normal [ULN], or ALT or AST >3x ULN with bilirubin >2x ULN) and laboratory tests should be closely followed until abnormalities resolve. Following resolution of transaminase elevations, consider the benefits and risks of resuming treatment
Hypersensitivity Reactions, Including Anaphylaxis
- Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue SYMDEKO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with SYMDEKO
Concomitant Use With CYP3A Inducers
- Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by concomitant use of CYP3A inducers, which may reduce the therapeutic effectiveness of SYMDEKO. Co-administration of SYMDEKO with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort, is not recommended
Cataracts
- Cases of non-congenital lens opacities have been reported in pediatric patients treated with SYMDEKO, as well as with ivacaftor monotherapy. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with SYMDEKO
ADVERSE REACTIONS
Serious Adverse Reactions
- Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with SYMDEKO compared to placebo included distal intestinal obstruction syndrome, 3 (0.6%) patients treated with SYMDEKO vs. 0 placebo patients
Most Common Adverse Reactions
- The most common adverse reactions in Trials 1 and 3 occurring in ≥3% of patients treated with SYMDEKO (N=334) and at a higher rate than for placebo (N=343) were headache, nausea, sinus congestion, and dizziness
- The safety profile in patients age 6 to less than 12 years from an open-label Phase 3 trial (N=70) was similar to that observed in Trials 1 and 3
USE IN SPECIFIC POPULATIONS
Pediatric Use
- The safety and effectiveness of SYMDEKO in patients with CF younger than 6 years of age have not been studied
Click here to access full Prescribing Information.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del. N Engl J Med. 2017;377(21):2013-2023. 3. Cystic Fibrosis Foundation. Patient Registry Annual Data Report 2015. Bethesda, MD. Cystic Fibrosis Foundation; 2016. 4. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del. NEngl J Med. 2017;377(21)(suppl1-29):2013-2023. 5. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0258 (v2.0); 2019. 6. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0551 (v2.0); 2019. 7. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21):2024-2035. 3. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21)(suppl1-25):2024-2035. 4. CFQ-R Cystic Fibrosis Questionnaire-REVISED. Cystic Fibrosis Foundation. Quittner, Modi, Watrous and Messer, 2000. Revised 2002. CFQ-R—Parent, English Version 2.0. 5. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618.