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

  • 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
  • Key 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+5GA, 3272-26AG, 3849+10kbCT, 711+3AG, 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)
  • Key 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

ALT, alanine transaminase; AST, aspartate transaminase; AP, alkaline phosphatase; BMI, body mass index; CFQ-R, Cystic Fibrosis Questionnaire-Revised; FEV1, forced expiratory volume in 1 second; GGT, gamma-glutamyl transferase; q12h, every 12 hours; qd, once a day; ULN, upper limit of normal.

Additional mutations determined to be responsive to tezacaftor/ivacaftor based on in vitro data and were not studied in EXPAND or any other clinical setting were: A1067T, D110E, D1270N, E193K, E56K, F1052V, F1074L, K1060T, R74W1

Primary endpoint: 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

EXPAND (Trial 2)
  • 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 page for additional information1,2

Other efficacy analysis

2.1 percentage points significant improvement vs ivacaftor

in 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

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 CF

Key secondary endpoint: 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

  • The CFQ-R Respiratory Domain score evaluated respiratory symptoms including cough, sputum production, and difficulty breathing4

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

CI, confidence interval; CFQ-R, Cystic Fibrosis Questionnaire-Revised; LS, least squares; MCID, minimal clinically important difference; ppFEV1, percent predicted forced expiratory volume in 1 second.

EXPAND (Trial 2): Results for patients with splice mutations1

Splice Mutations

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 ppFEV1 (95% CI)a Absolute Change In CFQ-R Respiratory Domain Score (95% CI)a,c 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 Mutation

Results shown as mean (minimum, maximum) for change from study baseline for patients treated with SYMDEKO:

Mutation (n) Absolute Change in ppFEV1 (min, max)a,b Absolute Change In CFQ-R Respiratory Domain Score (min, max)a,c Absolute Change in Sweat Chloride (mmol/L) (min, max)a,c
2789+5GA (25) 8.6 (-1.5, 23.4) 12.0 (-8.3, 38.9) -3.2 (-16.5, 9.0)
3272-26AG (23) 5.7 (-2.1, 25.9) 5.7 (-22.2, 44.4) -3.8 (-22.3, 16.5)
3849+10kbCT (43) 5.8 (-7.2, 22.3) 8.2 (-25.0, 47.2) -5.6 (-27.0, 8.5)
711+3AG (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.

CI, confidence interval; CFQ-R, Cystic Fibrosis Questionnaire-Revised; N/A, not applicable; n, patient numbers analyzed; ppFEV1, percent predicted forced expiratory volume in 1 second.

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 ppFEV1 (95% CI)a Absolute Change In CFQ-R Respiratory Domain Score (95% CI)a,c 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 Mutations

Results shown as mean (minimum, maximum) for change from study baseline for patients treated with SYMDEKO:

Mutation (n) Absolute Change in ppFEV1 (min, max)a,b Absolute Change In CFQ-R Respiratory Domain Score (min, max)a,c 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.

CI, confidence interval; CFQ-R, Cystic Fibrosis Questionnaire-Revised; N/A, not applicable; n, patient numbers analyzed; ppFEV1, percent predicted forced expiratory volume in 1 second.