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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)
  • 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 cenocepaciaBurkholderia 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

PRIMARY ENDPOINT: MEAN ABSOLUTE CHANGE IN ppFEV

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 chart

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

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

PRIMARY ENDPOINT: LS MEAN ABSOLUTE CHANGE IN ppFEV
  • 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 information1,2

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

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)

 

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 information 

 

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

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 ppFEV1
(95% Cl)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 Mutation1

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

Absolute Change In

CFQ-R Respiratory Domain Score

(min, max)a,c

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→(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

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% Cl)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 Mutations1

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

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.

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.