CLINICAL TRIALS FOR AGE 6 YEARS THROUGH 11 YEARS

TRIAL 3: An open-label study in patients with CF aged 6
through 11 years1

Trial Design1,a

  • Phase 3, 24-week, open-label, multicenter study evaluating the safety and tolerability of TRIKAFTA
  • 66 patients received TRIKAFTA
    • Dosage was based on weight:
       
      • <30 kg (n=36): 100 mg/50 mg/75 mg qam and 75 mg qpm
      • ≥30 kg (n=30): 200 mg/100 mg/150 mg qam and 150 mg qpm

Trial 3 was an open-label study with no placebo-controlled arm; therefore, causality cannot be attributed to TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor)
 

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.1

 

Key inclusion criteria1,b

  • Confirmed CF diagnosis, clinically stable, aged 6 through 11 years
  • Weight ≥15 kg without shoes at screening visit
  • Patient genotype:
    • Homozygous for the F508del mutation OR
    • Heterozygous for the F508del mutation and one of the ~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

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.1


Study disclosures and impact of COVID-191

  • 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
     
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Safety analyses (primary endpoint)1    

  • 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
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Efficacy analyses (secondary endpoints)1

  • 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
PRIMARY ENDPOINT1
  • Safety and tolerability of TRIKAFTA from baseline as determined by AEs and clinical laboratory assessmentsc

cSafety and tolerability assessments were based on AEs, clinical laboratory values, electrocardiograms, vital signs, pulse oximetry, and ophthalmologic examinations.1

SELECT SECONDARY ENDPOINTS1

FROM BASELINE THROUGH WEEK 24:

  • 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
Baseline characteristics in Trial 31
  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)

Summary of Results
 

Safety results from Trial 3 were similar to those observed in Trials 1 and 2 in patients aged 12 years and older1

  • A total of 66 patients with CF aged 6 through 11 years received at least one dose of TRIKAFTA

Serious adverse reactions1

  • 1 patient (1.5%) experienced serious adverse reactions. These concurrent reactions were rhinovirus infection, metapneumovirus infection, and pneumonia

Most common adverse reactions in Trial 31

Incidence of adverse reactions occurring in ≥10% of patients
  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)
Rashd 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)

dIncludes preferred term of rash only.

Laboratory and vital sign abnormalities1

Liver function test elevations

Incidence of maximum transaminase and maximum total bilirubin elevations
  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
  • The incidence of adverse reactions of transaminase elevations (AST and/or ALT) was 10.6% in patients treated with TRIKAFTA. 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 events1,2

  • Rash events occurred in 15 (22.7%) patients. All rash events were mild or moderate in severity as determined by the study investigatore
  • 1 patient (1.5%) discontinued due to rash erythematous; all other rash events resolved without interruption of study drug


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

 

Secondary Endpoints

Efficacy analyses (secondary endpoints)1

  • 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 

Please see study disclosures and impact of COVID-19.

Secondary Endpoint

ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE THROUGH WEEK 241

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10.2

Percentage Points

INCREASE 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

Secondary Endpoint

ABSOLUTE CHANGE IN SWEAT CHLORIDE FROM BASELINE THROUGH WEEK 241

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-60.9

mmol/L

DECREASE 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

SECONDARY ENDPOINT

ABSOLUTE CHANGE IN CFQ-R RESPIRATORY DOMAIN SCORE FROM BASELINE THROUGH WEEK 241

awdaw
 

7.0

Points

 

INCREASE 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

The minimal clinically important difference 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.3

CFQ-R Respiratory Domain score measured composite patient-/caregiver-reported outcomes in the following respiratory symptoms4:

  • Waking up from coughing
  • Wheezing
  • Coughing
  • Congestion
  • Difficulty breathing
  • Mucus production
SECONDARY ENDPOINT

ABSOLUTE CHANGE IN BMI AND BMI-FOR-AGE Z-SCORE FROM BASELINE AT WEEK 241

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1.02

kg/m2

 

INCREASE 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
 

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0.37

INCREASE 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.5 For example, a child age 9 starting with a BMI around the 60th percentile would increase to around the 70th percentile.6

SECONDARY ENDPOINT

ABSOLUTE CHANGE IN LCI2.5 FROM BASELINE THROUGH WEEK 241

rghfh
 

-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.7

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AE, adverse event; ALT, alanine transferase; AST, aspartate transaminase; BMI, body mass index; CF, cystic fibrosis; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CI, confidence interval; LCI, lung clearance index; ppFEV1, percent predicted forced expiratory volume in 1 second; SD, standard deviation; ULN, upper limit of normal.