Clinical Trials

6 to <12 Years

STUDY DESIGN

TRIAL 3: A Phase 3, open-label safety study in patients aged 6 to <12 years1,2

  • Phase 3, 24-week, open-label, multicenter study evaluating the safety and tolerability of ALYFTREK2,3
  • Following a 4-week screening period and a 4-week run-ina with ETI, 78 patients received ALYFTREK2,3
    • Dosage was based on weight:
      • <40 kg: vanzacaftor 12 mg/tezacaftor 60 mg/deutivacaftor 150 mg once daily
      • ≥40 kg: vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg once daily

Trial 3 was an open-label study with no control arm; therefore, causality cannot be attributed to ALYFTREK.1,2

 

aRun-in period waived for children receiving stable ETI treatment.

Select Inclusion Criteria1,4

  • Confirmed CF diagnosis, clinically stable, aged 6 to <12 years
  • At least one triple combination responsive mutation in the CFTR gene (including F508del)
  • ppFEV1 ≥60% at screening
  • Weight between the 5th and 95th percentile for weight-for-age at screening visit

Select Exclusion Criteria4

  • Hepatic cirrhosis with 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)
  • Solid organ or hematologic transplantation
  • History of intolerance to the study drug (ETI or vanzacaftor/tezacaftor/deutivacaftor)
    • e.g., discontinuation or interruption of treatment due to adverse events

Primary Endpoint2

  • Safety and tolerability of ALYFTREK as determined by AEs and clinical assessments

Select Secondary and Other Endpoints2

  • Absolute change from baseline in ppFEV1 through Week 24
  • Absolute change from baseline in SwCl through Week 24
  • Number of pulmonary exacerbations through Week 24
  • Absolute change from baseline in CFQ-R Respiratory Domain score through Week 24
  • Absolute change from baseline in BMI and BMI-for-age Z-score at Week 24
  • Absolute change from baseline in LCI2.5 through Week 24

TCR, at least 1 CFTR mutation identified as responsive to ETI based on in vitro data.

Study Limitations and Disclosures1,2

  • Trial 3 was an open-label study with no control arm, designed to assess safety as the primary endpoint. Therefore, causality cannot be attributed to ALYFTREK
  • All patients in the study knew they were on active treatment, which may have introduced a bias related to that awareness 
  • Some results from Trial 3 are not included in the approved full Prescribing Information

Baseline Characteristics2

 

ALYFTREK

N=78

N=78

Sex: Male, n (%)

44 (56)

Ageb, years; mean (SD)

9.3 (7.6–10.4)

Baseline ppFEV1, percentage points; mean (SD)

99.7 (15.1)

Baseline SwCl concentration, mmol/L; mean (SD)

40.4 (20.9)

Baseline CFQ-R RD score; mean (SD)

84.8 (16.1)

Baseline BMI, kg/m2; mean (SD)

16.8 (2.1)

Prior CFTR modulator use, n (%)

66 (85)

ETI, n (%)

62 (79)

Genotype group, n (%)

-

F/MF

24 (31)

F/F

37 (47)

F/G

3 (4)

F/RF

1 (1)

F/other

2 (3)

Other TCR/any

11 (14)

 

ALYFTREK

N=78

N=78

Sex: Male, n (%)

44 (56)

Ageb, years; mean (SD)

9.3 (7.6–10.4)

Baseline ppFEV1, percentage points; mean (SD)

99.7 (15.1)

Baseline SwCl concentration, mmol/L; mean (SD)

40.4 (20.9)

Baseline CFQ-R RD score; mean (SD)

84.8 (16.1)

Baseline BMI, kg/m2; mean (SD)

16.8 (2.1)

Prior CFTR modulator use, n (%)

66 (85)

ETI, n (%)

62 (79)

Genotype group, n (%)

-

F/MF

24 (31)

F/F

37 (47)

F/G

3 (4)

F/RF

1 (1)

F/other

2 (3)

Other TCR/any

11 (14)

bAge at Day 1.

SUMMARY OF RESULTS

Trial outcomes for patients aged 6 to <12 years

Results from Trial 3 were based on a single-arm, open-label study. Please see study design and disclosures.

Primary Endpoint

Safety and tolerability of ALYFTREK

Adverse reactions in Trial 3 were generally similar to those established in patients aged 12 years and older1

Discontinuations, interruptions, and serious adverse reactions

  • A total of 78 patients with CF aged 6 to <12 years received at least one dose of ALYFTREK2
  • 8% of patients (6/78) experienced serious adverse reactions.c These reactions were infective pulmonary exacerbation (3%; 2/78), adenovirus infection (1%; 1/78), cough (1%; 1/78), failure to thrive (1%; 1/78), pulmonary function test decreased (1%; 1/78), and constipation (1%; 1/78)2
  • One patient (1%) treated with ALYFTREK discontinued due to adverse events of cough and fatigue2
  • One patient (1%) interrupted treatment with ALYFTREK due to adverse events2

cOne patient had 2 serious adverse events: infective pulmonary exacerbation of cystic fibrosis and failure to thrive.2

Liver function test elevations1,4

Incidence of maximum transaminase

ALYFTREK

N=78
n (%)

N=78
n (%)

Elevated ALT or AST

>3x ULN

3 (3.8)

>5x ULN

1 (1.3)

>8x ULN

0

Incidence of maximum transaminase

ALYFTREK

N=78
n (%)

N=78
n (%)

Elevated ALT or AST

>3x ULN

3 (3.8)

>5x ULN

1 (1.3)

>8x ULN

0

  • The incidence of adverse reactions of transaminase elevations (AST and/or ALT) was 5.1% (4/78) in patients treated with ALYFTREK. No patients discontinued due to transaminase elevations4
  • Total bilirubin elevations >1.5 x ULN occurred in 0% (0/78) in patients treated with ALYFTREK. Indirect bilirubin elevations >1.5x to ≤2x ULN occurred in 2.7% (2/74) and elevations >2x ULN occurred in 0% (0/74) of patients treated with ALYFTREK. Direct bilirubin elevations >1.5x ULN occurred in 0% (0/78). No patients (0/78) had transaminase elevations >3x ULN and total bilirubin >2x ULN4
  • One patient (1.3%) aged 6 to <12 years had creatine kinase levels >10x ULN. No patients (0%) aged 6 to <12 years had creatine kinase levels >5x ULN and ≤10x ULN5
  • There were no serious adverse events of elevated ALT or AST in Trial 34
  • There were no study drug interruptions or discontinuations due to elevated transaminases2

Rash events2

  • Rash events occurred in 5% (4/78) patients. All rash events were mild in severity as determined by the study investigator
  • There were no study drug interruptions or discontinuations due to rash events

Most common adverse reactions in Trial 32

Incidence of adverse reactions occurring in ≥10% of patients

 

ALYFTREK

N=78
n (%)

N=78
n (%)

Subjects with any treatment-emergent adverse events

75 (96)

Cough

36 (46)

Pyrexia

16 (21)

Headache

14 (18)

Infective pulmonary exacerbations

13 (17)

Oropharyngeal pain

13 (17)

Abdominal pain

9 (12)

Nasal congestion

9 (12)

Rhinorrhea

9 (12)

Vomiting

8 (10)

 

ALYFTREK

N=78
n (%)

N=78
n (%)

Subjects with any treatment-emergent adverse events

75 (96)

Cough

36 (46)

Pyrexia

16 (21)

Headache

14 (18)

Infective pulmonary exacerbations

13 (17)

Oropharyngeal pain

13 (17)

Abdominal pain

9 (12)

Nasal congestion

9 (12)

Rhinorrhea

9 (12)

Vomiting

8 (10)

Select Secondary Endpoints

ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE THROUGH WEEK 24

LUNG FUNCTION RESULTS WITH ALYFTREK FOLLOWING A 4-WEEK ETI RUN-IN2

ABSOLUTE CHANGE IN SwCl FROM BASELINE THROUGH WEEK 24

SwCl CONCENTRATIONS RESULTS WITH ALYFTREK FOLLOWING A 4-WEEK ETI RUN-IN2,4

The clinical relevance of these differences in SwCl has not been established in interventional
clinical trials.

Other Efficacy Endpoints2

Endpoint

Baseline (SD)

LS Mean Change on ALYFTREK (95% CI)

CFQ-R Respiratory Domain score through Week 24

84.8 (16.1)

3.90 (1.50, 6.30)

BMI at Week 24

16.8 (2.1)

0.22 (0.05, 0.38)

BMI Z-score at Week 24

0.1 (0.9)

-0.05 (-0.12, 0.02)

LCI2.5 through Week 24

6.6 (0.7)

-0.08 (-0.18, 0.02)

Pulmonary exacerbations through Week 24

-

0.15d (0.07, 0.34)

Endpoint

Baseline (SD)

LS Mean Change on ALYFTREK (95% CI)

CFQ-R Respiratory Domain score through Week 24

84.8 (16.1)

3.90
(1.50, 6.30)

BMI at Week 24

16.8 (2.1)

0.22
(0.05, 0.38)

BMI Z-score at Week 24

0.1 (0.9)

-0.05
(-0.12, 0.02)

LCI2.5 through Week 24

6.6 (0.7)

-0.08
(-0.18, 0.02)

Pulmonary exacerbations through Week 24

-

0.15d
(0.07, 0.34)

dAnnualized rate. Pulmonary exacerbation was defined as a new or change in antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of the following signs/symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38°C; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10%; radiographic changes indicative of pulmonary infection.

ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; CFQ-R RD, Cystic Fibrosis Questionnaire-Revised Respiratory Domain; CFTR, cystic fibrosis transmembrane conductance regulator; CI, confidence interval; ETI, elexacaftor/tezacaftor/ivacaftor and ivacaftor; F/F, homozygous for F508del; F/G, heterozygous for F508del and a gating mutation; F/MF, heterozygous for F508del and a minimal function mutation; F/RF, heterozygous for F508del and a residual function mutation; LS, least square; ppFEV1, percent predicted forced expiratory volume in 1 second; SD, standard deviation; SE, standard error; SwCl, sweat chloride; TCR/non-F, at least 1 CFTR mutation identified as responsive to ETI based on in vitro data and no F508del mutation; ULN, upper limit of normal.

Indications and Usage

Indications and Usage

ALYFTREK is indicated for the treatment of cystic fibrosis (CF) in patients 6 years of age and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

ALYFTREK is indicated for the treatment of cystic fibrosis (CF) in patients 6 years of age and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one indicated mutation.

If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one indicated mutation.

Important Safety Information

WARNING: DRUG-INDUCED LIVER INJURY AND LIVER FAILURE 

Elevated transaminases have been observed in patients treated with ALYFTREK. Cases of serious and potentially fatal drug-induced liver injury and liver failure were reported in patients taking a fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor, which contains the same or similar active ingredients as ALYFTREK. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of elexacaftor/tezacaftor/ivacaftor.

Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK, every month during the first 6 months of treatment, every 3 months for the next 12 months, and at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease or elevated liver function tests (LFTs) at baseline.

Interrupt ALYFTREK for significant elevations in LFTs or in the event of signs or symptoms of liver injury. Consider referral to a hepatologist. Follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If resolved, resume treatment only if benefit is expected to outweigh risk. Closer monitoring is advised after resuming ALYFTREK.

ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C). ALYFTREK is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need and benefit outweighs risk. If used, monitor patients closely.

Warnings and Precautions

Drug-Induced Liver Injury and Liver Failure

  • Elevated transaminases have been observed in patients treated with ALYFTREK. Cases of serious and potentially fatal drug-induced liver injury and liver failure have been reported in patients with and without a history of liver disease taking a fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor (ELX/TEZ/IVA), which contains the same or similar active ingredients as ALYFTREK. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of ELX/TEZ/IVA
  • Elevated transaminases have been observed in patients treated with ALYFTREK. Cases of serious and potentially fatal drug-induced liver injury and liver failure have been reported in patients with and without a history of liver disease taking a fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor (ELX/TEZ/IVA), which contains the same or similar active ingredients as ALYFTREK. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of ELX/TEZ/IVA
  • Assess LFTs (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK, every month during the first 6 months of treatment, every 3 months for the next 12 months, and at least annually thereafter. Consider more frequent monitoring in patients with a history of liver disease, elevated LFTs at baseline, or a history of elevated LFTs with drugs containing ELX, TEZ, and/or IVA
  • Interrupt ALYFTREK in the event of signs or symptoms of liver injury, which may include:
    • Significant elevations in LFTs (e.g., ALT or AST >5x the upper limit of normal (ULN) or ALT or AST >3x ULN with bilirubin >2x ULN)
    • Clinical signs or symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites)
  • Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If resolved and if benefit is expected to outweigh risk, resume ALYFTREK with close monitoring
  • ALYFTREK should not be used in patients with severe hepatic impairment. ALYFTREK is not recommended in patients with moderate hepatic impairment and should only be considered when there is a clear medical need and benefit outweighs risk. If used, monitor patients closely

Hypersensitivity Reactions, Including Anaphylaxis

  • Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting of drugs containing ELX, TEZ, and/or IVA (same or similar active ingredients in ALYFTREK). If signs or symptoms of serious hypersensitivity reactions develop during ALYFTREK treatment, discontinue ALYFTREK and institute appropriate therapy. Consider benefits and risks for the individual patient to determine whether to resume ALYFTREK

Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-Containing Drugs Due to Adverse Reactions

  • There are no available safety data for ALYFTREK in patients who previously discontinued or interrupted treatment with drugs containing ELX/TEZ/IVA due to adverse reactions. Consider the benefits and risks before using ALYFTREK in these patients. If ALYFTREK is used in these patients, closely monitor for adverse reactions as clinically appropriate

Reduced Effectiveness with Concomitant Use With CYP3A Inducers

  • Following concomitant use of strong or moderate CYP3A inducers with ALYFTREK, exposures of vanzacaftor, tezacaftor, and deutivacaftor were decreased, which may reduce ALYFTREK effectiveness. Concomitant use with strong or moderate CYP3A inducers is not recommended

Adverse Reactions with Concomitant Use With CYP3A Inhibitors

  • Following concomitant use of strong or moderate CYP3A inhibitors with ALYFTREK, exposures of vanzacaftor, tezacaftor, and deutivacaftor were increased, which may increase the risk of adverse reactions associated with ALYFTREK. Reduce the ALYFTREK dosage with concomitant use of strong or moderate CYP3A inhibitors

Cataracts

  • Non-congenital lens opacities have been reported in pediatric patients treated with drugs containing ivacaftor (similar to an active ingredient in ALYFTREK). Baseline and follow-up ophthalmological examinations are recommended in pediatric patients treated with ALYFTREK

Adverse Reactions

Serious Adverse Reactions

  • Serious adverse reactions that occurred more frequently with ALYFTREK than with ELX/TEZ/IVA in 2 or more patients (≥0.4%) were influenza (1.5%), increased AST (0.4%), increased GGT (0.4%), depression (0.4%), and syncope (0.4%)

Most Common Adverse Reactions

  • The most common adverse reactions to ALYFTREK (≥5% of patients and at a frequency higher than ELX/TEZ/IVA by ≥1%) were cough, nasopharyngitis, upper respiratory tract infection, headache, oropharyngeal pain, influenza, fatigue, increased ALT, rash, increased AST, and sinus congestion

Use in Specific Populations

Pediatric Use

  • The safety and effectiveness of ALYFTREK in patients <6 years of age have not been established

Please see full Prescribing Information, including Boxed WARNING, for ALYFTREK.

 

References:
1. ALYFTREK [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2024. 2. Hoppe JE, Kasi AS, Pittman JE, et al. Vanzacaftor–tezacaftor–deutivacaftor for children aged 6–11 years with cystic fibrosis (RIDGELINE Trial VX21-121-105): An analysis from a single-arm, Phase 3 trial. Lancet Respir Med. 2025. doi:10.1016/S2213-2600(24)00407-7 3. Evaluation of long-term safety and efficacy of vanzacaftor/tezacaftor/deutivacaftor in cystic fibrosis participants 1 year of age and older. ClinicalTrials.gov Identifier: NCT05844449. Updated April 11, 2024. Accessed January 1, 2025. https://clinicaltrials.gov/ct2/show/NCT05844449 4. Supplement to: Hoppe JE, Kasi AS, Pittman JE, et al. Vanzacaftor–tezacaftor–deutivacaftor for children aged 6–11 years with cystic fibrosis (RIDGELINE Trial VX21-121-105): An analysis from a single-arm, Phase 3 trial. Lancet Respir Med. 2025. doi:10.1016/S2213-2600(24)00407-7 5. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-28378 (v1.0); 2024.