STUDY DESIGN
TRIAL 1: A randomized, double-blind, Phase 3 trial in patients heterozygous for the F508del mutation and a minimal function mutation1-4
TRIAL 1: A randomized, double-blind, Phase 3 trial in patients heterozygous for the F508del mutation and a minimal function mutation1-4
- Phase 3, 52-week, double-blind, active-controlled study assessing the efficacy of ALYFTREK vs. ETI1,2
- Following a 4-week screening period and a 4-week run-in with ETI, patients were randomized 1:11,2
- 202 patients received ETI: elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg qam and ivacaftor 150 mg qpm with fat-containing food
- All patients remained on their standard-of-care CF therapies2
Please see additional safety information based on this trial in the safety profile.
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; qam, every morning; qd, every day; qpm, every evening; TCR/non-F, at least 1 CFTR mutation identified as responsive to ETI based on in vitro data and no F508del mutation.
Select Inclusion Criteria2,5
- Confirmed CF diagnosis, clinically stable, and at least 12 years of age
- Heterozygous for the F508del mutation and a minimal function mutation that results in
- No CFTR protein
- A CFTR protein that is not responsive to ivacaftor, tezacaftor, or tezacaftor/ivacaftor based on in vitro testing
- ppFEV1 between 40% and 90% at screening (for those currently taking ETI) or between 40% and 80% at screening (for those not currently taking ETI)
Select Exclusion Criteria5
- 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 Endpoint1,2a
- Absolute change in ppFEV1 from baseline through Week 24
aAssessed for noninferiority vs. ETI.
Select Key Secondary Endpoint2
- Absolute change in SwCl from baseline through Week 24
Select Secondary and Other Endpoints2,6
- Number of pulmonary exacerbations through Week 52b
- Absolute change from baseline in CFQ-R Respiratory Domain score through Weeks 24b and 52c
- Absolute change from baseline in ppFEV1 through Week 52b
- Absolute change from baseline in SwCl through Week 52b
- Safety and tolerabilityb
- Absolute change from baseline in BMI at Week 52c
bOther secondary endpoints.
cOther endpoints.
Baseline Characteristics Following a 4-Week Run-In with ETI2
ETI n=202 | ALYFTREK n=196 | |
|---|---|---|
Sex: Male, n (%) | 119 (59) | 116 (59) |
Age, years; mean (SD)d | 31.3 (21.9–38.5) | 30.3 (22.8–37.5) |
≥12 to <18, n (%)e | 31 (15) | 26 (13) |
Baseline ppFEV1, percentage points; mean (SD) | 67.2 (14.6) | 67.0 (15.3) |
Baseline SwCl, (mmol/L); mean (SD) | 54.3 (18.2) | 53.6 (17.0) |
Baseline CFQ-R RD score; mean (SD) | 82.9 (15.7) | 85.8 (14.7) |
Baseline BMI, kg/m2; mean (SD) | 23.0 (3.9) | 22.7 (3.4) |
Prior CFTR modulator use, n (%) | 177 (88) | 170 (87) |
ETI, n (%) | 177 (88) | 168 (86) |
ETI n=202 | ALYFTREK n=196 | |
|---|---|---|
Sex: Male, n (%) | 119 (59) | 116 (59) |
Age, years; mean (SD)d | 31.3 (21.9–38.5) | 30.3 (22.8–37.5) |
≥12 to <18, n (%)e | 31 (15) | 26 (13) |
Baseline ppFEV1, percentage points; mean (SD) | 67.2 (14.6) | 67.0 (15.3) |
Baseline SwCl, (mmol/L); mean (SD) | 54.3 (18.2) | 53.6 (17.0) |
Baseline CFQ-R RD score; mean (SD) | 82.9 (15.7) | 85.8 (14.7) |
Baseline BMI, kg/m2; mean (SD) | 23.0 (3.9) | 22.7 (3.4) |
Prior CFTR modulator use, n (%) | 177 (88) | 170 (87) |
ETI, n (%) | 177 (88) | 168 (86) |
dAge at Day 1.
eAge at screening.2
SUMMARY OF RESULTS
Trial outcomes for patients aged 12 years and older (F/MF)
Primary Endpoint
ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE THROUGH WEEK 24
ALYFTREK ACHIEVED NONINFERIOR LUNG FUNCTION VS. ETI1,2
Study disclosures1,2:
- This trial was not designed to demonstrate a difference between the treatment groups or to support noninferiority of other secondary endpoints
- The results were not tested for statistical significance as they were not in the pre-specified multiple testing procedure
- This endpoint is not included in the ALYFTREK full Prescribing Information
Select Key Secondary Endpoint
ABSOLUTE CHANGE IN SwCl FROM BASELINE THROUGH WEEK 24
ALYFTREK ACHIEVED STATISTICALLY SIGNIFICANT IMPROVEMENT IN SwCl CONCENTRATION VS. ETI1,2
- This trial was not designed to demonstrate a difference between the treatment groups or to support noninferiority of other secondary endpoints
- The results were not tested for statistical significance as they were not in the pre-specified multiple testing procedure
- This endpoint is not included in the ALYFTREK full Prescribing Information
Other Secondary and Other Endpoints
NUMBER OF PULMONARY EXACERBATIONS THROUGH WEEK 52f
ANNUALIZED PULMONARY EXACERBATION RATE2
Study disclosures1,2:
- This trial was not designed to demonstrate a difference between the treatment groups or to support noninferiority of other secondary endpoints
- The results were not tested for statistical significance as they were not in the pre-specified multiple testing procedure
- This endpoint is not included in the ALYFTREK full Prescribing Information
fPulmonary 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.5
ABSOLUTE CHANGE FROM BASELINE IN CFQ-R RESPIRATORY DOMAIN SCORE THROUGH WEEK 52g
CFQ-R RESPIRATORY DOMAIN SCORE6
Study disclosures1,6:
- This trial was not designed to demonstrate a difference between the treatment groups or to support noninferiority of other endpoints
- The results were not tested for statistical significance as they were not in the pre-specified multiple testing procedure
- This endpoint is not included in the ALYFTREK full Prescribing Information
gLS mean (SD) absolute change from baseline in CFQ-R Respiratory Domain through Week 24 was -1.7 (1.0) for ETI and 0.5 (1.1) for ALYFTREK.5
ABSOLUTE CHANGE FROM BASELINE IN BMI AT WEEK 52
BMI6
Study disclosures1,6:
- This trial was not designed to demonstrate a difference between the treatment groups or to support noninferiority of other endpoints
- The results were not tested for statistical significance as they were not in the pre-specified multiple testing procedure
- This endpoint is not included in the ALYFTREK full Prescribing Information
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; LS, least square; ppFEV1, percent predicted forced expiratory volume in 1 second; SE, standard error; SwCl, sweat chloride.
STUDY DESIGN
TRIAL 2: A randomized, double-blind, Phase 3 trial in patients homozygous for F508del, heterozygous for F508del and a gating or residual function mutation, or with at least 1 other triple combination responsive CFTR mutation and no F508del mutation1-4
- Phase 3, 52-week, double-blind, active-controlled study assessing the efficacy of ALYFTREK vs. ETI2
- Following a 4-week screening period and a 4-week run-in with ETI, patients were randomized 1:11-3
- 289 patients received ETI: elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg qam and ivacaftor 150 mg qpm with fat-containing food
- All patients remained on their standard-of-care CF therapies2
Please see additional safety information based on this trial in the safety profile.
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; qam, every morning; qd, every day; qpm, every evening; TCR/non-F, at least 1 CFTR mutation identified as responsive to ETI based on in vitro data and no F508del mutation.
Select Inclusion Criteria2
- Confirmed CF diagnosis, clinically stable, and at least 12 years of age
- Genotype in one of the following groups:
- Homozygous for F508del
- Heterozygous for F508del and a gating mutation
- Heterozygous for F508del and a residual function mutation
- ppFEV1 between 40% and 90% at screening (for those currently taking a Vertex CFTR modulator) or between 40% and 80% at screening (for those not currently taking a Vertex CFTR modulator)
Select Exclusion Criteria5
- 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 Endpoint1,2a
- Absolute change in ppFEV1 through Week 24
aAssessed for noninferiority vs. ETI.
Select Key Secondary Endpoint2
- Absolute change in SwCl from baseline through Week 24
Select Secondary and Other Endpoints2,6
- Number of pulmonary exacerbations through Week 52b
- Absolute change from baseline in CFQ-R Respiratory Domain score through Weeks 24b and 52c
- Absolute change from baseline in ppFEV1 through Week 52b
- Absolute change from baseline in SwCl through Week 52b
- Safety and tolerabilityb
- Absolute change from baseline in BMI at Week 52c
bOther secondary endpoints.
cOther endpoints.
Baseline Characteristics Following a 4-Week Run-In With ETI2
ETI n=289 | ALYFTREK n=284 | |
|---|---|---|
Sex: Male, n (%) | 144 (50) | 149 (52) |
Age, years; mean (SD)d | 33.8 (24.7-43.1) | 32.6 (24.1-41.5) |
≥12 to <18, n (%)e | 38 (13) | 41 (14) |
Baseline ppFEV1, percentage points; mean (SD) | 66.4 (14.9) | 67.2 (14.6) |
Baseline SwCl, (mmol/L); mean (SD) | 42.1 (17.9) | 43.4 (18.5) |
Baseline CFQ-R RD score; mean (SD) | 85.6 (13.2) | 85.7 (13.2) |
Baseline BMI, kg/m2; mean (SD) | 22.9 (3.3) | 23.3 (4.0) |
Prior CFTR modulator use, n (%) | 250 (87) | 241 (85) |
ETI, n (%) | 204 (71) | 185 (65) |
Genotype group, n (%) |
|
|
F/F | 224 (78) | 222 (78) |
F/G | 20 (7) | 19 (7) |
F/RF | 23 (8) | 23 (8) |
TCR/non-F | 22 (8) | 20 (7) |
ETI n=289 | ALYFTREK n=284 | |
|---|---|---|
Sex: Male, n (%) | 144 (50) | 149 (52) |
Age, years; mean (SD)d | 33.8 | 32.6 |
≥12 to <18, n (%)e | 38 (13.1) | 41 (14.4) |
Baseline ppFEV1, percentage points; mean (SD) | 66.4 (14.9) | 67.2 (14.6) |
Baseline SwCl, (mmol/L); mean (SD) | 42.1 (17.9) | 43.4 (18.5) |
Baseline CFQ-R RD score; mean (SD) | 85.6 (13.2) | 85.7 (13.2) |
Baseline BMI, kg/m2; mean (SD) | 22.9 (3.3) | 23.3 (4.0) |
Prior CFTR modulator use, n (%) | 250 (87) | 241 (85) |
ETI, n (%) | 204 (71) | 185 (65) |
Genotype group, n (%) |
|
|
F/F | 224 (78) | 222 (78) |
F/G | 20 (7) | 19 (7) |
F/RF | 23 (8) | 23 (8) |
TCR/non-F | 22 (8) | 20 (7) |
dAge at Day 1.
eAge at screening.2
SUMMARY OF RESULTS
Trial outcomes for patients aged 12 years and older (F/F, F/RF, F/G, TCR/non-F )
Primary Endpoint
ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE THROUGH WEEK 24
ALYFTREK ACHIEVED NONINFERIOR LUNG FUNCTION VS. ETI1,2
Study disclosures1,2:
- This trial was not designed to demonstrate a difference between the treatment groups or to support noninferiority of other secondary endpoints
- The results were not tested for statistical significance as they were not in the pre-specified multiple testing procedure
- This endpoint is not included in the ALYFTREK full Prescribing Information
Select Key Secondary Endpoint
ABSOLUTE CHANGE IN SwCl FROM BASELINE THROUGH WEEK 24
ALYFTREK ACHIEVED STATISTICALLY SIGNIFICANT IMPROVEMENT IN SwCl CONCENTRATION VS. ETI1,2
Study disclosures for SwCl concentrations through Week 52 (other secondary endpoint)1,2 :
- This trial was not designed to demonstrate a difference between the treatment groups or to support noninferiority of other secondary endpoints
- The results were not tested for statistical significance as they were not in the pre-specified multiple testing procedure
- This endpoint is not included in the ALYFTREK full Prescribing Information
Other Secondary and Other Endpoints
NUMBER OF PULMONARY EXACERBATIONS THROUGH WEEK 52f
ANNUALIZED PULMONARY EXACERBATION RATE2
Study disclosures1,2:
- This trial was not designed to demonstrate a difference between the treatment groups or to support noninferiority of other secondary endpoints
- The results were not tested for statistical significance as they were not in the pre-specified multiple testing procedure
- This endpoint is not included in the ALYFTREK full Prescribing Information
fPulmonary 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.5
ABSOLUTE CHANGE FROM BASELINE IN CFQ-R RESPIRATORY DOMAIN SCORE THROUGH WEEK 52g
CFQ-R RESPIRATORY DOMAIN SCORE6
Study disclosures1,6:
- This trial was not designed to demonstrate a difference between the treatment groups or to support noninferiority of other endpoints
- The results were not tested for statistical significance as they were not in the pre-specified multiple testing procedure
- This endpoint is not included in the ALYFTREK full Prescribing Information
gLS mean (SD) absolute change from baseline in CFQ-R Respiratory Domain through Week 24 was -1.2 (0.8) for both ETI and ALYFTREK.5
ABSOLUTE CHANGE FROM BASELINE IN BMI AT WEEK 52
BMI6
Study disclosures1,6:
- This trial was not designed to demonstrate a difference between the treatment groups or to support noninferiority of other endpoints
- The results were not tested for statistical significance as they were not in the pre-specified multiple testing procedure
- This endpoint is not included in the ALYFTREK full Prescribing Information
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; LS, least square; ppFEV1, percent predicted forced expiratory volume in 1 second; SE, standard error; SwCl, sweat chloride.
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
- 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. Keating C, Yonker LM, Vermeulen F, et al. Vanzacaftor–tezacaftor–deutivacaftor versus elexacaftor–tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): Results from two randomised, active-controlled, Phase 3 trials. Lancet Respir Med. 2025. doi:10.1016/2213-2600(24)00411-9 3. Keating C, Yonker LM, Vermeulen F, et al. Vanzacaftor/tezacaftor/deutivacaftor in adolescents and adults with cystic fibrosis: Results from two randomized, active-controlled Phase 3 trials. Poster presented at the North American Cystic Fibrosis Conference, Boston, MA, USA, September 26-28, 2024. 4. A study evaluating the long-term safety and efficacy of VX-121 combination therapy. ClinicalTrials.gov Identifier: NCT05444257. Updated August 13, 2024. Accessed January 1, 2025. https://clinicaltrials.gov/ct2/show/NCT05444257 5. Supplement to: Keating C, Yonker LM, Vermeulen F, et al. Vanzacaftor–tezacaftor–deutivacaftor versus elexacaftor–tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): Results from two randomised, active-controlled, Phase 3 trials. Lancet Respir Med. 2025. doi:10.1016/2213-2600(24)00411-9 6. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-28378 (v1.0); 2024.