Alyftrek (vanzacaftor/tezacaftor/deutivacaftor) / Vertex - LARVOL DELTA

Effect of Vanzacaftor/Tezacaftor/Deutivacaftor (VNZ/TEZ/D-IVA) on the PK of Rosuvastatin in Healthy Participants (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Not yet recruiting ➔ Recruiting

Enrollment open • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Effect of Vanzacaftor/Tezacaftor/Deutivacaftor (VNZ/TEZ/D-IVA) on the PK of Rosuvastatin in Healthy Participants (clinicaltrials.gov) - P1 | N=18 | Not yet recruiting | Sponsor: Vertex Pharmaceuticals Incorporated

New P1 trial • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Divergent neurobehavioral effects of CFTR modulators elexacaftor and ivacaftor in mice. (PubMed, Acta Psychol (Amst)) - "Among these, the elexacaftor-tezacaftor-ivacaftor combination (Trikafta) and vanzacaftor-tezacaftor-deutivacaftor (Alyftrek), represent major therapeutic milestones. Additionally, we confirmed the presence of Cftr mRNA in the amygdala and hippocampus, brain regions implicated in anxiety and depression. These findings provide preclinical support for the reported mental health side effects experienced by some people with CF and offer new insights into CFTR function within the central nervous system, potentially guiding the development of future CF therapies with improved neuropsychiatric profiles."

Journal • Preclinical • CNS Disorders • Cystic Fibrosis • Depression • Genetic Disorders • Immunology • Mood Disorders • Psychiatry • Pulmonary Disease • Respiratory Diseases • CFTR

ALYFTREK is now approved in the U.S., the United Kingdom (U.K.), the European Union (EU), Canada, New Zealand, Switzerland, and Australia for people with CF 6 years and older who have at least one F508del mutation or another mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to ALYFTREK. (Businesswire) - "Eligible patients in the U.S., England, Ireland, Germany, Denmark, Northern Ireland, Norway, and Wales currently have reimbursed access to ALYFTREK, and Vertex is working to secure access for eligible patients in additional countries. Vertex plans to share data from the global study of ALYFTREK in children 2 to 5 years of age and submit to global regulators in 2026. Vertex expects to initiate a pivotal study of ALYFTREK in children 1 to 2 years of age in 2026."

Approval • Clinical data • New trial • Reimbursement • Cystic Fibrosis

Rethinking CFTR variant responsiveness: Differential responses to vanzacaftor and elexacaftor. (PubMed, J Cyst Fibros) - "Cystic fibrosis (CF) care has been revolutionized by CFTR modulators, particularly the triple combination elexacaftor/tezacaftor/ivacaftor (ETI)...A nextgeneration modulator combination, vanzacaftor/tezacaftor/deutivacaftor (VTD), shows promise in addressing this gap...Broader access to raw data and individualized in vitro-clinical correlations are essential for informed therapeutic decisions. VTD offers new hope for pwCF with rare or previously unresponsive variants, reinforcing the importance of a personalized, datadriven approach to CF care."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Strategies for the identification of people with cystic fibrosis responsive to CFTR modulator triple combinations. (PubMed, J Cyst Fibros) - "The triple combinations of CFTR modulators, elexacaftor-tezacaftor-ivacaftor and more recently vanzacaftor-tezacaftor-deutivacaftor, have transformed the clinical course of cystic fibrosis (CF). Recent data show that CFTR modulator triple combinations may be effective in a large subset of pwCF with non-F508del, often rare, CFTR variants. The purpose of this review is to explore the various strategies that may contribute to the identification of all patients with modulator-responsive CFTR variants in order to expand access to these transformative therapies."

Clinical • Journal • Review • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Comparative efficacy and safety of CFTR modulators for people with cystic fibrosis with phe508del mutation: a systematic review and bayesian network meta-analysis. (PubMed, EClinicalMedicine) - "Our findings indicate that vanzacaftor-tezacaftor-deutivacaftor and elexacaftor-tezacaftor-deutivacaftor emerged as the most effective treatment options in adults. However, these results should be interpreted cautiously due to limited data and the low quality of existing evidence. None."

Journal • Retrospective data • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Improvements in health-related quality of life in people with cystic fibrosis ≥6 years of age treated with vanzacaftor/tezacaftor/deutivacaftor. (PubMed, J Cyst Fibros) - "VNZ/TEZ/D-IVA was associated with higher HRQoL in adolescents and adults aged ≥14 years compared to ELX/TEZ/IVA, with largest changes in participants with F/MF genotypes, and in children aged 6-11 years compared to ELX/TEZ/IVA baseline. These results highlight potential HRQoL benefits from greater CFTR function restoration with VNZ/TEZ/D-IVA."

HEOR • Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Graded Drug Challenge for Delayed Hypersensitivity to CFTR Modulator in a Teen With Cystic Fibrosis (ACAAI 2025) - "We describe a reproducible, non-immediate maculopapular eruption in a 13-year-old with CF following ALYFTREK (vanzacaftor/tezacaftor/deutivacaftor), suggestive of a delayed T-cell–mediated drug hypersensitivity...An outpatient Trikafta (elexacaftor/tezacaftor/ivacaftor) trial is planned and desensitization is being considered...This case illustrates a reproducible, delayed reaction following drug challenge—one that might be missed during standard in-office observation. CFTR modulators are vital in cystic fibrosis treatment; this case underscores the allergist’s crucial role in identifying hypersensitivity reactions that could influence long-term therapeutic decisions."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Insurance approval rates and barrier to access for vanzacaftor-tezacaftor-deutivacaftor at a single pediatric CF center (NACFC 2025) - "Results of clinical trials indicate that VTD is non-inferior to the current therapy, elexacaftor-tezacaftor-ivacaftor (ETI), for several efficacy outcomes including ppFEV1 and frequency of pulmonary exacerbations. The overall approval rate for VTD at CMKC CF Center is relatively low, with 63% of prior authorizations being approved. State Medicaid programs had higher approval rates compared to private insurance companies; we expect approval rates to rise, as Kansas Medicaid added VTD to its formulary in March 2025. We anticipate more private payors may add VTD to their formularies after it has been on the market for 6+ months."

Clinical • Reimbursement • US reimbursement • Cystic Fibrosis • Genetic Disorders • Immunology • Pediatrics • Respiratory Diseases

Pivotal Potential: Predictors of pancreatic function restoration in children with CF on CFTR modulators (NACFC 2025) - "IVA: Ivacaftor ETI: Elexacaftor/tezacaftor/ivacaftor LUM/IVA: Lumacaftor/ivacaftor TEZ/IVA: tezacaftor/ivacaftor VTD: vanzacaftor/tezacaftor/deutivacaftor Findings from this pilot study highlighted younger age at CFTRm initiation and CFTRm exposure history as potential predictors of pancreatic function restoration. Findings from this pilot study highlighted younger age at CFTRm initiation and CFTRm exposure history as potential predictors of pancreatic function restoration. These results support the development of a personalized approach to CF-related care and may inform future guidelines regarding PERT withdrawal. Ongoing research is warranted to further elucidate the safety and long-term outcomes associated with PERT discontinuation in this emerging cohort of individuals with CF who have achieved PS."

Clinical • Cystic Fibrosis • Diabetes • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Immunology • Metabolic Disorders • Pediatrics • Respiratory Diseases • Short Bowel Syndrome • CFTR

Maximizing benefits with early CFTR modulator treatment: Lower sweat chloride is associated with improved clinical outcomes in children aged 6 to 11 years (NACFC 2025) - " Data from elexacaftor/tezacaftor/ivacaftor (ETI) and vanzacaftor/ tezacaftor/deutivacaftor (VTD) Phase 3 clinical trials in pwCF with F508del/ minimal function mutation (F/MF) and F508del/F508del (F/F) genotypes were assessed to determine the relationship between SwCl concentrations achieved through Week 24 and age (≥18yrs, 12-17yrs, and 6–11yrs). In addition, data from lumacaftor/ivacaftor, tezacaftor/ivacaftor, ETI, and VTD Phase 3 clinical trials and open-label extension studies in children with CF aged 6-11yrs with F/MF and F/F genotypes were pooled to assess the relationship between SwCl concentrations on CFTRm and clinical outcomes in this age group... YOGA-CF is currently recruiting to time and target highlighting the desire of the CF community (patients and CF teams) to engage with real world remote clinical trials and the importance of identifying non-pharmacological strategies to improve outcomes. Final recruitment data available for NACFC 2025."

Clinical • Clinical data • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Implementing shared decision-making about vanzacaftor/tezacaftor/deutivacaftor during routine CF clinic visits (NACFC 2025) - "Background: While studies demonstrated Vanzacaftor/Tezacaftor/ Deutivacaftor (VTD) and elexacaftor/tezacaftor/ivacaftor (ETI) provide similar respiratory benefits, there is a need for frequent lab and side effects monitoring when starting or changing to VTD. Our QI initiative increased SDM discussions about VTD as a CFTRm option for eligible pwCF. Data dashboards and multidisciplinary PVP meetings aided identification of VTD-eligible PwCF prior to an upcoming clinic visit and revealed PwCF overdue for follow-up. Use of SDM discussions about VTD eligibility highlighted differing groups of pwCF: (1) ready to initiate/transition to VTD, (2) declined VTD, and (3) deferred VTD to a later time."

Pediatrics

Alyftrek in Adults (NACFC 2025) - No abstract available

Clinical

Changes in sweat chloride concentrations following CFTR modulator treatment and association with antibiotic usage in adolescents and adults with CF (NACFC 2025) - " Data from people with CF ≥12 years of age heterozygous for F508del and a minimal function variant or homozygous for F508del who took part in phase 3 clinical trials of tezacaftor/ivacaftor (n = 243), VX-659/ tezacaftor/ivacaftor (n = 480), elexacaftor/tezacaftor/ivacaftor (n = 590), and vanzacaftor/tezacaftor/deutivacaftor (n = 812) were pooled to assess relationships between on-treatment sweat chloride concentrations and use of intravenous (IV) and/or oral antibiotics. The goal of restoring CFTR function to normal levels using CFTR modulator therapy is supported by natural history data. Following initiation of CFTR modulator therapy, people with CF who achieved lower sweat chloride concentrations had lower rates of IV and/or oral antibiotics use than those with higher sweat chloride concentrations. The greatest benefit was seen in those who achieved sweat chloride concentrations below the diagnostic threshold (< 60 mmol/L) and with normal levels (< 30 mmol/L)."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Alyftrek in Peds (NACFC 2025) - No abstract available

Drug-Drug Interactions in Vanzacaftor-Tezacaftor-Deutivacaftor versus Elexacaftor- Tezacaftor-Ivacaftor. (PubMed, Pulm Pharmacol Ther) - No abstract available

Journal

The impact of vanzacaftor/tezacaftor/deutivacaftor on parent and child perceived psychosocial functioning in people with cystic fibrosis: a single center experience (NACFC 2025) - "Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective modulator therapy (HEMT) for children with cystic fibrosis (CwCF)...Prior to VTD, 31 (94%) CwCF were prescribed ETI, 1 LUM/IVA, and 1 was not on CFTR modulator therapy... Baseline PSC data showed 97% of scores in normal range with only one score considered elevated. The highest scoring questions highlight common trends in behavioral adverse events, correlating with concerns raised by the CF community. The increased scores for sleep indicate poor sleep quality and difficulties with sleep onset and maintenance among CwCF."

Clinical • CNS Disorders • Cystic Fibrosis • Genetic Disorders • Immunology • Pediatrics • Psychiatry • Respiratory Diseases • Sleep Disorder

Theratyping of 400 CF-associated variants in FRT cells to assess variant responsiveness to triple combination CFTR modulator vanzacaftor/ tezacaftor/ivacaftor (VNZ/TEZ/IVA) (NACFC 2025) - "We recently published findings from a large-scale theratyping study, evaluating 655 CFTR variants, including 478 variants without FDA approval at the time, for their responsiveness to elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), the active ingredients of Trikafta® [1]...A clinical investigation of the new Vertex triple combination (ALYFTREK®)i... We demonstrated significant rescue efficacy of VNZ/TEZ/IVA for a high percentage of CFTR variants currently not on the label for approved HEMT, indicating that confirmatory studies by Vertex would be valuable for future label expansions. VNZ/TEZ/IVA treatment may provide a therapeutically meaningful approach for several variants that did not positively respond to ELX/TEZ/IVA."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Implementing measurement-based care to screen and monitor mental and behavioral health symptoms in relation to modulator use (NACFC 2025) - "Background: The advent of modulator therapies like elexacaftor/tezacaftor/ivacaftor (ETI) have brought tremendous health improvements for many people with CF, but some have experienced new onset or worsening of mental/behavioral health (MBH) symptoms (e.g., anxiety, depressed mood, irritability, anger, sleep difficulties, hyperactivity, inattention, memory issues, brain fog) [1]...Our team implemented a standard workflow to monitor MBH side effects, particularly for those becoming modulator eligible (e.g. 2+ years of age) or making a change (e.g. dose adjustment, switching to vanzacaftor/tezacaftor/deutivacaftor—VTD)... We demonstrate early implementation of MBC to aid timely identification and response to MBH side effects related to ETI/VTD use with high caregiver acceptance. MBC integrated into modulator side effect screening and monitoring has potential to enhance collaborative care and outcomes. Table 1 (abstract 547): Count of patients screened, positive screens,..."

Behavior Disorders • Mood Disorders • Pediatrics • Psychiatry

Characterization of aging population in an adult cystic fibrosis clinic (NACFC 2025) - "Characteristics of an adult cystic fibrosis clinic Characteristic, n = 121 Age (y) 33.8 (18.678.2) Sex, n (%) Female 58 (48) Male 63 (52) Race, n (%) Caucasian 115 (95) African American 6 (5) Genetics, n (%) F508del, 1 mutation 104 (86) F508del, 2nd mutation 60 (50) Diagnosis, n (%) Cystic Fibrosis 119 (98) CFTR-related disorder 2 (2) Prescribed Modulator, n (%) Elexacaftor/Tezacaftor/Ivacaftor (ETI) 102 (84) Vanzacaftor/Tezacaftor/Deutivacaftor (VTdI) 6 (5) None 13 (11) Age at HEMT initiation (y) 28.3 (1373) PERT use, n (%) 97 (80) PERT daily dose (lipase units/kg/day) 5850.75 (1408.4513651.88) ppFEV1 (%) 81.1 (21.6131.1) Lung transplant status, n (%) 9 (7) Reported use, n (%) Tobacco 3 (2.5) Vape 4 (3.3) Cannabis 4 (3.3) Past Smoker 11 (9) Patients with biological children, n (%) 42 (34.7) Glucose tolerance, n (%) CFRD diagnosis 44 (36.3) IGT diagnosis 21 (17.4) Age of onset for CFRD (y) 23 (1041) Dyslipidemia, n (%) TC ≥ 200 mg/dL 9 (7.4) TC ≥ 200 mg/dL and on..."

Clinical • CNS Disorders • Cystic Fibrosis • Depression • Diabetes • Dyslipidemia • Genetic Disorders • Hepatology • Hypertension • Immunology • Metabolic Disorders • Mood Disorders • Obesity • Psychiatry • Respiratory Diseases • Rheumatology • Sleep Disorder • Urinary Incontinence • Urology

Making CF-MAGIC (CFTR ModulAtor PharmacoGenomICs): creation of a genomics-based clinical decision support program to improve time to initiation and optimization of CFTR modulator therapies (NACFC 2025) - " When compared to historical CFTRm approvals and expansions, CF-MAGIC correctly identified all PwCF with eligible mutations for CFTRm, capturing one PwCF eligible for elexacaftor/tezacaftor/ivacaftor (ETI) that was missed when SmartReport and other manual methods were previously utilized...At the time of implementation of the proactive report, CF-MAGIC identified three PwCF who were eligible for ETI but had not been noted by the clinical team; one patient who had a missed dose adjustment on lumacaftor/ivacaftor; three patients receiving the improper dosage form based on age; and eleven patients who are on the cusp of a dose adjustment based on weight...With the label expansion of ETI and approval of vanzacaftor/tezacaftor/deutivacaftor at the end of December 2024, our center ran a report of eligible mutations for the new expansions and approvals three days after the approval was announced... Early initiation of modulator therapy is critical, but multiple logistical..."

Biomarker • Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Pediatrics • Respiratory Diseases

High-throughput screening methods to discover new ribosomal inhibitors that rescue multiple classes of CFTR variants (NACFC 2025) - "Studies included treatment comparisons to established inhibitors of translation (G418, PTC-124, ELX-02, Escin) and CFTR modulators (elexacaftor-tezacaftor-ivacaftor, vanzacaftor-tezacaftor-deutivacaftor). Partial depletion of RPL12 levels represents a feasible strategy for CFTR modulation, which may be applicable to CFTR genotypes refractory to available clinical interventions. Our work serves as a foundation from which future investigations may be pursued to examine efficacy and tolerability of anti-RPL12 compounds or ASOs delivered to CF animal models."

CFTR

Pharmacist lab monitoring utilizing specialty pharmacy software for patients on HEMT in an adult cystic fibrosis center (NACFC 2025) - "Background: Patients with cystic fibrosis (CF) who are on highly effective modulator therapy (HEMT) such as elexacaftor/tezacaftor/ivacaftor (ETI) and vanzacaftor/tezacaftor/deutivacaftor (VTD) require routine lab monitoring of liver function tests (LFTs). It is important for patients taking HEMT to obtain regular lab draws to monitor liver function. Dose adjustments may be required based on lab results, even in patients who have been taking HEMT long-term. Using Therigy lab activities allowed the pharmacist to streamline the lab monitoring process using technology to improve efficiency and accuracy."

Clinical • Cystic Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Failure • Respiratory Diseases

Differential BK channel potentiation by vanzacaftor enantiomers enables therapy for modulator-ineligible people with cystic fibrosis (NACFC 2025) - "Acute experiments used increasing concentrations of R- and S-vanzacaftor; chronic experiments used elexacaftor at 5 μM and vanzacaftor enantiomers at 3 μM as these concentrations are reached at steady state in pwCF taking elexacaftor in Trikafta™ and S-vanzacaftor in Alyftrek™. Enhancing apical loop currents between ANO1 and BK by potentiating BK in pwCF with minimal function CFTR mutations can meaningfully and thus therapeutically enhance mucociliary function even in the absence of functional CFTR."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • ANO1 • BMI1 • CFTR