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

Evaluation of Depression and Anxiety Symptoms After Starting Vanzacaftor/Tezacaftor/Deutivacaftor (NACFC 2026) - "Postmarketing data for elexacaftor/tezacaftor/ivacaftor (ETI) describe serious neuropsychiatric events, such as anxiety, depression, suicidal thoughts or behaviors, and sleep disturbances [2]. Most patients initiating VTD did not report adverse mental health effects, and among those who perceived a change in mental health symptoms, the majority reported an improvement. However, a subset experienced worsening mental health symptom, underscoring the importance of routine mental health screening, multidisciplinary monitoring, and ongoing assessment during VTD initiation and treatment. Larger, multicenter longitudinal studies are needed to better characterize the long-term mental health effects of VTD."

CNS Disorders • Cystic Fibrosis • Depression • General Anxiety Disorder • Genetic Disorders • Immunology • Mood Disorders • Psychiatry • Respiratory Diseases • Sleep Disorder • Suicidal Ideation • CFTR

Bile Acids as Potential Immunomodulatory Signals (NACFC 2026) - " Plasma samples from pwCF pre- and post-elexacaftor/tezacaftor/ ivacaftor (ETI) were assessed for BAs and related metabolites...Additional human samples (plasma and airway) pre- and post-vanzacaftor/tezacaftor/deutivacaftor are under analysis for untargeted metabolomics, targeted BA and oxylipin quantification, RNA expression, and cytokines...However, BA-treated M2-polarized (dexamethasone) macrophages had a blunted transcriptional response to LPS stimulation... scRNA-seq data and in vitro experiments confirmed that lung macrophages express BA receptors at physiologically relevant levels, while metabolomics studies revealed persistent BA alterations in CF. Ongoing studies using alternative differentiation conditions, repeated BA exposure, and human samples will clarify whether BAs contribute to macrophage-mediated bacterial tolerance in CF."

Immunomodulating

NMD Inhibition Unlocks Readthrough-Free Modulator Rescue of Nonsense Variants in CFTR at TM12-NBD2: A G551D-Like Precision Path (NACFC 2026) - "While readthrough drugs were advanced to clinical trials (e.g., Ataluren, ELX- 02) to enable translation past PTCs and suppress NMD, these trials have failed to show meaningful benefit...In primary airway cultures (W1282X/W1282X, n = 4; S1255X, n = 1), activity improved from ∼0.1 to 3.4–3.9 μA/cm2 with KVS0001 + next-generation modulators (VTI/Alyftrek) ( ∼27% of WT), with similar rescue using ETI (Trikafta) or ivacaftor-based regimens... Taken together, for TM12–NBD2-proximal nonsense variants, NMD inhibition alone without readthrough agents unlocks clinically available modulator rescue, offering a path to expand therapy to pwCF currently who currently have no options. Because NMD is a core transcriptome surveillance pathway, large-animal PK/tox studies in a CFTR PTC reporter SRM2 pig model are warranted. Establishing this NMD-first model for PTC variants could provide a framework for treating all PTC variants."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Implementation of a Pharmacist-Led CFTR Modulator Initiation and Management Program Utilizing Expanded Scope of Practice Authority (NACFC 2026) - " This retrospective cohort study evaluated individuals with CF initiated on elexacaftor/tezacaftor/ivacaftor (Trikafta) or vanzacaftor/tezacaftor/deutivacaftor (Alyftrek) at an accredited CF center between January 2025 and February 2026. A pharmacist-led CFTR modulator initiation and management program utilizing expanded scope of practice authority enabled independent initiation, monitoring, and dose adjustment of CFTR modulators. This model optimized therapy management while reducing provider burden and improving care efficiency. Expanded pharmacist scope of practice represents a scalable strategy to enhance CFTR modulator management and multidisciplinary CF care delivery."

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

Standardizing Safety Monitoring of Highly Effective Modulator Therapy (HEMT) Across Adult and Pediatric Cystic Fibrosis (CF) Clinics (NACFC 2026) - "Updated FDA guidance in early 2025 recommended more frequent liver function test (LFT) monitoring when initiating elexacaftor/tezacaftor/ivacaftor (ETI) and vanzacaftor/tezacaftor/deutivacaftor (VTD) therapy, further emphasizing the importance of identifying adverse effects (AE). The project aim of ≥ 80% AE assessment was achieved in both clinics. AE documentation improved in the adult clinic as workflows became standardized, while rates declined in the pediatric clinic during a transition to a more intermittent, as-needed pharmacy model. Future efforts focus on maintaining consistent AE assessment when a pharmacist is not present and refining AE management approaches, including dose modification of HEMT in response to AEs."

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

Pharmacogenomics Guides Elexacaftor-Tezacaftor-Ivacaftor-Associated Adverse Effect Management and Prevention (NACFC 2026) - "Pharmacist and pulmonologist utilized PGx results to guide patient's individualized target dose and/or dosing titration plan if rechallenged on ETI or transitioned to vanzacaftortezacaftor-deutivacaftor. Incorporating a genotype guided approach for pediatric pwCF utilizing PGx to evaluate ETI adverse effects and guide individualized CFTR modulator dosing may reduce time offtherapy and prevent CFTR associated adverse effects."

Adverse events • Biomarker • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR • CYP3A4 • CYP3A5 • UGT1A1

Outcomes of Vanzacaftor/Tezacaftor/Deutivacaftor in People With Cystic Fibrosis Who Switch From Highly Effective Modulator Therapy (NACFC 2026) - "Vanzacaftor/tezacaftor/deutivacaftor (VTD) is a once daily CFTR modulator shown to be noninferior to elexacaftor/tezacaftor/ivacaftor (ETI) in clinical trials. This study found that switching from HEMT to VTD does not appear to affect ppFEV1 or liver enzymes in PwCF. It significantly improved adherence in pediatric PwCF and reduced the number of PEx in adult PwCF. Our study suggests that VTD is a comparable treatment option to ETI and may be beneficial for patients who struggle with adherence; additional monitoring for adverse effects is needed to optimize treatment."

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

Factors Predicting Return of Pancreatic Exocrine Function in People with Cystic Fibrosis (NACFC 2026) - "We included all pwCF who were taking HEMT (elexacaftor/tezacaftor/ivacaftor and vanzacaftor/tezacaftor/deutivacaftor.) Patients who were ineligible for HEMT were excluded, as were patients who have been PS since birth. Our data reinforces what has previously been identified, that age of initiation is an important factor in determining who achieves PS [3]. Likely due to the ability of HEMT to halt progression of irreversible pancreatic damage. This is also likely reflected in our finding that years on HEMT are also inversely correlated with achieving PS."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Move It, Move It, We Like You to Move It: A Quality Improvement Study of Physical Activity and Body Composition at a Single Center (NACFC 2026) - "However, with the advancement of cystic fibrosis transmembrane conductance regulator (CFTR) therapy with the approval of both elexacaftor/tezacaftor/ivacaftor (Trikafta) and vanzacaftor/tezacaftor/deutivacaftor (Alyftrek) for people with CF (PwCF). We assessed the baseline level self-reported PA with the IPAQ and BIA. The preliminary data shows a wide spectrum of PA and BIA in the percentage of body fat and lean muscle mass. In addition to other marks of health body composition, serial BIA and IPAQ can be used to modify level and type of exercise for participants."

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

Responding to Side Effects of CFTR Modulators: Results from a Cystic Fibrosis Learning Network Innovation Lab (NACFC 2026) - "Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) and Vanzacaftor/Tezacaftor/Deutivacaftor (VTD) have improved the health of many people with cystic fibrosis (pwCF). Multi-center collaboration, development, and implementation of process changes to respond to reported ETI and VTD SE led to sustained improvement or resolution of symptoms and achieved the project aim. Shared methods and best practices from this CFLN iLab can be adapted by other CF Foundation care center network programs to improve reliable identification, tracking, and response to ETI and VTD SE as they arise in routine practice."

Adverse events • CNS Disorders • Constipation • Cystic Fibrosis • Depression • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Immunology • Mood Disorders • Respiratory Diseases • Sleep Disorder

Transitioning to Vanzacaftor/Tezacaftor/Deutivacaftor: Real-World Drivers and Dosing Strategies in a Single Cystic Fibrosis Center (NACFC 2026) - "Among those transitioning prior regimens included elexacaftor/tezacaftor/ ivacaftor (ETI, n = 42), ivacaftor (IVA, n = 3), and tezacaftor/ivacaftor (TEZA/IVA, n = 5). Transition to VTD was generally well tolerated, with most patients achieving full-dose therapy, including many previously on reduceddose regimens. Mental health concerns were the most common driver for transition. Overall, once on VTD, most patients achieved and maintained fulldose therapy, though a subset required ongoing dose adjustments, reverted to prior therapy, or discontinued therapy, reflecting real-world variability in tolerability and treatment persistence."

Clinical • Real-world • Real-world evidence • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

The Effect of Inhaled Antibiotics on FEV1 in Pseudomonas-Colonized Cystic Fibrosis Patients on Highly Effective Modulator Therapy: Time to Re-Assess Routine Use? (NACFC 2026) - "Background: Highly effective modulator therapy (HEMT), specifically elexacaftor/tezacaftor/ivacaftor (ETI) and vanzacaftor/tezacaftor/deutivacaftor (VTD), has revolutionized cystic fibrosis...Inhaled antibiotics included Tobramycin, Aztreonam, or Colistin... There was no difference in mean ppFEV1 changes between inhaled antibiotic users and non-users on HEMT over a 6-year period. In fact, the overall trend of ppFEV1 change shows improvement in both groups. It is interesting to note that there were almost twice as many exacerbations in the inhaled antibiotic group than the comparison group."

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

A Better State of Mind? Mental Health Outcomes After CFTR Modulator Transition (NACFC 2026) - "Although clinical trials did not demonstrate increased neuropsychiatric adverse effects with elexacaftor/tezacaftor/ivacaftor (ETI), post-marketing reports have raised concern (1). With the recent approval of vanzacaftor/tezacaftor/deutivacaftor (VTD) and early data suggesting comparable efficacy, reduced sweat chloride, and potentially fewer side effects (2), we hypothesized individuals transitioning from ETI to VTD would have reductions in depression and anxiety symptoms... In pwCF transitioning from ETI to VTD, we observed significant improvements in depressive symptoms and neuropsychiatric symptom burden with a trend towards reduced anxiety. Although prior clinical trials have not demonstrated these findings, real-world reports and labeling updates suggest neuropsychiatric side effects may occur with CFTR modulators. Our findings support further evaluation of neuropsychiatric outcomes associated with CFTR modulator therapies."

HEOR • Cystic Fibrosis • Depression • Genetic Disorders • Immunology • Mood Disorders • Psychiatry • Respiratory Diseases • Sleep Disorder

The Impact of Vanzacaftor/Tezacaftor/Deutivacaftor on Parent-Perceived Psychosocial Functioning in People with Cystic Fibrosis: A Multi-Center Experience (NACFC 2026) - "Few parents endorsed challenges with psychosocial functioning and sleep among CwCF at each time point of this study. Exploratory paired t-tests indicated significant improvement in PSC Total at 3 months and Sleep-Related Impairment at 6 months. While these findings are based on a small sample, the consistent directional improvements support VTD as well tolerated with respect to psychosocial and sleep-related outcomes after switching from ETI."

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

Use of Highly Effective Modulator Therapy for Non-Pulmonary Indications in Post-Lung Transplant Cystic Fibrosis Patients: Retrospective Review (NACFC 2026) - "Regarding regimen selection, 11 patients (92%) were started on elexacaftor/tezacaftor/ivacaftor (ETI) and 1 patient (8%) on vanzacaftor/tezacaftor/deutivacaftor (VTD). In this cohort, HEMT was most commonly initiated for persistent sinus disease following LTx and was associated with clinical improvement. Most patients were treated with ETI and initiated on adjusted dosing, with many remaining on reduced doses while achieving symptom control. These findings suggest that individualized dosing strategies, including cautious dose escalation, may optimize clinical benefit and tolerability."

Retrospective data • Review • Cystic Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Immunology • Mood Disorders • Otorhinolaryngology • Pulmonary Disease • Respiratory Diseases • Transplantation

Referrals, Recruitment, and RETRIAL—Oh My! Expanding the Reach of the Restarting Triple Therapy with Robust Monitoring for Adverse Events Study (NACFC 2026) - "Background: To describe national recruitment and referral strategies in Restarting Triple Therapy with Robust Monitoring for Adverse Events (RETRIAL), a prospective, observational study of neuropsychiatric adverse events (AEs) and drug-induced liver injury (DILI) following initiation of vanzacaftor/tezacaftor/deutivacaftor (VTD) among people with cystic fibrosis ( ≥ 6 years) who modified or discontinued elexacaftor/tezacaftor/ivacaftor due to neuropsychiatric AEs/DILI. RETRIAL highlights the feasibility and value of decentralized, remote monitoring to expand recruitment reach. This approach has been most effective in the MH and Liver/LC arms, which rely on remote surveys and record abstraction, compared with the Neuro arm, which requires in-person visits due to performance-based measures not validated for remote use. To date, referrals represent 24% of all participants consented despite launching 5 months after study start."

Adverse events • CNS Disorders • Cystic Fibrosis • Depression • Genetic Disorders • Hepatology • Immunology • Liver Failure • Respiratory Diseases

Long-Term Benefits of VNZ/TEZ/D-IVA in Reducing IV Antibiotic Use in People with CF Aged 12 Years and Older: Post-Hoc Analyses of 96-Week Open-Label Extension Analysis (NACFC 2026) - "Background: Vanzacaftor/tezacaftor/deutivacaftor (VNZ/TEZ/D-IVA) is a CFTR modulator therapy that provides greater improvements in CFTR function, as demonstrated by significant reductions in sweat chloride levels, compared to elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA).[1] Post-hoc analyses of 52-week Phase 3 parent studies showed that VNZ/TEZ/D-IVA was associated with lower intravenous (IV) antibiotic use (any indication) in participants with one potentially responsive CFTR allele, i.e., F508del /minimal function (F/MF) genotypes, versus ELX/TEZ/IVA; no differences were observed in participants with two potentially responsive CFTR alleles, i.e., non- (F/MF) genotypes.[2] This post-hoc analysis evaluates the long-term benefit of VNZ/TEZ/D-IVA on IV antibiotic use and PEx over 96 weeks in an open label extension (OLE) study (Study 121-104, Part A) in participants aged ≥ 12 years. Post-hoc analyses over 96 weeks showed that participants treated with VNZ/TEZ/D-IVA..."

Clinical • Retrospective data

S02-- Tinker, Topple or Tighten? Optimization of CFTR Modulator Therapies: Right Drug, Dose & Patient (NACFC 2026) - "Compare the benefits and limitations of vanzacaftor/tezacaftor/deutivacaftor versus elexacaftor/tezacaftor/ivacaftor to inform individualized CFTR modulator selection2. Discuss the role and clinical utility of therapeutic drug monitoring in optimizing CFTR modulator dosing and patient outcomes3. Evaluate considerations for CFTR modulator use in pregnancy and off label indications"

Clinical

TPS01-- Grab the Peaches & Popcorn: Pharmacotherapy Thematic Poster Session (NACFC 2026) - "Discuss the impact and tolerability of highly effective modulators (HEMT), including switching to vanzacaftor/tezacaftor/deutivacaftor, and propose mechanisms for standardizing adverse effect monitoring.2...3. Evaluate emerging evidence regarding precision medicine approaches, including pharmacogenomics and cystatin C-based assessment of renal function, to support individualized pharmacotherapy."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CST3

The New Landscape of Cystic Fibrosis in the Era of Highly Effective Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy. (PubMed, J Mother Child) - "As patient life expectancy continues to increase, comorbidities such as arterial hypertension, hypercholesterolaemia, cardiovascular disease, and malignancies will assume greater clinical importance. Selecting optimal therapeutic strategies remains a significant clinical challenge due to the numerous potential interactions between modulators and other medications."

Journal • Review • Cardiovascular • Cystic Fibrosis • Dyslipidemia • Genetic Disorders • Hypertension • Immunology • Oncology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CFTR

Neuropsychiatric adverse effects following switch to vanzacaftor-tezacaftor-deutivacaftor in adults with cystic fibrosis: early experience from a regional centre. (PubMed, J Cyst Fibros) - "Vanzacaftor-tezacaftor-deutivacaftor (VTD) is the newest triple-combination CFTR modulator, licensed as an alternative to elexacaftor-tezacaftor-ivacaftor (ETI)...Three had no prior psychiatric history; one had pre-existing depression on long-term sertraline that markedly worsened...These findings highlight the need for early mental health screening after VTD initiation and a low threshold for psychiatric review. All cases have been reported to the MHRA Yellow Card scheme."

Adverse events • Journal • CNS Disorders • Cystic Fibrosis • Depression • Genetic Disorders • Immunology • Psychiatry • Pulmonary Disease • Respiratory Diseases • Suicidal Ideation

Medical issues and pulmonary outcomes in cystic fibrosis and bronchiectasis. (PubMed, Curr Opin Pulm Med) - "Management of all forms of bronchiectasis is increasingly shifting toward individualized, endotype-directed care. Integration of disease-modifying therapies, systematic assessment of comorbidities, validated severity stratification tools, and patient-reported outcomes will be essential to optimizing long-term clinical outcomes and advancing precision medicine approaches across this heterogeneous disease spectrum."

Journal • Bronchiectasis • Cystic Fibrosis • Gastroenterology • Gastroesophageal Reflux Disease • Genetic Disorders • Immunology • Non‐Cystic Fibrosis Bronchiectasis • Pulmonary Disease • Respiratory Diseases

RCT Abstract - Safety and efficacy of vanzacaftor/tezacaftor/deutivacaftor in children with cystic fibrosis aged 2 to 5 years (TIMBERLINE Trial VX21-121-105): a phase 3, open-label study (ERS 2026) - "Background Vanzacaftor/tezacaftor/deutivacaftor (VNZ/TEZ/D-IVA) was efficacious and safe in people with cystic fibrosis (CF) aged ≥6 years, providing further restoration of CFTR function compared to elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA). Sweat chloride decreased, with 65·2% of children reaching levels <30 mmol/L, indicating additional CFTR function improvement beyond ELX/TEZ/IVA. These results show the safety and potential for greater restoration of CFTR function with VNZ/TEZ/D-IVA in preschool children with CF."

Clinical • P3 data • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Validation of an in vitro model for measuring CFTR function using a Ussing chamber on cell cultures of human nasal airway epithelium – a tool for research and personalized treatment in clinical practice (ERS 2026) - "However, they are not approved for all genotypes, and individual responses to modulators such as Kaftrio®/Alyftrek® are difficult to predict. This model enables reliable quantification of CFTR function and a clear distinction between HC and PwCF. It allows assessment of genotype-specific responses to modulators and mRNA-based therapies and may facilitate personalised treatment strategies and preclinical drug development."

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

Late-Diagnosed Cystic Fibrosis in an Octogenarian With an Atypical Phenotype of Pancreatic Sufficiency and Preserved Pulmonary Function. (PubMed, Cureus) - "Management included airway clearance with an oscillatory positive expiratory pressure device, individualized bronchodilator therapy due to tachycardia with albuterol, surveillance respiratory cultures, nutritional and weight monitoring, otolaryngology follow-up for chronic sinusitis and nasal polyps, osteoporosis management, and treatment with vanzacaftor/tezacaftor/deutivacaftor, to which she reported symptomatic improvement. This case highlights an uncommon late-diagnosed CF phenotype in an octogenarian with pancreatic sufficiency, intermediate sweat chloride, chronic sinopulmonary disease, preserved lung function, and new isolation of Pseudomonas aeruginosa. The case emphasizes that preserved pancreatic function and advanced age do not exclude CF and that adult patients with chronic bronchiectasis, sinus disease, and atypical respiratory infections should be evaluated for CFTR dysfunction when clinically appropriate."

Journal • Bronchiectasis • Cardiovascular • Chronic Rhinosinusitis With Nasal Polyps • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Musculoskeletal Diseases • Nasal Polyps • Orthopedics • Osteoporosis • Otorhinolaryngology • Pulmonary Disease • Respiratory Diseases • Rheumatology • Sinusitis • CFTR