vanzacaftor (VX-121) / Vertex - LARVOL DELTA

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

Clinical benefit without sweat chloride response after ETI therapy in an adult with cystic fibrosis bearing the L467F;F508del complex CFTR allele: a case report and the role of AI-assisted chest CT in longitudinal monitoring. (PubMed, Front Med (Lausanne)) - "Elexacaftor/tezacaftor/ivacaftor (ETI) is the standard of care for most people with cystic fibrosis (CF) who carry at least one F508del allele. An exploratory in vitro rescue study with vanzacaftor/tezacaftor supports the evaluation of emerging CFTR modulators. It suggests that similar studies should be conducted in other cases involving complex CFTR alleles."

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

In Vitro Responsiveness of 417 CFTR Variants to Vanzacaftor/Tezacaftor/Ivacaftor. (PubMed, J Cyst Fibros) - "We evaluated 417 CFTR variants for VTI responsiveness, including 272 tested for the first time and 145 previously categorized as non-responsive (NR) or borderline-responsive (BR) to ETI. Overall, ∼76% of variants achieved ≥10% of WT improvement, the threshold for responsiveness. This included 87% of newly tested variants and 55% of ETI NR/BR variants. Notably, 50 variants classified as NR/BR to ETI reached the responsive threshold with VTI using empirical Bayes criteria. Compared with ETI, VTI demonstrated broader efficacy across this dataset. These results expand the number of CFTR variants likely to benefit from highly effective modulator therapy and highlight remaining variants that may require alternative therapeutic strategies."

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

Pharmacogenomic analyses of corrector-resistant cystic fibrosis (NACFC 2026) - "To validate that our platform can identify hits that influence PM expression of disease variants, we conducted a genome-wide CRISPR knockout screen to identify hits that modulate the surface display of the correctorresponsive F508del variant in the presence of vanzacaftor-tezacaftor (VT). Our preliminary data demonstrate that we have developed a powerful methodology that will be extended to conduct genome-wide CRISPR screens with VT-resistant variants. This methodology enables us to screen thousands of guide RNAs against cellular machinery to identify drug targets for enhancing CFTR stability and PM expression. Consequently, we aim to identify strategies for restoring CFTR function for pwCF who are underserved by existing therapies."

Biomarker • Genomic analysis • Cystic Fibrosis • Genetic Disorders • Hematological Malignancies • Immunology • Leukemia • Respiratory Diseases • Targeted Protein Degradation

From Trikafta to Alyftrek: Progress in treatment access or persistence of inequality? (NACFC 2026) - "Background: Deutivacaftor/tezacaftor/vanzacaftor (Alyftrek) is the most recently approved drug for the treatment of cystic fibrosis (CF), positioned as an alternative to established therapies such as Elexacaftor/tezacaftor/ivacaftor (Trikafta). Global access to Alyftrek remains more restricted than that of Trikafta. Despite its recent introduction, its annual cost is comparable to existing therapies and is likely to continue limiting uptake, particularly in low- and middle-income countries. These findings highlight the need for alternative strategies to expand access to CF medication beyond traditional manufacturer-led distribution."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

A novel LC-MS/MS method for simultaneous quantification of vanzacaftor, tezacaftor, deutivacaftor, elexacaftor, ivacaftor, and metabolites in plasma matrix (NACFC 2026) - " Internal standard (temazepam, 0.01 ng/mL) was added to 0.2 mL plasma samples, which were extracted with methyl tert-butyl ether. A rapid, sensitive, and robust UHPLC-MS/MS method was successfully developed and validated for the simultaneous quantification of CFTR modulators and their active metabolites in human plasma. The method offers advantages, including low sample volume, short analytical run time, and improved sensitivity compared to previously published methods. This assay is well-suited for therapeutic drug monitoring in clinical settings as well as pharmacokinetic and research applications."

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

Sensitivity of rare F508del-CFTR complex alleles to clinically approved modulators (NACFC 2026) - "From a large cohort of Italian people with Cystic Fibrosis (pwCF), we enrolled unrelated patients who were heterozygous for the F508del variant and a minimal function variant, who exhibited negligible clinical responses to Elexacaftor/tezacaftor/ivacaftor (ETI). Our findings elucidate the sensitivity of ultra-rare F508delCFTR complex alleles to the novel Vanzacaftor combination. The data suggest that pwCF carrying specific F508del CAs who do not benefit from ETI may respond to VT, further advancing precision medicine strategies for rare genotypes."

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

Inhaled, First-in-Class BK Channel Potentiator Rescues Mucociliary Dysfunction in Preclinical Models of Minimal Function CFTR Variants (NACFC 2026) - "Selective potentiation of BK channels restores mucociliary function in preclinical models of cystic fibrosis independent of mutant CFTR modulation. Inhaled R-vanzacaftor demonstrates durable efficacy, favorable airway-restricted pharmacokinetics, and compatibility with existing CFTR modulators. An early NTC-AMP version has preserved function."

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

Inhibition of Translation Initiation as a Unifying Mechanism for Rescue of CFTR Nonsense Variants (NACFC 2026) - "Studies included treatment comparisons to established read-through agents (G418), nonsense mediated decay (NMD) inhibitors (SMG1i), mRNA amplifiers (PTI-428), and CFTR modulators (elexacaftor-tezacaftor-ivacaftor, ETI; vanzacaftor-tezacaftor-ivacaftor, VTD). Earlier work has established that RPL12 knockdown diminishes rates of translation initiation and elongation through effects on GC-rich codons. RPL8 suppression reduces ribosome fidelity by causing structural changes to functional centers of the 40S and 60S subunits. We therefore propose that RPL12 knockdown elicits CFTR PTC read-through by abrogating release factor interactions and inducing peripheral stabilization of partially synthesized proteins through interference with initiation and elongation factors."

CFTR • EIF4A3 • EIF4E • EIF4G1 • RPL8

SPL23, an Exon-Skipping Antisense Oligonucleotide for PwCF Carrying the W1282X Variant (NACFC 2026) - " The effects of SPL23 following basal or apical free uptake, either alone or in combination with modulators (Elexacaftor/tezacaftor/ivacaftor - ETI or Vanzacaftor/Tezacaftor/Ivacaftor - VTI), were evaluated in human nasal epithelial (HNE) and human bronchial epithelial (HBE) cells derived from pwCF carrying the W1282X variant. These results highlight the therapeutic potential of SPL23, part of the clinically validated SpliSense ASO platform, in combination with CFTR modulators for pwCF carrying the W1282X nonsense variant - addressing a critical unmet need for patients who do not benefit from existing modulator therapies. SPL23 is a potent and safe preclinical lead, and these data support initiation of clinical studies in the near future."

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

Functional and biochemical characterization of Alyftrek® components reveals high-potency rescue of F508del-CFTR. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "Alyftrek® (vanzacaftor/tezacaftor/deutivacaftor, VTD) is a triple CFTR modulator therapy for patients with cystic fibrosis (CF). Collectively, these findings demonstrate the high potency of S-vanzacaftor at nanomolar concentrations, both alone and in combination with tezacaftor. The potentiator deutivacaftor exhibited efficacy comparable to that of ivacaftor."

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

Profiling the CFTR Variant Selectivity and Off-Target Interactions of VX-121. (PubMed, bioRxiv) - "The approval of VX-121, a VX-445 analog that serves as a key component of Alyftrek, potentially provides a new therapeutic option for those with rare CF variants. Finally, using photo-crosslinking, we show that VX-121 avoids a key off-target interaction of VX-445. Together, our findings provide new insights into the similarities and differences between current approved CF therapeutics."

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

Vanzacaftor-Tezacaftor as an alternative therapeutic resource for the ETI-Resistant L467F-F508del Allele: Ex vivo prediction and exploratory clinical assessment. (PubMed, J Cyst Fibros) - "Our findings demonstrate that the Vanzacaftor/Tezacaftor combination possesses superior corrective potency capable of rescuing the severe trafficking defect of the L467F-F508del complex allele. This study identifies a promising therapeutic solution for patients currently orphaned by standard-of-care modulators and highlights the utility of integrating ex vivo screening with clinical monitoring in defining precision medicine strategies."

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

Characterization of two ultra-rare CFTR variants, P.Leu999del and P.Glu1104Lys, with unknown theratyping profiles. (PubMed, Orphanet J Rare Dis) - "E1104K and L999del exhibit measurable residual CFTR function and in vitro responsiveness to two CFTRm triple-combination regimens. These findings support theranostic approaches to guide therapy in individuals with ultra-rare CFTR genotypes, while clinical use remains dependent on regulatory approval and individualized patient assessment."

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

Keeping up with CFTR modulator eligibility. (PubMed, Paediatr Respir Rev) - "Since ivacaftor's approval for a single gating variant in 2012, eligibility has broadened to over 180 variants with the highly effective therapies elexacaftor/tezacaftor/ivacaftor and recently launched vanzacaftor/tezacaftor/deutivacaftor...However, clinical response remains variable, influenced in part by baseline characteristics, pharmacokinetics, pharmacogenetics, and environmental exposures. We outline evolving approaches to determining eligibility and strategies to improve methods to predict, verify, and monitor clinical response in an era of personalised medicine."

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

Smallest Bicycles in Medicinal Chemistry: Where Are We Now? (PubMed, Chem Rev) - "At least eight structures based on the smallest skeletons have advanced to clinical trials, with one, vanzacaftor, recently receiving U.S. FDA approval...While bicyclo[1.1.1]pentane and spiro[3.3]heptane have become routine and indispensable in medicinal chemistry over the past decade, ladderane and housane remain exotic and unexplored. We highlight knowledge gaps, aiming to stimulate interest in small saturated skeletons for innovative molecular engineering."

Journal • Review

Effect of vanzacaftor/tezacaftor/ivacaftor on cystic fibrosis nasal epithelial cells and intestinal organoids compared to elexacaftor/tezacaftor/ivacaftor. (PubMed, Respir Med) - "VAN/TEZ/IVA demonstrated superior CFTR functional rescue in F508del/F508del HNECs than ELX/TEZ/IVA. These findings highlight the greater discriminatory power of airway epithelial electrophysiology compared to PDIOs when comparing highly effective CFTR modulator therapies."

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

Clinical, functional and therapeutic evaluation of CFTR variant I507del. (PubMed, J Cyst Fibros) - "In primary human nasal epithelial (HNE) cultures from two donors carrying I507del and a null variant (2184delA or 621+1G>T), baseline CFTR activity was <1% of wild-type (WT) (0.11-0.16 µA/cm²) and elexacaftor-tezacaftor-ivacaftor (ETI) failed to increase function...Vanzacaftor/tezacaftor/ivacaftor (VTI) reproducibly restored ∼6.4% WT (1.14 ± 0.4 µA/cm²) activity in donor-derived HNEs and produced mature CFTR protein in Flp-In-CFBE models...The robust RNA-function relationship highlights RNA amplification strategies as potential adjuncts to increase rescue. These findings identify I507del as an ETI-refractory allele with minimal responsiveness to VTI suggesting careful consideration before embarking upon modulator treatment of individuals with CF carrying this variant."

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

Understanding Pharmacokinetic-Drug Interactions With Drugs Approved by the US Food and Drug Administration in 2024 to Better Manage the Risk of Drug Interactions With Concomitant Medications: A Review of Clinical Data From New Drug Applications. (PubMed, Curr Ther Res Clin Exp) - "Of these, 7 drugs were substrates of CYP3A, 3 of CYP2C9, one of CYP1A2, and one of CYP2C8, including the sensitive substrates vanzacaftor (CYP3A) and vorasidenib (CYP1A2). As precipitants, 6 drugs (acoramidis, cefepime/enmetazobactam, givinostat, lazertinib, mavorixafor, and resmetirom) were clinical inhibitors of CYP enzymes (2C8, 2C9, 2D6, 2E1, and 3A), with mavorixafor being a CYP2D6 strong inhibitor. Two drugs (elafibranor and tovorafenib) showed weak induction of CYP3A. Regarding transporter data, 3 drugs were substrates of transporters, including seladelpar (BCRP and OAT3), sulopenem (OAT3), and vadadustat (OAT1/3), and 8 drugs (arimoclomol, danicopan, givinostat, lazertinib, mavorixafor, resmetirom, vadadustat, and vazacaftor/tezacaftor/deutivacaftor) were inhibitors of transporters...Several DDIs with an AUC change <2 also had labeling recommendations, pertaining most often to the concomitant use of drugs with a narrow therapeutic index. Mechanistic DDI..."

Clinical data • FDA event • Journal • NDA • PK/PD data • Review • CYP1A2 • CYP2C9

Current drug hypersensitivity challenges facing patients with cystic fibrosis. (PubMed, J Cyst Fibros) - "The CFTR correctors (vanzacaftor, elexacaftor, tezacaftor, lumacaftor) and potentiators (ivacaftor, deuterated ivacaftor) target the underlying CFTR defect to improve protein function...Piperacillin has been defined as a leading drug culprit within non-immediate drug allergy in patients with CF, with a growing body of evidence alluding to the central role of T-lymphocytes...This phenomenon has led us to hypothesise that increased levels of inflammation and dysregulation of regulatory T-cells in CF patients could propagate adverse reactions to CFTR modulators that resolve alongside underlying infection. The introduction of CFTR modulator therapies has been highly transformative for patients with CF, therefore, adverse reactions to these compounds that lead to cessation of treatment are serious and important to understand."

Journal • Review • Allergy • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • CFTR

Have we been overlooking the basolateral membrane? BKCa channels in the era of CFTR modulators. (PubMed, Am J Physiol Cell Physiol) - No abstract available

Journal

Differentiating between BK activation and potentiation by vanzacaftor enantiomers. (PubMed, Am J Physiol Cell Physiol) - No abstract available

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

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

Evaluating Vanzacaftor-Based Triple Therapy in F508del/MF Cystic Fibrosis: Insights from the SKYLINE 102 and SKYLINE 103 Trials (ASHP 2025) - No abstract available

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Barriers to the Pharmacologic Rescue of W1282X CFTR. (PubMed, Biochemistry) - "Additionally, acute in vitro treatments with approved modulators VX-809 or VX-661 result in immediate potentiation of W1282X-dependent ion transport, showing that F508del CFTR correctors also augment W1282X CFTR channel activity...Clinically approved CFTR correctors VX-445, VX-121, and VX-809 elicited potentiation of G551D CFTR...Moreover, unlike other CFTR mutations such as F508del, proteasome blockade using ALLN partially rescues W1282X at the plasma membrane. These results highlight ways in which detailed mechanistic analysis and modulator profiling are needed to characterize CFTR mutations such as W1282X and that modulator function in rare variants can be quite distinct from classical findings based strictly upon F508del CFTR."

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