vanzacaftor (VX-121) / Vertex - LARVOL DELTA

Effects of elexacaftor (VX-445) and vanzacaftor (VX-121) on KCNT1 (slack) and KCNT2 (slick) potassium channels (NACFC 2024) - "The most widely effective therapy for CF is the combination drug therapy that consists of elexacaftor (VX-445), tezacaftor (VX-661), and ivacaftor (VX-770). Our results show that VX-445 and VX-121 have activity on the slack and slick Na+-activated potassium channels. The term "slack" refers to the acronym "sequence like a calcium-activated K+ channel" and was given to this channel when it was discovered that a portion of the pore domain and the entire S6 transmembrane segment is similar to BKCa. The channels have only 7% similarity, overall."

CNS Disorders • Cystic Fibrosis • Epilepsy • Genetic Disorders • Immunology • Respiratory Diseases

Differential effects of (S)- and (R)-vanzacaftor on BKCa potentiation and CFTR correction (NACFC 2024) - "Correction of CFTR folding by VX-445 (elexacaftor) has been shown to be enantiomer dependent, with (S)-VX-445 being more efficacious than (R)-VX-445. Our results demonstrate that the next-generation C2 CFTR corrector VX-121 exhibits clear enantiomer-dependent CFTR correction. Incubation in (S)-VX-121 converts a population of band B F508del CFTR to band C, consistent with F508del CFTR correction, but (R)-VX-121 fails to correct F508del CFTR. (S)- and (R)-VX-121 both stimulate K+ secretion across HBECs and potentiate BKCa channels during whole-cell patch-clamp recording."

CFTR

Enhancing apical loop currents in airway epithelia carrying minimal function CFTR mutations (NACFC 2024) - "Potentiation of BK was assessed using elexacaftor (VX-445; 10 µM) and potentiation of G551D CFTR using ivacaftor (1 µM). BK plays an important role in enabling fluid delivery to the airway surface. Enhancing apical loop currents even in inflammatory environments by potentiation of BK in PwCF with minimal function CFTR mutations is feasible. Newer potentiators such as vanzacaftor might be more potent, and combinations with TMEM16A potentiators could have beneficial effects for PwCF with minimal function CFTR mutations."

Cystic Fibrosis • Genetic Disorders • Immunology • Inflammation • Respiratory Diseases • CFTR • TGFB1

Potentiation of BKCa channels by cystic fibrosis transmembrane conductance regulator (CFTR) correctors VX-445 and VX-121. (PubMed, J Clin Invest) - "Here, we show the CFTR corrector, VX-445 (Elexacaftor), a component of Trikafta, induces K+ secretion across WT and F508del CFTR primary human bronchial epithelial cells (HBEs), which was entirely inhibited by the BKCa antagonist paxilline. VX-445 effects were observed at low micomolar concentrations (1-10 µM) - within the range reported in plasma and tissues from CF patients. We raise the possibilities that CFTR correctors gain additional clinical benefit by activation of BKCa in the lung, yet may lead to adverse events through BKCa activation, elsewhere."

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

Vanzacaftor: Completion of cohort 1 of P3 RIDGELINE trial (NCT05844449) for cystic fibrosis in 2023 (Vertex) - Q3 2023 Results: Data from cohort 1 of P3 RIDGELINE trial for cystic fibrosis in early 2024

P3 data • Trial status • Cystic Fibrosis

Vanzacaftor: Data from P3 SKYLINE 102 trial (NCT05033080) for cystic fibrosis in early 2024 (Vertex) - Q3 2023 Results: Data from P3 SKYLINE 103 trial (NCT05076149) for cystic fibrosis in early 2024

P3 data • Cystic Fibrosis

An Electrocardiogram Study to Evaluate the Effect of Vanzacaftor on the QT/QTc Interval in Healthy Participants (clinicaltrials.gov) - P1 | N=56 | Completed | Sponsor: Vertex Pharmaceuticals Incorporated | Active, not recruiting ➔ Completed

Monotherapy • Trial completion • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

An Electrocardiogram Study to Evaluate the Effect of Vanzacaftor on the QT/QTc Interval in Healthy Participants (clinicaltrials.gov) - P1 | N=56 | Active, not recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

An Electrocardiogram Study to Evaluate the Effect of Vanzacaftor on the QT/QTc Interval in Healthy Participants (clinicaltrials.gov) - P1 | N=56 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated

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

Comparing F508del cystic fibrosis transmembrane conductance regulator modulator responses in human primary enteric monolayer and human bronchial epithelial cultures (NACFC 2022) - "CFTR currents werestimulated with in-assay additions of 10 mM forskolin and 1 mM ivacaftor.The potency order in both in vitro models was identical (Table 1).Both first-generation (lumacaftor, tezacaftor) CFTR modulators had lowerpotency in hPEMs than hBEs. Higher potency was observed in hPEMs forVX-121 and the corrector combinations, whereas VX-121 and elexacaftor,when tested alone in hPEMs, generated a maximum effect close to thatachieved with the corrector combinations...Primary hBE cells remain the gold standard for in vitro CFTRfunctional measurements, but an alternative primary cell model would behighly valuable, particularly for testing future potential nonsense CFTRtherapeutic approaches. Data presented here compare the sensitivity andassay window of the hPEM model with those of the hBE model. This, alongwith more readily accessible material of a wide genotype range and greaterexpansion capability, makes the hPEM model an attractive platform forassessing CFTR..."

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

Vertex Reports Fourth Quarter 2021 and Full Year Financial Results (Businesswire) - P3, N=98; NCT03150719; Sponsor: Vertex Pharmaceuticals Incorporated; "The Phase 3 study of ORKAMBI in patients 12 to 24 months of age met its primary endpoint. ORKAMBI was well tolerated in this patient population, and no new safety concerns were identified...Based on these data, Vertex intends to submit regulatory filings in the U.S. in Q1 and in Europe in Q2 2022....The SKYLINE 102 and SKYLINE 103 trials are expected to include 950 patients in total and will compare the performance of VX-121/tezacaftor/VX-561 to TRIKAFTA. Enrollment in both trials is expected to be completed by late 2022 or early 2023....IND-enabling studies are underway, and we plan to submit an IND for this program in 2022."

Enrollment status • European regulatory • IND • P3 data • sNDA • Cystic Fibrosis

A Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Who Are Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function (F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive (TCR) CFTR Mutation and No F508del Mutation (clinicaltrials.gov) - P3; N=550; Recruiting; Sponsor: Vertex Pharmaceuticals Incorporated; Not yet recruiting ➔ Recruiting

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

A Phase 3 Study of VX-121 Combination Therapy in Subjects With Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation (F/MF) (clinicaltrialsregister.eu) - P3; N=400; Sponsor: Vertex Pharmaceuticals Incorporated

Clinical • Combination therapy • New P3 trial • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 3 Study of VX-121 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function (F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive CFTR Mutation and No F508del Mutation (clinicaltrialsregister.eu) - P3; N=550; Sponsor: Vertex Pharmaceuticals Incorporated

Clinical • Combination therapy • New P3 trial • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 3 Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Who Are Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function (F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive (TCR) CFTR Mutation and No F508del Mutation (clinicaltrials.gov) - P3; N=550; Not yet recruiting; Sponsor: Vertex Pharmaceuticals Incorporated

Clinical • Combination therapy • New P3 trial • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 3 Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Heterozygous for F508del and a Minimal Function Mutation (F/MF) (clinicaltrials.gov) - P3; N=400; Recruiting; Sponsor: Vertex Pharmaceuticals Incorporated; Not yet recruiting ➔ Recruiting

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

A Phase 3 Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Heterozygous for F508del and a Minimal Function Mutation (F/MF) (clinicaltrials.gov) - P3; N=400; Not yet recruiting; Sponsor: Vertex Pharmaceuticals Incorporated

Clinical • Combination therapy • New P3 trial • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Vertex to Initiate Phase 3 Development Program for New Once-Daily Triple Combination Regimen in People With Cystic Fibrosis (Businesswire) - P2, N=87; NCT03912233; Sponsor: Vertex Pharmaceuticals Incorporated; "Vertex Pharmaceuticals...announced the company will initiate a Phase 3 development program for the new once-daily investigational triple combination of VX-121/tezacaftor/VX-561 (deutivacaftor) in the second half of 2021....The combination of VX-121/tezacaftor/VX-561 was evaluated in a Phase 2 study in people with cystic fibrosis (CF) ages 18 and older with one F508del mutation and one minimal function mutation (F/MF) and in people with CF ages 18 and older with two F508del mutations (F/F). The regimen was generally well-tolerated, and the study met the primary efficacy endpoint of absolute change from baseline in ppFEV....'TRIKAFTA has demonstrated high levels of efficacy in people with CF who have at least one F508del mutation'....Complete data from the Phase 2 clinical study of VX-121/tezacaftor/VX-561 and the VX-561 Phase 2 monotherapy study will be presented at a later date"

New P3 trial • P2 data • Cystic Fibrosis • Genetic Disorders

3 Things About Vertex Pharmaceuticals That Smart Investors Know (Nasdaq) - "With patents that run through 2037, Vertex has set the foundation for an incredibly durable franchise....Vertex's stock is down 35% from its 52-week high. Vertex may be a victim of its own success...Another positive development is the potential for a new therapy combining tezacaftor with VX-121 (a 'next generation corrector') and VX-561 (a new potentiator) to restore the function of the defective protein causing cystic fibrosis....Phase 3 trials are expected later this year."

New P3 trial • Patent • Stock price • Cystic Fibrosis • Genetic Disorders

"Any update on VX-121 triple combo?" (@MerandaCF)

"Has anyone attending #NACFC2020 heard an update on @VertexPharma VX-121 triple combo?" (@MerandaCF)

A Study to Evaluate the Safety and Efficacy of VX-121 Combination Therapy in Subjects With Cystic Fibrosis (clinicaltrials.gov) - P2; N=87; Completed; Sponsor: Vertex Pharmaceuticals Incorporated; Active, not recruiting ➔ Completed

Clinical • Combination therapy • Trial completion

A Study to Evaluate the Safety and Efficacy of VX-121 Combination Therapy in Subjects With Cystic Fibrosis (clinicaltrials.gov) - P2; N=87; Active, not recruiting; Sponsor: Vertex Pharmaceuticals Incorporated; Recruiting ➔ Active, not recruiting

Clinical • Combination therapy • Enrollment closed

Study of VX-121 in Healthy Subjects and in Subjects With Cystic Fibrosis (clinicaltrials.gov) - P1/2; N=114; Completed; Sponsor: Vertex Pharmaceuticals Incorporated; Active, not recruiting ➔ Completed

Clinical • Trial completion

A Study to Evaluate the Safety and Efficacy of VX-121 Combination Therapy in Subjects With Cystic Fibrosis (clinicaltrials.gov) - P2; N=81; Recruiting; Sponsor: Vertex Pharmaceuticals Incorporated; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open