deutivacaftor (VX-561) / Vertex - LARVOL DELTA

Fetal drug exposure after maternally administered elexacaftor/tezacaftor/ivacaftor in a rat model (ECFS 2025) - "We aimed to investigate the fetal tissue distribution pattern of maternally administered ETI by placental transfer in the rat fetuses.Study Design and Sprague Dawley pregnant rats were administered ETI (6.7 mg/kg/d elexacaftor + 3.5 mg/kg/d tezacaftor + 25 mg/kg/d ivacaftor) traced with [3H]-ivacaftor in single dose acute experiments (intraperitoneal injection) or treated orally with ETI (the same dose) for 7 days in sub-chronic experiments. Fetal rats are exposed to maternally ingested ETI after sub-chronic exposure, potentially impacting fetal development. The brain entry data highlights the need for attention be paid to any long-term potential effects ETI exposure could have on normal brain development."

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

Evaluation of VX-828 in Healthy Participants and in Participants With Cystic Fibrosis (clinicaltrials.gov) - P1 | N=255 | Recruiting | Sponsor: Vertex Pharmaceuticals Incorporated | Trial primary completion date: Apr 2025 ➔ Feb 2026

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

Fetal drug exposure after maternally administered CFTR modulators Elexacaftor/Tezacaftor/Ivacaftor in a rat model. (PubMed, Biomed Pharmacother) - "Fetal rats are exposed to maternally ingested ETI after sub-chronic exposure, potentially impacting fetal development. The brain entry data highlights the need for attention be paid to any long-term potential effects ETI exposure could have on normal brain development."

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

Triple HEMT in Pregnancy and Lactation: effects on the developing lung, gut and pancreas (ECFS 2023) - "Introduction/aim: The development of new cystic fibrosis (CF) drugs, including the highly effective modulator therapies (HEMT) such as elexacaftor-tezacaftor-ivacaftor (ETI), has enabled more women with CF to reach child-bearing age...We aim to investigate placental and milk transfer of maternally administered ETI in pre- and postnatal wildtype and F508del-CFTR rats and their bioaccumulation into the developing lungs, gut and pancreas. 1) ETI permeability: Wildtype Sprague Dawley rats at embryonic day (E) 19 and adult rats were administered an intraperitoneal injection of ETI (40mg/kg/d ivacaftor + 6.7mg/kg/d/elexacaftor + 3.5mg/kg/d tezacaftor) traced with [3H] ivacaftor... ETI does not appear to cause structural damage in small intestine villi and pancreas, suggesting the possible safety to breastfed human newborns. Further work is needed to understand the effects on ETI on the fetus during gestation."

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

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 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

Concert Pharmaceuticals Announces Sale of VX-561 Milestones to Vertex for $32 Million (Businesswire) - "Concert Pharmaceuticals...announced that Vertex Pharmaceuticals Incorporated (NASDAQ: VRTX) has purchased the potential future milestones under the companies’ 2017 asset purchase agreement relating to VX-561 (deutivacaftor) for $32 million....Under the asset purchase agreement, Vertex acquired worldwide development and commercialization rights to VX-561 (formerly known as CTP-656) and other assets related to the treatment of cystic fibrosis."

Licensing / partnership • Cystic Fibrosis • Fibrosis

Clinical relevance of patient-reported outcomes: new threshold proven feasible in practice (Eurekalert) - "On the occasion of the addenda published today on early benefit assessments of the drugs...ivacaftor (for cystic fibrosis)...IQWiG's Drug Assessment Department emphasizes: ‘The concerns were unfounded. We see that the new threshold is suitable for use in practice’….'Based on analyses with the new response thresholds, we were able to show the advantages and disadvantages of treatments, such as the advantage of ivacaftor for the quality of life of children with cystic fibrosis'."

Clinical • Cystic Fibrosis

A Phase 2 Study to Evaluate Efficacy and Safety of VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis (clinicaltrials.gov) - P2; N=77; Completed; Sponsor: Vertex Pharmaceuticals Incorporated; Active, not recruiting ➔ Completed

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

"Same can be said for #ivacaftor (#Kalydeco) being in #Trikafta. @VertexPharma How’s the VX-561?" (@Original00Boone)

A Phase 2 Study to Evaluate Efficacy and Safety of VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis (clinicaltrials.gov) - P2; N=77; Active, not recruiting; Sponsor: Vertex Pharmaceuticals Incorporated; Recruiting ➔ Active, not recruiting

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

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

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

A Phase 2 Study to Evaluate Efficacy and Safety of VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis (clinicaltrials.gov) - P2; N=88; Recruiting; Sponsor: Vertex Pharmaceuticals Incorporated; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

A Phase 2 Study to Evaluate Efficacy and Safety of VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis (clinicaltrials.gov) - P2; N=88; Not yet recruiting; Sponsor: Vertex Pharmaceuticals Incorporated

Clinical • New P2 trial

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

Clinical • Combination therapy • New P2 trial

Treating cystic fibrosis patients before birth could safeguard organs (Science News) - “Ivacaftor can reduce lung problems in patients with the G551D protein defect, with treatment usually starting when a patient is a year old. But if the results of the new animal study carry over to humans, an even earlier start date could prove more effective in preventing damage to multiple organs.”

Clinical