Elexacaftor/Ivacaftor/Tezacaftor

Cystic fibrosis is a life-threatening genetic disorder that causes sticky mucus to build up in the lungs and digestive system. Credit: Iren_Geo via Shutterstock. Vertex Pharmaceuticals has secured two simultaneous US Food and Drug Administration (FDA) approvals for cystic fibrosis (CF) treatments, but both therapies come with boxed warnings for potential drug-induced liver injury including liver failure. The approvals include Alyftek (vanzacaftor/tezacaftor/deutivacaftor), described as a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) modulator, and an expanded label for Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor). Alyftek is approved for use with CF patients aged six years or older who have at least one F508del mutation or another CFTR mutation responsive to the therapy. It builds on the success of Trikafta by covering all mutations included in its label, along with an additional 31 CF-causing mutations. Trikafta was initially approved in 2019 for patients aged 12 years and older, but has now been approved for use in children as young as two years with at least one F508del mutation or a responsive CFTR mutation. Both therapies now carry boxed warnings for liver-related risks, the FDA’s most stringent safety label. Trikafta previously carried a precaution about elevated liver enzymes, but this has been elevated to a boxed warning. Patients using either therapy will require regular liver function monitoring. Alyftek’s approval follows positive results from three Phase III clinical trials, including two 52-week studies – SKYLINE 102 and SKYLINE 103 – comparing its efficacy to Trikafta in patients aged 12 years and older, and a 24-week open-label study, RIDGELINE 105, assessing safety and efficacy in children aged six to 11 years. The trials demonstrated that Alyftek met its primary and key secondary endpoints. Vertex used a priority review voucher to reduce the FDA’s review time for Alyftrek. These approvals further cement Vertex’s dominance in the CF market, which remains a significant revenue driver for the company. Trikafta generated $9.9bn in sales in 2023 and is projected to reach $10.1bn by 2030, according to GlobalData. Alyftek is forecasted to bring in $5.3bn in sales by the same year. GlobalData is the parent company of Pharmaceutical Technology. Cystic fibrosis is a life-threatening genetic disorder that causes sticky mucus to build up in the lungs and digestive system, causing lung infections and problems with digesting food. CFTR modulators like Alyftek and Trikafta work to improve protein function and slow disease progression but still don’t benefit every patient with cystic fibrosis. This leaves a gap in treatment options, a challenge that researchers are continuing to address through alternative therapeutic approaches, including messenger RNA (mRNA) therapies. Vertex teamed up with Moderna in 2020 to identify and develop lipid nanoparticles (LNPs) and mRNAs for the delivery of gene-editing therapies to treat CF. In December 2022, the FDA cleared an investigational new drug (IND) application for VX-522, a product of the collaboration that is delivered to the lung through inhalation of a CFTR mRNA encapsulated by a lipid nanoparticle. The candidate is currently being investigated in a Phase I/II study (NCT05668741).

The FDA on Friday issued two simultaneous cystic fibrosis approvals for Vertex Pharmaceuticals but included high-level safety warnings for both. The first approval is for Vertex’s “vanza triple” combination, a new product that will be branded as Alyftrek, for use in cystic fibrosis patients aged six years and older. Like some of Vertex’s older products, it is a modulator of the CFTR gene. Its list price is about $370,000 per year, according to SEC documents . Vertex’s second approval is a label expansion for Trikafta, an older CFTR modulator that covers 94 new cystic fibrosis mutations. Alyftrek includes all mutations covered by Trikafta, as well as an additional 31 cystic fibrosis-causing mutations. Both therapies will come with boxed warnings for potential drug-induced liver injury and failure. Previously, Trikafta came with a regular warning and precaution to watch for elevated liver enzymes, but the FDA elevated that to a boxed warning. Alyftrek is made up of three different compounds: vanzacaftor, tezacaftor and deutivacaftor. The combo therapy succeeded in its Phase 3 trials earlier this year, and Vertex used a priority review voucher to reduce the FDA’s review time for Alyftrek to six months. Trikafta brought in $9.8 billion in sales last year, and $7.5 billion through the first three quarters of 2024. It’s not yet clear how or if the new boxed warning will affect Trikafta sales going forward. Vertex is expected to release updated financial guidance during its fourth-quarter earnings call early next year.