Vertex Pharmaceuticals has developed medicines that represent a shift in the management of cystic fibrosis (CF). Historically, treatment for this genetic disorder focused on managing symptoms. The introduction of Vertex’s drugs has altered this landscape by providing a therapeutic approach that addresses the underlying biological cause of the disease. This evolution in treatment strategy is the result of decades of research into the genetic and cellular basis of the illness.
The Underlying Cause of Cystic Fibrosis
Cystic fibrosis is a genetic condition that originates from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene holds the instructions for creating the CFTR protein. To have cystic fibrosis, a person must inherit two copies of a mutated CFTR gene, one from each parent. There are over 2,000 identified mutations in the CFTR gene, with the most common being the F508del mutation.
The CFTR protein functions as a channel on the surface of epithelial cells in organs like the lungs, pancreas, and sweat glands. This channel transports chloride ions, a component of salt, across the cell membrane. This movement helps regulate the balance of salt and water, which is necessary for creating thin, free-flowing mucus.
In individuals with CF, mutations in the CFTR gene lead to a defective protein that is either misshapen, non-functional, or produced in insufficient quantities. When the CFTR protein does not work correctly, the transport of chloride and water is disrupted. This disruption causes the mucus that lines various organs to become thick and sticky, leading to the primary complications of the disease, such as lung infections and digestive problems.
How Vertex CFTR Modulators Work
Vertex has developed a class of drugs known as CFTR modulators, which are designed to correct the function of the faulty protein that causes cystic fibrosis. These oral medications do not fix the gene itself but instead work directly on the defective CFTR protein to help it function more effectively. This approach targets the root cause of the disease at a cellular level.
CFTR modulators are categorized into two main types: correctors and potentiators. Correctors help misshapen CFTR proteins fold into the correct three-dimensional shape, allowing the protein to be properly trafficked to the cell surface. Potentiators work on the CFTR protein channels that have already reached the cell surface, holding the channel open so that more chloride ions can pass through.
The company’s drugs include Kalydeco (ivacaftor), which is a potentiator. Other treatments are combination therapies. Orkambi combines the corrector lumacaftor with the potentiator ivacaftor, and Symdeko combines the corrector tezacaftor with ivacaftor. The most recent development, Trikafta, is a triple-combination therapy that includes two correctors, elexacaftor and tezacaftor, along with the potentiator ivacaftor.
This triple-combination approach is effective for patients with the most common F508del mutation. The combination of two correctors helps a greater quantity of the misshapen F508del-CFTR protein reach the cell surface, and the potentiator then enhances the function of those proteins. This leads to a more significant restoration of chloride transport than earlier modulator therapies.
Patient Eligibility and Clinical Impact
Eligibility for Vertex’s CFTR modulators is specific, determined by a patient’s age and the particular mutations they have in the CFTR gene. Genetic testing is required to confirm a patient’s mutations to determine if they are a candidate. For example, Trikafta is approved for patients aged two years and older who have at least one copy of the F508del mutation or another responsive mutation.
The clinical impact of these treatments, especially the triple-combination therapy Trikafta, has been notable for eligible patient populations. A key measure of lung health in CF is the forced expiratory volume in one second (FEV1), which assesses how much air a person can forcefully exhale. In clinical trials, patients taking Trikafta showed improvements in their percent predicted FEV1, with some studies showing an increase of 10 to 14 percentage points compared to placebo or other modulators.
Beyond lung function, these drugs have demonstrated broader health benefits. Clinical studies have reported:
- A significant reduction in the number of pulmonary exacerbations, which are episodes of worsening lung symptoms that often require hospitalization.
- Improvements in body mass index (BMI).
- Improvements in overall quality of life, as measured by patient-reported outcome tools.
- A reduction in sweat chloride concentration, which is a direct indicator of improved CFTR protein function.
Access, Costs, and Future Developments
A challenge associated with Vertex’s CFTR modulators is their high cost, with annual list prices often exceeding $300,000 per patient. This has created hurdles for patient access, requiring complex negotiations between the company, governments, and private insurance providers to secure reimbursement. The high price remains a barrier in many parts of the world.
Patient advocacy groups have actively campaigned for lower prices to improve global access, arguing that the cost does not align with manufacturing expenses. In response to access challenges, Vertex has established some patient assistance and donation programs. However, the financial burden on healthcare systems and individuals continues to be a central point of discussion and debate within the CF community.
Looking ahead, research continues to address the needs of all individuals with CF. While current modulators are effective for about 90% of the patient population, approximately 10% have mutations that do not respond to these treatments. Vertex and other companies are exploring new therapeutic strategies for this group, including mRNA therapies and gene-editing technologies, with the goal of developing treatments that can help every person with cystic fibrosis. A next-generation once-daily modulator, a combination of vanzacaftor, tezacaftor, and deutivacaftor, has also shown promising results in clinical trials.