Beyond the lungs: How CFTR modulators benefit cystic fibrosis patients

For patients with cystic fibrosis (CF), treatment historically has been limited. But a new classification of drugs – cystic fibrosis transmembrane conductance regulator modulators (CFTR modulators) – provides an opportunity to slow progression of the disease for more than 90 percent of CF patients.

CF is a genetic condition that causes thick secretions in the lungs, pancreas, and other organs. To date, more than 2,000 CF genetic mutations have been identified, many of which cause symptoms. There currently are three CFTR modulator drugs approved by the U.S. Food and Drug Administration (FDA), all of which are oral tablets that have the potential to affect not only the lungs but also the sinuses and pancreas. 

Though these drugs are relatively new and not currently curative for CF, we’re seeing promising results in symptom management and slowing disease progression. Let’s take a look at how these drugs work and dive into a patient’s experience with a personalized therapy plan. 

How CFTR modulators work

Patients with CF have mutations in the CFTR gene, which is supposed to create a protein that regulates the flow of water and chloride in and out of the cells that line the lungs, pancreas, and other organs. However, CFTR mutations can lead to the production of defective proteins or to producing no protein at all. This results in thick secretions that can cause infections, damage, and problems with the lungs, pancreas, and sinuses among other organs.

CFTR modulators target the defective proteins and work to control their effects by moving them to the cell surface and helping them function properly. Drugs are designed to target proteins based on specific CFTR gene mutations. These drugs currently are available in oral tablet form.   

Available CFTR drugs and eligibility

The very first CFTR drug, ivacaftor (KalydecoⓇ) became available in 2012. Patients who have been on the drug since have shown multiple benefits, such as:

● Increased body mass index, which is important because many CF patients with digestive symptoms become malnourished and lose significant weight without proper therapy

● Lung function improvement often as high as 10 to 15 percent

● Improvement of sinus symptoms 

Ivacaftor generally targets class 3 or 4 CFTR mutations (also called gating mutations), which tend to cause milder symptoms than other mutations. Since 2012, the FDA has approved two more CFTR modulators:

1. Ivacaftor plus lumacaftor (OrkambiⓇ): The FDA approved this drug in 2015. It targets the most common CFTR mutation, which is characterized by a patient having two copies of the F508del gene. This medication also has been recently approved for a few additional, less common mutations.
2. Ivacaftor plus tezacaftor (Symdeko™): Approved by the FDA in early 2018, this drug also targets dual copies of the F508del gene, as well as other mutations. 

CF is one of the first diseases to have genetically targeted personalized medicine, and the sooner a patient starts on a therapy, the slower the disease is likely to progress. Though not every patient is eligible for a drug today, the anticipation is that 90 percent of patients will have an available therapy within the next few years. In order to achieve that, patients should be cared for as children, or as early as possible in adulthood, by a CF team at a clinic that is accredited by the Cystic Fibrosis Foundation, such as UT Southwestern. We are one of just a few accredited clinics in the area, along with one in Fort Worth and one in Tyler.

As such, we have a robust database that includes more than 95 percent of our patients. As new drugs are developed and approved, we screen our database and proactively reach out to patients who have specific mutations to let them know about the opportunity to take these medications if they’re interested. This process has proven effective for patients such as Ryan Monahan from Dallas, who transitioned from pediatric to adult CF care in 2006. I’ve invited Ryan to share his story of CFTR modulator therapy below.

Ryan’s story: Life with CFTR modulator therapy

When I turned 18 in 2005, I transitioned from the Children’s Medical Center cystic fibrosis program to the adult program at UT Southwestern. A few years later, Dr. Jain joined the staff and became my doctor. 

I have the double-delta F508del mutation of my CFTR gene, which didn’t benefit from the original CFTR modulator drug, Kalydeco. However, when Orkambi came out in 2015, Dr. Jain suggested that we try it out. My first week on the therapy was rough. I had an unusually severe reaction and felt so poorly that I could hardly get out of bed. However, Dr. Jain acted quickly and worked with me to tailor a dosage that effectively controlled my symptoms without unpleasant side effects. After we worked out my dosage, which took less than two weeks, I didn’t notice any game-changing or significant pulmonary improvements. However, my digestive symptoms improved a bit. I didn’t necessarily feel better than before, but I didn’t feel worse while taking the CFTR modulator on its own. 

A year later, Dr. Jain prescribed a bronchodilator, a drug that relaxes the airways to keep them open. I take this drug in the morning along with my Orkambi, which I take again at night. Not long after I started this regimen, we began to see positive spikes in my pulmonary function tests. Since I’ve been on this combined therapy, I’ve had only one major illness, which is impressive because CF always poses the risk of getting sick. Even then, I was able to undergo IV therapy at home rather than stay in the hospital.

About a year ago, we wanted to see how well the drug combination was working, so I went off the therapy for a few weeks to gauge my response. Right away, I noticed that I felt sluggish. Though the combination therapy doesn’t make me feel drastically different from how I felt before I took a CFTR modulator, I now know that it’s working to slow the progression of my disease.

So many doctors know what to do from a medical standpoint but have a hard time making it work for individuals. CF patients have to live with the disease every day, but that doesn’t mean we can stop everything, rotate treatment, and build our lives around the disease. Dr. Jain makes treatment work around my life. It’s a next-level experience when a doctor personalizes treatment to you, particularly for a disease as complex as CF. I’ve had nothing but great experiences with the UT Southwestern team. Their clinic is phenomenal, and when we run into challenges such as my medication reaction, they work quickly to help me feel better.

Ongoing CF research at UT Southwestern

Success stories like Ryan’s give us the motivation to push forward and find more therapies for more CF patients. The next trial in which we will participate is a combination of the three drugs for people like Ryan with two copies of the F508del mutation, as well as those with one copy and certain minimally functioning second mutations for whom no genetically targeted therapy is yet available today. This trial combines a new compound VX-445 with 2 existing therapies (ivacaftor and tezacaftor). Initial clinical trials showed a 12 to 15 percent improvement in symptoms, so we’re hopeful that ongoing research will lead to approval of these additional therapies for more patients. 

Connect with a cystic fibrosis expert today to access the most advanced CF therapies available. Call us at 214-645-8300 or request an appointment online.