Cystic Fibrosis: One Patient’s Story, Current Treatments and Exciting New Therapies on the Horizon
“The recent progress of cystic fibrosis drugs has been amazing and, in my case, miraculous,” said Kelly Peters, who lives with cystic fibrosis. “The new drugs are not a cure, but they feel pretty close.”
Cystic fibrosis (CF) is a rare, progressive genetic disease that affects the lungs, causing those affected to develop persistent lung infections and reduces their ability to breathe over time. Thick mucus builds up in the lungs, clogging the airway and trapping germs, causing inflammation, infections, and respiratory failure. Mucus also builds up in the pancreas, preventing digestive enzymes from being released, impairing food absorption and ultimately leading to malnutrition and poor growth.
BioSpace spoke with Kelly Peters about living with CF, as well as a spokesperson at the Cystic Fibrosis Foundation about the current treatments, the late-stage drug pipeline, and exciting drugs in development to watch.
For more in-depth information about CF, current CF drugs, and the CF drug development pipeline, check out our “Cystic Fibrosis Insight Report: Current Therapies, Drug Pipeline and Outlook.”
What causes cystic fibrosis (CF)?
All of CF’s problems can be traced back to one misbehaving protein, aptly named the cystic fibrosis transmembrane conductance regulator (CFTR). Various mutations in the CFTR gene can affect different portions (and therefore functions) of the resulting protein.
In fact, there are over 1,700 different mutations in the CFTR gene that are known to cause CF! Mutations are grouped into five classes based on how they affect the CFTR protein’s functioning.
“I have two mutations: the most common one, Deltaf508, and another rare mutation, p67L, which is associated with milder symptoms,” explained Peters. “There are only around 200 people in the world with my particular mutation combination. I was only diagnosed with the Deltaf508 mutation when I first had sequencing done; it wasn’t until I went through sequencing for a possible lung transplant in 2016 that they identified the second gene mutation.”
To have CF, a person must inherit two mutated copies of the CFTR gene, one from each parent. People who only have one mutated CFTR gene (called carriers) usually don’t have symptoms; more than 10 million (about one in 35) Americans are symptomless CF carriers. However, if two carriers have a child, the child has a 25 percent chance of having CF. Genetic testing (called carrier tests) is available for those who want to find out their CFTR mutation status before having children.
CF symptoms include persistent, phlegmy cough; shortness of breath; frequent lung infections (pneumonia or bronchitis); very salty sweat or salty-tasting skin; poor growth and weight gain despite good appetite; frequent greasy, bulky stools; difficulty with bowel movements; and male infertility.
CF can be diagnosed during routine newborn genetic screening tests, other genetic testing, or a sweat test (which measures the amount of salt in a person’s sweat). The first newborn CF genetic testing program was established in Colorado in 1982 and grew slowly to five states in 2005; thanks to the advocacy efforts of the CF Foundation, newborn screening became mandatory in all 50 states in 2010. If a baby has a positive screening test, they are typically referred to a CF care center for a sweat test to confirm a CF diagnosis.
Living with CF: Kelly Peters’ story
Life with CF has many unique challenges and looks different for each CF patient, depending on the severity of their CF and their treatment plan.
“In 1955, when the CF Foundation was founded, many children diagnosed with cystic fibrosis did not live to reach kindergarten,” the CF Foundation spokesperson said. “Now, because of advances in care and research, and with the development of new highly effective therapies, people with CF are achieving milestones that were unimaginable back then, like graduating high school and college, getting married, and starting families of their own. While people with CF are still not living long enough, life expectancy has increased dramatically in recent decades, with people living into their 30s, 40s, and beyond.”
One of these “and beyond” examples is Kelly Peters, a CF patient who is now 55. “I’m way past the typical life expectancy, so every year is a blessing,” Peters said. “I’m a grandmother now. I’m happy to extend the curve!”
Peters' story is a bit unusual for a CF patient – she wasn’t diagnosed until age 24 in 1989 (ironically the same year the CFTR gene was discovered). Throughout college, she got more and more upper respiratory infections; they were successfully treated with antibiotics, so she didn’t think twice about them. “I also had walking pneumonia during my honeymoon,” Peters added. “The older you get, the less likely doctors are to consider it CF, at least at that time 30 years ago.”
But when she was pregnant with her first child, she had many upper respiratory infections that weren’t going away despite antibiotic treatment. Around 38 weeks, her doctors decided to do a last resort chest x-ray. The radiologists saw markers of CF and sent her to specialists to be evaluated, confirming her CF diagnosis with a sweat test.
“Looking back, there were symptoms, but I never considered CF growing up,” commented Peters. “I’m on the milder end of the disease, but it’s definitely getting worse as I’ve gotten older because every infection does a little damage to your lungs.”
How is CF currently treated?
CF treatment is multifactorial, combining physical airway clearance techniques (using tapping on the chest or a vibrating vest to loosen mucus and coughing to get rid of the mucus), medications, fitness, and nutritional therapies.
“Every morning and evening, I do the vibrating vest treatment for 30-45 minutes, where I also use a nebulizer to take Pulmozyme, albuterol, and an inhaled antibiotic (colistimethate), only taking the antibiotic every other month,” Peters explained. “I also take azithromycin three times a week, Trikafta twice a day, omeprazole (Prilosec), calcium and other multivitamins once a day, and digestive enzymes whenever I eat. Before I started taking the newer CF drugs, I had to do the vibrating vest treatment four times a day.”
“The CF Foundation funds and accredits 133 adult and pediatric care centers nationwide with dedicated health care professionals who partner with people living with CF and their families,” a spokesperson at the Cystic Fibrosis Foundation explained. “People with CF visit their care centers regularly and are treated by a multidisciplinary care team, including a nurse, respiratory therapist, dietitian, program coordinator, and social worker. Additional care team members may include a psychologist, pharmacist, research coordinator, and physical therapist.”
Currently available CF drugs
CF drugs have flourished within the past decade, now including treatments that not only improve quality of life, but directly address the underlying cause.
“Pulmozyme came out in 1993 and, really, there wasn’t much after that until these more recent drugs,” Peters commented. “Kalydeco, Orkambi, Symdeko, and now Trikafta all came really quickly – it just kept progressing within a few years and they keep advancing them, which is pretty amazing.”
There are currently a wide array of CF therapies:
- Anti-inflammatories: drugs that reduce inflammation throughout the body. Although it is not specific to CF, high dose ibuprofen is approved for CF patients; however, doctors often will not prescribe high dose ibuprofen due to its unwanted side effects, such as ulcers and kidney problems.
- Anti-infectives: drugs that treat CF-related infections. Five antibiotics are currently approved for CF patients: azithromycin, inhaled tobramycin, tobramycin inhaled powder (TOBI® Podhaler™), aztreonam (Cayston®), and amikacin liposome inhalation suspension (Arikayce®).
- Nutritional/gastrointestinal: drugs that address gastrointestinal issues and nutritional deficiencies, such as pancreatic insufficiency, CF-related diabetes, CF-associated liver disease, and colorectal cancer. There are three approved drugs: Pancrelipase enzyme products (digestive enzymes), RELiZORB® (a digestive enzyme cartridge that connects to feeding tubes), and AquADEKs® (an oral antioxidant vitamin formulation).
- Mucociliary clearance: drugs that prevent mucus buildup, thin mucus, or break up mucus in the airways to promote its clearance. There are two drugs available: hypertonic saline and dornase alfa (Pulmozyme®).
- CFTR modulators: drugs that correct the malfunctioning CFTR protein. This is the newest class of CF drugs. Four are currently available: ivacaftor (Kalydeco®), lumacaftor/ivacaftor (Orkambi®), tezacaftor/ivacaftor (Symdeko®), and elexacaftor/tezacaftor/ivacaftor (Trikafta®).
“I started Kalydeco in November 2017 and, within a month, I couldn’t believe it – the difference was amazing,” Peters explained. “I went from about 26 percent lung function and being evaluated for a lung transplant to about 40 percent lung function and no longer transplant eligible. After starting with Kalydeco, I went on Symdeko, and now I’m on Trikafta – they all made my symptoms a little better.”
“Trikafta® represents one of the most important therapeutic advancements in the history of CF,” the CF Foundation spokesperson commented. “It offers a treatment for the underlying cause of the disease that is significantly more effective than current modulator therapies and can be used by a much larger segment of the CF community.”
Improving the lives of people with CF
People with CF are living longer and longer, so their quality of life is becoming ever more important. Better treatments, like Trikafta, are key to improving CF patients’ daily lives.
“Between 2010 and 2016, my health and lung function started to significantly decline, so I went through a lung transplant evaluation” explained Peters. “I was on oxygen for pretty much everything except sitting. At that point in time, CF significantly impacted my quality of life. After starting Kalydeco and the other new drugs, I only needed oxygen when I exercise or fly – I can pretty much do all my daily activities without oxygen now.”
But the newer medications are just one part – reducing the frequency of illness and improving the management of CF patients when they get sick is important too.
“When I was younger, I got upper respiratory infections four or five times a year and was in the hospital for 10 days each to receive IV antibiotics, which starts to impact your life,” Peters said. “Now, I only get sick once or twice a year and I have a port, so I’m able to administer the IV antibiotics at home, after visiting an infusion center for my first dose.”
“We continue to see outcomes for people with CF improve and have seen steady progress in key measures correlated with survival, such as improved lung function and nutritional status, and decreased presence of harmful lung bacteria,” noted the CF Foundation spokesperson. “However, people with CF continue to need treatments to manage complications from CF, regardless of whether they are taking CFTR modulators.”
Late-stage CF drug pipeline overview
The CF Foundation hosts the largest CF clinical trials network in the world, called the Therapeutics Development Network. This network is funding or facilitating an extensive amount of drugs in development, including more and improved CFTR modulators and therapies to address the wide array of complications CF patients may encounter.
“More than 20 drugs are being developed for complications, including anti-infective agents, anti-inflammatories, mucociliary clearance therapies, and nutritional agents,” said the spokesperson for the CF Foundation.
The foundation also began its Infection Research Initiative in 2018, awarding more than $58 million of its allotted $100 million to “improving the detection, diagnosis, treatment, and outcomes of CF-related infections,” the spokesperson added.
According to the CF Foundation’s Drug Development Pipeline, there are 25 drugs in clinical development (Phases 1-3), including 3 anti-inflammatory drugs, 10 anti-infective agents, 1 nutritional enzymatic drug, 4 mucociliary clearance drugs, and 7 CFTR modulators.
The next generation of CF drugs
The CF Foundation’s Path to a Cure initiative challenges CF researchers to come up with new, next-generation therapies, such as CF gene therapies, and accelerate therapies through development. The three core strategies this initiative addresses go straight for the underlying causes of CF by “repairing the broken CFTR protein, restoring the CFTR protein when none exists, and fixing or replacing the underlying genetic mutation,” according to the CF Foundation spokesperson. “The latter genetic-based treatments could potentially help all people with CF, regardless of their mutation, and hold the greatest promise of a cure.”
In fact, last year the CF Foundation invested $14 million in 4D Molecular Therapeutics to advance their preclinical CF gene therapy candidate (4D-710), an adeno-associated virus (AAV) vector that can deliver a healthy copy of the CFTR gene into the lung cells of CF patients. Circumventing the lung cells’ aggressive protection measures against foreign invaders (including AAV vectors) has been a huge challenge for developing an effective CF gene therapy.
The UK Cystic Fibrosis Gene Therapy Consortium, a group of researchers from Imperial College London, the University of Oxford, and the University of Edinburgh, partnered with Boehringer Ingelheim in 2018 to advance CF gene therapy. Their gene therapy candidates use either a liposome (a ‘bubble’ of fat molecules) or a modified lentivirus as vectors to deliver a healthy CFTR gene.
Outlook for CF
The future of CF therapeutics looks bright and there are even more benefits of the current, improved treatments, such as starting young CF patients on disease-altering drugs sooner.
“I’m excited for the youth – if they can start the drugs early, they won’t have the lung damage or infections, and they could lead pretty normal lives,” Peters said. “There’s so much hope now with the available medications – it’s not the terminal diagnosis it used to be.”
In fact, Vertex Pharmaceuticals, which makes Trikafta, announced that their drug is effective in children 6-11 years old after completing a Phase III trial. The company filed a supplemental New Drug Application (sNDA) to the Food and Drug Administration (FDA) in 2020 and was accepted in early 2021. (Trikafta is currently approved for CF patients ages 12 and older).
Of course, COVID-19 has also significantly impacted the lives of CF patients recently, who are at a higher risk of severe disease due to decreased lung function.
“I’ve been working from home since it all started – if I do return to the office, it won’t be five days a week, so I’m very thankful to have a job where I can do that,” Peters said. “I pretty much stay home, my husband does anything outside the house, always wearing a mask and being very careful. COVID-19 has definitely impacted my life because I like to go out and see my friends.”
Kelly is also on the board of her local CF Foundation chapter and enjoys speaking to CF patients and their families at events. “CF has amazing grassroots – lots of really passionate parents,” Peters commented. “The CF Foundation also has a really unique approach to research, investing in pharmaceutical companies to get them to create drugs, which has been amazingly successful. The foundation’s effectiveness and percentage of dollars that go to research versus administration are really strong.”
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