PROGRESS IN CYSTIC FIBROSIS: HOW CFTR MODULATORS ARE CHANGING LIVES FOR THE BETTER

Recent progress in Cystic Fibrosis means that most patients with the disease can now live for an extra decade longer than previously anticipated. Due to breakthroughs in precision genetic medicine and the invention of third-generation CFTR modulators, the lives of these patients have permanently changed for the better moving forward.

The following article summarises what is currently known about CFTR modulators, including how they improve cystic fibrosis symptoms and which genetic mutations they can help to treat. Potential future therapeutics that are currently being investigated have also been included below.

What is Cystic Fibrosis?

Cystic fibrosis (CF) is a rare genetic illness that affects less than 0.03% of the population. The disease is characterized by defects in the cystic fibrosis gene, which is responsible for creating the CFTR (cystic fibrosis transmembrane conductor) protein. Under usual circumstances, this protein forms part of the cell wall across many cell types and acts as a channel for chloride and bicarbonate to move in and out of the cell. In those with cystic fibrosis, the cystic fibrosis gene can be mutated in roughly 2000 different ways. This results in either dysfunctional CFTR protein production, faulty protein translocation to the cell membrane, complete protein loss or a combination of similar faults.

Underlying Cellular Mechanisms and Symptoms. These mutations naturally disrupt the movement of chloride and bicarbonate in and out of cells, causing many vital cellular functions to become impaired. The main symptoms pertain to an increase in sodium reabsorption, water retention, lower cellular reserves of chloride and increased chloride loss through sweat. This causes less water to be available to the cell, increases mucus production and typically creates thicker cellular secretions due to less water incorporation. This results in the clogging of multiple organs and a host of systemic problems pertaining to hydration and fat metabolism. The thicker secretions can also serve as a bacterial growth medium, often causing patients with CF to have chronic infections.

Type of CF Gene Mutations. CF gene mutations have been structured and divided into five main classes, each of which point towards a specific group of CFTR protein dysfunction. Class II mutations are the most frequent. However, an individual with CF can have a combination of them contributing to symptoms. Most currently available CF medications treat those with one or more copies of the Delta F508 (or Phe508del) mutation. This is the most common CF gene mutation, affecting between 70-90% of those with the disease who are usually of Caucasian descent. It pertains to the dysfunctional folding of the protein, resulting in a protein that cannot be used at all and that is usually prematurely destroyed before being incorporated into the cell membrane.^[1]

Learn more about cystic fibrosis here.

Cystic Fibrosis is No Longer a Life-Threatening Condition

Prior to the invention and testing of genetic therapies for CF, patients with the disease had an average life expectancy of 38 years, usually as a result of lung failure. Since the advent of a class of medications known as CFTR modulators, the average life expectancy for most members of this population group born between 2017 and 2022 has increased to 53 years on average. It is estimated that in the next couple of years, this figure will continue to rise until all those with the disease can expect to lead full lives.^[2]

Following this recent progress, the Make-A-Wish Foundation has recently declared that cystic fibrosis no longer qualifies as a life-threatening condition and that children with the condition no longer automatically qualify to meet their requirements^[3]. Moving forward, the foundation will screen children with cystic fibrosis on a case-by-case basis. Those with the rarest forms of the disease for which treatment is currently unavailable or who have equally as severe comorbidities may still apply to make a wish through the organization.

CFTR Modulators: A New Breakthrough in Cystic Fibrosis Treatment

Just over 10 years ago, the first generation of CFTR modulators was manufactured to treat cystic fibrosis. CFTR modulators treat various components of CFTR protein dysfunction and are currently divided into potentiators, correctors, stabilizers and amplifiers.^[4]

The most widely available of these medications are discussed below, along with future medications that are currently under development.

First Generation CFTR Modulators were the first medications that proved efficacious against CF. They are still in use as of this writing, able to modestly improve symptoms in up to approximately 60% of patients. Of these medications, the two employed the most include:

• Ivacaftor was originally designed to help those with a less common class III mutation known as G551D. G551D is known to affect between 2-5% of those with CF. CFTR proteins in patients with this mutation typically do not open or close properly at the cell membrane, resulting in 100 times less activity by comparison to normal CFTR. With the invention of Ivacaftor, many symptoms of those with G551D noticeably improved, including enhanced weight gain and breathing. Ivacaftor improved the functionality of CFTR located at the cell membrane and now belongs to a group of CFTR modulators known as a potentiator. This was also the beginning of a major breakthrough in the treatment of cystic fibrosis, which was previously thought to be an entirely irreversible disease. Ivacaftor is routinely used in combination with other CFTR modulators to treat class II mutations. Since its invention, it has also been shown to improve the symptoms of those with class III and IV mutations and several other rare genetic variations of CF. Despite these improvements, Ivacaftor is known to induce potentially life-threatening withdrawal symptoms within a few days of stopping treatment.
• Lumacaftor. As the majority of those with CF carry the DF508 mutation and not G551D, most with CF are not responsive toward ivacaftor treatment. Shortly after ivacaftor came lumacaftor (also known as VX809), which was the pioneering CF medication for CFTR correctors. CFTR correctors help CFTR to bypass protein-folding checks in the cell, which prevent the mutated protein from being discarded before being relocated to the cell membrane. While lumacaftor is capable of doing so, patients with DF508 only benefitted marginally from the drug, suggesting that their CFTR variant is unable to perform optimally, even if it makes it to the cell membrane after folding. When combined with ivacaftor, lumacaftor showed better efficacy and substantial symptom improvement in some patients with DF508. However, the side effects of both drugs were also shown to increase in these patients, including sensitivity toward other medications and the inactivation of other medications such as contraceptives, antidepressants and antifungals. Other reports have documented depression, higher blood pressure and markers of kidney inflammation in patients who take this combination.

Second Generation Modulators have not replaced first-generation medications for the treatment of CF. Instead, they have furthered our understanding of how the disease works and improved upon the effectiveness of prior therapies, as described below:

• Tezacaftor was developed as a safer, second-generation alternative to lumacaftor. It has proven to have a similar efficacy with fewer respiratory side effects, whether used alone or in combination with ivacaftor. Tezacaftor is a class I corrector and serves to correct class I CF mutations. When used in combination with ivacaftor, it serves to treat class II mutations. Common side effects include diarrhea, abdominal pain, nausea, headaches, coughs and fatigue. While tezacaftor and lumacaftor present with similar efficacy, they only proved helpful to patients with a double copy of DF508. 30% of those carrying DF508 only carry one copy in conjunction with another rarer mutation. These patients often failed to benefit from tezacaftor or lumacaftor, whether alone or in combination with ivacaftor. This finding preceded the invention of third-generation modulators, which have since begun to spur monumental improvements in the lives of those with cystic fibrosis.

Third Generation Modulators. While steady progress was made with the introduction of the previous two generations of modulators, the real breakthrough occurred with the invention of the following third-generation CFTR correctors:

• Elexacaftor (VX445) and VX-659 are the third generations of correctors, following from lumacaftor and tezacaftor. Upon further investigation, it was revealed that most of the medications prior to elexacaftor worked through enhancing the structure and function of half of the CFTR protein^[5] when localized at the cell membrane. Elexacaftor works by improving the other half of CFTR protein and helps to correct class III mutations. When coupled with tezacaftor and ivacaftor, the triple combination proved to correct all defects seen in up to 90% of those with CF. Results from trials revealed that CF patients on this triple combination had normal sweat chloride levels and significant reductions in all other symptoms. After one month of treatment, patients reported better digestive function, enhanced weight gain, and drastic improvements in lung function.
• Trikafta. The combination of elexacaftor, tezacaftor and ivacaftor has since been formulated into the drug Trikafta, which is now sold through several select pharmacies and may also be ordered online to help those with CF. Trikafta was shown to have few potential side effects, a minimal impact on liver enzymes and is not likely to interfere with most other classes of medication. Currently known possible side effects of trikafta include diarrhea, vomiting, abdominal pain, fatigue, increasing biliary colic, temporary testicular pain and interaction with the antibiotic azithromycin, which resulted in heart block in one patient. It may also increase female fertility.

Future CFTR Modulators. Aside from current treatment modalities that are now widely available, scientists are busy investigating the following medications for enhancing CF therapy:

• Codon Correcting Agents. The recent breakthrough with third-generation modulator trikafta has managed to successfully increase the lifespan and quality of up to 90% of those with CF. The remaining 10-11% of cases are still unable to receive adequate treatment for their symptoms and most often suffer from the rarest types of CF mutation (Class IA and IB). Preliminary research suggests that these rare mutations result in premature termination of the codon, the part of the gene that codes for the production of the protein^[6]. Currently, several genetic therapies are in the pipeline for preventing the premature termination of the codon, which may allow for the expression and manufacture of CFTR proteins in the cell. More research is needed to verify the efficacy of such agents.
• CFTR Stabilizers are a type of CFTR modulator still undergoing development with the intention of improving upon currently available treatment. While Trikafta is able to enhance the production, function and translocation of CFTR to the cell wall in 90% of those with CF, the proteins are still unstable and may still be susceptible to removal by the immune system. While no drugs have been developed that could specifically stabilize CFTR proteins at the membrane, various cellular products are known to do so. These include hepatocyte growth factor, vasoactive intestinal peptide and glutathione promoters.
• CFTR Amplifiers are being developed as a means to increase the genetic expression of CFTR, which acts to boost CFTR protein production. So far, there are limited clinical trials that have investigated the effects of CFTR amplifiers. One study using the amplifier Nesolicaftor (PTI-428) showed a modest improvement of 5.2% in a prominent biomarker for CF.^[7]

Genetic Testing, Modulator Selection and Prescription Ages

Genetic Diagnostics. As part of the diagnosis and treatment selection process, it’s important to opt for genetic testing with a skilled healthcare practitioner that specializes in treating those with CF. The physician ought to make an informed decision based on the specific mutations found in the test results.^[8]

Prescription Age. After a clear genetic diagnosis has been reached, CFTR modulator treatment can begin and typically benefits the majority of patients at any stage of the disease course. However, those who begin when diagnosed in infancy show the greatest benefit and are likely to live longer than those who start at later phases of the disease.^[9]

Modulator Selection. The below list denotes currently available CFTR modulators with respect to their prescription CF gene mutations and age groups^[10]:

• Kalydeko (Ivacaftor; first generation) can treat the following class III and IV mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, R117H, and several additional rare mutations. Ivacaftor can be started in pediatric CF patients aged 6 months and older. Those with specific mutations, such as R117H, may be prescribed ivacaftor from 4 months on.
• Orkambi (Ivacaftor and Lumacaftor; first generation) can only modestly treat DF508 homozygous mutations (meaning a carrier with two copies of this gene variant). Therapy may begin as early as 2 years of age.
• Symdeko (Ivacaftor and Tezacaftor; second generation) is able to improve symptoms in those with class II mutations and rare mutations, including DF508, E56K, P67L, R74W, D110E, D110H, R117C, E193K, L206W, R347H, R352Q, A455E, D579G, 711 + 3A→G, E831X, S945L, S977F, F1052V, K1060T, A1067T, R1070W, F1074L, D1152H, D1270N, 2789 + 5G→A, 3272−26A→G, 3849 + 10kbC→T. Treatment can be prescribed for children aged 6 years and up.
• Trikafta (Ivacaftor, Tezacaftor and Elexacaftor; third generation) can treat almost all the above CFTR gene mutations, with the exception of class IA and IB mutations. Trikafta can be prescribed to children aged 12 and older.

CFTR Modulator Contraindications. All CFTR modulators containing either ivacaftor or lumacaftor have been shown to be contraindicated while on medications that require CYP3A liver enzymes to metabolize. These include macrolide antibiotics, azole antifungal drugs, amiodarone, grapefruit, monoamine oxidase inhibitors, contraceptives, warfarin, fluoxetine, omeprazole and voriconazole. Elexacaftor may be contraindicated for those on statins.

Other Discoveries That May Aid in CF Symptom Management

Alongside the recent breakthrough in the treatment of CF, other promising studies have suggested further lifestyle modifications for this patient group that can enhance therapy, lower symptoms and improves their quality of life. These include:

Whole Body Cooling may be an effective complementary therapy to CFTR modulators in treating CF. In vitro studies revealed that cells with the CF DeltaF508 mutation functioned much better when cooled to 26-30C. The results of the studies revealed that the CFTR protein was able to be properly assembled under these conditions, which allowed for it to move to the membrane and function optimally as a chloride channel. While it is not possible to maintain such low cellular temperatures for all cells in the body, genetic CF mice studies revealed that whole-body cooling techniques greatly improved the structure of CFTR proteins in the intestines, increased the lifespan of the test subjects by as much as 15% and reduced symptom severity, including noticeable decrements in intestinal mucus load. ^[11] The mice were allowed to cool in a 15C environment for several hours, which reduced the core temperature to around 16C. While acute exposure to cold offered temporary benefits, cold exposure twice a week seems to extend the lifespans of mice with CF and may have an accumulative benefit. Human trials have not explored cooling in depth. However, there has been preliminary research showing that those with CF are highly temperature responsive and that their symptoms are known to peak in warmer ambient conditions alongside lung infections.^[12]

HDAC Inhibitors are a class of medications that have been observed to promote stability in mutated CFTR proteins by blocking the activity of HDACs (histone deacetylases). There are 18 different types of HDAC in the body, and each one is involved in regulating gene transcription and function. HDAC inhibitors have conventionally been prescribed for combating various malignant tumors. However, many studies have alluded to a number of other benefits they possess, particularly with regard to treating rare genetic disorders such as CF. There are four FDA-approved HDAC inhibitors currently prescribed in the US (Belinostat, Panobinostat, Romidepsin and Vorinostat) and all four of them have been shown to enhance the efficacy of CFTR modulators, specifically the CFTR corrector lumacaftor (VX809)^[13]. Studies suggest that HDAC inhibitors, specifically HDAC6 (class II) inhibitors^[14], may be incorporated into future generations of CFTR modulators as they contribute towards the stability of CFTR proteins and improve their actions as chloride channels. Additional data highlights that HDAC inhibitors can lower the expression of heat shock proteins (mimicking body cooling) and improve overall protein folding and stability in the cell^[15]. Despite these promising findings, HDAC inhibitors appear to pose different effects depending on the cell and tissue in question. Therefore more research is required before firm conclusions can be drawn.

Glutathione-Enhancing Agents. Glutathione is one of the primary cellular antioxidants employed by cells to deal with pro-oxidant compounds. It consists of cysteine, glycine and glutamate, each of which can be used interchangeably as required within the cell to mop up free radicals. Glutathione is known to be radically deficient in the lungs of those with CF and levels can be improved through increasing body levels of glycine and cysteine. CFTR stabilizers are noted to increase cellular glutathione levels in CF patients, suggesting that glutathione may be an underlying target for promoting cell membrane protein stability. A small handful of trials in patients with CF have demonstrated that supplementation with modestly high doses of both N-Acetyl-Cysteine (NAC) and glycine serves to protect against long-term deficits in lung function, which were shown to occur in the control groups across studies.^{[16] [17]}

Probiotics can help those with CF manage their symptoms in a variety of different ways. The gut microbiome in CF is shaped by inflammation, excessive mucus production, bacterial overgrowth, increased intestinal permeability and a lower degree of helpful gut bacteria. When probiotic bacteria are coupled with the right nutrients, they serve to regulate many aspects of the gut dysbiosis associated with CF. For instance, short-chain fats, such as butyrate, that are produced by Lactobacilli and Bifidobacterium strains act as HDAC inhibitors, may reduce lung fibrosis^[18] and help to regulate fat metabolism, while Akkermansia species are able to degrade mucin and help to remove excess mucus. Probiotic bacteria may also be able to out-compete pathogens common to CF as well as promote their extinction through releasing antimicrobial by-products. Despite these findings, clinical trials pertaining to probiotic use have shown mixed results across those with CF^[19], with some studies revealing that probiotics help to lower inflammation and the occurrence of pulmonary fibrosis^[20]. It is recommended to use probiotics in moderation in the context of a diet rich in antimicrobial foods, water-soluble fiber and nutrients. More research is required to ascertain which strains and dosages are right for those with CF.

Potential Future Complementary Therapies. Many with CF are already taking advantage of nutritional supplementation, despite there being no quality evidence to support their use in improving symptoms. The below food supplements and dietary nutrients have been studied in vitro for their anti-CF properties, indicating that they may become useful complementary enhancements to future CFTR therapies:

• Specific Dietary Nutrients. Several dietary nutrients were tested for their ability to improve chloride movement in and out of CF cells. Amongst these, apigenin, kaempferol, and quercetin proved to mildly enhance chloride emissions. The results were dose-dependent, suggesting that supplementing these nutrients may enhance CFTR modulator therapies.^[21]
• Ginseng has proven to be a potentially useful food supplement for those with CF. The nutrients found in ginseng can inhibit HDACs specifically known to be problematic in the disease. Preliminary in vitro studies show that ginseng may improve CFTR function^[22], reduce lung fibrosis^[23] and reduce the incidence of common lung infections^[24] found in those with CF.
• Resveratrol proved to increase the efficacy of ivacaftor in vitro by a factor of 4-5 times^[25]. Other studies suggest that it may be able to help promote the localization of mutant CFTR proteins to the cell membrane yet is unable to improve cellular chloride efflux.^[26]

Conclusion

Up to 90% of those with cystic fibrosis can now lead longer, healthier lives thanks to the latest CFTR modulators, such as ivacaftor and Trikafta. Trikafta has been shown to have the highest efficacy, with the least side effects. Those diagnosed and prescribed CFTR modulators during infancy are estimated to live currently a decade longer than their older CF counterparts, averaging a life expectancy of 53 years. Despite this, CF patients of any age have proven to benefit tremendously from the currently available CFTR modulator therapies. Growing bodies of evidence suggest that CF patients may also benefit from body cooling techniques, genetic HDAC inhibitors, probiotics, glutathione and antioxidant-enhancing agents, as well as loading up on various dietary nutrients that maintain similar properties.

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