Cystic fibrosis: new treatment approach for children


Cystic fibrosis remains an incurable genetic disorder that impairs lung function and significantly reduces life expectancy. A new combination drug therapy that addresses the disorder’s underlying defects offers a promising new treatment approach.

The use of this therapy had previously been limited to adolescents and adults. Designed to meet the highest standards of clinical practice, a study co-led by Charité – Universitätsmedizin Berlin has now confirmed that this combination therapy regimen is also beneficial to primary school-aged children.

Earlier treatment means disease progression is likely to be significantly slowed. The researchers’ findings have been published in the American Journal of Respiratory and Critical Care Medicine.

Characterized by the build-up of thick, sticky mucus, cystic fibrosis, also known as mucoviszidosis, is the most common fatal genetic disease in Germany. A defect in the CFTR ion channel (which sits on the surface of airway epithelial cells and transports salt and water) disrupts the normal fluid balance, resulting in highly viscous mucus.

Cystic fibrosis primarily impairs the lungs, which get clogged by this viscous mucus and thus become less effective at clearing away pathogens.

The result is chronic infection and airway inflammation, progressively impaired lung function, and difficulty breathing. In severe cases, a lung transplant may become necessary. People affected by the disease used to die before reaching adulthood. Today, average life expectancy is around 55 years. These gains in life expectancy are mainly due to improvements in symptomatic treatment.

Drugs which target not just the disease’s symptoms but also its underlying molecular defects by improving CFTR channel function – known as CFTR modulators – only became available a few years ago. In approximately 90 percent of patients with cystic fibrosis, the underlying CFTR channel defect is caused by a specific fault in the CFTR gene known as the F508del mutation.

A triple therapy combining three CFTR modulators (elexacaftor, tezacaftor and ivacaftor) has been available in Europe since August 2020. In patients with one copy of the F508del mutation, this triple combination therapy can restore ion channel function to approximately half the normal level, thereby producing noticeable improvements in lung function and quality of life.

“It was a milestone in the treatment of cystic fibrosis,” explains first author Prof. Dr. Marcus Mall, Head of Charité’s Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Charité’s Cystic Fibrosis Center. He adds that “unfortunately, until now, this treatment has only been available to patients aged 12 and over.

This is because, traditionally, new drugs are first tested on and then authorized for use in adults. What we want to do, however, is administer this causal treatment as early as possible during the course of the disease in order to prevent irreversible lung damage. This is of course only possible if treatment starts during childhood. What we have been able to do now is to show that this can be done both safely and very effectively in primary school-aged children.”

Prof. Mall and his international research partners studied the effects of this triple combination therapy in 121 children with cystic fibrosis. Participants were aged between 6 and 11 years and had at least one copy of the F508del mutation. The children were randomized to receive either the triple combination regimen or placebo for a duration of approximately six months. The study, which was conducted at centers in ten different countries, was designed as a randomized controlled trial—the gold standard in clinical research.

“This type of clinical study remains too much of a rarity in pediatric drug development,” says Prof. Mall, Einstein Professor at Charité and cystic fibrosis research lead at the German Center for Lung Research (DZL). “The inclusion of control groups is often neglected in pediatric research. Instead, adult data are used to extrapolate effects from adults to children. But children are not simply small adults. High-quality studies are therefore crucial to the development of safe and effective drugs for children.”

Their recently published study showed that treatment significantly improved CFTR channel function, thereby enhancing the children’s lung function and quality of life. The treatment had a good overall safety profile and was well tolerated, with side effects comparable to those observed in older patients.

“I was both surprised and delighted to see that, even this early in the disease trajectory and despite the brief treatment duration, the children experienced noticeable improvements,” says Prof. Mall. “These findings contributed to the decision by the European Medicines Agency to expand the marketing authorization for this triple combination regimen to include children aged 6 and over. That means we are already in a position to treat children in this age group. I expect that the earlier initiation of treatment targeting the disease’s causative defect will produce significant improvements to the long-term health of patients with cystic fibrosis.”

As a next step, the research team plan to test whether the drug combination might be suitable for use in even younger children. Given cystic fibrosis forms part of the newborn screening program, the disease can now be diagnosed within the first few weeks of life.

“That would place us in a position to start causal treatment for cystic fibrosis as early as early infancy, which would hopefully prevent even early-stage damage to the lungs and possibly even other organs like the pancreas. Very gradually, we are working our way closer to this target. Currently, we are testing the safety and efficacy of this triple combination therapy in children aged between 2 and 5 years,” explains Prof. Mall.

About this study

The study discussed here was the first randomized, double-blind, placebo-controlled multicenter clinical trial to evaluate the safety and efficacy of the elexacaftor/tezacaftor/ivacaftor triple combination regimen in children with cystic fibrosis who were aged between 6 and 11 years and had at least one copy of the F508del mutation in addition to a second CFTR mutation which is unaffected by this treatment. A phase 3b clinical trial, the study was conducted across 34 trial centers in Germany, France, Spain, Denmark, the Netherlands, Switzerland, the United Kindgom, Australia, Canada and Israel.

ystic fibrosis (CF) is a rare autosomal recessive, progressive genetic disease caused by dysfunction of the CF transmembrane conductance regulator (CFTR) protein. CFTR is responsible for transporting anions, such as chloride and bicarbonate, and is located at the apical surfaces of epithelial cells. If the quantity and/or function of CFTR is diminished, loss of chloride secretion and deficient fluid transport result (Habib et al., 2019), thus ultimately inducing abnormal mucus secretion and multiorgan dysfunction, including pancreatic insufficiency and airway infection and obstruction (Elborn, 2016). The chronic airway impairment leads to progressive lung damage and respiratory failure, and eventually premature death (Heijerman et al., 2019).

Bialleic mutations in CFTR genes cause CF, and more than 2000 genetic variants have been found. The most common mutation is the p.Phe508del CFTR mutation, which is found in 90% of caucasian population (Habib et al., 2019). The p.Phe508del CFTR mutation causes severe dysfunction in CFTR processing and trafficking, thus limiting the quantity and function of CFTR at the cell surface (Dalemans et al., 1991). Nearly 50% of patients have homozygous p.Phe508del CFTR mutations (p.Phe508del-p.Phe508del genotype, F/F), and almost 33% have heterozygous minimal-function CFTR mutations (p.Phe508del minimal-function, F/MF). Another category of CFTR mutations resulting in lesser impairment of CFTR protein activity is residual function mutations (RF), including some genetic mutations associated with the CFTR protein channel-gating defects, denoted gating mutations (Barry et al., 2021). Most patients with these residual function (F/RF) or gating (F-gating) CFTR mutations are heterozygous for the p.Phe508del mutation (Barry et al., 2021).

Recently, small molecules have been developed to treat the molecular consequences of CFTR mutations and restore CFTR protein function (Davies et al., 2018; Keating et al., 2018; Heijerman et al., 2019; Middleton et al., 2019; Barry et al., 2021). Generally, the modulators can be classified as CFTR potentiators (e.g., ivacaftor), which augment the gating of mutant CFTR protein, or first-generation CFTR correctors (e.g., lumacaftor and tezacaftor), which aid in processing and trafficking of the protein to the cell surface (Heijerman et al., 2019; Barry et al., 2021). A single modulator regimen (CFTR potentiator) (Ramsey et al., 2011; De Boeck et al., 2014) or a combination of two modulator regimens (Boyle et al., 2014; Rowe et al., 2017) (CFTR potentiator and CFTR corrector) has been found to ameliorate sweat chloride, lung function, respiratory-related quality of life, bodyweight, and pulmonary exacerbation. However, neither of these treatments fully restores function to the p.Phe508del CFTR protein. Therefore, more effective CFTR modulations are needed to treat the underlying cause of CF (Davies et al., 2018).

Recently, a next-generation corrector [VX-659 or elexacaftor (previously known as VX-445)] with a different structure and mechanism of action, has been found to increase CFTR processing, trafficking and function in vitro (Veit et al., 2020; Becq et al., 2022). The combination of a next-generation corrector and tezacaftor increases the efficacy of CFTR function to a greater extent than either compound alone (Davies et al., 2018); moreover, ivacaftor further potentiates chloride transport. However, the data on triple combination therapy (next-generation corrector plus corrector plus potentiator) are limited. This meta-analysis examines current studies on triple combination therapy and assesses the available data in terms of efficacy and safety, according to different mutation genotypes and comparators.

Previous studies have revealed that monotherapy (ivacaftor), compared with placebo, improved the ppFEV1 in patients with Gly551Asp gating mutations (Ramsey et al., 2011). Subsequent studies have indicated that double combination therapy (corrector and potentiator, such as tezacaftor and ivacaftor), relative to placebo, improved ppFEV1, sweat chloride concentration and CFQ-R (Taylor-Cousar et al., 2017). However, not all double combination therapies have been found to effectively result in improvements in patients. Lumacaftor and ivacaftor slightly increased the ppFEV1 in patients with p.Phe508del homozygous mutation (Boyle et al., 2014; Wainwright et al., 2015), whereas no clinical benefits have been observed for patients with p.Phe508del heterozygous mutation (Boyle et al., 2014).

A potential treatment rationale is that if the second mutation is responsive to ivacaftor alone, then double combination therapies may provide benefits (Meoli et al., 2021). Because the mechanism of the next-generation corrector differs from that of tezacaftor, the hypothesis that triple combination therapy would restore CFTR protein function has been suggested.

In this meta-analysis, triple combination therapy was found to increase ppFEV1 by 13.6% relative to triple placebo in patients with F/MF mutations, with almost no heterogeneity. In the therapy group, as compared with the active control group, the ppFEV1 also markedly increased, by 8.74%; however, the heterogeneity was significant across studies. Clearly heterogeneous data came from Barry et al. (2021). After removal of the data from Barry et al., the heterogeneity of the pooled results clearly decreased.

The CFTR mutations in Barry’s study were F-gating/RF, which are relatively less responsive to triple combination therapy. Sweat chloride concentration is the standard indicator of CFTR function (Middleton and Taylor-Cousar, 2021). The pooled sweat chloride concentration under triple combination therapy was much lower than that under triple placebo, thus indicating that triple therapy significantly restored the function of CFTR.

Although the heterogeneity clearly came from Davies et al. (2018), the sweat chloride concentration in that study was much lower than those in the other two studies (Keating et al., 2018; Middleton et al., 2019). The next-generation corrector used in Davies et al. (2018) was VX659, and the effective data were extracted from the highest dose group (VX659 400 mg + TEZ + IVA), in contrast to Keating et al. (2018) and Middleton et al. (2019) (ELX 200 mg + TEZ + IVA).

We attempted to use the data from a similar dose group (VX659 240 mg + TEZ + IVA) to decrease the heterogeneity; however, clear heterogeneity was still observed (I2 = 91%). Because the baseline demographic characteristics in the three patients were similar, the potential reason for the significant heterogeneity might have been that the structure and mechanism of VX659 differed from those of ELX. Fortunately, the presented effects VX659 were favorable for the patients.

More studies are needed in the future to elucidate the specific mechanistic differences between VX659 and ELX. Similarly, triple combination therapy, in contrast to the active control, greatly decreased the pooled concentration of sweat chloride. The heterogeneity among studies might be explained by the data from Barry et al. (2021), which included F-gating/RF mutations. After exclusion of the heterogeneous data, the pooled results for sweat chloride concentration had only slight heterogeneity.

The CFQ-R respiratory domain score was used to evaluate the quality of life of patients with CF. The pooled results of the CFQ-R respiratory domain scores in the triple therapy combination were more satisfactory than those in the triple placebo group. Moreover, the consistency across studies was acceptable. The pooled estimate was also higher in the triple therapy combination group than the active control group; however, the data from Barry et al. (2021) clearly differed because of the inclusion of patients with F-gating/RF mutations. The heterogeneity decreased to insignificance in patients with only F/F mutations, and the pooled results were also elevated slightly.

Beyond the prominent benefits of the triple therapy combination, the safety was also favorable, as compared with that of placebo or active control, regardless of gene mutation type. The adverse events in the triple therapy combination group were nearly the same as those in the placebo or active control groups, with almost no heterogeneity.

The specific adverse events (cough, infective pulmonary exacerbation, oropharyngeal pain, headache and increased sputum) were also similar between the triple therapy combination group and triple placebo or active control groups. Moreover, no dose-responsive relationship in adverse events was seen with the triple therapy combination (Davies et al., 2018; Keating et al., 2018). Overall, the safety of the triple therapy combination was similar to that in previous studies of CFTR modulators (Wainwright et al., 2015; Rowe et al., 2017; Taylor-Cousar et al., 2017). Hence, triple therapy combination appeared to achieve efficacy and safety simultaneously.

A recent systematic review about the efficacy and safety of CFTR modulators was conducted by Gramegna et al. (2020). The authors provided a comprehensive review of clinical results for monotherapy, dual combination and triple combination in CF patients with various genotyoe mutations. They concluded that CF patients with one gating mutation receiving IVA can benefit mostly in lung function, moreover, CF patients with homozygous or heterozygous p.Phe508del receiving ELX/TEZ/IVA can benefit in lung function, pulmonary exacerbation decrease and symptom improvement (Gramegna et al., 2020).

Due to the multiple mixed comparisons in Gramegna’s research, they only made qualitative synthesis. By contrast, a quantitative synthesis (meta-analysis) is conducted in this research, which could manifest a pooled estimate for efficacy and safety of triple therapy combination compared with placebo and active-control group. Moreover, the result of NCT04058353 (which was ongoing when Gramegna’s article published) is included in our meta-analysis, confirming triple combination could offer additional benefit relative to previous CFTR modulators (Barry et al., 2021).

To our knowledge, this study is the first meta-analysis evaluating the efficacy and safety of the triple therapy combination in treating CF. The strengths of this meta-analysis were as follows. First, all included studies were multicenter RCTs, thus minimizing bias within the studies. Second, the comparison was conducted according to the type of control group (triple placebo or active control) and the type of mutation (F/MF or F/F); hence, the heterogeneity among the studies was as low as possible. Third, no clear adverse events were found in the triple therapy combination group, thus providing a basis for larger RCTs in the future.

Despite the advantages of triple combination therapy, some limitations of this study should also be considered: First, all patients included in the studies were 12 years or older, and data on the safety and efficacy of triple therapy combination in patients younger than 12 years were limited. However, a recent phase 3 open-label study has indicated that the treatment was safe and efficacious in children 6–11 years of age with at least one F508del-CFTR allele, thus supporting its use in this patient population (Zemanick et al., 2021).

Furthermore, if the triple therapy combination does not have any significant safety issues in younger patients, the therapy is likely to be commenced in children after newborn screening, before the development of clinical disease (Middleton and Taylor-Cousar, 2021). Second, the mutation types differed in the included studies with an active control group, thus resulting in clear heterogeneity.

However, the final effects were consistent across the included studies, and the difference was only in the extent of response to the triple therapy combination. In fact, researchers expect highly effective therapies to be available for all patients with CF, regardless of their variants, in the near future (Middleton and Taylor-Cousar, 2021). Third, the results from the included studies were mostly short-term; however, two included studies (Middleton et al., 2019; Sutharsan et al., 2021) used triple therapy for a relatively long period (24 weeks). Additional long-term results remain necessary to confirm the results.

In conclusion, the triple therapy combination had highly significant efficacy and safety in treating CF, as compared with placebo or active control, for patients with F/F, F/MF, F/RF or F-gating mutations. More well-designed RCTs are needed to support the efficacy and safety, and extend the indications for younger patients diagnosed with CF, to achieve radical treatment for CF before the development of the disease.

reference link :

More information: Marcus A Mall et al, Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3B, Randomized, Placebo-Controlled Study, American Journal of Respiratory and Critical Care Medicine (2022). DOI: 10.1164/rccm.202202-0392OC


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