A New Era for Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator Modulator Trials in Infants

In 2012, the United States Food and Drug Administration approved the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator ivacaftor for patients with cystic fibrosis (CF) aged 6 years and older with at least one copy of the G551D CFTR variant. Approval was further extended to other responsive CFTR variants and in 2020 to infants aged 4 months or older. Ivacaftor is a potentiator that is used as a single CFTR modulator in approximately 4–10% of people with CF, depending on the prevalence of responsive CFTR variants in the population. Over the last 10 years, there has been rapid drug development and clinical trials of new CFTR modulators that restore functional CFTR protein in a wider range of CFTR variants including the most common F508del CFTR, thus increasing access to CFTR modulation for a much greater proportion of the CF population (1). The use of CFTR modulators has been associated with great improvement in health outcomes with evidence of disease modification (2, 3) that is likely to increase life expectancy for people with CF. Pancreatic insufficiency occurs relatively quickly and may be evident at diagnosis through newborn screening but may also develop over the first few months in children even with severe CFTR dysfunction and in later life in some with residual function CFTR variants and a generally milder phenotype (4). Lung disease starts in infancy and although generally mild, structural changes are evident within a few months of life (5, 6). Functional abnormalities are also recognized in preschool children with CF with abnormal multiple breath washout and lung clearance index related to CFTR dysfunction (7). Lung clearance index also tends to increase over time (8), providing clear evidence that CF lung disease is present and progresses in early life. The biggest potential gains therefore in treating with CFTR modulator therapy will be in preventing or delaying the onset disease progression at an earlier age.

In this issue of the Journal, Rayment and colleagues (pp. 1239–1247) have reported the outcomes from an open label trial of the CFTR modulator lumacaftor/ivacaftor in children aged between 12 and 24 months with CF homozygous for F508del-CFTR (9). The initial part A of the trial (n = 14) was designed to determine the pharmacokinetics over 15 days of treatment with the dosing based on weight in two age cohorts studied sequentially first in children aged from 18 to 24 months, and then in children aged 12 to 18 months. The second part B of the trial (n = 46) was designed to examine safety and tolerability based on adverse event reporting over 24 weeks. In part B, secondary outcomes included pharmacokinetics and sweat chloride with additional endpoints examining pancreatic function. The results overall were consistent with data in older populations with regards to drug exposures, safety and CFTR functional change as measured by sweat chloride. There were also hints of possible pancreatic functional improvement with an overall increase in fecal elastase −1 and a decrease in immune reactive trypsinogen and fecal calprotectin. Sweat chloride improvement of −29.10 mmol/L was consistent with the improvements seen in preschool children aged 2 to 5 years homozygous for F508del CFTR on lumacaftor/ivacaftor combination of −29.6 mmol/L (10). These changes in sweat chloride are greater than changes reported in adults of around −9.1 mmol/L (11), which may be related to the higher ivacaftor exposures in younger children seen in this and the preschool trial compared with adult exposure levels. In older children and adults, the greatest clinical impact from lumacaftor/ivacaftor combination has really been a reduction in pulmonary exacerbations (12). Fewer pulmonary exacerbations were noted for infants in the infant trial than expected; however, the trial occurred across the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and effective sheltering strategies may have impacted this result. One of the strengths of the trial incudes the safety follow-up time point that provided an opportunity to see clear changes on and off the study drug for the patient cohort both at the start and end of the trial, thus demonstrating the drug impacts more clearly. This trial will pave the way to earlier access to CFTR modulation and maybe to modifying the course of disease for up to 50% of very young children with CF.

As CFTR modulator therapy in infants and young children becomes established, a new approach to clinical care is likely to evolve and as people with CF live longer lives, ensuring healthy aging will become a priority (13).

Pancreatic function is variable in infancy even in children with severe CFTR dysfunction (4), and to date while the open label trials have provided hope that there is a window of opportunity to improve pancreatic function, the lack of randomized placebo controlled trials means that we do not yet have definitive evidence of pancreatic function restoration. The open label trials of CFTR modulators in infants and young children, including this trial, in which one child discontinued study drug and nearly 11% of children had transaminase elevation greater than 3 times the upper limit of normal, have also raised concern about elevation of transaminase levels in young children on CFTR modulators (14). Elevation of transaminase levels however, also occurs without exposure to CFTR modulator therapy in CF (15), and therefore the risks related to drug rather than to background disease, are not completely clear in this age group. Trial designs for infants remain challenging as clinical benefits and potential harms may take time to determine, and outcome measures are less well established. The trial design of lumacaftor/ivacaftor in infants follows the pattern of open label trials previously used in examining ivacaftor in young children, and now appears to be the established trial design for extending CFTR modulator therapy to infants. The pace of change is now accelerating and newer 3 drug CFTR modulator combinations are rapidly being developed and entering the clinic. As more drugs are added with potentially greater clinical benefits, risks also increase of unrecognized adverse effects on a developing child, and will that be adequately measured in small open label trials? Infants are a vulnerable population with a greater potential for both benefit and harm and is there enough potential clinical benefit to early use of CFTR modulation to continue to undertake open label trials in this way? Also, is there already equipoise?

As CFTR modulation becomes established clinically, the window for randomized placebo-controlled trials that provide the best quality evidence has almost closed. Consumers, clinicians, and researchers need to rapidly determine how we move forward in developing new CFTR modulator therapy for infants and decide whether infants are indeed “little adults” and benefits can effectively be inferred or whether they deserve the same degree of evidence that older people expect?