The era of CFTR modulators: improvements made and remaining challenges

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene [1]. The CFTR protein is an ion channel that mediates chloride and bicarbonate transport in epithelial cells of multiple organs including lungs, pancreas and intestine [2, 3]. A defective CFTR protein produces an impaired ion and fluid secretion in the epithelial cells affecting several organs and leading to severe lung disease. More than 2000 CF-causing mutations have been identified [4, 5]. The most common mutation, the deletion of phenylalanine at position 508 (F508del), induces misfolding of the protein that is retained in the endoplasmic reticulum and degraded by proteasomal pathways [6].

Until the last decade, the only available treatments for CF were focused on managing the symptoms of the disease. CFTR correctors are pharmacological compounds that rescue the CFTR protein to the cell surface. Thus, these treatments that target the underlying cause of CF have the potential to change the course of CF clinical disease [7, 8]. In the present study we reviewed the CFTR modulators currently in the clinic, the improvements made as well as the challenges that still need to be overcome in the field of CF treatments.

CFTR modulators currently in the clinic

The clinical introduction of CFTR modulators, which are able to restore some CFTR function, has significantly improved the disease course of CF patients over the past years. The first U.S. Food and Drug Administration (FDA) approved drug was ivacaftor (VX-770; Kalydeco, Vertex Pharmaceuticals) [9], a “potentiator” that affected the gating properties of mutant CFTR channel activity (e.g. G551D, S549N, R117H, R347P) [10]. The clinical trial of ivacaftor showed a reduction of sweat chloride concentration under the CF diagnostic range and an increase in lung function of 10% [9, 11]. Subsequently, a CFTR “corrector” drug, lumacaftor (VX-809), in combination with ivacaftor (lumacaftor/ivacaftor or Orkambi, Vertex Pharmaceuticals) [12] also showed a modest clinical improvement for patients bearing F508del mutation [13]. After 24 weeks of treatment with Orkambi, patients homozygous for F508del experienced a reduction in the rate of pulmonary exacerbations (30–39%), an absolute change in body mass index (BMI, 0.13–0.41) and an increment of percentage of predicted forced expiratory volume in 1 s (FEV₁ % pred) between 4.3% and 6.7% [13]. It has been demonstrated that lumacaftor acts to stabilise the mutant CFTR in the early stages of biogenesis by interacting directly with the CFTR protein [14, 15]. However, long-term treatment (24–48 h) of lumacaftor in combination with ivacaftor in vitro diminishes the pharmacological correction of F508del-CFTR [16, 17].

Instead, tezacaftor/ivacaftor (Symdeko, Vertex Pharmaceuticals) appeared to have a more favourable adverse event and drug-drug interaction profile [7, 18, 19] than lumacaftor/ivacaftor. Symdeko was approved, alongside F508del, for a large number of “residual function” CFTR mutations based on in vitro culture responses, paving the way for the triple CFTR modulation [7]. Symdeko was associated with a significantly lower frequency of pulmonary exacerbations and improvement of FEV₁ % pred (3.4% mean) compared to baseline, although no significant differences were observed in BMI. This was followed by phase 2 clinical studies where a triple combination of CFTR modulators was tested in patients who were heterozygous for the F508del CFTR mutation and a minimal-function mutation (F508del–minimal function genotype), demonstrating improvements in CFTR function and clinical outcomes. These encouraging results led to the first phase 3, multicentre, randomised, double-blind, placebo-controlled clinical trial where the triple-combination, elexacaftor, tezacaftor, and ivacaftor, was randomised versus placebo for 403 patients with F508del–minimal function genotypes for 24 weeks [20]. A second phase 3 clinical trial was done for 107 patients homozygous for the F508del mutation, who were randomised for the triple combination versus tezacaftor/ivacaftor for 4 weeks [21]. Moreover, at trial completion, participants were given the option to enrol in a 96-week open-label extension trial.

The results of these phase 3 clinical studies were similar for the F508del–minimal function and F508 homozygous patients, showing an improvement of FEV₁ % pred (in the range of 10.4–13.8%) compared to the control [20] or actively-controlled patients [21], reduction of the sweat chloride concentration (−39.1 to −43.4) and higher patient-reported quality of life. Moreover, a reduction of exacerbations was observed for patients with F508del–minimal function genotypes compared to placebo [20], as well as improvements of BMI [20, 21], which in CF, usually correlates with better survival. The triple CFTR modulation therapy demonstrated good tolerability with only mild or moderate adverse effects and very low rate of discontinuation [20, 21]. However, there is a main and highly relevant difference between these two studies. While patients homozygous for F508del are usually prescribed either lumacaftor plus ivacaftor or tezacaftor plus ivacaftor, patients with only one copy of F508del are rarely prescribed these treatments given their reported inefficacy. Although the triple-combination therapy achieved an improvement in patients homozygous for F508del much higher than previous CFTR modulators, reaching levels comparable to the benefit of ivacaftor for G551D patients, the benefit observed for patients with only one F508del copy involved more profound significance for the CF treatment paradigm of these patients.

Overall the triple-combination, elexacaftor, tezacaftor, and ivacaftor (marketed as Trikafta, Vertex Pharmaceuticals), demonstrated statistically significant and/or clinically meaningful improvements in lung function (10–14% of FEV1 % pred) and respiratory-related quality of life for patients with one copy of the F508del mutation and a minimal-function mutation and patients with two F508del copies [20, 21]. While this discovery constituted an improvement for numerous CF patients F508del homozygous, it is a life changing treatment for those patients with F508del–minimal function genotypes, in whom previous CFTR modulators were ineffective. The triple-combination or Trikafta has recently received FDA approval for patients aged 12 years or older who have at least one copy of the F508del CFTR mutation [22, 23]. However, the effectiveness of the same CFTR modulator combination therapy to rescue the processing defect for other rare CFTR mutations remains to be determined.

Patient response to CFTR modulators

Among the approved CFTR modulators, Trikafta can be applicable to the largest number of CF patients [20, 22], as it aims to target those with at least one copy of the F508del CFTR mutation, accounting for up to 90% of people with CF [24]. However, accumulating evidence from previous CFTR modulators prescriptions suggest that not all the patients who are predicted to respond to these treatments might experience the expected benefit. This patient-to-patient variability has been represented in vitro using patient samples, where it was observed that patient responses to lumacaftor or Orkambi can largely vary even among people carrying the same CFTR mutation [25–27]. Driving causes proposed for this variability [28] as well as disease severity [29] have been the genetic variants within and outside the CFTR locus [30]. Differences have also been described between the response observed in females and males under treatment with ivacaftor [31].

Therefore, in order to better tailor personalised treatment choices, new research directions need to identify reliable in vitro systems to predict individual patient responses [32–35]. The identification of reliable individual response prediction tools is even more important for those patients carrying refractory CFTR variants not addressed by available modulators and for those who carry extremely rare CFTR mutations [35–37]. It has been demonstrated that Orkambi showed a modest response to some of these rare mutations (A455E, M1101K, N1303K) in heterologous expression systems [38, 39]. However, this correction was not recapitulated in patient-derived tissues [40]. On the other hand, it has been recently demonstrated that a combination of CFTR modulators alongside a small molecule that inhibits the nonsense-mediated RNA decay can rescue the functional expression of W1282X-CFTR in heterologous systems and primary nasal epithelial cells [41–43].

Experts in the CF field still maintain that “structural biology and functional studies are a powerful combination to elucidate fundamental knowledge about CFTR and are key for the development of better drugs to enable people with CF to live full and active lives” [44, 45]. In addition, scientists are comparing and trying to elucidate the robustness of current methods and markers used to evaluate the benefit of these new modulation therapies [27, 46, 47]. Specific nasal potential difference measurements [46], circulating inflammatory proteins [48], for example, have been highlighted as reliable biomarkers of CFTR activity [46] or lung disease severity [48] in the clinical setting.

In contrast to non-responding patients, there are many people with CF experiencing a great benefit under the mentioned CFTR modulator therapies [49]. As a recent study identified, in these cases, the goal would be to study the effects of withdrawing one or more chronic treatments to reduce the CF treatment burden [50].

Management of CF lung infections

Even in the era of CFTR modulation therapies, the detection, diagnosis, and treatment of some CF micro-organisms remains challenging, especially for patients with more advanced stages of lung disease [51]. The Cystic Fibrosis Foundation has put forth efforts through the Infection Research Initiative to tackle these issues, including the development of new anti-infective therapies. It has been demonstrated that in-vitro exposure of Pseudomonas aeruginosa (P. aeruginosa) reduced Orkambi-mediated rescue of CFTR function in human bronchial epithelial cells and stimulated the expression of pro-inflammatory cytokines (IL-6 and IL-8) [52, 53]. Thus, differences in the type of microbial infections across patients and even within a single patient over time could explain the low efficacy in some cases and the high patient-to-patient variability in Orkambi response. However, treatment with antibiotic tobramycin and antimicrobial peptide, has been shown to restore Orkambi-mediated rescue of F508del-CFTR function in human bronchial epithelial cells infected with clinical strains of P. aeruginosa [54]. Recent studies are evaluating the impact that CFTR modulators such as lumacaftor/ivacaftor have on infections, including patients with severe lung disease [55]. In this study, although treatment with lumacaftor/ivacaftor reduced exacerbations, the unacceptably frequent adverse events resulted in a very high discontinuation rate [55]. Research efforts to evaluate the clinical effectiveness and impact on infections is ongoing in future triple-combination CFTR modulator therapy studies [51].

CF is not only a lung disease

In addition to the lung disease symptoms, CF usually affects pancreas, liver and digestive system, often leading to pancreatic insufficiency, CF-related diabetes, CF liver disease, severe malabsorption and meconium ileus [56–58]. Thus, in addition to focusing on the lung disease paradigm, clinical measures to predict the effect of new CFTR modulators on other CF related symptoms [59, 60] and even on establishing organ function early in life [61] are needed. It may be foreseeable that additional therapies or changes to standard of care are needed for these patients, in hopes of changing the scenario from a life-shortening disease to a treatable chronic condition. Finally, as the median survival for CF continues to increase and the CF population ages, new models for CF care will need to be adopted to tackle an increasing CF population with both CF morbidities and additional diseases of ageing [8].

Summary

This last decade has created historical moments for CF, primarily driven by the development of CFTR modulators. First for patients with gating mutations who benefited from Kalydeco, then for those patients with one F508del copy who could benefit from Orkambi, and most recently, patients with at least one F508del copy who can benefit from Trikafta. Despite heterogeneity in patient response, the majority of CF patients will be greatly impacted by using a CFTR modulator therapy, thus changing the trajectory of their life. Furthermore, it remains to be determined whether the next generation of modulators will be effective for individuals bearing rare mutations that are Orkambi resistant. However, it should not be forgotten that there still remains 10% of the CF population who do not have a targeted CFTR modulator treatment. In addition, even with these novel drug therapies, managing infections will continue to be a challenge, thus the CF community will need to adapt the standards for an improving, but ageing CF population.