How Clinically Efficient Is Lumacaftor/Ivacaftor for Cystic Fibrosis Patients? An Updated Literature Review

Cystic fibrosis (CF) is an autosomal recessive illness caused by the defective cystic fibrosis transmembrane conductance regulator (CFTR) gene. These patients suffer from repeated chronic sinuses and lung infections, resulting in frequent hospital admissions and antibiotic (Abx) courses. These are the major contributing factors responsible for a low health-related quality of life (HRQoL) and increasing the disease burden. The introduction and approval of CFTR modulators-lumacaftor (LUM) and ivacaftor (IVA) in 2015 by the US Food and Drug Administration (FDA) reduced the mortality and morbidity rates associated with the disease. In 2018, the FDA approved these drugs from age two and five years with two copies of F5806 del. This literature review aims to present the studies centered on the clinical effects of LUM/IVA. We searched for the relevant articles, from 2016 to 2020, in PubMed Central (PMC), Google Scholars, and Journal of Cystic Fibrosis. LUM/IVA has a broader range of effects. They showed marked improvement in the reduction of pulmonary exacerbations (PEx), Hospitalization rates, Abx use, and modification in forced expiratory volume in one second (FEV1) status of pre-existing severe lung disease. Now, there is a need for an initiative to conduct more clinical trials and studies in the future to assess and evaluate the long-term clinical benefits and safety of LUM/IVA therapy in all age groups.


Introduction And Background
Cystic fibrosis (CF) is a chronic, progressive, and genetic disease affecting more than 90,000 people worldwide. There are approximately 1000 new cases diagnosed each year. The primary defect is the mutant cystic fibrosis transmembrane conductance regulator (CFTR) gene, which codes for CFTR protein, either absent or defective [1][2]. Defective CFTR protein acts as abnormal channels present on the body's mucous membranes as in the respiratory, gastrointestinal, and reproductive systems. These protein channels are responsible for chloride and fluid movement from cells of specific regions. The regular activity of the channel is halted by mutations either caused by protein production or processing, gating or, conduction abnormalities [3,4]. The results are the thick and sticky secretions instead of thin, normal secretions in targeted regions that are pathognomonic of these patients' signs and symptoms.
This disease shows its clinical impact as early as in the newborns and becomes a progressive disease from childhood to adulthood. It is a long-term and life-shortening disease affecting the health-related quality of life (HRQoL). The patients presented with the repeated chest infections, pulmonary exacerbations (PEx), decreased basal metabolic index (BMI), nutritional deficiencies, social life impact, and fertility/pregnancy issues [3].
The treatment was initially considered a supportive therapy in terms of antibiotic, anti-inflammatory, and rehabilitation before developing CFTR modulators in the last two decades. The main target of CFTR modulators is the CFTR protein mutation-expressions. There are >19,000 of these mutations; the most common transformation is F508 del, with an allelic frequency of 75%. It presents in at least one copy in nearby 90% of patients in which CFTR protein cannot make its standard 3D shape [1]. It becomes a misfolded protein exposed to endoplasmic reticulum-associated degradation (ERAD) and unable to carry out average conductance of chloride ions due to trafficking defects as well [1,4]. The gating mutation 3 is G551D in which the CFTR channels display regular cell surface expression with gates unable to open, and thus, the normal chloride movement is interrupted through this [1].
The importance of early initiation of CFTR modulators in patients can be measurable with the overall first benefits of treatment on sufferers. These modulators will be a miracle drug, lessen their agony, improve their quality of life, decrease mortality, morbidity [5,6], and repeat hospitalization [7]. Adherence to therapy has additional beneficial effects as compared to non-adherence patients. The full results give some comfort and relief to patients and caregivers as it minimizes the social burden.

CFTR: cystic fibrosis transmembrane conductance regulator
This review article will sum up and give readers the overall clinical effects of LUM and IVA on the patients under one umbrella. It also covers the clinical outcome associated with HRQoL, PEx frequency and pulmonary function, pathogen acquisition, pregnancy, macrophage function, physical activity, and exercise tolerance, along with hospitalization rate.

Review Methods
We searched comprehensively using PMC, Google Scholars, and Journal of the European Cystic Fibrosis Society (Journal of Cystic Fibrosis) with the help of the following keywords/medical subject headings (MeSH) terms, both alone or in combination, cystic fibrosis, cystic fibrosis/therapy, cystic fibrosis/drug therapy, lumacaftor, ivacaftor/lumacaftor combination, ivacaftor, Orkambi. The initial search generated 80 studies; we shortlisted only 64 relevant studies after removing the irrelevant and duplicate tasks. Finally, we included 38 studies for the review after eliminating the 26 tasks in a final scan. Quality assessment wasn't done.

Inclusion/exclusion criteria
We selected studies related to our research question and chosen the research papers published in the English language from 2016 to 2020 for our review, including full texts and abstracts. We had studies of all types and designs from all geographical areas and included only human studies. Figure 2 shows the collaborative study summary representation.

Effects of Lumacaftor and Ivacaftor in Lung Functions and Pathogen Acquisition
CF disease-causing defective epithelial ion transport in an airway tract causes trapping of mucus inside the lung's lining responsible for the chronic inflammation and easy nidus for bacteria to attack as there is a faulty airway defense mechanism. The overall cascade results in repeated lung infection/ PEx in both the pediatric group and adult. All the above process is the main reason for the compromised and damaged lungs in this disease. These patients seek medical attention repeatedly and need intravenous or either inhalation Abx to overcome their respiratory deterioration.

Changes in airway microanatomy and PEx
LUM and IVA combination have a tremendous role in lung disease as they enhance the CFTR epithelial ion transport, increased ciliary beat, clearance with increased airway surface liquid penetration, and decrease mucous viscosity. Birket et al. conducted an in-vitro study in 2016 and found that IVA had displayed augmented airway ciliary transportation in F508del CFTR with reduced mucous active viscosity [1]. These improvements at the microanatomical levels in vitro showed improved lung function activity and ion transport as intensified sweat chloride variations. LUM restored the partial action of the F505del mutant to some extent when used alone [1]. However, the beneficial effects are obtained with IVA's addition in the treatment, reflected as patients' improved spirometry findings.
PEx is the causative factor for increased mortality and morbidity in patients in all age groups. With advancements in the medical field, LUM and IVA's introduction means being the patients' real-life. In 2019, McColley et al. designed a randomized control trial (RCT). They used the post hoc analysis of pooled phase 3 data (NCT01807923, NCT01807949) and, after screening and randomization, included 1108 patients who received one of the study drugs [12]. The trial's primary purpose was to compare the rates of PEx in the LUM/IVA group vs. placebo group based on ppFEV1 (percent predicted forced expiratory volume in one second). The conclusion was LUM treated patients (n=369) demonstrated considerably fewer PEx rates, and for those with LUM/IVA, the PEx rate was 0.60/patient/year. They noted the above findings for even patients with no early improvement in lung function. The extension of TRAFFIC AND TRANSPORT was carried out as PROGRESS in RCT of 2017, by Konstan et al. They enrolled 1030 patients in PROGRESS. They assessed the safety of LUM/IVA in a long-term fashion with the findings of a decreasing trend of PEx, for a 12-month duration with LUM/IVA. The same safety picture of LUM/IVA was constant to the previous RCT. They also observed the overall benefit of continued treatment for a long duration [13]. The non-adherence to treatment resulted in increased PEx frequency, as shown by a study exhibited on a Medicaid Population of one state by Tessel et al. in 2019. The 21 patients in the trial showed no decreased PEx rates after LUM/IVA therapy initiation as the study group left the treatment due to many safety concerns. They also concluded that LUM/IVA treatment reduced the Hospitalization rate along with the first visit to the emergency room [7]. The LUM/IVA adherence resulted in improved lung disease, as one of the observational studies by Diab-Caceres et al. in 2018 on 20 patients, reflecting the enhanced lung function in patients who were therapy adherent over a long period [14]. Hassan et al., in their retrospective cohort study in 2016, studied the full picture of IVA effects on PEx, Hospitalization, and Abx use. The study displayed the reduced rates of PEx and declined rates in other areas of study interest in IVA-treated cases [15].

Changes in FEV1
The patients exhibited a decreased FEV1 as the illness progresses with chronic inflammation, additional PEx rates, and, eventually, lung tissue damage. Although the baseline FEV1 is essential to reflect the clinical effect of LUM/IVA. As to how low or better the value of FEV1 at the start of LUM/IVA therapy depicted the treatment response and how much further decline can be expected in the patients by the researchers. The better the FEV1 value in the patients means the reserve capacity of lung function, the best will be the treatment response seen in early weeks to months of the start of therapy with LUM/IVA. This effect was demonstrated in a clinical trial in 2017 by Labaste et al. The study included 32 pediatric patients, and the conclusion was that the sufferers with advanced lung disease and low FEV1 at the time of drug therapy were at more risk for a further decline in FEV1 [16]. Another clinical trial by Burgel et al. in 2020 enrolled 845 patients. This clinical trial assessed and compared the effects of LUM/IVA based on FEV1 values. They established that group less than 40 FEV1 showed more discontinuation rates of therapy than other groups. They also found reduced Abx use and increased BMI in all three groups [17].
Tong et al. estimated the clinical efficacy and safety of LUM/IVA in a case-control study of the 12-month duration. They conducted this study on 105 patients and revealed the decreased trend of FEV1 along with reduced PEx rates together with a declined rate of first PEx episode, which required Abx [18]. A retrospective study by Grady et al. in 2019 also supported the research mentioned above. The study group's 15 patients showed a lower rate in FEV1 after therapy with LUM/IVA [19]. Figure 3 shows the overall outline of the drug's effect on the lung.

FIGURE 3: The overall outline of the drug's effect on lung
PEx: pulmonary exacerbation; FEV1: forced expiratory volume in one second

Changes in macrophages and bacterial acquisition
LUM/IVA has a wide range of coverage over CF monocyte-derived macrophages (MDMs). As defective CFTR gene generated faulty and reduced CFTR over MDMs, it weakens in enhanced apoptosis and reduced phagocytic activity [20]. An experimental study in 2018 by Zhang et al. evaluated the effects of both LUM/IVA over the macrophages. They observed that IVA had a remarkable impact on macrophage's primary phagocytosis compared to LUM/IVA [20]. A clinical trial by Barnbey et al. in 2018 also evaluated the effects of LUM and IVA in macrophage phagocytic activity. The study of 20 enrolled patients (13 CF patients and 07 healthy patients with wild type CFTR) depicted LUM's enhanced effects over macrophage-phagocytic action against Pseudomonas aeruginosa (PA). However, IVA reduced this effect of LUM if given in combination. This study's primary result was an improved macrophage ability to kill PA and increased the chances of reduced Hospitalization and Abx use [21].
Lower respiratory tract infections with PA are more commonly observed among these patients. Abx is necessary to clear these infections to increase their survival and improve the quality of life they are spending. In a cohort study in 2019, Singh  IVA alone or with LUM (Orkambi) acts synergistically with polymyxin B. An in vitro-study by Schneider et al. in 2016 revealed these three drugs did not affect PA infection if used alone. However, it showed favorable results as a 100-fold decrease in overall bacterial load or count when used in combinations [23]. These findings were even persistent after 24 hours of observation as well. It is a perfect combination for the patients who have been fighting against their chronic lung infections for many years.
Another impressive effect of Orkambi is the repair of primary lung epithelium. An in-vitro study was published in 2018 over the airway cultures. Adam et al. estimated the influence of Orkambi over the repairing of lung epithelium. They exhibited that only the combination named Orkambi showed a substantial repairing effect over the lung epithelium even in the presence of PA infections [24]. The results of the reviewed studies are summarized in Table 1.

HRQoL and PEx
This chronic illness is affecting the HRQoL of patients. The best indicator to reflect the overall health and treatment is via patient-reported outcomes (PROS), so what they feel and what type of treatments benefit their real-life [5]. A valid -disease-based tool is the Cystic Fibrosis Questionnaire-Revised (CFQ-R) that covers the specific areas of HRQoL and those related to the disease. A cross-sectional study by Bell [26]. A cross-sectional study on 80 patients by Flume et al. in 2019 evaluated the effects of PEx on HRQoL by using CFQ-R. The result was a score of 8 out of 12 domains of HRQoL in the 1st-week of PEx and took several weeks to recover to reach pre-PEx levels [27].

Physical Activity and Exercise Tolerance
The disease mostly affects the lungs and makes the lung's reserve capacity to the level to which patients cannot do physical activities and exercise. The repeated episodes of a bacterial infection caused the condition worse even to breathe normally. However, LUM/IVA has a well-established role in physical activity and exercise tolerance. A two-years, clinical trial was designed on 03 patients by Savi et al. in 2019. They exhibited the advanced effects of LUM/IVA (pre-and post-initiation) on physical activity and exercisetolerance [28]. Another study was conducted by Wark et al. on 10 patients. They observed these effects in patients with severe lung disease with FEV1<40 and concluded an improvement at four-week treatment as 78 meters with LUM/IVA in a six-minute walk test (6MWT), which was conserved at 52-week (118.1 m) as well [29].

Effects on BMI
The nutritional status of the patients is directly related to their pancreatic and enzymatic activities. A progressive and chronic illness led them to many nutritional deficiencies by a repeated bacterial infection and unable to gain a normal BMI.

Pituitary Gland
This disease is affecting almost all the essential organs of the patients. The pituitary gland is the crucial organ affected by this illness, resulting in Growth hormone deficiency (GHD) [35]. LUM/IVA also covered this defect in terms of causing significant improvement in levels of GH. Pascucci et al., in 2019, conducted a clinical trial over 10 patients, enlisted from previous studies of GHD with Growth hormone-releasing hormone (GHRH) and arginine test, and five patients were LUM/IVA treated [35]. They found that two patients with severe GHD showed a normal response to the Growth hormone-insulin-like growth factor-1 axis test (GH-IGF-1 axis), and two patients with partial deficiency showed normal test response.

Anemia
The malabsorption in the gut in these patients is responsible for losing essential nutrients necessary for their average growth. And like other chronic ailments, anemia is the prominent factor affecting the general well-being of an individual. One of the studies, by Gifford et al. in 2019, testified the concept of LUM/IVA impact on the rise of hemoglobin (Hgb) level [36]. In a registry-based study of 13929 CF patients, they concluded that IVA increases 0.54 gm/dL in males and 0.18 gm/dL in females, and LUM/IVA increased 0.58gm/dL in males and 0.26 gm/dL in females.

Pregnancy/Fertility and Fetus Exposure
Pregnancy was a challenging milestone before the introduction of CFTR modulators. The ailment coverage over the reproductive system and cervical mucous viscosity imposed them on subfertility and infertility. In 2019, a review article by Jennifer et al. summarized the overall efficacy of CFTR modulators in pregnancy, fertility, and lactation. IVA treatment resulted in pregnancy, even in females using contraceptives during the study duration, as treatment increased the CFTR expression and general health benefits. They didn't find specific studies on the CFTR modulator's effects on neonatal exposure in this review [37]. The study displayed evidence of no congenital anomalies reported in many case reports with women treated with IVA in all three trimesters, with only a few cases showed premature birth in these pregnant ladies with compromised lung capacity. The effects of LUM/IVA in lactation exposed a slight variation in liver function test with a healthy eye examination of neonates.
Trimble et al. reported a study of a pregnant lady on LUM/IVA treatment during her pregnancy, who delivered a healthy baby and successfully breastfed her baby with no significant elevations in liver function tests were observed [38]. However, they suggested further data for the safety of these drugs in pregnancy and breastfeeding. Table 3 shows studies related to the general impact over other systems.

Author Name
Year of Publication LUM/IVA showed significant correction in GHD.
Jennifer et al. [37] 2019 Review article -They reviewed the efficacy of CFTR modulators in pregnancy and fertility.
They reported fertility and successful pregnancies in females with the CFTR modulators.
Trimble et al. [38] 2018 In vitro Study 01 The study reflected the impact of LUM/IVA on one pregnant lady and breastfeeding.
They reported delivery of health baby in mother of CF patient and no significant liver function test elevations on breastfeeding.

Conclusions
This review article focused on the clinical efficacy of LUM/IVA in CF patients. It covers all the fields of interest regarding better impact over lung functions, PEx, Hospitalization rates, HRQoL, physical activity, exercise tolerance, and BMI. LUM/IVA combination resulted in a declined mortality rate by reducing the episodes of severe lung infections and making the life of these patients comfortable with the achievement of adequate pulmonary function without further worsening along with reduced Hospital visits. The hopeful impact of treatment on lung tissue repair is making the lung condition better. The early initiation of these drugs gives long-term benefits to patients of all age groups and premature discontinuation, resulting in a relapse of their disease. The better HRQoL makes them participate and continue their everyday life activities like school, college, office, household activities. The improved growth velocities rates among the prepubertal age with LUM/IVA help them achieve BMI close to their expected years. Patients getting ordinary SOC instead of LUM/IVA faced many complications related to their disease and disease progression. The essential findings of progressed lung functions are positively affecting their general health.
Despite all the studies that we collected and reviewed, more studies on the clinical effects of LUM/IVA in all age groups are necessary to be conducted by others on a large number of the study sample for better and reliable results. There are fewer data available on LUM/IVA safety profile in pregnancy, fertility, and breastfeeding; additional studies are necessary to look for drug safety and efficacy.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.