Efficacy and adverse effects of drugs used to treat adult cystic fibrosis.

Review

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Efficacy and adverse effects of drugs used to treat adult cystic fibrosis 1.

Introduction

2.

Drugs

3.

Conclusion

4.

Expert opinion

Ravi Chopra†, Lisa Paul, Rajapriya Manickam, Wilbert S Aronow & George P Maguire †

New York Medical College/Westchester Medical Center, Division of Pulmonary, Critical Care and Sleep Medicine, Valhalla, NY, USA

Introduction: Cystic fibrosis (CF) is an autosomal recessive disease and is the most commonly seen monogenetic disease in Caucasians. The disease has various manifestations resulting from the abnormal thick secretions, most common being chronic lung infection and airway obstruction. Many new promising drugs have appeared on the horizon over the years. This review here is an attempt to bring together the various treatments being used to prolong and enhance the quality of life of CF patients. Areas covered: A literature review of published as well as ongoing clinical trials, meta-analysis and systematic reviews regarding the drugs used in CF management was carried out using PubMed and Ovid databases. Expert opinion: New concepts have been formed and some positive results in this direction have already led to the approval of cystic fibrosis transmembrane conductance regulator potentiator drug. Gene therapy and stem cell therapy are under development. The current therapies such as dornase alfa and pancreatic enzymes targeting the symptoms continue to evolve as they play an important complementary role. Development of new simple and cost-effective markers, which help assess the efficacy and safety of these constantly emerging new drugs, is also being investigated. Keywords: antibiotics, bronchodilators, cystic fibrosis transmembrane conductance regulator modulators, cystic fibrosis, new treatments Expert Opin. Drug Saf. (2015) 14(3):401-411

1.

Introduction

The dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis (CF) alters transepithelial fluid and electrolyte movement throughout the body and therefore, the function of many organs, most notably the respiratory airways [1,2]. Pathophysiology of CF lung disease is characterized by continual cycles of airway obstruction, infection, and inflammation [3]. Consequently, many treatments target one or more of these pathophysiologic components; for example, there are numerous therapies currently addressing airway infections, inflammation, and mucus alteration [4]. The life expectancy of individuals afflicted by this autosomal recessive genetic disease has improved significantly in recent years due to early diagnosis, patient care in dedicated CF centers and advances in symptomatic therapy [2]. As the identification of the gene for CFTR in 1989, there has been continued hope and research to develop a therapy that will correct the underlying defect through genetic manipulation [4]. There are > 1900 CFTR gene mutations and they classified into six classes according to the mechanism causing the disease [5]. Class I mutations lead to a premature stop codon in the messenger RNA, which prevents translation of the complete protein. Class II mutations lead to an abnormal protein that is removed by the endoplasmic reticulum before 10.1517/14740338.2015.994503 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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Article highlights. .

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The inhaled antibiotics have reduced the side effects as they can achieve high drug concentration in the lungs and can have the similar beneficial effects at lower doses. Dornase alfa cleaves the DNA and thus makes the bacteria more susceptible to the killing action of antibiotics. Pancreatic replacement therapy has become an important part of management of patients with cystic fibrosis as it helps support normal growth in infants and children and prevents weight loss in adults. Disease-modifying therapies have allowed us to target the cause rather than just manage the manifestations of the disease process.

This box summarizes key points contained in the article.

reaching the cell surface. F508del mutation, the most common mutation, belongs to this class. Class III mutations lead to decreased channel activation. Class IV mutations cause decrease in ion conductance through the channel. Class V mutations lead to reduced CFTR on the surface. Class VI mutations lead to CFTR with shortened half-life. The CFTR modulator drugs have provided hope for many individuals afflicted with this life-limiting disease. The repertoire to manage this complex multisystem disease includes many antibiotics, mucolytic agents, bronchodilators and anti-inflammatory medications. The purpose of this review article is to profile the various drugs available for managing CF in terms of their safety and efficacy. These various drugs are used simultaneously in the management of patients with CF (Table 1) [6]. 2.

Drugs

Inhaled antibiotics Antibiotics are one of the main therapies used in the chronic management of CF. Oral and intravenous antibiotics have been used in the past; however, their side effects led to the development of inhaled antibiotics. The inhaled antibiotics have reduced the side effects as they can achieve high drug concentration in the lungs and can have the similar beneficial effects at lower doses [7]. 2.1

Tobramycin Efficacy: inhaled tobramycin has been shown to be beneficial against P. aeruginosa (Pseudomonas aeruginosa) in CF [8]. A randomized cross over study compared aerosolized tobramycin with placebo and showed an increase of 9.7% (p < 0.001) in percent predicted FEV1 (forced expiratory volume in 1 s) [8]. Similarly, a significant increase in FVC (forced vital capacity) of 6.2% (p = 0.014) and a significant decrease in sputum density of P. aeruginosa by a factor of 100 (p < 0.001) compared to placebo was seen [8]. 2.1.1

402

Based on this and subsequent studies, inhaled tobramycin has been used extensively in these patients. With advancements in technology, dry powder inhaled forms have also been developed, which are much faster and easier to administer and do not require the care and cost of maintenance of a nebulizer [9]. Two clinical trials were done to study the efficacy of powder form against placebo. In the EDIT trial (Establish tobramycin Dry powder efficacy in CF), an improvement of 5.9% from the baseline in the percent predicted FEV1 was noted, which did not reach statistical significance [10]. The EVOLVE trial (EValuate tObramycin inhaLed dry powder efficacy versus placebo in CF patiEnts) showed statistical significance in the improved lung function by 13.3% (95% CI: 5.31 -- 21.28) [11]. The EDIT and EVOLVE trials demonstrated a decrease in sputum density of P. aeruginosa in patients on Tobramycin inhaled powder (TIP) when compared to patients receiving placebo [10,11]. Similarly in both the trials, the requirement of additional antipseudomonal antibacterials was lower in patients on TIP compared to patients receiving placebo [10,11]. Notably, none of the patients receiving TIP were hospitalized due to respiratory complications [10,11]. TIP 112 mg twice daily was shown to be non-inferior to that of tobramycin-inhaled solution (TIS) 300 mg/5 ml twice daily in improving lung function in CF patients in the EAGER trial (Establish A new Gold standard Efficacy and safety with tobramycin in CF) [12]. Patients on both TIP and TIS group were found to have decreased sputum density of P. aeruginosa with a greater reduction noted in patients on TIP [12]. The number of patients whose sputum cultures tested negative was slightly more in the group receiving TIP than TIS (11.6 vs 9.9%) [12]. Despite the apparent benefits of TIP, it was shown that patients on TIP required significantly higher additional antipseudomonal antibacterials (64.9 vs 54.5%; p = 0.0148) and also resulted in more hospitalizations (24.4 vs 22.0%) when compared to patients on TIS [12]. The reason for these divergent effects is not clear. Adverse effects: the tobramycin inhaled solution did not result in any nephrotoxic, vestibular or ototoxic effects as compared to placebo [8]. TIP is generally well tolerated and most of the adverse effects are mild to moderate in nature. The most commonly seen adverse effect in EDIT and EVOLVE trials was cough [10,11]. Other adverse effects were throat pain and fever. Most of these adverse effects resolved with time. Pulmonary hemorrhage, considered as a serious adverse effect, occurred in one patient in the EDIT trial [10]. In the EAGER trial, cough was seen more in the TIP group than in the TIS groups [12]. A change in taste was more common in the TIP group but did not reach statistical significance [12]. Bronchospasm occurrence was similar in both TIP and TIS groups [12]. Renal adverse effects such as dysuria and proteinuria occurred in some patients in the EAGER trial [12]. Hearing loss was similar in both TIP and TIS groups; however it was only intermittent and transient [12]. Hearing loss was defined as 10 decibel loss at three consecutive

Expert Opin. Drug Saf. (2015) 14(3)

Efficacy and adverse effects of drugs used to treat adult cystic fibrosis

Table 1. CFTR mutations classes with examples. Class I

Class II

Class III

Class IV

Class V

Class VI

Defective or absent CFTR protein synthesis with premature termination of CFTR production

Impaired processing: typically a defect in protein trafficking and degradation by endoplasmic reticulum F508DEL,N1303K

Defective regulation: the CFTR reached the apical cell surface but is not activated by ATP or cAMP

Impaired function: transport of chloride ions is reduced at the apical membrane

Reduced synthesis of normal functioning CFTR

Decreased CFTR stability

G551D

R117H,R347P

A445E

Q1412X, 4326delTC

R1162X, G542X, W1282X


CFTR: Cystic fibrosis transmembrane conductance regulator.

frequencies, 15 decibel loss at two consecutive frequencies and 20 decibel loss at any frequency for either ear [12]. Aztreonam Efficacy: various trials have studied the efficacy of inhaled aztreonam, which is called AZLI (aztreonam lysine for inhalation) (Table 2). A Phase II study compared two different doses of AZLI, 75 mg twice daily and 225 mg twice daily, with placebo [13]. When compared at day 7, both the 75 mg and 225 mg groups showed improvement from the baseline in FEV1 (6.9 and 6.8%); however this improvement from the baseline was sustained only in the 75 mg group. Compared to placebo, the absolute increase in FEV1 from the baseline to day 14 was not statistically significant in either group. The absolute increase in FEV1 from the baseline to day 14 in the 75 mg group was 1.99% (95% CI: -3.1, 7.1) and 0.71% (95% CI: -5.8, 4.4) for the 225 mg group [13]. There was a significant decrease in bacterial density of P. aeruginosa in both AZLI 75 mg and 225 mg groups; however no change in the susceptibility of P. aeruginosa to AZLI was seen [13]. The sputum cultures positive for other pathogens in both AZLI groups were similar [13]. Another study called AIR-CF1 (Aztreonam Lysinate for Inhalation in CF with P. aeruginosa), a Phase III study, evaluated AZLI 75 mg --three times daily in comparison with placebo [14]. There was a statistically significant improvement of 9.7 points (95% CI: 4.3 -- 15.1, p < 0.001) on the CF Questionnaire-Revised (CFQ-R) [14]. A statistically significant improvement of 10.3% (95% CI: 6.3 -- 14.3; p < 0.001) was seen in FEV1. There was a significant decrease in bacterial density of P. aeruginosa (-1.45 log cfu/g; p < 0.001) [14]. The number of hospitalizations was lower in the AZLI group compared to the placebo group, 5 versus 14%, but it was not statistically significant (p = 0.064) [14]. Another study called AIR-CF2, a Phase III study, evaluated AZLI 75 mg twice daily and 75 mg three times daily compared to placebo two or three times daily [15]. The study showed that patients on AZLI required antipseudomonal antibiotics later than the placebo group, 92 versus 71 days, p = 0.007 [15]. Also, there was a statistically significant improvement in FEV1 from the baseline of 6.3% (95% 2.1.2

CI: 2.5, 10.1; p = 0.001) [15]. There was a statistically significant effect of 5.01 points (95% CI: 0.81, 9.21; p = 0.02) on CFQ-R [15]. There was a significant decrease in bacterial density of P. aeruginosa (-0.66 log10 cfu/g; 95% CI: -1.13, -0.19; p = 0.006) [15]. Another study called AIR-CF3, an open-label extension of the above two trials AIR-CF1 and AIR-CF2, was done to evaluate the effect of nine repeated AZLI courses over time [16]. There was an improvement seen in CFQ-R respiratory symptoms score and FEV1 with each course of AZLI [16]. The thrice daily regimen showed greater improvement than the twice daily regimen [16]. There was a decrease in bacterial density of P. aeruginosa with each subsequent AZLI course [16]. Adverse effects: AZLI was tolerated well in all trials. Most commonly seen adverse effects were productive cough, nasal congestion, throat pain and wheezing and no statistically significant differences between the different dose groups were seen [13-16]. A trend of more adverse effects with higher doses was seen in Phase II [13] as well as AIR-CF1 and AIR-CF2 trials [13-15]. Colistimethate Efficacy: colistimethate has once again become an agent of use with the emergence of multi-drug-resistant bacteria such as Acinetobacter baumannii, P. aeruginosa and Klebsiella pneumonia [17]. Inhaled colistimethate is one of the antipseudomonal antibacterials used in CF [6]. Colistimethate is available in a nebulized solution form as well as dry powder for inhalation [18]. The dry powder form has been shown to be easier to use as it does not need a nebulizer and takes much less time to be administered [18]. The efficacy of powder form of colistimethate against P. aeruginosa in patients with CF was evaluated in a randomized study where it was compared with nebulized tobramycin [18]. Colistimethate dry powder for inhalation was found to be noninferior to nebulized tobramycin when changes in percent predicted of FEV1 were calculated [18]. The predefined noninferiority margin was negative 3 % and the actual adjusted mean difference (MD) observed was negative 0.97 % (95 % CI: -- 2.74, 0.86) showing that the lower limit was above the set parameters for the change from the baseline in 2.1.3


403

404

Indications in CF patients (6 years of age and older)


6 years of age and older -- recommended 6 years of age and older -- strongly recommended

Staphylococcus aureus persistently present in cultures of the airways, there is insufficient evidence to recommend for or against the chronic use of oral antistaphylococcal antibiotics Improve lung function and reduce exacerbation Improve lung function and reduce exacerbation

Hypersensitivity to dornase alfa B or Chinese hamster ovary cell A products; pregnancy category: B

I

--

--

Reduce exacerbation

Known hypersensitivity to B macrolides, patients with known QT prolongation; Pregnancy Category: B C

A

Improve lung function and reduce exacerbation

Improve lung function and quality of life -- recommended

B

Known hypersensitivity to any aminoglycoside; Pregnancy Category: D

Improve lung function and quality of life

B

Pulmonary therapies committee of cystic fibrosis foundation recommendation [17]

A

Known allergy to aztreonam; Pregnancy Category: B

Contraindications



Effect observed

Patients should be screened for NTM before initiating azithromycin, and reassessed periodically at 6- to 12-month intervals. Monotherapy should be withheld in those infected with NTM

Bronchospasm can occur. Recent studies show that oral azithromycin may antagonize the therapeutic benefits of inhaled tobramycin in CF patient with P. aeruginosa infection

Bronchospasm can occur

Comments

Severity of lung disease is defined by FEV1% predicted as follows: normal, > 90% predicted; mildly impaired, 70 -- 89% predicted; moderately impaired, 40 -- 69% predicted; and severely impaired, < 40% predicted. Level of recommendation: A. The Committee recommends the service. There is high certainty that the net benefit is substantial. B. The Committee recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. C. The Committee recommends against routinely providing the service. There may be considerations that support providing the service to an individual patient. There is moderate or high certainty that the net benefit is small. D. The Committee recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harm outweighs the benefits. I. The Committee concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. CF: Cystic fibrosis.

Dornase alfa a. Asymptomatic to mild disease b. Moderate -- severe disease

Oral antistaphylococcal antibiotics, chronic use

Pseudomonas aeruginosa persistently present in cultures of the airways b. Moderate -- severe P. aeruginosa persistently disease present in cultures of the airways -- strongly recommended Inhaled tobramycin a. Mild disease P. aeruginosa persistently present in cultures of the airways -- recommended b. Moderate -- severe P. aeruginosa persistently disease present in cultures of the airways -- strongly recommended Oral azithromycin P. aeruginosa persistently present in cultures of the airways Without P. aeruginosa persistently present in cultures of the airways

Inhaled Aztreonam a. Mild disease

Drugs

Table 2. Drugs for chronic use in adult cystic fibrosis patients.


R. Chopra et al.

Effect observed

Insufficient evidence to recommend for or against the chronic use of inhaled anticholinergic bronchodilators to improve lung function and quality of life or reduce exacerbations. Insufficient evidence


--

--

None; Pregnancy Category: B

--

--


A

D

D

I

I

Pulmonary therapies committee of cystic fibrosis foundation recommendation [17]

Short-term administration of b2-adrenergic receptor agonists can benefit those individuals with airway hyperresponsiveness, and also have value in preventing bronchospasm associated with inhaled therapies.

Comments

Severity of lung disease is defined by FEV1% predicted as follows: normal, > 90% predicted; mildly impaired, 70 -- 89% predicted; moderately impaired, 40 -- 69% predicted; and severely impaired, < 40% predicted. Level of recommendation: A. The Committee recommends the service. There is high certainty that the net benefit is substantial. B. The Committee recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. C. The Committee recommends against routinely providing the service. There may be considerations that support providing the service to an individual patient. There is moderate or high certainty that the net benefit is small. D. The Committee recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harm outweighs the benefits. I. The Committee concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. CF: Cystic fibrosis.

--

--

caution in patient with history B of airway hyper-responsiveness -I

Contraindications

--

--

6 years of age and Improve lung function and older -- recommended reduce exacerbation Insufficient evidence insufficient -to recommend for or against chronic use of inhaled b2-adrenergic receptor agonists to improve lung function and quality of life or reduce exacerbations

Indications in CF patients (6 years of age and older)

Chronic use of Leukotriene modifiers Inhaled corticosteroids CF patients without asthma or allergic bronchopulmonary aspergillosis, recommended against the routine use of inhaled corticosteroids Oral corticosteroids Recommended against the routine use of inhaled corticosteroids without asthma or allergic bronchopulmonary aspergillosis Ivacaftor 6 years of age and older, with at least one G551D CFTR mutation chronic use of ivacaftor is strongly recommended

Chronic inhaled anticholinergics

Inhaled hypertonic saline Chronic-inhaled b2-adrenergic receptor agonists

Drugs

Table 2. Drugs for chronic use in adult cystic fibrosis patients (continued).



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percent predicted FEV1 [18]. There was no statistically significant difference seen in change in FVC from the baseline [18]. The study also looked at susceptibility of P. aeruginosa and did not find any change in the MIC50 (the minimum concentration required for 50% growth inhibition) in either the colistimethate dry powder inhalation group or the nebulized tobramycin group [18]. Adverse effects: the nebulized colistimethate has side effects such as sore throat or sore mouth [19]. The colistimethate dry powder for inhalation had more side effects and hence more discontinuations of treatment when compared to the nebulized tobramycin group [18]. Most side effects were mild to moderate in nature [18]. Serious adverse effects were more in the nebulized tobramycin group [18]. Adverse effects such as cough, abnormal taste and throat irritation were seen more with the colistimethate dry powder for inhalation than nebulized tobramycin [18]. Most of these adverse effects with colistimethate dry powder for inhalation decreased after 4 weeks and were then similar to nebulized tobramycin [18]. Other side effects seen were dyspnea, wheezing, chest pain and hemoptysis [18]. No effects on weight, body mass index, growth or any hematological changes were seen in either group [18]. 2.2

Anti-inflammatory Azithromycin

2.2.1

Efficacy: azithromycin has both antimicrobial and antiinflammatory effects such as decreased production of proinflammatory cytokines by monocytes and epithelial cells though it may not have any direct effects on P. aeruginosa [20]. Azithromycin has been shown to be associated with improved lung function in studies [21,22]. These studies have also demonstrated a reduction in the number of exacerbations in CF, the length of hospital stays as well as the requirement of other antibiotics [21,22]. The improvement in lung function was seen in patients who had chronic P. aeruginosa but not in patients without this organism. But the other beneficial effects such as reduction in the number of exacerbations were seen in both groups [23,24]. There was an improvement in FEV1, MD of 3.97% (95% CI: 1.74, 6.19%) [25]. This improvement was sustained at the end of 6 months. There were fewer exacerbations as the likeliness to be free of exacerbations was 1.96-times higher in the patients treated with azithromycin [25]. Adverse effects: azithromycin is generally well tolerated. Common side effects include gastrointestinal symptoms such as nausea and diarrhea [25]. The daily regimen is better tolerated than the weekly dosing because of lesser gastrointestinal effects [26]. Some studies reported ototoxicity but no difference was found when it was compared to placebo [27]. Increased incidence of resistant non-tuberculous Mycobacterial infections has also been reported [28]. As azithromycin may cause QTc prolongation, caution should be ascertained when using along with other drugs that also prolong QTc. However, for general population with no cardiovascular risk factors azithromycin does not increase the risk of cardiac death [29]. 406

Corticosteroids Inhaled corticosteroids are topical anti-inflammatory drugs, which can be associated with adverse effects such as reduced growth in childhood [30]. A recent Cochrane review did not find any significant benefit of inhaled corticosteroids in CF [31]. The CF Foundation also recommends against the use of inhaled corticosteroids or oral corticosteroids to improve lung function, quality of life or reduce pulmonary exacerbations in patients aged 6 or more [6]. Inhaled corticosteroids are associated with adverse effects such as oral thrush, pharyngitis, and hoarseness of voice [32]. High-dose inhaled corticosteroids may affect growth in children [30]. 2.2.2

Monteleukast Monteleukast has been useful in asthma because eosinophils play an important role in the inflammatory process there. Some studies have shown that CF patients also have elevated eosinophil products such as eosinophilic cationic protein (ECP), eosinophil protein X, major basic protein and leukotrienes [33] and hence monteleukast, which is a leukotriene receptor antagonist, may be helpful. A study found significant improvement in FEV1, FEF25 -- 75 (forced expiratory flow between 25 and 75% of FVC) as compared placebo [34]. The study also demonstrated a significant decrease in serum and sputum levels of ECP and Interleukin-8 and an increase in IL-10 [34]. This resulted in an improvement in cough and wheezing scale scores [34]. There were no significant changes seen in thoracic gas volume, airway resistance (Raw), residual volume and vital capacity, which could be because of the reason that monteleukast does not have any effect on consolidated lung tissue damage and hyperinflation [34]. 2.2.3

Mucolytics One of the important features of CF is thick mucus secretions. Initially it was thought that mucus has a lot of mucin and hence mucolytics should help in the therapy [35]. However, it is not mucin but the pus-containing DNA from the degraded neutrophils, markers of inflammation, which make the mucus thick and tenacious [36]. Hence, mucolytics may not be helpful but drugs such as dornase alfa, which target the DNA rather than the mucin, have been found to be effective. Dornase alfa cleaves the DNA and thus makes the bacteria more susceptible to the killing action of antibiotics [37]. It has also been shown to have anti-inflammatory effects in the airways [38]. Dornase alfa is delivered by a special nebulizer. 2.3

Dornase alfa Efficacy: a 2010 Cochrane systematic review describes the efficacy of dornase alfa [39]. The review looked at percentage change in FEV1 and FVC as well as quality of life score. The trials were heterogeneous with respect to the lung function outcomes FEV1 and FVC and only few had long-term follow-up; hence the strength of evidence is not the best. There was an improvement in FEV1 in the short term, the 2.3.1




MD for percentage change in FEV1 at 1 month being 8.36 (95% CI: 0.33, 16.40) [39]. However, the improvement in FEV1 was not sustained and it was not significant at the end of 3 years [39]. There was a statistically significant shortterm improvement in the percentage change in FVC, MD 7.52 (95% CI: 1.34, 13.69) [39]. However, the improvement did not sustain and it was not significant at the end of 2 years, MD 0.70 (95% CI: -1.24, 2.64) [39]. Data from an epidemiologic study suggests that there is a decrease in the rate of decline of lung function, in terms of FEV1, from 3.26 to 2.32% in patients 18 years of age and older [40]. In addition, it also showed an improvement in FEV1, which was more in patients < 18 years of age [40]. Survival benefit has also been shown in a study where the odds ratio was 0.85 (95% CI: 0.76, 0.95), p < 0.005 [41]. Adverse effects: dornase alfa is generally well tolerated. The common side effects are dysphonia and rash [42]. Other less common side effects include cough, dyspnea, chest pain, conjunctivitis, gastrointestinal obstruction and weight loss [42]. Hypertonic saline Efficacy: hypertonic saline (HTS) has been shown to be helpful in airway mucus clearance in CF [43]. Different mechanisms have been proposed for its action such as the increase in the surface liquid layer hydration, changes in mucus characteristics, inhibition of the epithelial sodium channel and immunomodulatory effects in the sense it increases IL-8 release from glycosaminoglycans making the chemokines susceptible to degradation and hence decreasing inflammation [44]. The first study to demonstrate effectiveness of 7% HTS was a double-blind, parallel-group trial in which the primary outcome of rate of change of FEV1 and FVC was not statistically significant but there was an absolute difference between HTS and inhaled normal saline [45]. There was an increase in FVC by 82 ml (95% CI: 12, 153) and FEV1 by 68 ml (95% CI: 3, 132) [45]. The number of exacerbations were reduced significantly with HTS as compared to normal saline (relative reduction 56% p = 0.02) [45]. The decrease in pulmonary exacerbations was demonstrated in a stratified retrospective analysis [46]. The odds ratio in patients with mild airway obstruction was 0.17 (95% CI: 0.05, 0.58; p = 0.004), moderate obstruction 0.39 (95% CI: 0.16, 0.93; p = 0.034) and severe obstruction 0.02 (95% CI: 0.001, 0.45; p = 0.015) [46]. The efficacy of HTS also depends on volume given as higher improvements in the lung function are seen with higher volumes though it increases the time required to administer the dose [44]. Higher concentration of saline may be more useful but then the side effects such as throat irritation become bothersome at concentrations of saline > 12% [44]. A comparison of dornase alfa and HTS demonstrated that dornase alfa is more effective than HTS [47]. Adverse effects: HTS inhalation may cause marked bronchospasm [48]. Other possible adverse effects include throat irritation, cough or chest tightness and salty taste [49]. 2.3.2

Mannitol Efficacy: mannitol is available in dry powder form for inhalation for improving mucus clearance in CF patients. The possible mechanism of action is that it may change the viscous properties of mucus or may increase hydration in the airway or increase the ciliary motility [50,51]. Two randomized, double-blind, multinational, Phase III trials, CF-301 and CF-302, evaluated the safety and efficacy of mannitol dry powder for inhalation in CF patients [52,53]. The pooled analysis of these two studies suggested that inhaled mannitol had a significant effect on percent change in FEV1 from the baseline as compared to placebo, 4.81 versus 0.08% [54]. Also, the absolute increase in FEV1 from the baseline was statistically significant, treatment difference 99.5 ml; p < 0.001 [54]. A significant increase in FVC was also seen in the pooled analysis [54]. The risk of exacerbation was also significantly reduced in the mannitol group, RR 0.71 (95% CI 0.51, 0.98 p = 0.039) [54]. Adverse effects: mannitol is generally well tolerated. The most common side effects are cough, hemoptysis, dyspnea and chest discomfort [54]. Some patients may have bronchospasm [54]. 2.3.3

Pancreatic enzymes Pancreatic insufficiency is commonly seen in CF in ~ 85 -- 90% of patients [55]. This leads to inadequate levels of digestive enzymes such as amylase and lipase resulting in malabsorption, which over a period of time causes abdominal symptoms such as cramping, diarrhea and steatorrhea. This affects the growth of infants and children and causes weight loss in adults [56]. Hence, pancreatic replacement therapy has become an important part of management of patients with CF. The dosage is 500 lipase units/kg/meal for those over age 4 years [57]. 2.4

Efficacy The efficacy of pancreatic enzymes used is measured as coefficient of fat absorption (CFA) and coefficient of nitrogen absorption (CNA), which is a surrogate for protein absorption. This was evaluated in a randomized, placebo-controlled pancreatic enzyme replacement therapy withdrawal study [58]. A much higher CFA was seen in the pancreatic enzyme replacement group in the withdrawal phase compared to the placebo group [58]. Also, the change in CFA from baseline was +8% to -16% in the pancreatic enzyme replacement group compared to 0 to -75% in the placebo group [58]. Similarly, a much higher CNA was seen in the pancreatic enzyme replacement group in the withdrawal phase compared to the placebo group [58]. The change in CNA from the baseline was +9 to -7% in the pancreatic enzyme replacement group compared to -3 to -62% in the placebo group [58]. Other measures of efficacy such as the stool consistency also showed that the pancreatic enzyme replacement group did better. The median stool consistency score 2.0 remained similar to the baseline whereas it dropped to 2.9 in the placebo group [58]. 2.4.1


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2.4.2

Adverse effects

The most common adverse effects seen were abdominal pain, diarrhea and flatulence [58]. There were no significant changes in blood pressure, heart rate or any biochemistry values [58]. No serious adverse effects or deaths were seen [58]. Bronchodilators Respiratory manifestations are a common presentation in CF and hence bronchodilators are commonly used. However, there is limited evidence about their efficacy in CF. A Cochrane database systematic review revealed a short-term benefit on FEV1 and a long-term benefit on peak expiratory flow when short-acting b-2 agonists were used in CF patients with either bronchial hyper reactivity or a documented bronchodilator response [59]. The long-acting b-2 agonists also showed a beneficial effect on FEV1 and FEF25 -- 75 but it was only a short-term effect, which was not sustained over time [59]. The effects of short-acting anticholinergics on either FEV1, FVC or FEF25 -- 75 were not consistent [59].


2.5

Disease-modifying therapies Various therapies such as antibiotics, mucolytics, pancreatic enzymes treat the consequences of CF and not the disease itself. Many mutations have been identified and the identification and classification of these into groups has led to two different approaches aimed at correcting the basic defect. Gene therapy targets the genetic alteration and molecule therapy corrects the functional defect at the protein level. Ivacaftor is an oral drug, which is now approved for use in CF patients with the CFTR gating mutation G551D [60]. The G551D is a class III mutation in which the CFTR protein is unable to open and transport chloride properly [61]. The G551D mutation is the third most common mutation and is present in ~ 3% of CF patients [62]. Efficacy: the safety and efficacy of ivacaftor was evaluated in two randomized, double-blind, placebo-controlled trials, STRIVE (patients ‡ 12 years) and ENVISION (patients 6 -- 11 years) [63,64]. In adults and adolescents, ivacaftor was shown to be better than placebo as there was a significant increase in percent predicted FEV1 and also absolute FEV1 from the baseline [63]. Sweat chloride levels were significantly reduced; however no correlation was seen between the decrease in sweat chloride levels and change in FEV1 in patients on ivacaftor [65]. The risk of pulmonary exacerbations was significantly reduced by 55% [63]. The mean adjusted weight gain from the baseline was significantly higher in the ivacaftor group as compared to the placebo group, 3.1 versus 0.4 kg p < 0.0001 suggesting better efficacy [63]. Improvement in health-related quality of life, as measured by the CFQ-R, was evident by the significant improvements seen in respiratory symptoms score and physical and social functioning [63]. Adverse effects: ivacaftor was generally well tolerated. No deaths were reported [63,64]. The common adverse effects included headache, nasal congestion, throat pain, abdominal 2.6

408

pain, rash, diarrhea and dizziness and these were all mild to moderate in severity [60]. No treatment discontinuations related to the drug were seen [60]. The serious adverse effects included pulmonary exacerbation, productive cough, hemoptysis and hypoglycemia [63,64]. No clinically significant effects of ivacaftor were seen on vitals or laboratory parameters though some studies have shown elevated transaminases especially in patients with elevated enzymes at baseline [60,63,64]. 3.

Conclusion

Drugs used in CF have been shown to improve the lung function as evident by the increase in FEV1 and FVC. The antibiotics and the mucolytics have this effect. This effect at times may not be long lasting or sustained but it does help in the short term. This helps the patients as lungs are one of the prime target of CF disease. The inhaled antibiotics, such as tobramycin, aztreonam, colistimethate, in addition to being easy to use and having lower toxicity, have reduced the burden of infective organisms without development of resistance. Mucolytics such as dornase alfa, HTS, inhaled mannitol powder improve mucus clearance, which in turn helps decrease the burden of infective organisms. More sputum cultures are coming back negative than that in the past. The use of systemic antibiotics has also declined. The number of exacerbations and hospitalizations has reduced. All these point towards the better control of lung infections, the main cause of mortality in CF patients. There has also been an improvement in growth and weight gain seen with the use of pancreatic enzymes. These drugs have not only prolonged life but they have also improved the quality of life as seen in surveys and questionnaires such as CFQ-R. There have been some side effects of these drugs such as cough, throat pain, change in taste, occasional bronchospasm but they have been mostly mild to moderate in intensity and those also have resolved with time in most of the cases. There have been few serious adverse effects resulting in discontinuation of the drugs. Thus, the drugs have been safe in addition to being efficacious. The gene modulators in addition may have a promising role in treating CF. 4.

Expert opinion

Traditionally the treatment for CF has been centered around on how to manage the manifestations and it has been a success story so far as evidenced by the increase in life expectancy seen in CF patients. The development of inhaled antibiotics, use of azithromycin, mannitol and HTS, the pancreatic enzymes have all played their invaluable part in this successful journey. As the discovery of CF gene in 1989, many new possible treatments have appeared on the horizon [66]. The identification of the gene has allowed us to target the cause rather than just manage the manifestations of the disease process. This has led to the development of concept of gene therapy, stem cell therapy and CFTR protein modulators. The gene therapy




and stem cell therapy are still evolving; however, once they are in use they may benefit all CF patients regardless of their genotype. The concept of gene therapy is to introduce a normal copy of the CFTR gene into the airway cells. Though the concept is a simple one, the execution has been difficult because of low expression of the CFTR transgene and the inability to find a vector, which can integrate easily and is at the same time non-immunogenic. Adenovirus has been used as a vector but without much success. Lentivirus is being developed now as it has shown some success in the murine model [67]. Stem cell therapy using human amnionic mesenchymal cells has shown positive results in vitro but this modality is still in its nascent stages of development [68]. The most successful new development has been the CFTR protein modulators, which are of three types: potentiators, correctors and read-through agents. Potentiators improve gating and conductance defects by augmenting the open configuration of the CFTR channel [69,70]. One of the potentiators, ivacaftor, is already in use; however it is class specific and can benefit only a small percent of CF patients. Hence, correctors such as lumacaftor are being investigated as they can target the most commonly seen F508del mutation. The F508del mutation results in an unstable protein, which gets rapidly degraded and hence only a minimal functioning channel is present in the membrane. Thus the potentiators would not be able to provide much benefit as there is very less functioning protein for it to act on. Hence the corrector would be much more helpful in this situation as it will increase the total amount of functional protein at the cell surface. Combination therapies of a corrector and potentiator are also being studied as they may have synergistic effects. There is a subset of patients who carry the non-sense mutation and hence the potentiators and correctors may not be effective. This has Bibliography

led to the development of read-through agents such as ataluren, which help the formation of a complete protein by rendering the premature termination codon ineffective [71]. Though these therapies target the cause they would not be able to benefit all of the CF patients because of the numerous mutations. Hence, the development of other therapies targeting the clinical manifestations of CF will continue. Drugs are under trial, which aim to downregulate the hyperactive epithelial sodium channel and hence increase the airway surface liquid layer. With all the new developments, we would also need new markers for better assessment of disease severity and more objective assessment of outcomes of the new treatments. These markers should be cost effective and minimally invasive or non-invasive. Some new evaluation techniques are lung clearance index, nasal potential difference, intestinal conductance measurements and rectal biopsies. Some new biomarkers assess the microbiology and inflammation when used on bronchoalveolar lavage, induced sputum or the exhaled breath. The gold standard for the CFTR protein modulators has been the measurement of chloride secretion. Studies in the coming years will tell if these turn out to be clinically important or not. The drug development is a slow process and it requires patience and team approach. Fortune favors the brave.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation

Ravi Chopra†1 MD, Lisa Paul1 MD, Rajapriya Manickam1 MD, Wilbert S Aronow1,2 MD & George P Maguire1 MD † Author for correspondence 1 New York Medical College/Westchester Medical Center, Division of Pulmonary, Critical Care and Sleep Medicine, 100 Woods Road, Valhalla, NY 10595, USA Tel: +1 914 493 7518; Fax: +1 914 493 8130; E-mail: [email protected] 2 New York Medical College/Westchester Medical Center, Division of Cardiology, Valhalla, NY, USA

411

Ibuprofen in children with cystic fibrosis: pharmacokinetics and adverse effects.

Cystic Fibrosis Lung Infections: Polymicrobial, Complex, and Hard to Treat.

Cystic Fibrosis and Piperacillin-tazobactam: Adverse Reactions.

Emerging drugs for cystic fibrosis.

Pathophysiology of cystic fibrosis and drugs used in associated digestive tract diseases.

Cystic fibrosis in adult age.

Diagnostic of cystic fibrosis in adult.

Systemic effects of medications used to treat glaucoma.

Adverse effects of commonly used systemic drugs on the human eye. Part III.

Adverse effects related to antithyroid drugs and their dose regimen.

Cystic fibrosis and non-cystic fibrosis bronchiectasis.

The safety of novel drugs used to treat irritable bowel syndrome.

Pancreatic morphology and function in adult patients with cystic fibrosis.

[Adverse effects of anti-epileptic drugs].

Some adverse effects of drugs on nutrition.

Cystic Fibrosis: Breakthrough Drugs at Break-the-Bank Prices.

Can Antiretroviral Drugs Be Used to Treat Porcine Endogenous Retrovirus (PERV) Infection after Xenotransplantation?

Predicting CFTR activity with front-runner cystic fibrosis drugs.

Cystic fibrosis - characterization of the adult population in Portugal.

Multidimensional clinical phenotyping of an adult cystic fibrosis patient population.

Omeprazole enhances the efficacy of pancreatin (pancrease) in cystic fibrosis.

New antipsychotics: classification, efficacy, and adverse effects.

Cystic Fibrosis Foundation and European Cystic Fibrosis Society Survey of cystic fibrosis mental health care delivery.

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis.