Aztreonam lysine for inhalation Cayston® (AZLI)

The Leeds Method of Management. June, 2015.Aztreonam lysine for inhalation[online]. Leeds Regional Adult and Paediatric Cystic Fibrosis Units, St James's University Hospital, Leeds, UK. Available from http://www.cysticfibrosismedicine.com

Introduction

The use of Inhaled antibiotics for suppressive therapy of chronic pulmonary infections due to Pseudomonas aeruginosa (PA) is considered standard of care and is recommended in International, European and local guidance (1,2,3,4). There is strong published evidence that rigorous antibiotic treatment designed to eradicate early onset PA infection is beneficial for CF patients. Eradication therapy has decreased the prevalence of PA in younger CF patients but the majority develop chronic infection in adulthood and require suppressive, inhaled antibiotic therapy to preserve and maintain lung health for as long as possible.

What is aztreonam lysine for inhalation (AZLI)?

AZLI is a monbactam antibiotic which binds with high affinity to the penicillin-binding protein PBP3 of susceptible gram negative bacteria, including Pseudomonas aeruginosa, leading to inhibition of bacterial cell wall synthesis, followed by cell lysis. Cayston® is specifically formulated with the amino acid lysine, which has been shown to be well tolerated in the airways, and which may itself confer an element of mucolytic activity (5,6,7). AZLI is indicated for the suppressive therapy of chronic pulmonary infections due to Pseudomonas aeruginosa in patients with cystic fibrosis (CF) aged 6 years and older (5)

Evidence for the use of aztreonam lysine for inhalation

Azli was evaluated over a period of 28 days of treatment (one course) in two randomised, double-blind, placebo-controlled, multi-centre studies: AIR-CF1 and AIR-CF2. Patients participating in these studies could subsequently join a follow-on study, AIR-CF3 and receive multiple open-label courses of Cayston®. Entry criteria included chronic PA lung infection with a baseline FEV1 between 25% and 75% of predicted normal values. Overall, 344 predominantly adult patients (77%) were treated in these studies, conducted using the E-Flow rapid nebuliser system and an Altera for Cayston handset.

AIR-CF1 enrolled 164 (predominantly) adult and paediatric patients. Treatment was randomised in a 1:1 ratio comparing inhaled Cayston® 75 mg (80 patients) or 5mg lactose placebo (84 patients) administered TID for 28 days (one course).On average, patients had received approximately two courses of inhaled tobramycin in the year preceding the study and were required to have been off anti-pseudomonal antibiotics for at least 28 days before treatment with the study drug. Patients treated with AZLI experienced clinically significant improvements in respiratory symptoms (as measured with CFQ-R) relative to those treated with placebo (adjusted mean treatment difference of 9.7; p<0.001). A significant improvement in pulmonary function (FEV1) was observed at day 28 for the AZLI group relative to the placebo group (adjusted mean treatment difference of 10.3%; p<0.001).

PA sputum density decreased significantly more for patients who received AZLI than for those who received placebo (adjusted mean treatment difference of -1.453 log10 CFU/g; p<0.001). Patients receiving AZLI had significantly greater weight increases from baseline to day 28 (1.1% increase) than those receiving placebo (0.1% increase; p=0.004) (8)

AIR-CF2 enrolled 246 patients. All patients had been heavily treated with tobramycin in the previous year and were also pre-treated with Tobramycin Nebuliser Solution (TNS) 300mg BID in the four weeks immediately prior to receiving AZLI. Patients continued with their baseline medications, including macrolide antibiotics. Patients were randomised in a 2:2:1:1 ratio to be treated with AZLI 75mg BID or TID or volume matched placebo BID or TID for 28 days immediately following the 28-day run-in course of open-label TNS. The median time to need for IV or inhaled anti-pseudomonal antibiotics was prolonged by 21 days for patients treated with AZLI compared to placebo (median: 92 days vs. 71 days, p=0.007). Pulmonary function increased significantly with AZLI therapy. At day 28, adjusted mean treatment difference in FEV1 for the pooled AZLI group versus the pooled placebo group was 6.3% (p=0.001). Patients who received AZLI had significant improvements in respiratory symptoms, as measured by the CFQ-R Respiratory Symptoms scores. The treatment difference at day 28 relative to placebo was 5.01, p=0.020). At day 28, the difference in the adjusted mean PA CFU density change (log10 CFU/g of sputum) for the pooled AZLI group versus placebo was statistically significant (0.66; p=0.006) (9)

AIR-CF3 evaluated long-term AZLI use over 9 on/off cycles (total 18 months). This open-label, follow-on study to AIR-CF1 and AIR-CF2 examined the safety of repeated exposure to AZLI and its effect on disease related endpoints over multiple 28 day courses. Patients received AZLI at the same frequency (BID or TID) as in the preceding randomised studies. Baseline medications were continued, and whenever indicated, additional antibiotics were used to treat exacerbations. Mean change in respiratory symptoms, as measured with CFQ-R score, increased after every course of AZLI given TID. Improvements in FEV1 and CFQ-R Respiratory Symptoms scores were more consistent for patients who were compliant than for those who were not. Compliance overall was high; 92% for BID and 88% for TID patients. Improvements were sustained and repeated courses of AZLI resulted in consistent weight gain sustained over an 18 month period (9 cycles) (10).

AIR-CF4 evaluated AZLI efficacy in patients with mild lung impairment (FEV1 > 75% predicted). This study did not meet its primary endpoint set as a significant improvement in CFQ-R RSS compared to placebo but analysis of the subgroup with FEV1 < 90% predicted revealed clinically important effects. Day 28 treatment effects were 1.8 points for CFQ-R-Respiratory Symptoms Scale (95%CI: −2.8, 6.4; p=0.443; primary endpoint); −1.2 for log10 sputum PA colony-forming units (p=0.016; favouring AZLI), and 2.7% for relative FEV1% predicted (p=0.021; favouring AZLI). Treatment effects favouring AZLI were larger for patients with baseline FEV1 <90% predicted compared to ≥ 90% predicted. Patients with FEV1 >75 to < 90% predicted had measurable improvement in respiratory symptoms and statistically significant improvements in FEV1% predicted, compared to patients with FEV1 ≥90% predicted. AZLI was well tolerated (11)

AZLI compared to tobramycin for inhalation (TNS):
AZLI efficacy relative to tobramycin was studied in an active comparator study GS-US-205-0110. This multicentre, randomised, parallel-group trial compared inhaled aztreonam with tobramycin inhalation solution (active comparator) in 268 patients. The study was designed with two co-primary endpoints:
• Relative change from baseline in FEV1 per cent predicted at day 28 among all subjects (non-inferiority analysis)
• Actual change from baseline in FEV1 per cent predicted across 3 treatment courses among all subjects (superiority analysis)

The study met both co-primary endpoints, demonstrating superiority of AZLI to TNS in lung function improvement as measured by mean relative change from baseline FEV1 % predicted after 28 days (Δ 7.8 (p < 0.001)) and mean actual change in FEV1 % predicted across 3 treatment courses (Δ 2.7 (p 0.002).

Treatment differences for AZLI versus TNS were greater in the subset of subjects who had received TNS for ≥ 84 days for 12 months prior to entering the trial. Subjects treated with AZLI experienced a prolonged time to need for IV antipseudomonal antibiotics for a respiratory event and significantly fewer respiratory hospitalisations and respiratory events requiring the use of additional IV or inhaled antipseudomonal antibiotics than tobramycin treated subjects. The mean change from baseline in log10 PA CFU/g sputum (average across 3 treatment courses) indicated that there was a larger decrease in AZLI treated subjects compared to TNS treated subjects but this difference was not statistically significant.

Longer term use was also investigated in the Single Arm Extension Study where the EU cohort, comprising 68 patients randomised to AZLI and 65 patients randomised to TNS in the comparator phase of the study, entered an extension phase. All subjects in the extension phase received AZLI 75mg TID for three additional treatment cycles. During the three additional treatment months the change from baseline in FEV1 % predicted was:
+8.6%, +6.9% and +7.4% for the group previously randomised to AZLI
+7.3%, +6.4% and +3.8% for the group previously randomised to TNS.
In the comparator phase, AZLI patients experienced a mean relative change from baseline of 0.55%, 0.86% and 0.94% in BMI after the 1st, 2nd and 3rd courses and weight continued to increase by 1.30%, 1.76% and 1.93% over the following three cycles of the extension phase. In contrast patients randomised to the TNS arm in the 3 cycles of the comparator phase lost weight, (BMI -0.83%, -0.82%, and -0.20%) but began to gain weight when switched over to AZLI in the extension phase (0.64%, 1.43% and 1.43%) (12)

Paediatric population

A total of 137 paediatric patients aged 6 to 17 years with chronic P. aeruginosa infection and FEV1 ≤ 75% predicted have received Cayston in Phase 2 and Phase 3 clinical studies. Paediatric patients had clinical improvements with Cayston as determined by an increase in FEV1, improvement in CFQ-R respiratory symptoms scores and decline in P. aeruginosa sputum density. Cayston is indicated for use in paediatric patients aged 6 years and older with repeated cycles of 28 days on therapy followed by 28 days off Cayston therapy based on the above clinical experience.5

Eradication of new isolates of PA

In a Phase 2 open-label study (GS-US-205-0162) 105 paediatric patients aged 3 months to < 18 years (24 patients aged 3 months to < 2 years; 25 patients aged 2 to < 6 years; 56 patients aged 6 to < 18 years) with CF and documented initial/new onset P. aeruginosa infection/colonisation received AZLI 3 times a day for a single course of 28 days. Sputum or throat swab cultures were collected at study entry (baseline) and at weeks 4 (end of treatment), 8, 16, and 28. The primary endpoint was the percentage of patients with cultures negative for PA at all post-treatment time points. Of the 101 patients who completed treatment, 89.1% (n = 90) were free of PA at the end of treatment and 75.2% (n = 76) were free of PA 4 weeks after the end of treatment. Of the 79 patients evaluable for the primary endpoint, 58.2% were free of PA at all post-treatment time points (13).

Pharmacokinetics and bioavailability

For aztreonam, as with all β-lactam antibiotics, the time that the concentration is kept above MIC is the PK/PD parameter best correlated with efficacy, hence the TID dosing regimen. Inhalation of 75mg of AZLI is associated with significantly higher sputum concentrations than those achieved following intravenous administration. For combined Phase 3 placebo-controlled studies, ten minutes following a single dose of 75 mg Cayston on Days 0, 14, and 28, the mean sputum concentrations in 195 patients with CF were 726 µg/g, 711 µg/g, and 715 µg/g, respectively, indicating no increased accumulation of aztreonam following repeated dosing (5). In vitro studies show that activity of AZLI is not inhibited by CF sputum or porcine gastric mucin (14).

Dosage and administration

One prescribed treatment course of Cayston® is presented as a 28-day pack containing 84 vials of 75 mg lyophilised Cayston® and 88 solvent ampoules. The four additional solvent ampoules are provided in case of spillage. Cayston® should be taken 3 times a day over the 28-day treatment course. Doses may be fitted in with daily activities as long as there is a minimum four hour window between each dose. Cayston® may be taken in repeated cycles of 28 days on therapy followed by 28 days off Cayston® therapy.

Each dose consists of one vial of Cayston® to be dissolved in one ampoule of solvent to give a final volume of 1ml. Cayston® is administered by inhalation over a 2 to 3 minute period, using an Altera® nebuliser handset (supplied in each box) attached to an E-Flow Rapid nebuliser base unit (not supplied). Cayston® should not be used with any other type of handset or aerosol head. Cayston® should not be mixed with any other medicinal products in the Altera® Nebuliser Handset. No other medicinal products should be put into the Altera® Nebuliser Handset.

The 75 mg dose is the same for patients regardless of age or weight. For patients taking multiple inhaled therapies, the recommended order of administration is as follows:
1. bronchodilator
2. mucolytics
3. and lastly, Cayston. 5

Safety

The safety profile of AZLI is consistent with the expected symptoms of the patients’ underlying CF lung disease. The most commonly reported AEs are cough, nasal congestion, wheezing, pharyngolaryngeal pain, dyspnoea and cough. 5

Microbiology

In the Phase 3 placebo-controlled studies of Cayston, local aztreonam concentrations generally exceeded aztreonam MIC values for P. aeruginosa, regardless of the level of P.aeruginosa susceptibility.

In a 24-week active-controlled study of Cayston therapy, no increases in P. aeruginosa MIC50 (± 2 dilution change) were observed, whereas MIC90 increased to 4 times the initial MIC. At the end of the study, the percentage of patients with aztreonam MIC for P. aeruginosa above the parenteral breakpoint (> 8 µg/ml) increased from 34% at baseline to 49%, the percentage of patients with P. aeruginosa resistant to at least 1 beta-lactam antibiotic increased from 56% at baseline to 67%, and the percentage of patients with P. aeruginosa resistant to all 6 beta-lactam antibiotics tested increased from 13% at baseline to 18%. There is a risk that P. aeruginosa isolates may develop resistance to aztreonam or other beta-lactam antibiotics in patients treated with Cayston. The emergence of parenteral P. aeruginosa resistance to aztreonam and other beta-lactam antibiotics may have potential consequences for the treatment of acute pulmonary exacerbations with systemic antibiotics. However, similar improvements in lung function were seen after treatment with Cayston among patients with aztreonam susceptible or resistant P. aeruginosa isolates.

In studies of up to nine 28-day courses of Cayston therapy, no increases of clinical significance were observed in the treatment-emergent isolation of other gram-negative bacterial respiratory pathogens (Burkholderia species,Stenotrophomonas maltophilia and Alcaligenes species). During the 6-month randomised phase of study GS-US-205-0110, treatment-emergent isolation of MSSA and MRSA was observed more commonly among Cayston-treated patients than Tobramycin Nebuliser Solution (TNS)-treated patients. The majority of the treatment-emergent isolations were intermittent. Treatment-emergent persistent isolation (defined as absent at screening/baseline then present at 3 or more subsequent consecutive visits) of MSSA occurred in 6% of Cayston-treated patients compared to 3% of TNS-treated patients. Treatment-emergent intermittent isolation of MRSA occurred in 7% of Cayston-treated patients compared to 1% of TNS-treated patients and treatment-emergent persistent isolation of MRSA occurred in 3% of Cayston-treated patients compared to no TNS-treated patients. An association between persistent isolation of MRSA and more severe disease and increased mortality has been reported in the literature. During clinical studies of Cayston, isolation of MRSA did not result in worsening of lung function (5)

The intermittent administration of Cayston® (AZLI) in patients with cystic fibrosis and chronic PA colonisation has been shown to be effective in improving and stabilizing lung function, decreasing the requirement for intravenous antibiotic therapy and hospital admissions, improving quality of life score and increasing body weight.

Key points

•The intermittent administration ofn AZLI in patients with cystic fibrosis and chronic PA colonisation has been shown to be effective in improving and stabilizing lung function, decreasing the requirement for intravenous antibiotic therapy and hospital admissions, improving quality of life score and increasing body weight.

References

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14. Gibson RL, et al. Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis. Pediatr Pulmonol. 2006;41(7):656-665 [PubMed]

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