Summary Basis of Decision for Cayston ™

3.3.1 Pharmacodynamics

Clinical pharmacodynamic studies are not directly applicable to topically acting antibacterial agents, and therefore pharmacodynamic studies were not provided with this submission. Antibacterial agents differ from other drugs by, ideally exhibiting their pharmacological effects on susceptible bacteria, and not on animal or human cells.

Aztreonam exhibits activity in vitro against a broad spectrum of gram-negative aerobic pathogens including P. aeruginosa. Aztreonam binds to penicillin-binding proteins of susceptible bacteria, which leads to inhibition of bacterial cell wall synthesis, followed by filamentation and cell lysis.

3.3.2 Pharmacokinetics

Absorption

Administration of Cayston via the Altera Nebulizer System delivers the drug directly to the lower airways, with minimal systemic exposure. Mean sputum aztreonam concentrations were more than 1000-fold greater than corresponding mean plasma concentrations reflecting the direct deposition of aztreonam at sites of infection.

Concentrations of aztreonam in sputum following Cayston administration were noted to be highly variable. Despite the variability in sputum concentrations, aztreonam concentrations were noted above the MIC values for P. aeruginosa. Ten minutes following a single dose of Cayston 75 mg, the mean sputum level was 726 µg/g (range: 0 - 6010 µg/g), which is more than 10 times the P. aeruginosa minimum inhibitory concentration for 90% of isolates in adults, and 10- to 15-times the P. aeruginosa minimum inhibitory concentration for 90% of isolates in the adolescent cohort.

In general, aztreonam concentrations in plasma were also highly variable, but simultaneously, systemic concentrations were noted to be low. One hour following a single dose of Cayston 75 mg (at approximately peak plasma concentration), the mean plasma level in patients with cystic fibrosis was 0.59 μg/mL (range: 0-2.92 μg/mL). Mean peak plasma levels for Cayston 75 mg dosing three times daily (TID) at Days 0, 14, and 28 were 0.55 µg/mL (range: 0-1.62 µg/mL), 0.67 µg/mL (range: 0.01-1.66 µg/mL), and 0.65 µg/mL (range: 0-1.74 µg/mL), respectively showing no evidence of accumulation over 28 days of dosing.

Distribution

Local and systemic tissue distribution following exposure to Cayston has not been clinically characterized.

Metabolism

Cayston is not extensively metabolized. The principal metabolite is microbiologically inactive.

Excretion

Systemic clearance of Cayston occurs primarily by renal excretion and it remains relatively unchanged. Only a small quantity of the drug and metabolites are excreted in the faeces.

Drug Interactions

Certain antibiotics [for example (e.g.) cefoxitin and imipenem] may induce high levels of beta-lactamase in vitro in some gram-negative aerobes such as Enterobacter and Pseudomonas species, resulting in antagonism to many beta-lactam antibiotics including Cayston. These in vitro findings suggest that such beta-lactamase inducing antibiotics should not be used concurrently with Cayston.

Special Populations

Geriatrics (>65 years of age)

Clinical studies with Cayston did not include sufficient numbers of patients ≥65 years of age to determine whether they responded differently from younger patients.

Pediatrics (<18 years of age)

Safety and efficacy have not been studied in patients under the age of 6 years old.

Pregnant and nursing women

No adequate and well-controlled studies of Cayston have been conducted in pregnant women for ethical reasons. In addition, the safety of Cayston in breast-feeding women has not been established.

Renal Impairment

Given systemic clearance of Cayston occurs primarily by renal excretion, caution should be taken when administering Cayston to patients with renal impairment.

Hepatic Impairment

There is no data on the use of Cayston in patients with severe hepatic impairment (defined as alanine aminotransferase or aspartate aminotransferase levels greater than 5 times the upper limit of normal).

3.3.3 Clinical Efficacy

Two pivotal studies (AIR-CF1 and AIR-CF2) were conducted to evaluate the efficacy of Cayston in patients with cystic fibrosis who had P. aeruginosa infections. Both clinical studies were randomized, double-blind, placebo-controlled, multicentre Phase III studies. In both studies, cystic fibrosis patients received one course (28 days) of inhalation treatment with either Cayston 75 mg or a volume-matched placebo.

AIR-CF1 study enrolled 164 patients and randomized them in a 1:1 ratio to receive either inhaled Cayston 75 mg TID or volume-matched placebo TID for 28 days. Patients were required to have been off antibiotics for at least 28 days prior to receiving treatment with either Cayston or placebo. The primary efficacy endpoint was improvement in respiratory symptoms as measured by the Respiratory Symptoms scale of the Cystic Fibrosis Questionnaire - Revised (CFQ-R). Results from the study showed a clear clinical and statistical advantage in favour of patients treated with Cayston over placebo both at 14 and 28 days of treatment.

Study AIR-CF2 was designed to assess the safety and efficacy of Cayston 75 mg and its ability to maintain or improve clinical status in cystic fibrosis patients with pulmonary P. aeruginosa following a 28-day treatment. In this study, patients had extensive prior antibiotic therapy and were treated with a course of tobramycin inhalation solution (TOBI^®) prior to receiving Cayston or placebo inhalation treatment. A total of 211 patients were randomized in a 2:2:1:1 ratio to receive either inhaled Cayston 75 mg (BID or TID) or a volume-matched placebo (BID or TID) for 28 days. Following completion of the 28-day course of therapy, patients were followed for up to 56 days. The primary efficacy endpoint was time to need for inhaled or intravenous administration of antipseudomonal antibiotics with documented symptom(s) predictive of pulmonary exacerbation. Results from the pooled Cayston groups indicate that treatment with Cayston 75 mg (administered BID or TID) resulted in improved outcomes for patients with cystic fibrosis both clinically and statistically; however, the data did not show a clear difference between the Cayston 75 mg BID and TID groups, given the responses were similar and no dose-response was observed.

Given that both AIR-CF1 and AIR-CF2 study data were limited to one treatment period, an additional study AIR-CF3 was designed to assess longer-term efficacy and safety of Cayston over multiple courses of treatment. Study AIR-CF3 was an open-label, follow-on, Phase III study evaluating the safety of repeated exposure to Cayston and its effects on several disease-related endpoints (e.g. lung function, symptom reduction, and P. aeruginosa colony-forming units). Patients who completed either AIR-CF1 or AIR-CF2 were eligible to subsequently participate in the follow-on AIR-CF3 study. A total of 111 patients from the AIR-CF1 study enrolled in the open-label study and received Cayston 75 mg on the same TID regimen. A total of 163 patients from the AIR-CF2 study also enrolled in the open-label study and received Cayston 75 mg in the same regimen to which they were formerly randomized (either BID or TID). Each treatment course consisted of 28 days on treatment with Cayston followed by 28 days off treatment. Patients could receive up to nine courses of treatment. Results from the study showed a significant clinical benefit for patients receiving Cayston TID. In addition, improvement in cystic fibrosis disease-related endpoints, particularly lung function, patient-reported CFQ-R respiratory symptoms score, and reduction in P. aeruginosa colony-forming units was noted. For each of these endpoints patients showed mean improvement compared with the previous visit at the end of each treatment course, with a return toward baseline at the end of each off-treatment interval.

Although no dose-response was shown for Cayston administered BID versus TID in the AIR-CF2 study, there was a dose-response observed in the open-label AIR-CF3 study. In the AIR-CF3 study there was an apparent dose-response with Cayston for improvement in lung function, with a greater mean percent increase from Visit 1 in FEV₁ observed following eight of the nine treatment courses in the TID regimen than in the BID regimen. In both regimens, patients showed mean improvement from baseline at the end of each treatment course, with a return toward baseline at the end of the off-treatment intervals. A dose-dependent reduction in log₁₀ P. aeruginosa CFUs in sputum between BID and TID regimens was observed following on-treatment intervals. Log₁₀ P. aeruginosa CFUs in sputum decreased from Visit 1 over each of the nine treatment courses for both the BID and TID regimens. Log₁₀ P. aeruginosa CFUs generally decreased from the start of each course to the end of each course, and the decrease in log₁₀ P. aeruginosa CFUs was generally larger in TID-treated than BID-treated patients. During the off-treatment intervals, log₁₀P. aeruginosa CFUs increased between visits; these increases were generally slightly higher for the TID regimen compared with the BID regimen, which is consistent with the larger decreases observed following Cayston TID therapy. Finally, the mean change in CFQ-R Respiratory symptoms score from Visit 1 was greater at the end of each of the nine treatment courses in the TID regimen compared to the BID regimen. In both regimens, patients showed mean improvement compared with the previous visit at the end of each treatment course, with a return toward baseline at the end of each off-treatment interval.

3.3.4 Clinical Safety

The clinical safety of Cayston was evaluated primarily from two pivotal studies (AIR-CF1 and AIR-CF2) described in the 3.3.3 Clinical Efficacy section. However, also consulted was safety data from the following studies: a Phase 2 (CP-AI-003) study, AIR-CF3 and four studies ongoing at the time of NDS review (EA-US-205-0111, GS-US-205-0117, GS-US-205-0110, EA-US-205-0122).

In general, Cayston was well-tolerated with an adverse event profile consistent with the signs and symptoms of the patients' underlying condition, cystic fibrosis. Pooled safety data results from the completed studies revealed the main adverse events (AEs) observed during the clinical development of Cayston were respiratory in nature. Furthermore, most serious adverse events (SAEs) were associated with hospitalizations for pulmonary exacerbations.

No patients died during the placebo-controlled studies; however, one patient died in the AIR-CF3 study. The events which led to this patient's death included a massive hemoptysis and cardiac arrest; the investigator did not believe the death was attributable to Cayston administration.

Most study discontinuations due to AEs were associated with signs and symptoms of pulmonary exacerbations, and most of the associated AEs were considered by the investigator to be unrelated to Cayston administration.

No severe allergic reactions [e.g. anaphylactic reactions (defined as cardiovascular and/or respiratory compromise)] have been reported during the clinical development program for Cayston. Three of the 411 patients who received at least one dose of Cayston were discontinued from study due to possible allergic reactions. Of these three patients, one patient had a pre-existing allergy to beta-lactams; although not re-challenged with Cayston, this patient experienced a rash that reflects a probable allergic reaction.

A controlled study, GS-US-205-0110 (TOBI^® versus Cayston) is currently underway in Europe and the United States and the randomized portion of the study should be complete in the third quarter of 2010. This study will include three courses of therapy comparing Cayston to TOBI^®, and will include efficacy, safety and microbiology data for that period. After the initial three courses of therapy the two arms will continue on Cayston therapy for another three courses.

3.3.5 Additional Issues

Demonstration of long-term safety and efficacy of Cayston is limited to uncontrolled, open-label clinical trial data obtained over nine cycles of therapy. Given cystic fibrosis is a chronic condition; Cayston would be used over repeated cycles of therapy. Additional data is therefore required to confirm the clinical benefit, efficacy and safety of Cayston. Under the Notice of Compliance with Conditions (NOC/c) policy, the sponsor is required to submit the following data:

• The final clinical study report from the open-label, controlled, randomized trial GS-US-205-0110, summarizing Cayston efficacy, safety, and microbiology data over the complete 12-month study period. This data is required to confirm the long-term efficacy and safety of Cayston (aztreonam for inhalation solution) in the management of cystic fibrosis patients with chronic pulmonary P. aeruginosa infection. Availability of the 12-month data is anticipated by the first quarter of 2011. Upon satisfactory review of these results the NOC/c will be converted to a NOC without commitments.
• A summary of all available safety data from the expanded access program, including studies EA-US-205-0111 and EA-US-205-0122.
• Periodic Safety Update Reports (PSUR-Cs) should be provided every 12 months and up to submission of final safety and efficacy data from the above named studies. PSURs should be prepared in accordance with ICH Guidelines and should include events reported for Cayston (aztreonam for inhalation solution).