Study of Dose Escalation of Liposomal Amikacin for Inhalation (ARIKAYCE™) - Extension Phase

A major factor in the respiratory health of cystic fibrosis (CF) patients is acquisition of chronic Pseudomonas (P.) aeruginosa infections. The infection rate with P. aeruginosa increases with age and by age 18 years, 80% of patients with CF in the U.S. are infected. Liposomal amikacin for inhalation (LAI; Arikayce™) is a sterile aqueous liposomal suspension consisting of amikacin sulfate encapsulated in liposomes. This formulation of amikacin maximizes the achievable dose and delivery to the lungs of infected patients when delivered via a nebulizer. Because liposome particles are small enough to penetrate and diffuse through sputum into the bacterial biofilm, they deposit drug close to the bacterial colonies (Meers, et al., 2008) (Clancy, et al., 2013), thus improving the bioavailability of amikacin at the infection site. The clinically achievable doses of amikacin in the LAI formulation can effectively increase the half-life of the drug in the lungs, and decrease the potential for systemic toxicity. LAI offers several advantages over current therapies in treating patients with CF with chronic infection caused by P. aeruginosa.

Cystic fibrosis (CF) is a genetic disease resulting from mutations in a 230 kb gene on chromosome 7 known as the cystic fibrosis transmembrane conductance regulator (CFTR). Patients with CF manifest pathological changes in a variety of organs that express CFTR. The lungs are frequently affected, the sequelae being chronic infections and airway inflammation. The principal goal of treatment of patients with CF is to slow the chronic deterioration of lung function.

This study is a Phase 2 study to evaluate the longer term safety, tolerability and efficacy of 560 mg once daily dose of Arikayce™ administered for 6 cycles over 18 months. Each cycle comprises 28 days of treatment followed by 56 days off treatment.

All study patients will receive study drug by inhalation via a PARI® eFlow nebulizer. All study patients will be followed for safety, pharmacokinetics (PK), clinical, and microbiologic activity for 28 days post completion of study treatment.

The original TR02-105 study was a Phase 2a study of safety and tolerability of 28 days of daily dosing of two dose cohorts (280 mg and 560 mg) of Arikayce™ versus placebo. Study subjects were randomized to receive either study drug or placebo (1.5% NaCl) by inhalation via a PARI® eFlow nebulizer. Cohort 1 (280 mg) completed 28 days of daily dosing with Arikayce™ and 14-day post-dosing safety evaluation by the Safety Committee before initiation of enrollment in Cohort 2 (560 mg). Cohort 2 completed 28 days of daily dosing, and a 14-day post-dosing safety assessment by the Data Safety and Monitoring Board (DSMB) to evaluate safety data. All study patients were followed for safety, PK and clinical and microbiologic activity for 28 days post completion of study treatment. Details of the original study are provided at ClinicalTrials.gov ID NCT00777296.

DSMB has recommended the amendment of the main study to evaluate safety and efficacy of additional cycles of treatment with Arikayce™. All patients who were randomized in the main study, were compliant with the study protocol, and continue meeting study eligibility criteria can be consented to participate in the open-label extension to evaluate the safety, tolerability, and efficacy of 560 mg once daily dose of Arikayce™ administered for 6 cycles over 18 months. Each cycle comprises 28 days of treatment followed by 56 days off treatment.

Clinical laboratory parameters, audiology testing, clinical adverse events and pulmonary function will be evaluated for all study subjects in order to determine the longer term safety, tolerability, and efficacy of Arikayce™. Serum specimens will be collected at periodic intervals to assess PK for safety. Additionally, sputum samples will be collected to determine changes in bacterial density. Pulmonary function testing and Cystic Fibrosis Questionnaire-Revised (CFQ-R) measurements will be assessed at selected time points throughout the study. Arikace™, Arikayce™, Liposomal Amikacin for Inhalation (LAI), and Amikacin Liposome Inhalation Suspension (ALIS) may be used interchangeably throughout this study and other studies evaluating amikacin liposome inhalation suspension.

Eligibility Criteria:
Inclusion Criteria:

1. Written informed consent obtained from the patient or designated legal guardian prior to the performance of any study related procedures.
2. Male or female study subjects ≥ 6 years of age or older.
3. Confirmed diagnosis of CF defined as a positive sweat chloride \> 60 milliequivalents (mEq)/liter (by pilocarpine iontophoresis) and/or a genotype with 2 identifiable mutations consistent with CF accompanied by one or more clinical features of the CF phenotype.
4. History of chronic infection with P. aeruginosa (defined as 3 documented positive cultures in the prior 2 years of which at least one was obtained in the 3 months prior to randomization). The cultures could be obtained from the following respiratory secretions: sputum, throat swabs, nasopharyngeal swabs, or broncho-alveolar lavage fluid specimens.
5. Study subjects must produce a screening specimen (expectorated or induced sputum, throat swabs, nasopharyngeal swabs, or broncho-alveolar lavage fluid) that is positive for growth of P. aeruginosa.
6. FEV1 ≥ 40% of predicted at Screening.
7. SaO2 ≥ 90% at Screening while breathing room air.
8. Ability to comply with study medication use, study visits, and study procedures as judged by the investigator.
9. Ability to produce 0.5 grams sputum or be willing to undergo an induction to produce sputum for clinical evaluation.
10. Clinically stable with no evidence of acute upper or lower respiratory tract infection or history of pulmonary exacerbation within the 4 weeks prior to Screening.

Main criteria for inclusion of patients participating in the 18-month extension period:

1. Written informed consent obtained from the patient or designated legal guardian prior to the performance of any study-related procedures in the extension period.
2. Patient meets all of the above listed inclusion criteria (1-10) of the main protocol.

Exclusion Criteria:

1. Administration of any investigational drug within 8 weeks prior to Screening.
2. Emergency room visit or hospitalization for CF or respiratory-related illness within the 4 weeks prior to Screening.
3. History of alcohol, medication, or illicit drug abuse within the 1 year prior to Screening.
4. History of lung transplantation.
5. Female of childbearing potential who is lactating or is not practicing an acceptable method of birth control (e.g., abstinence, hormonal or barrier methods, partner sterilization, or IUD).
6. Positive pregnancy test. All women of childbearing potential will be tested.
7. Use of any anti-pseudomonal antibiotics (IV antibiotics, all inhalation antibiotics, oral fluoroquinolones) within the 28 days prior to Screening.
8. Initiation of chronic therapy (i.e. TOBI®, high-dose ibuprofen, rhDNase, macrolide antibiotics) within the 28 days prior to Screening.
9. History of sputum or throat swab culture yielding Burkholderia cepacia within 2 years of Screening.
10. History of mycobacterial and/or Aspergillus infection requiring treatment within 2 years prior to Screening, and/or history of allergic bronchopulmonary aspergillosis (ABPA).
11. History of biliary cirrhosis with portal hypertension, or splenomegaly (refer to study manual).
12. GGT, AST, or ALT ≥ 3 times the upper limit of normal at Screening visit.
13. ANC ≤ 1000 performed at Screening visit.
14. Serum creatinine \> 1.5 times normal performed at Screening visit.
15. History of daily, continuous oxygen supplementation or requirement for more than 2 L/min at night.
16. Change in chest x-ray at Screening (or within the 3 months prior to Screening) with new onset infiltrates or that which compromise the safety of the study patient or the quality of the study data.

Main criteria for exclusion of patients participating in the 18 months extension period:

1. Patient meets any criteria for exclusion as listed above in the main protocol.
2. Patient who met any criteria for study drug discontinuation in the main protocol (TR02-105).