Study to Evaluate Arikayce™ in CF Patients With Chronic Pseudomonas Aeruginosa Infections

Randomized, Open-Label, Active-Controlled, Multicenter Study to Assess the Efficacy, Safety and Tolerability of Arikayce™ in Cystic Fibrosis Patients With Chronic Infection Due to Pseudomonas Aeruginosa

A major factor in the respiratory health of Cystic Fibrosis (CF) participants is the prevalence of chronic Pseudomonas aeruginosa (Pa) infections. The Pa infection rate in CF patients increases with age and by age 18 years approximately 85% of CF patients in the US are infected. Liposomal amikacin for inhalation (Arikayce™) was developed as a possible treatment for chronic infection due to Pa in CF patients. The purpose of this study is to determine whether Arikayce™ is effective in treating chronic lung infections caused by Pa in CF participants. The effectiveness, safety, and tolerability of Arikayce™ will be compared to Tobramycin TOBI®, an inhalation antibiotic already available for use.

CF is a genetic disease resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Patients with CF manifest pathological changes in a variety of organs that express CFTR. The lungs are frequently affected often resulting in chronic infections by bacteria such as Pseudomonas aeruginosa and airway inflammation. Treatment of chronic lung infections is one of the principal goals of CF therapy. Arikayce™ LAI (liposomal amikacin for inhalation) is a sustained-release formulation of amikacin encapsulated inside nanoscale liposomal carriers designed for administration via inhalation. It is hypothesized that the sustained-release pulmonary targeting and biofilm penetration properties of this formulation will have several advantages over current therapies in treating CF patients with chronic lung infection caused by Pseudomonas aeruginosa. This Phase 3 study has been designed to evaluate the efficacy, safety and tolerability of Arikayce™ in treating CF patients with chronic bronchopulmonary infection compared to a currently available antibiotic, TOBI® Inhalation Solution. Eligible participants will be randomized 1:1 to receive 590 mg of Arikayce™ once daily via a PARI Investigational eFlow® Nebulizer or 300 mg TOBI® BID via a PARI LC® PLUS nebulizer. Participants will receive 3 cycles of treatment with each cycle being comprised of 28 days on treatment followed by 28 days off-treatment. Total study duration is up to 186 days (~6 months) including an up to 18 day Screening period. Participants will be evaluated for safety, tolerability and efficacy bi-weekly during the first 4 weeks of treatment, and thereafter every 4 weeks for the duration of the study. Pharmacokinetics (PK) of Arikayce™ in blood, sputum and 24-hour urine will be determined in a subgroup of study participants who consent to PK evaluation. At the completion of the TR02-108 protocol, participants who have consented and meet study safety criteria may enroll in the long-term, open-label, multi-cycle extension study of 590 mg of Arikayce™ (under a separate protocol TR02-110). 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.

Cystic Fibrosis, Respiratory Infections, Pulmonary Cystic Fibrosis, CFTR, Amikacin, Anti-bacterial Agents, Amikacin liposome inhalation suspension (ALIS)

Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. liposomal amikacin for inhalation will be administered for 3 cycles where each cycle consists of 28 days on-treatment followed by 28 days off-treatment.

300 mg tobramycin inhalation solution is administered twice a day using a PARI LC® Plus nebulizer. Nebulization time is approximately 20 minutes for each administration. Tobramycin inhalation solution will be administered for 3 cycles where each cycle consists of 28 days on-treatment followed by 28 days off-treatment

Number of participants experiencing a pulmonary exacerbation measured by number with event and number censored

Number of participants to first antipseudomonal antibiotic treatment for pulmonary exacerbation measured by number with event and number censored

Number of participants to first all cause hospitalization measured by number with event and number censored

Quality of Life was measured by the absolute change from baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory scale. Disease specific instrument designed to measure impact on overall health, daily life, perceived well-being and symptoms in patients with a diagnosis of cystic fibrosis. Scores range from 0 to 100, with higher scores indicating better health. Scores for each Health Related Quality of Life (HRQoL) domain; after recoding, each item is summed to generate a domain score and standardized.

Key Inclusion Criteria: Written informed consent or assent Confirmed diagnosis of CF History of chronic infection with Pseudomonas aeruginosa Sputum culture positive for Pseudomonas aeruginosa at Screening FEV1 ≥ 25% of predicted value at Screening Key Exclusion Criteria: FEV1 <25% of predicted at Screening History of major complications of lung disease within 8 weeks prior to Screening Hemoptysis of ≥60 mL in a 24-hour period within 4 weeks prior to Screening History of positive culture for Burkholderia cepacia within 2 years prior to Screening History of pulmonary tuberculosis or non-tuberculous mycobacterial lung disease treated within 2 years prior to Screening or requiring treatment at the time of screening History of Allergic Broncho-Pulmonary Aspergillosis or any other condition requiring systemic steroids at a dose ≥ equivalent of 10 mg/day of prednisone within 3 months prior to Screening Presence of any clinically significant cardiac disease History of lung transplantation Daily, continuous oxygen supplementation or nighttime supplemental oxygen requirement of greater than 2 L/min Administration of any investigational products within 8 weeks prior to study Day 1 Smoking tobacco or any substance within 6 months prior to screening or anticipated inability to refrain from smoking throughout the study

Bilton D, Pressler T, Fajac I, Clancy JP, Sands D, Minic P, Cipolli M, Galeva I, Sole A, Quittner AL, Liu K, McGinnis JP 2nd, Eagle G, Gupta R, Konstan MW; CLEAR-108 Study Group. Amikacin liposome inhalation suspension for chronic Pseudomonas aeruginosa infection in cystic fibrosis. J Cyst Fibros. 2020 Mar;19(2):284-291. doi: 10.1016/j.jcf.2019.08.001. Epub 2019 Aug 23.