A82-02 Amikacin Liposome Inhalation Suspension For Newly Diagnosed Mycobacterium Avium Complex Lung Disease: Efficacy And Safety From A Phase 3b Study (ENCORE)

Rationale

Mycobacterium avium complex lung disease (MACLD), the leading cause of nontuberculous mycobacterial lung disease, is a chronic infection with high symptom burden, lung function decline, impaired quality of life, and a 5-year all-cause mortality rate up to 42%. A substantial proportion of patients who receive multidrug therapy do not achieve treatment success. The optimal drugs, regimens, and recommended duration of therapy for treatment of MACLD have not been evaluated in specifically designed clinical studies. Amikacin liposome inhalation suspension (ALIS) has previously demonstrated efficacy in patients with refractory MACLD (NCT02344004 [CONVERT]). In a 6-month prospective study to validate patient-reported outcome measures (Quality of Life-Bronchiectasis Respiratory Domain [QOL-B RD] and Patient-Reported Outcomes Measurement Information System Short Form v1.0-Fatigue 7a [PROMIS F SF-7a] in patients with newly diagnosed MACLD (NCT04677543 [ARISE]), ALIS demonstrated a positive trend in multiple secondary efficacy endpoints. A large, statistically powered randomized controlled trial (RCT) to evaluate efficacy is necessary to understand the role of ALIS in this patient population. Additionally, most studies in MACLD have focused on microbiologic endpoints such as culture conversion, but there is limited experience with validated, patient-reported outcome tools as primary endpoints in this population. ENCORE (NCT04677569) is a global, phase 3b, randomized, double-blind, multicenter, placebo-controlled trial designed to evaluate the efficacy and safety of ALIS plus azithromycin and ethambutol against an active comparator (empty liposome control [ELC] plus azithromycin and ethambutol) in adults with a new occurrence of MAC lung infection who have not received antibiotics (Figure).

Study Design

Adults with a current diagnosis of noncavitary MACLD, documented respiratory symptoms attributable to current MAC lung infection (average QOL-B RD score ≤85), and 2 positive sputum cultures (1 prior to and 1 at screening) were enrolled. Patients who had received antimycobacterial treatment for their current MAC lung infection were excluded. Eligible patients were randomized 1:1 to receive once-daily ALIS 590 mg or ELC plus azithromycin 250 mg and ethambutol 15 mg/kg for 12 months. Randomization was stratified by region and history of MAC lung infection (initial or subsequent). After stopping study drugs at month 12, patients were followed for 3 months off treatment. Efficacy endpoints will be analyzed hierarchically. The primary endpoint is change from baseline to month 13 in patient-reported respiratory symptom score (RSS; derived from QOL-B RD). Secondary efficacy endpoints are sputum culture conversion by month 13, durability of culture conversion at month 15, culture conversion by month 12, culture conversion by month 6, and change from baseline to month 13 in patient-reported fatigue symptoms (PROMIS SF-Fatigue 7a). Treatment-emergent safety data will be summarized from the day of the first dose to 28 days after discontinuation of ALIS or ELC.

Key Data

Primary, principal secondary, and safety endpoints will be presented.

Outcomes/Timeline

ENCORE is the first phase 3, double-blind, RCT to use a fully validated PRO tool to evaluate clinical treatment efficacy in the MACLD population along with microbiological outcomes. The last patient’s last visit has been completed, and topline data is expected in the March/April timeframe.

This abstract is funded by: