ENCORE: ARIKAYCE Meets End Points, Improves Respiration in MAC Lung Disease

Insmed announced today that the phase 3b ENCORE study of amikacin liposome inhalation suspension (Arikayce) plus guideline-based multidrug therapy met its primary endpoint and all multiplicity-controlled secondary culture conversion endpoints in patients with a new occurrence of Mycobacterium avium complex (MAC) lung infection who had not previously received antibiotics.¹

The results fulfill a United States Food and Drug Administration (FDA) post-marketing requirement and position Insmed to file a supplemental new drug application (sNDA) in the second half of 2026, seeking both label expansion into antibiotic-naïve MAC lung disease and conversion of the drug's existing accelerated approval for refractory MAC lung disease to traditional approval. A parallel submission to Japan's Pharmaceuticals and Medical Devices Agency (PMDA) is also planned.¹

ENCORE Trial Design

ENCORE was a randomized, double-blind, placebo-controlled study enrolling 425 patients at 177 sites globally. Patients were randomized 1:1 to receive once-daily amikacin liposome inhalation suspension 590 mg plus multidrug therapy (azithromycin 250 mg plus ethambutol 15 mg/kg) or inhaled placebo plus the same multidrug backbone for 12 months, followed by a 3-month treatment-free observation period for assessment of culture conversion durability. The enrolled population was predominantly treatment-naïve: 82.4% were experiencing their first MAC infection, while 17.6% had a second or third occurrence.¹

The primary endpoint was change from baseline in Respiratory Symptom Score at Month 13, derived from 8 items in the Quality of Life–Bronchiectasis (QoL-B) Respiratory Domain. Multiplicity-controlled secondary endpoints included culture conversion rates at months 6, 12, and 13; durable culture conversion at month 15; and change from baseline in PROMIS Fatigue T-score at month 13. A Japan-specific primary endpoint required achievement of both culture conversion by month 6 and durable culture conversion at month 15.¹

Efficacy Results

The primary endpoint was met. Patients receiving amikacin liposome inhalation suspension achieved a 17.77-point improvement from baseline in Respiratory Symptom Score at month 13 versus 14.66 points in the placebo arm, a treatment difference of 3.11 points (P =.0299).¹

All four multiplicity-controlled culture conversion endpoints were met with high statistical significance. Culture conversion by month 6 was achieved in 87.8% of amikacin liposome inhalation suspension-treated patients versus 57.0% of those receiving placebo — a difference of 30.8 percentage points (P <.0001). Rates remained substantially higher in the amikacin liposome inhalation suspension arm at months 12 (84.7% vs 61.3%; difference 23.3%; P <.0001) and 13 (82.4% vs 55.6%; difference 26.8%; P <.0001). Durable culture conversion at month 15, assessed after treatment discontinuation, was achieved in 76.2% of amikacin liposome inhalation suspension patients compared to 47.6% in the placebo arm (difference 28.6%; P <.0001).¹

The PROMIS Fatigue T-score endpoint did not reach statistical significance (-5.07 vs -4.27; difference -0.81; P =.2900).¹

Safety

The overall safety profile was consistent with amikacin liposome inhalation suspension established label. Treatment-emergent adverse events (TEAEs) occurred in 98.1% of patients in the amikacin liposome inhalation suspension arm and 97.2% in the placebo arm, reflecting the serious underlying disease and the active multidrug backbone in both groups.¹ Severe TEAEs were observed in 15.0% and 10.4% of patients respectively, and serious TEAEs in 14.1% versus 11.3%. One death occurred in each treatment arm; neither was considered related to study treatment.¹

TEAEs occurring in ≥10% of patients and at higher rates in the amikacin liposome inhalation suspension arm included dysphonia (58.7% vs 8.5%), cough (32.9% vs 14.6%), fatigue (17.4% vs 11.3%), dyspnea (16.4% vs 5.7%), nausea (15.5% vs 12.7%), and headache (12.7% vs 11.8%).¹ The treatment discontinuation rate was 18.3% in the amikacin liposome inhalation suspension arm versus 11.8% in the placebo arm; study completion rates exceeded 90% in both groups (90.6% vs 93.4%).¹

Among AEs of special interest, bronchospasm (23.0% vs 11.8%) and hypersensitivity pneumonitis (2.3% vs 0%) occurred at notably higher rates with amikacin liposome inhalation suspension. In contrast, ototoxicity rates were comparable between arms (25.8% vs 22.6%), as were rates of pulmonary disease exacerbation (10.8% vs 9.9%), hemoptysis (10.3% vs 10.4%), neuromuscular disorders (2.3% vs 2.8%), and nephrotoxicity (0.5% vs 0%).¹

Clinical Significance

Amikacin liposome inhalation suspension currently holds accelerated approval in the US for adults with limited or no treatment alternatives who have refractory MAC lung disease — defined as failure to achieve culture negativity after at least 6 consecutive months of multidrug background therapy. That indication was granted on the basis of culture conversion data and carries a confirmatory trial requirement; ENCORE is the study intended to satisfy it.¹

The ENCORE population is meaningfully different from the refractory population in which ARIKAYCE was originally studied. Enrolling antibiotic-naïve patients with a new MAC infection represents an earlier, broader, and potentially larger patient population. MAC lung disease affects an estimated tens of thousands of patients in the US, predominantly women and older adults, with an increasing incidence particularly among those with bronchiectasis or other structural lung disease. Treatment is prolonged, culture conversion rates with guideline-based multidrug therapy alone are suboptimal, and relapse after apparent cure is common — all of which underscore the clinical significance of a 30-percentage-point improvement in culture conversion at month 6 and durable conversion rates exceeding 76% at month 15.

The multidrug regimen used in ENCORE — azithromycin plus ethambutol — reflects current guideline-recommended first-line therapy for MAC lung disease. Per the 2020 ATS/ERS/ESCMID/IDSA joint treatment guideline, macrolide-based combination therapy is the cornerstone of MAC management, with treatment continuing for at least 12 months following culture negativity.² Culture conversion rates with background multidrug therapy alone, however, remain suboptimal in clinical practice — a gap the ENCORE placebo arm's 57% conversion rate at month 6 reflects directly.

"These groundbreaking results show that patients may have significant clinical benefit from including ARIKAYCE as part of their multidrug treatment earlier in their MAC lung disease journey," said David Griffith, MD, ENCORE Steering Committee Member and Professor of Medicine at National Jewish Health. "The improvements in Respiratory Symptom Score alongside durable culture conversion highlight the potential for this medicine to make a substantial difference in outcomes for patients facing this serious and often progressive infection."¹

Insmed plans to present full ENCORE data at a future medical congress. The sNDA filing is anticipated in the second half of 2026, with the PMDA submission planned on the same timeline.¹

References

1. Insmed Announces Positive Topline Results from Phase 3b ENCORE Study of ARIKAYCE® (Amikacin Liposome Inhalation Suspension) in Patients with MAC Lung Disease. News release. Insmed Incorporated. March 23, 2026. https://investor.insmed.com/2026-03-23-Insmed-Announces-Positive-Topline-Results-from-Phase-3b-ENCORE-Study-of-ARIKAYCE-R-Amikacin-Liposome-Inhalation-Suspension-in-Patients-with-MAC-Lung-Disease

2. Daley CL, Iaccarino JM, Lange C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J. 2020;56(1):2000535. doi:10.1183/13993003.00535-2020