Insmed (NASDAQ:INSM) reported top-line results from its phase III ENCORE trial evaluating ARIKAYCE in adults with non-cavitary lung disease and a newly diagnosed or recurrent Mycobacterium avium complex (MAC) lung infection who had not yet begun antibiotics for their current infection. Company executives described the trial as a “clear success,” citing statistically significant benefits on patient-reported respiratory symptoms and multiple culture conversion endpoints, along with a safety profile consistent with prior experience.
Trial design and endpoints
Chief Medical Officer Martina Flammer said ENCORE enrolled 425 adult patients. Participants were randomized 1:1 to receive either:
- ARIKAYCE plus azithromycin and ethambutol, or
- an empty liposome placebo plus azithromycin and ethambutol.
Multiplicity-controlled secondary endpoints included culture conversion by month 13, durable culture conversion at month 15, culture conversion at months 12 and six (in that hierarchical order), and change from baseline in PROMIS Fatigue score at month 13. Randomization was stratified by geographic region and prior MAC history; Flammer said baseline characteristics were relatively balanced, though mean baseline RSS was modestly higher in the ARIKAYCE arm, with the primary analysis adjusting for baseline RSS and the stratification factors.
Primary endpoint: respiratory symptom improvement
Flammer reported that at month 13, patients receiving ARIKAYCE showed a least squares mean RSS improvement of 17.77 points versus 14.66 points in the control arm, a difference of 3.11 points that was statistically significant (p=0.0299).
She added that the symptom benefit widened after treatment ended: at month 15 (three months off treatment), the difference between arms increased to 4.8 points with a nominal p=0.0015, which the company characterized as highlighting durability. The company also discussed a responder analysis using covariate-adjusted cumulative distribution function (CDF) curves, stating the ARIKAYCE arm outperformed the comparator across a range of FDA-preferred “meaningful within-patient change” thresholds (16.67 to 20.83 points).
Culture conversion: earlier, higher, and more durable
Culture conversion was defined as two consecutive months of negative cultures for MAC. Durable culture conversion at month 15 required all cultures to be negative at months 11, 12, 13, and 15.
At month 13, the company reported culture conversion rates of 82.4% in the ARIKAYCE arm versus 55.6% in the active control arm, a difference of about 27 percentage points (p<0.0001). At month 15, durable culture conversion was 76.2% with ARIKAYCE versus 47.6% in the control arm, a separation of about 29 percentage points (p<0.0001). Flammer noted durable conversion is particularly important to Japanese regulators and many prescribers.
Insmed also said culture conversion at months 12 and six were highly statistically significant (each p<0.0001). Median time to culture conversion was month two in the ARIKAYCE arm (the first possible time point, requiring negative cultures at months one and two) versus month three in the comparator arm; the company reported a hazard ratio of 2.03 with a nominal p<0.0001.
Safety, discontinuations, and real-world considerations
Flammer said the tolerability profile in ENCORE was consistent with ARIKAYCE’s known safety profile, with no new or unexpected safety signals. The ARIKAYCE discontinuation rate was 18.3%, compared with 34.8% in the CONVERT study (refractory MAC) and 22.9% in the ARISE study (newly diagnosed). The empty liposome control discontinuation rate was 11.8%. The company said over 90% of patients in both arms completed the study.
Treatment-emergent adverse events were reported by 98.1% of patients on ARIKAYCE and 97.2% on control. Adverse events occurring in at least 10% of ARIKAYCE patients and more frequently than in control included dysphonia, cough, fatigue, dyspnea, nausea, and headache. Serious treatment-emergent adverse event rates were 14.1% (ARIKAYCE) and 11.3% (control).
In the Q&A, executives attributed lower discontinuation to increased familiarity with ARIKAYCE administration and improved patient education on managing respiratory side effects (such as gargling with warm water or dosing before bedtime). Flammer said dysphonia occurred in 50.7% of ARIKAYCE patients versus 8.5% of controls. Management also discussed the ENCORE background regimen, noting the trial used azithromycin and ethambutol without rifampin, which executives characterized as controversial in frontline practice due to safety concerns and variable perceived benefit.
Regulatory plans and label expansion expectations
Chief Executive Officer Will Lewis said Insmed plans to pursue regulatory submissions with the FDA and Japan’s PMDA in the second half of this year, anticipating an expanded label that would include all patients with MAC lung infection. Lewis also said the company expects the results to support conversion of ARIKAYCE’s current conditional U.S. approval to traditional approval, describing ENCORE as the study intended to fulfill the FDA’s post-marketing requirement.
On commercialization, executives reiterated that ARIKAYCE was originally priced for a broader label and said they do not anticipate changing the wholesale acquisition cost. Management also discussed patient support infrastructure, noting the company expects to extend its inLighten patient assistance program to a broader MAC population and estimating that about 60% of current ARIKAYCE patients are on Medicare, with out-of-pocket spending capped at $2,000 across medicines under the IRA.
About Insmed (NASDAQ:INSM)
Insmed Incorporated is a biopharmaceutical company focused on developing and commercializing therapies for patients with rare and serious diseases, with a particular emphasis on difficult-to-treat pulmonary infections. Headquartered in Bridgewater, New Jersey, the company concentrates its research and development efforts on targeted drug delivery technologies and novel formulations intended to improve clinical outcomes for patients who have limited treatment options.
The company’s principal marketed product is ARIKAYCE (amikacin liposome inhalation suspension), an inhaled liposomal formulation of the antibiotic amikacin that is approved by the U.S.
