乌鸦传媒

SAN DIEGO -- Adding amikacin liposome inhalation suspension (ALIS; Arikayce) to a macrolide-based regimen appeared to reduce respiratory symptoms and improve culture conversion rates in patients with newly diagnosed or recurrent Mycobacterium avium complex (MAC) lung infections, the randomized ARISE trial showed.

As measured by the nine-item Quality of Life-Bronchiectasis Respiratory Domain (QOL-B RD), 43.8% of patients in the ALIS arm achieved a meaningful improvement in symptoms from baseline to 7 months, as compared with 33.3% of those assigned to the macrolide-based regimen plus placebo, reported Charles Daley, MD, of National Jewish Health and the University of Colorado School of Medicine in Denver.

Culture conversion rates were numerically higher in the ALIS arm both following the 6-month period of daily treatment (80.6% vs 63.9% P=0.071) and at 7 months, a month after stopping treatment (78.8% vs 47.1%, nominal P=0.001), according to findings presented here at the American Thoracic Society annual meeting.

The main goal of the ARISE study was to validate patient-reported-outcome (PRO) tools using modern psychometric methods for key symptoms of MAC lung disease -- with respiratory symptoms and fatigue previously established as the most prevalent and bothersome to patients.

"It turns out there's no currently validated fit-for purpose PRO instrument for people with MAC lung disease," said Daley. "The symptoms that are most important to our patients are covered in two instruments" -- the QOL-B RD and the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue 7a.

Daley's presentation focused on the validation of the QOL-B RD (against the Patient Global Impression of Severity-Respiratory scale); the impact of ALIS on patients' respiratory symptoms using the QOL-B RD; and microbiologic outcomes with ALIS as part of a macrolide-based regimen for this patient population.

The QOL-B RD is a self-administered questionnaire with nine items to assess sputum, coughing, congestion, wheezing, chest pain, and other symptoms -- with eight of the items scored on a Likert Scale (a lot, a moderate amount, a little, not at all) and the sputum question requiring a descriptive answer.

Each score is standardized on a 0-100 scale, with 100 indicating no symptoms. Ultimately a 14.8-point change in an individual patient was deemed to be a meaningful difference on the QOL-B RD, said Daley.

While the study was not powered to show a significant difference between arms, the least-squares mean change from baseline to 7 months on the QOL-B RD favored the ALIS arm (12.24 vs 7.76, P=0.1073).

Results of the ARISE trial are "a significant step toward an area of unmet need in patients with non-cavitary [MAC lung disease]," said Sarah Taimur, MD, of the Icahn School of Medicine at Mount Sinai in New York City, who was not involved in the study.

"It provides much-needed evidence for validation of a self-administered, patient-reported outcome measure that has been previously lacking in this patient population, and could serve as a critical tool that patients and their medical teams can use to gauge response to treatment," Taimur told 乌鸦传媒.

ALIS is currently approved only for patients with MAC lung infections that do not respond to traditional treatments; the validated QOL-B RD instrument will help support the evaluation of the inhaled therapy in an ongoing phase III registrational study () testing a macrolide-based regimen plus either ALIS versus placebo in patients with newly diagnosed or recurrent MAC lung infections who have not received antibiotics for their current infection.

Daley presented findings from (Validation of Patient-Reported Outcome Measures in Participants With Nontuberculous Mycobacterial Lung Infection Caused by Mycobacterium Avium Complex), which randomized 99 adults with newly diagnosed or recurrent MAC lung infections and non-cavitary disease who had not yet been treated with antibiotics for their current infection. Patients were enrolled at 76 sites across 15 countries, including the U.S.

All patients received azithromycin and ethambutol as their macrolide-based regimen and were randomized 1:1 to ALIS or an empty liposomal control (placebo) once daily for 6 months, followed by a month off of treatment for follow-up. All patients had a mean QOL-B RD score of 85 or less. Patients with mixed infections were allowed in the trial so long as MAC was the dominant species present.

Exclusion criteria included refractory or relapsed MAC infections, more than three previous MAC lung infections, prior ALIS exposure, a smoking history, and certain comorbidities (cystic fibrosis, prior lung transplant, active malignancy).

Participants had a median age of 67-72 years, three-fourths were women, and 81% were white. Most were enrolled from either North America (39%) or Europe (38%). Concurrent respiratory illnesses included bronchiectasis in 49%, asthma in 21%, chronic obstructive pulmonary disease in 16%, cough in 16%, and allergic rhinitis in 11%.

For 73% of the patients, this was their initial MAC infection. Overall, 32% had M. avium infections, 43% had M. intracellulare infections, and the rest had other or unspecified MAC infections.

Culture conversion was defined as no growth of MAC in sputum cultures on agar and broth media. Four sputum samples were collected from patients at each monthly visit during the study.

Patients in the ALIS arm achieved culture conversions a median 1 month earlier than those in the comparator arm. Overall, 12.8% of patients who achieved culture conversion in the ALIS arm experienced recurrence at any point in the study compared with 50% of those in the placebo arm. No patients in either group developed MAC isolates with resistance to ALIS.

Treatment-emergent adverse events (TEAEs) were reported in 92% of patients in the ALIS arm and 80% of those in the placebo arm, the most common of which included dysphonia (42% vs 4%, respectively), cough (27% vs 8%), diarrhea (27% vs 25%), and COVID-19 (13% vs 10%). Treatment discontinuation of ALIS specifically occurred in 19%, as compared with 6% with the placebo.

Serious TEAEs were reported in 15% of the ALIS arm and 6% of the comparator arm. No deaths were reported.

Adverse events of special interest included dizziness (4.2% in the ALIS arm vs 9.8% in the placebo arm), tinnitus (4.2% vs 7.8%, respectively), vertigo (4.2% vs 2%), deafness (2.1% vs 2%), dyspnea (10.4% vs 7.8%) or dyspnea on exertion (2.1% vs none), wheezing (6% vs none), hemoptysis (10.4% vs 5.9%), exacerbation of an underlying pulmonary disease (none vs 3.9%), and neuromuscular disorders (2% in each arm).