Amikacin Eases MAC Lung Disease in First-Line Treatment

Amikacin liposome inhalation suspension (ALIS) improved symptoms and infection clearance in treatment-naive Mycobacterium avium complex (MAC) lung disease, the ENCORE trial showed.

For the primary endpoint, the aminoglycoside antibacterial improved respiratory symptom score by 3.11 more points on the 100-point scale than did placebo, which was statistically significant albeit modest (mean change 17.77 vs 14.66 from baseline to month 13, P=0.0299). More than half of the ALIS group met the minimal clinical important difference of 16.67.

Three months after the end of treatment, the difference had widened to 4.80 points (P=0.0015), Charles L. Daley, MD, of National Jewish Health and the University of Colorado School of Medicine in Denver, reported at the American Thoracic Society annual meeting in Orlando.

The findings could expand use from the current indication as part of a multi-drug regimen for adults with limited or no alternative treatment options for refractory MAC lung disease.

“I think all of our views are that this is a drug that clearly works. It’s been shown now in multiple trials in both refractory and now treatment naive. So I would like to give it if I can,” even if it takes a dose reduction for some patients, Daley said.

“There are a lot of gaps that exist in our evidence base and the best ways to treat MAC, particularly in terms of achieving durable culture conversion, improving symptoms in our patients,” he added, “If you look at guideline-based therapy now, the best we can do is about 60% treatment success — obviously suboptimal.”

However, culture conversion rates in ENCORE also favored ALIS at every time point from 2 months through month 15. Durable conversion at that final time point was 28.6 percentage points higher with ALIS (76.2% vs 47.6%, P<0.0001).

The trial enrolled 425 adults in 22 countries who had been newly diagnosed with MAC lung disease within 6 months prior to screening and had not initiated antibiotics at baseline. They were randomly assigned to 12 months of treatment with the combination of azithromycin (250 mg) and ethambutol (15 mg/kg) with either ALIS (590 mg) or an empty liposome control placebo once daily.

Patients were assessed for the primary endpoint at 1 month after the end of treatment and for the key secondary endpoint at 3 months off treatment. More than 90% of patients in both groups completed the study. Average age was around 68, and around 80% of participants were women. North America accounted for a quarter of participants. Respiratory symptom score at baseline averaged around 62.

It was the first MAC lung infection for 82% of participants. More than half had bronchiectasis, and 13% had asthma. Exclusion criteria included active smoking, cystic fibrosis, lung transplant, active malignancy in treatment, and lung cavities of 2 cm or larger in diameter.

Culture positivity was tested at every visit, with conversion defined by no MAC growth on either agar or broth media in all sputum cultures at two consecutive visits (eight total samples), which Daley called a “high bar.” Ability to produce sputum (spontaneously or with induction) was required for enrollment.

No new or unexpected safety signals emerged, and treatment-emergent adverse events were similar between groups. Dysphonia and cough were markedly more common with ALIS than the control group (58.7% vs 8.5% and 32.9% vs 14.6%, respectively). Ototoxicity was fairly similar with ALIS as the comparator (25.8% vs 22.6%), but bronchospasm was more common (23.0% vs 11.8%).

Daley noted five cases of hypersensitivity pneumonitis with ALIS and none in the comparator arm, “which is interesting because they did get a liposomal comparator that they inhaled.” Two were hospitalized and recovered after treatment with steroids, and the rest had cases discovered incidentally or noted at the end of therapy and “did fine.”

When asked by a member of the audience about immediately switching to this new regimen for patients with MAC lung infection, Daley said, “I personally see no reason not to do that. The only reason will be the same reason we struggle. It will be insurance and whether or not they’re willing to pay.”

He acknowledged that such use would be off-label, with its indication only for refractory disease. “We need to review these data and decide in terms of should they alter our guideline recommendations and should we be implementing this now in practice,” he said.

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