Amikacin liposome inhalation suspension (ALIS) showed the same efficacy and similar safety profile as tobramycin inhalation solution (TIS) for the treatment of cystic fibrosis (CF) patients with Pseudomonas aeruginosa lung infection, a comparative clinical study showed.
CF patients often have chronic P. aeruginosa lung infections. These bacteria infect approximately 30% of CF patients ages 6–10, and 60% of CF patients ages 18–24. Compared to other CF pathogens, P. aeruginosa is difficult to eradicate and can lead to clinical decline.
One of the current approaches for treating P. aeruginosa infection is the inhaled antibiotic tobramycin. Tobramycin inhalation solution (TIS) can reduce the levels of bacteria, and therefore improve clinical outcomes.
However, inhaled antibiotics have limited efficacy because of poor penetration into the infected areas. Furthermore, some CF patients don’t respond to TIS treatment, or do not tolerate it well. For these patients, alternative antibiotic treatments are necessary to manage P. aeruginosa infections.
ALIS, an antibiotic manufactured by Insmed under the name Arikayce, is composed of small spherical sacs of phospholipid molecules (liposome) that contain the antibiotic amikacin. This formulation helps amikacin penetrate thick mucus and deliver higher doses of the antibiotic to the lungs.
A Phase 3 clinical trial named CLEAR-108 (NCT01315678) was initiated to compare the effectiveness and safety of ALIS and TIS therapies to manage P. aeruginosa infections in CF patients.
In total, 294 CF patients infected with P. aeruginosa were analyzed. These patients were age 6 and up (mean age 22.4 years), and had stopped using inhaled antibiotics for 28 days prior to the study.
Patients were divided into two groups, randomly selected to take either one daily 590-mg dose of ALIS (148 patients), or twice-daily 300-mg doses of TIS (146 patients), for a period of 28 days (on treatment), followed by 28 days without treatment (off treatment). This was repeated twice more for a total of three cycles of treatment followed by a 28-day off-treatment period. Overall, the study lasted for 24 weeks.
The primary outcome of the study was to compare changes in lung function (through measurements of forced expiratory volume in one second, or FEV1) from baseline to day 168.
Researchers also looked at secondary endpoints, including changes in respiratory symptoms as measured by the Cystic Fibrosis Questionnaire-Revised (CFQ-R), and changes in the number of P. aeruginosa bacteria.
Efficacy and safety were assessed by regular visits to the clinic, and followed up by telephone calls.
Results showed that after 168 days of treatment, ALIS was not inferior to TIS in effects on lung function — patients treated with TIS showed improved FEV1 levels of 2.87% over baseline, while those in the ALIS treatment group improved by 1.56%. The difference between ALIS and TIS treatments was -1.31%; which is within the 5% limit that indicates the ALIS treatment was similar in efficacy to TIS (meaning non-inferior).
Regarding the different cycles, at the end of the first treatment cycle (day 28), TIS treatment improved FEV1 by 7.32%, while the ALIS group showed an improvement of 4.39%. These same comparative improvements were also demonstrated at the end of the second cycle (day 84), and the third cycle (day 140).
These improvements were consistent across all demographic subgroups regardless of age, sex, or ethnicity.
In addition, both treatments also showed clinically meaningful improvements in CFQ-R Respiratory Symptoms scores at the end of cycle 1.
Reductions in the number of P. aeruginosa bacteria in sputum were also similar between the ALIS and TIS treatment groups at the end of the treatment period, compared to baseline.
The safety of ALIS and TIS treatments were also similar. In both groups, most patients experienced more than one mild or moderate treatment-emergent adverse event (TEAE) — 84.5% in ALIS vs. 78.8% in TIS. Most of the side effects were respiratory events and exacerbations.
The number of TEAEs in the ALIS group (52.0%) was higher than in the TIS group (34.6%) after the first treatment cycle, but progressively decreased (to 39.6%) during the study to levels similar to the TIS group (37.4%).
“Patients reported improvement in their respiratory symptoms and had a lower treatment burden as measured by CFQ-R, with trends in favor of ALIS compared with TIS despite a higher frequency of pulmonary exacerbations reported in the ALIS arm,” the researchers said.
Altogether, the results demonstrated that once-daily ALIS treatment for P. aeruginosa infection had similar outcomes to the standard twice-daily treatment with TIS, showing improvements in lung function, and reduction in the number of P. aeruginosa bacteria in sputum, regardless of age, sex, or ethnicity.
Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.