ALIS (Amikacin Liposome Inhalation Suspension): The Beginning of a Wonderland?

When I used to read fairy tales, I fancied that kind of thing never happened, and now here I am in the middle of one!

—Alice in Wonderland

Fairy tales do come true. Once upon a time, 1868 to be exact, someone noticed that chickens developed “tuberculosis” (1). The cause of this disease was an “avian” mycobacteria. Probable human cases of “avian tuberculosis” were reported as early as the late 1880s. However, it was not until the 1930s that the causative strains were identified as human pathogens (1–3), and by 1942, only 25 cases of human avian tuberculosis had been reported (4, 5). Eventually, these causative organisms were identified as Mycobacterium avium (6), followed by identification of Mycobacterium intracellulare in 1949 (7). Today, these organisms, as well as at least 10 other species (8), are collectively referred to as Mycobacterium avium complex or MAC.

Early experience with treating MAC pulmonary disease was fraught with failure (9). It was not until the availability of macrolides that we began to see improvement in treatment outcomes (10). However, even today, treatment success rates average only 66% among patients with macrolide-susceptible disease who take the American Thoracic Society recommended regimen (9) for at least a year (10). When patients fail therapy, we have few options for treatment. We can continue the current treatment regimen in hopes of slowing progression, try to “strengthen” the regimen by adding additional antibiotics (none of which are approved for treatment of MAC), offer surgical resection, or simply stop treatment and hope for the best.

Enter the Mad Hatter to the rescue. The study (CONVERT) by Griffith and colleagues (pp. 1559–1569) in this issue of the Journal reports the results of a phase III randomized, controlled, open-label trial of a novel formulation of inhaled amikacin referred to as amikacin liposome inhalation suspension (ALIS) (11). Adults with amikacin-susceptible MAC pulmonary disease who had sputum cultures positive for MAC despite at least 6 months of stable guidelines-based therapy (GBT) were randomly assigned to receive once-daily ALIS plus GBT versus GBT alone. The primary endpoint of the trial was culture conversion, defined as three consecutive monthly MAC-negative cultures by Month 6.

This multicenter study enrolled 336 patients (11). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS plus GBT compared with 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08–8.57; P < 0.001). These results are remarkably similar to the phase II trial that reported culture conversion status at Day 84 of treatment (12). Although culture conversion is a laudable goal for treatment of any infectious disease, there were no significant differences between arms in terms of patient-reported outcomes on the St. George’s Respiratory Questionnaire and no difference between treatment arms in change in 6-minute-walk distance (unlike in the phase II trial) (12).

The bacteriologic success of ALIS plus GBT is all the more notable when you consider who was enrolled into the study. Although inclusion criteria required at least 6 months of prior therapy, patients had been on treatment for much longer, averaging more than 3 years. Moreover, the primary endpoint required that subjects who converted cultures by 6 months had to have done so by Month 4 and then have at least nine negative cultures before they could be considered to have reached the primary endpoint. Both trials demonstrated something that had not been heretofore quantified: if you continue treating with the same initial regimen, culture conversion occurs in only 9% of patients. If nothing else, these studies should drive us to find better ways to treat out patients.

Not all is wonderful in Wonderland, however. Adverse reactions were very common and occurred in more than 90% of subjects in each arm. In the ALIS plus GBT arm, 82.5% of treatment-emergent adverse events (TEAEs) were considered ALIS related by the investigator, and 17.4% of patients had TEAEs leading to discontinuation of ALIS. TEAEs reported in 10% or more of patients in the ALIS plus GBT arm included dysphonia, cough, hemoptysis, dyspnea, fatigue, diarrhea, nausea, and oropharyngeal pain. All were more frequent with ALIS plus GBT than with GBT alone excluding hemoptysis, which occurred at similar rates in both arms. However, these events infrequently led to early discontinuation of ALIS (dyspnea, 3.1%; dysphonia, 2.2%; all others, <1%) or withdrawal from the study. Audiological TEAEs were generally similar in both arms although tinnitus was reported in 17 patients (7.6%) in the ALIS plus GBT arm compared with one event (0.9%) in the GBT arm. Serious TEAEs were reported in 45 patients (20.2%) and 20 patients (17.9%) in the ALIS plus GBT and GBT-alone arms, respectively.

On the basis of the results of this study and those from the previous trials, the U.S. Food and Drug Administration approved ALIS for treatment-refractory MAC pulmonary disease on Friday, September 18, 2018 under a novel mechanism, Limited Population Pathway for Antibacterial and Antifungal Drugs. This is more than a century after the chickens developed tuberculosis and humans were reported with avian tuberculosis. Why has it taken so long to get an approved drug for treatment of MAC pulmonary disease? There are many reasons for this delay, including the lack of recognition that MAC was a significant pulmonary pathogen in humans, the poor understanding of the epidemiology of disease, and a general lack of funding for research. Things are changing. In North America, the prevalence of nontuberculous mycobacterial pulmonary disease is increasing at extraordinary rates, while the number of tuberculosis cases has reached an all-time low and continues to decrease (13, 14).

Would you tell me, please, which way I ought to go from here?

—Alice in Wonderland

Although we are not yet in a Wonderland of new drugs for MAC, a small pipeline is developing that includes novel antimicrobials as well as host-directed therapies (15). The novel approval pathway for ALIS marks a milestone for spurring drug development targeting infections that lack effective therapies. However, the challenge for ALIS, as well as for subsequent drugs entering this space, will be to identify clinical correlates to microbiologic outcomes that demonstrate improvement in quality or quantity of life. As new agents move into clinical stages of development, there is likely to be a bottleneck, given the limited number of patients eligible for clinical trials. Stakeholders will need to work together in a coordinated fashion using novel trial designs to overcome the impending bottleneck. We hope this is just the beginning or our tale, and we will follow the advice of the Mad Hatter when he told Alice that something is impossible “only if you believe it is.”