Liposomal Amikacin (ARIKAYCE® Formerly ARIKACE)

ARIKAYCE contains 70 mg/mL amikacin in ~300 nm liposomes composed of DPPC and cholesterol (2:1 by weight), both endogenous to the lung [32,100]. Nebulization of ARIKAYCE with the PARI eFlow vibrating mesh nebulizer, the current delivery system, causes ~30% of the encapsulated drug to be released [100]. In rats, ARIKAYCE demonstrated delayed clearance from the lung, as designed, and an enhanced ability to penetrate into biofilms and infected mucus, and it was superior to free amikacin in a chronic PA infection model [101]. Inhaled ARIKAYCE was well tolerated with no incidence of adverse events in healthy subjects and CF patients [53,55]. After 14 days of once-daily treatment (500 mg ARIKAYCE) in CF patients, an increase in FEVj (% predicted) over baseline of 5.6% (p = 0.03) was observed [53], which supported further development in CF.

The longest exposure to inhaled ARIKAYCE of 504 days comes from an open-label extension period in a Phase 2 CF trial (n = 49) evaluating 6 cycles of a 28-day on treatment (560 mg) followed by a 56-day off treatment [52]. There was a mean 0.6 log CFU reduction over baseline (p = 0.003) at the end of each of the six 28-day dosing periods [52]. There was also a statistically significant improvement in lung function compared to baselines of 7.9% (p < 0.0001) and 5.9% (p = 0.0001) at the end of each 28-day

Change in lung function

FIGURE 8.7 Change in lung function (FEVj, % predicted) from baseline through cycle 6 for 49 cystic fibrosis patients in an open-label extension. Each cycle consists of once-daily administration of 560 mg ARIKACE for 28 days followed by a 56-day off treatment. (From Okusanya, O.O. et al., Antimicrob. Agents Chemother, 53(9), 3847, 2009. With permission.)

treatment cycle and 56-day off-treatment cycle, respectively (Figure 8.7). ARIKAYCE met the primary endpoint of noninferiority to TOBI (tobramycin inhalation solution) in a phase 3 trial of ARIKAYCE in CF [51]. These data supported regulatory filings with the EMA [102]; however, approval in the EU is not anticipated in 2016.

In NCFB, inhaled once-daily ARIKACE (280 or 560 mg) was shown to be safe and well tolerated versus placebo after 28 days [24]. However, there has been no further recent activity in this patient population.

As discussed earlier, there are no approved inhaled treatments for NTM infections in the lung. The ability of liposomes to accumulate in alveolar macrophages, the site of NTM infections, provides strong rationale for an inhaled liposomal antiinfective to combat this disease. To that end, a Phase 2 trial evaluating once-daily inhaled ARIKACE for 84 days in NTM was recently completed [103]. While the primary efficacy endpoint of a change in mycobacterial density was not met, a secondary endpoint of culture conversion was achieved with 11 out of 44 patients treated with ARIKAYCE demonstrating negative cultures by day 84 of the study compared to 3 out of 45 patients treated with placebo (p = 0.01) [103]. A Phase 3 trial in treatment refractory patients with NTM lung infections is ongoing [102].

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