Doctors currently use oral and injectable formulations of ciprofloxacin to treat respiratory tract infections. Apulmiq was intended to be an inhalable form for patients with non-cystic fibrosis bronchiectasis and chronic lung infections due to Pseudomonas aeruginosa bacteria.
Savara discontinued work on Apulmiq in December 2020, while working on a regulatory request for another Phase 3 trial, to focus its resources elsewhere.
How does Apulmiq work?
Ciprofloxacin, the active ingredient in Apulmiq, is a broad-spectrum antibiotic that belongs to the class of quinolone antibiotics. It inhibits enzymes that bacteria require for replication and thereby interferes with the growth of certain bacteria, such as P. aeruginosa.
The inhaled formulation was thought to have an advantage over oral and injectable forms as it allows targeted delivery to the lungs. This more targeted delivery could lead to a high local concentration of the medication in the lungs and a lower concentration in the blood, potentially resulting in fewer side effects.
Apulmiq in clinical trials
Two randomized, double-blind, placebo-controlled Phase 3 clinical trials, ORBIT-3 (NCT01515007) and ORBIT-4 (NCT02104245), assessed Apulmiq’s safety and effectiveness as a once-a-day inhaled treatment (6 mL) in non-cystic fibrosis bronchiectasis patients with chronic P. aeruginosa infections.
Researchers designed the two trials identically, and conducted them over 48 weeks at clinical sites around the world. Patients received Apulmiq or a placebo once daily in six cycles of 28 treatment days, followed by 28 days off-treatment. Both trials included an open-label extension phase, in which all received Apulmiq for 28 days. Their primary goal was median time to a first mild, moderate, or severe pulmonary exacerbation or flare. A secondary measure was the frequency of flares throughout the 48-week treatment period.
ORBIT-4 included 304 participants. The median time to the first mild, moderate, or severe flare was 230 days in the Apulmiq group and 163 days in the placebo group. Researchers also observed a statistically significant 37% reduction in the frequency of flares in Apulmiq-treated patients compared with those on a placebo.
But the ORBIT-3 trial, with 278 participants, showed a median time to a first mild, moderate, or severe flare of 221 days in the Apulmiq group and 136 days in the placebo group, a finding that was not statistically significant. The frequency of flares — a reduction of 15% compared with placebo — was also not statistically significant.
Based on data from the ORBIT-3 and ORBIT-4 trials, Aradigm sent an application to the U.S. Food and Drug Administration (FDA) requesting Apulmiq’s approval in 2017. The FDA rejected the application in 2018 due to concerns that included the clinical data, discordant trial results, and product quality. A subsequent review led to a similar decision in February 2019, with the FDA recommending a new, confirmatory Phase 3 trial.
The company was moving toward that trial when it decided to stop work on Apulmiq.
A similar approval request was filed with the European Medicines Agency (EMA) in March 2018. Aradigm withdrew this application in October 2019 after a review by an EMA office concluded trial data did not show a “positive benefit-risk balance.”
Last updated: Feb. 4, 2021
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