Apulmiq (ciprofloxacin), known as Linhaliq in Europe and previously called Pulmaquin, is an experimental inhaled antibiotic for the treatment of non-cystic fibrosis bronchiectasis with chronic Pseudomonas aeruginosa lung infection.
It is, at least for time being, no longer being developed by Aradigm after approval requests — supported by clinical trial data — were questioned by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Regulatory officials noted data discrepancies between the two trials, ORBIT-3 and -4.
Oral and injectable formulations of ciprofloxacin are currently used to treat respiratory tract infections. Apulmiq is designed as an inhalable form of ciprofloxacin for patients with non-cystic fibrosis bronchiectasis and chronic lung infections due to P. aeruginosa bacteria.
How Apulmiq works
The active ingredient of Apulmiq, ciprofloxacin, is a broad-spectrum antibiotic that belongs to the class of quinolone antibiotics. It inhibits enzymes that are required for bacterial replication and thereby interferes with the growth of certain bacteria, such as Pseudomonas aeruginosa.
The advantage of the inhaled formulation over oral and injectable forms is that it allows targeted delivery to the lungs. This leads to a high local concentration of the medication in the lungs and a lower concentration in the blood, resulting in fewer side effects.
Apulmiq contains a 1:1 mixture of 20 mg/mL of free ciprofloxacin and 50 mg/mL of liposomes filled with ciprofloxacin. Liposomes are tiny vesicles that are made of the same material as cell membranes. They allow the slow release of the antibiotic, which reduces the dosing frequency. The free ciprofloxacin is available immediately. Apulmiq is administered once daily at a dose of 6 mL by inhalation.
Apulmiq in clinical trials
Two randomized, double-blind, placebo-controlled Phase 3 clinical trials assessed Apulmiq’s safety and effectiveness as a once-a-day inhaled treatment (6 mL) for non-cystic fibrosis bronchiectasis patients with chronic Pseudomonas aeruginosa infections.
These trials, ORBIT-3 (NCT01515007) and ORBIT-4 (NCT02104245), were identically designed and conducted multi-nationally over 48 weeks. Participants 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 patients received Apulmiq for another 28 days.
The primary objective was an increase in the 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-treated group compared to 163 days in the placebo-treated group. A 37 percent reduction in the frequency of flares was observed in the Apulmiq-treated group compared to the placebo-treated group. These were statistically significant improvements.
ORBIT-3 included 278 participants. The median time to the first mild, moderate, or severe flare was 221 days in the Apulmiq-treated group compared to 136 days in those given placebo, a finding that was not statistically significant. The frequency of flares was reduced by 13 percent compared to placebo in the Apulmiq-treated group, also not a statistically significant result.
Combined analysis of both studies showed 27 percent fewer flares and a 33 percent reduction in moderate or severe flares in patients treated with Apulmiq compared to those treated with placebo over 48 weeks. This represented a statistically significant reduction in the number of flares. The density of P. aeruginosa was significantly reduced at the end of the first cycle (day 28), and the magnitude of this effect remained persistent until the end of all treatment cycles.
Based on data from these trials, Aradigm submitted a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for Alpumiq in 2017. The FDA rejected the application due to concerns that included the clinical data, discordant trial results, and product quality in 2018; a subsequent review led to a similar decision in February 2019, with the FDA recommending a further trial.
Aradigm also submitted a marketing authorization request for Alpumiq to the European Medicines Agency (EMA) in March 2018; it withdrew this application in October 2019, citing a ruling by an EMA office that trial data for Linhaliq did not show a “positive benefit risk balance.”
The ORBIT-3 and ORBIT-4 studies supported Apulmiq’s safety. The medication had no detrimental effects on lung function or symptoms of airway irritation, compared with the placebo groups. The most frequent treatment-related side effects were respiratory in nature.
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