Treatment with Apulmiq (ciprofloxacin) can delay the first acute respiratory episode in non-cystic fibrosis bronchiectasis (NCFBE) patients with chronic Pseudomonas aeruginosa infection, a new independent analysis of ORBIT-4 trial data shows.
The report, “Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials,” was published in The Lancet Respiratory Medicine.
This finding contrasted with the Phase 3 ORBIT-3 trial results, and the pooled data of two studies, which have failed to demonstrate the potential of the treatment.
Aradigm, the company developing Apulmiq (previously known as Linhaliq and Pulmaquin), believes these ORBIT-4 results, verified by an independent third-party evaluation (TPE) in December, supports resubmitting the New Drug Application (NDA) that was initially filed with the U.S. Food and Drug Administration (FDA) in 2017.
The FDA rejected Aradigm’s request early last year to approve Apulmiq, due to errors discovered in the Phase 3 trial assessment. This followed an advisory committee’s recommendation not to approve the therapy.
Currently, Aradigm is also addressing other issues of concern the FDA raised in its NDA response letter, including an ongoing new Human Factor study (to assess the interaction between users and the device), and work on product quality problems.
The company has scheduled a meeting with the FDA for Friday, to discuss the TPE-verified Phase 3 data, and to seek agreement for a resubmission of Apulmiq’s application to treat bronchiectasis and chronic P. aeruginosa lung infection.
“Aradigm remains confident in the efficacy, safety, and quality of Apulmiq and is committed to continue working toward the approval of Apulmiq for NCFBE patients with chronic lung infection with P. aeruginosa, who have very severe disease with high morbidity and mortality, and no available treatment options,” the company’s spokesperson said in a press release.
The TPE assessment included data collected from 278 patients with NCFBE, who were part of the ORBIT-3 (NCT01515007), and 304 patients from the ORBIT-4 (NCT02104245) trials.
In ORBIT-4, treatment with Apulmiq delayed the occurrence of the first episode of pulmonary exacerbation by 72 days, compared to placebo. The therapy was also associated with a 37% reduction in the frequency of exacerbations of all severities, compared with placebo, and a 42% reduction of moderate and severe acute episodes.
The results of the ORBIT-3 study were less conclusive. The treatment delayed the mean time to the first exacerbation by 78 days compared to placebo, but this difference was not statistically significant. Reductions of 15% in the frequency of pulmonary flares were also reported, but this effect was also not statistically relevant compared to placebo.
Additional analysis of pooled data collected from the two studies followed the same trend, failing to demonstrate statistically significant differences on median time to first pulmonary exacerbation between Apulmiq and placebo groups.
Still, according to patients’ one-year history of prior flares, Apulmiq could promote a greater reduction in their frequency in people who had at least four pulmonary exacerbations (40%) in the past year (high-risk group), compared with those with two or three (21%).
“The pooled data from ORBIT-3 and ORBIT-4 showed a risk reduction in all pulmonary exacerbations and severe pulmonary exacerbations, differences that are clinically relevant in a population of patients with a high burden of disease,” researchers wrote.
Researchers believe that the inconsistency in the two trials indicates that “further research is needed into the heterogeneity of NCFBE and optimal outcome measures for inhaled antibiotics.”