The U.S. Food and Drug Administration (FDA) has stood by its initial refusal to approve Apulmiq for the treatment of non-cystic fibrosis bronchiectasis (NCFBE) associated with chronic Pseudomonas aeruginosa lung infection.
The agency recommended that Apulmiq’s developer, Aradigm, conduct another, well-controlled trial to demonstrate a significant effect of the therapy using a clinically meaningful objective, such as the frequency of pulmonary exacerbations.
Apulmiq (previously known as Linhaliq and Pulmaquin) is an inhaled formulation of the antibiotic ciprofloxacin and is currently used for the treatment of patients with NCFBE and chronic lung infection with P. aeruginosa. According to Aradigm, this is a rare patient population with severe disease that is affected by frequent flares, and high morbidity and mortality, and there are no available treatment options.
Based on positive data obtained in two Phase 3 trials — ORBIT-3 (NCT01515007) and ORBIT-4 (NCT02104245) — in 2017, Aradigm submitted a New Drug Application (NDA) for Apulmiq to the FDA. But in January 2018, the agency refused its approval, expressing concerns about product quality and its clinical relevance.
According to Aradigm, the ORBIT studies showed that Apulmiq is able to reduce the time to a first pulmonary exacerbation, and induce a 34% to 49% reduction in all exacerbations, compared with a placebo, while keeping a good safety profile and reducing the density of P. aeruginosa bacteria.
However, the FDA was not convinced given the discrepant results between the two trials.
The time it took for patients to develop a first pulmonary exacerbation (the studies’ primary goal) and the reduction in the rate of all or severe exacerbations (the secondary objectives) differed between ORBIT-3 and 4, justifying a recommendation against approval by an FDA advisory committee.
In ORBIT-4, Apulmiq delayed the appearance of pulmonary exacerbations by a median of 72 days, and reduced the frequency of all flares by 37%, compared with a placebo. But in ORBIT-3, the treatment did not lead to statistically significant delays in the occurrence of the first exacerbation, or to a significant reduction in the rate of pulmonary flares.
In light of these discrepancies, the FDA recommended at the time that an independent third party evaluate the results of the ORBIT trials. Recently, the conclusions of the evaluation were released, which confirmed the primary and secondary objectives of the studies and the beneficial effect of Apulmiq.
However, at a meeting recently held between Aradigm and the FDA, the agency stood by its concerns about the discordant trial results, and recommended an additional study with exacerbation rate/frequency as the primary objective.
Currently, Aradigm is also addressing other issues raised by the FDA in its NDA response letter, including an ongoing new Human Factor study (to assess the interaction between users and the device), and product quality deficiencies pointed out by the agency.
Aradigm says it remains confident in the efficacy, safety, and quality of Apulmiq, and restates its commitment to continue working toward the approval of the treatment.
The product, under the name Linhaliq, is being reviewed in Europe as a therapy for the same patient population — NCFBE patients with chronic P. aeruginosa infection.
Earlier this month, Aradigm filed for protection under Chapter 11 of the U.S. Bankruptcy Code. It intends to commence a process of selling its assets to interested parties, subject to Bankruptcy Court approval.
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