Last month, Hayward, Calif.-based Aradigm Corp. filed for protection under Chapter 11 of the U.S. Bankruptcy Code in the Alameda County Court District to sell its assets, and about a week later the company made known the bad news in notes from the type B meeting held with the FDA.

During the discussion with regulators, Aradigm offered results of the third-party evaluation (TPE) that confirmed the primary and secondary exacerbation endpoint analyses in the trials known as Orbit-3 and Orbit-4 trials, experiments from which data were submitted as part of the NDA in the summer of 2017.

The studies tested Apulmiq (formerly Linhaliq) dual release inhaled ciprofloxacin for the treatment of Pseudomonas aeruginosa infections in non-cystic fibrosis bronchiectasis (NCFBE). Regulators agreed that the TPE findings were consistent with the original phase III results, but they were still concerned about discordance in the results of the pre-specified primary and secondary endpoints between Orbit-3 and Orbit-4.

Aradigm also said it was continuing to address matters raised in the agency's complete response letter, which arrived in late January. Following FDA guidance provided in a type C meeting, a new human factor study along with work to address the product quality deficiencies are nearing the finish line, and a "comprehensive method development report for the in vitro release assay has been submitted" for review, the firm said.

NCFBE is a chronic inflammatory lung disease characterized by irreversible dilation of the bronchi, symptoms of persistent cough and expectoration, and recurrent infective exacerbations. The prevalence is on the increase in the U.S. and Europe, noted an article last June in the Journal of Aerosol Medicine and Pulmonary Drug Delivery. "Although there are many similarities between NCFBE and cystic fibrosis in terms of respiratory symptoms, airway microbiology and disease progression, there are key differences, for example, in response to treatment, suggesting differences in pathogenesis." The article concluded that "inhaled antibiotics have antipseudomonal activity, have fewer systemic side effects, and could provide alternative treatment options to address some of the treatment challenges that exist in the management of severe cases of NCFBE."

Other approaches might work, too. Consider the work underway by Insmed Inc., of Bridgewater, N.J., with INS-1007, an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP1). The enzyme is known to catalyze the activation of neutrophil serine proteases, which play a key role in the pathology of NCFBE.

Getting most of the airtime for Insmed lately is last fall's accelerated approval of Arikayce (amikacin liposome inhalation suspension), the first and only FDA-approved therapy for refractory non-tuberculous mycobacterial lung disease caused by Mycobacterium avium complex in adults. The drug, which addresses a rare and often chronic infection that can cause irreversible lung damage, was also the first to be granted approval under the agency's limited population pathway for antibacterial and antifungal drugs, created by the FDA to spur development of antibiotics for unmet medical needs. (See BioWorld, Sept. 17, 2018, and Oct. 2, 2018.)

During a conference call on earnings last month, CEO William Lewis said officials at Insmed "have a lot of confidence in how the launch is progressing" and felt comfortable estimating Arikayce revenue in the range of $80 million to $90 million for this year. "As we go forward, we may add some additional detail," he said. "But at this stage, six weeks into the launch, we thought we would cut to the chase and just put the revenue guidance out there." SVB Leerink analyst Joseph Schwartz was pleased, saying in a report last week that the company "continues to work with payers, and this is translating to rapid reimbursement" for Arikayce. "Currently, all patients are going through the medical exception process" to get the drug but "despite the extra hurdle, Insmed is seeing time to fill less than 30-45 days, demonstrating [the firm's] dedication to executing across the board," as well as the market's receptivity. Demand should stay at satisfying levels, the company believes, "although the impact on formulary resets and patients entering the donut hole remains to be seen," he said.

'Multiple modes' of therapy

Though Arikayce gets most of the press, the DPP1 inhibitor INS-1007 seems to hold potential in NCFBE. A six-month phase II trial called Willow remains on track to finish enrolling in the middle of this year and, if it's successful, Insmed aims to push the candidate into a registration trial. Also this year, the company will advance INS-1007 in two small phase II efforts that will explore its worth in treating granulomatosis with polyangiitis, a rare neutrophil-driven autoimmune disease that is fatal when untreated.

Historically in NCFBE, Foster City, Calif.-based Gilead Sciences Inc.'s Cayston (aztreonam for inhalation solution) also has been tried. In a pair of phase III trials, AIR-BX1 and AIR-BX2, the treatment showed no clinically relevant effect on the primary outcome of quality of life (QoL), as published in Lancet Respiratory Medicine in 2014. The studies compared Cayston to placebo in more than 500 patients. The AIR-BX1 experiment yielded no statistically significant improvement in the QoL-Bronchiectasis Respiratory Symptoms score determined after one course of treatment at four weeks. In AIR-BX2, a 4.6-point improvement in QoL emerged – statistically significant (p=0.011), though a point increase of 8 or greater is typically considered clinically relevant in NCFBE. And when QoL was measured at 12 weeks, no effect was measured in either trial. "Not surprisingly, patients exposed to [Cayston] showed a greater than 2.5 log improvement in gram-negative bacterial burden," remarked H.C. Wainwright analyst Andrew Fein in a report last week, and "this effect on decreasing the mass of infecting organisms alone was not enough to generate a consistent improvement in clinical endpoints." A post-hoc analysis found the patient populations were "not well matched" across the pair of tests, and thus "possibly did not reflect the real-world NCFBE population."

Fein appreciates INS-1007's odds in any case, acknowledging that "inhaled antibiotic therapy is not going away anytime soon," he wrote. "However, with respect to NCFBE we believe that trials must carefully evaluate the inclusion criteria to ensure that patients are presenting with a homogeneous disease profile, i.e., frequent exacerbations and preferably chronically infected with P. aeruginosa. Secondly, it will be important to get clarity from the regulators regarding the approvable endpoint and the length of time that may be required to achieve that endpoint. For example, longer trials with a large number of patients may be necessary to adequately determine if time to first exacerbation can be sufficiently powered to demonstrate efficacy," in his view.

Bottom line: NCFBE has proved complex, and "multiple modes of therapy may be required," Fein said. Although inhibiting DPP1 hasn't been validated, Insmed may be able to leverage its understanding of inhaled antibiotics such as Arikayce alongside INS-1007 to take on NCFBE. He called it "likely" that an inhaled antibiotic would still be required to reduce bacterial burden in the disease. Insmed previously tested its amikacin in bronchiectasis, he pointed out, and "can use the learning from that trial to improve" a possible combo experiment that might involve INS-1007. The study he referenced was a 64-subject bid completed in May 2009.