FDA Committee Denies Support for Ciprofloxacin for NCFBE Patients with Pseudomonas aeruginosa


A FDA committee decided against recommending approval for Linhaliq to treat NCFBE patients with chronic lung Pseudomonas aeruginosa infections.

The US Food and Drug Administration’s Antimicrobial Drugs Advisory Committee (ADAC) decided against recommending approval for Linhaliq (ciprofloxacin) to treat non-cystic fibrosis bronchiectasis (NCFBE) patients with chronic lung Pseudomonas aeruginosa infections.

When faced with the question of if Aradigm Corporation provided substantial evidence underscoring the safety and efficacy of Linhaliq in delaying the time to first exacerbation after starting treatment in NCFBE patients with chronic lung P. aeruginosa infections, the majority of the committee voted “no.” The vote was 12 “no,” 3 “yes,” and 1 abstention.

The vote of recommendation came 2 weeks prior to the therapy’s Prescription Drug User Fee Act (PDUFA) action date of January 26, 2018. While the FDA will take the committee’s guidance into consideration, it will make its own decision when reviewing Aradigm’s application.

Linhaliq’s candidacy for use in NCFBE patients with chronic lung Pseudomonas aeruginosa infections is based on data yielded from 3 clinical trials. The 2 phase 3 studies included in Aradigm’s application (ORBIT-3, ORBIT-4) were 48-week, multinational, randomized 2:1 double-blind trials with a placebo-controlled population. The primary endpoint in both trials was an increase in the median time to first mild, moderate, or severe pulmonary exacerbation (PE).

In ORBIT-3, the median time to first mild, moderate, or severe PE was 221 days in the once-daily ciprofloxacin treatment group, versus 136 days in the placebo group, a similar rate to that of ORBIT-4 (230 days versus 163 days, respectively) but not statistically significant (P = ­0.8488).

ORBIT-4 ciprofloxacin patients reported a 37% reduction in PE frequency over 48 weeks, versus placebo (P = 0.0007). In ORBIT-3, the therapy group reported a 13% reduction in 48-week PE frequency versus placebo (P = 0.3125).

Aradigm combined the efficacy results with that of a phase 2b trial (ORBIT-2) to prove ciprofloxacin’s clinical efficacy to the FDA. The therapy also showed safety and tolerability in patients during the phase 3 trials.

In a recent interview, Marin H. Kollef, MD, professor of Medicine and Virginia E. & Sam J. Golman chair of the Respiratory Intensive Care department at Washington University School of Medicine, discussed with Contagion® how Pseudomonas infections have developed resistance over time to currently available antibiotics, underscoring the need for more options.

“If you go back over the last 20 to 30 years, we would start out with a certain drug class. The organism would become resistant to that drug class—let’s say the fluoroquinolones. Then, we’d move to another drug class—extended-spectrum cephalosporins or anti-Pseudomonal penicillins—and then as the organism developed resistance to those classes, we would then go to the carbapenems, but now we have carbapenem resistance as high as 20% or 30% in some hospital settings,” Dr. Kollef said. “If it’s not dosed properly an organism like Pseudomonas progressively become more resistant over time; if it becomes more resistant over time, it becomes more difficult to treat; if it’s more difficult to treat, then the patient outcomes are worse.”

Igor Gonda, PhD, President and Chief Executive Officer of Aradigm, expressed disappointment in the ADAC vote, but confidence in the therapy’s benefits for patients with NCFBE.

“We will work closely with the FDA to address the issues discussed by the panel today as they complete their review of Linhaliq,” Dr. Gonda said in a statement. “We are committed to helping NCFBE patients, who presently have no available treatment options.”

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