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FDA adcom votes down nebulized cipro developed by Aradigm, Grifols

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By Michael Fitzhugh
Staff Writer

FDA advisors considering Linhaliq, an experimental Aradigm Corp. drug for a rare but severe respiratory disease in patients with chronic lung infections, declined to support a new drug application for it, citing inconsistent efficacy data and concern over the endpoint of pivotal trials. The drug, a liposomally encapsulated ciprofloxacin under review as a treatment for non-cystic fibrosis bronchiectasis (NCFBE) patients with chronic lung Pseudomonas aeruginosa infections, has been co-developed with Grifols SA, Aradigm's biggest shareholder (NASDAQ:ARDM). Disappointment over the outcome drove Aradigm shares 33.9 percent lower to close at $2.26 on Friday.

Twelve of 16 members of the FDA Antimicrobial Drugs Advisory Committee (ADAC) voted no when asked whether Aradigm had provided "substantial evidence of the safety and efficacy of ciprofloxacin dispersion for inhalation in delaying the time to first exacerbation after starting treatment" in patients with NCFBE chronic lung infections with P. aeruginosa. Three advisory committee (adcom) members voted yes and one abstained.

The FDA, which set a Jan. 26 PDUFA data for Linhaliq, is not bound by the guidance of its adcom. However, during the past 15 years, the agency has not once gone on to approve an investigational product after a majority no vote by the adcom, according to Cortellis Regulatory Intelligence data. If approved, it would be the first treatment in the U.S. indicated for NCFBE.

"While we are disappointed with the outcome of the ADAC vote, we remain confident in the efficacy, safety and tolerability of Linhaliq in NCFBE patients," Aradigm CEO and president Igor Gonda, said in a company statement about the outcome. "We will work closely with the FDA to address the issues discussed by the panel today as they complete their review of Linhaliq," he said.

Neither Hayward, Calif.-based Aradigm nor Barcelona-based Grifols responded to a requests for interviews Friday, so it was not immediately clear whether the companies intended to run further trials responsive to adcom members' concerns.

NCFBE, which affects more than 150,000 people in the U.S. and more than 200,000 people in Europe, according to Aradigm, is characterized by abnormal and irreversible airway dilation, persistent cough, excessive sputum, and recurring lung infections. It is also associated with high rates of morbidity and mortality. NCFBE patients who have chronic infections with P. aeruginosa, an opportunistic, gram-negative bacterium, have a 6.5-fold increase in hospitalizations, three times higher mortality, and a worse quality of life compared with those without P. aeruginosa infections, according to Aradigm.

Linhaliq, formerly known as Pulmaquin, is composed of a mixture of liposome encapsulated and unencapsulated ciprofloxacin. Once deposited into the respiratory tract, ciprofloxacin is released slowly; the liposomal design is intended to "provide sustained delivery of the drug at the site of action" with minimum concentration elsewhere in the body. The drug, intended for once-daily administration via a nebulizer, has been awarded both orphan and qualified infectious disease product status from the FDA and is slated for a priority review.

The Linhaliq (ciprofloxacin dispersion for inhalation [DI]) NDA, accepted for filing in September 2017, is based on data from three clinical studies. Two phase III studies, the identically designed Orbit-3 and Orbit-4, were randomized, double-blind and placebo controlled trials, run concurrently in similar geographies over 48 weeks, with an additional four weeks of open-label treatment and a 30-day safety follow-up. Despite those similarities, there was no overall difference in efficacy between the ciprofloxacin DI and placebo arms in Orbit-3, leaving the trial short of meeting its primary endpoint, time to first pulmonary exacerbation (PE) after starting ciprofloxacin DI treatment. The Orbit-4 trial, by contrast, met both the primary endpoint and all of the secondary PE endpoints as well.

Both the FDA and AMDAC members expressed confusion about how two trials that were almost identical in design could yield different results, according to a Clarivate Cortellis AdComm bulletin.

Furthermore, ADAC members disagreed with Aradigm's choice of primary endpoint, which some called "a surrogate" for what they believed to be a more appropriate endpoint: frequency of exacerbations. Other issues that arose during the meeting included concerns about the potential for increased resistance to fluoroquinolones with longer exposures to ciprofloxacin DI, consistency of adherence to treatment, and the severity of disease in enrolled patients.

Aradigm also submitted data from the phase IIb Orbit-2 study to support its application.

An application seeking approval for Aradigm's inhaled ciprofloxacin formulation has also been accepted for review by EMA under the Centralized Authorization procedure drug review process.

The ADAC's decision on Linhaliq echoes a November 2017 vote by the group declining to support Bayer AG's NDA for ciprofloxacin dry powder for inhalation, in which the company proposed marketing the drug for the reduction of exacerbations in NCFB patients age 18 years or older with respiratory bacterial pathogens.

Other companies seeking to address NCFBE include Zambon SpA and Insmed Inc. Bresso, Italy-based Zambon is investigating whether use of inhaled colistimethate sodium, administered twice daily for 12 months, delays the time to the first pulmonary exacerbation when compared to placebo in NCFB subjects who are chronically infected with P. aeruginosa. The estimated completion date for the study is April 2019.

Bridgewater, N.J.-based Insmed has planned a phase II trial of INS-1007, a reversible inhibitor of the enzyme dipeptidyl peptidase 1. As in Aradigm and Zambon's trials, Insmed's randomized, double-blind, placebo-controlled trial is also designed to use time to first pulmonary exacerbation as its primary endpoint.