AstraZeneca acknowledged today that its NDA for ZS-9 (sodium zirconium cyclosilicate)—the hyperkalemia drug candidate it is co-developing with its subsidiary ZS Pharma—has been rejected by the FDA for the second time in less than a year.

The pharma giant said it received a Complete Response Letter (CRL) from the FDA that followed an inspection by the agency of the ZS-9 manufacturing facility. The company did not disclose details of the concerns raised by the FDA that led to the CRL.

“AstraZeneca and ZS Pharma are committed to working with the FDA to resolve the remaining matters under review as soon as possible,” AstraZeneca stated. “AstraZeneca remains dedicated to developing and commercializing sodium zirconium cyclosilicate for patients with hyperkalemia, and is confident in the profile of this potential medicine.”

The CRL does not require the generation of any new clinical data, AstraZeneca said.

The CRL marks ZS-9’s second such letter—and thus, a second setback—with the FDA. On May 27, 2016, AstraZeneca said it received a CRL, saying at the time only that it “refers to observations arising from a preapproval manufacturing inspection,” without offering details.

AstraZeneca inherited ZS-9 when it acquired ZS Pharma for $2.7 billion in 2015, in a deal designed to expand the pharma’s cardiovascular and metabolic disease portfolio.

ZS-9—ZS Pharma’s first product candidate—was a fit with AstraZeneca’s increased focus on chronic kidney disease and chronic heart failure, two disorders with which hyperkalemia is associated, the buyer reasoned at the time.

On February 24, AstraZeneca announced that ZS-9 received a positive opinion by the Committee for Medicinal Products for Human Use in the EU. The recommendation is expected to be followed by approval of the drug’s marketing authorization application by the European Commission.

ZS-9 is an insoluble, nonabsorbed compound with a structure designed to preferentially trap potassium ions. According to AstraZeneca, the drug’s potassium selectivity enables high in vitro binding capacity for potassium ions, even in the presence of other competing ions.

As of last year, ZS-9 had been assessed in three double-blind, placebo-controlled trials and an ongoing 12-month open label clinical trial in patients with hyperkalemia, representing more than 1600 patients treated.

The FDA is not required to disclose its CRLs for rejected drug candidates. On March 13, Joshua M. Sharfstein, M.D., of Johns Hopkins Bloomberg School of Public Health and Michael Stebbins, Ph.D., of the Laura and John Arnold Foundation issued a series of 18 recommendations to promote greater transparency at the agency.

One of the recommendations urges the FDA to “disclose communications to companies when products are not approved”—something also reportedly favored by President Donald Trump’s nominee for FDA commissioner, Scott Gottlieb, M.D.

These transparency recommendations are the topic of the current GEN Poll.

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