AstraZeneca’s Gout Drug Lesinurad May Face Risk Management Issues

Company already offering boxed warning and post-marketing cardiovascular study as advisory committee meeting nears.

FDA’s safety concerns about AstraZeneca PLC’s proposed gout drug lesinurad, if approved, might lead to risk mitigation efforts.

The agency identified potential renal and cardiovascular safety issues with the drug, proposed trade name Zurampic, as it heads toward an Arthritis Advisory Committee meeting Oct. 23.

Lesinurad, an inhibitor of uric acid transporter URAT1, is proposed for treatment of hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor (XOI). The proposed dose is 200 mg tablet taken orally once daily.

And even though more of the safety events were associated with a 400 mg dose of lesinurad – double the dose proposed for approval – FDA's briefing documents noted concern about potential broader use of the product.

“The exposure of the 200 mg and 400 mg dose is largely overlapping, raising questions about whether the safety profile of the 200 mg dose will be consistent if used in a larger population with more variability,” the agency wrote.

However, the agency's safety concerns have not risen to the level of an operational safety question for the advisory committee: There is one voting question on whether the product’s safety profile is adequate to support approval and a discussion question on renal and cardiovascular safety.

Committee members will not be asked any questions about whether a risk evaluation and mitigation strategy or any other risk management program is needed.

But it appears AstraZeneca already may be attempting to avoid such an outcome.

AstraZeneca's briefing documents said its proposed labeling includes a boxed warning on the risk of acute renal failure when lesinurad is used as monotherapy and the importance of co-administration with an XOI.

AstraZeneca also proposed contraindicating the product for those with severe renal impairment, end-stage renal disease and patients on dialysis.

Post-marketing safety activities would include a communication program on the product’s risks for providers as well as a study to assess cardiovascular events and further characterize renal safety with lesinurad, although it said no CV signal has been identified.

FDA noted renal and CV safety, as well as other problems, during its September 2014 pre-NDA meeting with AstraZeneca, according to the briefing documents.

The agency said it was unclear whether a REMS “would be sufficient to address the identified concerns and that the need for REMS would be a review issue.”

AstraZeneca acquired lesinurad when it bought Ardea Biosciences Inc. in 2012 (Also see "AstraZeneca’s Ardea Acquisition: A Rich Deal Spurred By Phase III Gout Candidate" - Pink Sheet, 23 Apr, 2012.).

Safety Problems From Cofounders – Or Dose Dependency?

The lesinurad clinical program included four Phase III studies. Three combined the product with an XOI and a fourth looked at it as monotherapy.

Three of the studies also evaluated the product at 400 mg and 200 mg doses. The monotherapy study looked at a 400 mg dose.

FDA found that the 400 mg dose was associated with increased incidences of adverse events, serious adverse events, serious renal adverse events, major CV adverse events and death compared to placebo.

The same increases in adverse events were not seen with the 200 mg dose, but FDA noted there still was a smaller increased risk of adverse events, “suggesting toxicity with lesinurad was dose-dependent.”

The company convened a blinded Renal Events Adjudication Committee to look at renal problems once they began emerging during the trials. The committee found that 97% of the renal adverse events adjudicated “were associated with one or more potential confounder(s),” including chronic renal disease, gout flare, and dehydration.

But FDA said the best evidence of lesinurad’s renal risk is the monotherapy study, where the drug was “clearly associated with an increased risk of renal adverse events, including reversible and non-reversible creatinine elevation and serious renal-related adverse events.”

That study found no renal-related adverse events in the placebo group and 19 in the lesinurad group, including three renal failures, three acute renal failures and four renal impairments.

The agency also noted concerns about the whether the renal effects were reversible.

“Unanswered questions remain regarding the true extent of the reversibility of [the] drug’s nephrotoxicity particularly since some patients continued to have serum elevations for more than 84 days,” agency reviewers wrote.

AstraZeneca said in its briefing documents that renal adverse events were comparable between those on an XOI and those on lesinurad and XOI.

The company also said the product should only be used in combination with an XOI because it reduces the uric acid available for excretion and decreases the potential for renal events.

Wall Street analysts were concerned about the renal problems seen when the trial results were released in 2014, suggesting it could limit the product label and its commercial potential (Also see "AstraZeneca’s Gout Drug Lesinurad Hobbled By Renal Risk" - Pink Sheet, 13 Aug, 2014.).

CV Conclusions Difficult To Determine

FDA noted more deaths among patients taking lesinurad during the Phase III trials: six versus none among those on placebo.

But the agency said the adjusted death rates were low overall and had highly overlapping confidence intervals, making conclusions difficult to formulate, according to the briefing documents.

Four deaths among those taking lesinurad were determined to be CV related, but FDA said major adverse cardiac events (MACE) were seen in all study arms, including the placebo arm.

The agency said a dose-dependent increase in MACE events observed in the lesinurad 400 mg plus XOI treatment group and an increase in MACE events when the product is co-administered with Takeda Pharmaceutical Co. Ltd.’s Uloric (febuxostat), whose label includes a CV warning, remain unexplained.

The FDA user fee goal for a decision on lesinurad is in December (Also see "User Fee Goal Dates" - Pink Sheet, 6 Jul, 2015.).