FDA's announcement that it had strengthened the existing label warning about the risk of acute kidney injury with Johnson & Johnson's Invokana (canagliflozin) and Invokamet (canagliflozin/metformin) and AstraZeneca PLC's Fraxiga (dapagliflozin) and Xigduo ER (dapagliflozin/metformin extended release) could give an added boost to Boehringer Ingelheim GMBH and Eli Lilly & Co.'s Jardiance (empagliflozin) in the competitive diabetes market.

The agency issued a drug safety alert for the two sodium-glucose cotransporter-2 (SGLT2) inhibitors on June 14. FDA said that from March 2013 to October 2015, it had received reports of 101 confirmed cases of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin or dapagliflozin use. The agency said these reports were submitted to the FDA Adverse Event Reporting System (FAERS) and there are likely to be additional cases that were not reported to the agency.

FDA noted that in approximately half the cases, the events of acute kidney injury, a condition in which the kidneys suddenly stop working, occurred within one month of starting the drug and most patients improved after discontinuing it. Hospitalization was required for 96 cases and 22 cases involved admission to an intensive care unit. Four of those hospitalized died, and two of the deaths were cardiac-related. Eleven patients did not recover, including the four who died. Fifteen patients received dialysis, three of which had a history of chronic kidney disease or previous acute kidney injury.

The agency did not apply the strengthened warning about acute kidney injury to Jardiance, which already has an advantage over Invokana and Farxiga as the only diabetes drug to show cardiovascular benefit in a large outcomes trial. Last year, BI and Lilly announced results of the 7,000-patient EMPA-REG OUTCOME study, in which empagliflozin reduced the risk of major adverse cardiovascular events (MACE) – a composite endpoint consisting of CV death, nonfatal myocardial infarction and nonfatal stroke – by 14% ([A#14150917005]).

The CV benefit is expected to be class wide and J&J and AstraZeneca are conducting cardiovascular outcomes studies for their drugs. J&J's outcomes study for Invokana, CANVAS, is scheduled to be completed in June 2017 and AstraZeneca's trial for Farxiga is scheduled to be competed in 2019.

Invokana has been leading the class as the first SGLT2 inhibitor to be approved by FDA in March 2013. Farxiga was approved in January 2014 and Jardiance launched in September 2014.

Jardiance CV Outcomes Trial Shows Kidney Disease Risk Reduction

The same day FDA issued the new safety warning, BI and Lilly presented new data from the EMPA-REG OUTCOME trial at the American Diabetes Association's annual meeting in New Orleans. The data showed Jardiance reduced the risk for new-onset or worsening kidney disease by 39% versus placebo when added to standard of care in adults with type 2 diabetes and established CV disease.

"Given that Jardiance was not included in the FDA warning combined with the additional data released from the landmark EMPA-REG study regarding kidney disease, it's possible that all SGLT2s may not be equal," David Kliff, publisher of Diabetic Investor, said in a note. "Taken as a whole all this data appears to give Lilly a major advantage, something that will not be lost on payors."

"Put bluntly, EMPA-REG is producing an avalanche of positive data for Jardiance and the boulders are falling right on top of Invokana and Farxiga," he said.

FDA's Endocrinologic and Metabolic Drugs Advisory Committee will review the results for the EMPA-REG OUTCOME trial at its June 28 meeting when it considers a supplemental NDA to give Jardiance new indications for reduced risk of all-cause mortality, CV death and heart failure hospitalization in adults with type 2 diabetes and high CV risk ([A#14160517002]).

The new kidney risk communication from FDA comes a year after the agency issued a safety warning for the entire SGLT2 class after it received reports of 20 cases of ketoacidosis, a life-threatening build-up of ketones, which are produced when the body is short of insulin and burns fat instead of sugar Also see "FDA Warning On SGLT-2 Drugs Raises Specter Of Labeling Change" - Pink Sheet, 15 May, 2015..

FDA subsequently added a warning of the risk of ketoacidosis and serious urinary tract infections to the label of SGLT2 inhibitors and required manufacturers to conduct a post-marketing study, which is to include analyses of spontaneous reports of ketoacidosis in patients treated with the drugs ([A#14151204004]).

The agency issued a safety alert about canagliflozin alone in May, reporting that an ongoing clinical trial found an increase in leg and foot amputations in patients treated with Invokana and Invokamet. The agency said it had not determined if canagliflozin increases amputations and that it is investigating the safety issue.

Canagliflozin was the subject of another safety communication in September 2015 when the agency added a new Warning and Precaution to the label about the risk of bone fracture. The agency said the information was based on updated information from several clinical trials that confirmed bone fractures occur more frequently with canagliflozin than placebo.

FDA also added new information about the risk of decreased bone mineral density based on the results of a study in 714 elderly individuals over two years which showed canagliflozin caused greater loss of bone mineral density at the hip and lower spine than placebo.

Invokana, Farxiga New Safety Warning May Give Jardiance Market Edge

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