FDA panel favors diabetes drug despite CV safety concerns

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An FDA advisory panel recommended Jan. 10 on a 10-5 vote approval for canagliflozin (Invokana, Janssen Research & Development) to treat type 2 diabetes in adult patients. But the panel also expressed concerns about the drug’s cardiovascular safety. In a separate vote on cardiovascular safety, the panel voted 8-7.

Canagliflozin is an investigational, oral, once-daily medication for the treatment of adult patients with type 2 diabetes. A selective sodium glucose co-transporter 2 (SGLT2) inhibitor, the drug blocks the reabsorption of glucose by the kidney, increasing glucose excretion and lowering blood glucose levels in people with diabetes who have elevated blood glucose levels.

The recommendation was based on the efficacy and safety results of a Phase 3 clinical program that enrolled 10,285 patients in nine studies. Canagliflozin was evaluated at 100 mg and 300 mg once-daily doses in placebo- and active comparator-controlled studies, as well as three large studies in special populations: older patients, patients with moderate renal impairment and patients who had or were at risk for cardiovascular disease. Results showed that in addition to the improvements in glycemic control, both doses of canagliflozin were associated with weight loss and reductions in blood pressure across clinical studies.

The cardiovascular risk was assessed in a prespecified meta-analysis of cardiovascular events using an endpoint that combined cardiovascular death, nonfatal MI, nonfatal stroke and hospitalization for unstable angina, according to the FDA. Panel members were instructed to discuss their level of concern “regarding the apparent imbalance not favoring canagliflozin” in observed early major adverse cardiovascular events (MACE-plus).

The prespecified meta-analysis of the number of events from all trials showed a MACE-plus rate of 18.9 percent in the canagliflozin group vs. 20.5 percent in the comparator group, but for the stroke component the rate was 6.8 percent vs. 4.6 percent.

An analysis of CANVAS, an ongoing study to evaluate canagliflozin compared to placebo on cardiovascular events, the FDA reported “a higher rate of MACE-plus was observed among subjects on canagliflozin during the first 30 days after the first randomized treatment dose, and a lower rate was observed on canagliflozin after 30 days.” The MACE-plus rate within the first 30 days in CANVAS was 0.45 percent in the canagliflozin group vs. 0.07 percent in the placebo group. After the first 30 days, there were 29.9 events per 1,000 patient-years in the canagliflozin group vs. 33.6 events per 1,000 patient-years in the placebo group.

If approved by the FDA, canagliflozin would be the first in this new class of diabetes therapies available in the U.S. The FDA has given previous applications for SGLT2 inhibitors a cool reception, including the new drug application (NDA) for Bristol-Myers Squibb and AstraZeneca's investigational compound dapagliflozin.

FDA will consider the advisory committee recommendation in its review of the NDA for canagliflozin. The agency often, but no always, follows the panel’s recommendation.