FDA Advisory Committee Recommends Approval of Canagliflozin, But…

 

The FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 10-5 to recommend approval for canagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes but there may be a warning included….

If approved, canagliflozin (Invokana, Janssen) will be the first sodium-glucose co-transporter 2 (SGLT2) approved for marketing in the United States. The recommendation follows the recent denial of dapagliflozin (Forxiga; Bristol-Myers Squibb), another SGLT2 inhibitor, by the agency in August 2011.

However, the recommendation for approval came amid concern about an increase in LDL levels, cardiovascular events, renal function and bone safety.

Panelist Edward W. Gregg, PhD, from the CDC, said during the meeting after voting against approval, "The risk–benefit judgment is unfortunately subjective and this one was particularly difficult." "We saw a diverse set of benefits here, but they were largely surrogate outcomes wherein the mechanism that’s novel could conceivably affect the long-term impact. I found this clouded by the fact that the benefits were less in a large segment of the target population, and we had a variety of lingering questions ranging from bones and fractures to renal function to stroke and volume depletion."

Canagliflozin was evaluated at 100 mg and 300 mg once-daily doses in placebo- and active comparator-controlled studies. It was also evaluated in three larger studies, including in older patients, patients with moderate renal impairment and patients who had or were at risk for developing CVD.

According to phase 3 trials, renal safety findings suggest an early and dose-dependent decrease in estimated glomerular filtration rate (eGFR). However, this decrease did not tend to worsen as therapy continued.

The manufacturer submitted nine phase 3 studies that evaluated canagliflozin in patients with type 2 diabetes. Data on canagliflozin’s CV safety profile were of particular interest to panelists.

During the first 30 days of the ongoing Canagliflozin Cardiovascular Assessment Study (CANVAS), 13 major adverse cardiac events-plus, defined as a composite of CV death, nonfatal myocardial infarction, nonfatal stroke and hospitalization for unstable angina, were observed in 2,886 patients receiving canagliflozin and one major adverse cardiac event-plus occurred in 1,441 patients administered placebo, according to the FDA meeting materials.

Mat Soukup, PhD, for the FDA presented information that, canagliflozin did not appear to increase risk for major adverse cardiac events-plus after 30 days in the CANVAS trial, but some panelists still harbored concerns.

Peter Savage, MD, from the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH, who voted against approval, said during the meeting, "I have concerns about the fact that although the CV data look reassuring, you’re making an educated guess if you actually draw final conclusions based upon that, I think clearly some long-term follow-up is necessary to find out if there’s any adverse effect of the lipid changes that have been documented."

However, in an 8-7 vote, the panel also determined that canagliflozin is not associated with an unacceptable CV risk profile.

Furthermore, clinical data demonstrate that canagliflozin is associated with weight loss and reductions in blood pressure, as well as improvements to HbA1c levels. Some manageable tolerability issues included genital mycotic infections and urinary tract infections.

Although the FDA is not required to follow the recommendations of the advisory committee, it usually does

J&J News Release, Jan 07, 2013