FDA panel backs approval of canagliflozin for type 2 diabetes
FROM A MEETING OF THE FDA'S ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE
Adverse effects associated with canagliflozin included genital mycotic infections in both men and women. Urinary tract infections, urinary frequency or thirst, and other adverse events related to osmotic diuresis, and adverse events related to reductions in intravascular volume, such as postural hypotension, were also higher among those on canagliflozin. However, the discontinuation rate from adverse events was low, and the incidence of serious adverse events and deaths were similar among those on canagliflozin and controls. There was also a "modest" dose-dependent increase in bone resorption associated with the drug in studies, which the company said could be caused by weight loss. Renal adverse events were higher among those on canagliflozin, compared with placebo, and led to a higher discontinuation rate among those on 300 mg.
The cardiovascular outcome study CANVAS, is comparing the rate of a composite major adverse cardiovascular event (MACE) endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina) in about 4,300 patients at high risk of CV disease, with a 2:1 randomization. In the first 30 days of treatment, there were 13 events among those on canagliflozin (including six strokes, one of which was a fatal ischemic stroke), and one event in placebo patients in the first 30 days of treatment, an imbalance the company said reflected the month-to month variability and was not associated with adverse events related to volume depletion. The hazard ratio for MACE-plus events in the first 30 days of the cardiovascular outcomes study was 6.49, dropping to 0.89 after 30 days, and was 0.64 in other studies, according to the FDA.
Janssen is recommending a starting dose of 100 mg for patients on a loop diuretic, patients with moderate renal impairment (eGFR 30 to less than 60 mL/min per 1.73m2), or those who are aged 75 years and older, because these groups of patients were at higher risk of adverse reactions related to volume depletion in the studies. Because it would not be effective, canagliflozin would not be used in patients with severe renal impairment (eGFR less than 30 mL/min per 1.73m2), end stage renal disease, or in patients on dialysis.
Another SGLT2 inhibitor, dapagliflozin, was not approved by the FDA, presumably because of potential increases in the risk of bladder and breast cancers associated with the drug. If approved, Janssen plans to market canagliflozin as Invokana.* In December 2012, the company submitted an application for approval of a combined fixed dose formulation of canagliflozin with immediate-release metformin.
Canagliflozin, which is also under review for approval in the European Union, has not yet been approved anywhere. The FDA’s deadline for making a decision on approval is the end of March. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.
*Correction, 1/15/13: An earlier version of this story misspelled Invokana.
