12:00 AM
Jan 21, 2013
 |  BioCentury  |  Regulation

Still invoking caution

J&J's Invokana: Despite panel vote, caution still watchword for FDA in diabetes

If FDA takes the advice of its Endocrinologic and Metabolic Drugs Advisory Committee, Johnson & Johnson's Invokana canagliflozin will be the first sodium-glucose cotransporter 2 inhibitor approved for diabetes in the U.S. But FDA's analysis of the cardiovascular safety data for the compound suggests the agency is still being very cautious in evaluating CV adverse events for diabetes therapies.

On Jan. 10, the Endocrinologic and Metabolic Drugs panel voted 10-5 that efficacy and safety data for Invokana support approval. Invokana was studied in the largest diabetes program to date, including seven Phase III efficacy trials and the Phase III CANVAS trial, a 4,327-patient CV outcomes trial.

A CV safety meta-analysis conducted by J&J showed Invokana had a slight CV benefit, with a hazard ratio of 0.91 and a 95% confidence interval of 0.68-1.22. That's well below the 1.8 upper bound set out in 2008 FDA guidance for evaluating CV risk in new diabetes therapies. The meta-analysis included more than 9,700 patients.

But FDA reviewers still appear to be handling the CV risk of diabetes drugs with extra caution - particularly for compounds with a new mechanism of action - in the wake of its experience with Avandia rosiglitazone (see BioCentury, July 19, 2010).

At the Invokana meeting, the agency and panel spent considerable time discussing the relevance of a post hocanalysis on data from CANVAS conducted by FDA. The analysis showed a higher incidence of CV events within the first 30 days for patients receiving Invokana compared to placebo.

While some panel members found the analysis to be arbitrary, others felt there was a mechanistic rationale that warranted further investigation.

Panel members also expressed concern over whether Invokana should be used in patients with moderate renal impairment, where the efficacy of the molecule is diminished and patients are at higher risk of adverse events.

The issue helped lead four panelists to vote against approval.

The benefits

Doctors have been hoping to use SGLT2 inhibitors as second-line treatment because they are oral, cause weight loss, have no intrinsic risk of hypoglycemia, have the potential to provide cardiovascular benefit and appear to be as efficacious as some second-line diabetes drugs (see BioCentury, July 4, 2011).

SGLT2 is a transporter protein found exclusively in the kidneys that promotes reabsorption of glucose into the bloodstream. Blocking the protein increases the amount of glucose excreted in urine, thus lowering plasma glucose and reducing hyperglycemia.

At the meeting, FDA and panel members did not question Invokana's overall efficacy. Invokana monotherapy led to placebo-adjusted HbA1c reductions of up to 1.2%.

The compound's insulin-independent mechanism also provides an additive effect when combined with other anti-diabetic therapies. In...

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