The FDA's decision to reject AstraZeneca plc and Bristol-Myers Squibb Co.'s Type II diabetes drug dapagliflozin last week was no surprise, given the drug's spotty safety record and a negative advisory panel vote. But the rejection isn't necessarily a death sentence for dapagliflozin, or for other SGLT2 inhibitors in development.

Sodium-dependent glucose cotransporters (SGLT) facilitate reabsorption of glucose into the bloodstream, and their inhibition results in excretion of glucose in the urine instead. It's a powerful mechanism to combat hyperglycemia, and several pharma and biotech firms have SGLT inhibitors in development including Johnson & Johnson, Pfizer Inc., Boehringer Ingelheim GmbH partnered with Eli Lilly and Co., Lexicon Pharmaceuticals Inc., BHV Pharma Inc. and Sirona Biochem Corp.

Yet dapagliflozin is the most advanced: AstraZeneca and BMS have shown in numerous Phase III trials that the drug lowers HbA1c levels, fasting plasma glucose and body weight as a monotherapy and in combination with other diabetes drugs like metformin or sulphonylureas. Even so, an FDA advisory committee voted nine-to-six against approval of the drug, mainly because of concerns regarding breast and bladder malignancies. Then last week, the FDA issued a complete response letter requesting additional data from ongoing studies and potentially from new trials.

Does this setback reflect negatively on the other SGLT2 inhibitors in development? "Absolutely not," according to William Wilkison, chief scientific officer at BHV Pharma. Wilkison said it's not clear what's causing the malignancies – that's why the FDA wants more data – but it's not likely to be SGLT2 inhibition. Although SGLT2 inhibitors as a class have been associated with certain infections, they have not been linked to cancer.

Wilkison also noted that SGLT2 inhibitors have another safety card in their favor: a good cardiovascular profile. Cardiovascular issues were the downfall of diabetes drug Avandia (rosiglitazone, GlaxoSmithKline plc), which has been removed from the market in Europe and restricted in the U.S. The uproar around Avandia also led the FDA to issue guidance requiring large cardiovascular safety studies for all new diabetes drugs. (See BioWorld Today, Sept. 24, 2010.)

But SGLT2 inhibitors actually seem to have cardioprotective effects, said BHV Pharma Chief Business Officer James Green.

Even if cardiovascular safety isn't an issue for dapagliflozin, cardiovascular efficacy might be, according to a research note from ISI Group analyst Mark Schoenebaum. He said a BMS email revealed that the FDA is looking for evidence of "additional benefit" with dapagliflozin, which he hypothesized could mean the agency wants to see cardiovascular outcomes data prior to approval. Conducting such a study could delay approval by five years or more, he said, although such a request would be unusual in the pre-marketing setting.

Regardless, AstraZeneca and BMS are not throwing in the towel on dapagliflozin. The companies said they remain committed to the drug and are working with the FDA regarding next steps. And it's not likely the other developers of SGLT2 inhibitors are slowing their progress, either.

"I do think SGLT2 as a class will be successful," Green said.