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SILVER SPRING, Md. – An FDA advisory committee is split down the middle on whether to recommend the SGLT-1/2 inhibitor sotagliflozin (Zynquista) for approval.

In a vote of 8-8, members of the Endocrinologic and Metabolic Drugs Advisory Committee couldn't reach a consensus whether or not the benefits outweighed the risks of Sanofi's investigational drug, which the drugmaker wants OK'd as an add-on to insulin therapy in patients with type 1 diabetes.

Calling this "a very difficult decision," Jack Yanovski, MD, PhD, of the National Institute of Child Health and Human Development in Bethesda, said that he didn't think the drug was "ready for prime time" despite its advantages.

"I think there are additional studies that need to be done before this is released on a wider public," he said, specifically pointing out a need for data to support a risk evaluation and mitigation strategy for reducing diabetic ketoacidosis (DKA) with the drug. Clinical trial data had shown an 8-fold increase in DKA risk relative to placebo.

After voting "yes," Rebecca Brown, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases, said she expected "a subset of patients for whom the benefits of this drug will outweigh the risks, but that's certainly not going to be true for every patient."

Some members who voted yes said this vote hinged on future research on risk reduction and monitoring strategy for reducing DKA. Many members who voted yes also only voted for a dose of 200 mg to be recommended for approval, rather than the 400-mg dose also tested.

If approved, this would be the first oral therapy indicated for adults with type 1 diabetes as an adjunct to insulin therapy. Dosage of the once-daily oral therapy is recommended in a 200 mg dose before the day's first meal; Sanofi proposed that it could then be increased to 400 mg once daily if well-tolerated in patients not yet achieving glycemic control.

Throughout Thursday's meeting, efficacy of the drug was only lightly debated, as the risk of DKA served as the main topic of discussion. As efficacy was established through a phase III clinical program, including three safety and efficacy studies, superiority of sotagliflozin was reported in all studies when compared with placebo for a significant reduction in HbA1c levels -- a drop ranging from 0.3% to 0.45% after 24 weeks of adjunct treatment. Although the reduction in HbA1c levels was significant at both doses tested -- 200 mg and 400 mg -- the magnitude of benefit was slightly greater at the higher dose. This was also paired with a reduction in body weight seen with the drug, as well as higher patient satisfaction with the treatment regimen.

However, both doses were also accompanied by an increased risk for DKA, which served as the main topic of debate throughout the meeting.

"While all patients with type 1 diabetes may to some degree be at risk for DKA, sotagliflozin therapy clearly increases that risk, and the risk may be unpredictable," noted FDA .

In order to mitigate it, Sanofi proposed educational materials and patient leaflets on DKA risks. The firm also suggested blood or urine ketone monitoring of patients on the drug, and following the : hydration, carbohydrate intake, insulin, and calling a healthcare provider.

During a more than hour-long public comment period, the panel heard from healthcare providers arguing both sides. Advocates for approval pointed to a lack of effective treatment options in addition to insulin for type 1 diabetes. Some also offered successful anecdotal evidence of using SGLT-2 inhibitors off-label in patients with type 1 diabetes, while others offered strategies for reducing DKA risk, including daily ketone monitoring. But others argued that the DKA risk is an insurmountable hurdle. (In a Thursday press release, the consumer group and urged rejection of the drug.)

Prior to the vote when the panel was discussing the risk/benefit profile, the potential for reducing microvascular complications -- although there were no data on this -- seemed to sway some of the members. Weight loss was also brought up several times during discussion as a major benefit tipping the scales in favor of sotagliflozin. Despite many panel members calling the HbA1c benefit modest, some suggested other benefits such as time in range would make the drug's overall benefit in real-world practice even greater.

But the DKA issue hung over panel members all day. Several voiced doubts over whether patients would adhere to the risk mitigation strategy proposed by Sanofi, with many noting the sponsor didn't actually provide hard proof that it works. The increased risk for genital mycotic infections, seen with other SGLT-2 inhibitors, also raised concerns among members.

"I think it's impossible to understate the concern about DKA really just because the absolute increase is really remarkable," stated Michael Blaha, MD, of Johns Hopkins Ciccarone Center for the Prevention of Heart Disease in Baltimore. "I am concerned about the prospect that this could be worse in the real world [outside of the trial setting]."

"One thing I was surprised to see is very little data presented by the sponsor, at least right now, about proof that the risk-management strategy works or the best way to do it. It would be great if we had that data before we approved a drug -- say this is the best risk strategy rather than figuring it out later when patients are at risk," he continued. He added, however, that the drug appears beneficial.

Another topic of discussion was differentiating between the two proposed doses: 200 mg versus 400 mg.

"I am not convinced that it makes any sense to go beyond the 200 mg," said Marvin Konstam, MD, of Tufts Medical Center in Boston, citing the increased DKA risk at the 400-mg dose as his reasoning. "There's no great difference in terms of glycemic control."

In response, Brown said the drug's serum levels vary with body weight. "What we're looking for with the 400-mg dose is an effect comparable to the 200-mg dose in a smaller individual."

Although the FDA is not required to follow its advisory committees' recommendations, it typically does. However, split votes are generally taken as no recommendation one way or the other.

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