A panel of outside expert advisers to the U.S. Food and Drug Administration was split over whether the agency should grant approval to Sanofi and Lexicon Pharmaceuticals Inc. to market their experimental diabetes drug Zynquista.
At the end of an all-day meeting on Jan. 17, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 8 to 8 over whether the available data suggested the benefits of Zynquista, also known as sotagliflozin, outweigh its risks.
Trading in Lexicon shares was halted in advance of the meeting.
The companies are seeking approval to market Zynquista as an adjunct to insulin therapy to improve glycemic control in adults with type 1 diabetes mellitus, which affects about 1.25 million Americans.
The drug is an inhibitor of both sodium-glucose co-transporter 1, or SGLT1, and sodium-glucose co-transporter 2, or SGLT2.
The FDA, which is not required to take its advisory panels' advice, but generally does so, is expected to make a decision by March 22.
At issue was a serious adverse event observed in trials of Zynquista, known as diabetic ketoacidosis, or DKA, a potentially life-threatening complication that occurs when the body produces high levels of blood acids, or ketones, resulting in a deficiency of insulin.
SGLT2 inhibitors appear to increase the risk of DKA, according to the FDA.
"The mechanisms are beginning to be explored, but likely both indirect effects, through insulin dose reduction and volume contraction, and direct effects, through ketogenesis, are implicated," the FDA said in briefing documents ahead of the Jan. 17 meeting.
The FDA's panelists pondered over whether Zynquista could be restricted to a certain population that would be closely monitored for DKA under a risk evaluation and mitigation strategy plan, or REMS, a series of mechanisms put in place to ensure the benefits of a drug outweigh its risks.
Sanofi and Lexicon argued that more innovative drugs like Zynquista are needed, given the limited treatments available for type 1 diabetes.
Right now, the only adjunct to insulin therapy approved in the U.S. is pramlintide, an injectable synthetic analogue of human amylin.
Pramlintide is administered by injection three times daily and its use carries with it a risk of severe hypoglycemia, Sanofi and Lexicon noted in separate documents.
Risks concerns raise doubts
Half of the panelists on the FDA's advisory committee were skeptical about whether Zynquista's risks could be mitigated, while even some who voted for approval said they had some concerns about the drug's safety and wanted the regulator to impose a REMS.
"There's clearly a desperate need" for new medicines for type 1 diabetes, said panelist Jack Yanovski, chief of the growth and obesity division of intramural research at the U.S. National Institute of Child Health and Human Development.
But Zynquista is "not ready for prime time," Yanovski said. "The degree of benefit is small enough that it's not clear it could overwhelm the increased risk."
The drug clearly showed a significant benefit on glycemic control, said panelist Abigail Shoben, an associate professor of biostatistics at the Ohio State University.
But Shoben said she was "uncertain on how much true clinical benefit that was going to mean against a very real, very serious negative consequence," though she admitted it was a small percentage of patients who experienced the DKA in the trials.
"This drug has not been demonstrated to be safe," said panelist James de Lemos, chair of cardiology at the University of Texas Southwestern Medical Center in Dallas. "It doesn't make a lot of sense to me to give a drug that causes ketosis to type 1 diabetes in general. I didn't see anything in any of the data that would suggest this risk is potentially modifiable."
Panelist Martha Nason, a mathematical statistician at the U.S. National Institute of Allergy and Infectious Diseases, said she was unconvinced there was a reasonable trade-off between the drug's ability to improve glycemic control and the risk of DKA, even with the best monitoring, and once the drug gets out into the real world, many patients would be harmed.
Susan Ellenberg, a professor of biostatistics and medical ethics and health policy at the University of Pennsylvania, who voted in favor of Zynquista, noted the FDA has put a number of drugs on the U.S. market that carry serious risks, such as the schizophrenia medicine clozapine and the acne medicine isotretinoin.
Rebecca Brown, a clinical investigator at the National Institute of Diabetes and Digestive and Kidney Diseases, said that even though she voted in favor of Zynquista's approval, "I have serious hesitations about the safety of this drug in the broad community with type 1 diabetes."
"I think there's got to be a subset of patients for whom the benefits of this drug will outweigh the risks of this drug," Brown said. "That is certainly not going to be true for every patient. The task going forward will be having a risk evaluation and mitigation strategy that is going to effectively select and maintain the patients and providers who can use this drug in the safest way possible."
"We will continue to work with the FDA through its review process to hopefully bring to patients a new treatment that can help people living with type 1 diabetes control their blood sugar and address some of the challenges of insulin-only therapy," Rachele Berria, global vice president and head of diabetes medical affairs at Sanofi, said in a statement.