Safety concerns lead to a split FDA panel vote on Sanofi/Lexicon diabetes drug
The first potential pill for patients with the less common type 1 diabetes, who produce no insulin, was the subject of an atypical hung jury vote at an FDA panel on Thursday, in which experts were divided evenly over whether the life-threatening risk of diabetic ketoacidosis associated with the drug offset its benefit.
The drug, sotagliflozin, from Lexicon Pharma and Sanofi is being developed for both type I and type II diabetes. It is designed to inhibit two proteins involved in glucose regulation: SGLT1, which is responsible for glucose reabsorption in the GI tract and SGLT2, which is responsible for glucose reabsorption by the kidney. Many existing diabetes drugs only target SGLT2. Although the molecule is currently being tested in a plethora of trials in patients with type II diabetes, the oral drug is currently under FDA review for type 1 diabetics, who face multiple daily injections of insulin, or use an insulin pump, to achieve glycemic control.
The application for type 1 diabetics was on the basis of three late-stage trials. However, an increase in the risk of diabetic ketoacidosis (DKA) was observed with sotagliflozin treatment — and it was this issue that was central to the split 8-8 vote on Thursday. Although the FDA is not obligated to follow the recommendations of the panel, it usually does. In this case, the regulator has received a decidedly mixed message, and is set to make its decision by March 22. The drug is also under EMA review.
In a report published on Tuesday, FDA reviewers acknowledged that the risk of DKA has been observed with SGLT2 inhibitor use in type II diabetics, and existing approved drugs in the class carry warnings to highlight the risk. “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,” regulatory staff wrote.
In the meeting of independent experts on Thursday, nearly all panelists, regardless of their final vote, agreed the drug — to be sold as Zynquista — would only be appropriate for a small subset of particularly attentive type I diabetes patients, in context of the DKA risk.
Stifel’s Stephen Willey said he was surprised at the emergence of a more-negative tone from the agency’s presentation relative to what was included within the FDA staff report posted two days prior, despite valid points made about the company’s risk mitigation plan.
Willey wrote: “…the agency’s attempt to frame sotagliflozin-mediated DKA risk relative to post-marketing DKA events associated with off-label SGLT2i utilization was inherently flawed. We’re not trivializing the risk here…However, we do believe the assumption of risk – particularly for a drug which has surpassed the required efficacy threshold in a disease which has been absent of innovation since the advent of insulin itself – should be an individualized decision made between patient/physician…this same story has already played out in the world of insulin pumps – whereby transitioning a type I diabetes patient from injectable to pump-delivered insulin significantly increased DKA rates. Yet with sufficient patient awareness/education, these rates became manageable over time.”
Most analysts trimmed their expectations of the drug’s approval for type I diabetics.
Willey said his model still assumed a commercial launch in the US and EU in 2019, acknowledging that the timing was unclear given the result of FDA panel meeting. He cut his 2021 US sales estimate to $245 million from $385 million. “If approved, we still believe this could prove to be a >$750M product in both the U.S. and EU with <12% market share amongst a growing number of type I diabetic adults,” he noted.
Other analysts were somewhat more pessimistic. Needham’s Alan Carr said he now believes an FDA approval in type I diabetes is possible, but not probable, and that he had eliminated the revenue stream from his model. Cowen analysts, meanwhile, were ready to throw in the towel, saying they now expect an FDA rejection in March.