乌鸦传媒

The SGLT-1/2 inhibitor sotagliflozin will come before the FDA's Endocrinologic and Metabolic Drugs Advisory Committee on Thursday as potentially the first drug in its class to be approved for type 1 diabetes, although agency staff aired concerns about increased risk for diabetic ketoacidosis (DKA).

While SGLT-2 inhibitors are a popular therapy option for type 2 diabetes, Sanofi's oral sotagliflozin -- a dual inhibitor of sodium-glucose cotransporter 1 (SGLT-1) as well as its SGLT-2 cousin -- could be the first oral adjunctive therapy for people with type 1 diabetes. Developer Sanofi is seeking approval for sotagliflozin as an insulin add-on in patients with type 1 diabetes inadequately controlled with insulin alone. It has tentatively picked Zynquista as a brand name if it's approved.

SGLT inhibitors delay and reduce glucose reabsorption after a meal by increasing urinary glucose excretion. The proposed dosing of the drug is 200 mg once daily prior to the first meal of the day, with increase to 400 mg daily when necessary.

Currently, the only FDA-approved therapeutic options for type 1 diabetes include insulin and injectable pramlintide (Symlin) as an adjunct to insulin, which was approved back in 2005.

"FDA recognizes there is an unmet need for patients with T1DM to help achieve glycemic goals and improve quality of life and treatment satisfaction," they wrote in , but were then quick to point out safety concerns with adding adjunctive therapies.

"During development of pramlintide ... an increased risk of severe hypoglycemia in combination with insulin relative to insulin alone was observed," FDA staff wrote in their briefing material. "Further assessment identified a patient population and method of use that lowered the risk of severe hypoglycemia to an incidence comparable to insulin alone, providing a favorable benefit risk profile, and supporting an approval decision."

A similar situation could play out with the convening of the advisory panel, who will review the benefit-risk profile of sotagliflozin from its clinical trial data, most notably from the phase III inTandem3 study.

In the program, which included three safety and efficacy studies, all reported superiority versus placebo for achieving HbA1c reduction at both the 200-mg and 400-mg doses after 24 weeks. At the 200-mg dose, the drop in HbA1c ranged from 0.3% to 0.35%, while those on the 400-mg dose saw a reduction of 0.35% to 0.45%. Significantly more participants at both doses achieved the primary endpoint of HbA1c under 7% at week 24 without severe hypoglycemia or DKA.

In all studies, there was also a significant weight benefit seen with both doses, although was greater at the 400-mg dose. This additional benefit could help tip the scales in favor for the drug as the panel assessed the benefit/risk profile.

FDA staff raised few questions about the agent's efficacy in the briefing document, but they pointed to a markedly increased risk for DKA in the clinical trial data -- specifically, an 8-fold increase relative to placebo (95% CI 3.1-19.9) and a number needed to harm of 26 patient-years of drug exposure to yield one DKA event. Episodes were more common at the 400-mg dose. The briefing document called this safety signal "notable and concerning."

When the pivotal trial data were presented in September 2017, lead author Satish K. Garg, MD, of the University of Colorado Denver, told 乌鸦传媒 "there may be some post-marketing studies if and when the drug is approved by the FDA." The agency is currently considering revisions to its policy to require cardiovascular outcomes trials for diabetes drugs, but in the meantime, one would presumably be mandated for sotagliflozin. The DKA issue could also be seen as needing a specific post-marketing study.

At Thursday's meeting, panel members will vote on whether the available data presented by Sanofi suggests the benefits of oral, once-daily sotagliflozin, as adjunct to insulin outweigh the risks. If in favor, members may recommend labeling restrictions, whether additional studies are needed after approval and which of the proposed doses are recommended for approval.

While the FDA is not required to abide by the advisory committee's recommendation, it typically does.

For the type 1 diabetes indication, the FDA has a decision deadline of March 22. Sanofi is also aiming at some point to win approval for sotagliflozin in type 2 diabetes. More than a dozen trials in the latter indication are planned or underway, .