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Expert Critique

FROM THE ASCO Reading Room

Justin B. Echouffo Tcheugui MD, PhD Johns Hopkins University

Sotagliflozin (brand name Zynquista), a dual SLGT-1 and SLGT-2 inhibitor, is the first oral medication to be evaluated as an adjunct to insulin therapy among adults with type 1 diabetes. If approved for use, sotagliflozin will be the second adjunct therapy for type 1 diabetes after the injectable pramlintide. Sotagliflozin holds potential for tremendous benefit for type 1 diabetes patients. However, its commercialization prospects are uncertain, heading into the U.S. Food and Drug Administration approval vote scheduled to take place in March 2019. A prior examination by an FDA regulatory panel reached a stalemate, as the vote by experts ended in a deadlock, which may influence the upcoming approval vote of the FDA.

The main argument of the proponents of sotagliflozin use among type 1 diabetes patients is the significant reduction in HbA1c levels over a short period of time (0.3% to 0.45% over 24 weeks), in an exceptionally large-scale clinical trial. The sotagliflozin in Tandem phase III program is the largest-ever conducted phase III trial among type 1 diabetes patients (involving ~3,000 patients in three studies) with the longest treatment duration of 52 weeks. Compared with placebo, a larger proportion of sotaglifozin users achieved an HbA1c <7% at week 24. The program examined two sotaglifozin doses; the 200 mg dose led to a 0.3-0.35% drop in HbA1c, and the 400 mg dose to a 0.35-0.45% reduction.

Several of the FDA regulatory panel members voted for the 200 mg dose because of the higher risk of diabetic ketoacidosis (DKA) associated with the 400 mg dose.

An eight-fold increase in the risk of DKA was associated with the use of sotagliflozin versus placebo in clinical trials. This safety concern was the main driver of the FDA regulatory panel decision. Although sotagliflozin was not used as an insulin-sparing drug, a reduction in the dose of insulin among patients who experienced lower blood glucose levels may have led to DKA. A lack of net benefit in the overall risk assessment of the drug also motivated the decision of the FDA regulatory panel. The estimated number needed to harm was ~26 person-years of exposure to sotagliflozin to observe one additional DKA event, otherwise expressed as one new case of DKA expected to occur among 26 cases of people treated with sotagliflozin. Moreover, most observed DKA events resulted in hospitalizations, at times requiring additional interventions such as intubation.

At this stage, it appears that additional studies are needed to shed light on the risk of DKA and on approaches to prevent it among people taking sotagliflozin, before the drug is approved for use in type 1 diabetes.

Full Critique

Drugmakers say sotagliflozin holds tremendous benefit for people with type 1 diabetes. The U.S. Food and Drug Administration, however, is not so sure.

After a key vote ended in an 8-8 deadlock, the prospects for sotagliflozin, which would be marketed under the brand name Zynquista, are uncertain heading into the approval vote on March 22.

In January, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC), the opinions of which are influential but not binding, reached a stalemate after hearing from a range of experts regarding sotagliflozin, a combination SLG-1 and SLG-2 inhibitor that, if approved, would be the first oral therapy for adults with type 1 diabetes designed to serve as an adjunct to insulin therapy. As it stands, only one insulin adjunct -- the injectable drug pramlintide -- exists for adult patients with type 1 diabetes.

Proponents of sotagliflozin, including drug makers Sanofi and Lexicon, pointed to the significant reduction in HbA1c levels achieved in phase III clinical trials.

Skeptics decried the eight-fold increase in the risk of diabetic ketoacidosis (DKA) that occurred in study participants who took sotagliflozin compared with those who took a placebo.

The drug faces a murky future as it moves toward the FDA's anticipated approval date, also known as the Prescription Drug User Fee Act (PDUFA) date, when the administration will determine sotagliflozin's future.

"We will continue to work closely with the FDA as the agency completes its review," said Chas Schultz, executive director of corporate communications and patient advocacy for Lexicon, which is developing the drug with Sanofi. "To the best of our knowledge, the FDA plans to move forward and complete their review of sotaglifozin by the anticipated PDUFA date ... We are confident in the data we submitted for sotagliflozin's new drug application."

The Pros

As its supporters pointed out, sotagliflozin achieved a decrease in HbA1c levels ranging from 0.3% to 0.45% following 24 weeks of treatment in a large clinical trial. Drug makers reinforced the large size and scope of the investigation.

"The sotagliflozin in Tandem phase III program is the largest phase III trial among type 1 diabetes patients to date, comprising three studies involving approximately 3,000 adults with type 1 diabetes with the longest treatment duration of 52 weeks," Schultz said. "Sotagliflozin has the potential to be the first oral antidiabetic drug approved in the United States together with insulin therapy to improve glycemic control in adults with type 1 diabetes."

The trials examined two separate dose levels. At 200 mg daily, HbA1c levels dropped 0.3-0.35%; the 400 mg dose saw a 0.35-0.45% reduction. Compared with placebo, more people taking sotaglifozin achieved the primary outcome of HbA1c levels below 7% at week 24 compared with the placebo group.

Although reductions were slightly higher for those taking 400 mg of the drug, several EMDAC members who voted in favor of sotagliflozin did so only for the 200 mg dose given higher DKA risks at 400 mg, according to coverage of the meeting by 番茄社区.

The Cons

The increased DKA risk for sotagliflozin users may have been downplayed by drugmakers seeking to accentuate sunnier data points from the trial, one FDA official suggested.

"The sponsor stated that sotagliflozin is not intended to be an insulin-sparing drug and yet in trials, some patients had to reduce insulin dosing, likely due to decreasing blood glucose," said Mitra Rauschecker, MD, an endocrinologist and FDA medical officer who presented findings on sotagliflozin at the EMDAC meeting. "This action may in part have contributed to DKA risk ... We emphasize that the regulatory decision must be based on the overall risk assessment of the product in question, and we do not agree that the sponsor's composite endpoint truly assesses the net benefit of the product or helps to inform the overall benefit-risk assessment."

According to the clinical data, the estimated number needed to harm was approximately 26 person-years of exposure to sotagliflozin to observe one additional DKA event (95% CI 20.1-38.5). In other words, one case of DKA is expected to occur among 26 cases of people treated with sotagliflozin.

"These are clinically significant events that resulted in hospitalizations in the vast majority of the cases," Rauschecker said. "Sometimes they required additional interventions, such as intubation."

Drug makers have indicated a willingness to develop and make available different tools to help reduce DKA risk in people taking sotagliflozin, but such tools have yet to be put forward or evaluated.

Speaking to 番茄社区 following the EMDAC vote, committee member Jack Yanovski, MD, PhD, of the National Institute of Child Health and Human Development in Bethesda, who voted no on approval, claimed the drug was not "ready for prime time."

"I think there are additional studies that need to be done before this is released on a wider public," Yanovski said. "This is a very difficult decision."

Although EMDAC votes are not binding, they are generally believed to carry substantial weight in the FDA's approval deliberations. It is unclear whether or to what extent the deadlocked voted will influence the approval vote.