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After an FDA denial and a lost sponsor, sotagliflozin shows it can cut cardiovascular events and possibly treat a form of heart failure that has no approved therapies.
More than a year after Sanofi abandoned a unique diabetes drug that sought to compete in a crowded market, results from a pair of trials show the drug, sotagliflozin, is the first with signs it can treat a type of heart failure that has no approved therapies.
Results from the SOLOIST-WHF and SCORED trials, presented this evening at the American Heart Association Scientific Sessions, found some evidence that the dual SGLT1/2 inhibitor offers benefits for patients with heart failure with preserved ejection fraction, or HFpEF.
The class of drugs known as sodium glucose co-transporter 2 (SGLT2) inhibitors were developed to treat type 2 diabetes by targeting a protein in the kidney that normally allows the body to retain blood glucose. After FDA safety trials showed unexpected benefits in heart failure and preserving renal function, companies raced to launch studies to show new uses for the drugs.
Competitors Farxiga (dapagliflozin, AstraZeneca) and Jardiance (empagliflozin, Eli Lilly/Boehringer Ingelheim) have shown benefits in heart failure with reduced ejection fraction (HFrEF), and earlier this year FDA approved Farxiga for this use.
Right now, both drugs are in a race with Novartis’ Entresto to demonstrate benefits in HFpEF. FDA accepted Novartis’ application for this use in June.
For Lexicon Pharmaceuticals, it’s a turn of events officials insisted would come more than a year ago, when the company parted ways with Sanofi after setbacks at FDA and disagreements over the meaning of early trial results in chronic kidney disease (CKD).
Lead investigator Deepak L. Bhatt, MD, of Harvard Medical School said the findings from SOLOIST-WHF and SCORED show that patients with severe kidney disease may be among the particular groups that would benefit most from sotagliflozin, which also targets the SGLT1 protein in the gut to further limit the body’s retention of blood glucose.
In a preview for reporters, Bhatt said the findings suggest that sotagliflozin could be an option for patients with significant comorbidities, and, if given to those hospitalized for heart failure, sotagliflozin could keep them from being readmitted—a priority in managed care.
Targeted to the right patients, he said, sotagliflozin could offer unique benefits because of its mechanism of action. “One particular niche could be patients with severe kidney disease.”
Trial data presented today come from SOLOIST-WHF, which randomized 1222 patients with type 2 diabetes who had been recently hospitalized for worsening heart failure, and SCORED, a much broader, 10,584 patient trial that studied the drug’s ability to prevent cardiovascular events in patients with diabetes and CKD.
Investigators had to revise end points in both trials to focus on total events after losing funding due to the COVID-19 pandemic, and the results concentrate on CV deaths, hospitalizations for heart failure and urgent emergency room visits for heart failure.
Results for SOLOIST-WHF showed a CV event rate that was 33% lower for patients taking sotagliflozin compared with those taking placebo, as well as fewer deaths. In SCORED, patients taking sotagliflozin had an event rate that was 26% lower than that of placebo.
Notably, Bhatt presented data for SCORED that showed the drug produced twice as large a drop in A1C than placebo, and this held across patients with moderate and severe renal decline—which had been the sticking point between Lexicon and Sanofi after much smaller trials reported topline results.
Bhatt said other evidence has suggested that SGLT2 inhibition could offer benefits in HFpEF, but until now investigators have not found a signal in a prospective trial.
“For the first time we've actually demonstrated prospectively that an SGLT2 inhibitor with SGLT1 inhibition capability is something that is useful for heart failure with preserved ejection fraction,” he said, noting that there are 2 ongoing trials, DELIVER for dapagliflozin and EMPEROR-Preserved for empagliflozin, that are examining this question for SGLT2 inhibitors.
“I would predict based on the results of SOLOIST, and the combined SOLOIST/SCORED [results], for that those trials will also be positive,” Bhatt said.
The road ahead for sotagliflozin is unclear. Although it was approved to be marketed as Zynquista to treat type 2 diabetes, officials had hoped for an approval in type 1 diabetes, to add to insulin and reduce the highs and lows of glycemic variability, which contribute to long-term damage to eyesight and the kidneys. But FDA said no, over concerns about diabetes ketoacidosis.
Bhatt said that while he is cautious about the HFpEF findings, he believes there’s good reason for FDA to consider new uses for the drug. “I have recommended to the company leadership that they file for FDA approval and they seem interested in doing that, given the very positive results of both trials and the strength of the data,” he said.