FDA Approves Sotagliflozin for Treatment of Heart Failure

^{Credit: Food and Drug Administration}

The US Food and Drug Administration has approved sotagliflozin (Inpefa) for the treatment of heart failure across the full range of left ventricular ejection fraction.

Announced by Lexicon Pharmaceuticals on May 26, 2023, the approval, which is the first approval for an SGLT1/2 inhibitor in agency history, indicates the agent for reducing the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure or type 2 diabetes, chronic kidney disease, and other cardiovascular risk factors.¹

“The approval of INPEFA along with the breadth of the label, is a major milestone in Lexicon’s path to fulfilling its mission of pioneering medicines that transform patients’ lives,” said Lonnel Coats, Lexicon’s chief executive officer.¹ “We expect this important innovation to be commercially available in the U.S. market by the end of June 2023.”

The path to this historic approval for sotagliflozin has not been straightforward. Once pushed as a type 1 diabetes medication, the agent was the subject of a 4-year partnership between Sanofi and Lexicon Pharmaceuticals, which was terminated following receipt of a CRL for the type 1 diabetes in July 2019.^2,3

With the May 26, 2023 approval, sotagliflozin becomes the first SGLT1/2 inhibitor to receive such and joins dapagliflozin and empagliflozin as the third drug boasting SGLT2 inhibition as a mechanism of action to receive an indication in heart failure across the spectrum of ejection fraction. The NDA for sotagliflozin as a treatment for heart failure, which was submitted by Lexicon Pharmaceuticals in July 2022, was supported by data from the SOLOIST-WHF and SCORED trials.⁴

A phase 3, double-blind, randomized, placebo-controlled trial, SOLOIST-WHF enrolled and randomized a population of 1222 patients with type 2 diabetes who were recently hospitalized for worsening heart failure. The trial’s primary endpoint was a composite of total cardiovascular deaths and worsening heart failure events.⁵

Although stopped early due to a loss of funding during the COVID-19 pandemic, results of the study indicated the rate of primary endpoint events was significantly reduced among those receiving sotagliflozin relative to their counterparts receiving placebo therapy during a median follow-up of 9.0 months (51.0 vs 76.3 events per 100 patient-years; Hazard ratio [HR], 0.67 [95% confidence interval [CI], 0.52-0.85]; P < .001). Further analysis data from the trial indicated sotagliflozin was associated with reductions in risk of cardiovascular mortality (HR, 0.84 [95% CI, 0.58-1.22]) as well as all-cause mortality relative to placebo therapy. In a posthoc analysis of the trial, results suggested the treatment effect for the primary composite endpoint achieved significance by 28 days of follow-up.⁵

SCORED was also a phase 3, double-blind, randomized, placebo-controlled trial, but, unlike SOLOIST-WHF, enrolled a patient population with type 2 diabetes, chronic kidney disease, and risks for cardiovascular disease. As a result of being stopped early due to a loss of funding, the primary endpoint of the trial was changed for the first occurrence of major adverse cardiovascular events (MACE) to a composite endpoint of cardiovascular death or worsening heart failure events. Of note, the MACE endpoint included cardiovascular death, myocardial infarction, and stroke.⁶

The trial enrolled a population of 10,584 patients and this cohort was followed for a median of 16 months. Results of the trial indicated the rate of primary endpoint events was significantly reduced among those receiving sotagliflozin relative to their counterparts receive placebo therapy (5.6 vs 7.5 events per 100 patient-years; HR, 0.74 [95% CI, 0.63-0.88]; P = .0004). When assessing for first occurrence of MACE, results indicated . In a posthoc analysis of the trial, results suggested the treatment effect for the cardiovascular death and worsening heart failure endpoint achieved significance by 95 days of follow-up.⁶

In SOLOIST-WHF, adverse events occurring at a greater rate with sotagliflozin use relative to placebo were diarrhea (6.9% vs 4.1%; P = .032), genital fungal infections (0.8% vs 0.2%; P = .12), and serve hypoglycemia (1.5% vs 0.3%; P = .037). In SCORED, diarrhea (8.5% vs 6.0%; P < .0001), genital mycotic infections (5.3% vs 4.0%; P = .003), and volume depletion (2.4% vs 0.9%; P < .0001) were more common with sotagliflozin than placebo.^5,6

“Based on outcomes observed in the SOLOIST-WHF study, initiating treatment with INPEFA prior to or upon hospital discharge has the potential to reduce the burden of readmissions on patients, caregivers, providers, and health systems,” said Craig Granowitz, MD, PhD, Lexicon’s senior vice president and chief medical officer.¹ “With today’s FDA approval, INPEFA is now a valuable option for physicians to consider when treating patients transitioning out of the hospital and working to break the cycle of repeated hospitalizations.”

References:

1. Lexicon Pharmaceuticals, Inc. Lexicon announces FDA approval of INPEFATM (sotagliflozin) for treatment of heart failure. Lexicon Pharmaceuticals, Inc. May 26, 2023. Accessed May 26, 2023. https://www.lexpharma.com/media-center/news/2023-05-26-lexicon-announces-fda-approval-of-inpefa-sotagliflozin-for-treatment-of-heart-failure.
2. FDA issues complete response letter for Zynquista(TM) (sotagliflozin). Sanofi. March 22, 2019. Accessed May 26, 2023. https://www.sanofi.com/en/media-room/press-releases/2019/2019-03-22-18-15-00-1759502.
3. Lexicon Pharmaceuticals, Inc. Lexicon Pharmaceuticals announces termination of Alliance and Settlement with Sanofi. Lexicon Pharmaceuticals, Inc. September 10, 2019. Accessed May 26, 2023. https://www.globenewswire.com/news-release/2019/09/10/1913802/0/en/Lexicon-Pharmaceuticals-Announces-Termination-of-Alliance-and-Settlement-With-Sanofi.html.
4. Lexicon Pharmaceuticals, Inc. Lexicon announces FDA acceptance of New Drug Application for Sotagliflozin to treat heart failure. Lexicon Pharmaceuticals, Inc. July 27, 2019. Accessed May 26, 2023. https://www.globenewswire.com/news-release/2022/07/27/2486783/0/en/Lexicon-Announces-FDA-Acceptance-of-New-Drug-Application-for-Sotagliflozin-to-Treat-Heart-Failure.html.
5. Effect of Sotagliflozin on cardiovascular events in patients with type 2 diabetes post worsening heart failure. American College of Cardiology. November 16, 2020. Accessed May 26, 2023. https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2020/11/11/22/00/SOLOIST-WHF.
6. Effect of Sotagliflozin on cardiovascular and renal events in patients with type 2 diabetes and moderate renal impairment who are at cardiovascular risk. American College of Cardiology. November 16, 2020. Accessed May 26, 2023. https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2020/11/11/22/02/SCORED.