INPEFA Tablet Ref.[107315] Active ingredients: Sotagliflozin

Cardiac Electrophysiology

In a randomized, placebo-controlled, active-comparator, crossover study, 58 healthy subjects were administered a single oral dose of sotagliflozin 800 mg or sotagliflozin 2000 mg (5 times the maximum recommended dose), moxifloxacin, and placebo. No increase in QT corrected for heart rate (QTc) was observed with either 800 mg or 2000 mg sotagliflozin.

Plasma C_max and AUC of sotagliflozin increased in a dose-proportional manner in the therapeutic dose range of 200 mg to 400 mg once daily. Accumulation of sotagliflozin was observed with an approximate 50-100% increase in both C_max and area under the concentration-time curve from 0 to 24 hours (AUC_0-24h) at steady state verses the first day of dosing.

Absorption

The absolute bioavailability of oral sotagliflozin 400 mg dose was approximately 25% (90% confidence interval [CI] 16% to 39%) for area under the concentration-time curve from time 0 to last measurable concentration (AUC_0-last). The contribution of enterohepatic circulation to the overall exposure is estimated to be approximately 50%. The median time to maximum plasma concentration (T_max) ranged from 1.25 to 3 hours, over a single-dose range of 200 mg to 2000 mg. Following administration of multiple doses (400 mg and 800 mg), the median T_max values ranged from 2.5 to 4 hours.

Food Effect

When sotagliflozin tablets were administered with a high-caloric breakfast compared to fasting conditions, plasma exposure to sotagliflozin as measured by C_max and AUC_0-inf increased by 149% and 50%, respectively. Multiple doses of sotagliflozin 400 mg given immediately before breakfast, 30 minutes prior to breakfast, and 1-hour before breakfast in healthy subjects showed a consistent effect of sotagliflozin on urine glucose excretion (UGE), insulin, and postprandial glucose (PPG) across all dose schedules. It is recommended that INPEFA be taken not more than one hour before the first meal of the day.

Distribution

Both sotagliflozin and its major human metabolite sotagliflozin 3-O-glucuronide exhibited high binding to human plasma proteins in vitro (>93% bound), which was not dependent on the concentration of sotagliflozin and sotagliflozin 3-O-glucuronide and was not influenced by the degree of renal or hepatic function.

Following administration of a single 400 mg dose of [¹⁴C]-sotagliflozin, the mean blood/plasma ratios for total radioactivity were 0.5 and 0.4 for C_max and AUC_0-last, respectively, and the mean whole blood to plasma concentration ratio of sotagliflozin ranged from 0.5 to 0.6.

The mean apparent volume of distribution of sotagliflozin following administration of a single 400 mg oral dose of [¹⁴C]-sotagliflozin was 9000 L.

Elimination

Metabolism

Following the administration of a single dose of 400 mg [¹⁴C]-sotagliflozin in healthy subjects, sotagliflozin was extensively metabolized predominantly to sotagliflozin 3-O-glucuronide and it represented 94.3% of the radioactivity in plasma.

The key enzymes responsible for the metabolism of sotagliflozin were UGT1A9 and, to a lesser extent, CYP3A4. Following incubation of sotagliflozin with UGT1A9, the 3-O-glucuronide metabolite of sotagliflozin was the main conjugate observed. No acyl glucuronides of sotagliflozin were identified.

Excretion

Following the administration of a single dose of 400 mg [¹⁴C]-sotagliflozin, 57% and 37% of the radioactivity was recovered in the urine and feces, respectively. These results indicate that the main route of elimination was renal. The predominant metabolite detected in urine was sotagliflozin 3-O-glucuronide, representing a mean of 33% of the administered radioactive dose. Unchanged [¹⁴C]-sotagliflozin was the predominant radioactive peak detected in fecal extracts representing a mean of 23% of the total administered radioactive dose. Sotagliflozin undergoes enterohepatic circulation. Following administration of 200 mg and 400 mg, mean terminal half-life (T_1/2) ranged from 21 to 35 hours for sotagliflozin and from 19 to 26 hours for sotagliflozin 3-O-glucuronide. Effective half-life of sotagliflozin ranged from 5 to 10 hours. Steady state was generally achieved after 5 days of once daily dosing with sotagliflozin 200 mg and 400 mg.

In healthy volunteers, mean oral clearance (CL/F) of sotagliflozin ranged from 260 to 370 L/hr following administration of 200 mg and 400 mg sotagliflozin. The median population PK model predicted CL/F in type 2 diabetes mellitus patients with normal renal function was about 300 L/hr.

Specific Populations

Renal Impairment

Exposure of sotagliflozin was evaluated in a dedicated PK study in subjects with mild (eGFR 60 to <90 mL/min/1.73 m²) and moderate (eGFR 30 to <60 mL/min/1.73 m²) renal impairment and with normal renal function (eGFR ≥90 mL/min/1.73 m²). Exposure to sotagliflozin following a single dose of 400 mg was approximately 70% higher in subjects with mild and up to 170% higher in subjects with moderate renal impairment compared to subjects with normal renal function [see Use in Specific Populations (8.6)].

Hepatic Impairment

In a study with subjects with reduced hepatic function, AUC of sotagliflozin was not increased in mild (Child Pugh A) hepatic impaired subjects but was increased by approximately 3-fold in moderate (Child Pugh B) and approximately 6-fold in severe (Child Pugh C) hepatic impaired subjects compared to subjects with normal hepatic function [see Use in Specific Populations (8.7)].

Effects of Age, Sex, Race, and Body Weight on Pharmacokinetics

Based on population PK analysis, age, body weight, sex and race (non-white versus primarily whites) do not have a clinically meaningful effect on the PK of sotagliflozin.

Drug Interactions

In Vitro Studies

The major human metabolite of sotagliflozin, sotagliflozin 3-O-glucuronide, was shown to have an in vitro potential to inhibit CYP3A4 and CYP2D6 and to induce CYP3A4.

Sotagliflozin was shown to have inhibitory effects on P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sotagliflozin is a substrate of the human uptake transporters organic anion transporter (OAT)3, organic-anion-transporting polypeptides (OATP)1B1, and OATP1B3, but not OAT1 and organic cation transporter 2 (OCT2). Sotagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations.

In Vivo Studies

Figure 1 summarizes the effect on sotagliflozin by concomitantly administered drugs. The observed changes in overall exposure (AUC) of sotagliflozin following coadministration with hydrochlorothiazide, ramipril, metformin, mefenamic acid, and oral contraceptives are not considered to be clinically relevant. Rifampicin (UGT inducer) decreases exposure to sotagliflozin [see Drug Interactions (7.2)].

Figure 1. Effect of Various Medications on the Pharmacokinetics of Sotagliflozin, Displayed as Geometric Mean AUCs and C_max Ratios:

Vertical reference lines indicate 100% (solid) and the 80%-125% range (dashed)
^a 400 mg sotagliflozin, administered as a single dose
^b 400 mg sotagliflozin, at steady state
AUC_0-last = area under the concentration-time curve from time 0 to last measurable concentration; AUC_0-tau = area under the concentration-time curve from time 0 to end of the dosing period; C_max = maximum drug concentration; EE = ethinyl estradiol; NO = norgestimate

Figure 2 summarizes the effect on concomitantly administered drugs by sotagliflozin. The increases in exposure (AUC) of metoprolol (CYP2D6 substrate) and rosuvastatin (BCRP substrate), as well as the decrease in exposure to midazolam (CYP3A4 substrate) are not considered to be clinically relevant. The increased exposure (C_max and AUC) in ramipril is not considered clinically significant because the exposure of ramiprilat, the primary active metabolite, is minimally increased.

The increase in exposure (C_max and AUC) of digoxin, a P-gp substrate, when coadministered with sotagliflozin, requires monitoring of patients [see Drug Interactions (7.1)].

Figure 2. Effect of Sotagliflozin on the Pharmacokinetics of Various Medications, Displayed as Geometric Mean AUCs and C_max Ratios:

Vertical reference lines indicate 100% (solid) and the 80%-125% range (dashed)
^a 400 mg sotagliflozin, administered as a single dose
^b 400 mg sotagliflozin, at steady state
^c Norelgestromin is the primary active metabolite of NO
^d Ramiprilat is the primary active metabolite of ramipril
AUC_0-last = area under the concentration-time curve from time 0 to last measurable concentration; AUC_0-tau = area under the concentration-time curve from time 0 to end of the dosing period; C_max maximum drug concentration; EE = ethinyl estradiol; NO = norgestimate

Carcinogenesis

Carcinogenesis was evaluated in a 6-month study in RasH2 transgenic mice and in a 2-year study in Sprague Dawley rats. Sotagliflozin did not increase the incidence of tumors in RasH2 transgenic mice at doses up to 100 mg/kg/day or in rats at doses up to 15-fold (males) and 45-fold (females) clinical exposure at the MRHD.

Mutagenesis

Sotagliflozin was not mutagenic or clastogenic, with or without metabolic activation, in the in vitro Ames bacterial mutagenicity assay, the in vitro Chinese hamster ovary cell chromosomal aberration study, and an in vivo micronucleus assay in rats.

Impairment of Fertility

Sotagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at doses up to 300 mg/kg/day, which represents an exposure multiple of 55 times the human exposure at the MRHD in both males and females.

14.1 SOLOIST Study

The SOLOIST (Effects of Sotagliflozin on Clinical Outcomes in Hemodynamically Stable Patients with Type 2 Diabetes Post Worsening Heart Failure) study (NCT03521934) was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study in patients with type 2 diabetes mellitus who had been admitted to the hospital, a heart failure unit, infusion center, or emergency department for worsening heart failure to determine if INPEFA reduces the risk of total occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit. Patients were randomized to treatment if they met the following criteria for clinical stability: no need for oxygen therapy, a systolic blood pressure of at least 100 mmHg, no need for intravenous inotropic or vasodilator therapy (excluding nitrates) and transitioned from intravenous to oral diuretic therapy.

Of the 1,222 randomized patients, 608 were randomized to INPEFA and 614 to placebo. Assigned treatment was initiated in the hospital or within a median of 2 days following hospital discharge.

The dose of study drug was to be up-titrated from 200 mg to 400 mg sotagliflozin or matching placebo as soon as 2 weeks or up until 8 months after initiation of treatment. The dose was increased to 400 mg once daily for 336 patients (56%) in the sotagliflozin group and 325 patients (53%) in the placebo group. The median time to up-titration was 16 days. Up-titration was to be performed based on the judgment of the investigator, who considered whether the patient’s clinical condition was satisfactory, whether the drug was well tolerated, and whether AEs typical of SGLT2 inhibitors had occurred, such as those associated with volume depletion.

At baseline, median age was 70 years, 34% were female, 93% were White and 4% were Black or African American. Median A1C was 7.1%, median body mass index (BMI) was 31 kg/m², and median eGFR was 50 mL/min/1.73 m². Median left ventricular ejection fraction (LVEF) was 35% (79% with LVEF <50%), median N-terminal pro B-type natriuretic peptide (NT-proBNP) was 1806 pg/mL, and the median Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) score was 41.

At baseline, 86% were treated with at least one antihyperglycemic medication, including 52% with a biguanide, 36% with insulin, 19% with a sulfonylurea, 16% with a dipeptidyl peptidase-4 (DPP4) inhibitor, and 3% with a glucagon-like peptide 1 (GLP-1) receptor agonist. At baseline, 91% were treated with inhibitors of the renin-angiotensin-aldosterone system, 92% with a beta blocker, 95% with a loop diuretic, and 10% with another diuretic.

INPEFA was superior to placebo in reducing the risk of the primary composite endpoint (Hazard Ratio [HR] 0.67 [95% confidence interval (CI) 0.53, 0.85]; p = 0.001). (Table 2).

Table 2. Treatment Effect for the Primary Composite, Components and Secondary Endpoint in the SOLOIST Study:

^a Based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization.
^b Predefined primary endpoint.
^c Predefined secondary endpoint and tested with multiplicity control.
^d Time-to-event analysis was performed; event rates are percentages of patients with events.

Figure 3 displays a cumulative events plot of the primary composite endpoint. The INPEFA and placebo event curves diverged early and remained separated over the study period.

Figure 3. Primary Composite Endpoint (Total Occurrences of Cardiovascular Death, Hospitalization for Heart Failure, and Urgent Heart Failure Visit) Over Time in the SOLOIST Study:

Primary composite endpoint was based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization.

The results of the primary composite endpoint were generally consistent across prespecified subgroups (Figure 4), including screening LVEF < 50 or ≥ 50% and timing of first dose (post-discharge versus prior to discharge).

Figure 4. Treatment Effect for Primary Composite Endpoint (Total Occurrences of Cardiovascular Death, Hospitalization for Heart Failure, and Urgent Heart Failure Visit) Subgroup Analysis (SOLOIST Study):

HF = heart failure; LVEF = left ventricular ejection fraction; MRA-mineralocorticoid receptor antagonist; NT-proBNP = N-terminal pro B-type natriuretic peptide; PY = patient-years

Primary composite endpoint was based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization.

Discharge may have been from hospital or urgent treatment facility where urgent heart failure visit occurred.

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

14.2 SCORED Study

The SCORED (Effects of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes Mellitus, Cardiovascular Risk Factors and Moderately Impaired Renal Function) study (NCT03315143) was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study in patients with type 2 diabetes mellitus (A1C >7%), chronic kidney disease (eGFR 25 to 60 mL/min/1.73 m²), and additional cardiovascular risk factors, such as a history of heart failure, obesity, dyslipidemia, hypertension, or elevated cardiac and inflammatory biomarkers, to determine if INPEFA reduces the risk of total occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit. Of the 10,584 randomized patients, 5,292 were randomized to INPEFA and 5,292 to placebo.

The dose of study drug was to be up-titrated from 200 mg to 400 mg sotagliflozin or matching placebo as soon as 4 weeks or up until 6 months after initiation of treatment. The dose was increased to 400 mg once daily for 3,934 patients (74%) in the INPEFA group and for 3,987 patients (75%) in the placebo group. The median time to up-titration was 29 days. Up-titration was to be performed based on the judgment of the investigator, who considered whether the patient’s clinical condition was satisfactory, whether the drug was well tolerated, and whether AEs typical of SGLT2 inhibitors had occurred, such as those associated with volume depletion.

At baseline, median age was 68 years, 45% were female, 82% were White, 3% Black or African American, 6% Asian, and 4% American Indian or Native Alaskan. Median A1C was 8.3%, median BMI was 32 kg/m², median eGFR was 45 mL/min/1.73 m² (8% with eGFR <30, 44% with eGFR 30 to <45, and 48% with eGFR ≥45 mL/min/1.73 m²), and median urinary albumin-to-creatinine ratio (UACR) was 82 mg/g (32% with UACR ≥300 mg/g). A history of heart failure was present in 31%, prior myocardial infarction had occurred in 20%, a prior cerebrovascular event had occurred in 9%, and coronary revascularization had been performed in 22% of patients prior to study entry.

At baseline, 97% were treated with at least one antihyperglycemic medication, including 56% with a biguanide, 64% with insulin, 27% with a sulfonylurea, 20% with a DPP4 inhibitor, and 6% with a GLP-1 receptor agonist. At baseline, 88% were treated with inhibitors of the renin-angiotensin-aldosterone system, 14% with a beta blocker, 42% with a calcium channel blocker, 35% with a loop diuretic, and 30% with another diuretic.

INPEFA was superior to placebo in reducing the risk of the primary composite endpoint (HR 0.75 [95% CI 0.63, 0.88]; p<0.001) (Table 3).

Table 3. Treatment Effect for the Primary Composite, Components and Secondary Endpoint in the SCORED Study:

^a Based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization.
^b Predefined primary endpoint.
^c Predefined secondary endpoint and tested with multiplicity control.
^d Time-to-event analysis was performed; event rates are percentages of patients with events.

Figure 5 displays a cumulative events plot of the primary composite endpoint. The INPEFA and placebo event curves separated early and continued to diverge over the study period following randomization.

Figure 5. Primary Composite Endpoint (Total Occurrences of Cardiovascular Death, Hospitalization for Heart Failure, and Urgent Heart Failure Visit) Over Time in the SCORED Study:

Primary composite endpoint was based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization.

The results of the primary composite endpoint were generally consistent across prespecified subgroups, including history of cardiovascular disease, history of heart failure, and screening LVEF <50 or ≥50% (Figure 6).

Figure 6. Treatment Effect for Primary Composite Endpoint (Total Occurrences of Cardiovascular Death, Hospitalization for Heart Failure, and Urgent Heart Failure Visit) Subgroup Analysis (SCORED Study):

CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; LVEF = left ventricular ejection fraction; HF = heart failure; PY = patient-years

Primary composite endpoint was based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization.

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.