Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2: Analysis of a Phase 1/2 Study.

Importance: Enasidenib mesylate, a mutant isocitrate dehydrogenase 2 (IDH2) protein inhibitor that promotes differentiation of leukemic myeloblasts, was recently approved by the US Food and Drug Administration for use in relapsed/refractory (R/R) mutant IDH2 acute myeloid leukemia (AML). During the first study of enasidenib in humans, a minority of patients with advanced myeloid neoplasms experienced unexpected signs/symptoms of a differentiation syndrome (DS), a potentially lethal entity. Objective: To characterize IDH-inhibitor-associated DS (IDH-DS) and its effective management. Design, Setting, and Participants: Using data obtained from a multicenter, open-label, pivotal phase 1/2 study of enasidenib, a differentiation syndrome review committee retrospectively evaluated potential cases of IDH-DS in enasidenib-treated patients with R/R AML. Data were collected between August 27, 2013, and October 14, 2016. The committee identified and agreed on signs and symptoms characteristic of IDH-DS and developed an algorithm for identification and treatment. Among 281 patients with R/R AML enrolled in the trial, the committee identified 72 patients for review based on investigator-reported cases of DS (n = 33) or reported adverse events or signs and symptoms characteristic of IDH-DS. Interventions: Treatment with enasidenib at a dosage of 50 to 650 mg/d was evaluated during the dose-escalation phase, and a dosage of 100 mg/d was used in the phase 1 expansion and phase 2, all in continual 28-day cycles. Main Outcomes and Measures: Unexpected adverse events of IDH-DS during the phase 1/2 study. Results: Thirty-three of the 281 patients (11.7%) were identified as having possible or probable IDH-DS. Median age of those 33 patients was 70 years (range, 38-80 years); 20 (60.6%) were male. The most frequent manifestations were dyspnea, fever, pulmonary infiltrates, and hypoxia. Median time to onset was 30 days (range, 7-129 days). Patients who experienced IDH-DS were less likely to have less than 20% bone marrow blasts (6% vs 22%, P = .04) and more likely to have undergone fewer previous anticancer regimens (median, 1.0 [range, 1-4] vs 2.0 [range, 1-14], P = .05) at study entry than those who did not. Thirteen patients (39.4%) had concomitant leukocytosis. Isocitrate dehydrogenase differentiation syndrome was effectively managed with systemic corticosteroids. The enasidenib regimen was interrupted for 15 patients (45.5%), but permanent discontinuation of treatment was not required. Conclusions and Relevance: Isocitrate dehydrogenase differentiation syndrome is a recognizable and potentially lethal clinical entity, occurring in approximately 12% of enasidenib-treated patients with mutant-IDH2 R/R AML. It requires prompt recognition and management. As use of mutant IDH inhibitors increases, these findings and recommendations are increasingly germane to care of patients with mutant-IDH neoplasms. Trial Registration: clinicaltrials.gov Identifier: NCT01915498.

Impact of Age and Estimated Glomerular Filtration Rate on the Glycemic Efficacy and Safety of Canagliflozin: A Pooled Analysis of Clinical Studies.

OBJECTIVE: Reduced efficacy has been reported in the elderly; it may be a consequence of an age-dependent decline in estimated glomerular filtration rate (eGFR) rather than ageing per se. We sought to determine the impact of these 2 parameters, as well as sex and baseline body mass index (BMI), on the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in people with type 2 diabetes. METHODS: Data were pooled from 6 randomized, double-blind, placebo-controlled studies (18 or 26 weeks; N=4053). Changes in glycated hemoglobin (A1C) and systolic blood pressure (BP) from baseline with canagliflozin 100 mg and 300 mg and placebo were evaluated in subgroups by sex, baseline BMI, baseline age and baseline eGFR. Safety was assessed by reports of adverse events. RESULTS: Placebo-subtracted reductions in A1C with canagliflozin 100 mg and 300 mg were similar in men and women. A1C reductions with canagliflozin were seen across BMI subgroups and in participants aged <65 years and ≥65 years. Significantly greater placebo-subtracted reductions in A1C were seen with both canagliflozin doses in participants with higher baseline eGFR (≥90 mL/min/1.73 m(2)). Reductions in systolic BP were seen with canagliflozin across subgroups of sex, BMI, age and eGFR. A1C reductions with canagliflozin were similar for participants aged <65 or ≥65 years who had baseline eGFR ≥60 mL/min/1.73 m(2) and were smaller in older than in younger participants with baseline eGFR 45 to <60 mL/min/1.73 m(2). The overall incidence of adverse events was similar across treatment groups regardless of sex, baseline BMI, baseline age or baseline eGFR. CONCLUSIONS: Canagliflozin improved glycemic control, reduced BP and was generally well tolerated in people with type 2 diabetes across a range of ages, BMIs and renal functions.

Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus.

The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure (BP) and osmotic diuresis- and intravascular volume reduction-related adverse events (AEs) were evaluated using pooled data from four placebo-controlled, phase 3 studies in patients with type 2 diabetes mellitus (T2DM; N=2313). At baseline, 1332 (57.6%) patients were taking an antihypertensive medication. Canagliflozin 100 mg and 300 mg provided reductions (95% confidence interval [CI]) from baseline in systolic BP (SBP) compared with placebo (-4.3 mm Hg [-5.0 to -3.5], -5.0 mm Hg [-5.8 to -4.2], and -0.3 mm Hg [-1.2 to 0.5], respectively) and in diastolic BP (DBP; -2.5 mm Hg [-2.9 to -2.0], -2.4 mm Hg [-2.9 to -1.9], and -0.6 mm Hg [-1.1 to -0.02], respectively). Placebo-subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were -4.0 mm Hg (-5.1 to -2.8) and -4.7 mm Hg (-5.8 to -3.5) and reductions in DBP were -1.9 mm Hg (-2.6 to -1.2) and -1.9 mm Hg (-2.6 to -1.1), respectively. Compared with the overall population, patients with elevated baseline SBP (≥140 mm Hg) had numerically greater absolute SBP reductions (95% CI) with canagliflozin 100 mg and 300 mg and placebo (-12.8 mm Hg [-15.2 to -10.5], -14.2 mm Hg [-16.4 to -12.0], and -6.8 mm Hg [-9.1 to -4.5], respectively). Numerically greater DBP reductions were seen in patients with DBP ≥90 mm Hg at baseline (-5.9 mm Hg [-8.2 to -3.6], -9.0 mm Hg [-11.1 to -6.9], and -7.4 mm Hg [-9.6 to -5.1], respectively). In patients with elevated SBP at baseline, placebo-subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were -6.0 mm Hg (-9.1 to -2.9) and -7.4 mm Hg (-10.4 to -4.4), respectively. Placebo-subtracted changes in DBP were 1.5 mm Hg (-1.6 to 4.5) and -1.6 mm Hg (-4.5 to 1.2), respectively, in those with elevated DBP at baseline. Canagliflozin 100 mg and 300 mg were associated with increased incidence of osmotic diuresis-related AEs (e.g., pollakiuria [increased urine volume] and polyuria [increased urine frequency]) vs placebo (6.7%, 5.6%, and 0.8%). The incidence of intravascular volume reduction-related AEs (eg, orthostatic hypotension and postural dizziness) was low across groups (1.2%, 1.3%, and 1.1%). In summary, canagliflozin was associated with reduced BP in patients with T2DM across a range of baseline BPs, with increased incidence of AEs related to osmotic diuresis but not intravascular volume reduction.

Efficacy and safety of canagliflozin in patients with type 2 diabetes and stage 3 nephropathy.

BACKGROUND/AIMS: Some sodium glucose co-transporter 2 (SGLT2) inhibitors are approved for the treatment of patients with type 2 diabetes mellitus (T2DM) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m(2). The efficacy and safety of canagliflozin, an approved SGLT2 inhibitor, was evaluated in patients with stage 3 chronic kidney disease (CKD; eGFR ≥30 to <60 ml/min/1.73 m(2)). METHODS: This analysis used integrated data from four randomized, placebo-controlled, phase 3 studies that enrolled patients with T2DM and stage 3 CKD. RESULTS are presented for the overall population as well as subgroups with stage 3a CKD (eGFR ≥45 and <60 ml/min/1.73 m(2)) and stage 3b CKD (eGFR ≥30 and <45 ml/min/1.73 m(2)). RESULTS: Among all subjects studied with stage 3 CKD, placebo-subtracted reductions in HbA1c (-0.38 and -0.47%; p < 0.001), body weight (-1.6 and -1.9%; p < 0.001), and systolic blood pressure (-2.8 and -4.4 mm Hg; p < 0.01) were seen with canagliflozin 100 and 300 mg, respectively. Decreases in HbA1c, body weight, and systolic blood pressure were examined in the stage 3a and 3b CKD subgroups, with greater decreases in HbA1c, -0.47% (-0.61, -0.32) and body weight in subjects in stage 3a CKD, -1.8% (-2.3, -1.2) with canagliflozin 100 mg. Initial declines in eGFR were seen early following treatment initiation with canagliflozin, but trended towards baseline over time. The most common adverse events with canagliflozin included genital mycotic infections and adverse events related to reduced intravascular volume likely secondary to osmotic diuresis. CONCLUSION: In subjects with T2DM and stage 3 CKD, canagliflozin reduced HbA1c, body weight, and blood pressure, and was generally well tolerated.

Safety and tolerability of canagliflozin in patients with type 2 diabetes mellitus: pooled analysis of phase 3 study results.

BACKGROUND: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed for treating type 2 diabetes mellitus (T2DM). METHODS: The safety/tolerability profile of canagliflozin 100 and 300 mg over 26 weeks was assessed using an integrated analysis of data pooled from 4 placebo-controlled, phase 3 studies representing a broad range of patients with T2DM (N = 2313; mean age, 56.0 years; glycated hemoglobin [HbA1c], 8.0%; body mass index, 32.1 kg/m2; estimated glomerular filtration rate, 88.1 mL/min/1.73 m2) on various prespecified background diabetes mellitus treatments. Safety/tolerability evaluations included adverse event (AE) reporting, with additional data collection prespecified for selected AEs, and assessments of renal-related, lipid, and other safety laboratory parameters. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690. RESULTS: The overall incidence of AEs was similar with canagliflozin 100 and 300 mg and placebo; incidences of serious AEs and AEs leading to study discontinuation were low across groups. Canagliflozin was associated with higher incidences than placebo of genital mycotic infections and osmotic diuresis-related AEs; these were generally considered by the investigator to be mild to moderate in intensity and infrequently led to discontinuation. Canagliflozin was associated with transient reductions in estimated glomerular filtration rate that trended toward baseline over the assessment period; incidences of renal-related AEs were low across groups. Dose-related increases in the incidence of hypoglycemia episodes were seen with canagliflozin versus placebo in patients on background sulfonylurea; incidences of severe hypoglycemia were low across groups. Hypoglycemia incidence was low overall in patients not on background sulfonylurea, but slightly higher with canagliflozin versus placebo. Relative to placebo, favorable changes in high-density lipoprotein cholesterol and triglycerides were seen with canagliflozin; increases in low-density lipoprotein cholesterol were also seen. Canagliflozin was associated with small changes in other safety laboratory parameters that were not clinically meaningful. CONCLUSIONS: Canagliflozin as monotherapy and as combination therapy was generally well tolerated in patients with T2DM inadequately controlled on their current diabetes mellitus treatment.

Effect of canagliflozin on serum electrolytes in patients with type 2 diabetes in relation to estimated glomerular filtration rate (eGFR).

OBJECTIVE: Effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on serum electrolytes were evaluated using pooled data from studies of patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Analyses were performed using two datasets, each including four placebo-controlled studies: Population 1 (N = 2215), patients with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m(2) (mean = 89.6 mL/min/1.73 m(2)) and Population 2 (N = 721), patients with baseline eGFR ≥45 and <60 mL/min/1.73 m(2) (mean = 53.3 mL/min/1.73 m(2)). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690; NCT01032629; NCT01064414; NCT01106651. MAIN OUTCOME MEASURES: Mean percent changes from baseline in serum electrolytes (potassium, sodium, magnesium, bicarbonate, phosphate, calcium) and outlier analyses were assessed in patients receiving canagliflozin 100 and 300 mg or placebo. Potassium changes were further evaluated based on baseline therapy with anti-hypertensive agents that interfere with potassium excretion (renin-angiotensin aldosterone system-acting agents and/or potassium-sparing diuretics). RESULTS: Mean percent changes from baseline in potassium with canagliflozin 100 and 300 mg and placebo were 0.6%, 1.0%, and 0.5%, respectively (Week 26; Population 1); and 1.7%, 2.8%, and 0.7%, respectively (Week 18/26; Population 2). The proportion of patients who had potassium elevations meeting pre-defined outlier criteria (>5.4 mmol/L [5.4 mEq/L] and >15% increase from baseline) with canagliflozin 100 and 300 mg and placebo was 4.5%, 6.8%, and 4.7% (Population 1); and 5.2%, 9.1%, and 5.5% (Population 2). In both populations, potassium elevations were usually <6.5 mmol/L for patients treated with canagliflozin or placebo; elevations ≥6.5 mmol/L were rare but more frequent in patients taking anti-hypertensive agents that affect potassium excretion in both the canagliflozin and placebo groups. Small mean percent changes in sodium, bicarbonate, and calcium were seen across groups in both populations; small mean percent increases in magnesium and phosphate were seen with canagliflozin vs placebo, but without an increase in patients meeting outlier criteria. Adverse events related to changes in electrolytes were low across groups. CONCLUSIONS: In patients with T2DM, canagliflozin was generally associated with small mean percent changes in serum electrolytes. Infrequent episodes of potassium elevation occurred with canagliflozin 300 mg, but occurred more often in patients with reduced eGFR.