Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension.

BACKGROUND: Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is essential but difficult to achieve because cortisol synthesis is catalyzed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels. METHODS: In this multicenter, placebo-controlled trial, we randomly assigned patients who had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or higher, and who were receiving stable doses of at least three antihypertensive agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary end point was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group. RESULTS: A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of -20.3 mm Hg, -17.5 mm Hg, -12.1 mm Hg, and -9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was -11.0 mm Hg (95% confidence interval [CI], -16.4 to -5.5; P<0.001), and the difference in this change between the 1-mg group and the placebo group was -8.1 mm Hg (95% CI, -13.5 to -2.8; P = 0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level to 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug. CONCLUSIONS: Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure. (Funded by CinCor Pharma; BrigHTN ClinicalTrials.gov number, NCT04519658.).

Meta-analysis of risk of major adverse cardiovascular events in adults with type 2 diabetes treated with bexagliflozin.

AIM: To explore the risk of major adverse cardiovascular events (MACE) associated with exposure to bexagliflozin. METHODS: The analysis included 4090 participants with type 2 diabetes (T2D) enrolled in nine phase 2 and 3 double-blind randomized controlled trials. All potential MACE were adjudicated by a blinded committee. The primary endpoint for the meta-analysis was the hazard ratio (HR) for the time to first occurrence of non-fatal stroke, non-fatal myocardial infarction (MI), cardiovascular (CV) death or hospitalization for unstable angina (MACE+), tested for non-inferiority to a ratio of 1.8. The secondary endpoints were time to first occurrence of (i) non-fatal stroke, non-fatal MI or CV death (MACE), tested for non-inferiority to a ratio of 1.3; and (ii) CV death or hospitalization for heart failure, tested for superiority. RESULTS: The HR for the primary endpoint of MACE+ was 0.80 (95% confidence interval [CI] 0.58, 1.09), which fulfilled the non-inferiority objective with a P value of less than 0.0001. Non-inferiority for the first key secondary endpoint of MACE was also shown (HR = 0.82; 95% CI 0.59, 1.13; P = 0.0023). Superiority for time to CV death or first hospitalization for heart failure was not shown. CONCLUSIONS: Bexagliflozin did not increase the risk of MACE in participants with T2D when compared with placebo or active control. Both the preapproval and postapproval thresholds for CV safety were met and bexagliflozin has been approved by the US Food and Drug Administration.

Bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes in adults: A 24-week, randomized, double-blind, placebo-controlled trial.

AIM: To evaluate the relative safety and effectiveness of bexagliflozin as an adjunct to metformin for the treatment of type 2 diabetes mellitus. METHODS: In total, 317 participants were randomized to receive bexagliflozin or placebo plus metformin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24, with secondary endpoints for systolic blood pressure (SBP), fasting plasma glucose and weight loss. An open label arm enrolled participants with HbA1c >10.5% and was analysed separately. RESULTS: The mean change in HbA1c was -1.09% (95% CI -1.24%, -0.94%) in the bexagliflozin arm and -0.56% (-0.71%, -0.41%) in the placebo arm, a difference of -0.53% (-0.74%, -0.32%; p < .0001). Excluding observations after rescue medication, the intergroup difference was -0.70% (-0.92, -0.48; p < .0001). The open label group change in HbA1c was -2.82% (-3.23%, -2.41%). Placebo-adjusted changes from baseline SBP, fasting plasma glucose and body mass were -7.07 mmHg (-9.83, -4.32; p < .0001), -1.35 mmol/L (-1.83, -0.86; p < .0001) and -2.51 kg (-3.45, -1.57; p < .0001). Adverse events affected 42.4% and 47.2% of subjects in the bexagliflozin and placebo arms, respectively; fewer subjects in the bexagliflozin arm experienced serious adverse events. CONCLUSIONS: Bexagliflozin produced clinically meaningful improvement in glycaemic control, estimated glomerular filtration rate and SBP when added to metformin in a population of adults with diabetes.

A 96-week, double-blind, randomized controlled trial comparing bexagliflozin to glimepiride as an adjunct to metformin for the treatment of type 2 diabetes in adults.

AIM: To compare the effects of bexagliflozin tablets 20 mg, with those of optimally titrated glimepiride when used to treat adults with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin. METHODS: Adults with type 2 diabetes (n = 426) taking metformin, and with a glycated haemoglobin (HbA1c) level between 53 and 91 mmol/mol [7.0% and 10.5%], were randomized to receive bexagliflozin tablets 20 mg or titrated glimepiride. The primary endpoint was the intergroup difference in the change from baseline to Week 60 in percent HbA1c. Secondary endpoints included changes from baseline in body mass and systolic blood pressure (SBP), and proportion of subjects experiencing severe or documented symptomatic hypoglycaemia. RESULTS: The intergroup difference in percent HbA1c (bexagliflozin minus glimepiride) from baseline to Week 60 was -0.55 mmol/mol (95% confidence interval [CI] -2.30, 1.20)-[-0.05% (-0.21, 0.11)], establishing noninferiority of bexagliflozin to glimepiride by the prespecified margin of 3.83 mmol/mol [0.35%]. Prespecified tests gave, in order, a difference in body mass of -4.31 kg (95% CI -5.10, -3.52; P < 0.0001), a difference in SBP of -6.53 mm Hg (95% CI -10.56, -2.51; P = 0.0008), and an odds ratio of 0.12 (95% CI 0.05, 0.28; P < 0.0001) for severe or documented symptomatic hypoglycaemia. At the follow-up visit the mean difference in estimated glomerular filtration rate (eGFR) between arms was 6.05 mL min-1 per 1.73 m2 (95% CI, 3.24, 8.87; P < 0.0001). CONCLUSIONS: Bexagliflozin was noninferior to glimepiride in lowering HbA1c, was superior to glimepiride for decreases in body mass and SBP, and was associated with significantly fewer hypoglycaemic events than glimepiride. A favourable effect on eGFR was observed.

A 12-week, randomized, double-blind, placebo-controlled, four-arm dose-finding phase 2 study evaluating bexagliflozin as monotherapy for adults with type 2 diabetes.

AIM: To compare the safety and efficacy of bexagliflozin administered as monotherapy at three dosage strengths over a 12-week period to patients with type 2 diabetes who were either naïve to pharmacotherapy or were previously prescribed one oral hypoglycaemic agent and underwent a 6-week period of medication abstinence. METHODS: Adults with type 2 diabetes (n = 292) having an HbA1c of between 7.0% and 8.5% were randomized to receive one of three dosage strengths of bexagliflozin (5, 10 or 20 mg) or placebo. The primary endpoint was the change from baseline to week 12 in the %HbA1c. Secondary endpoints included the changes from baseline in fasting plasma glucose (FPG), systolic blood pressure and diastolic blood pressure, body mass and fraction of patients achieving an HbA1c of <7%. RESULTS: The mixed model repeated measure estimates of the placebo-adjusted change in %HbA1c from baseline to week 12 for the 5, 10 and 20 mg groups were -0.55% (95% CI: -0.76%, -0.34%, P < 0.0001), -0.68% (95% CI: -0.89%, -0.47%, P < 0.0001) and -0.80% (95% CI: -1.01%, -0.59%, P < 0.0001), respectively. Significant and dose-dependent placebo-adjusted mean reductions from baseline to week 12 in FPG and body mass were observed. The fraction of subjects achieving an HbA1c of <7% was significantly greater in the 20 mg bexagliflozin group. The incidence of adverse events was similar for participants in all active arms (42.3%) compared with the rate measured in those receiving placebo (40.3%). CONCLUSIONS: Bexagliflozin confers substantial and dose-dependent benefits on subjects with type 2 diabetes and has an acceptable safety profile. Further evaluation of bexagliflozin for the control of type 2 diabetes in adults is warranted.

Safety and Effectiveness of Bexagliflozin in Patients With Type 2 Diabetes Mellitus and Stage 3a/3b CKD.

RATIONALE & OBJECTIVE: Hyperglycemia exacerbates the progression of chronic kidney disease (CKD), but most glucose-lowering therapies do not address morbidities associated with CKD. Sodium/glucose cotransporter 2 (SGLT2) inhibitors offer potential benefits to patients with diabetes and CKD, but their effectiveness may be diminished with decreased kidney function. We aimed to evaluate the safety and effectiveness of bexagliflozin, a novel SGLT2 inhibitor, in patients with type 2 diabetes and CKD. STUDY DESIGN: Phase 3, double-blind, placebo-controlled, multicenter, multinational, randomized trial. SETTING & PARTICIPANTS: 54 sites across 4 countries. Patients with CKD stage 3a or 3b, type 2 diabetes mellitus, and hemoglobin A1c level of 7.0% to 10.5% and estimated glomerular filtration rate (eGFR) of 30 to 59mL/min/1.73m2 who were taking oral hypoglycemic agents for 8 weeks. INTERVENTIONS: Bexagliflozin, 20mg, daily versus placebo for 24 weeks. OUTCOMES: Primary outcome was change in percent hemoglobin A1c from baseline to week 24. Secondary end points included changes in body weight, systolic blood pressure, albuminuria, and hemoglobin A1c level stratified by CKD stage. RESULTS: 312 patients across 54 sites were analyzed. Bexagliflozin lowered hemoglobin A1c levels by 0.37% (95% CI, 0.20%-0.54%); P<0.001 compared to placebo. Patients with CKD stages 3a (eGFR, 45-<60mL/min/1.73m2) and 3b (eGFR, 30-<45mL/min/1.73m2) experienced reductions in hemoglobin A1c levels of 0.31% (P=0.007) and 0.43% (P=0.002), respectively. Bexagliflozin decreased body weight (1.61kg; P<0.001), systolic blood pressure (3.8mm Hg; P=0.02), fasting plasma glucose level (0.76mmol/L; P=0.003), and albuminuria (geometric mean ratio reduction of 20.1%; P=0.03). Urinary tract infection and genital mycotic infections were more common in the bexagliflozin group; otherwise, frequencies of adverse events were comparable between groups. LIMITATIONS: Not designed to evaluate the impact of treatment on long-term kidney disease and cardiovascular outcomes. CONCLUSIONS: Bexagliflozin reduces hemoglobin A1c levels in patients with diabetes and stage 3a/3b CKD and appears to be well tolerated. Additional observed benefits included reductions in body weight, systolic blood pressure, and albuminuria. FUNDING: Trial was sponsored by Theracos Sub, LLC.

A 24-week, randomized, double-blind, active-controlled clinical trial comparing bexagliflozin with sitagliptin as an adjunct to metformin for the treatment of type 2 diabetes in adults.

AIM: To compare the relative safety and effectiveness of bexagliflozin and sitagliptin as adjuncts to metformin for the treatment of adults with type 2 diabetes. METHODS: Participants (n = 386) were randomized to receive bexagliflozin (20 mg) or sitagliptin (100 mg) in addition to their existing doses of metformin. The primary endpoint was the non-inferiority of bexagliflozin to sitagliptin for change in HbA1c from baseline to week 24. Changes from baseline to week 24 in fasting plasma glucose (FPG), body mass (in subjects with baseline body mass index ≥25 kg m-2 ) and systolic blood pressure (SBP) were secondary endpoints. RESULTS: The mean change from baseline to week 24 in HbA1c was -0.74 (95% CI -0.86%, -0.62%) in the bexagliflozin arm and -0.82% (95% CI -0.93%, -0.71%) in the sitagliptin arm, establishing non-inferiority. The changes from baseline FPG, body mass and SBP were -1.82 mmol L-1 , -3.35 kg and -4.23 mmHg in the bexagliflozin arm and -1.45 mmol L-1 , -0.81 kg and -1.90 mmHg in the sitagliptin arm, respectively. These differences were significant for the first two measures (one-sided P = 0.0123, P < 0.0001 and P = 0.0276, respectively.) Adverse events were experienced by 47.1% of subjects in the bexagliflozin arm and 56.0% of subjects taking sitagliptin. Serious adverse events affected 3.7% of subjects in the bexagliflozin arm and 2.1% of subjects in the sitagliptin arm. CONCLUSIONS: Bexagliflozin was non-inferior to sitagliptin and provided benefits over sitagliptin in FPG and body mass. Adverse event incidences in the two arms were similar.

A 96-week, multinational, randomized, double-blind, parallel-group, clinical trial evaluating the safety and effectiveness of bexagliflozin as a monotherapy for adults with type 2 diabetes.

AIM: To explore the safety and effectiveness of extended exposure to bexagliflozin as a monotherapy for type 2 diabetes. METHODS: Adults with diabetes (n = 288) from the USA, Colombia and Mexico were randomized 1:1 to receive bexagliflozin (20 mg) or placebo for 96 weeks. The primary endpoint was the placebo-adjusted change in HbA1c at 24 weeks. Dosing was continued an additional 72 weeks to assess safety and the durability of the treatment effect. Secondary endpoints measured changes from baseline in body mass and systolic blood pressure (SBP) and diastolic blood pressure (DBP) at week 24, and the change, over study duration, in HbA1c. RESULTS: The placebo-adjusted change in HbA1c from baseline to week 24 was -0.79% (-8.6 mmol/mol) [95%CI -0.53, -1.06 (-5.8, -11.6), P < .0001]. The unadjusted change from baseline through week 96 was -0.55% (-6.0 mmol/mol) ± 1.184% (12.9) (SD) for the bexagliflozin arm compared with 0.53% (5.8 mmol/mol) ± 1.215% (13.3) for the placebo arm (P < .0001). Significant decreases in body mass, SBP and DBP could be attributed to bexagliflozin exposure. The incidence of serious adverse events was lower in the bexagliflozin-treated group (2.8%) than in the placebo group (8.5%). Urinary tract infections occurred less frequently in the active arm (14.5%) than in the placebo arm (20.6%). CONCLUSIONS: Bexagliflozin at 20 mg/d was well tolerated and provided a durable, clinically meaningful improvement in glycaemic control over 96 weeks to participants in this phase 2 trial. A substantial reduction in weight and blood pressure was produced by bexagliflozin, with no increase in significant adverse event rates.

Future translational applications from the contemporary genomics era: a scientific statement from the American Heart Association.

The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care.

Patiromer induces rapid and sustained potassium lowering in patients with chronic kidney disease and hyperkalemia.

Patients with chronic kidney disease (CKD) have a high risk of hyperkalemia, which increases mortality and can lead to renin-angiotensin-aldosterone system inhibitor (RAASi) dose reduction or discontinuation. Patiromer, a nonabsorbed potassium binder, has been shown to normalize serum potassium in patients with CKD and hyperkalemia on RAASi. Here, patiromer's onset of action was determined in patients with CKD and hyperkalemia taking at least one RAASi. After a 3-day potassium- and sodium-restricted diet in an inpatient research unit, those with sustained hyperkalemia (serum potassium 5.5 - under 6.5 mEq/l) received patiromer 8.4 g/dose with morning and evening meals for a total of four doses. Serum potassium was assessed at baseline (0 h), 4 h postdose, then every 2-4 h to 48 h, at 58 h, and during outpatient follow-up. Mean baseline serum potassium was 5.93 mEq/l and was significantly reduced by 7 h after the first dose and at all subsequent times through 48 h. Significantly, mean serum potassium under 5.5 mEq/l was achieved within 20 h. At 48 h (14 h after last dose), there was a significant mean reduction of 0.75 mEq/l. Serum potassium did not increase before the next dose or for 24 h after the last dose. Patiromer was well tolerated, without serious adverse events and no withdrawals. The most common gastrointestinal adverse event was mild constipation in two patients. No hypokalemia (serum potassium under 3.5 mEq/l) was observed. Thus, patiromer induced an early and sustained reduction in serum potassium and was well tolerated in patients with CKD and sustained hyperkalemia on RAASis.

Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial.

IMPORTANCE: Hyperkalemia is a potentially life-threatening condition predominantly seen in patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors with stage 3 or greater chronic kidney disease (CKD) who may also have diabetes, heart failure, or both. OBJECTIVES: To select starting doses for a phase 3 study and to evaluate the long-term safety and efficacy of a potassium-binding polymer, patiromer, in outpatients with hyperkalemia. DESIGN, SETTING, AND PARTICIPANTS: Phase 2, multicenter, open-label, dose-ranging, randomized clinical trial (AMETHYST-DN), conducted at 48 sites in Europe from June 2011 to June 2013 evaluating patiromer in 306 outpatients with type 2 diabetes (estimated glomerular filtration rate, 15 to <60 mL/min/1.73 m2 and serum potassium level >5.0 mEq/L). All patients received RAAS inhibitors prior to and during study treatment. INTERVENTIONS: Patients were stratified by baseline serum potassium level into mild or moderate hyperkalemia groups and received 1 of 3 randomized starting doses of patiromer (4.2 g [n = 74], 8.4 g [n = 74], or 12.6 g [n = 74] twice daily [mild hyperkalemia] or 8.4 g [n = 26], 12.6 g [n = 28], or 16.8 g [n = 30] twice daily [moderate hyperkalemia]). Patiromer was titrated to achieve and maintain serum potassium level 5.0 mEq/L or lower. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was mean change in serum potassium level from baseline to week 4 or prior to initiation of dose titration. The primary safety end point was adverse events through 52 weeks. Secondary efficacy end points included mean change in serum potassium level through 52 weeks. RESULTS: A total of 306 patients were randomized. The least squares mean reduction from baseline in serum potassium level at week 4 or time of first dose titration in patients with mild hyperkalemia was 0.35 (95% CI, 0.22-0.48) mEq/L for the 4.2 g twice daily starting-dose group, 0.51 (95% CI, 0.38-0.64) mEq/L for the 8.4 g twice daily starting-dose group, and 0.55 (95% CI, 0.42-0.68) mEq/L for the 12.6 g twice daily starting-dose group. In those with moderate hyperkalemia, the reduction was 0.87 (95% CI, 0.60-1.14) mEq/L for the 8.4 g twice daily starting-dose group, 0.97 (95% CI, 0.70-1.23) mEq/L for the 12.6 g twice daily starting-dose group, and 0.92 (95% CI, 0.67-1.17) mEq/L for the 16.8 g twice daily starting-dose group (P < .001 for all changes vs baseline by hyperkalemia starting-dose groups within strata). From week 4 through week 52, statistically significant mean decreases in serum potassium levels were observed at each monthly point in patients with mild and moderate hyperkalemia. Over the 52 weeks, hypomagnesemia (7.2%) was the most common treatment-related adverse event, mild to moderate constipation (6.3%) was the most common gastrointestinal adverse event, and hypokalemia (<3.5 mEq/L) occurred in 5.6% of patients. CONCLUSIONS AND RELEVANCE: Among patients with hyperkalemia and diabetic kidney disease, patiromer starting doses of 4.2 to 16.8 g twice daily resulted in statistically significant decreases in serum potassium level after 4 weeks of treatment, lasting through 52 weeks. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01371747.

Endogenous ß-glucocerebrosidase activity in Abca12⁻/⁻epidermis elevates ceramide levels after topical lipid application but does not restore barrier function.

ABCA12 mutations disrupt the skin barrier and cause harlequin ichthyosis. We previously showed Abca12(-/-) skin has increased glucosylceramide (GlcCer) and correspondingly lower amounts of ceramide (Cer). To examine why loss of ABCA12 leads to accumulation of GlcCer, de novo sphingolipid synthesis was assayed using [(14)C]serine labeling in ex vivo skin cultures. A defect was found in ß-glucocerebrosidase (GCase) processing of newly synthesized GlcCer species. This was not due to a decline in GCase function. Abca12(-/-) epidermis had 5-fold more GCase protein (n = 4, P < 0.01), and a 5-fold increase in GCase activity (n = 3, P < 0.05). As with Abca12(+/+) epidermis, immunostaining in null skin showed a typical interstitial distribution of the GCase protein in the Abca12(-/-) stratum corneum. Hence, we tested whether the block in GlcCer conversion could be circumvented by topically providing GlcCer. This approach restored up to 15% of the lost Cer products of GCase activity in the Abca12(-/-) epidermis. However, this level of barrier ceramide replacement did not significantly reduce trans-epidermal water loss function. Our results indicate loss of ABCA12 function results in a failure of precursor GlcCer substrate to productively interact with an intact GCase enzyme, and they support a model of ABCA12 function that is critical for transporting GlcCer into lamellar bodies.

Results from a Phase 1 Study Assessing the Pharmacokinetics of the Aldosterone Synthase Inhibitor Baxdrostat in Participants with Varying Degrees of Renal Function.

Baxdrostat is a selective small-molecule aldosterone synthase inhibitor in development for treatment of hypertension and chronic kidney disease. This phase 1, open-label, parallel-group study assessed the safety and pharmacokinetics (PK) of baxdrostat in participants with varying degrees of renal function. Participants were enrolled into control (estimated glomerular filtration rate [eGFR] ≥60 mL/min), moderate to severe renal impairment (eGFR 15-59 mL/min), or kidney failure (eGFR <15 mL/min) groups and received a single 10-mg baxdrostat dose followed by 7 days of inpatient PK blood and urine sampling. Safety was assessed by adverse events, clinical laboratory evaluations, vital signs, physical examinations, and electrocardiograms (ECGs). Thirty-2 participants completed the study. There were no deaths and only 1 mild drug-related adverse event (diarrhea). No clinically meaningful changes in laboratory values, vital signs, physical examinations, or ECGs occurred. Plasma concentration-time curves of baxdrostat were similar among all groups. Urine PK parameters were similar (approximately 12% excreted) in the moderate to severe renal impairment and control groups. Inadequate urine production in the kidney failure group resulted in minimal urinary baxdrostat excretion. Renal impairment had no significant impact on systemic exposure or clearance of baxdrostat, suggesting that dose adjustment due to PK differences in patients with kidney disease is unnecessary.

Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the pharmacokinetics and demonstrating the safety and selectivity of the aldosterone synthase inhibitor baxdrostat in healthy volunteers.

Baxdrostat is a selective inhibitor of aldosterone synthase designed for the treatment of disorders associated with elevated aldosterone. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of baxdrostat in healthy volunteers. Subjects were randomized to receive oral baxdrostat (0.5, 1.5, 2.5, or 5.0 mg) or placebo once daily for 10 days and were placed on either a low-salt or normal-salt diet for the duration of the study. Blood samples were collected before and after dosing on days 1 and 10 to characterize pharmacokinetics and pharmacodynamics. Safety was assessed by adverse events, physical examinations, electrocardiograms, orthostatic vital signs, and clinical laboratory evaluations. Fifty-four subjects completed the study. There were no deaths or serious adverse events, and all treatment-emergent adverse events in subjects receiving baxdrostat were mild in severity. Plasma levels of baxdrostat increased proportionally with ascending doses, with peak concentrations observed within 4 h after dosing and a mean half-life of 26 to 31 h. A dose-dependent reduction of plasma aldosterone occurred with baxdrostat doses ≥1.5 mg, regardless of diet. Decreases in plasma aldosterone were sustained, with levels reduced by approximately 51 to 73% on day 10. Baxdrostat had no meaningful impact on plasma cortisol levels and resulted in mild dose-dependent decreases in plasma sodium levels and increases in potassium levels. Baxdrostat was safe and well tolerated with a half-life that supports once-daily dosing. The dose-dependent reduction in plasma aldosterone and lack of effect on cortisol demonstrate the selective blockade of aldosterone synthase.

Results From a Randomized, Open-Label, Crossover Study Evaluating the Effect of the Aldosterone Synthase Inhibitor Baxdrostat on the Pharmacokinetics of Metformin in Healthy Human Subjects.

BACKGROUND: Due to the high comorbidity of diabetes and hypertension, co-administration of metformin with anti-hypertensive drugs is likely. Baxdrostat is an aldosterone synthase inhibitor in development for the potential treatment of hypertension. In vitro data indicated that baxdrostat inhibits the multidrug and toxin extrusion 1 (MATE1) and MATE2-K renal transporters. Metformin is a MATE substrate, so this study assessed potential effects of baxdrostat on the pharmacokinetics of metformin. METHODS: Twenty-seven healthy volunteers received 1000 mg metformin alone and 1000 mg metformin in the presence of 10 mg baxdrostat in a randomized, crossover manner. Each treatment was separated by 10 or more days. Blood and urine samples were collected over a 3-day period after each treatment to measure plasma and urine concentrations of metformin. Safety was assessed by adverse events (AEs), physical examinations, electrocardiograms, vital signs, and clinical laboratory evaluations. RESULTS: There were no deaths, serious AEs, discontinuations due to treatment-emergent AEs, or noteworthy increases in AEs with either treatment, indicating that metformin and baxdrostat were well-tolerated when co-administered. Baxdrostat did not significantly affect plasma concentrations or renal clearance of metformin. CONCLUSION: The results of this study suggest that diabetic patients with hypertension receiving both metformin and baxdrostat are unlikely to require dose adjustment. REGISTRATION: ClinicalTrials.gov identifier no. NCT05526690.

Safety and dosing of bevacizumab (avastin) for the treatment of recurrent respiratory papillomatosis.

OBJECTIVES: Increasing evidence supports the use of laryngeal injections of the antiangiogenic agent bevacizumab (Avastin) for the adjuvant treatment of recurrent respiratory papillomatosis (RRP). A recent prospective open-label investigation, approved by the US Food and Drug Administration, employing 12.5 mg of sublesional bevacizumab demonstrated single-site efficacy without complications; however, the safety of multiple-site injections and higher dosing has not yet been reported. The primary objective of this study was to report on the safety of increased doses of bevacizumab for the treatment of RRP. METHODS: Two cohorts of adult patients were evaluated. In the first group, a prospective analysis was performed on patients with a diagnosis of laryngeal RRP after t heir participation in th e initial clinical trial with a single-site lowerdose (7.5 to 12.5 mg). They received higher doses of sublesional laryngeal bevacizumab (15 to 50 mg total) with detailed physiologic, hematologic, and serum chemistry measurements performed before and after each bevacizumab injection. A second cohort of patients received sublesional laryngeal injections of bevacizumab (15 to 88 mg total) without physiologic measurements and underwent a retrospective analysis of reported complications. RESULTS: One hundred consecutive laryngeal injection sessions (office, 87; operating room, 13) with bevacizumab were performed in 43 patients, with a mean dose of 30 mg total per treatment (range, 15 to 88 mg). Sixty-three of the 100 sessions were accompanied by KTP laser photoangiolysis of the papilloma prior to bevacizumab injections. Eighteen patients (cohort 1) underwent detailed physiologic assessment, and no dysfunction was observed. There were no local or systemic complications of bevacizumab administration. The second group of 25 patients (cohort 2) also reported no significant local or systemic complications. Neither patient group was observed to have a local wound problem in the larynx. CONCLUSIONS: This investigation provides evidence that higher doses of bevacizumab are relatively safe in adult patients with laryngeal RRP. Further refinements in pharmacologic concentration and drug delivery will determine the optimal treatment regimens in the future.