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Aficamten is a next‐in‐class, cardiac myosin inhibitor in development as a potential chronic oral treatment for patients with hypertrophic cardiomyopathy (HCM). A population pharmacokinetic (PK) model was developed using data from nine clinical studies to characterize aficamten PK and identify covariates that may alter aficamten exposure. Aficamten PK was best described by a 2‐compartment model with linear elimination and first‐order absorption following a time lag (Tlag). Population parameter estimates for a typical male participant with obstructive HCM (oHCM) and weighing 80 kg were: apparent clearance (CL/F), 2.62 L/h; apparent volume of the central compartment (Vc/F), 18.1 L; apparent intercompartmental clearance (Q/F), 57.6 L/h; and apparent volume of the peripheral compartment (Vp/F), 295 L. Estimated interindividual variability on CL/F and overall residual error (includes within‐subject variability) was low; the coefficient of variation was 28.7% and 20.3%, respectively. Body weight on volume and clearance, population and sex on CL/F and Vp/F were identified as statistically significant covariates. A male patient with a baseline body weight of 56 kg (5th percentile of the population) exhibited a 23% higher AUCtau compared with a male patient with a typical body weight of 80 kg. Female patients demonstrated a 14.7% higher AUCtau than male patients of the same body weight. Healthy participants had a 23% lower AUCtau compared with participants with oHCM. This population PK analysis demonstrated that aficamten has a linear and predictable PK profile, with a favorable half‐life and time‐to‐steady state, and low interindividual variability on CL/F and overall residual error (includes within‐subject variability).

Aficamten is a next‐in‐class, small‐molecule, cardiac myosin inhibitor in development for treating hypertrophic cardiomyopathy (HCM). This 2‐part study evaluated aficamten's impact on QTc interval in healthy participants. Part A (n = 10) was an open‐label study to find the appropriate dose for thorough QT (TQT) evaluation in Part B. Part B (n = 34) was a double‐blind, 3‐way crossover TQT study conducted as per ICH E14 guidance using negative (placebo) and positive (moxifloxacin) controls. A single 50 mg aficamten dose achieved exposures (Cmax range: 124–1660 ng/mL) comparable to the highest clinical dose (20 mg QD) in obstructive HCM patients (NCT05186818; [Cmax range: 131–1230 ng/mL]) and was chosen for TQT evaluation. Using concentration‐QT (C‐QT) modeling, the placebo‐ and baseline‐corrected QT interval using Fridericia's correction (ΔΔQTcF) was −1.82 msec (90% CI: −3.43, −0.214) at peak aficamten concentrations (298.3 ng/mL) following the 50 mg dose. The 90% CI upper bound of ΔΔQTcF for aficamten was < 10 msec at all post‐dose time points. Assay sensitivity was established by the 90% CI lower bound for moxifloxacin (ΔΔQTcF) exceeding 5 msec. Aficamten did not cause QTc prolongation (using C‐QT and by time point analyses) within observed plasma concentrations up to 1660 ng/mL (aficamten), 213 ng/mL (metabolite CK‐3834282), and 343 ng/mL (metabolite CK‐3834283). No clinically meaningful effect on electrocardiogram parameters, including absolute QTcF (≤ 450 msec) and change from baseline in QTcF (≤ 30 msec) was noted in aficamten‐treated participants. Aficamten was generally well tolerated. In conclusion, there was no evidence of aficamten‐mediated QTc prolongation across the therapeutic concentration range in a formal TQT study.

Composite end points of major adverse cardiovascular events (MACEs) are standard measures for comparing treatment in large cardiovascular outcome studies. This analysis from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive) evaluated the effects of pioglitazone on the prespecified MACE end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE1) and on 6 post hoc MACE composites (various combinations of all-cause, cardiovascular, or cardiac mortality; plus nonfatal myocardial infarction; plus nonfatal stroke; and/or acute coronary syndrome) in patients with type 2 diabetes. PROactive was a cardiovascular outcome study that randomized patients with type 2 diabetes to pioglitazone (n = 2605) or placebo (n = 2633), in addition to existing glucose-lowering and cardiovascular medications. Pioglitazone was titrated from 15 to 45 mg/d based upon tolerability. Mean follow-up was 34.5 months. At final visit, 257 (9.9%) pioglitazone-treated and 313 (11.9%) placebo-treated patients had a first event that contributed to the MACE1 end point (hazard ratio 0.82, 95% CI 0.70-0.97, P = .0201). There were statistically significant differences in favor of pioglitazone in 5 of the other MACE end points ( P < .05) and a trend to benefit in the sixth ( P = .052), with hazard ratios of 0.79 to 0.83. In patients with advanced type 2 diabetes at high risk for cardiovascular events, pioglitazone treatment resulted in significant risk reductions in MACE composite end points to 3 years.

Concerns raised regarding adverse cardiovascular (CV) outcomes with new therapies for type 2 diabetes mellitus (T2DM) have led to several large-scale CV outcome trials. The EXAMINE trial confirmed noninferiority of the dipeptidyl dipeptidase 4 inhibitor alogliptin to placebo on major adverse cardiac event rates in a post–acute coronary syndrome (ACS) T2DM population. We present data on additional ischemic cardiac events and CV hospitalizations in EXAMINE. Patients with T2DM and an ACS event in the previous 15 to 90 days were randomly assigned to alogliptin or placebo on a background of standard treatment for diabetes. The incident rates of a 5-component composite end point of CV death, stroke, myocardial infarction, unstable angina, and coronary revascularization as well as CV hospitalization were calculated in all participants and according to macrovascular disease at baseline. There were no significant differences between alogliptin (n = 2,701) and placebo (n = 2,679) in the event rate of the 5-component composite endpoint with median follow-up 533 days (21.0% vs 21.5%, hazard ratio [HR] 0.98 [0.87-1.10], P = .72). No differences were observed in terms of CV hospitalization (25.0% vs 25.4%, HR 0.98 [0.88-1.09], P = .70) or coronary revascularization (10.6% vs 10.2%, HR 1.05 [0.88-1.09], P = .60). No interactions were observed for treatment and prior macrovascular disease. EXAMINE demonstrates that there was no increase in the risk of cardiac ischemic events and CV hospitalizations with alogliptin in a high-risk post-ACS patient population. Because these are major driver of overall health care costs, these data suggest that there would be no adverse impact on health care resource utilization.

One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

With one possible exception, the last decade of clinical trials in hospitalized heart failure (HHF) patients has failed to demonstrate improvement in long-term clinical outcomes. This trend necessitates a need to evaluate optimal drug development strategies and standards of trial conduct. It has become increasingly important to recognize the heterogeneity among HHF patients and the differential characterization of novel drug candidates. Targeting these agents to specific subpopulations may afford optimal net response related to the particular mode of action of the drug. Analyses of previous trials demonstrate profound differences in the baseline characteristics of patients enrolled across global regions and participating sites. Such differences may influence risks for events and interpretation of results. Therefore, the actual execution of trials and the epidemiology of HHF populations at the investigative sites must be taken into consideration. Collaboration among participating sites including the provision of registry data tailored to the planned development program will optimize trial conduct. Observational data prior to study initiation may enable sites to feedback and engage in protocol development to allow for feasible and valid clinical trial conduct. This site-centered, epidemiology-based network environment may facilitate studies in specific patient populations and promote optimal data collection and clear interpretation of drug safety and efficacy. This review summarizes the roundtable discussion held by a multidisciplinary team of representatives from academia, National Institutes of Health, industry, regulatory agencies, payers, and contract and academic research organizations to answer the question: Who should be targeted for novel therapies in HHF?

Beta-blockers have been the initial treatment for symptomatic obstructive hypertrophic cardiomyopathy (HCM) despite limited evidence of their efficacy. Aficamten is a cardiac myosin inhibitor that reduces left ventricular outflow tract gradients, improves exercise capacity, and decreases HCM symptoms when added to standard medications. Whether aficamten as monotherapy provides greater clinical benefit than beta-blockers as monotherapy remains unknown. We conducted an international, double-blind, double-dummy trial in which adults with symptomatic obstructive HCM were randomly assigned in a 1:1 ratio to receive aficamten (at a daily dose of 5 mg to 20 mg) plus placebo or metoprolol (at a daily dose of 50 mg to 200 mg) plus placebo. The primary end point was the change in peak oxygen uptake at week 24; secondary end points were improvement at week 24 in New York Heart Association (NYHA) functional class and changes at week 24 in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), left ventricular outflow tract gradient after the Valsalva maneuver, N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, left atrial volume index, and left ventricular mass index. A total of 88 patients were assigned to the aficamten group and 87 to the metoprolol group. The mean age of the patients was 58 years, 58.3% were men, and the mean left ventricular outflow tract gradient was 47 mm Hg at rest and 74 mm Hg after the Valsalva maneuver. At 24 weeks, the change in the peak oxygen uptake was 1.1 ml per kilogram of body weight per minute (95% confidence interval [CI], 0.5 to 1.7) in the aficamten group and -1.2 ml per kilogram per minute (95% CI, -1.7 to -0.8) in the metoprolol group (least-squares mean between-group difference, 2.3 ml per kilogram per minute; 95% CI, 1.5 to 3.1; P<0.001). Patients who received aficamten had significantly greater improvements in NYHA class, KCCQ-CSS, left ventricular outflow tract gradient, NT-proBNP level, and left atrial volume index than patients who received metoprolol. No significant difference in left ventricular mass index was observed. Adverse events appeared to be similar in the two treatment groups. Among patients with symptomatic obstructive HCM, aficamten monotherapy was superior to metoprolol monotherapy in improving peak oxygen uptake and hemodynamics and decreasing symptoms. (Funded by Cytokinetics; MAPLE-HCM ClinicalTrials.gov number, NCT05767346.).

Hypertension is generally considered a risk factor for CV disease; however, limited data are available on the impact of BP reduction on CV outcomes in the hypertensive, CAD population. We evaluated the effects of verapamil SR-based (Ve) and atenolol-based (At) strategies on BP control and relationship to CV outcomes. In the prospective, randomized ternational VErapamil SR/trandolapril STudy (INVEST), 22,576 patients with hypertension and CAD were assigned to Ve or At strategies and followed for 2.7 years (mean). Dose titration and additional drugs (trandolapril and/or HCTZ) were recommended to achieve JNC VI BP targets (<140/<90 mmHg or <130/<85 mmHg in patients with diabetes or renal impairment). The primary outcome (PO) was time to first occurrence of death (all cause), nonfatal MI or nonfatal stroke. At 2 years, the Ve and At strategies had comparable BP control (71.7 vs 70.7% for BP <140/<90 mmHg, P=0.18), systolic BP reduction (18.7 vs 19.0 mmHg, P=0.41) and number of antihypertensive drugs (2.6 mean for both). Incidences of PO, death, MI, and stroke were similar between strategies. In all patients, mean systolic BP >140 mmHg during treatment was associated with increased frequency for the PO (figure). In patients who had not achieved BP control at 6 months, the subsequent frequency of the PO was higher compared with patients who had achieved BP control at 6 months (10.3 vs 6.9%, P<0.001). A verapamil SR-based or atenolol-based strategy results in equivalent BP control and CV outcomes in hypertensive patients with CAD. Increased systolic BP is associated with increased frequency of adverse CV outcomes in this population. Am J Hypertens (2004) 17, 116A–116A; doi: 10.1016/j.amjhyper.2004.03.304