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Aficamten, a small-molecule, selective cardiac myosin inhibitor, is under development for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Aficamten is primarily eliminated by hepatic metabolism with renal excretion playing a minor role. The objective of this investigation was to evaluate the pharmacokinetics (PK) of aficamten in moderate hepatic impairment or mild to moderate renal impairment to inform dosing recommendations in HCM patients with mild or moderate hepatic impairment or mild to moderate renal impairment.
Methods
The impact of hepatic impairment on the PK of single-dose aficamten 20 mg was evaluated in a phase 1 single-dose, open-label, parallel-group study, in healthy participants with moderate (n = 8) hepatic impairment (Child-Pugh B classification) versus participants with normal hepatic function (n = 8). Safety was monitored throughout. The effect of renal impairment on aficamten PK was assessed using population PK (PopPK) modelling of phase 2/3 clinical data in patients with oHCM.
Results
Aficamten PK was similar in participants with moderate hepatic impairment and those with normal hepatic function. No serious or severe treatment-emergent adverse events or clinically significant laboratory abnormalities were reported. There were no clinical meaningful differences in aficamten exposure in patients with oHCM with mild or moderate renal impairment and those with normal renal function.
Conclusions
No clinically relevant changes in aficamten PK were observed in participants with moderate hepatic impairment. Population PK analysis indicated mild or moderate renal impairment and had no statistically or clinically significant impact on aficamten PK in patients with oHCM. Aficamten dose adjustment may not be necessary in patients with mild or moderate hepatic or renal impairment.
The pharmacokinetics of aficamten were found to be comparable between healthy participants with moderate hepatic impairment and those with normal hepatic function.
Using population pharmacokinetic modelling, there were no meaningful differences in aficamten exposure in patients with symptomatic obstructive hypertrophic cardiomyopathy with mild or moderate renal impairment versus those with normal renal function.
1 Introduction
Hypertrophic cardiomyopathy (HCM) is estimated to affect up to 20 million people worldwide, including 750,000 in the USA, and is amongst the most prevalent of genetic cardiovascular diseases [1]. There are considerable variations in the clinical manifestations of HCM, from patients who are asymptomatic to those who experience exercise-related symptoms, dyspnea, chest pain, palpitations and/or syncope. Sudden cardiac death can sometimes be the first manifestation of HCM [2]. Hypertrophic cardiomyopathy can be a debilitating and life-changing disease leading to both reduced functional capacity and quality of life [3]. Patients with HCM often limit their physical activity, resulting in other disease sequelae, including obesity and depression [4, 5]. Obstructive hypertrophic cardiomyopathy (oHCM) is the most common form of the disease [6], and can be caused by left ventricular outflow tract obstruction due to abnormal interaction of the mitral valve with the thickened ventricular septum during systole [7]. Excessive actin-myosin cross-bridge formation within the cardiac sarcomere is one of the main causes of cardiac hypercontractility leading to outflow obstruction [8].
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Aficamten (formerly CK-3773274) is a next-in-class, small-molecule, selective inhibitor of cardiac myosin that has demonstrated a favorable benefit-risk profile for the treatment of oHCM [9, 10]. By targeting cardiac myosin, aficamten reduces myocardial hypercontractility, which underlies the pathophysiology of oHCM. The pivotal, phase 3 SEQUOIA-HCM (NCT05186818) trial has reported positive results with aficamten in patients with symptomatic oHCM, significantly increasing peak oxygen uptake versus placebo, with least squares mean (LSM) changes from baseline at Week 24 of 1.8 and 0.0 mL/kg/min, respectively, and a treatment difference of 1.7 mL/kg/min (95% confidence intervals [CI]: 1.0, 2.4; p < 0.001) [11]. The trial also assessed 10 prespecified secondary endpoints, which demonstrated improvements in health status, New York Heart Association (NYHA) class, left ventricular outflow tract obstruction, and guideline eligibility for septal reduction therapy. The results for all 10 secondary endpoints were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the 2 groups [11].
In a phase 1 study in healthy volunteers, the pharmacokinetics (PK) of aficamten were generally dose proportional (single and multiple doses), with steady state achieved after 10–12 days, supporting once-daily dosing and the potential for rapid reversal of effects [9, 10]. Consistent with the estimated t½, the mean accumulation ratio for aficamten, based on area under the plasma concentration–time curve (AUC), ranged from approximately 4.6 to 4.9 with once daily (QD) dosing. This accumulation at steady state was predicted by the single-dose PK, indicating that the PK behavior did not change over time and single-dose PK is adequate to characterize multiple-dose PK [10]. A human mass balance study has demonstrated that aficamten is predominantly cleared by hepatic metabolism and biliary excretion, with minimal parent-drug recovery from urine [12]. CK-3834282 and CK-3834283 are the main circulating metabolites in plasma, both of which are pharmacologically inactive [12]. In vitro, aficamten was moderately (approximately 89.6%) bound to plasma proteins, and protein binding was independent of drug concentration up to 3400 ng/mL, which is approximately 10-fold of the maximal concentrations achieved at the highest dose of aficamten 20 mg QD in patients (data on file).
Since aficamten was anticipated to undergo hepatic metabolism, the impact of hepatic impairment on the PK of aficamten and its metabolites was evaluated in a dedicated phase 1 study in healthy volunteers to inform dosing recommendations in patients with HCM with mild or moderate hepatic impairment. The primary objective of this study was to evaluate the PK of aficamten and its metabolites CK-3834282 and CK-3834283 following a single oral dose in participants with moderate hepatic impairment compared with participants with normal hepatic function. The secondary objective was to assess the safety and tolerability of a single oral dose of aficamten in participants with moderate hepatic impairment and with normal hepatic function. Exploratory objectives assessed the impact of moderate hepatic impairment on plasma protein binding of aficamten and explored the relationship between hepatic function parameters and aficamten PK parameters.
Renal excretion plays a minor role in aficamten elimination (renal clearance < 0.1% of total clearance) [12]; hence, clinically significant increases in aficamten exposure due to renal impairment were considered unlikely and the use of aficamten was allowed in patients with estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 in phase 2 and 3 studies. While a dedicated clinical study of aficamten in subjects with renal impairment was not conducted as part of the phase 1 program, the effect of mild or moderate renal impairment on the PK of aficamten was subsequently characterized using population PK (PopPK) analyses from phase 2 and 3 data in patients with oHCM. Here we report data from both investigations.
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2 Methods
2.1 Hepatic Impairment
2.1.1 Study Design and Participants
The hepatic impairment study was a phase 1, single-dose, open-label, parallel group study in participants with moderate hepatic impairment (Child-Pugh class B; Child-Turcotte-Pugh score 7–9) and with normal hepatic function. Participants in the moderate hepatic impairment group (n = 8) were matched 1:1 for age (±10 years), sex, and body mass index (BMI; ±20%) with participants in the normal hepatic function group. Participants with mild hepatic impairment were due to be enrolled in Part 2 of the study but following a review of the PK and safety data from participants with moderate hepatic impairment and normal hepatic function, Part 2 was not conducted.
Participants were screened for eligibility within 28 days of receiving a single oral dose of aficamten 20 mg (Day 1) after fasting overnight for at least 10 hours and at least 4 hours post-dose. Aficamten 20 mg represents the highest dose evaluated in the phase 3 SEQUOIA-HCM (NCT05186818) study [11] and previous clinical studies support the safety and tolerability of this single dose in healthy participants [10, 13]. Aficamten single doses were studied up to 75 mg and aficamten was well tolerated up to 50 mg [10], so any increase in exposure due to the impact of moderate hepatic impairment was expected to be within previous clinical experience. In light of the thorough safety monitoring planned throughout this study, the proposed single dose of aficamten 20 mg was deemed appropriate. A follow-up period of an additional 9 (±2) days was scheduled following a sampling period of approximately 21 days.
Eligible participants were aged 18–75 years, with a BMI of 18 to 42 kg/m2 at screening. Participants in the moderate hepatic impairment group met the criteria for class B of the Child-Pugh classification score (7–9 points) and were required to have a chronic (>6 months) or stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) hepatic insufficiency with features of cirrhosis due to any etiology but were otherwise sufficiently healthy for study participation. Participants in the normal hepatic group were required to be in good health with no clinically significant findings as determined by medical history, physical examination, screening clinical laboratory profiles, vital signs, or electrocardiograms (ECGs).
2.1.2 Sampling and Assessments
Serial blood samples for concentrations of aficamten and its metabolites, CK-3834282 and CK-3834283, were collected pre-dose and up to 480 hours post-dose. Serial blood samples for the determination of unbound aficamten were collected at 1, 2.5, and 24 hours post-dose, corresponding to the expected maximum and trough concentrations. Free fractions of
CK-3834282 and CK-3834283 were not measured because these metabolites are not pharmacologically active at therapeutic exposures [12]. Pharmacokinetic parameters were estimated using noncompartmental methods with Phoenix WinNonlin® version 8.3.
The PK parameters assessed included AUC from time zero to the last non-zero concentration (AUClast), AUC extrapolated from time zero to infinity (AUC0–inf), the maximum observed concentration (Cmax), the time to reach Cmax (tmax), the apparent terminal elimination half-life (t1/2), the apparent total plasma clearance (CL/F; parent only), and free (unbound) fraction (fu) and free Cmax for aficamten.
Safety was assessed by monitoring adverse events (AEs), 12-lead ECGs, vital signs, clinical laboratory data, and physical examinations. All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 25.1.
2.1.3 Statistical Methods
An analysis of covariance (ANCOVA) was performed to compare the PK in participants with moderate hepatic impairment (test) and matching participants with normal hepatic function (reference). The natural-log (ln)-transformed PK parameters (AUC0–t, AUC0–inf, and Cmax) were analyzed using a model that included factor “hepatic impairment group” and sex as fixed effects and the covariates age and BMI. The LSM of the PK parameters for each hepatic function group, difference in LSMs between the test and reference groups, and corresponding 90% CIs were calculated, and back-transformed to give the geometric LSM (GLSM), ratio of GLSMs, and corresponding 90% CIs. For the PK parameters t1/2 and CL/F, the non-parametric Wilcoxon Rank Sum Test was performed, and the p-value was presented for comparison of test versus reference. Regression analysis was used to assess the relationships between PK and Child-Pugh classification parameters (serum albumin concentration, total bilirubin concentration, prothrombin, international normalized ratio [INR], and Child-Pugh score). Statistical analyses were performed using SAS® version 9.4. Safety variables were summarized using descriptive statistics.
2.2 Renal Impairment
2.2.1 Study Design and Participants
The PopPK modelling was conducted to characterize the aficamten PK in participants with oHCM, and to identify covariates that could potentially alter aficamten exposure. Since the PK of the pharmacodynamically inactive circulating aficamten metabolites, CK-3834282 and CK-3834283, has been sufficiently characterized in the clinical program, the PopPK analyses were limited to aficamten.
Full details on the PopPK model will be reported separately. Briefly, PopPK model estimation was performed using NONMEM (v7.5). A 2-compartment model with linear absorption and elimination best described the PK of aficamten.
One objective of the PopPK analysis was to assess the effect of mild and moderate renal impairment on aficamten PK using results from patients with symptomatic oHCM enrolled in the randomized, placebo-controlled, phase 2 REDWOOD-HCM (NCT04219826) and phase 3 SEQUOIA-HCM studies (NCT05186818) [6, 11, 14]. In these studies, patients with oHCM received QD doses of aficamten at different dose levels (5 mg, 10 mg, 15 mg, 20 mg, or 30 mg); the doses were selected according to an individualized echocardiography-based dose titration scheme. The analysis included participants with mild (eGFR of 60–89 mL/min) or moderate (eGFR of 30–59 mL/min) renal impairment, or normal renal function (eGFR of ≥90 mL/min). Individuals with severe renal impairment (eGFR of < 30 mL/min) were excluded from the aficamten phase 2 and 3 studies.
2.2.2 Sampling and Assessments
Pharmacokinetic samples were collected at pre-dose, 1 hour post-dose on Day 1, and pre-dose, 0.5, 1 and 2 hours post-dose at Weeks 2, 4, 6 and 10 in the REDWOOD-HCM study, and at pre-dose and 2 hours post-dose at Weeks 2, 4, 6, 8, 12, 16, 20 and 24 in the SEQUOIA-HCM study.
The post hoc aficamten steady-state exposures (area under the plasma concentration–time curve between dose intervals [AUCtau], Cmax, and trough concentration [Ctau]) following QD dosing of aficamten 15 mg (median last stable dose in SEQUOIA-HCM) were estimated.
Renal function treatment-emergent adverse events (TEAEs) of interest were analyzed by eGFR subgroups of 30 to < 60, 60 to < 90, and ≥ 90 mL/min/1.73 m2 in an integrated safety analysis.
2.2.3 Statistical Methods
Participants with oHCM were stratified by renal function (normal function vs mild renal impairment vs moderate renal impairment). Aficamten steady-state exposures for each renal impairment subgroup relative to normal renal function were evaluated via calculation of GLSM ratios with 90% CI.
2.3 Bioanalysis
All plasma concentrations were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods validated at Celerion (Lincoln, Nebraska). The analytical range for total plasma concentrations of aficamten and its metabolites was 1.00–500 ng/mL, and 0.200–200 ng/mL for unbound aficamten. For each method, quantitation was determined using a weighted linear regression analysis (1/concentration2) of peak area ratios of the analyte(s) and internal standard. The method for total aficamten employed a protein precipitation procedure and the method for total metabolites employed a liquid-liquid extraction procedure. For unbound aficamten, a sample dialysis procedure was followed. Unbound aficamten analysis was conducted using rapid equilibrium dialysis. Plasma samples were placed in the inner chamber of a dialysis plate, with 1× PBS in the outer chamber, and incubated at 37 °C for 16–20 hours. After dialysis, total aficamten samples were mixed with 1× PBS, and free aficamten samples were mixed with blank control plasma for quantification. All samples underwent protein precipitation before HPLC-MS/MS analysis. During sample analysis, inter-day accuracy of the QC samples for total aficamten, metabolites CK-3834282 and CK-3834283, and unbound aficamten ranged from −2.4 to 6.8%, −2.4 to −1.6%, −2.4 to −2.0%, and −3.3 to 1.6%, respectively. Precision for total aficamten, metabolites CK-3834282 and CK-3834283, and unbound aficamten was within 6.8%, 3.8%, 4.7%, and 4.8%, respectively.
2.4 Ethics
All study protocols were reviewed by site-specific institutional review boards. The ethical approval numbers for the phase 1 hepatic impairment study are SSU00213764 and SSU00213523. The details pertinent to the approval of the phase 2 and phase 3 studies are presented elsewhere [11, 14]. Study procedures were conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with International Council for Harmonisation Good Clinical Practice guidelines and applicable laws and regulations. All participants provided written informed consent.
3 Results
3.1 Hepatic Impairment
3.1.1 Disposition, Demographics, and Baseline Characteristics
Twenty-four participants were screened for eligibility, of whom 16 (n = 8 with moderate hepatic impairment and n = 8 with normal hepatic function) were enrolled and received a single dose of aficamten 20 mg and completed the study. Demographics were similar between the two groups (Table 1). The majority of participants were White (87.5% in the moderate hepatic impairment group and 100% in the normal hepatic group) and 62.5% of participants were male. The demographics and baseline characteristics summarized in Table 1 are consistent with the typical phase 1 special population study in participants with hepatic impairment [15, 16].
Table 1
Demographics and baseline characteristics of participants in the hepatic impairment study
Characteristic
Moderate hepatic impairment (n = 8)
Normal hepatic function (n = 8)
Age, mean (SD), years
57 (7.0)
57 (4.5)
Male, n (%)
5 (62.5)
5 (62.5)
BMI, mean (SD), kg/m2
31.4 (3.2)
29.7 (4.1)
Race, n (%)
White
7 (87.5)
8 (100.0)
Black or African American
1 (12.5)
0
Ethnicity, n (%)
Hispanic or Latino
6 (75.0)
7 (87.5)
Not Hispanic or Latino
2 (25.0)
1 (12.5)
Child-Pugh score, n (%)
7
4 (50.0)
–
8
1 (12.5)
–
9
3 (37.5)
–
BMI body mass index, SD standard deviation
3.1.2 Pharmacokinetics
Aficamten PK parameters in participants with moderate hepatic impairment and normal hepatic function were generally comparable following a single oral dose of aficamten (Fig. 1, Table 2). Overall exposure parameters (AUClast and AUC0–inf) of aficamten were comparable between the 2 groups. Compared with participants with normal hepatic function, the total plasma and unbound aficamten Cmax were numerically higher (38% and 59%, respectively) in participants with moderate hepatic impairment, with 90% CIs for both parameters crossing 100%. Aficamten Cmax was reached earlier in participants with moderate hepatic impairment compared with participants in the normal hepatic groups (median Tmax: 0.75 vs 1.50 hours, respectively). There were no statistically significant differences in t1/2 (p = 0.7209) and CL/F (p = 1.0000) of aficamten in participants with moderate hepatic impairment and normal hepatic function.
Fig. 1
Mean (+SD) aficamten plasma concentration-time profile after a single dose of aficamten in the hepatic impairment study on a linear and semilogarithmic scale over 480 hours (A) and over 24 hours (B). SD, standard deviation
Pharmacokinetic parameters and statistical comparisons after a single dose of aficamten in the hepatic impairment study
Analyte
PK parametera (n = 8)
Reference
Test
Test vs referenceb
Normal hepatic function
Moderate hepatic impairment
Ratio of GLSM (90% CI)
Aficamten
AUC0–inf (ng·h/mL)
7990 (70.8)
7040 (42.3)
0.95 (0.64–1.41)
AUClast (ng·h/mL)
7357 (59.3)
6691 (41.0)
0.95 (0.66–1.36)
Cmax (ng/mL)
109 (48.6)
153 (56.0)
1.38 (0.83–2.30)
Cmax,u (ng/mL)d
6.3 (60.1)
9.6 (49.2)
1.59 (0.92–2.73)
tmax (h)
1.50 (1.00, 2.00)
0.75 (0.50, 1.25)
–
t1/2 (h)
88.2 (76.8, 101.8)
106.4 (69.9, 114.5)
0.7209c
CL/F (L/h)
3.1 (32.6)
3.4 (45.4)
1.0000c
CK-3834282
AUC0–inf (ng·h/mL)
3834 (21.3)
3096 (42.0)
0.82 (0.66–1.02)
AUClast (ng·h/mL)
3615 (17.2)
2929 (43.8)
0.80 (0.64–1.02)
Cmax (ng/mL)
37 (33.3)
25 (52.7)
0.70 (0.47–1.04)
tmax (h)
4.00 (3.49, 6.00)
4.00 (3.25, 6.00)
–
t1/2 (h)
80.49 (71.49, 102.26)
98.50 (69.84, 107.37)
–
MRAUC0–inf
0.5 (27.0)
0.5 (45.6)
0.87 (0.59–1.27)
CK-3834283
AUC0–inf (ng·h/mL)
6404 (22.2)
6296 (24.8)
1.04 (0.83–1.31)
AUClast (ng·h/mL)
6141 (23.7)
6025 (24.0)
1.04 (0.83–1.31)
Cmax (ng/mL)
69 (44.6)
51 (35.7)
0.88 (0.57–1.35)
tmax (h)
3.50 (2.50, 6.00)
4.00 (2.75, 4.00)
–
t1/2 (h)
82.96 (69.62, 105.63)
101.97 (69.52, 112.13)
–
MRAUC0–inf
0.9 (40.7)
0.9 (31.2)
1.12 (0.78–1.60)
AUC area under the plasma concentration-time curve, AUC0–inf AUC from zero to infinity, AUClast from zero to last measured concentration, CI confidence interval, CL/F apparent total plasma clearance, Cmax maximum observed concentration, Cmax,uCmax for unbound fraction, CV coefficient of variation, fu free (unbound) fraction, GLSM geometric least squares mean, LSM least squares means, MR metabolite to parent molar ratio, PK pharmacokinetic, SD standard deviation, t1/2 apparent terminal elimination half-life, tmax time to reach Cmax
aArithmetic mean (%CV) statistics presented; tmax and t1/2 are presented as median (Q1, Q3)
bThe ratio of GLSMs and corresponding CIs were obtained by taking the exponential of the LSMs, differences in LSMs, and corresponding CIs on the natural-log scale
cp-values presented
dCmax,u = fu × Cmax, mean fu (SD) for moderate hepatic impairment and normal hepatic function were 6.4% (1.1) and 5.6% (0.7), respectively
Similar AUC ratios of metabolite (CK-3834282 and CK-3834283) to aficamten were observed between participants with moderate hepatic impairment and normal hepatic function (Table 2). Administration of aficamten in participants with moderate hepatic impairment resulted in an ~30% decrease in CK-3834282 Cmax with ~20% decrease in AUC, and ~12% lower CK-3834283 Cmax without a corresponding change in AUC, compared with participants with normal and moderate hepatic impairment hepatic function, respectively. The 90% CIs for each of these parameters crossed 100%. The mean plasma concentration-time profiles for the metabolites are presented in Supplementary Figs. S1 and S2.
Similar plasma aficamten free (unbound) fraction was observed between participants with moderate hepatic impairment and normal hepatic function (geometric mean [geometric coefficient of variation %]: 0.063 [17.1%] vs 0.055 [13.7%]). Exploratory regression analyses indicated minimal to no correlation between the aficamten PK parameters (AUC and Cmax) and the measures of hepatic function Child-Pugh score (Fig. 2A), serum albumin concentration (Fig. 2B), bilirubin concentration (Supplementary Fig. S3A), prothrombin time (Supplementary Fig. S3B), and INR (Supplementary Fig. S3C).
Fig. 2
Plasma aficamten AUC0–inf and Cmax versus Child-Pugh score (A) and serum albumin concentration (B) in the hepatic impairment study. AUC0–inf area under the plasma concentration-time curve from zero to infinity, CI confidence interval, Cmax maximum observed concentration
There were no serious AEs, AEs of special interest, or other significant AEs reported by the 16 participants during this study. A total of 3 TEAEs were reported by 3 (19%) participants following a single oral dose of aficamten, comprising 2 participants with moderate hepatic impairment and 1 participant with normal hepatic function. The 2 events in the moderate hepatic impairment group (gastroesophageal reflux disease and headache) were mild in severity and the 1 event in the normal hepatic group (headache) was moderate in severity. There were no safety concerns identified from the evaluation of clinical laboratory, vital signs, ECGs, or physical examinations in this study with respect to participant safety.
3.2 Renal Impairment
3.2.1 PopPK Analysis
A total of 183 patients with oHCM (41 from phase 2 REDWOOD-HCM study, and 142 from the phase 3 SEQUOIA-HCM study) were included in the PopPK analysis, including 116 with normal renal function, 54 with mild renal impairment, and 13 with moderate renal impairment. In these studies, median weight was numerically lower and the proportion of females was numerically higher with increasing severity of renal impairment (Table 3). Decreased body weight and female sex were identified as significant covariates that modestly increased aficamten exposure. The PopPK model determined that renal function (eGFR) was not a statistically significant covariate on aficamten PK.
Table 3
Demographics and baseline characteristics of participants by renal function
PopulationPK-estimated aficamten steady-state exposures in patients with oHCM, stratified by renal function, are presented in Table 4. A general numerical increase in aficamten exposure (14–28%) was observed with increasing renal impairment (Table 4; Supplementary Fig. S4). This result is likely due to the decreased weight and increased proportion of female participants with increasing renal impairment in the dataset.
Table 4
Summary of Population PK-predicted exposures at steady-state for aficamten following once-daily dosing of aficamten 15 mg in participants with oHCM by renal function (studies REDWOOD-HCM and SEQUOIA-HCM; N = 183)
PK parameter, mean (%CV)
Normal renal function (n = 116)
Mild renal impairment (n = 54)
Moderate renal impairment (n = 13)
GMR (90% CI)
Mild/normal
Moderate/normal
AUCtau (ng·h/mL)
6050 (37.6)
6960 (44.9)
7540 (29.1)
1.14 (1.04–1.26)
1.28 (1.09–1.51)
Cmax (ng/mL)
260 (37.9)
304 (44.1)
331 (28.8)
1.17 (1.06–1.28)
1.31 (1.11–1.55)
Ctau (ng/mL)
227 (41.1)
262 (49.0)
282 (31.4)
1.15 (1.04–1.27)
1.28 (1.07–1.53)
Exposures were simulated using post hoc PK parameters of participants with oHCM given aficamten 15 mg tablet once daily (median last stable dose in SEQUOIA-HCM) with or without food
AUCtau area under the plasma concentration-time curve between dose intervals, CI confidence interval, Cmax maximum observed concentration, Ctau trough concentration, CV coefficient of variation, GMR geometric mean ratio, oHCM obstructive hypertrophic cardiomyopathy, PK pharmacokinetic
Integrated safety analyses indicated that the incidence of renal function AEs was low and comparable across renal function groups (1.2–6.3%).
4 Discussion
In view of the global prevalence of patients with oHCM [6], there is a need to determine whether treatments are affected by impaired hepatic or renal function in this patient population. The impact of hepatic and renal impairment on the PK of aficamten was evaluated in a phase 1 clinical trial and by using a PopPK analysis approach, respectively. No clinically relevant changes in the PK of aficamten were observed in otherwise healthy participants with moderate hepatic impairment versus participants with normal hepatic function following a single oral dose of aficamten 20 mg. Considering linear PK of aficamten, and comparable aficamten PK between healthy participants and patients with oHCM (data on file), these results can be extrapolated to multiple doses in patients with oHCM. Aficamten was readily absorbed following administration, with the moderate hepatic impairment group showing a numerical increase in Cmax but a similar AUC, half-life, and clearance to the normal hepatic group. Similar aficamten free (unbound) fractions were observed in both groups, indicating lack of effect of hepatic impairment on protein binding.
The AUC aficamten metabolite (CK-3834282 and CK-3834283) to parent ratios were similar between participants with moderate hepatic impairment and normal hepatic function, suggesting that moderate hepatic impairment did not impact formation of the metabolites. Exploratory analyses indicated minimal to no correlations between aficamten PK and Child-Pugh classification parameters at baseline.
The insignificant impact of moderate hepatic impairment on aficamten PK is likely due to its pharmacological profile. As a low extraction ratio drug, aficamten clearance is less influenced by liver blood flow, minimizing the potential for PK alterations in the setting of hepatic impairment. Similarly, drugs metabolized through multiple P450 pathways that are not sensitive CYP3A substrates are not generally subject to significant increases in exposure in moderate hepatic impairment (e.g., ledipasvir as part of Harvoni, velpatasvir as part of Epclusa, asciminib, aripiprazole, etc.). Furthermore, the absence of any observed impact on plasma protein binding of aficamten in participants with moderate hepatic impairment further supports that aficamten PK is not altered by moderate hepatic impairment.
Aficamten was well tolerated after a single oral dose of 20 mg in participants in the hepatic impairment study. No serious or severe TEAEs or clinically significant laboratory abnormalities were reported. These safety results are comparable to those previously observed in other aficamten studies in healthy participants [2, 3]. These findings for aficamten in participants with moderate hepatic impairment can be extrapolated to patients with mild hepatic impairment, suggesting that dose adjustment of aficamten may not be necessary in patients with mild or moderate hepatic impairment.
Of note, severe hepatic impairment in oHCM is rare, as evidenced by data from a search in the IBM Clinical Electronic Medical Record data (less than 0.7% prevalence), with 58 cases of moderate or severe liver disease out of 8791 patients with oHCM [17] and the HealthCore Medical and Pharmacy Claims data (less than 0.5% prevalence), with fewer than 10 cases of moderate or severe liver disease among 1841 patients with oHCM [18]. As such, the effect of severe hepatic impairment on the PK of aficamten was not specifically examined. However, substantial increases in exposure due to severe hepatic impairment are uncommon for drugs that are metabolized through multiple P450 pathways, are not sensitive CYP3A substrates and do not demonstrate large PK alteration in participants with moderate hepatic impairment [19‐22], suggesting that clinically meaningful increases in aficamten exposure in participants with severe hepatic impairment are unlikely.
Evaluation of the effect of renal impairment on the PK of aficamten was limited to mild or moderate renal impairment. The incidence of severe renal impairment in patients with oHCM is remarkably low. Of the 543 participants screened for Phase 3 Study SEQUOIA-HCM, only 2 participants (0.4%) failed screening due to having an eGFR 30 mL/min/1.73 m2. This observation is consistent with the findings of a comprehensive search in the ShaRe registry (data on file), a multicenter, international repository of clinical data on individuals and families with genetic heart disease, which indicated that 1.4% and 0.7% of patients with oHCM had severe and end‑stage renal disease, respectively. As such, aficamten has not been evaluated in patients with severe renal impairment, and they were not specifically assessed in the current analysis. Furthermore, the human mass balance study indicated aficamten was primarily eliminated by metabolism, with renal excretion of unchanged aficamten playing only a minor role (urine recovery of unchanged parent drug was 0.554% of the dose administered) [12], assessment of aficamten in subjects with severe renal impairment in a dedicated phase 1 clinical study was deemed unnecessary.
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Based on the PopPK analysis, renal impairment did not have a statistically or clinically significant impact on aficamten PK. When comparing steady-state exposures for aficamten among participants with oHCM and normal renal function, mild renal impairment, and moderate renal impairment, the apparent differences in PK profile between renal impairment groups is likely related to the uneven patient distribution across groups by sex and weight, two statistically significant covariates identified by PopPK analyses (data on file).
In conclusion, the PK of aficamten and its metabolites was not meaningfully affected in participants with moderate hepatic impairment suggesting aficamten dose adjustment may not be necessary in patients with oHCM and mild or moderate hepatic impairment. Findings from PopPK modelling of data from patients with oHCM indicated there were no meaningful differences in aficamten exposure in those with mild or moderate renal impairment compared with patients with normal renal function, signifying aficamten may be administered without dose adjustment in this patient population.
Acknowledgments
The authors thank Edward Kim for helpful contributions. Medical writing support was provided by Iain McDonald, Ph.D., of Engage Scientific Solutions, UK, funded by Cytokinetics, Incorporated.
Declarations
Ethics Approval
All study protocols were reviewed by site-specific institutional review boards.
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Consent to Participate
All participants provided written informed consent.
Consent for Publication
Not applicable.
Code Availability
Not applicable.
Funding
This study was funded by Cytokinetics, Incorporated.
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Author Contributions
All authors participated in the conception and planning of the study; Donghong Xu, Justin Lutz, Punag Divanji, Youcef Benattia, Adrienne Griffith and Polina German participated in the design of the study. Donghong Xu, Justin Lutz and Polina German participated in the acquisition, analysis, and interpretation of data. All authors critically revised and approved the final version of the manuscript.
Competing Interests
Donghong Xu, Justin D. Lutz, Punag Divanji, Adrienne Griffith, Stephen B. Heitner, Stuart Kupfer, and Polina German: Employees of and hold stock in Cytokinetics, Incorporated. Youcef Benattia, and Jianlin Li: Paid consultant for Cytokinetics, Incorporated.
Availability of Data and Material
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials and can also be obtained from the corresponding author upon reasonable request.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
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