A Phase 1 Dose-Escalation Study of the Cardiac Myosin Inhibitor Aficamten in Healthy Participants

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SUMMARY
This phase 1, randomized, double-blind, placebo-controlled study of aficamten (formerly CK-3773274) in healthy adults identified a pharmacologically active range of doses and exposures. At doses that were pharmacologically active (single doses of #50 mg or daily dosing of #10 mg for 14 or 17 days), aficamten appeared to be safe and well tolerated. Adverse events were generally mild and no more frequent than with placebo.
Pharmacokinetic assessments showed dose proportionality over the range of single doses administered, and in young adults and adolescents, 2 and it may be associated with syncope, 1 heart failure, 3 and atrial fibrillation, which in turn increases the risk of stroke. 4

HCM is inherited
in an autosomal dominant pattern and is reported to be one of the most common inherited heart conditions, although prevalence estimates for clinically evident disease are lower. 5,6 Pathogenic sequence variants in multiple genes can result in HCM, with most of these genes encoding sarcomere-associated proteins 1,7 that are responsible for generating and regulating cardiac muscle contraction.
These sequence variants produce changes in protein function, leading to a hypercontractile state of the sarcomere, and initiating a series of secondary effects at the cellular and organ levels, 1 such as development of myocyte disarray, interstitial fibrosis, and cardiac hypertrophy-phenotypic hallmarks of HCM. 1,7,8 Therapeutic correction of the contractile phenotype may limit the adverse clinical outcomes in patients with HCM. 9 Cardiac myosin inhibitors might therefore have the potential to reduce hypercontractility, impaired relaxation, and adverse LV remodeling in patients with HCM, 10 Obstructive Hypertrophic Cardiomyopathy). 11 The trial showed that mavacamten was superior to placebo for improving exercise capacity and health status in patients with obstructive HCM. 11 Mavacamten also reduced the LV outflow tract pressure gradients that are a hallmark of obstructive HCM, the most

First-in-Human Study of Aficamten
A U G U S T 2 0 2 2 : 7 6 3 -7 7 5 entering a force-producing state. 13 The inhibition of contractility was achieved without disrupting calcium transients within the myocyte. 13

First-in-Human Study of Aficamten
A U G U S T 2 0 2 2 : 7 6 3 -7 7 5 2-way crossover design, participants were to receive 2 single doses of 10 mg of aficamten, separated by $14 days. Participants were randomized in a 1:1 ratio to 1 of 2 sequences: fasted/fed or fed/fasted. In the fasted period, aficamten was administered after an overnight fast; in the fed period, aficamten was administered 30 minutes after the start of a high-fat breakfast.
ASSESSMENTS. S a f e t y a n d t o l e r a b i l i t y . Safety was assessed by the incidence of adverse events (AEs) and by the incidence of reduced LVEF. Treatmentemergent AEs (TEAEs) were defined as AEs that began or increased after study drug administration.    All timepoints for which both PK data and PD measures were available were pooled for the analysis.
A nominal significance level of 5% was used for statistical comparisons, without adjustment for multiplicity.  Most common TEAEs

RESULTS
Values are n (%). The most common TEAEs are based on preferred terms, reported in $2 participants in the total cohort. a "Bubbling sensation to the left chest" consistent with a gastrointestinal association rather than a cardiac association. b Onset approximately 60 hours postdose.
Malik et al   Tables 2 and 3). Overall, the most common TEAE was headache in both the SAD and MAD cohorts ( Tables 2 and 3).

Echocardiogram-related AEs of decreased LVEF
of <45% based on the study echocardiogram expert assessment were reported in 3 participants: 1 each in the SAD 40-mg, 50-mg, and 75-mg cohorts (Supplemental Table 1). All were grade 1, and all resolved at the next echocardiogram assessment   Figure 3).
Values are geometric mean (geometric CV%), median (range), or mean AE SD.  PHARMACODYNAMICS. E c h o c a r d i o g r a p h y . At baseline, mean LVEF ranged from 61.0% to 67.5% across cohorts ( Table 1). In the SAD cohorts, mean decreases in LVEF were observed in the groups receiving the highest doses of aficamten ( Figure 4A). Maximum mean reduction from baseline in LVEF was seen in the 50-mg cohort at 1.5 hours postdose (placebo corrected least-squares mean difference: 5.5%; P < 0.001). LVESV and LVEDV were statistically significantly increased by 8.1 and 6.6 mL, respectively (Supplemental Table 4). Other echocardiographic parameters such as stroke volume, cardiac output, cardiac time intervals, and measures reflective of diastolic function did not significantly change (Supplemental Table 4). The single participant who received 75 mg of aficamten exhibited reduction in LVEF of 31.5% at 1.5 hours postdose, which resolved 2.5 hours after onset but led to concluding escalation of doses in the SAD portion of the study, as discussed earlier.
In the MAD cohorts, a clear decrease in LVEF emerged as dosing continued in the 10-mg cohort ( Figure 4B). The largest mean maximum percent reduction from baseline, of 5.0%, was seen in the 10-mg cohort at 1.5 hours postdose on day 14 ( Figure 4B). The placebo-corrected reduction of 3.2% (least-squares mean difference) did not reach statistical significance (P ¼ 0.21), likely because of the lack of statistical power in this small group comparison. For the 7.5-mg cohort, dosing was extended to 17 days with a 3-day follow-up, and it was confirmed that the steady state was achieved after 10 to 12 days. qd ¼ once daily. Values are geometric mean (geometric CV%), median (range), or arithmetic mean AE SD.
AUC24 ¼ area under the plasma drug concentration-time curve from time 0 to 24 h; AUCtau ¼ area under the curve to the end of the dosing period; CLss/F ¼ apparent total body clearance after oral administration (at steady state); Cmax ¼ maximum plasma concentration; Cmax,ss ¼ maximum plasma concentration at steady state; CV% ¼ percent coefficient of variation; MAD ¼ multiple ascending dose; qd ¼ once daily; RA,AUC ¼ accumulation ratio calculated from AUCtau at the steady state and following a single dose; t1/2 ¼ half-life; Tmax ¼ time to maximum plasma concentration; Tmax,ss ¼ time to reach maximum plasma concentration following drug administration at steady state. In the MAD cohort, absolute reduction in LVEF of $5% from baseline was observed in 4 participants: 1 of 6 (17%) participants receiving placebo, 1 of 6 (17%) receiving 7.5 mg of aficamten once daily, and 2 of 6 (33%) receiving 10 mg of aficamten once daily. Of these, reductions were $10% in the 2 participants in the 10-mg cohort. Reduction in LVEF to <50% was not observed in any of the MAD cohorts per core laboratory assessment. SAFETY OF AFICAMTEN. We observed no serious AEs in the study, and all participants completed the intended dosing as planned. Generally, AEs were mild and similar in frequency between participants treated with aficamten and placebo. Importantly, there were no associated symptoms or adverse changes in vital signs for participants whose LVEFs fell below 50%, and the LVEFs in these individuals returned to baseline within 24 hours. This study was not intended to find a maximum tolerated dose, and hence, dose Data points are offset for clarity. In both the SAD and MAD cohorts, reductions in LVEF within the target range (5%-15% reduction) were observed. In the SAD cohorts, there were generally small decreases in LVEF, with mean maximum reduction of 5.8% in the 50-mg group (at 1.5 hours postdose). In the MAD cohort, the greatest mean reduction in LVEF from baseline occurred in the 10-mg group (mean change of 5.0% 1.5 hours after dosing on day 14). Abbreviations as in Figure 1.

CONCLUSIONS
Aficamten demonstrated a favorable safety profile in healthy participants, without serious AEs or meaningful changes in laboratory tests, ECGs, or health assessments. The PK in humans supports once-daily dosing and attainment of the steady state within 2 weeks. There was no effect of food or CYP2D6 phenotype on the PK of aficamten. Pharmacologically active doses of aficamten that may serve as starting doses for a study in patients with HCM were identi-