CYTK
J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y
V O L . -, N O . -, 2 0 2 4
ª 2 0 2 4 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E A M E R I C A N
C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R
T H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o m m o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .
Effect of Aficamten on Health
Status Outcomes in Obstructive
Hypertrophic Cardiomyopathy
Results from SEQUOIA-HCM
Charles F. Sherrod IV, MD, MSC,a,b Sara Saberi, MD,c Michael E. Nassif, MD,a,b Brian L. Claggett, PHD,d Caroline J. Coats, MD, PHD,e Pablo Garcia-Pavia, MD, PHD,f James L. Januzzi, MD,g,h Gregory D. Lewis, MD,g Changsheng Ma, MD,i Martin S. Maron, MD,j Zi Michael Miao, MS,d Iacopo Olivotto, MD,k Josef Veselka, MD, PHD,l Michael Butzner, DRPH, MPH,m Daniel L. Jacoby, MD,m Stephen B. Heitner, MD,m Stuart Kupfer, MD,m
Fady I. Malik, MD, PHD,m Lisa Meng, PHD,m Amy Wohltman, ME,m John A. Spertus, MD, MPHa,b
ABSTRACT
BACKGROUND A primary goal in treating obstructive hypertrophic cardiomyopathy (oHCM) is to improve patients' health status: their symptoms, function, and quality of life. The health status benefits of aficamten, a novel cardiac myosin inhibitor, have not been comprehensively described.
OBJECTIVES This study sought to determine the effect of aficamten on patient-reported health status, including symptoms of fatigue, shortness of breath, chest pain, physical and social limitations, and quality of life.
METHODS SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) randomized symptomatic adults with oHCM to 24 weeks of aficamten (n ¼ 142) or placebo (n ¼ 140), followed by a 4-week washout. The Kansas City Cardiomyopathy Questionnaire (KCCQ) and Seattle Angina Questionnaire 7-item (SAQ7) were serially administered. Changes in mean KCCQ-Overall Summary Score (KCCQ-OSS) and SAQ7-Summary Score (SAQ7-SS) from baseline to 24 weeks and following treatment withdrawal were compared using linear regression adjusted for baseline scores and randomization strata. Proportions of patients with clinically important changes were compared.
RESULTS Among 282 participants, the mean age was 59 13 years, 115 (41%) were female, and 223 (79%) were White.
Baseline KCCQ-OSS (69.3 20.1 vs 67.3 18.8) and SAQ7-SS (72.0 21.0 vs 72.4 18.3) were similar between afi-
camten and placebo groups. Treatment with aficamten, compared with placebo, improved both the mean KCCQ-OSS
(13.3 16.3 vs 6.1 12.6; mean difference: 7.9; 95% CI: 4.8-11.0; P < 0.001) and SAQ7-SS (11.6 17.4 vs 3.8 14.4;
mean difference: 7.8; 95% CI: 4.7-11.0; P < 0.001) at 24 weeks, with benefits emerging within 4 weeks. No heterogeneity in treatment effect was found across subgroups. A much larger proportion of participants experienced a very large health status improvement ($20 points) with aficamten vs placebo (KCCQ-OSS: 29.7% vs 12.4%, number needed to treat: 5.8; SAQ7-SS: 31.2% vs 13.9%, number needed to treat: 5.8). Participants' health status worsened significantly more after withdrawal from aficamten than placebo (KCCQ-OSS: 16.2 19.0 vs 3.0 9.6; P < 0.001; SAQ7-SS: 17.4
21.4 vs 2.5 13.3), further confirming a causal effect of aficamten.
CONCLUSIONS In patients with symptomatic oHCM, treatment with aficamten resulted in markedly improved health status, including significant improvement in chest pain-related health status, than placebo. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM];NCT05186818) (JACC. 2024;-:---) © 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
From the aUniversity of Missouri-Kansas City's Healthcare Institute for Innovations in Quality, Kansas City, Missouri, USA; bSaint Luke's Mid America Heart Institute, Kansas City, Missouri, USA; cDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA; dCardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; eSchool of Cardiovascular and Metabolic Health, University of Glasgow,
ISSN 0735-1097
https://doi.org/10.1016/j.jacc.2024.08.014
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Obstructive hypertrophic cardiomy- opathy (oHCM) is a condition characterized by excessive actin- myosin cross-bridges, resulting in left
physical and social function and patients' disease- specific quality of life, it does not capture frequency and impact of chest pain, which were assessed by the SAQ7-SS. This prespecified report provides the first
left ventricular
left ventricular outflow
ventricular (LV) hypercontractility, LV hy- pertrophy, myocardial fibrosis, and obstruction of the left ventricular outflow tract (LVOT).1 Abnormal myocardial structure and function also affect coronary blood flow through distal vessel compression and impaired microcirculation.2,3 Accordingly,
in-depth analyses of the health status outcomes of aficamten, along with patient-centered descriptions of the clinical magnitude of these effects, so that patients and providers can have a better understanding of treatment benefit from patients' perspectives.
number needed to treat those living with oHCM frequently experience shortness of breath, palpitations, fa- tigue, and chest pain that can affect their function and quality of life.4 A primary goal in managing oHCM is to improve patients' health status. However, medical therapies,
Summary Scoreaside from mavacamten,5 the first-in-class cardiac myosin inhibitor, have limited data and uncertain clinically meaningful effects on health status.
Aficamten, a next-in-classsmall-molecule cardiac myosin inhibitor, reduces actin-myosin cross- bridging and relieves myocardial hypercontractility.6 In early phase studies, aficamten demonstrated important reductions in left ventricular outflow tract gradients (LVOT-Gs) and markedly improved patients' symptoms.7-9 More recently, the SEQUOIA- HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM; NCT05186818) study demonstrated that aficamten significantly improved measures of exercise capacity (peak VO2), as measured by cardiopulmonary exercise testing.10 The 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ)-Overall Summary Score (OSS) and the 7-item Seattle Angina Questionnaire (SAQ7)-Summary Score
METHODS
SEQUOIA-HCM was a phase 3, multicenter, random- ized, double-blind,placebo-controlled trial that enrolled adult participants with symptomatic oHCM. Details of the study design have previously been published.11 Participants were randomized 1:1 to either aficamten or placebo with the KCCQ, SAQ7, and other measures of disease burden collected at each study visit. Doses of aficamten (range 5-20 mg) or matching placebo were adjusted during the first
6 weeks of the study according to site-interpreted echocardiographic criteria with goal of reducing LVOT-Gs while maintaining left ventricular ejection fraction (LVEF) at $50%. Key inclusion criteria were LV septal hypertrophy $15 mm, or $13 if genetic testing or family history were indicative of oHCM, an LVOT-G$30 mm Hg at rest and $50 mm Hg with Valsalva physiology, and an LVEF $60%. Participants were excluded if they had significant valvular heart disease other than mitral regurgitation caused by systolic anterior motion, ventricular hypertrophy from infiltrative diseases, uncontrolled atrial or ven- tricular arrhythmias, prior or planned septal reduc- tion therapies, inability to complete cardiopulmonary exercise testing, or prior cardiac myosin inhibitors treatment. Ethical approval of the study was approved institutionally by the Internal Review Board at each participating site and each participant signed informed consent prior to randomization.
Glasgow, United Kingdom; fHospital Universitario Puerta de Hierro Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana (IDIPHISA), Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; gDivision of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; hBaim Institute for Clinical Research, Boston, Massachusetts, USA; iBeijing Anzhen Hospital, Capital Medical University, Beijing, China; jLahey Hospital and Medical Center, Burlington, Massachusetts, USA; kMeyer Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Florence, Italy; lDepartment of Cardiology, Angiology and Intensive Care, Klinikum Chemnitz gGmbH, Medical Campus Chemnitz of the Technische Universität Dresden, Dresden, Germany; and mCytokinetics, Incorporated, South San Francisco, California, USA.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Manuscript received July 18, 2024; revised manuscript received August 7, 2024, accepted August 10, 2024.
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Effect of Aficamten on Health Status: SEQUOIA-HCM
PATIENT-REPORTED OUTCOMES. The KCCQ is a 23-item patient-reportedoutcome, originally developed for patients with heart failure to quantify symptoms, function, and quality of life12 and has recently been validated in the oHCM population.13 Individual KCCQ domains measure symptoms, physical and social limitations, and quality of life and are combined into a Clinical Summary Score (the average of the total symptom and physical limitation do- mains) and an OSS (including all 4 domains) to provide a more complete description of patients' health status.14 The KCCQ has a 2-weekrecall period and was collected at baseline and 2, 4, 6, 8, 12, 16, 20, 24, and 28 weeks.
Although the KCCQ captures many of the key symptoms experienced by those with oHCM, it does not quantify chest pain (angina).4 The SAQ7 is a 7-itempatient-reported outcome that was collected to capture the frequency and impact of chest pain on participants ' health status.15 Like the KCCQ, the SAQ7 includes the frequency of chest pain, the physical limitations associated with chest pain, and its impact on patients' quality of life. Domains are combined into the SS (SAQ7-SS) that most comprehensively quan- tifies the impact of chest pain on patients' health status.16 Although not yet validated in oHCM, it was included to provide a more comprehensive assessment of aficamten on clinical outcomes important to patients with oHCM, given the prevalence and relevance of chest pain on patients' quality of life.4 The SAQ7 has a 4-week recall period and was collected at baseline and 4, 8, 12, 16, 20, 24, and 28 weeks.
Both the KCCQ and SAQ7 range from 0 to 100, with higher scores indicating better health status. Scores from 0 to 24 represent very poor to poor health status, from 25 to 49 are poor to fair, from 50 to 74 are fair to good, and from 75 to 100 are good to excellent.12,16 For the SAQ7-Angina Frequency Score, scores from 0 to 30 reflect daily chest pain, 31 to 60 indicate weekly symptoms, 61 to 99 monthly chest pain, and a score of 100 indicates no chest pain over the prior month.16
When assessing the magnitude of treatment benefit for an individual participant, decreases in scores # 5 points indicate clinically important dete- rioration; scores between 5 and <5 represent clinical stability; 5 and <10 reflect small but important im- provements; and 10 and <15 suggest a moderately large improvement; changes in scores of 15 to <20 are a large improvement; and improvements by $20 are very large changes from both patients' and clinicians' perspectives.17 These thresholds were selected because they have been validated for the KCCQ in oHCM,13 but thresholds for interpreting the SAQ7 are
extrapolated from its use in chronic epicardial coronary disease. Because the majority of chest pain in oHCM is due to increased wall stress and microvas- cular disfunction, data relating SAQ7 scores to myocardial blood flow reserve and those with micro- vascular disease support its application to the oHCM population.18,19 Culturally and linguistically appropriate versions of each questionnaire were used in each country.20
STATISTICAL ANALYSIS. Participants were included in this prespecified analysis if they had baseline and follow-uppatient-reported outcome data. Whereas the KCCQ-Clinical Summary Score was a prespecified secondary endpoint in SEQUOIA-HCM given its qualification by the U.S. Food and Drug Administra- tion, the OSS includes the Social Limitation Score and Quality of Life score to more completely quantify the impact of treatment on patients' symptoms, function, and quality of life. Accordingly, for this analysis, the primary endpoints were the change in KCCQ-OSS and SAQ7-SS from baseline to week 24. We additionally analyzed the impact of treatment withdrawal between weeks 24 and 28 on patients' health status.
Baseline characteristics by treatment group were summarized using mean SD or median (Q1-Q3) for continuous variables, as well as counts and percentages for categorical variables. To evaluate the treatment effect of aficamten, changes in KCCQ-OSS and SAQ7-SS were evaluated using linear regression models adjusted for the baseline and randomization stratification variables (beta-blocker use, cardiopul- monary exercise test modality). This method was chosen given the low prevalence of missing data. Heterogeneity of treatment benefit was explored among predefined patient characteristics (sex, age, body mass index, LVEF, N-terminalpro-B-type natriuretic peptide, peak VO2, cardiopulmonary exercise test modality, baseline oHCM treatment, and baseline health status) and tested with interaction terms as exploratory endpoints. Effect sizes are reported as point estimates with 95% CIs. A prespecified
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TABLE 1 Baseline Characteristics By Treatment Group
Placebo
Aficamten
(n ¼ 140)
(n ¼ 142)
Demographics
Age, y
59.0
13.3
59.2
12.6
Female
59 (42.1)
56 (39.4)
White
115 (82.1)
108 (76.1)
Asian
25 (17.9)
29 (20.4)
Black
0 (0)
3 (2.1)
Other
0 (0)
2 (1.4)
North American
45 (32.1)
49 (34.5)
Chinese
22 (15.7)
24 (16.9)
European and/or Israeli
73 (52.1)
69 (48.6)
Medical history
Hypertension
70 (50.0)
75 (52.8)
Known pathogenic sarcomere variant
25 (17.9)
24 (16.9)
Family history of HCM
34 (24.3)
41 (28.9)
Paroxysmal atrial fibrillation
20 (14.3)
21 (14.8)
Coronary artery disease
16 (11.4)
19 (13.4)
Diabetes mellitus
9 (6.4)
14 (9.9)
Permanent atrial fibrillation
1 (0.7)
2 (1.4)
BMI at baseline, kg/m2
28.2
3.7
28.0
3.8
Baseline HCM therapy
Beta-blocker
87 (62.1)
86 (60.6)
Calcium-channel blocker
36 (25.7)
45 (31.7)
Disopyramide
20 (14.3)
16 (11.3)
Implantable cardioverter-defibrillator
17 (12.1)
22 (15.5)
Baseline measures of HCM severity
NYHA functional class
II
106 (75.7)
108 (76.1)
III
33 (23.6)
34 (23.9)
IV
1 (0.7)
0 (0.0)
NT-proBNP, pg/mL
692 (335-1,795)
818 (377-1,630)
hs-cTnI, ng/L
12 (8, 25)
13 (8, 34)
Peak LVOT-G at rest, mm Hg
55
32
55
27
Peak LVOT-G with Valsalva, mm Hg
83.3
32
82.9
32
LVEF, %
75
6
74.8
5.5
LV maximal wall thickness, cm
2.1
0.3
2.1
0.3
Cardiopulmonary exercise testing
CPET modality: cycle ergonometer
63 (45.0)
64 (45.1)
CPET modality: treadmill
77 (55.0)
78 (54.9)
Total workload, W
125
42
120
39
Peak VO2. mL/kg/min
18.6
4.5
18.4
4.4
Predicted oxygen uptake, %
57.6
13.0
56.2
10.6
Peak respiratory exchange ratio
1.18
0.09
1.19
0.11
Baseline health status
KCCQ
OSS
67.3
18.8
69.3
20.1
CSS
73.7
17.6
75.6
18.4
TSS
73.7
19.6
76.6
19.9
PLS
73.7
18.2
74.6
19.3
SLS
67.7
24.1
68.6
24.3
QOL
53.7
22.6
56.8
26.4
Continued on the next page
independent academic research group using STATA version 18 (StataCorp LLC). No statistical adjustments were made for the multiple comparisons, given the high correlation among the health status outcomes.21
RESULTS
TRIAL POPULATION. A total of 282 participants were randomized and subsequently included in the ana- lyses, of whom 142 (50.3%) received aficamten. The mean age was 59.2 12.6 years and 115 (40.8%) were women. The overall baseline characteristics were similar between treatment arms, including baseline
KCCQ-OSS (69.3
20.1 vs 67.3
18.8) and
SAQ7-SS
(72.0
21.0 vs
72.4
18.3)
and
their
domain
scores (Table 1).
TREATMENT EFFECTS. The mean
SD KCCQ-OSS
and SAQ7-SS by study visit and treatment assignment are shown in Figure 1. The KCCQ-OSS (Figure 1A, Central Illustration) increased in both aficamten and placebo groups, but diverged in magnitude of improvement early during drug titration. Changes were sustained with statistically significant improvements until week 24, the end of the treatment period. The change in KCCQ-OSS from baseline to week 24 was 13.3 16.3 in aficamten vs 6.1 12.6 in placebo-treated participants (mean difference: 7.9; 95% CI: 4.8-11.0;P < 0.001). Similarly, the SAQ7-SS (Figure 1B, Central Illustration) improved more in those treated with aficamten (11.6 17.4) than those treated with placebo (3.8 14.4; mean difference: 7.8; 95% CI: 4.7-11.0; p < 0.001). The health status differences over time between aficamten and placebo for all domains of the KCCQ and SAQ7 are similar and are included in Supplemental Tables 1 to 8.
EFFECTS OF TREATMENT WITHDRAWAL. When treatment was withdrawn between weeks 24 and 28 (Figure 1), a decline in the health status of both treatment groups was observed, with much larger decrements in those who had been treated with afi- camten. Compared with week 24, those in the afi- camten arm experienced greater decreases in their
KCCQ-OSS (
16.2
19.0 vs 3.0
9.6; P < 0.001) and
SAQ7-SS ( 17.4
21.4 vs 2.5
13.3; P < 0.001).
RESPONDER ANALYSES OF PATIENT-LEVEL, CLINICALLY
IMPORTANT
HEALTH STATUS
CHANGES. The pro-
portions of the population experiencing different magnitudes of KCCQ-OSS and SAQ7-SS changes from baseline to week 24 are shown in Figure 2 and the Central Illustration. The largest differences in these distributions for the KCCQ-OSS were for those who experienced very large health status improvements ($20 points). Of those treated with aficamten, 41 (29.7%) as compared with 17 (12.4%) of those treated with placebo experienced a $20 point improvement. This absolute difference of 17.3% equates to an estimated NNT of 5.8 (95% CI: 3.7-12.7) for 1 patient treated with aficamten to feel markedly better after
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24 weeks, as compared with placebo treatment. These results were similar for the SAQ7-SS, with 43 (31.2%) of those assigned to aficamten experiencing a very large ($20 point) improvement compared with 19 (13.9%) of those assigned to placebo. These differences also equate to an NNT of 5.8 (95% CI: 3.7-13.1) for 1 patient to have a very large improvement in SAQ7-SS with aficamten as compared with placebo.
SUBGROUP ANALYSES. Figures 3A and 3B demonstrates the treatment benefit of aficamten across subgroups for the KCCQ-OSand SAQ7-SS,respec- tively. No heterogeneity of treatment benefit was observed by participants' demographics (ie, sex, age, body mass index), echocardiographic characteristics
FIGURE 1 KCCQ and SAQ7 Scores
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Effect of Aficamten on Health Status: SEQUOIA-HCM
TABLE 1 Continued
Placebo
Aficamten
(n ¼ 140)
(n ¼ 142)
SAQ7
SS
72.4
18.3
72.0
21.0
AF
83.5
16.5
83.3
15.7
PLS
71.4
23.8
72.0
24.9
QOL
61.5
28.5
60.5
29.8
Values are mean
SD, n (%), or median (Q1-Q3).
AF ¼ Angina Frequency Score; BMI ¼ body mass index; CPET¼ cardiopulmonary exercise test; CSS¼ Clinical Summary Score; HCM ¼ hypertrophic cardiomyopathy; hs-cTnI ¼ high-sensitivity cardiac troponin I; KCCQ ¼ Kansas City Cardiomyopathy Questionnaire; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; LVOT-G ¼ left ventricular outflow tract gradient; NT-proBNP ¼ N-terminalpro-B-type natriuretic peptide; OSS ¼ Overall Summary Score; PLS ¼ Physical Limitation Score; QOL ¼ Quality of Life Score; SAQ7 ¼ Seattle Angina Questionnaire 7-item; SLS ¼ Social Limitation Score; SS ¼ Summary Score; TSS ¼ Total Symptom Score.
KCCQ-OSS
80
70
60
0
2
4
6
8
12
16
20
24
28
Weeks
SAQ7-SS
80
0
4
8
12
16
20
24
28
Weeks
Placebo Aficamten
Mean Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (KCCQ-OSS) (A) and Seattle Angina Questionnaire 7-item-Summary Score (SAQ7-SS) (B) are shown from baseline until study completion. Titration occurred between week 0 and week 6. Drug discontinuation occurred at week 24 and washed-out by week 28.
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CENTRAL ILLUSTRATION Effect of Aficamten on Health Status Outcomes in Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM
In the SEQUOIA-HCM trial, patients with obstructive hypertrophic cardiomyopathy on aficamten vs placebo for
24 weeks were more likely to have:
Reduced
Very large
Reduced
Reduced
improvements
shortness
chest pain
fatigue
in health status:
of breath
NNT <6
Mean Kansas City Cardiomyopathy Questionnaire
Distribution of Participants Changing by Clinically
Overall Summary Scores (KCCQ-OSS)
Important KCCQ-OSS Thresholds at 24 Weeks
KCCQ-OSS = 7.9 (95% CI: 4.8-11.0)
85
*
30
80
25
75
20
KCCQOSS-
Participants
15
70
%
10
65
Titration
Maintenance
Washout
5
0
No Change
Small
Moderate
Large
Very Large
0
2
4
6
8
12
16
20
24
28
Worse
Improvement Improvement Improvement Improvement
Weeks
≤-5
>-5 to <5
≥5 and <10
≥10 and <15
≥15 and <20
≥20
Placebo
Aficamten
Category of Change
*P< 0.001 for between group difference in mean change from baseline to week 24
Placebo
Aficamten
Mean Seattle Angina Questionnaire
Distribution of Participants Changing by Clinically
Summary Scores (SAQ7-SS)
Important SAQ7-SS Thresholds at 24 Weeks
SAQ7-SS = 7.8 (95% CI: 4.7-11.0)
85
*
40
35
80
30
SAQ7-SS
75
% Participants
25
20
70
15
10
65
Titration
Maintenance
Washout
5
0
No Change
Small
Moderate
Large
Very Large
0
2
4
6
8
12
16
20
24
28
Worse
Improvement Improvement Improvement Improvement
Weeks
≤-5
>-5 to <5
≥5 and <10
≥10 and <15
≥15 and <20
≥20
Placebo
Aficamten
Category of Change
*P< 0.001 for between group difference in mean change from baseline to week 24
Placebo Aficamten
Sherrod IV, CF, et al. JACC. 2024;-(-):---.
Mean KCCQ-OSS and SAQ7-SS scores over time and distributions of clinically important changes. KCCQ-OSS ¼ Kansas City Cardiomyopathy Questionnaire-Overall Summary Score; NNT ¼ number needed to treat; SAQ7-SS ¼ Seattle Angina Questionnaire 7-item-Summary Score; SEQUOIA-HCM ¼ Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM.
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FIGURE 2 KCCQ and SAQ Responder Analyses
A
KCCQ-OSS Responder Analysis - 24 Weeks
% Participants
40%
35%
30%
25%
20%
15%
10%
5%
0%
Worse
No Change
Small
Moderate
Large
Very Large
Improvement
Improvement
Improvement
Improvement
Category of Change
B
SAQ-SS Responder Analysis - 24 Weeks
% Participants
50%
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
Worse
No Change
Small
Moderate
Large
Very Large
Improvement
Improvement
Improvement
Improvement
Category of Change
Placebo Aficamten
Proportions of clinically meaningful changes are described from baseline to week 24 for KCCQ-OSS (A) and SAQ7-SS (B). Changes in participants' health status were categorized as deteriorated (# 5), no clinically important change (> 5 to <5), small to moderate improvement ($5 and <10), moderate to large improvement ($10 and <15), large improvement ($15 to <20), or very large improvement ($20). Abbreviations as in Figure 1.
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FIGURE 3 KCCQ and SAQ Subgroup Analyses
A
Sex Male Female
Age (y) <65 ≥65
BMI (kg/m2) <30 ≥30
NYHA functional class
II III/IV
Core LVEF (%) ≤75.6 >75.6
NT-proBNP (pg/mL) ≤788 >788
Peak VO2 (mL/kg/min)
≤18.4
>18.4
Resting LVOT-G (mm Hg) ≤51.1 >51.1
CPET modality Bicycle Treadmill
Beta-blocker use No
Yes
Baseline SAQ-AF
Daily/Weekly Monthly None
Baseline KCCQ-OSS 0 to <50
50 to <75
75 to 100
Point Estimates
P Value
(95% CI)
6.2 (2.3-10.1)
0.16
10.8 (5.7-15.9)
6.3 (2.2-10.3)
0.18
10.4 (5.6-15.1)
7.6 (4.2-11.0)
0.66
8.8 (2.5-15.2)
7.0 (3.9-10.1)
0.29
10.7 (2.4-19.1)
9.7 (5.3-14.1)
0.19
5.5 (1.1-10.0)
5.8 (1.6-9.9)
0.17
10.3 (5.7-14.8)
9.3 (4.8-13.8)
0.30
6.4 (2.3-10.6)
6.2 (1.9-10.5)
0.34
9.5 (5.0-14.1)
8.5 (4.0-12.9)
0.53
7.0 (2.8-11.2)
8.7 (3.8-13.6)
0.70
7.7 (3.8-11.6)
10.0 (1.1-18.9)
9.5 (4.4-14.5)
0.45
5.3 (1.5-9.1)
5.0 (1.8-8.3)
0
5
10
15
20
25
KCCQ-OSS Change From Baseline to 24 Weeks
Interactions by participants' characteristics are depicted for the KCCQ-OSS (A) and SAQ7-SS (B). AF ¼ Angina Frequency Score; BMI ¼ body mass index; CPET¼ cardiopulmonary exercise test; LVEF ¼ left ventricular ejection fraction; LVOT-G ¼ left ventricular outflow tract gradient; NT-proBNP ¼ N-terminalpro-B-type natriuretic peptide; Abbreviations as in Figure 1.
Continued on the next page
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Sherrod IV et al
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Effect of Aficamten on Health Status: SEQUOIA-HCM
FIGURE 3 Continued
B
Sex Male Female
Age (y) <65 ≥65
BMI (kg/m2) <30 ≥30
NYHA functional class
II III/IV
Core LVEF (%) ≤75.6 >75.6
NT-proBNP (pg/mL) ≤788 >788
Peak VO2 (mL/kg/min)
≤18.4
>18.4
Resting LVOT-G (mm Hg) ≤51.1 >51.1
CPET modality Bicycle Treadmill
Beta-blocker use No
Yes
Baseline SAQ-SS 0 to <50
50 to <75
75 to 100
Point Estimates
P Value
(95% CI)
6.5 (2.4-10.6)
0.35
9.5 (4.5-14.5)
6.4 (2.3-10.6)
0.26
10.2 (5.3-15.1)
8.3 (4.7-12.0)
0.66
6.9 (0.7-13.2)
7.9 (4.5-11.4)
0.98
8.2 (0.2-16.1)
8.2 (3.9-12.5)
0.68
7.1 (2.4-11.8)
5.3 (0.8-9.8)
0.11
10.4 (5.9-14.9)
9.6 (5.0-14.1)
0.28
6.2 (1.7-10.7)
6.1 (1.5-10.7)
0.31
9.6 (5.1-14.1)
10.3 (5.5-15.0)
0.17
5.8 (1.6-10.1)
8.5 (2.7-14.3)
0.77
7.5 (3.8-11.2)
15.6 (4.7-26.4)
9.4 (3.6-15.2)
0.040
4.2 (0.7-7.6)
0
5
10
15
20
25
SAQ-SS Change From Baseline to 24 Weeks
(ie, LVEF and LVOT-G at rest), exercise capacity (ie, peak VO2), N-terminalpro-B-type natriuretic peptide levels, randomization strata (beta-blocker use at baseline, cardiopulmonary exercise test modality), or
baseline KCCQ-OSS (all Pinteraction > 0.05). Further, the baseline frequency of chest pain did not appear to affect KCCQ benefit. However, there was a signal that those with poor to fair overall angina-related health
10
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J A C C V O L . -, N O . -, 2 0
2 4
Effect of Aficamten on Health Status: SEQUOIA-HCM
-, 2 0 2 4 : --
-
status (SAQ7-SS<50) attained greater benefit from aficamten (greater change with aficamten in SAQ7-
DISCUSSION
A primary goal of oHCM treatment is to improve patients ' health status. Therefore, understanding the impact of new treatments on symptoms, function, and quality of life from patients' perspectives is essential. This prespecified analysis of the SEQUOIA- HCM trial provides the first comprehensive description of the health status benefits of aficamten, along with insights into the clinical magnitude of these improvements from patients' perspectives, as measured by the KCCQ-OSS and SAQ7-SS. This occurred as early as week 2 with consistent and sustained benefit through 24 weeks of therapy. These improvements were similar across clinical subgroups, with little evidence of heterogeneity in treatment effect. The observed population-level mean treatment effects were driven by a substantially greater proportion of aficamten-treated patients obtaining very large ($20 points) clinical benefits from myosin inhibition after 24 weeks of therapy. The NNT for 1 patient to obtain this very large improvement in their health status ($20 points) for both the KCCQ and SAQ7 was between 5 and 6. Further confirming the direct causal effect of aficamten, these health status benefits rapidly dissipated after treatment was stopped. Collectively, these data provide compelling support for aficamten significantly improving the health status of patients with symptomatic oHCM.
These findings support and substantially extend the current published data for oHCM treatment. Although traditional oHCM studies have focused on physiological outcomes, such as exercise capacity and imaging parameters (eg, LVOT-G), these may not reflect patients' lived experiences because patients rarely exert themselves to the limit of their capacity and do not "feel" their anatomy or physiology. This highlights the importance of understanding disease severity from patients' perspectives using patient- reported outcomes. Historically, medical approaches to treating oHCM have been limited to negative inotropic drugs, including beta-blockers, calcium- channel blockers, or disopyramide, where symptoms have generally been quantified from clinicians' rather than patients' perspectives.22,23 Among these only metoprolol has described a mean greater
improvement in the KCCQ-OSS by 2.4 points after
2 weeks of treatment.24 While septal reduction ther- apy has been an effective treatment option at high- volume centers,25,26 only 1 uncontrolled, observa- tional study evaluated its efficacy on the KCCQ.27,28 The introduction of mavacamten, a first-generation cardiac myosin inhibitor, demonstrated marked im- provements in the KCCQ, similar to that observed with aficamten in SEQUIOA-HCM, but suffered from substantially more missing data than in the current study.29 Moreover, SEQUOIA-HCM also assessed chest pain from patients' perspectives using the SAQ7, which has never been previously described, to our knowledge. Finally, this study extends the orig- inal report from SEQUOIA-HCM10 by providing a more complete assessment of participants' health status, along with the distributions of patient-level change.
The unique insights from the SEQUIOA-HCM trial on chest pain symptoms are important since prior studies have not assessed the effect of treatment on these symptoms. Chest pain is common in oHCM, and potential explanations for aficamten's efficacy in relieving chest pain may be due to improving blood flow in distal epicardial vessels and myocardial microcirculation through attenuation of hyper- contractility, reduced wall stress, and oxygen de- mand due to relief of obstruction or direct aficamten effect on myosin adenosine triphosphatase activ- ity.2,3 Regardless of the mechanism, because chest pain is an important symptom in those with oHCM,4 these data provide important insights into the health status benefits of aficamten.
Interpreting the clinical significance of new thera- pies can be challenging, particularly for anatomical or physiological measures of disease severity. In contrast, patient-reported outcomes, such as the KCCQ and SAQ7, are direct measures of the impact of treatment from patients' perspectives. Nevertheless, focusing on mean treatment differences between groups requires interpreting those mean differences from patients' perspectives by examining the distri- bution of clinically important changes between groups.12 The KCCQ categories of intraindividual changes used to reflect clinical significance have been well established in the scientific literature, including among patients with oHCM.13,17 In this trial, the mean treatment benefits with aficamten were primarily driven by a much greater proportion of patients having very large clinical changes in their health status. When compared with prior work in other car- diomyopathies, aficamten improves population-level scores more similarly to invasive valvular in- terventions than to traditional pharmacologic thera- pies.30,31 Very large improvements ($20 points) have
Disclaimer
Cytokinetics Incorporated published this content on 02 September 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on September 02, 2024 at 05:53:03 UTC.