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Aficamten for Drug-Refractory Severe Obstructive Hypertrophic Cardiomyopathy in Patients Receiving Disopyramide: REDWOOD-HCM Cohort 3

2023; Elsevier BV; Volume: 29; Issue: 11 Linguagem: Inglês

10.1016/j.cardfail.2023.07.003

1532-8414

Anjali Owens, Ahmad Masri, Theodore P. Abraham, Lubna Choudhury, Florian Rader, John D. Symanski, Aslan T. Turer, Timothy C. Wong, Albree Tower‐Rader, Caroline Coats, Michael A. Fifer, Iacopo Olivotto, Scott D. Solomon, Hugh Watkins, Stephen B. Heitner, Daniel Jacoby, Stuart Kupfer, Fady I. Malik, Lisa Meng, Regina Sohn, Amy Wohltman, Martin S. Maron,

Williams Syndrome Research

•Aficamten is a next-generation cardiac myosin inhibitor (CMI)•CMIs are a novel treatment for obstructive hypertrophic cardiomyopathy (oHCM)•We report efficacy and safety of aficamten with disopyramide for refractory oHCM•In Cohort 3 of REDWOOD-HCM, aficamten plus disopyramide was well tolerated•Patients had improved left ventricular outflow tract gradient and NYHA class How this work applies to patients•Disopyramide is used to help relieve symptoms as a second-line option when patients with obstructive HCM have persistent limiting symptoms despite treatment with either a beta-blocker or calcium channel blocker.•REDWOOD-HCM Cohorts 1 & 2 showed that aficamten may safely help reduce obstruction in patients receiving treatment with beta-blockers and/or calcium channel blockers.•REDWOOD-HCM Cohort 3 now shows that aficamten appears to be a safe and effective add-on treatment in patients who remain refractory to all other medical therapies, and of the 13 patients studied, 11 (85%) showed some improvements in symptoms and 10 (77%) showed improvements in the degree of obstruction. The REDWOOD-HCM trial investigated aficamten, a drug designed to target the underlying cause of obstructive hypertrophic cardiomyopathy (oHCM). REDWOOD-HCM was a "Phase 2 trial" – a particular type of study for investigational therapies that are not yet approved. The trial tests whether the drug can be safely used in patients and makes a preliminary assessment of how well the drug works. Here, aficamten was tested in patients taking disopyramide as part of background treatment for their oHCM. The researchers conclude aficamten appeared safe and also showed promising treatment results. Further studies should be done to confirm the benefit of aficamten. Hypertrophic cardiomyopathy (HCM) is a heritable cardiomyopathy characterized by left ventricular (LV) hypertrophy and hypercontractility. Approximately 70% patients with HCM have LV outflow tract (LVOT) obstruction at rest or with provocation, and this is a strong determinant of adverse outcomes. Pharmacotherapy with beta-blockers or non-dihydropyridine calcium channel blockers (CCB) represents first-line treatment for symptomatic obstructive HCM (oHCM); the addition of disopyramide, a class 1A antiarrhythmic agent with negative inotropic effects, may provide additional relief as second-line therapy.1Sherrid MV Barac I McKenna WJ Elliott PM Dickie S Chojnowska L et al.Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. 2005; 45: 1251-1258Crossref PubMed Scopus (273) Google Scholar The use of disopyramide was exclusionary from the pivotal Phase 3 study for mavacamten, EXPLORER-HCM,2Ho CY Olivotto I Jacoby D Lester SJ Roe M Wang A et al.Study design and rationale of EXPLORER-HCM: evaluation of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy.Circ Heart Fail. 2020; 13e006853Crossref Scopus (39) Google Scholar likely out of concern for exacerbation of QT-interval prolongation potential with mavacamten, as reported in both Phase 1 evaluation in healthy volunteers and preclinical experiments with mavacamten.3CAMZYOSTM (mavacamten) capsules for oral use. Prescribing Information; revised September 2022. Available at https://packageinserts.bms.com/pi/pi_camzyos.pdf (accessed June 9 2023). Bristol-Myers Squibb Company, Princeton, NJ, USA.Google Scholar Aficamten, a next-in-class small molecule inhibitor of cardiac myosin, reduces pathologic hypercontractility in HCM. In the randomized, double-blind cohorts 1 and 2 of the Phase 2 REDWOOD-HCM study, aficamten added to beta-blockers and/or CCB was well tolerated and reduced LVOT gradients (LVOT-G).4Maron MS Masri A Choudhury L Olivotto I Saberi S Wang A et al.Phase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. 2023; 81: 34-45Crossref Scopus (12) Google Scholar Patients treated with disopyramide as part of their therapeutic regimen for recalcitrant symptoms had been excluded from the prior cohorts in REDWOOD-HCM. As such these were included in a separate cohort primarily designed to evaluate the impact of aficamten on safety, although aficamten had already been shown to have a neutral effect on the QT interval in the Phase 1 study.5Malik FI Robertson LA Armas DR Robbie EP Osmukhina A Xu D et al.A phase 1 dose-escalation study of the cardiac myosin inhibitor aficamten in healthy participants.JACC Basic Transl Sci. 2022; 7: 763-775Crossref Scopus (9) Google Scholar Efficacy was also measured, with the key objective of establishing optimal doses for double-blind trials. Cohort 3 of REDWOOD-HCM is the first prospective study of aficamten with disopyramide in these medically refractory oHCM patients. New York Heart Association (NYHA) class II/III patients with oHCM (resting LVOT-G ≥50 mmHg or resting LVOT-G ≥30 mmHg and Valsalva LVOT-G ≥50 mmHg) on medical therapy (beta-blockers and/or CCB) plus disopyramide were enrolled in an open-label fashion. A placebo control was not felt to be necessary, as Cohorts 1 and 2 had already enrolled a combined 13 placebo-treated patients. In addition, the primary electrocardiographic safety metric of change from baseline in the corrected QT interval (QTc) did not require a placebo control in this cohort. Thus, all patients were assigned aficamten for a 10-week treatment period, with 2-weeks' washout after Week 10. Aficamten (5, 10, 15 mg) was titrated based on site-read echocardiograms at 2-week intervals over 6 weeks. Doses were increased for left ventricular ejection fraction (LVEF) ≥50% and persistent obstruction (resting or Valsalva LVOT-G ≥30 mmHg or 50 mmHg, respectively), reduced if LVEF <50%, or discontinued if LVEF <40%. Serial biomarkers and patient-reported outcomes were measured. Continuous variables were summarized using descriptive statistics: number of patients with observations (n), mean, standard deviation (SD), median, and interquartile ranges (IQR). Categorical variables were summarized using counts and percentages. A paired t-test was performed to test the change from baseline at Week 10. A repeated measures mixed model with fixed effects of cohort, visits, and cohort by visits and baseline as covariate was fit to the echocardiographic parameters to test the null hypothesis that the change from baseline at each visit was 0. Site-specific Institutional Review Boards approved the protocol. Participants provided informed consent, and trial conduct was according to the Declaration of Helsinki and Good Clinical Practice. Thirteen patients (median [IQR] age 62 [58–65] years, 53.8% female) were enrolled (Table 1). Ten (77%) were on beta-blockers, 2 (15%) on CCB, and 1 (8%) received both. The mean (SD) disopyramide dose was 346 (130) mg/day. Baseline mean (SD) LVEF was 74% (7.5%); resting and Valsalva gradients were 50 (25) mmHg and 78 (27) mmHg, respectively. Five patients (38.5%) were NYHA class II and 8 (61.5%) were class III. Baseline serum median (IQR) N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1108 (668–2572) pg/mL. Baseline characteristics of participants in Cohort 3 were generally similar to those of Cohorts 1 and 2 aside from a greater proportion being NYHA class III and a higher NT-proBNP level (Table 1).Table 1Baseline characteristicsCohort 3N = 13 AficamtenCohort 1N = 14 AficamtenCohort 2N = 14 AficamtenCohort 1 & 2 Pooled PlaceboN = 13Age, median (IQR) [range], years62 (58–65) [23, 82]59 (39–67) [33, 69]57 (53–72) [35, 78]59 (53–64) [36, 69]Female, n (%)7 (53.8)4 (28.6)11 (78.6)8 (61.5)BMI, median (IQR) [range], kg/m230.0 (25–36) [22.7, 41.2]30 (26–34) [22.0, 39.9]28 (26–32) [23.6, 48.4]26 (25–32) [20.2, 40.6]NYHA class, n (%) Class II5 (38.5)10 (71)7 (50)11 (85) Class III8 (61.5)4 (29)7 (50)2 (15)Beta blocker use, n (%)11 (86)10 (71)11 (79)11 (85)NT-proBNP, median (IQR), pg/mL1108 (668–2572)206 (123–755)549 (297–1438)532 (129–958)hs cTnI, median (IQR), ng/L10.0 (7.8–22.0)16.0 (7.3–83.3)7.8 (4.5–19.0)7.9 (3.4–37.7)LVEF*Site-reported echocardiographic values at screening., median (IQR), %,68 (65–75)70 (65–78)70 (65–80)75 (69–75)Resting LVOT-G*Site-reported echocardiographic values at screening., median (IQR), mmHg45 (38–62)45 (37–67)66 (50–81)71 (44–94)Valsalva LVOT-G*Site-reported echocardiographic values at screening., median (IQR), mmHg86 (78–103)83 (68–90)91 (69–100)89 (80–105)LAVI, median (IQR), mL/m233 (27–39)32 (25–37)34 (27–38)30 (28–37)LVEDD, median (IQR), mm38 (37–43)39 (35–44)39 (35–42)40 (37–42)Baseline characteristics for patients in Cohort 3 are shown in the left-hand column. For comparison, patients treated with aficamten or placebo from Cohorts 1 and 2 are shown in the 3 columns to the right.BMI, body mass index; hs cTnI, high-sensitivity cardiac troponin I; IQR, interquartile range; LAVI, left atrial volume index; LVEDD, left ventricular end diastolic dimension; LVEF, left ventricular ejection fraction; LVOT-G, left ventricular outflow tract gradient; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association. Site-reported echocardiographic values at screening. Open table in a new tab Baseline characteristics for patients in Cohort 3 are shown in the left-hand column. For comparison, patients treated with aficamten or placebo from Cohorts 1 and 2 are shown in the 3 columns to the right. BMI, body mass index; hs cTnI, high-sensitivity cardiac troponin I; IQR, interquartile range; LAVI, left atrial volume index; LVEDD, left ventricular end diastolic dimension; LVEF, left ventricular ejection fraction; LVOT-G, left ventricular outflow tract gradient; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association. The final dose achieved was 5 mg in 2 patients, 10 mg in 5 patients, and 15 mg in 6 patients. Resting and Valsalva LVOT-G were substantially lowered, with mean (SD) Week 10 resting LVOT-G reduced by 27 (22) mmHg (p<0.0001) and Valsalva LVOT-G reduced by 28 (32) mmHg (p=0.0002) (Figure 1A). Mean (SD) LVEF was reduced modestly from 74% (7.5%) to 69% (7.2%) (p=0.018) and returned to baseline after 2-weeks' washout. The LVEF and hemodynamic changes seen in Cohort 3 were similar to those seen with Cohort 1, where the same dose strengths were used. Changes at the individual patient level in LVEF and hemodynamic measures are shown in Figure 2. At the end of treatment, a total of 10/13 (77%) patients experienced an improvement in hemodynamic measures; either a complete improvement (n = 6 with resting LVOT-G <30 and Valsalva LVOT-G <50) or partial improvement (n = 4 with resting LVOT-G ≥30 and Valsalva LVOT-G <50 or resting LVOT-G <30 and Valsalva LVOT-G ≥50). Eleven patients (85%), including all 8 with baseline NYHA class III, demonstrated ≥1 NYHA class improvement (Figure 3). The 2 patients who did not report an improvement in NYHA class still experienced improvement in LVOT-G. Changes in hemodynamics and NYHA class were accompanied by mean (SD) changes relative to baseline in NT-proBNP of –42.5% (30.7, p<0.01) and high-sensitivity cardiac troponin-I of –9.1% (32.8, p=NS) (Figure 1B). These improvements mirror those observed in REDWOOD-HCM Cohorts 1 and 2.4Maron MS Masri A Choudhury L Olivotto I Saberi S Wang A et al.Phase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. 2023; 81: 34-45Crossref Scopus (12) Google ScholarFigure 2Echocardiographic values over time for individual patientsShow full captionAssessment of LVEF and echocardiographic hemodynamic parameters during the treatment and washout phases, showing core lab reported values for individual patients. A, LVEF; B, Resting LVOT-G and C, Post-Valsalva LVOT-G.LVEF, left ventricular ejection fraction; LVOT-G, left ventricular outflow tract gradient; NYHA, New York Heart Association.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3NYHA functional class transition from baseline to Week 10Show full captionTransitions for individual patients in NYHA functional class from baseline until the end of treatment at Week 10. The left column shows the overall number of patients in each class at baseline, and the right column shows the number of patients in each class at Week 10, with arrows indicating the individual transitions.NYHA, New York Heart Association.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Assessment of LVEF and echocardiographic hemodynamic parameters during the treatment and washout phases, showing core lab reported values for individual patients. A, LVEF; B, Resting LVOT-G and C, Post-Valsalva LVOT-G. LVEF, left ventricular ejection fraction; LVOT-G, left ventricular outflow tract gradient; NYHA, New York Heart Association. Transitions for individual patients in NYHA functional class from baseline until the end of treatment at Week 10. The left column shows the overall number of patients in each class at baseline, and the right column shows the number of patients in each class at Week 10, with arrows indicating the individual transitions. NYHA, New York Heart Association. There were no dose interruptions, treatment discontinuations, or serious adverse events. No patients experienced LVEF <50% (Figure 2A), and there were no meaningful changes in QTc interval [mean (SD) change QTcF at Week 10 compared with baseline was −4.2 (23.2) msec] or vital signs. REDWOOD-HCM Cohort 3 is the first prospective study to evaluate the safety and efficacy of aficamten in patients with oHCM and persistent heart failure symptoms despite treatment with disopyramide. Primarily, the study was designed to evaluate the safety of coadministration of aficamten with disopyramide and to inform the doses to be evaluated in the Phase 3 study, and thus the analyses of efficacy must be interpreted with caution. However, it was observed that in this cohort of mostly NYHA class III patients, adding aficamten reduced LVOT-G and improved NYHA class and notably, all patients with baseline NYHA class III improved by ≥1 class. Limitations of these analyses include both the lack of a placebo control arm and the small sample size, which precluded analyses of subgroups or correlation of responses with biomarkers. Incomplete hemodynamic and symptomatic responses may have been partially related to limiting both the maximal dose to 15 mg and uptitration criteria, but this could not be evaluated within the current study design. This question should be addressed by the FOREST-HCM (open-label extension) and SEQUOIA-HCM (pivotal Phase 3) trials, which will investigate a 20 mg dose of aficamten and lower titration target Valsalva LVOT-G (<30 mmHg). Importantly, the study achieved the primary objective, showing coadministration of aficamten with disopyramide was well tolerated and demonstrated reversibility in severely obstructed patients refractory to dual negative inotropic therapy. Reduction in LVEF was similar to REDWOOD-HCM cohorts 1 and 2 patients.4Maron MS Masri A Choudhury L Olivotto I Saberi S Wang A et al.Phase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy.J Am Coll Cardiol. 2023; 81: 34-45Crossref Scopus (12) Google Scholar In conclusion, this cohort adds to the evidence from REDWOOD-HCM Cohorts 1 and 2 that aficamten appears to be a safe and efficacious therapy as both add-on to first-line treatment and for those with medically refractory oHCM concurrently taking disopyramide. Dr Owens has received consultant/advisor fees from Cytokinetics, Bristol Myers Squibb/MyoKardia, and Pfizer. Dr Masri has received consultant/advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, Eidos, Pfizer, Alnylam, Haya, Intellia and Ionis, and research grants from Ionis, Akcea, Pfizer, Ultromics, and Wheeler Foundation. Dr Abraham has no disclosures to report. Dr Choudhury has no disclosures to report. Dr Rader has received speaker bureau fees from Bristol Myers Squibb and Medtronic, and consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, ReCor, and Medtronic. Dr Symanski has received research funding from Cytokinetics, Bristol Myers Squibb, and Imbria Pharmaceuticals, lecturing honoraria from the HCM Academy, and has participated on an advisory board (2020-2021) for Bristol Myers Squibb. Dr Turer has received consultant/advisor fees from Cytokinetics. Dr Wong has received speaker bureau fees from Projects in Knowledge, PCM Scientific, and served as an unpaid consultant/advisor for Bristol Myers Squibb and Cytokinetics. Dr Tower-Rader has received research grants from Cytokinetics and Bristol Myers Squibb. Dr Coats has received speaker fees from Alnylam and Roche, and advisory fees from Cytokinetics. Dr Fifer has received consultant/advisor fees from Cytokinetics and research grants from Bristol Myers Squibb and Novartis. Dr Olivotto has received speaker bureau fees from Boston Scientific, Amicus, and Novartis, consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, and Rocket Pharma, and research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, and Boston Scientific. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI, and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GSK, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, DiNAQOR, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. Dr Watkins has received consultant/advisor fees from Cytokinetics, BioMarin, and BridgeBio. Drs Heitner, Jacoby, Kupfer, Malik, Meng, Sohn, and Wohltman are employees of Cytokinetics and hold stock in the company. Dr Maron has received consultant/advisor fees from Imbria and Takeda, and steering committee fees for REDWOOD-HCM from Cytokinetics. All authors were involved in the acquisition, analysis, or interpretation of data for this study. Dr Owens drafted the manuscript, and authors provided critical review of manuscript drafts for important intellectual content. All authors have approved the final version of the manuscript. The REDWOOD-HCM trial was funded by Cytokinetics, Incorporated. The study was designed and conducted by the steering committee, which included representatives of the sponsor. Cytokinetics, Incorporated were also responsible for site monitoring and data management, as well as data analysis. Interpretation of the data and preparation of the manuscript was carried out by the steering committee, including representatives of Cytokinetics, Incorporated. Review and approval of the manuscript, as well as the decision to submit the manuscript for publication, were conducted by all authors, including representatives of Cytokinetics, Incorporated. Cytokinetics, Incorporated had no veto of the right to publish or control over to which journal to submit.