Journal article
Aficamten and cardiopulmonary exercise test performance: a substudy of the SEQUOIA-HCM randomized clinical trial
JAMA cardiology, Vol.9(11), pp.990-1000
11/01/2024
DOI: 10.1001/jamacardio.2024.2781
PMCID: PMC11375526
PMID: 39230885
Abstract
Importance: Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures.
Objective: To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates.
Design, Setting, and Participants: This was a prespecified analysis from SEQUOIA-HCM, a double-blind, placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO₂] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024.
Interventions: Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks.
Main Outcomes and Measures: The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-component z score of pVO₂ and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO₂] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed.
Results: Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory–validated exercise testing at baseline and week 24. Integrated composite exercise performance improved in the aficamten group (mean [SD] z score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z score, −0.19 [0.45]), yielding a placebo-corrected improvement of 0.35 (95% CI, 0.25-0.46; P <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold (all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO₂ were more common than large reductions (32% and 2%, respectively) compared with placebo (16% and 11%, respectively). Improvements in both components of the primary outcome, pVO₂ and VE/VCO₂ slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05).
Conclusions and Relevance: This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten.
Trial Registration: ClinicalTrials.gov Identifier: NCT05186818
Details
- Title: Subtitle
- Aficamten and cardiopulmonary exercise test performance: a substudy of the SEQUOIA-HCM randomized clinical trial
- Creators
- Matthew M.Y LeeAhmad MasriMichael E NassifRoberto Barriales-VillaTheodore P AbrahamBrian L ClaggettCaroline J CoatsJuan Ramón GimenoIan J KulacIsabela LandsteinerChangsheng MaMartin S MaronIacopo OlivottoAnjali T OwensScott D SolomonJosef VeselkaDaniel L JacobyStephen B HeitnerStuart KupferFady I MalikLisa MengAmy WohltmanGregory D LewisAndrew WangMark V SherridJacob P KellyAli J MarianOmar Wever-PinzonDavid OwensMatthew T WheelerSherif F NaguehFlorian RaderFrank A McGrewTimothy WongThomas O'NeillRichard G BachMatthew MartinezNeal K LakdawalaElias ColladoAslan TurerMilind Y DesaiZainal HussainAlbree F Tower-RaderBashar HannawiJeffrey GeskeSara SaberiDermot PhelanChristopher KramerNitasha SarswatFerhaan AhmadLubna ChoudhuryJeremy S MarkowitzSounok SenPatrick BeringMartin S MaronSandeep JaniDouglas BrinkleySrihari NaiduMathew S MaurerNoah MossOzlem BilenJorge Silva EncisoRobert FraserOlakunle AkinboboyeCraig AsherSitaramesh EmaniAbhinav SharmaDavid FerminMelissa LyleDavid RaymerAndrew DarlingtonFrederic ResnicChristopher D NielsenMarco MetraBeatrice MusumeciMichele EmdinMattia TargettiMarco CanepaMichelle MichelsChristian KnackstedtAhmad S AminPablo Garcia PaviaJuan Ramon Gimeno BlanesRafael Jesus Hidalgo UrbanoLuis Miguel Rincon DiazTomas Vicente V Ripoll VeraAna Garcia AlvarezDavid ZemanekMortenK JensenJens MogensenJens J ThuneHenning BundgaardPhilippe CharronJean-Noel TrochuGilbert HabibThibault LhermusierPatricia ReantAlbert A HagegeDamien LogeartVeselin MitrovicFrank EdelmannTim SeidlerBenjamin MederPaul Christian SchulzeStefan StoerkTarek BekfaniTienush RassafBela MerkelyMichael AradMajdi HalabiDonna ZwasXavier PiltzOffir PazManhal HabibDariusz DudekArtur OreziakWojciech WojakowskiAlexandra M Toste BatistaJose Adelino Mesquita BastosPerry M ElliottMasliza MahmodCaroline CoatsRobert CooperWilliam BradlowAntonios PantazisMaria Teresa Tome EstebanShaina McGinnisJoseph CampainDiane Cocca-SpoffordIlya GivertsCatherine GriskowitzChloe NewlandsFabely Moreno Moreno
- Resource Type
- Journal article
- Publication Details
- JAMA cardiology, Vol.9(11), pp.990-1000
- Publisher
- American Medical Association; CHICAGO
- DOI
- 10.1001/jamacardio.2024.2781
- PMID
- 39230885
- PMCID
- PMC11375526
- ISSN
- 2380-6583
- eISSN
- 2380-6591
- Grant note
- Cytokinetics, Incorporated
The SEQUOIA-HCM trial is funded by Cytokinetics, Incorporated.
- Language
- English
- Date published
- 11/01/2024
- Academic Unit
- Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984775264202771
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