Mavacamten Treatment for Obstructive Hypertrophic Cardiomyopathy: A Clinical Trial
Stephen B. Heitner, MD; Daniel Jacoby, MD; Steven J. Lester, MD; Anjali Owens, MD; Andrew Wang, MD; David Zhang, PhD, MBA; Joseph Lambing, PhD; June Lee, MD; Marc Semigran, MD; and Amy J. Sehnert, MD
Abstarct:
Background: Mavacamten, an orally administered, small- molecule modulator of cardiac myosin, targets underlying bio- mechanical abnormalities in obstructive hypertrophic cardiomy- opathy (oHCM).
Objective: To characterize the effect of mavacamten on left ven- tricular outflow tract (LVOT) gradient.
Design: Open-label, nonrandomized, phase 2 trial. (Clinical Trials.gov: NCT02842242)
Setting: 5 academic centers.
Participants: 21 symptomatic patients with oHCM.
Intervention: Patients in cohort A received mavacamten, 10 to 20 mg/d, without background medications. Those in cohort B received mavacamten, 2 to 5 mg/d, with β-blockers allowed.
Measurements: The primary end point was change in post- exercise LVOT gradient at 12 weeks. Secondary end points in- cluded changes in peak oxygen consumption (pVO2), resting and Valsalva LVOT gradients, left ventricular ejection fraction (LVEF), and numerical rating scale dyspnea score.
Results: In cohort A, mavacamten reduced mean postexercise LVOT gradient from 103 mm Hg (SD, 50) at baseline to 19 mmypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease that is caused by mutations in genes encoding sarcomere proteins (1, 2) and has an autosomal dominant pattern of inheritance. Obstructive HCM (oHCM), defined as a resting or provoked peak instantaneous left ventricular (LV) outflow gradient of at least 30 mm Hg, occurs in approximately 70% of patients with HCM. The phenotype of oHCM is characterized by LV hypercontractility, hypertrophy, reduced compliance, and LV outflow tract (LVOT) obstruction, which may result in exertional dyspnea, fatigue, chest pain, and limited ex- ercise capacity (3). Despite management with β-blockers or nondihydropyridine calcium-channel blockers, symp- toms and disease burden persist for many patients with oHCM, and therapeutic options are limited (2, 4). For those with refractory symptomatic disease, septal reduc- tion therapies (such as surgical myectomy or percutane- ous alcohol septal ablation) can be effective, but these invasive procedures carry risk and are not widely accessi- ble, and their success depends on operator experience (5). Hg (SD, 13) at 12 weeks (mean change, —89.5 mm Hg [95% CI,—138.3 to —40.7 mm Hg]; P = 0.008). Resting LVEF was also reduced (mean change, —15% [CI, —23% to —6%]). Peak VO2 increased by a mean of 3.5 mL/kg/min (CI, 1.2 to 5.9 mL/kg/ min). In cohort B, the mean postexercise LVOT gradient de- creased from 86 mm Hg (SD, 43) to 64 mm Hg (SD, 26) (mean change, —25.0 mm Hg [CI, —47.1 to —3.0 mm Hg]; P = 0.020), and mean change in resting LVEF was —6% (CI, —10% to —1%). Peak VO2 increased by a mean of 1.7 mL/kg/min (SD, 2.3) (CI, 0.03 to 3.3 mL/kg/min). Dyspnea scores improved in both co- horts. Mavacamten was well tolerated, with mostly mild (80%), moderate (19%), and unrelated (79%) adverse events. The most common adverse events definitely or possibly related to mava- camten were decreased LVEF at higher plasma concentrations and atrial fibrillation.
Limitation: Small size; open-label design.
Conclusion: Mavacamten can reduce LVOT obstruction and im- prove exercise capacity and symptoms in patients with oHCM.
Introduction:
The primary objective of the PIONEER-HCM study was to characterize the effect of 12 weeks of mava- camten treatment on reducing postexercise peak LVOT gradient in patients with symptomatic oHCM. binding to actin (9, 10). It is intended to reduce resting and dynamic LVOT obstruction in patients with oHCM by normalizing the function of myosin protein in hypercon- tractile hearts (11), regardless of the presence of a sarco- meric gene mutation. In a feline model of oHCM, treat- ment with mavacamten reduced contractility and relieved obstruction in an exposure-dependent manner (12). Three phase 1 clinical studies in 86 healthy volunteers and 15 patients with HCM documented the pharmacokinetic profile to inform phase 2 dose selection, and a favorable safety profile was observed across a meaningful dose range (Sehnert AJ. Personal communication). The totality of the pharmacokinetic, pharmacodynamic, and tolerabil- ity data from these studies led to the design of the phase 2, open-label PIONEER-HCM study.
Mutations in cardiac myosin heavy chain and other sarcomere proteins seem to increase net power genera- tion by the sarcomere, consistent with the hypercontrac- tile state and, secondarily, impaired myocardial compli- ance that is clinically observed (6 – 8). Mavacamten is a proof of concept for mavacamten-induced reduction in contractility (targeted relative reduction in LV ejection fraction [LVEF] of 15% to 20%) and to characterize the pharmacokinetic and pharmacodynamic relationship with a starting dose of 10 mg/d for patients weighing 60 kg or less and 15 mg/d for those weighing more than 60 kg. In cohort A, use of calcium-channel blockers, β-blockers, and disopyramide was discontinued at least 14 days before the first dose of mavacamten. Patients underwent weekly evaluations, including echo-
cardiography, with change in LVEF at week 4 used to titrate the dose (Appendix Figure 1). Dose adjustment or interruption was also permitted after consultation between the investigator and the medical monitor. Co- hort B was designed to further characterize dose re-
sponse at lower concentrations of mavacamten, and patients previously receiving β-blockers were permit- ted to continue treatment at the same dose throughout the study. The starting dose of mavacamten in cohort B was 2 mg/d for all patients, with an increase to 5 mg/d
at the end of week 4 if there was a relative decrease in
METHODS
Trial Design and Oversight
PIONEER-HCM was a prospective, phase 2, multi- center, open-label study conducted at 5 U.S. academic centers between 7 October 2016 and 17 November 2017. Its goals were to characterize pharmacokinetics and pharmacodynamics, evaluate safety and tolerabil- ity, and demonstrate proof of concept for mavacamten in treating patients with symptomatic oHCM. The study protocol was approved by the site-specific institutional review boards and funded by MyoKardia. The employ- ees of MyoKardia as well as the academic investigators participated in data analysis and vouch for the accuracy and completeness of the data and the fidelity of the trial to the final protocol. Statistical analysis was per- formed by clinical research organizations (Pharmaceu- tical Product Development [PPD] and Advance Re- search Associates [ARA]) on behalf of the sponsor, and data tables were provided to the investigators who were involved in interpretation of the data. An indepen- dent data monitoring committee (IDMC) regularly re- viewed the study data to help identify emerging safety or conduct issues. All patients provided informed con- sent, and the study was done in accordance with the provisions of the Declaration of Helsinki and the Inter- national Conference on Harmonization Good Clinical Practice guidelines.
The study was conducted in 2 sequential cohorts (A and B), each comprising a 12-week treatment phase with once-daily oral mavacamten followed by a 4-week posttreatment phase (Appendix Figure 1, available at Annals.org). Cohort A was designed to demonstrate Patients were eligible for inclusion if they had a di- agnosis of HCM based on the presence of LV hypertro- phy (LV wall thickness ≥15 mm [≥13 mm in those with a family history of HCM]), LVOT obstruction (resting LVOT gradient ≥30 mm Hg and postexercise LVOT gra- dient ≥50 mm Hg), and symptoms (New York Heart As- sociation [NYHA] functional class II or III). Those with exertional syncope in the previous 6 months, sustained ventricular tachycardia, LV systolic dysfunction (LVEF<45%), persistent atrial fibrillation (AF) or AF at screen- ing, history of paroxysmal AF with documented resting heart rate above 100 beats/min within 1 year of screen- ing, or history of obstructive coronary artery disease were excluded. The full eligibility criteria and descrip- tion of echocardiography assessments are included in the study protocol (Supplement, available at Annals.org).
Procedures
The schedule of procedures and assessments was identical for both cohorts (Appendix Figure 1). Details of procedures are included in the protocol. Patients were assessed at weekly visits for 8 weeks, followed by an end-of-treatment visit at week 12, a 4-week post- treatment period, and an end-of-study visit at week 16. The clinical status of patients was recorded serially throughout the study (physical examination, vital signs, NYHA functional class, numerical rating scale [NRS] dys- pnea score, and Kansas City Cardiomyopathy Question- naire Overall Summary Score [KCCQ OSS]). Comprehen- sive laboratory testing; plasma drug concentration measurement (pharmacokinetics); HCM genotyping; pharmacogenetic testing (CYP2C19 polymorphisms); electrocardiography; and rest, Valsalva, and postexercise echocardiography were performed as well as continuous cardiac rhythm monitoring. In addition, cardiopulmonary exercise testing was performed on day 1 and at week 12 for evaluation of peak oxygen consumption (pVO2), ventilatory efficiency (volume expired/carbon dioxide pro- duction slope [VE/VCO2]), and other variables.
Outcomes
The primary end point was change in postexercise LVOT gradient at 12 weeks compared with baseline. Secondary end points included the proportion of pa- tients achieving a postexercise LVOT gradient less than 30 mm Hg, change in NRS dyspnea score, change in pVO2 and VE/VCO2, effect on resting and Valsalva LVOT gradients, change in resting LVEF, and reversibil- ity after 4 weeks of washout. Exploratory end points included change in symptoms measured by the NYHA functional classification and the KCCQ OSS and change in serum N-terminal pro–B-type natriuretic peptide (NT- proBNP) concentration. The primary, secondary, and exploratory end points we report were designated a priori. Several secondary and exploratory end points (some echocardiographic parameters, derivatives from cardiopulmonary exercise testing, arterial pulse wave morphology assessment, and subgroups of patients achieving negligible gradients) are not reported here but will be reported elsewhere (Supplement).
Statistical Analysis
The sample size was based on practical consider- ations and was consistent with this early phase 2 study. Ten patients receiving mavacamten would provide 80% power to detect a 30 –mm Hg decrease from baseline in postexercise peak LVOT gradient and more than 99% power to detect a 50 –mm Hg decrease. This was under the assumption of a 1-sided α level of 0.05 and a com- mon SD of 35 mm Hg.
Changes from baseline to week 12 in the primary outcome of postexercise LVOT gradient were com- pared with zero (no change) using the Wilcoxon signed-rank test. A similar analysis was conducted for secondary echocardiographic end points (resting and Valsalva LVOT gradients). Other secondary and explor- atory end points were presented descriptively as means, SDs, and 95% CIs. A P value less than 0.05 was considered statistically significant for the primary end point. All observed data were included in data summa- ries and analyses. Patients with a missing baseline or week 12 value were not included in summaries of changes between these 2 time points. No imputation was performed for missing data. All statistical analyses were performed using SAS, version 9.2 or higher (SAS Institute).
Role of the Funding Source
Funding for the PIONEER-HCM study was provided by MyoKardia, which played a central role in the de- sign, conduct, and analysis of the study. This was a phase 2 study that followed the completion of 3 phase 1 studies by MyoKardia to determine dosing for the phase 2 study. The study was designed and the proto- col was written with input from experts in the HCM field, including the participating study site investiga- tors. MyoKardia funded and had primary oversight of the clinical research organization used for conduct of the study (PPD). MyoKardia also funded and had final approval over the work of the biostatistical teams at PPD and ARA who developed and executed the statis- tical analysis plans. The biostatistics and clinical science
IQR = interquartile range; KCCQ OSS = Kansas City Cardiomyopathy Questionnaire Overall Summary Score; LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; NRS = numerical rating scale; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; pVO2 = peak oxygen consumption; VE/VCO2 = volume expired/carbon dioxide production slope.
In cohort A, 2 patients did not have postexercise measures (1 was unable to exercise at baseline and 1 had an image that was technically difficult to interpret), and 1 who discontinued because of an adverse event did not have a 12-wk measurement. In cohort B, 1 patient did not have postexercise measures because of technical issues related to imaging. Indicates perception of severity. Scores range from 1 to 10, with 10 being the most severe. A clinically significant change is defined as ≥1. Measures perception of overall health. Scores range from 0 to 100, with higher scores reflecting better health status. A clinically significant change is defined as ≥6.
Figure 1. Effect of mavacamten on LVOT obstruction and LVEF.
Cohort A (n = 11) B had uninterpretable postexercise LVOT gradients (1 patient was unable to exercise at baseline because of mental fatigue, and Doppler signals for 2 patients were technically unsuitable for analysis).
Patient Characteristics
80 Baseline characteristics of all patients are shown in
70 Table 1. Nine of the patients were women, ages ranged from 22 to 70 years, 57% had NYHA class II disease,
60 and 43% had NYHA class III disease. Twenty of the 21
50 patients completed 12 weeks of therapy (Appendix Figure 2). Almost all were receiving at least 1 form of
40 standard medical therapy when they presented for
30 screening, and there was a high degree of resting and provoked LVOT obstruction. The mean LVEF at base-
20 line was 70% (SD, 7%) in cohort A and 75% (SD, 5%) in
10 cohort B. In cohort A, 4 patients started and continued use of mavacamten at 15 mg/d, and 1 patient started
0 and continued use of 10 mg/d throughout the study.
12 There were 6 dose titrations in 5 patients (3 increases and 3 decreases). The 11th patient discontinued use of mavacamten by week 4 (see the Safety section). In co- hort B, all patients started use of mavacamten at a dose of 2 mg/d, and all had an increase to 5 mg/d at week 4.
Effect of Mavacamten on LVOT Obstruction
The median mavacamten dose at 12 weeks in co- hort A was 15 mg/d (range, 10 to 20 mg/d). The mean postexercise LVOT gradient was 103 mm Hg (SD, 50) at baseline and 19 mm Hg (SD, 13) at 12 weeks (mean change, —89.5 mm Hg [95% CI, —138.3 to —40.7 mm Hg]; P = 0.008) (Table 2 and Figure 1 [top]). Eight of the
11 participants in cohort A achieved a postexercise LVOT gradient less than 30 mm Hg. Improvements were also seen in resting LVOT gradient (mean change,—48 mm Hg [CI, —72 to —23 mm Hg]; P = 0.006) and Valsalva LVOT gradient (mean change, —85 mm Hg [CI,n—114 to —56 mm Hg]; P = 0.002). In cohort B, all 10
Patients in cohort A (top) showed a protocol-directed decrease in mean LVEF from 70% to a normal level of 55%. A reduction in resting LVOT obstruction occurred by week 2 of therapy and was maintained throughout the treatment phase. There was a similar but less rapid resolution of postexercise LVOT gradient, and by week 12, the mean postexercise peak LVOT gradient was below the threshold for surgical consideration. Patients in cohort B (bottom) experienced a more grad- ual and less marked, albeit significant, reduction in mean LVEF (from 75% to 69%) and resting and postexercise LVOT gradients. LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract. * P < 0.05. teams at MyoKardia interpreted the results of analyses along with the study investigators. The decision to sub- mit the manuscript was made jointly by MyoKardia and the academic authors.
RESULTS
Twenty-five patients were assessed for eligibility; 2 in each cohort did not meet inclusion criteria and were excluded. Twenty of 21 patients completed the study; 1 patient terminated participation before week 4 be- cause of a serious adverse event (Appendix Figure 2, available at Annals.org). All patients entering the study were included for analysis of the primary and second- ary outcomes. Two patients in cohort A and 1 in cohort
patients received 5 mg/d at week 12, and they had smaller reductions in postexercise LVOT gradient (mean change, —25.0 mm Hg [CI, —47.1 to —3.0 mm Hg]; P = 0.020), resting LVOT gradient (mean change, —49 mm Hg [CI, —83 to —14 mm Hg]; P = 0.004), and Valsalva LVOT gradient (mean change, —47 mm Hg [CI, achieved a postexercise LVOT gradient less than 30 mm Hg.
Secondary and Exploratory End Points
The mean change in NYHA functional class was—0.9 in cohort A, with 2 patients improving by 2 classes, 5 improving by 1 class, 3 remaining un- changed, and 1 withdrawing from the study early. In cohort B, the mean change in NYHA functional class was —1.0, with 1 patient improving by 2 classes, 8 im- proving by 1 class, and 1 remaining unchanged. Tran- sitions in NYHA functional class are shown in Appendix Figure 3 (available at Annals.org). The NRS dyspnea score and KCCQ OSS also improved (Table 2).
Patients in cohort A had a greater mean increase in pVO2 (3.5 mL/kg/min [SD, 3.3]) than those in cohort B (1.7 mL/kg/min [SD, 2.3]). The difference in VE/VCO2 after 12 weeks of treatment was similar in both cohorts.
Serum NT-proBNP concentrations were reduced in both cohorts, with median changes of —425 pg/dL (in- terquartile range, —748 to —68 pg/dL) in cohort A and—81 pg/dL (interquartile range, —637 to —16 pg/dL) in cohort B (Table 2). Systolic anterior motion of the mitral valve was noted in 20 of the 21 patients at enrollment; by week 12, this had resolved in 9 of 11 patients in cohort A but none in cohort B.
Resting LVEF changed by —15% (CI, —23% to 6%) in cohort A and —6% (CI, —10% to —1%) in co- hort B. The LVEF returned to baseline levels 4 weeks after treatment. There was also a return toward base- line measures of LVOT obstruction and NT-proBNP concentration and a return of symptoms at week 16 (Appendix Table, available at Annals.org).
Of the 21 patients who consented to DNA se- quencing, 10 were found to have genetic variants, and 5 of these had known pathogenic variants in sarcomere protein genes (2 in MYH7 and3 in MYBPC3) (Figure 2). Although the pharmacodynamic response to mava-camten seen in persons with known variants seems to be similar to that in patients without identified muta- tions, the small number of patients studied precluded subgroup analysis.
Pharmacodynamics
Mavacamten decreased LVEF in a concentration- dependent manner, with substantial reductions in LVOT obstruction occurring at plasma concentrations between 350 and 695 ng/mL (Figure 3). In this range, all patients maintained an LVEF of 50% or greater. Plasma concentra- tions above 1000 ng/mL were associated with an exag- gerated decrement in LVEF beyond what is necessary to obliterate the LVOT gradient (34% to 49% at plasma con- centrations of 695 to 1500 ng/mL) in 4 patients. Of note, we observed a return of LVEF toward baseline values 4 weeks after treatment (Appendix Table). Safety
Mavacamten was generally well tolerated, with most adverse events described as mild (80%) to mod- Solid lines indicate patients without a sarcomeric gene mutation (gene-negative), and dashed lines indicate patients with either a known disease- causing variant or a variant of unknown significance (gene-positive). Of note, 1 gene-positive patient in cohort A who had a blunted pharmaco- dynamic response was taking only 10 mg/d throughout the study and had low pharmacokinetics (201 to 305 ng/mL). LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract.
figure shows a threshold (350 ng/mL) above which no patients are considered to have severe LVOT obstruction according to current clin- ical guidelines. Patients in cohort A showed a high frequency of attain- ing therapeutic drug concentrations. Patients in cohort B, a dose- finding cohort, showed that at plasma concentrations <300 ng/mL, actionable peak LVOT gradients persisted, albeit lower than when compared with baseline. All available data up to week 12 (5 to 11 visits per patient) are included in the plot. Each point represents 1 patient visit. LVOT = left ventricular outflow tracterate (19%) and considered by the treating physicians to be unrelated to the drug (79%) (Table 3). No safety concerns were highlighted by the IDMC. The most common adverse events related to mavacamten were decrease in LVEF (3 events definitely related) and AF (5 events possibly related). Two of the 5 AF events are described here, and the other 3 were intermittent and resolved in 2 patients. No sustained arrhythmias were observed by cardiac rhythm monitoring, and there was no evidence of QT prolongation, even at higher con- centrations. One serious adverse event that was possi- bly related to mavacamten occurred in a patient in cohort A with a history of paroxysmal AF who discon- tinued use of metoprolol and disopyramide 16 days before initiating use of mavacamten per protocol. The patient underwent electrical cardioversion for persis- tent AF after approximately 2 weeks of study; AF re- curred, leading to hospitalization and treatment with amiodarone. The patient elected to stop use of the study drug between weeks 3 and 4.
Patients were invited to participate in an open-label extension of the study, and 13 elected to do so. Ongo- ing safety monitoring in 10 patients through at least 12 weeks (as of 30 October 2018) revealed no additional safety concerns (Table 3).
DISCUSSION
In this small proof-of-concept and open-label study, treatment of patients with oHCM with 12 weeks of mavacamten, a reversible allosteric modulator of β-cardiac myosin, resulted in rapid and marked reduc- tion in postexercise LVOT gradient (82% mean reduction in cohort A and 29% mean reduction with lower doses in cohort B). Patients with plasma mavacamten concentrations of 350 ng/mL or higher frequently achieved an LVOT gradient less than 30 mm Hg (the threshold for obstruction in HCM) and less than 50 mm Hg (the threshold for consideration of septal reduction therapy) (13, 14) (Figure 2). This was matched by a clinically important improvement in symptoms (15, 16) and exertional capacity. Improvements were also seen in participants with and without background β-blocker therapy, with and without sarcomeric genetic variants, and over a wide age range, although small sample sizes precluded firm conclusions. Of note, we identified a drug concentration threshold at which LVOT obstruc- tion was eliminated without exaggerated negative inot- ropy. Overall, mavacamten was well tolerated by most patients at exposures that effectively reduced LVOT ob- struction, and reductions in LVEF beyond those neces- sary to alleviate LVOT obstruction were found to be reversible.
The phenotypic hallmarks of oHCM are myocardial hypercontractility, LVOT obstruction due to anterior mi- tral leaflet-septal contact, mitral regurgitation, and re- duced LV compliance. Mutations in cardiac myosin have been found to increase sarcomeric contractility (6, 7), which manifests clinically as supranormal LVEF. Ma- vacamten has been shown to attenuate hypercontrac- tility, LV hypertrophy, myofibrillar disarray, and fibrosis in animal models (12, 17). Septal reduction therapy (18, 19), the current gold standard for symptomatic oHCM that is refractory to maximally tolerated medical ther- apy, is recommended in the European and American guidelines (13, 14). Although septal reduction therapy is often effective, it is highly invasive and does not ad- dress the molecular underpinnings of oHCM. Further- more, experts believe that it should be done only by experienced operators in the context of a comprehen- sive HCM center (13, 14), which limits access for many patients with oHCM worldwide. The concept of normal- izing hypercontractility is well accepted (20 –22), but available medical therapies are often only partially ef- fective or poorly tolerated.
In both cohorts, patients experienced, to a variable extent, improvement in symptoms, pVO2, and LV wall stress (defined by a numerical reduction in NT-proBNP level) (23). Although this study had an open-label de- sign and the influence of placebo cannot be estimated, it is interesting that in cohort B, several patients expe- rienced improvements (for example, in pVO2 or NT- proBNP level) that seemed out of proportion to gradi- ent reduction. This suggests that there are additional mechanisms for symptoms or that the efficacy of mava- camten may extend beyond reducing hypercontractil- ity. Experimental data may provide a partial explana- tion and represent a potentially important area for ongoing investigation (24).
Mavacamten seems to be well tolerated. In this study, plasma concentrations between 350 and 695 ng/mL were associated with relief of LVOT obstruction while maintaining LVEF within normal limits. There was a single serious adverse event that resulted in discon- tinuation of the study drug in a patient with persistent AF, and the IDMC found the overall safety profile to be satisfactory. Atrial fibrillation may have been related to mavacamten in 3 other patients. Ongoing observational and trial data will provide additional safety infor- mation.
Our study has important limitations. As mentioned, this was an open-label phase 2 study, and the effect of placebo could not be assessed, particularly on the subjec- tive metrics. In addition, the study was small, excluded patients with NYHA functional class IV, and involved only 5 sites in the United States. On the basis of the results of this study, we have undertaken 2 larger studies: the phase 3 trial EXPLORER-HCM (Clinical Study to Evaluate Mava- camten in Adults with Symptomatic Obstructive Hypertro- phic Cardiomyopathy) (ClinicalTrials.gov: NCT03470545), a randomized, placebo-controlled, prospective, inter- national study (n = 220), and MAVERICK-HCM (A Phase 2 Study of Mavacamten in Adults with Symptomatic Non- obstructive Hypertrophic Cardiomyopathy) (ClinicalTrials-.gov: NCT03442764), a randomized, placebo-controlled study (n = 60). In addition, 13 of the original 21 PIONEER- HCM patients have been redosed in an open-label extension study of mavacamten (ClinicalTrials.gov: NCT03496168), and 10 of 13 had received at least 12 weeks of treatment by 30 October 2018.
In conclusion, in this proof-of-concept study, mava- camten treatment was clinically beneficial in patients with oHCM, with reduction in the degree of LVOT ob- struction and improvements in exertional capacity and symptoms, particularly among patients achieving plasma drug concentrations above 350 ng/mL. If confirmed in larger studies, these data suggest a potential role for ma- vacamten in the treatment of oHCM.
From Oregon Health & Science University, Portland, Oregon (S.B.H.); Yale New Haven Hospital, New Haven, Connecticut (D.J.); Mayo Clinic Arizona, Scottsdale, Arizona (S.J.L.); Hospi- tal of the University of Pennsylvania, Philadelphia, Pennsylva- nia (A.O.); Duke University Medical Center, Durham, North Carolina (A.W.); and MyoKardia, South San Francisco, Califor- nia (D.Z., J.L., J.L., M.S., A.J.S.).
Acknowledgment:
The authors thank the study participants and their families for giving their time despite the innate risks involved in early-phase research. They also thank the research staff, nurses, technologists, cardiac sonographers, and admin- istrators who were inextricably intertwined in the production of this article.
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Collection and assembly of data: S.B. Heitner, S.J. Lester, A. Wang, J. Lee, M. Semigran.
Patients in cohort A started use of mavacamten at 10 to 20 mg/d, with a dose titration at week 4 based on a targeted relative reduction in resting LVEF of 15% to 20% compared with baseline. Patients in cohort B started use of mavacamten at 2 to 5 mg/d, with the potential to increase to 5 mg/d at week 4 if the resting LVOT gradient had not decreased by >50% compared with baseline. Of note, all participants in cohort B increased the dose from 2 to 5 mg/d at week 4. CPET = cardiopulmonary exercise test; echo = echocardiogram; LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; PIONEER-HCM = Reduction in Left Ventricular Outflow Tract Gradient with Mavacamten (MYK-461) in Symptomatic Obstructive Cardiomyopathy Patients.