journal MAPLE-HCM TRIAL review presentation

journal MAPLE-HCM TRIAL review presentation

1. WEEKLY JOURNAL CLUB MAPLE-HCM trial Presenter- Dr. Dinu K. (IMR3) Moderator- Dr. Dessalew Mekonnen (Consultant Internist and Cardiologist ) 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 1

2. Pub. Aug 30/2025

3. OUTLINE Introduction Objective Methodology Result Discussion Conclusion Strength and limitation. Critical appraisal 3 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial

4. Hypertrophic Cardiomyopathy Prevalence and Characteristics Inheritance Pattern Autosomal Dominant Sex Distribution Women are diagnosed less often and later Disease Prevalence Estimated 1:500 Triggers for Evaluation Symptoms Cardiac Event Heart Murmur Abnormal EKG or Imaging Family history Underlying SDOH likely drive differences in prevalence, genetic testing, and cardiovascular outcomes by race and ethnicity Differential Diagnosis: Non-HCM Causes of LV Hypertrophy Metabolic & Multi-organ Syndromes RASopathies (Noonan Syndrome) Glycogen / Lysosomal storage diseases Cardiac Amyloidosis Sarcoidosis Danon disease Secondary Causes Athlete’s heart Uncontrolled Hypertension Valvular & subvalvular aortic stenosis Abbreviations: EKG indicates electrocardiogram; SDOH, social determinants of health; and RAS, reticular activating system. 4 +/- - / - +/-

5. Defining Hypertrophic Cardiomyopathy in 2024 Characterized by left ventricular hypertrophy Asymmetric septal hypertrophy is most characteristic No other cardiac, systemic or metabolic disease capable of producing the magnitude of increased LV wall thickness present Disease-causing variant in a sarcomere gene identified or genetic etiology unresolved Diagnostic Criteria in Adults 2D echocardiography or cardiac MRI Maximal end-diastolic LV wall thickness > 15 mm or Maximal end-diastolic LV wall thickness 13-14 mm if there is a family history of HCM or a pathogenic sarcomere gene is present Diagnostic Criteria in Children Abbreviations: 2D indicates two dimen s ional; MRI, magnetic resonance imaging; mm, millimeter 5 LV wall thickness z-score > 2.5 or LV wall thickness z-score  >2 if there is a family history of HCM or a pathogenic sarcomere gene is present 2D echocardiography or cardiac MRI

6. Types

7. Pathophysiology of Hypertrophic Cardiomyopathy Dynamic LVOT Obstruction Mitral Regurgitation Metabolic/Energetic Dysfunction Diastolic Dysfunction Myocardial Ischemia Abbreviations: LVOT indicates left ventricular outflow tract. 7 A trial and Ventricular Arrythmias

8. Pharmacologic Management of Obstructive and Non-Obstructive HCM Abbreviations: ACEi indicates angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; CCBs, calcium channel blockers; GDMT, guideline-directed medical therapy; HCM, hypertrophic cardiomyopathy; LVOTO, left ventricular outflow tract obstruction; and r/t, related to Obstructive If persistent dyspnea with volume overload, consider Low Dose Diuretics (Class 2b) Non-Obstructive HCM Preserved LVEF In highly selected patients with apical HCM with severe dyspnea or angina (NYHA class III or class IV) despite maximal medical therapy, and with preserved EF and small LV cavity size, apical myectomy by experienced surgeons at comprehensive centers may be considered to reduce symptoms (Class 2b) Consider Discontinuing: Vasodilators Digoxin High Dose Diuretics (Class 2b) Verapamil potentially HARMFUL in: Severe Dyspnea at Rest Very High Gradients (>100 mmHg) Children < 6 Weeks (Class 3: Harm) Intravenous Fluids Phenylephrine ± ß-Blocker (without inotropic activity) (Class 1) Step-Wise Approach: Non-Vasodilating ß-Blocker If not effective or not tolerated, switch to Non-Dihydropyridine CCBs If persistent severe symptoms, Add Myosin Inhibitor ( ie Mavacamten ) -OR- Add Disopyramide -OR- Septal Reduction Therapy performed at experienced centers (Class 1) ß-Blocker or Non-Dihydropyridine CCBs (Class 1) Oral Diuretic if evidence of congestion (Class 2a) Benefits of b-Blocker or CCBs is not well established (Class 2b) Valsartan may be considered to potentially slow adverse cardiac remodeling (Class 2b) Usefulness of ACEi / ARBs in symptomatic patients with LVEF>50% is not well established (Class 2b) ≤45 years Asymptomatic Pathogenic sarcomere variant carrier Mild phenotype: Symptomatic: Asymptomatic: 8 Symptoms r/t LVOTO Acute Hypotension

9. Invasive Management of Obstructive HCM Abbreviations: AF indicates atrial fibrillation; GDMT, guideline-directed medical therapy; LVOTO, HCM, hypertrophic cardiomyopathy; LAE, left atrial enlargement; left ventricular outflow tract obstruction; NYHA, New York Heart Association; and MR, mitral regurgitation; Obstructive HCM NYHA Class III / IV or symptoms attributable to LVOTO Septal Reduction Therapy at experienced centers (Class 1 ) Despite GDMT Alcohol Septal Ablation in eligible patients is recommended in patients whom: Surgery is contraindicated or declined Risk is considered unacceptable due to comorbidities or advanced age (Class 1) Surgical Myectomy is recommended in patients with associated cardiac disease requiring surgical treatment: Associated anomalous papillary muscle Markedly elongated anterior mitral valve leaflet Intrinsic mitral valve disease Multivessel coronary artery disease Valvular aortic stenosis (Class 1) Mitral Valve Replacement should not be performed for sole purpose of relieving LVOTO (Class 3:Harm) Septal Reduction Therapy should not be performed in asymptomatic patients with normal exercise capacity (Class 3:Harm) Septal Reduction Therapy may be considered as alternative to escalation of medical therapy after shared-decision making (Class 2b) Surgical Myectomy is reasonable in NYHA Class II if: Severe PH attributable to LVOTO or MR LAE with ≥1 episodes of symptomatic AF Poor functional capacity attributable to LVOTO Children or young adults Class with very high LVOT gradients (> 100 mmHg) (Class 2b) 9

10. cont'd... Beta-blockers have been the initial treatment for symptomatic obstructive hypertrophic cardiomyopathy (oHCM) despite limited evidence of their efficacy . Aficamten is a cardiac myosin inhibitor(CMI) reduces left ventricular outflow tract gradients, improves exercise capacity, and decreases HCM symptoms when added to standard medications. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 10

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13. Guideline Recommendations

14. 6/12/2024 Weekly Journal Club; MAPLE-HCM Trial 14

15. 6/12/2024 Weekly Journal Club; MAPLE-HCM Trial 15

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17. published on Aug 30/ 2025

18. objective the over all objectives of this head to head comparison trial is to evaluate the safety and efficacy of aficamten as : first line therapy for participants recently diagnosed with symptomatic oHCM and/or treatment naive: or monotherapy for participants previously receiving standard of care(SOC) medical therapy for symptomatic oHCM. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 18

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20. Methodology trial design multicenter, randomized , international, double-blind, double-dummy, a head-to-head, phase 3 trial study was conducted from June 2023, to August 2024, across 71 sites in North America, Brazil, Europe, Israel, and China; 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 20

21. Ethical clearance and funding the trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guidelines. An academic steering committee in collaboration with Cytokinetics ( the sponsor ) designed the trial, selected clinical trial centers, oversaw the conduct and monitoring of the trial All the patients provided written informed consent. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 21

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24. Procedure Patients underwent randomization within 6 weeks after the start of screening. patients underwent a washout of background standard therapy of up to 2 weeks beginning at the first screening visit. patients reduced the dose of standard medications every 2 days until standard medications were discontinued for at least 7 days before screening assessments. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 24

25. cont'd... To understand whether current or recent use of standard medications or time since HCM diagnosis influenced the effect of treatment, patients were divided into two groups: group 1 included patients who had recently (≤12 months) received a diagnosis of HCM or had not received standard medications in the past 12 months, regardless of the date of diagnosis; group 2 included patients with a long-standing (>12 months) HCM diagnosis who had received standard medications within the past 12 months. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 25

26. cont'd... Enrollment of patients who had previously received mavacamten and those who had undergone septal reduction therapy was capped at approximately 10% each, Enrollment of patients who used a cycle ergometer for exercise testing was capped at approximately 50%. The starting dose of aficamten was 5 mg and of metoprolol was 50 mg. At weeks 2, 4, and 6, the dose of aficamten could be escalated in 5-mg increments and the dose of metoprolol could be escalated in 50-mg increments, to a maximum dose of 20 mg and 200 mg, respectively. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 26

27. Statistical Analysis The statistical power for the primary end point was calculated under the assumption that the difference between groups in the change in peak oxygen uptake at week 24 would be 2ml/kg/minute, with a standard deviation of 3ml/kg/minute. With the estimated sample size of 170 patients would provide the trial with more than 90% power to detect a difference in peak oxygen uptake at a two-sided type I error level of 0.05. The primary end point was analyzed with the use of an analysis of covariance model, with treatment group, randomization stratification factors, baseline peak oxygen uptake. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 27

28. cont'd... Other secondary end points were analyzed with the use of a mixed model for repeated measures. Safety analyses were performed in the safety analysis population, which included all the patients who received at least one dose of aficamten or metoprolol. For all subgroup analyses, the widths of the 95% confidence intervals have not been adjusted for multiplicity and the intervals should not be used in place of hypothesis testing. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 28

29. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 29 Pablo Garcia-Pavia et al. J Am Coll Cardiol HF 2025; 13:346-357.

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34. Results . 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 34

35. cont'd... At week 24, in the aficamten group a total of : 66 (76%) were receiving 15mg or 20mg of aficamten the dose decreased to 0 mg for 1 patient (1%) owing to unacceptable side effects at the lowest dose, in accordance with the dose-adjustment algorithm. In comparison, in the metoprolol group: 53(63%) were receiving 150mg or 200mg of metoprolol the dose decreased to 0 mg for 10 patients (12%) owing to unacceptable side effects at the lowest dose. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 35

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38. Secondary End Points outcomes 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 38

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45. Discussion in patients with symptomatic oHCM, aficamten monotherapy was superior to metoprolol monotherapy on the basis of improved peak oxygen uptake after a 24wk. Aficamten treatment was also associated with decreased symptoms and improvements in LVOT gradient, NT-proBNP level, and left atrial volume index. The clinical benefits of aficamten as compared with metoprolol observed in this trial are probably secondary to a decrease in LVOT obstruction resulting from CMI . Parallel to the change in hemodynamics, aficamten reduced the NT-proBNP level, which is predictive of future adverse outcomes related to HCM, including heart failure. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 45

46. cont'd... The effect of aficamten on exercise capacity appeared to be consistent across all prespecified subgroups In addition to providing information on the use of aficamten as monotherapy (and as first-line therapy in a subpopulation of patients with oHCM), this trial also provides unique insights into the dose administration, treatment effects, and side effects of metoprolol in patients with oHCM. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 46

47. Strength the first Phase 3 multicenter, double-blind, head-to-head comparison of aficamten to current standard of care (metoprolol)in adults with symptomatic oHCM f irst RCT to recommend aficamten as monotherapy for treatment of oHCM . provides unique insights into the dose administration, treatment effects, and side effects of metoprolol in patients with obstructive HCM. t rial met its primary and secondary endpoints 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 47

48. Limitation short treatment period, the patients enrolled in this trial had objectively less-severe measures of disease burden We cannot exclude the possibility that other non vasodilating beta-blockers have effects different from those of metoprolol. bias regarding investigator assumption of treatment assignment was possible given the negative chronotropic effect of metoprolol. blacks were under represented 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 48

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50. Conclusion this trial aimed at producing the necessary evidence to inform the use of aficamten as potential first-line monotherapy, and its placement among the pharmacologic option for oHCM. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 50

51. QUESTIONS AND COMMENTS 19/09/2025 Weekly Journal Club; MAPLE-HCM trial 51

52. Critical Appraisal 19/09/2025 Weekly Journal Club MAPLE-HCM-trial Yes Can’t Tell No Comments Did the trial address a clearly focused issue? √ Was the assignment of patients to treatment randomized? √ Were all the patients who entered the trial properly accounted for its conclusion? √ Were patients, health care workers and study personnel “Blind” to treatment? √ Were the groups similar at the start of the trial? √ Aside from the experimental intervention, were the groups treated equally? √ Are the results statistically and clinically significant? √ Can the results be applied to the local population? √ Are the benefits worth the harms and costs? √

53. Thank you!!!. 19/09/2025 Weekly Journal Club; MAPLE-HCM Trial 53