ROLE OF AFICAMTEN IN THE TREATMENT of HOCM

Aficamten in HOCM

1. AFICAMTEN IN SYMPTOMATIC HOCM PRESENTOR: DR INDRANIL GHOSH

2. INTRODUCTION Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic condition affecting the sarcomere. Phenotypically, the disease manifests in hypertrophy in the absence of other causes. The prevalence is estimated >1:500 in individuals .  HCM can be subdivided into obstructive ( oHCM ) and nonobstructive ( nHCM ), with the former defined as a resting left ventricular outflow (LVOT) gradient >30mmHg. Symptoms in oHCM include dyspnea , exertional intolerance, chest pain, syncope or sudden cardiac death . Treatment options for oHCM can be divided into medication and invasive therapies. Traditional pharmacotherapy utilized for oHCM includes nonvasodilating beta blockers (BBs), nondihydropyridine calcium channel blockers (CCBs) and disopyramide . Interventions include alcohol septal ablation and surgical septal myectomy .  Left ventricular outflow tract obstruction, is one of the principal determinants of HCM-related complications and therefore is an important target for therapy

3. There is a strong genetic component to HCM, which affects myocardial sarcomeres. With more than 2000 mutations identified, the most common genes identified are beta myosin heavy chain 7 (MYH7), which codes for the major myosin isoform, and myosin-binding protein (MYBPC3). Gene identification is useful particularly for screening family members if the proband has a positive screen. However, there remains inconsistent genotype–phenotype correlations; some patients are gene positive but do not meet clinical criteria for HCM and others meet clinical criteria without identifiable genes. Furthermore, sporadic mutations do occur in patients with no family history of HCM . Given the inconsistencies in genetic testing, HCM remains largely a clinical diagnosis requiring identification of left ventricular hypertrophy by echocardiography or cardiac magnetic resonance imaging (CMR). Typically , left ventricle (LV) wall thickness >15mm or >13mm with pertinent family history should raise suspicion for HCM. Hypertrophy occurs most commonly in the basal septum but can vary in different morphologies of HCM . HCM mimickers such as hypertension, aortic stenosis, amyloidosis, muscular dystrophies, Fabry’s disease and lysosomal disorders should be excluded prior to diagnosing HCM.

4. The identification of an intracavitary gradient separates oHCM from nHCM . A peak gradient >30mmHg at rest is consistent with obstruction. If the peak gradient is <50mmHg, provocation with amyl nitrate, Valsalva maneuver or exercise echocardiography may reveal a concealed higher gradient.  Other features of obstruction include systolic anterior motion (SAM) of the mitral valve that yields a posteriorly directed mitral regurgitant jet.  Medical management of HCM has included avoiding hypovolemia, decreasing contractility, and managing tachycardia. For patients with oHCM , first-line therapy includes nonvasodilating BBs and nondihydropyridine CCBs. Current guidelines from the American Heart Association and American College of Cardiology recommend titrating these medications to either effectiveness or maximally tolerated dose. Unfortunately , use of these agents is often limited by side effects . If symptoms persist, then the addition of disopyramide or evaluation of intervention at an experienced center should be pursued. Disopyramide is a class IA antiarrhythmic that has negative inotropic effects. Patients started on disopyramide should continue their BB or CCB because this antiarrhythmic can increase conduction through the atrioventricular node; as such, patients with non-rate controlled atrial fibrillation may not be candidates for disopyramide . In addition, it has a strong side effect profile, including anticholinergic effects, QTc prolongation, and alterations of the cytochrome P450 system, necessitating time-intensive clinician oversight.

5. Cardiac hypercontractility, which results from an excessive number of actin–myosin cross-bridges within the cardiac sarcomere, is an important mechanism that promotes outflow obstruction Mavacamten selectively inhibits beta-cardiac myosin ATPase through allosteric binding, decreasing the amount of myosin-actin bridges. In addition, this first-in-class drug targets the rate limiting step by preventing phosphate release.  Furthermore, the drug slows the rates of myosin binding to actin in both the ADP-bound and ADP-released state. Combined , these mechanisms decrease the force generated by sarcomeres and reduce cardiac contractility. Its pharmacokinetic profile includes excellent oral bioavailability of >85% and rapid absorption, with time to maximum concentration of 1 hour .  The drug has a high distribution volume and long elimination phase. The mean half-life elimination is about 8 days in normal CYP2C19 metabolizers . Currently, the drug carries a boxed warning for risk of heart failure and recommends against starting mavacamten in patients with left ventricular ejection fraction (EF) <55%. Cessation of the drug is recommended if EF <50%, heart failure symptoms develop or worsening clinical status.

6. MECHANISMS OF EXERCISE LIMITATIONS IN O-HCM

7. AFICAMTEN Aficamten is a reversible inhibitor of cardiac myosin that reduces left ventricular contractility by decreasing the number of active actin–myosin cross-bridges within the sarcomere Aficamten was designed to have a shallow dose–response relationship and a plasma half-life that allows for personalized dose adjustments as often as every 2 weeks (features that differentiate it from mavacamten ) In a phase 2 trial, treatment with aficamten resulted in significant reductions in left ventricular outflow tract gradients in patients with obstructive HCM Maron MS, Masri A, Choudhury L, et al. Phase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2023; 81: 34-45

8. MECHANISM OF ACTION

9. COR LOE RECOMMENDATIONS 1 B-R For patients with obstructive HCM who have persistent symptoms attributable to LVOTO despite beta blockers or non dihydropyridine calcium channel blockers, adding a myosin inhibitor (adult patients only), or disopyramide (in combination with an atrioventricular nodal blocking agent), or SRT performed at experienced centres, is recommended Members WC et al. 2024 AHA/ACC/AMSSM/HRS/PACES / SCMR Guideline for the Management of Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology. 2024 May 8.

10. BACKGROUND Maron MS, et al. J Am Coll Cardiol . 2023;81(1):34–45. REDWOOD HCM TRIAL (PHASE II)

11. STUDY DESIGN Phase 3, International, Double-blind, Randomized, Placebo-controlled trial Patients with symptomatic obstructive HCM received aficamten or placebo in addition to standard drug therapy Total patients: 282

12. OVERVIEW OF TRIAL

13. INCLUSION CRITERIA Males and females between 18 and 85 years of age, BMI <35 kg/m2 Diagnosed with HCM per the following criteria: a. Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac disease and b. Has an end-diastolic LV wall thickness as measured by the echocardiography core laboratory of: • ≥15 mm in one or more myocardial segments OR • ≥13 mm in one or more wall segments and a known-disease-causing gene mutation or positive family history of HCM Has resting LVOT-G ≥30 mm Hg and post-Valsalva LVOT-G ≥50 mmHg during screening as determined by the echocardiography core laboratory LVEF ≥60% at screening as determined by the echocardiography core laboratory

14. New York Heart Association (NYHA) Functional Class II or III at screening Hemoglobin ≥10 g/dL at screening Respiratory exchange ratio (RER) ≥1.05 and pVO2 ≤90% predicted on the screening CPET per the core laboratory Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on a stable regimen for >6 weeks prior to randomization and anticipate remaining on the same medication regimen during the trial Patients treated with disopyramide must also be concomitantly treated with a beta blocker and/or calcium channel blocker

15. EXCLUSION CRITERIA Significant valvular heart disease- Moderate-severe valvular AS/AR, Moderate-severe MR not due to systolic anterior motion of the mitral valve Documented history of current obstructive coronary artery disease or H/O MI Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM ( eg , Noonan syndrome, Fabry disease, amyloidosis) Prior treatment with cardiotoxic agents such as doxorubicin or similar History of LV systolic dysfunction (LVEF <45%) or stress cardiomyopathy at any time during their clinical course Has any ECG abnormality considered by the investigator to pose a risk to patient safety ( eg , second degree atrioventricular block type II) Documented paroxysmal atrial fibrillation during the screening period

16. Paroxysmal or permanent atrial fibrillation is only excluded IF: - rhythm restoring treatment has been required ≤6 months prior to screening - rate control and anticoagulation have not been achieved for at least 6 months prior to screening History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening ICD placement within 3 months or planned ICD placement during the trial History of appropriate ICD discharge for life-threatening ventricular arrhythmia within 6 months prior to screening

17. Has been treated with septal reduction therapy Estimated glomerular filtration rate (eGFR) <30 mL/min or hepatic impairment Has received prior treatment with aficamten or mavacamten

18. PROCEDURE Eligible patients were randomly assigned in a 1:1 ratio to receive aficamten or placebo Randomization was performed with the use of an interactive Web-response system and stratified according to the use of beta-blockers (yes or no) and the method of CPET (treadmill or cycle ergometer) Enrollment of patients taking beta-blockers and disopyramide was capped at approximately 70% and 10% of the trial population, respectively Enrollment of those with persistent atrial fibrillation at screening was capped at 15% Enrollment of patients being tested with the use of a cycle ergometer was capped at 50%

19. Oral aficamten or placebo (manufactured by Patheon) was administered once daily for 24 weeks; the tablets were identical in appearance The starting dose of aficamten was 5 mg, with three subsequent opportunities (at weeks 2, 4, and 6) to increase the dose by 5-mg increments, to a maximum dose of 20 mg At each visit, an echocardiographic cardiologist who was unaware of the trial-group assignments assessed the left ventricular outflow tract gradient at rest and after the Valsalva maneuver and the left ventricular ejection fraction The site investigators and trial team members were unaware of the N-terminal pro–B-type natriuretic peptide (NT- proBNP ) levels and the echocardiography results

20. DOSE CHANGE REGIMEN

21. END POINTS PRIMARY END POINT : The change from baseline to week 24 in the peak oxygen uptake as assessed during cardiopulmonary exercise testing SECONDARY END POINTS : The change from baseline to week 24 in the KCCQ-CSS An improvement from baseline of at least one NYHA functional class at week 24 The change from baseline to week 24 in the LVOT gradient after the Valsalva maneuver The occurrence of a LVOT gradient of less than 30 mm Hg after the Valsalva maneuver at week 24 The duration of eligibility for septal reduction therapy during the 24-week treatment period among patients who were eligible for such therapy at baseline

22. The change from baseline to week 12 in the KCCQ-CSS An improvement from baseline of at least one NYHA functional class at week 12 The change from baseline to week 12 in the LVOT gradient after the Valsalva maneuver The occurrence of a LVOT gradient of less than 30 mm Hg after the Valsalva maneuver at week 12 The change in the total workload as assessed by cardiopulmonary exercise testing at week 24

23. An exploratory end point was the geometric mean proportional change in the NT- proBNP level

24. STATISTICAL ANALYSIS The statistical power was calculated under the assumption that the difference between the groups in the change from baseline in the peak oxygen uptake at week 24 would be 1.5 ml/kg/min, with a standard deviation of 3.5 ml/kg/min and that no more than 70% of the patients would be receiving beta blockers and no more than 50% of the patients would undergo CPET with the use of a cycle ergometer With the assumption that 10% of the primary end-point data would be missing, it was estimated that a sample of 270 patients with a randomization ratio of 1:1 would provide the trial with at least 90% power with a two-sided type I error level of 0.05

25. Primary end point was analyzed with the use of an analysis of covariance (ANCOVA) model, with trial group, randomization stratification factors, baseline peak oxygen uptake, and baseline weight as covariates The primary end point was tested first at a two-sided level of 0.05. If the primary end point showed a significant treatment effect at a two-sided P value of less than 0.05, then the secondary end points were tested sequentially at a two-sided level of 0.05 Secondary end points who had a response to aficamten were analyzed with the use of the Cochran–Mantel–Haenszel test The statistical analyses were performed with the use of SAS software, version 9.4 (SAS Institute)

26. RESULTS From February 1, 2022, to May 15, 2023, a total of 543 patients were screened for eligibility at 101 sites in 14 countries, of whom 282 underwent randomization and received aficamten or placebo At the end of the dose-escalation phase (week 8), 3.6%, 12.9%, 35.0%, and 48.6% of the patients assigned to the aficamten group were receiving aficamten at a dose of 5 mg, 10 mg, 15 mg, and 20 mg, respectively

27. BASELINE CHARACTERISTICS

28. PRIMARY END POINT Changes in Exercise Capacity from Baseline to Week 24

29. PRIMARY AND SECONDARY END POINTS

30. PRIMARY END POINT SUBGROUP ANALYSIS

31. SECONDARY END POINTS

32. ADVERSE EVENTS Serious adverse events were reported in 8 patients (5.6%) in the aficamten group and in 13 patients (9.3%) in the placebo group One adverse event (paranoia) resulted in early discontinuation of aficamten , and two adverse events (syncope and acute lymphocytic leukemia) resulted in early discontinuation of placebo Three adverse events resulted in temporary interruptions of aficemten or placebo, including acute cholecystitis in 1 patient in the aficamten group and bronchopneumonia and verrucous carcinoma removal in 1 patient each in the placebo group

33. ADVERSE EVENTS

34. DISCUSSION In this trial aficamten improved exercise capacity (as assessed by cardiopulmonary exercise testing) over a 24-week treatment period Aficamten treatment was also associated with significantly greater improvements than placebo in all the secondary end points The efficacy of aficamten was evident by week 12, with significantly greater improvements in left ventricular outflow tract gradients, health status, and symptoms In addition, the reduction in symptoms was associated with a clinically meaningful enhancement of overall health status as evidenced by increases in the KCCQ-CSS

35. In contrast to the results that were observed with mavacamten in the EXPLORER-HCM trial, which suggested an attenuation of benefit among patients who were receiving beta-blockers, the treatment effects of aficamten appeared to be similar with or without background beta-blocker use Aficamten was associated with other favorable outcomes, including a significantly greater improvement in limiting symptoms and a substantially greater reduction in the serum NT- proBNP level than placebo The unique pharmacologic properties of aficamten provide some notable distinctions between aficamten and mavacamten

36. The shorter half-life of aficamten enables more rapid dose escalation, which results in the ability to identify an effective dose within weeks, providing timely clinical benefit No patient in the aficamten group who had a left ventricular ejection fraction of less than 50% had an interruption of treatment or an exacerbation of heart failure Furthermore, the return to baseline measures of the left ventricular outflow tract gradient, symptoms, and the left ventricular ejection fraction after the washout period reflects a rapid reversal of the pharmacodynamic effects

37. MERITS OF THE TRIAL The outcomes observed in this trial with aficamten appear to be generalizable to the broad, global population of patients with obstructive HCM encountered in clinical practice Women were well represented (40.8%) in this trial The clinical profile of the trial population included patients with typical characteristics of obstructive HCM, including those with a range of left ventricular outflow tract gradients and left ventricular wall thicknesses The trial was inclusive of all conventional HCM background therapy use

38. LIMITATIONS Majority population in the trial were white The relatively short treatment period, precluding assessment of longer-term cardiovascular outcomes They observed that some patients who received aficamten did not have an improvement in NYHA class. Further trials are needed to clarify the reasons for this finding and to determine whether those patients would have symptom relief with longer exposure to aficamten

39. CONCLUSION Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo

40. THANKS