Fine-Tuning Hypertrophic Cardiomyopathy Care in the CMI Era: Redefining Management for the Modern Heart Failure Specialist

Co-Chairs and Presenters, Milind Desai, MD, MBA, and Anjali Tiku Owens, MD, discuss hypertrophic cardiomyopathy in this CME/MOC/AAPA/IPCE activity titled “Fine-Tuning Hypertrophic Cardiomyopathy Care in the CMI Era: Redefining Management for the Modern Heart Failure Specialist.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at http://bit.ly/4kVBYna. CME/MOC/AAPA/IPCE credit will be available until October 27, 2026 .

1. Fine-Tuning Hypertrophic
Cardiomyopathy Care in the CMI Era

Redefining Management for the
Modern Heart Failure Specialist

Milind Desai, MD, MBA
Haslam Family Endowed Chair in CV Medicine
Professor of Medicine

Vice Chair and Director, HCM Center

Heart Vascular Thoracic Institute

Cleveland Clinic

Cleveland, Ohio

Anjali Tiku Owens, MD

Director, Center for Inherited Cardiovascular Disease
Section of Heart Failure

Transplantation and Mechanical Circulatory Support
University of Pennsyivania Perelman School of Medicine
Philadelphia, Pennsylvania

Go online to access full CME/MOC/AAPA/IPCE information, including faculty disclosures.

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2. Our Goals for Today

During this symposium we will learn that...

Recognizing oHCM early and distinguishing it from other causes
of LVH is critical

Guideline-based oHCM management has evolved and
incorporates disease-modifying medication (ie, CMIs)

CMls offer a disease-modifying treatment option to improve
symptoms and reduce LVOT gradients in patients with oHCM

Ongoing management of patients with oHCM includes shared
decision-making, personalized treatment plans, and follow-up
monitoring

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3. Getting It Right From the Start
Mastering the Diagnosis of HCM

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4. oHCM vs nHCM: Anatomy???

An LV wall thickness of 215 mm or 213 mm in individuals with a family history
of HCM or in conjunction with a positive genetic test is diagnostic for HCM

LVOT gradient Possible obstruction
230 mmHg? or cavity obliteration
Normal a. & 8 8

\ Without With
a > _, Obstruction Obstruction Midcavity Apical
€ Progression from one phenotype to another may occur »
‘Thier hemor’ 2. Wing Commis Were: Gramen GR etal Orten LOS vor Degree mm PeerView

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5. HCM Affects All Sexes, All Races, and All Ages in All Places

HCM is not rare, but it IS clinically underdiagnosed

Prevalence Median Age Underdiagnosis Effect in

of HCM! at Diagnosis? Rate? the US4
Between 1:200 46 Two cases missed Potentially
and 1:500 years for every one ~700,000
Estimated; based on disease diagnosed Americans

phenotype by imaging

Sex, race, insurance status, rural location, region of the country,

Bie Disparities in treatment and in-hospital mortality have been documented
hospital size, and hospital nonprofit status?1-8

Ronin Et al J An Hoot Asoc 20188201204. 2 Ho CY el Colon. 2018-38 1087-12, 9. Moser ea tJ Card 2023.82 4.674. Maron 8S
“Yam Cot Carl 202279 372-9808 Johnson DY el van Moat Asso: 2003.12 0023000. 6. us RAB, Sina. J An Col Card 2021 1020730819. DEET VIEW

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6. hen Should | Suspect HCM

A Symptoms

Family History

Cardiac Exam

+ Exertional dyspnea
Dizziness
Syncope

+ Chest discomfort

+ Palpitations

+ Symptoms may vary
day-to-day

Autosomal dominant
inheritance

Unexpected deaths
Sudden deaths
Heart failure

Stroke

HCM can be completely asymptomatic

1. Wing Committee Membors: Ommon SR e al. Cieuaton.2024:89:2324:2408. 2. Goske JB ot al. J Am Call Cardo! HE. 2018.8:364-375, 3. Lawor PR ta
raión 2010 15 17081711 A Cova data Prog Cards De 201261917822 5 Abo at al Eur Hoon J. 2025443603 2828

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+ Systolic murmur

+ Augmentation with
Valsalva or maneuvers
that decrease preload

+ Abnormal ECG

+ Arrhythmia

Download the
Screening &

Follow-Up
Practice Aid!

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7. Characteristics and s of People Wi

Asymptomatic oHCM!

Survival Analysis

+ Cohort of 3,393 asymptomatic (NYHA class |) 100
patients > 1,329 (39.2%) classified as oHCM

Normal age-sex matched

so United States population

8
+ Of those with oHCM: mean age 61 + 17 y, 58% male, 3 60
61% with HTN E Obstructive HOM
5 40
+ During mean follow-up of 10.5 y, 19% progressed to dd
NYHA Class Il, 8% to Class Ill, and 1% to Class IV dl
+ 83% on B blockers, 17% CCBs, 29% disopyramide ° o 4 8 12 16 20
Time,
+ 31.8% mortality rate during follow-up period un
A as? Ge 80a

Current guidelines suggest medication may not be well-established in asymptomatic patients
with oHCM; however, earlier initiation of disease-modifying therapies may be beneficial

1. Jadam S et al. J Am Coll Coral. 2025 Aug 21:80735-1087(25)07980-1.

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8. Imaging Studies for HCM:
2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guidelines!

Transthoracic ñ Transesophageal
echocardiography ia echocardiography
(TTE) (TEE)

+ Primary modality for + Alternative to TTE if + Used intraoperatively
most patients TTE is inconclusive during septal
+ Characterizes + Complementary reduction therapy
dynamic LVOTO, to TTE, eg, for + Used for surgical
mitral valve precise thickness planning if TTE is

+ Used for screening measurements inconclusive

and follow-up

ee, Scintigraphy is used to evaluate other cardiomyopathies,
such as transthyretin amyloidosis?

1. Wing Commitee Members: Onmen SR el, Grouaton 2024592324405. 2 Käteson MM tal JA Col Car 202984 1076-1126 PeerView

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9. Diagnostic Clues to Differentiate HCM Subtypes From HFpEF

Nonobstructive HCM (nHCM) Obstructive HCM (oHCM)

+ nHCM and HFpEF share a pathophysiologic + OHCM is characterized by dynamic
basis of diastolic dysfunction, elevated LV filling LVOT gradients and mitral valve systolic
pressures, and preserved systolic function anterior motion, which are not features

of HFpEF

+ nHCM with preserved EF can closely mimic
HFpEF, especially in the absence of LVOTO + While exertional symptoms are common
in both, the presence of obstruction
and associated murmurs in oHCM
distinguish it from the typical HFpEF
— nHCM typically presents with symptoms due to phenotype
impaired relaxation and restrictive physiology, similar
to HFpEF, and is often seen in patients with comorbid
HTN and AF

— Both conditions may present with similar clinical and
echocardiographic findings

1 Wing Commitee Members: Onmen SR tai Crowston. 2024323242406. 2 Chen OF tl, Cin Ros Carta! 2024:1146)761769 .
3 Gannata At aN Engl Mod 2026:992:173-184 PeerView

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10. An Artificial Intelligence System Can Identify ECGs Requ
Further Evaluation for HCM

Mobile App23

+ Validated algorithm automatically
identifies ECGs for further follow-up'?

+ Notifications and viewing links are sent
to team via a mobile app?

+ Does not replace current SOC
methods for the diagnosis of HCM3

+ Viz.ai is the first FDA-approved HCM
detection algorithm*

+ More models are being validated®

1 Ko WY otal. Am Col Cardo! 20205-72233, 2 pal iz inawvz-ecavs- be corovalby nea fos-ah-algorinm forhyportophiccatomyepathy
2 Mis hit alhyperopnc-cardcnyopathy. Ds nn accnseala on on ed nano ci h-DENES0008 5
5. Orne Letal. Monde Cardovese Med 2025 35:126-134 PeerView

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11. Al Is Improving Point-of-Care Ultrasonography (POCUS)
Detection of HCM!

Investigators at Yale-New Haven Health System set out to develop and
validate an Al-enabled approach to detect HCM from real-world POCUS clips

Methods Key findings

+ Used >290,000 standard echo videos + HCMAUROG * 0:90 on eingle.aplcat-4-
from YNHHS to train the Al system chamber view

+ Tested on >90,000 POCUS videos + AI-POCUS flagged 58% of patients with
from YNHHS an Mount Sinai confirmed HCM a median of 2 years

before their clinical diagnosis
Outcomes

+ Diagnostic accuracy (AUROC), time
to clinical diagnosis

Implications
+ Enable scalable, POC screening for HCM
+ Identify at-risk individuals earlier

1.Okonomeu EK et, Lorca Dit Heath, 202572)e113-2129. PeerView

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12. Presenting for Well-Woman Exam

Medical History

+ Hypertension Visit Notes
Social History + Catherine reports
+ Nonsmoker, occasional alcohol use symptoms
Family History consistent with
+ Unremarkable for cardiac conditions or cardiac-related death PVCs, increasing
Evaluation fatigue over the
+ BP 130/82 mmHg, HR 78 bpm, pulse ox 97% on RA, BMI 25 kg/m? past year
+ CBC, chem7, NT-proBNP all WNL + Baseline ECG
Current Medications performed
+ Metoprolol succinate, occasional naproxen use
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13. Catherine’s ECG Data Indicates LVH

12-Lead ECG

| Baseline u
Visit Notes

+ Baseline ECG
indicates LVH

+ TTE warranted to
assess for
structural
disease

Image cred: Mess A Austn a. J Am Cal Cord! Case Rep 2024; 2 PeerView

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14. Not All LVH is HCM erential Diagnosis Widens With Ag

& ae Hypertension

AMC
__ Stenosis ?

‚ Athlete's —
heart

Frequency

TE. ARR,
| Pompe ) @ Danon )
Age
1. Kubo. Koka H. Cu Coot Ro. 2011945. PeerView

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15. Catherine’s Baseline Echocardiography Data

Doppler During Valsalva Doppler at Rest

nsos mes € roa mos

0 2. EN

& |
ay

Image cred: Desai MY etal. Am Col Cardio Case Rep. 2025;30(8} 103228,

16. Image credit: Desai MY eta. JAm Coll Cardo! Case Rep. 2025;30(8) 103228,

Echo Findings

Basal septal thickness:
2.1 cm

LVEF: 65%

Mitral valve: moderate-
severe SAM with mild
posteriorly directed
regurgitation

Resting LVOT gradient:
35 mmHg
Post-Valsalva LVOT
gradient: 80 mmHg

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17. Following the Evidence
How Is Long-Term Clinical and Real-World
Experience With CMIs Reshaping oHCM Care?

18. led Therapies for HCM

2024
1960s-1970s 2000s-2010s
. AHAIACC HCM
B blockers Disopyramide guidelines

1970s-1980s 2020
Calcium channel AHA/ACC HCM
blockers guidelines

2023
ESC HOM
guidelines

Conventional Medications for oHCM

+ Do not target the disease process

+ May not provide sufficient symptom relief

+ Are often poorly tolerated

+ Use is based on studies that are underpowered,

not randomized, with short follow-up and
mixed results

2022
First CMI,
Mavacamten,
FDA-approved

1. Sawan MA et a. Cn Coco. 202947 624207. 2. Znu M 0 al. J Am Co Caro Advances. 20282100822. i
3 Wing Commitee Members: Ommon SR at a, Citulaton. 2024832324 2408 PeerView

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19. Il-Molecule Cardiac Myo: Inhibitors Targeting HCM

Unlike previous medications used in HCM, CMis are!
+ Designed as potentially disease-modifying treatments specifically for HCM
+ Supported by data from prospective, randomized controlled trials

Mavacamten?* Aficamten?*
+ Reduces myosin head availability + Slows phosphate release from myosin
+ Stabilizes the myosin super-relaxed state + Stabilizes weak actin-binding

myosin conformation

1. Alslamı K, Marton S It J Molec Sei 2020:21:9509, 2. Tu Owens A. ACC 2022. Oral presentaton: 683-610. y
3 Lehman 3 eta. Nat Rov Card 2022.19:353-369, PeerView

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20. What Have We Learned About Cardiac Myosin Inhibito
for oHCM?'

Selected Published Phase 3 Clinical Trials

EXPLORER-HCM (phase 3, mavacamıen vs placebo), NCT03470545
o
MAVA-LTE (mavacamien LTE), NCTO3723655
See + + noe |
VALOR-HCM (phase 3, mavacamten vs placebo), NCT04349072
———————— |

FOREST-HCM (aficamten OLE), NCT04848506

SEQUOIA-HCM (phase 3, aficamten vs placebo), NCT05186818
ee
MAPLE-HCM (phase 3, aficamten vs metoprolol), NCT05767346

2018 2019 2020 2021 2022 2023 2024 zus pos 2027

We are here
1. hips iteniatiats gov. PeerView

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21. MAVA-LTE: Sustained Improve s in Cardiac Functio

and Symptoms at 3.5 Years With Mavacamten!

Participants from Resting LVOT Gradient NYHA Classification
EXPLORER-HCM Mi irproves by orecass Ronald tw save
(N = 231) sustained IM Contrat-read LVOT improved y wo clases. Worseed by one cass
reductions at wk 180 I Siteread LVOT Site sion naar, Ad

+ LVOTG -40.3 mmHg

Resting LVOT
Gradiont, mmHg
ee.

u I
+ NT-proBNP -562 Visivweok do
+ EQ-5D-5L score 0.09 o Valsalva LVOT Gradient £
+ LVEF decreased from Sf 5

73.9% to 63.9% Bee =

: Ë

+ 77.9% improved by aye É

21 NYHA class 78 o

RRA q a a

Mean LVEF remained within normal limits at all visits

1. Garcia Pavia P ot al. Eur Hear J 202445:5071-5089. PeerView

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22. Mavaca

With Favorable Cardiac Remodeling!

en Treatment Over 30 Weeks Is Associated

+ Integrated CMR analysis using data from double-blind RCTs EXPLORER-HCM and EXPLORER-CN
(N = 93) compared trends with patients in the open-label HORIZON-HCM study (N = 17)

Difference in Change From
Baseline, mean (95% Cl)

LVMI, g/m?

LAVI, mLim?

Maximum LV wall thickness, mm
LVEDVI, mL/m?

LVESVI, mLim?

Global mass of LGE 65D, g
MCF, %

LVEF, %

1. Kramer © ot al. Oral presentation at: ESC Congress 2025; August 31, 2025, Madrid, Spain.

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MAVA-RCT vs
Placebo-RCT

-25.2 (-28.3, -16.3)
15.6 (-18.2, -8.3)
-3.1 (3.7, -2.0)
-7.2(-11.9, -3.3)
08 (-1.3, 29)
1.1 (2.1, 0)
9.0 (3.1, 14.4)

4.1 (6.6, -1.5)

¿esa

eae 8

, Change From Baseline LVMI, gim?

Correlations for Change From Baseline

NT-proBNP vs Change in LVMI

OMAVARCT © Placebo-RCT

‘Spearman's coreltion coefficient
NAVARCT (n= 56}: 04792
Placebo-RCT (a= 37) -0.0545

05 10 15 20 25 30 35 40
Ratio to Baseline NT-proBNP

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23. VALOR-HCM: Sustained Freedom From SRT Observed

at 128 Weeks in Severely Symptomatic Patients Wi

At week 128, 15.7% of patients met the composite
endpoint (7 underwent SRT, 1 SRT-eligible,
and 9 SRT-status unevaluable)

Primary Composite Endpoint Improvement in NYHA Class

NYHA class

929

8

Composite SRT cited. EN

ol ‘Decision to proceed wihSRT gq ©
L © =SRT-elgtie 58 om a
asm =SRT-saus NE sin issing value
ER Ho
Ep Ed
ihe 320
Sn abe
ay
< 0 ES BF 0
a o
Bam Wook 128 CET

METTENT

h oHCM'!
Changes in Health Status and Biomarkers
KCCQ-23 CSS

a i

> a
i
in

=

FRANSTRIRSBIEIEE

Serum NT-proBNP, ng/L. Troponind, ng/L.
s
LE]
| 5
cames À 0 Mavocamten
Pa 1 mavens Prato to mavaeamtan

NENAS
Time Since Randomization, wk

Mavacamten reduced the need for patients with highly symptomatic oHCM to undergo SRT

1. Desai MY et al Cirulotion. 2025,151:1378-1990.

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24. VALOR-HCM: Serial Echocardiography Shows Sustained

Favorable Impact on Left Atrial and Ventricular Strain’

VALOR-HCM Trial Sample

19US Sites

+ Randomized, double-blind,
placebo-controlled (N = 112)

+ Mavacamten at baseline (n = 56)

+ Placebo transitioned to
mavacamten at week 16 (n = 52)

Main LA Findings
Baseline to Week 56

Total Study Sample
Mavacamten — improved
Lavi
Mavacamten — improved

LA conduit contraction and
reservoir strain

AF Subgroup

Mavacamten — no
worsening of LA strain

Main LV Findings
Baseline to Week 56

Total Study Sample
Y Mavacamten — improved
= LV-GLS

Mavacamten — unchanged
A free-wall and 4-chamber
RV strain
LVEF 550% Subgroup

Mavacamten — no
worsening LV-GLS

Ed

Conclusions

Mavacamten improved LV-GLS, LAVI, and LA strain at 56 weeks without significant changes in RV strain,
suggesting sustained favorable remodeling and function of the LV, LA, and RV

1. Desai MY et al. Cire Cariovese Imaging. 2024:17,0017185.2.Dosai MY etal. Am Coll Codi! Ing. 2025.18:251-262.

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25. Pooled Safety Data for Mavacamten in oHCM Across 5 Trials
Over 5 Years: Well Tolerated and TEAEs Decreased Over Time!

TEAEs AEs of Clinical Interest

Patients (N= 368) > "AF mEjection fraction deceased = Heart failure
3

Patients, %

o
Day 110 Week 60 "Day 110 Wook 108” Day 1 to Week 156” Day 110 Week 204” Day 110 Wook 252
— Teas ih cate testing o (Year 1) (Year 2) (Year 3) (Year 4) Years)
death

interruption Cumulative Time Periods of Exposure

2

o ass
Seo dias Rs rose an OR ONG ats 102 1080

1. Owons À et al Gta, 2024 45O(opo 1) Absract 4194320. PeerView

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26. Participants from Change in NYHA Functional Class
a 1 D, mows Guests Moon
could enroll (N = 213);

48-week data available 1

forn=46

+ LVOTG -40 mmHg

+ vLVOTG -53 mmHg

+ NT-proBNP -63%

+ LVEF decreased from
69% to 64%

+ 82% improved by
21 NYHA class

Patients, %

0246 12 24 36 48
Time, wk Time, wk

Mean LVEF remained within normal limits at all visits

4. Saber et al JACC Heart Fe 2026:18 102496. PeerView

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27. MAPLE-HCM: Phase 3 Trial of Aficamten vs Metoprolol

in Patients With oHCM??

+ First head-to-head study of a CMI (aficamten) vs a ß blocker (metoprolol) for oHCM
+ Aim: evaluate the safety and efficacy of aficamten as 1L treatment or as monotherapy for oHCM

Aficamten Primary endpoint: change in
SOC washout + placebo for metoprolol PVO: assessed using CPET
Group 1: treatment-naive or from baseline to wk 24

currently untreated (no
medical therapy within 12 mo) een

Group 2: >12-mo history of — Patient-reported
OHCM treated with SOC health status
agents within past 12 mo — Biomarkers (NT-proBNP,
= hs-cTnl)
LUS — Remodeling (LAVI
and LVMI)
— Valsalva LVOT-G
24 weeks
of treatment
1. Garce-Pavia Pet JACC Heart Fa 202513-48-357. 2, Garci-Pava P tal, N Engl Med. 202539340060. PeerView

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28. MAPL

Uptake vs Metoprolol Monotherapy’

Mean Peak Oxygen Uptake, mL/kg/min

19

CM: Aficamt

Monother:

Peak Oxygen Uptake

Aficamten

Metoprolol

Baseline

1. Garcia-Pavia Petal. N Eng! J Med. 2025:303:949:60.

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Week 24

Improves Peak Oxygen

Change in Peak Oxygen Uptake
2

a

Least-squares
ss... mean difference
vs metoprolol, 2.3
P<.001

Mean Change in Peak
Oxygen Uptake, mL/kg/min

HAIR

2
Metoprolol Aficamten

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29. MAPLE-HCM: Improvements in NYHA Class and NT-proBNP
With Aficamten vs Metoprolol!

NYHA Functional Class According to Week NT-proBNP Level Over Time
NYHA class
su 4 Washout
750
sus $ Metoprolol
Metoprolol Aficamten e
‘Washout Washout @
100 a
© 500
so 2
a z
2° A
a Z 20
30 =
a 2 Aficamten
20 Fons
o E 81% relative difference at wk 24; P< 001
go 228 81216202628 9240 8216200028 À EL à M0 eue 2
$ Time, wk e Time, wk A Time, wk
1. Garde Pari Pet. Eng Med. 2025 368 949-060, PeerView

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30. MAPLE-HCM: Improvements in Cardiac Structure
e vs Metoprolol

Over

Resting Left Ventricular Tract
Gradient Over Time

Left Ventri

jar Outflow Tract Gradient
After Valsalva Maneuver Over Time

d Functi

Left Atrial Volume Over Time

D a 2%

D À à

Washout Mass m
so a
E ©
E © E
32 =
zee go
sE E Aiea
o 13

3° 2 ES E
ew Leastequares maan ditonnce «= EE Lorsque mean desc 3° ‘Least-squares mean diferonee
$ itt wk 298 mn 3° a 349 nmi 5 Ton
i 18 ol Peu j.

=:

6

,
# Time, wk

7166 2 à
# Time, wk

y Py
# Time, wk

Treatment with aficamten monotherapy, compared with metoprolol monotherapy, resulted in favorable
cardiac remodeling and significant improvement in LVOT gradients and LA volume

1. Garcia-Pavi Petal. N Eng! J Med. 2025:393:949:60.

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31. MAPLE-HCM: Safety Comparable Between Aficamten
Monotherapy and Metoprolol Monotherapy!

Adverse Event, n (%) eee en
Any serious AE 7 (8) 6 (7)
Any AE 65 (74) 66 (76)
Any AE that led to early treatment

withdrawal aq) so)
Any AE that led to temporary

treatment interruption 10 10
AE that led to dose reduction 1 (1) 4 (5)

+ LSM between-group difference in LVEF with aficamten treatment of -4.2 percentage points at week 24 (95% Cl, -5.3 to -3.1)
+ LVEF <50% occurred in one patient (1%) in the aficamten group and none of the patients in the placebo group

+ Most common (>10%) on-treatment AEs were URTI, hypertension (aficamten) and dizziness, URTI, fatigue (metoprolol)

“gh teas 2 marc = a to 01 R
Vta Pad Pat al Eng J ed 2025303520000 PeerView

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32. Mavacamten Monotherapy Can Improve LVO

adients,

Symptoms, and Biomarkers in oHCM'

+ In the double-blind period of a subgroup analysis

of EXPLORER-HCM, VALOR-HCM, and
EXPLORER-CN

— Mavacamten monotherapy (n = 9)
— Placebo monotherapy (n = 20)
+ Mavacamten monotherapy
— Was associated with improvements in LVOT
gradients, symptoms, and biomarkers
— Showed improvements consistent with those

observed with longer-term mavacamten +
background ß blocker or CCB therapy

— Had a comparable safety profile to mavacamten

paired with either a ß blocker or CCB

+ Further studies are needed to validate
these findings

4
1. Olvotto Letal. ESC Congress 2025. Oral presentation August 30, 2025. Madrid, Spain

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Median (IQR) Resting
LVOT Gradient, mmHg
sesez3883

Patients, n

Change From Baseline in Resting LVOT Gradient

4 MAVAMT = Placeno-MT
Median (OR) change rom baseline to Wook 30
MAVAMT: 34,7 (87.7 to 10.4) n = 6
Placobo MT: -1.5(-18.4 10 236). n= 16

Py EJ

a 4 2 ”
Study Visit, wk

Change From Baseline in NYHA Class Distribution

Mava-MT

| __ Placebo-MT

NYHA class
NYHA dass
NYHA class!

Baccino Wook 16 Week 30 Basalino Wok 16 Wook 30

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33. Rewriting the Playbook
Modern Approaches to HCM in the Era of
Disease-Modifying Therapies

34. 024 AHA/ACC Recommendations for Managing Symptoms
in Patients With oHCM!

Download the

Treatment Algorithm
B blocker or non-DHP CCB Practice Aid!

If symptoms persist

Myosin 7 :
inhibitor Disopyramide

4. Wing Commitee Members; Ommen SR tal. Craton, 2024:88:2324-2406, PeerView

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35. Need to Know Abo

Reduced LVEF DDIs can increase the
may occur risk of HF

Everyone needs to be
on the same page

+ Some CYP450 inhibitors or inducers

REMS includes a brief

Mavacamten reversibly + Strong CYP2C19 inhibitors Fe
reduces hypercontractility | |» Mod-to-strong CYP2C19 inducers CO aoa all
+ Mod-to-strong CYP3A4 inducers
A
4

+ Check medication list at every visit

Monitor LVEF + Review DDIS before initiating any new
Don't initiate if LVEF <55% Rx or OTC medication
Interrupt use if LVEF <50%, Few patients needed to switch/discontinue
i ‘medications or adjust dosing
HF sx, or worsening status (REMS )

1. Camzyos (mavacamten) Preserbing information. hips www acoosscata.a.govlnugsatfa_docstabaL2025/21409850108 pt.
2 Marinez MW et al, ACC 2024 Abstract 1075.07.

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Training is required
for physicians, pharmacists,
pharmacies, and patients

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36. Real-World Experience From
Mavacamten REMS Program Is Fulfi

Events During First 22 Months of REMS

mPatients, % (N = 5,573)

= Submitted PSFs, % (N= 29,111)

First 22 Mo

5 46
4
st
83
8
3
82
> 13
a
1 09
0.3 03 44
0 = —
LVEF <50% HFH LVEF <50% + HFH

1. Desai Metal. Cre Heart Fal, 2025:18:0012441,

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S:

ing Intended Purpose’

>6,000 patients with symptomatic
oHCM receiving commercial
mavacamten and enrolled in

the REMS program.

Among patients with 21 year of
treatment (N = 1,929)

+ 4.0% LVEF reduction to <50%

+ 1.5% HFH

+ 0.2% LVEF <50% + HFH but later
resumed treatment

Of over 52K drug interaction
checklists completed

+ 0.25% resulted in mavacamten
dose reduction

+ 0.32% resulted in discontinuation of a
‘concurrent medication

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37. Mavacamten REMS Pro:

irst 22 M

for >2/3 of Patients at 6 Months; >50% Reduced to <20 mmHg!

3

Patients, %
3853883388

o 3

Treatment With Mavacamten for 6 Months:
LVOT Gradients

1. Desai M et al. Cie Hoart Fall 2025.18:0012441.

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Baseline

Time Post-Treatment Initiation, mo

2 230 mmHg
= 220 and <30 mmHg
= <20 mmHg

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38. Avoiding and Mitigating Potential Mavaca
ug-Drug Interactions

+ Mavacamten is contraindicated for use with some CYP450 inhibitors and inducers
— Strong CYP2C19 inhibitors or moderate-to-strong CYP2C19 inducers
— Moderate-to-strong CYP3A4 inducers

+ Some of the more relevant contraindications include

— Ritonavir- or cobicistat-boosted antivirals
Download the DDI
- Omeprazole (use pantoprazole instead) Practice Aid!
— Fluoxetine, fluvoxamine (use another antidepressant instead)
= Fluconazole and other antifungals
+ Dose adjustments are needed with concomitant amiodarone use

+ Additionally, clinical experience suggests probable interactions
with alcohol and marijuana (get a thorough social history)

+ Multidisciplinary collaboration has been used successfully in a
real-world setting to assess DDIs and ensure medication access?

1. maps (mavacamton)Preszbing formation. sum cas da a oups docstaser202514998801001 A
2 Wierd etal Greunvon AA ARSS ee = PeerView

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39. ce at Cleveland Clinic

Facilities in Ohio and Florida!

+ Observational study of N = 244 adults with oHCM treated with mavacamten for 23 months

— Mean age, 64 years; 82% on ß blockers; 51% NYHA class III at entry
+ Initiated on 5 mg/d; dose titration by symptom assessment, LVOT gradient, and LVEF measurements
+ At12 weeks, real-world outcomes aligned with clinical trial results

NYHA Class Change (BL to 12 mo) Change From Baseline Over the Study Duration
NYHA Class! mNYHA Classi uNYHACBSSIII y Lver co y Post LNOT rad Posts LVOT Orient
x Diferenco-Sa7 mg. 2 owterenen 31233 mn À Pe
gor Pm E an eS a Set a
E 60 si ess Ela
ö E do
< 50 3» 4
z È ë
> 40 $ 5
& 30 5 » 3°
2 Es
g 20 Po E
3 10 H mn Fa
ES 3 se
In
Baseline 3mo 6mo 12mo Base 3° 6 12 Baseline 3 6 12
1. Deseity etal. J Am Moor Asse: 2025 Sep 1:9JAHAZOZSOAASOTT. Time, mo PeerView

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40. Next Steps for Catherine’s oHCM Treatme

Newly diagnosed with
oHCM confirmed by
echocardiography
Currently Treated With

+ Metoprolol succinate

+ Occasional naproxen use

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Following an interprofessional case conference,
Catherine is determined to be a candidate for a
CMI (mavacamten) ...

+ REMS enrollment, prior authorization

+ 4 weeks: Valsalva LVOT gradient 40 mmHg

+ 8 weeks: Valsalva LVOT gradient 35 mmHg and has
noticed more energy since starting treatment

+ 12 weeks: Valsalva LVOT gradient 29 mmHg and
LVEF 62%

+ Plan: maintain current mavacamten dose

Download the
Monitoring and

Dose Adjustments
Practice Aid! = PeerView

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41. Symposium Summary

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42. ) HCM affects all sexes, all races, and all ages in all places and can be
completely asymptomatic

Cardiac myosin inhibitors (CMIs) are the first targeted therapies for oHCM
+ Mavacamten was FDA-approved in 2022 and is available through a REMS program
+ Aficamten PDUFA date is set for December 2025

Real-world, long-term experience with mavacamten has been positive, with efficacy,
safety, and tolerability outcomes comparable to or superior to those in clinical trials

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43. Audience =?)