Adapting Managed Care Strategies in the Era of Precision Medicine for Hypertrophic Cardiomyopathy

Co-Chairs Milind Desai, MD, MBA, FACC, FAHA, FESC, and Andrew Willeford, PharmD, PhD, BCCP, discuss hypertrophic cardiomyopathy in this CME/MOC/CPE/AAPA/IPCE activity titled “Adapting Managed Care Strategies in the Era of Precision Medicine for Hypertrophic Cardiomyopathy.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/CPE/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/4bb7eKc. CME/MOC/CPE/AAPA/IPCE credit will be available until May 16, 2025.

1. Adapting Managed Care Strategies
in the Era of Precision Medicine
for Hypertrophic Cardiomyopathy

Milind Desai, MD, MBA, FACC, FAHA, FESC Andrew Willeford,
Haslam Family Endowed Chair in CV Medicine PharmD, PhD, BCCP
Professor of Medicine Assistant Health Sciences

Cleveland Clinic Lerner College of Medicine Professor

Vice Chair of Education UC San Diego Skaggs

Co-director, Cardiovascular Imaging Laboratories wa School of Pharmacy and

(CT and CMR) Pharmaceutical Sciences
Director, HCM Center y La Jolla, California
Medical Director, Aorta Center
Heart Vascular Thoracic Institute
Director of Clinical Operations
of Cardiovascular Medicine
Cleveland Clinic
Cleveland, Ohio

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

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2. Our Goals for Today

Recognize the multifaceted burdens of HCM and the
consequences at the individual and societal levels

¡|—————— Better grasp the management guidelines and treatment
data that inform HCM decision-making in a managed
care environment

———————4 Apply relevant considerations—including
pharmacoeconomics, equitable access to care, and
patient QoL—in updating HCM management protocols

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3. Sizing Up
What Are the Obstructions
to Optimal HCM Care?

Andrew Willeford, PharmD, PhD, BCCP
Assistant Health Sciences Professor

UC San Diego Skaggs School of Pharmacy and
Pharmaceutical Sciences

La Jolla, California

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4. What Is Hypertrophic Cardiomyopathy?"

V wall thickness of mol mm in individuals with a family histor

or in conjunction with a positive genetic test is diagnostic for HCM

+ Wall thickness that is not explained by abnormal loading conditions
— 2/3 of cases are obstructive, 1/3 nonobstructive
— 13-14 mm if family history

+ Most common inherited cardiomyopathy

— Most common variants are in myosin heavy chain and myosin binding
protein c (MYH7, MYBPC3)

Symptoms include dyspnea, fatigue, chest pain, palpitations, and syncope
+ Associated with elevated risk for arrhythmias, heart failure, sudden cardiac death

4. Ommen SR et al. J Am Coll Caro. 2020:76:6159-6240. 2. rbeloE etal; ESC Scientific Document Group. Eur Heart J, 2023:44:3509-3628, PeerView.com

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

Disparities in treatment
and in-hospital mortality
have been documented
by sex, race, insurance
patients Shoes status, rural location,
region of the country,
hospital size, and hospital
nonprofit status25

Y
Underdiagnosis and undertreatment®

+ Estimated prevalence of HCM is 1:500 (based on disease phenotype
by imaging)

+ HCM is not rare but clinically underdiagnosed by a factor of almost 3x

+ Potentially affects -700,000 Americans

1.Rowin E ot al J Am Heart Assoc. 20198:0012041. 2. Maron BJ tal. J Am Col Carl 2022,70:372.309.3. Nusi NAB, Stwa K. J Am Col Cardo 202178:2573- fa
2579.4: Ho CY etal. Crculaton. 2018;138:1387-1998. 5. Massera D eta. Int J Cardo. 2023;382:64-87. 6. Johnson DY etal. JAm Heart Assoc. 2023:12-e029030. PeerView.com

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6. Download the

oHCM vs nHCM: Anatomy? Practice Aid!

Possible
obstruction
or cavity
obliteration

LVOT
gradient 230
mmHg?

Normal

Without With

Obstruction Obstruction Midcavity Apical

*Papilay muscles not shown in al images. * The diagnoste threshold for OHCM or latent OHCM i a resting or Valsalva LVOT gradient 230 mm, gi
1. hips./ähem org. 2 Ommen SR ot al Crculaion. 2020:142.0858.0631 PeerView.com

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7. Most Frequently Reported Symptoms of HCM!

HCMA Voice of the Patient Survey

28.8% Symptoms may fluctuate daily
+ Activity
16.7%
14.7% ‘eae
i Il :

Shortness Exercise Lightheadedness/ Arrhythmias/ Chest pain!
of breath intolerance dizziness/fainting _ palpitations pressure
1. ps them orp wp-contentiploads/2021/06VValesofhe-HOM: patent RopornalJanuay-9:2021 pat PeerView.com

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8. Treatments for HCM14

Potential outcomes of HCM |

+ AV nodal

Symptomatic
LV outflow AF

nd stroke

Advanced

tract HE

obstruction

+ RF ablation

* GOMT for HEFEF includes: ACEIS/ARBS or ARNI, beta blockers, SGLT24, MRA, and diuretics as needed +
4. Adapted om Maron BJ et al JAMA Cord. 2016.1.98-105. 2. Ommen SR ota. Creulaton. 2020.142:6558-0631. 3. AlsulamiK, Marston S. Int J Mole Sel
2020.21:9599. 4. Heidenreich PA ot al. Am Coll Cardiol. 2022.9:0263-0421. 6, Sawan MA etal. Clin Cardo! 2023:47:¢24207,

6. Zhu Metal. J Am Col Cardo: Advances. 2023/2:100622.

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Download the
Practice Aid!

Conventional medications
for HCM

+ Have not been evaluated in
prospective RCTS

+ Are not disease-modifying

Mechanical reduction of
obstruction for persistently
‘symptomatic oHCM

+ Septal myectomy

+ Alcohol ablation

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9. Introducing Angelica, A Woman Aged 59 Years With oHCM

Angelica

Diagnosed 3 years ago
NYHA class III, LVEF 65%, LVOT gradient > 80 mmHg, mitral value regurgitation

Experiences shortness of breath, chest pain, and functional limitations
(eg, unable to tie her shoes, be on her feet for more than 3 hours)

Despite her HCM diagnosis, she does not qualify for disability
She fears that her health challenges and frequent absences
will cause her to lose her job

Annual visits to an HCM center require 2 days off from

work for her and her partner with out-of-pocket

travel costs

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10. Catching Up
Are Current Guidelines & Policy
Recommendations Aligned With the
Latest Evidence for Managing HCM?

Milind Desai, MD, MBA, FACC, FAHA, FESC

Haslam Family Endowed Chair in CV Medicine
Professor of Medicine
Cleveland Clinic Lerner College of Medicine
Vice Chair of Education
Co-director, Cardiovascular Imaging Laboratories (CT and CMR)
Director, HCM Center Le
Medical Director, Aorta Center of
Heart Vascular Thoracic Institute %
Director of Clinical Operations of Cardiovascular Medicine
Cleveland Clinic
Cleveland, Ohio

/

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11. Angelica’s Treatment

Angelica

Diagnosed 3 years ago Currently treated with

ee eng. au — Losartan (50 mg/day)
regurgitation ins

Experiences shortness of breath, chest — Amlodipine (10 mg/day)

Bein) end functional imitations — Metoprolol XL (100 mg/day)

Despite her HCM di: is, she de " te n
Et ay Di sabi m Previously treated with disopyramide but found

She fears that her health challenges side effects intolerable
and frequent absences will cause her . à a
to lose her job How does Angelica's treatment align with the

Annual visits to an HCM center require ?
2 days off from work for her and her standard of care?

partner with out-of-pocket travel costs Is this treatment regimen serving her well?

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12. Treating Symptomatic HCM:
2020 AHA/ACC Current Guidelines!

Nonobstructive HCM
With LVEF 250%

Nonobstructive HCM
With LVEF <50%

Obstructive
HCM

B-blockers, diltiazem,
or verapal

+ GDMT per HF guidelines

er B blockers, diltiazem, + D/C diltiazem, verapamil, aan
Bein or verapamil and/or disopyramide chen u
gp consider Ic) Avoid vasodilators
+ Diuretics
Second Apical myectomy, in highly + CRT, in selected patients? Add disopyramide
line selected patients + Heart transplant, SRT (myectomy
Heart transplant, in highly in selected patients? or alcohol ablation)

selected patients?

{NYA ase HV and LBBB WA class HA escu vrs rs «For part ih EM and severe son ars. pets,
or vary high resing radients (eg, 100 mmHg), as wel as lf chidron aged <6 weeks, verapami is potentially harm À
Y Onmon SR tal reunion 2020420088 081.2 Ron EJ oral Gre Hoon Fi. 20147907975, PeerView.com

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13. 2023 ESC Guidelines: Treating oHCM!

Resting/provocable LVOTO 250 mmHg

B blockers or
verapamil may
be considered

B-blockers (Class |) (Class IIb)

Still symptomatic or intolerant/contraindication to B-blockers

Verapamil (Class I) OR Diltiazem (Class I)

Still symptomatic

Disopyramide (Class |) OR Mavacamten (Class lla,

Still symptomatic

Class I: Recommended or indicated
anal Septal reduction therapies (Class !)

Class llb: May be considered .
Eur Hoar J. 2023:44:3508-2626, PeerView.com

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14. Expert Centers Have Markedly Better SRT Outcomes,
But Access to Specialty Centers Is Limited’

Myectomy Ablation

Gradient <10
PPM 1%-2%
Mortality <1%
LOS 5 days
Pain ++
Return to activity Weeks
Symptoms Improved
Reintervention <2%
Late SCD Very low
Long-term survival Good

<25
5%
1%-2%
2-4 days
+
Days
Improved
7%-10%
Low
Good

1,600:
1,400:
1,200:
1,000:
800
600
400
200

0

Consecutive Myectomies

6

Low
volume

Without a Death
>1,500
-10 ~26
Middle High Expert
volume volume centers

1. Ommen SR. 70th Annual Scontife Session & Expo ofthe ACC 2022. Oral presentation: 683-11.2. Mentias A et al. JAm Col Cardio, 2023:81:105-115.

3. Ashraf Metal. Am J Cardiol 2023:191:51-8,

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15. Better Mortality Outcomes for SRT and Alcohol Septal
Ablation in High-Volume vs Low-Volume Centers‘?

Mortality Hazard Ratio as Function of Mortality Hazard Ratio as Function of
Annualized SM Center Volume Annualized ASA Center Volume
12
10
= 10 RES SS
= S
sg ES 95% Cl
ES 0.6 95% Cl 208
& x
zZ Ed Mean
É 04 Mean 06

use 95% CI

o 20 40 60 o 2 4 6 8 10
Annualized Volume of SM Annualized Volume of ASA

js were reported in a larger study of dispar in surgical outcomes in community hospitals?

Unfortunate Healthcare Reality

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1.Mentas A etal. J Am Col Card. 2023/81:108-115. 2. Ashral Meta. Am J Cardo, 2023:191:51-58,

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16. Family History Affects Angelica’s Treatment Preferences

Angelica

Diagnosed 3 years ago
NYHA class Ill, LVEF 65%, LVOT
gradient > 80 mmHg, mitral value + Acousin with a similar history underwent SRT

regurgitation E
+ Experiences shortness of breath, chest for his oHCM

PEAS os os + During the perioperative period, the cousin

Currently treated with A rs nat
he) suffered a stroke with significant complications
= Amlodipine (10 mg/day) + Angelica is adamant about avoiding an invasive
= Metoprolol XL (100 mg/day) procedure

Previously treated with disopyramide

but found side effects intolerable

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17. Pre-CMI Medical Treatment Options’

Overall, Studies Detailed in Guidelines Are of Low Level of Evidence

2022
1960s-1970s 2000s-2010s
Mavacamten
B blockers Disopyramide earn
1970s-1980s 2020 2023
Calcium channel AHA/ACC HCM ESCHCM
blockers guidelines guidelines

Despite guideline recommendations, medications traditionally used to treat oHCM
(eg, B blockers, calcium channel blockers, disopyramide)

+ Do not target the disease process
+ May not provide sufficient symptom relief

+ Are often poorly tolerated
+ Their use is based on studies that are underpowered, not randomized, with short follow-up,
and mixed results

1.Sawan MA et al. Gin Cardiol. 2023:47:024207. 2. Zhu M et al. J Am Coll Cardio; Advances. 2023:2:100622. PeerView.com

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18. Back to Angelica

Angelica

Diagnosed 3 years ago A cousin with a similar history underwent SRT
NYHA class Ill, LVEF 65%, LVOT for his oHCM
gradient > 80 mmHg, mitral value

regurgitation During the perioperative period, the cousin
BETETE SENTE suffered a stroke with significant complications

pain, and functional limitations

Currently treated with Angelica is adamant about avoiding an invasive
— Losartan (50 mg/day) procedure
— Amlodipine (10 mg/day) a 7 a
= Metoprolol XL (100 mg/day) She might be a candidate for treatment with

Previously treated with disopyramide a CMI, but she wants to know more about
but found side effects intolerable this novel class

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19. Small-Molecule Myosin Inhibitors
Approved or Being Evaluated for HCM in Clinical Trials

Mavacamten!3
US FDA-approved for symptomatic NYHA Aficamten24
class II-Ill obstructive HCM to improve Investigational agent
functional capacity and symptoms

Half-life: 6-9 days Half-life: 2.8 days

1. htos:fpubchem ncbinim ni govicompoundiMavacamten 2. Chuang Cet a. J Med Chom 2021.64:14142-14182,
3. Camayos (mavacamten Proserbing Intomaton. hips acosada Ida govcnugsatfi. oca1abe12023214008800 1 pt N
4. ns /pubchomncbinim nih gov/compoundlAfcamten. PeerView.com

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20. Small-Molecule Cardiac Myosin Inhibitors Targeting HCM

Mavacamten: reduces myosin head availability; stabil
super-relaxed state’? sem

Unlike previous medications
used in HCM, CMls are?

CLS
E + Designed as potentially
disease-modifying treatments

a i ch i j Fi Eu ji specifically for HCM
camten: slows phosphate release from myosin; stabilizes weal Sri daa

ctin-bindi in conformation’?
actin-binding myosin conformation tn
controlled trials

ï
if
Ww

E

z

E

1. Thu Owens A. ACC 2022. Oral presentation: 683-6102. Lohman Se a. Nat Rov Cardo! 202219:353-363, —
3. AlsulamK. Marston 8. Int J Molec Sol. 2020219699. PeerView.com

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21. EXPLORER-LTE Cohort of MAVA-LTE:
Study Design and Schedule of Assessments’

+ MAVA-LTE is an
ongoing, 5-year study
to evaluate long-term
safety and efficacy of
mavacamten

+ Participants are
patients with oHCM
who completed the r

Screening 28 days.

pivotal EXPLORER- Time, wk 4
HCM trial
Mavacamten
+ Safety and tolerability à = DA AA
profile was consistent X
with EXPLORER- NT-proBNP . . . . Y as à %
HCM findings TE . Ed he
NYHA

functional class

1. Rader F et al. JACC Heart Fall 2024:12:164-177 PeerView.com

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22. Interim Results From the EXPLORER-LTE Cohort
of MAVA-LTE: LVEF and NYHA'

NYHA Functional Class Change From Baseline in
NYHA Functional Class

LVEF

e OF 2 Conta taboratory valo # .
$ $ $8 we mo | H
ên CRE | É
go ye 3
a $ $
En he H
ss She nbomeyus & È
atthe s&s a © mm 65
Time, wk >] 15
pisos! BL Week 12 Week 48 Week 12 Week 48
—- 200212212199208 215 209 197 sai 100 0. (n=231) (n=192) (n= 206) (n= 192) (n= 206)
a D 2% OU er M Gus! 1 improved by 2 classes
M Class il I improved by 1 class
M Class Il! M Remained the same
IE Worsened by 1 class
|B Worsened by 2 classes
pastview:
1. Rader F et al. JACC Heart Fail, 2024;12:164-177. ‘eerView.com

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23. Interim Results From EXPLORER-LTE Cohort of MAVA-LTE:
Durable Improvements in Resting LVOT and Valsalva LVOT!

Resting LVOT Gradient

«2

Resting LVOT Gradient,
Mean + SD, mmHg

‘Site laboratory value

»
7
wo] 2! vs
188 Contra laboratory value
me ns
a a as

=

ion À EJ 8 $0 72
Time, wh
No, at Risk
ME 20 27 2 ur 1
© HMS 20 A7 25 US 16

1.Rader F et al. JACC Heart Fall 2024:12:164-177.

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y

Mean + SD, %

Valsalva LVOT Gradient,

Valsalva LVOT Gradient

m
10
so
= antral abortory value
Ll Fr 2 ns ns
2 m» mM
»
o
RE nw ao À à
Time, wk
No thik
mnt m mm er
“mw m 27 2 M er

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24. EXPLORER-HCM: Mavacamten Was Associated
With a Substantial Mean Improvement in KCCQ-OS'

Is Reporting Mean Difference of Change in KCCQ-OS Scores
307] PARTNER
2500
257 °
añ Remaining Questions EXPLORER-HCM
g Ho PARTNERS
8 Long-term safety 9.1 (95% Cl, 5.5-12.8) PARTNER2 16.00"
CM Hi ®
8 ATTRACT 1590"
& 107 Pace a
E , FARE 949"
6 54 Ro TOC PAE SU ue o
€ var “ee Deren
i, + * mofrcnr ° Heatrion 270
a 150 193
. + 086 o A
pcom TI
-5+ 20 20
107

1. Sportus JA ot al. Lancet. 2021.397:2467-2475,

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25. VALOR-HCM Study Design: Does Mavacamten Offer
an Alternative to SRT in Severe oHCM?'

Blinded active placebo to
mavacamıen crossover treatment

10,5,0r25 mg | [15. 10. 5,0125 ma

Titration allowed if LVEF <50% or
persistently elevated LVOT gradients

Titration at weeks 24 and 28 in placebo
‘crossover group

1. Desai MY ot a. JAMA Caro. 2023:8-068-977. PeerView.com

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26. Mavacamten Reduces Eligibility for Surgical Intervention
for oHCM in Late-Stage Disease: VALOR-HCM Phase 3 Study’?

VALOR-HCM Crossover Trial: Primary Outcome

Septal Reduction Therapy Composite Outcome

60

40

Patients, %

20

Original Mavacamten Group (n = 56) Placebo to Crossover Mavacamten Group (n= 52)

Baseline mWeek 16 mWeek32 mWeek 56
1..Desai MY eta. Circulation. 2023:147:850-863. 2. Desai MY et al. JAMA Cardiol 2023:8:968-977. PeerView.com
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27. Mavacamten Reduced LVOT Gradients in Patients With
oHCM and Late-Stage Disease: VALOR-HCM Phase 3 Study!

LVOT Gradient at Rest LVOT Gradient After Valsalva Maneuver

8
3

Placebo-to-mavacamten

8

3

Placebo-to-mavacamten

3

3

3
8

Mavacamten
Mavacamten

Peak LVOT Gradient at Rest, mmHg
a
3

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Peak LVOT Gradient After Valsalva, mmHg

o
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
Time Since Randomization, wk Time Since Randomization, wk

1. Desai MY et a. JAMA Carol. 2023:8:968-977. PeerView.com

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28. VALOR-HCM: Selected Safety Endpoints at 56 Weeks!

Safety Ende ome “on
Exposure) Exposure)
n=52,n(%) n= 56,n(%)
Permanent study drug.
Bes
+» LVEF <30% 2(38) o
* Two consecutive LVEF 1(19) o
measurements of <50%
despite dose reduction to
25mg
‚One temporary interruption
for LVEF (>30% to <50%) 268) 029)
E 7125)
Cc dot su o
Hospitalization for HF 1(1.9) 0

patients with LVEF

at a lower dos

Total
Mavacamten

983)

42 (11.1)

LV Ejection Fraction

Placebo-to-mavacamten

& 604 Mavacamten
$
2 50
Original placebo (40-wk exposure) -4.0 (95% Cl, -6.1 to -1.9)
nal mavacamten (SO exposure) 4 0 (85% 158025)
“o
20
0 4 8 12 16 20 26 20 W206 do da de 82 SO
No. at Risk Time Since Randomization, wk
Proctor 6 54 54 82 82 . 2 3

Maracamten 96 56 55 56 55 se . ss

nptomatic and able to resume mavacamten

after temporary interruption

1. Desai MY ot a. JAMA Cardio. 2023:8:968-977.

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29. Mavacamten Improved NYHA Class in Most Patients With
oHCM in Late-Stage Disease: VALOR-HCM Phase 3 Study’?

VALOR-HCM Crossover Trial: Results at 56 Weeks

Proportion of Patients With NYHA Class Improveme:

80

60

40

Patients, %

20

Original Mavacamten Group (n = 56)

Placebo to Crossover Mavacamten Group (n= 52)
56-Wk Exposure

40-Wk Exposure
m Atleast 1 class mAtleast2 classes

1. Desai MY et al. Circulation, 2023:147:850-863. 2. Desai MY etal. JAMA Cardio. 2023:8:968-977. PeerView.com

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30. EXPLORER-CN: Mavacamten Is Efficacious and Safe
in a Chinese oHCM Population’

+ 81 patients randomized (54 mavacamten, 27 placebo)
+ Mavacamten starting dose was 2.5 mg due to lower mean body weight and higher prevalence of poor
CYP2C19 metabolizers among the Chinese population

Mean Resting LVOT Peak

Mean Valsalva LVOT Peak

Br Gradients Over Time 2 Gradients Over Time

Eu 100

Emo =

€ 5 ©

po Placebo 3 Placebo

ge 3°

io Mavacamten É y

5 ©

go 3

a 22%

22 g

3 3 Mavacamten

= 0 7 go = an

Er 2 w mae 90 Beem 15 m 1 Zu20 ©
Time, wk Time, wk

100

Patients, %
588582388

o

NYHA Functional Class

Mavacamton (n= 54) Placebo (n = 27)

IGess 1 Class 1 MCIass I Missing

+ Mavacamten doses were 10 mg (30%), 5 mg (59%), and 2.5 mg (11%) at 30 weeks
+ No patients reported LVEF <50% and no notable cardiotoxicities were recorded

1. Tan Zei al. JAMA Carlo. 2023:8957-965

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31. Patients with oHCM
treated with SOC
with resting LVOT-G
230 mmHg and
post-Valsalva Peak
LVOT-G
250 mmHg and
NYHA class I/II

Aficamten + SOC

Study visits Screen vi IM AM ee €
Echocardiogram a A At Cane Cy Cl à à à à a
CPET a a
Keca NARA RRR RR a
NYHA a A A A OA kk à à à a
Dose titration Rit A
FES CS eat AE oo Fas, 202412100216 PeerView.com

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32. Topline SEQUOIA-HCM Results!

+ According to data released by the manufacturer, aficamten use
was associated with significant change in peak oxygen uptake
from baseline to week 24

— Least square mean difference in peak oxygen uptake of 1.74
(95% confidence interval, 1.04 - 2.44; [P = .000002] mL/kg/min
relative to placebo)

« Outcomes on secondary endpoints included
— Statistically significant improvement in KCCQ-CSS at weeks 12 and 24
— Improvement 21 NYHA functional class at weeks 12 and 24
— Change in guideline eligibility for SRT

+ These findings have not yet been published in a peer-reviewed journal or
presented at a meeting

1. ips www hnepive.comiviewicytokinetics-announces-positve-topline-datafor-aicamten-n-sequoia-hem. PeerView.com

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33. Where Do Cardiac Myosin Inhibitors Fit
in the Management of oHCM?1-8

Functional capacity improves with mavacamten
whether or not B-blockers are used

Treat comorbidities

Avoid vasodilators Bblockade MAMAS
First-line and diuretics Mavacamten?** Download
therapies = (EXPLORER-HCM) the Practice
Verapamil 1

Re-evaluate or diltiazem

‘Symptoms with NYHA class IV or Il with near or

exertional syncope on maximally tolerated therapy? Disopyramide»

Surgical candidate? FES Mavacamten””
Advanced MEETS Surgical candidat SRT willing rs

therapies
Other indication

Myectomy or ablation | Still SRT eligible?

+ Mavacamon is à frsti.cios cardiac myosin inhibitor hat was FDA approved ater 2020 AHAIACC guidelines wre published fr further infomation on ths agent.
‘ease reer tos preserbng infomation « AHATACC guidelines do ot stpulate NYHA dass or maximal therapy

1. Ommen SR. ACC 2022. Oral presentation: 683-6112. Olvoto | et al. Lance. 2020.39659.769. 3. Camayos (mavacanten) Prescrbing Informatio.

ps www accosedata fa. govirugstida.docafabal202372 4908500 1 dA. Wheeler MT ota. Eur J Hoar Fal, 202225260210, 8. Desa MY eta J Am Col en

Cardiol 2022:00:95-108. 6, Arbelo E etal; ESC Scientific Document Group. Eur Heart J 2023:44:3503-3628, PeerView.com

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34. What's Next for Cardiac Myosin Inhibitors?12

Phase 3 Clinical Trial Milestone Dates

MAVA-LTE (MAVERICK-HCM [nHCM] and EXPLORER-HCM [oHCM] cohorts; mavacamten vs placebo), NCT03723655

as

VALOR-HCM (phase 3, oHCM, mavacamten vs placebo), NCT04349072

Oey
ODYSSEY-HCM (phase 3, nHCM, mavacamten vs placebo), NCT05582395

o—————2

SEQUOIA-HCM (phase 3, oHCM, aficamten vs placebo), NCT05186818

0
MAPLE-HCM (phase 3, oHCM, aficamten vs metoprolol succinate), NCT05767346
O>-—— ———$
ACACIA-HCM (phase 3, nHCM, aficamten vs placebo), NCT06081894
—
2018 2019 2020 2021 2022 2023 2024 Â 2025 2026 2027
We are here
1. tips cinicalial gov, 2, hiips:Jwwwthepharmaleter.comlarticlefadaptable-approach-augurs-wellorcytokinetics-even-afte-a-t. PeerView.com

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35. What You Need to Know About the Mavacamten REMS'2

MATA - Mavacamten reversibly reduces a ER menlonngleneeded

Pr Don't initiate if LVEF <55%
may occur ie el) + Interrupt use if LVEF <50%

+ Some CYP450 inhibitors or inducers =]

+ Weak CYP2C19 inhibitors de
+ Moderate CYP3A4 inhibitors Y

Everyone needs u
Sr th + REMS includes a brief training : ES, pharmacists,
e on tne program for all key stakeholders pharmacies, and patients al
same page require training

|: Camps (racimo) Pre nornan, pss acest a goign doatael 2029245060018 5 —
2. Martinez MW ot al. Abstract 1075-07. Presented at ACC 2024 PeerView.com

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36. Mavacamten Requires Ongoing Echocardiography
to Monitor Cardiac Structure and Function

Prior to 4 weeks 8 weeks 12 weeks 4 weeks Every 3

initiating after after after I after months once

therapy initiating initiating initiating every dose a stable dose
therapy therapy therapy | increase is achieved

Mavacamten is associated with substantial net health benefits for patients with symptomatic
obstructive HCM, including improved symptoms and QoL!

However, the imaging burden should be discussed with patients before initiating therapy?

1. Desai Net al. Cin Thor 2022:44:52-6, 2. Alb A et al. Curr Cardo! Rep. 2023;25:589-586. PeerView.com

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37. Avoiding DDIs!

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

+ Some of the more prominent DDIs include
— Nirmatrelvir with ritonavir (contraindicated)

Download the
Practice Aid!

Omeprazole (use pantoprazole instead)
— Cimetidine

Fluconazole and other antifungals

— Amiodarone (dose adjustment needed)

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

1. Camzyos (mavacarten) Prescrbing Information. ts: www accessdata ia.govidrugsatita_docs/abel2020/214998800'Ib pl PeerView.com

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38. Angelica Wants to Try a CMI

Angelica

Diagnosed 3 years ago
NYHA class Ill, LVEF 65%, LVOT

Gradients 80 mig miei valle + After discussion with members of her

regurgitation healthcare team, including evaluation by her
Experiences shortness of breath, chest cardiologist and a pharmacist, Angelica is

pain, and functional limitations 5 ri
Cnty wessen indeed a candidate for mavacamten
— Losartan (50 mg/day) + REMS enrollment ensues, prior authorization
— Amlodipine (10 mg/day) is sought
— Metoprolol XL (100 mg/day)
+ What next?

Previously treated with disopyramide
but found side effects intolerable

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39. Patient Counseling Considerations for Mavacamten!

+ Patients should be counseled on
— Recognizing and responding to symptoms of HFrEF

— The need for echocardiography to monitor response
to therapy

— The need to inform healthcare professionals of any
prescription or OTC medications or supplements they use (eg, PPIs)

— The need to adhere to the REMS requirements

— Potential fetal risk and the need for effective contraception during and for
4 months after mavacamten use

+ Nurse navigator and medication access information is available at the
manufacturer’s patient website

1. Camzyos (mavacarten) Prescrbing Information. hitps www accessdata.ida.govierugsata_docs/label2023/2149988001 pl. PeerView.com

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40. Summing Up
What We've Learned About CMIs
From Real-World Experience

Milind Desai, MD, Andrew Willeford, PharmD,

MBA, FACC, FAHA, FESC PhD, BCCP
Cleveland Clinic Lerner College Assistant Health Sciences
of Medicine Professor

HCM Center UC San Diego Skaggs

Heart and Vascular Institute School of Pharmacy and
Cleveland Clinic Pharmaceutical Sciences

Cleveland, Ohio I La Jolla, California

Copyright © 2000-2024, PeerView

41. Real-World Experience at a Tertiary Care Center’

+ Prospective, observational study of 150 consecutive adult patients with
persistently symptomatic oHCM treated with mavacamten

+ Mean age, 65 years; 83% on ß blockers; 61% NYHA
class Ill at entry

+ Initiated on 5 mg/d; dose titration Mavacamten Number of patients
by symptom assessment, LVOT gradient, eee eee (0%)
and LVEF measurements oe > ED
Mm
+ At 12 weeks, real-world outcomes were Ema y 80 (53%)
comparable to trial results (ie, functional
een r 10 mg 37 (25%)
gains, improved LVOT gradients, and Ba 3 (2%)
reduced eligibility for SRT)
* Cleland Clic à
1. Desai MY ot al. Prog Cardiovase Dis. 2024:50033-0620(24)00022:7 [Epub ahead of print. PeerView.com

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42. Changes From Baseline: NYHA Class and Resting and
Valsalva LVOT Gradients’

NYHA Class Change From Baseline to 12 Weeks

"NYHA Class! mNYHA Class Il mNYHA Class Il
61

70
60
50
40
30
20
10

56 60

Patients By NYHA Class, %

Baseline

4Weeks 8Weeks 12 Weeks

At last follow up

+ 46% reported an improvement in at least
1 NYHA class

+ An additional 18% reported an
improvement in at least 2 NYHA classes

+ 27% reported no change in symptoms

Change From Baseline Over the Study Duration

LVEF Resting

Valsalva LVOT
Gradient

0 4 8 2 “9 4 8 92
Time, wk

1. Desai MY eta. Prog Cardiovasc Dis. 2024;$0083-0620(24)00022-7 [Epub ahead o print,

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Time, wk

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43. Safety and Tolerability Findings’

Only 2% of patients required
temporary interruption of mavacamten
due to LVEF <50%

Low rate of interruptions suggests that
echo monitoring may not need to be
as frequent as the trial data indicated
No patients underwent SRT,
developed LVEF <30%, or developed
heart failure requiring admission

22% of patients could reduce or
eliminate use of background HCM
treatment, potentially minimizing AEs
of B blockers and disopyramide

1. Desai MY et al. Prog Cardovase Dis. 2024;80033-0620(24)00022:7 [Epub ahead of print

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These results are possibly attributable

to symptom- and gradient-driven

titration, rather than the automatic,

algorithmic dose titration of the clinical

trial protocols

- In EXPLORER-HCM and

VALOR-HCM, titration began at 8
weeks vs current clinical
recommendation of 12 weeks

ER

ÈS

(
=

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44. Considering Patient Out-of-Pocket Costs’

+ After REMS enrollment, DDI, and safety assessments, potential
out-of-pocket costs were discussed with patients
+ Patient insurance coverage
— Commercial insurance: 54%
— Commercial insurance + Medicare: 21%
— Medicare: 21%
— Medicaid: 3%
— Military: 0.6%
+ Mean copay: $16 (range $0-$427}
— 69% had a monthly copay of $0; 25% had a monthly copay of $10

* Data avaiable for 108 patents ñ
1. Desai MY otal. Prog Cardiovasc Dis. 2024:50033-0620(24)00022:7 [Epub ahead of prin) PeerView.com

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45. Overall Observations on Operationalization!

+ While achievable, real-world use can involve logistical
complexities outside of the REMS and prior
authorization requirements

Download the

Practice Aid!

Although all were initially evaluated at Cleveland Clinic
facilities in Ohio and Florida, patients reside in 15 states
and the District of Columbia

+ 35% of patients used local practices for their follow-up
echocardiograms

+ Nine different specialty pharmacies dispensed the drug

+ All patients had access to mavacamten

1. Desai MY et al Prog Cardiovasc Dis. 2024;80033-0620(24)00022-7 [Epub ahead of print, PeerView.com

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46. Multidisciplinary Mavacamten Workflow: A Template’

This multidisciplinary workflow has been used successfully in a real-world setting
and has efficiently addressed cost limitations for most patients considering mavacamten

Physician assesses patient for initiation Nurse / Echo Coordinator orders weeks
with mavacamten 4,8, and 12 echos,
+ +" “Use echo dat calculator
+ Create echo due dato reminders

dinar — drug interactions Download the
a raception
y & | Pharmacist/ Physician assesses practica Aid]
Pharmacist counsels patient using the 2 echo
EMS brochure and enrolls patient into the H dificil
'REMS program online El y
dei 33 [Pharmacist calls the patient
E | 5: |. ‘assess symptoms and adverse events
Pharmacist / Nurse enrolls patient into ieee] + Assess now drug interactions
Support programs and submits prior 8°]: ‘Submit REIS patent stats form
authorization & cine
a 2

Pharmacist checks approval and cost
Nurse / Echo Coordinator orders

follow-up echocardiograms

+ Reterto Pl for cho timing

+ Use echo dato calculator

Pharmacist discusses cost and sets
treatment start date with patient

1. Wileford A et al. culation, 2023:148:A15509. PeerView.com

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47. Take-Home Messages

oHCM symptoms (eg, dyspnea, fatigue, chest pain) can limit patients’
functional abilities and markedly reduce QoL

+ Current guideline recommendations for oHCM management reflect
underpowered studies with short follow-up and mixed results

+ First-line, nonselective approaches (eg, beta-blockers, calcium-
channel blockers) are often insufficiently effective and poorly tolerated

+ Septal reduction therapy can be effective and safe—but is best
performed in a limited number of high-volume institutions

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48. Take-Home Messages, continued

+ Cardiac myosin inhibitors are the first disease-modifying therapies
for oHCM
— Mavacamten was FDA-approved in 2022 and is available through a
REMS program
— Aficamten completed its first phase 3 trial in 2023
+ Real-world experience with mavacamten has been positive, with
efficacy, safety, and tolerability outcomes comparable or superior to
those in clinical trials
+ Successful oHCM management depends on implementing an effective
multidisciplinary workflow and incorporating shared decision-making
u into treatment selection

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