Conditions: Primary Familial Dilated Cardiomyopathy
Keywords: Primary dilated cardiomyopathy (DCM) Familial dilated cardiomyopathy (DCM) Myosin Heavy Chain 7 (MYH7) Titin (TTN) MYK-491 danicamtiv
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 41
Healthy volunteers: no

Brief summary:
The purpose of this Phase 2a study is to establish safety and preliminary efficacy of treatment with danicamtiv in patients with primary dilated cardiomyopathy (DCM) due to MYH7 or TTN variants or other causalities.

Detailed description:

Arms:
arm 1: Primary DCM due to MYH7 or TTN Variant or due to other causalities not related to MYH7 or TTN variants

Interventions: intervention 1: danicamtiv
Intervention descriptions: intervention 1: Myosin activator

Protocol document:
Prot_SAP_000.pdf: 
Official Title of Study: 
An Open-Label, Exploratory Study of the Safety and Preliminary Efficacy of Danicamtiv in Stable 
Ambulatory Participants with Primary Dilated Cardiomyopathy due to either MYH7 or TTN Variants or 
Other Causalities 
 
 
NCT Number: NCT04572893 
Document Date (Date in which document was last revised): 28 Aug 2023 
 
 
 


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CLINICAL STUDY PROTOCOL 
Protocol Number: 
MYK-491-006 (CV028005) 
Study Title: 
AN OPEN-LABEL, EXPLORATORY STUDY OF THE 
SAFETY AND PRELIMINARY EFFICACY OF 
DANICAMTIV IN STABLE AMBULATORY 
PARTICIPANTS WITH PRIMARY DILATED 
CARDIOMYOPATHY DUE TO EITHER MYH7 OR TTN 
VARIANTS OR OTHER CAUSALITIES 
Brief Study Title: 
A Phase 2a Exploratory Study of Danicamtiv in Participants 
with Primary Dilated Cardiomyopathy 
Indication: 
Primary Dilated Cardiomyopathy due to MYH7 or TTN 
Variants or Other Causalities 
Phase: 
2a 
Investigational Medicinal 
Product: 
Danicamtiv (MYK-491; BMS‑986434) 
Sponsor: 
MyoKardia, Inc.  
1000 Sierra Point Parkway 
Brisbane, California 94005 USA 
IND Number: 
131452 
EU CT Number: 
2023-505492-68-00 
Coordinating Investigator: 
Key Sponsor Contacts: 
Clinical Operations, Study Lead 
Clinical Development, Medical Monitor 
Original Protocol Date:  
15 October 2019 
Amendment 1 
12 August 2020 
Amendment 2 
11 January 2021 
Protocol Clarification Letter 
08 Feb 2021 
Protocol Clarification Letter 
10 June 2021 
Protocol Clarification Letter 
24 Aug 2021 
Amendment 3 
11 March 2022 
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Protocol Clarification Letter 
09 May 2022 
Protocol Clarification Letter 
30 June 2022 
Amendment 4 
20 December 2022 
Administrative Letter 06 
01 March 2023 
Amendment 5 
28 Aug 2023 
 
Confidentiality Statement 
This document contains trade secrets or otherwise confidential and/or proprietary information of MyoKardia, 
Inc. Access to and use of this information is strictly limited and controlled by MyoKardia, Inc. Acceptance of 
this document constitutes agreement by the recipient that the contents will be not be copied, distributed, or 
otherwise disclosed to third parties, and will not be used in any way, except as expressly authorized by 
MyoKardia, Inc. 
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 5: 
Overall Rationale for the Amendment 
The purpose of this protocol amendment is to update the language around prohibited usage of drug 
classes, define flexibility around performing unscheduled procedures that support safety 
monitoring, add guidance of temporary discontinuation of study drug (danicamtiv) in case a short 
duration of a strong CYP3A4 inhibitor is expected to provide significant benefit for participants, 
and add a process to resume study drug after temporary discontinuation. Updates were also made 
to align with European Union (EU) Clinical Trials Regulation (CTR) requirements.  
Administrative Letter 06 has also been incorporated into this amendment. Those changes are not 
detailed in the table below.  
Summaries of additional changes are included in the table below to add clarity, consistency in 
terminology, and accuracy throughout the document. The Protocol Synopsis has been updated to 
reflect changes made in the protocol body. 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 5 
Section Number & Title 
Description of Changes 
Brief Rationale 
Title Page 
Added Brief Study Title. 
Updated to align with requirements set out 
in Annex 1 of the EU CTR. 
 
Replaced European Union Drug 
Regulating Authorities Clinical Trials 
(EudraCT) Number with EU CT Number. 
Section 14.1 
Added language referring to EU CTR 
536/2014 for clinical studies. 
Section 4.2: Rationale for 
Dose and Dosing Schedule 
Section 6.1.2: Part B 
Figure 3: Part B Study 
Schema 
Section 9.2.2: Part B 
Added another Part B starting dose 
regimen for the case with 10 mg twice 
daily (BID) and 25 mg BID in Part A. 
Clarified that 75 mg BID starting dose in 
Part B is specific for the participants who 
received Part A doses with 25 mg BID and 
50 mg BID which resulted in 
 
.  
• 
If both doses in Part A resulted in a 
 of 
 
with 10 and 25 mg BID, then the Part 
B dose for that participant is 50 mg 
BID.  
• 
If both doses in Part A resulted in a 
 of 
 
with 25 and 50 mg BID, then the Part 
B dose for that participant is 75 mg 
BID. 
Participants will receive either 10 mg BID 
or 50 mg BID in Part A Treatment 
Period 2 depending on a 
 
after 25 mg BID at end of Treatment 
Period 1. The Part B dose selection 
algorithm was updated to be able to select 
the next higher dose depending on Part A 
doses if both doses resulted in minimum 
 as defined as 
 from the Part A 
baseline.   
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 5 
Section Number & Title 
Description of Changes 
Brief Rationale 
Section 4.2: Rationale for 
Dose and Dosing Schedule 
 
Added Part B starting dose for 2 scenarios, 
in case one dose is 
 and 
one is 
 
• 
If 25 mg BID 
 
 and 10 mg BID
 
 10 mg BID. 
• 
If 25 mg BID 
 
 and 50 mg BID
 
 25 mg BID.  
To define Part B starting dose for all 
possible scenario of 
 in Part 
A. Thus far, no participant met these 
scenarios. The lower dose will be selected 
for Part B starting dose if participants met 
the 
 as described.  
Section 4.2: Rationale for 
Dose and Dosing Schedule 
Added text stating that Part B starting dose 
can be either one of 5 mg BID, 10 mg 
BID, 25 mg BID, 50 mg BID, or 75 mg 
BID. 
To summarize Part B starting dose which 
has been described in the protocol. 
Section 6.1.1: Part A 
Table 3: Schedule of 
Assessments, Part A 
Added text allowing rescreening upon 
discussion with and documented approval 
by the Sponsor’s Medical Monitor and 
clarified that repeat genetic testing is not 
necessary if rescreening is conducted. 
Added that up to 1 rescreen per participant 
is permitted. 
To accommodate the participants’ 
conditions which may vary depending on 
the time of assessment, and to allow 
rescreening in Part A. 
Additionally, removed repeat of the 
genetic testing in rescreening since 
genetic variants implicated in DCM are 
germline mutations and would not change 
over the participant’s lifetime. 
Section 6.1.2: Part B 
Added text allowing repeat of rescreening 
upon discussion with and documented 
approval by the Sponsor’s Medical 
Monitor. 
To accommodate the participants’ 
conditions, which may vary depending on 
the time of assessment, and allow 
additional rescreening. 
Section 6.2.1: Temporary 
Treatment Discontinuation 
(or Treatment Interruption) 
Added details for the dose at which 
treatment should be resumed in 
consultation with the Sponsor’s Medical 
Monitor. 
To accommodate possible changes in 
study participants which may occur over 
2 years of the study duration, such as the 
participant’s health conditions and 
concomitant medication. Danicamtiv dose 
for resumption after temporary 
termination to be determined based on 
adequate advice and oversight from 
Medical Monitor and/or safety reviewers.  
Section 7.2: Exclusion 
Criteria 
Added exclusion criterion #E17 in Part A 
and #E13 in Part B to exclude participants 
with a history of advanced heart failure 
therapy (ie, a heart transplant or left 
ventricular assisted device therapy). 
To exclude participants whose who may 
have different safety and tolerability 
response to danicamtiv due to their 
significantly different cardiac conditions. 
Furthermore, assessment and 
interpretation of PD responses by TTE 
may be difficult in those participants.  
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 5 
Section Number & Title 
Description of Changes 
Brief Rationale 
Section 9.6: Concomitant 
Therapy 
Added information for concomitant use of 
strong CYP3A4 inhibitors for short 
duration in Part B if it is expected to 
provide benefit to study participants. 
Described potential additional study visits 
if needed for additional safety monitoring, 
especially after a change in concomitant 
medication. 
 
 
 
 
 
 
 
 
 
   
Section 11.4.6: Troponin 
Levels 
Removed the following information 
regarding troponin increase: 
“roughly twice the 99th percentile value for 
the overall population, including equal 
proportions of both genders.” 
Removed since the information is 
irrelevant to the current assay of standard 
Troponin I. 
Section 11.6: Participant 
Restrictions During the 
Study 
Removed the restriction for study drug to 
be taken with a full meal BID. 
Food requirement was removed in the 
study Protocol Amendment 3, but the 
removal was not previously captured. 
 
 
Section 12.1.1: Adverse 
Event 
Revised example of protocol-mandated 
procedure. 
Changed to align with procedures 
performed in this study. 
Section 12.1.2: Serious 
Adverse Events 
Section 12.3: Reporting 
Period and Follow Up 
Moved reporting period detail from the 
serious adverse event (SAE) definition in 
Section 12.1.2 to Section 12.3.  The text 
was also reorganized.  
Reorganized text for clarification of SAE 
reporting. 
Appendix 1: Schedule of 
Assessments 
In Table 3, footnote k, increased time 
allowed to obtain samples at Visit 2A 
from within 1 hour predose to 3 hours 
predose. 
Expanded predose pharmacokinetic 
sampling time window to mitigate 
operational challenges at sites to conduct 
required assessments at predose. 
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PROTOCOL SYNOPSIS 
Study Title: An Open-Label, Exploratory Study of the Safety and Preliminary Efficacy of Danicamtiv in Stable 
Ambulatory Participants with Primary Dilated Cardiomyopathy due to either MYH7 or TTN Variants or Other 
Causalities 
Protocol Number: MYK-491-006 (CV028005) 
Study Phase: 2a 
Investigational Medicinal Product: Danicamtiv (BMS‑986434, MYK-491) 
Primary Objective: 
• 
To establish preliminary safety and tolerability of treatment with danicamtiv in participants with myosin 
heavy chain 7 (MYH7)-dilated cardiomyopathy (DCM), with titin (TTN)-DCM, or DCM by other 
causalities for Part A.  
Secondary Objective: 
• 
To establish the preliminary effect, compared with Baseline, of treatment with danicamtiv on cardiac 
pharmacodynamics (PD), as determined by transthoracic echocardiography (TTE) in participants with 
MYH7-DCM, or TTN-DCM, or DCM by other causalities.  
Exploratory Objectives: 
• 
To establish the preliminary effect of danicamtiv on overall activity level in participants with MYH7-
DCM or TTN-DCM, or DCM of other causalities. 
• 
To determine long-term preliminary safety and tolerability of treatment with danicamtiv in participants 
with MYH7-DCM or TTN-DCM, or DCM of other causalities for Part B. 
• 
To determine the timeline and durability of effects of danicamtiv on cardiac structure and function in 
participants with MYH7-DCM or TTN-DCM, or DCM of other causalities utilizing cardiac magnetic 
resonance (CMR) as well as continuing serial TTE assessments for Part B.  
• 
To explore the exposure-response relationship between danicamtiv exposure and TTE parameters in 
participants with MYH7-DCM, TTN-DCM, and DCM of other causalities. 
• 
To explore the effect of danicamtiv on soluble biomarkers of cardiac pathophysiology in participants 
with MYH7-DCM, TTN-DCM, and DCM of other causalities. 
• 
To explore the different effects of danicamtiv on safety and PD between the groups of MYH7-DCM, 
TTN-DCM, and primary DCM not related to MYH7 or TTN.   
• 
To explore the natural course of cardiac status in participants with MYH7-DCM or TTN-DCM, or DCM 
of other causalities who participate in the observational study.   
Study Design: 
This is a 3-cohort, baseline-controlled, sequential, 2-period, open-label study with an optional extension 
investigating the safety and efficacy of danicamtiv in stable, ambulatory participants with primary DCM due to 
either MYH7 or TTN variants, or DCM due to other causalities than MYH7 or TTN variants.  
Part A 
Screening 
Eligibility for the study, based on specific MYH7 or TTN variant and presence of DCM-causing variant of the 
other genes will be assessed centrally by the Sponsor and Coordinating Investigator (Section 7.1).  Pre-Screening 
using a historical genetic report may be conducted prior to Screening visit (VA1.1) where allowed by local 
regulations (APPENDIX 1).   
Participants will undergo 2 to 8 weeks of Screening and qualification assessments over 1 to 2 visits, as necessary 
(see Part A Schedule of Assessments, APPENDIX 1). Samples for genetic testing will be collected at Screening 
and assessed at a central genetic laboratory, where available.  Genetic testing results will be submitted for central 
review and approval for eligibility as described in the Central Genetic Review Charter.  For the participants who 
were enrolled based on genetic testing results that were not conducted at the central genetic laboratory, their 
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genetic status will be confirmed retrospectively via genetic testing at the central genetic laboratory after being 
enrolled into the study.  Screening will include, but not be limited to: medical history, physical examination, 
safety laboratory tests, triplicate 12-lead electrocardiogram (ECG) and 1 to 2 TTEs. If a qualifying prior TTE, 
performed within the past 12 months, is available, then another TTE is required at the first Screening visit.  The 
absolute difference of the left ventricular ejection fraction (LVEF) between the qualifying prior TTE and second 
TTE at Screening must be < 12%. If there is no prior TTE within the past 12 months, then 2 Screening TTEs are 
required. TTEs must be performed at least 7 days apart during the Screening period, and there should be < 12% 
difference between the 2 LVEF values. 
If a qualifying prior TTE is being used to qualify the participant, a cardiac rhythm monitoring patch will be 
placed after a TTE at Screening. If 2 Screening TTEs are required, the patch will be placed at the conclusion of 
the second TTE. Duration of cardiac rhythm monitoring will be at least 5 days and a maximum of 14 days. If a 
patch becomes detached before 5 days, a new patch should be placed.  
Rescreening is acceptable upon discussion with and documented approval by the Sponsor’s Medical Monitor. If 
rescreening is conducted, repeat of prospective genetic testing at Screening is not necessary. Up to one (1) 
rescreen per participant is permitted.  
Open-label Treatment Periods  
All enrolled participants will undergo 2 open-label treatment periods with active study drug. Each treatment 
period will last 5 to 8 days (see Schedule of Assessments, APPENDIX 1), and do not need to have the same 
duration. 
Treatment Period 1 (5 to 8 days):  
Visit 2A (Day 1 of Treatment Period 1): Baseline assessments will be completed prior to administration of the 
first dose of study drug given in the clinic.  
A cardiac rhythm monitoring patch will be placed at the conclusion of the visit. Participants will self-administer 
study drug orally twice daily (BID) at home for up to 8 days. On Day 1, if baseline assessments are completed in 
the afternoon, then first dose of study drug will only be administered once in the afternoon. 
Telehealth Visit (TH) 1A: One to 3 days before the end of Treatment Period 1, the participant will be contacted to 
ensure compliance with study drug administration, to check for new adverse events (AEs) and concomitant 
medications, to remind the participant of the next scheduled clinic visit, and to self-administer study drug 
approximately 7 hours prior to the next clinic visit. 
Visit 3A – End of Treatment Period 1: Participants will return to the clinic for assessments of safety, tolerability, 
study drug plasma concentration, and PD response (see Schedule of Assessments, APPENDIX 1). The 
Investigator will evaluate for the absence of permanent discontinuation criteria including, but not limited to, the 
absence of excessive prolongation of QT interval, corrected using Fridericia’s formula (QTcF) (Section 7.2). The 
cardiac sonographer at each local site will measure 
 (Section 11.1.1) and promptly 
communicate the 
 from Baseline value (change from 
 determined at Visit 2A) to the Study 
Coordinator and Investigator. This result will determine the dose for Treatment Period 2 (Section 6.1). 
Treatment Period 2 (5 to 8 days):  
From Visit 3A until Visit 4A: The study drug will be taken orally BID either starting in the evening of Visit 3A or 
the morning after Visit 3A, depending on the results of the 
 from the TTE performed at Visit 3A. Participants 
should continue taking study drug through Visit 4A (see below under Visit 4A).  
Telehealth Visit (TH) 2A: At 1 to 3 days before the end of Treatment Period 2, the participant will be contacted 
(APPENDIX 1) to ensure compliance with study drug administration, to check for new AEs and concomitant 
medications, to remind the participant of the next scheduled clinic visit, and to take study drug in the morning of 
the next visit approximately 7 hours prior to the scheduled time of the visit. 
Visit 4A – End of Treatment Period 2: Participants will return for a clinic visit, 5 to 8 days after Visit 3A of 
Treatment Period 2, for assessments of safety, tolerability, study drug plasma concentration, and PD response (see 
Schedule of Assessments, APPENDIX 1).  
Follow-up: 
Telehealth Visit (TH) 3A:  
The participant will be contacted 1 to 3 days following the last dose of study drug to assess safety. 
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Visit 5A: A study clinic visit to assess participant safety will occur 14 days (+ 7 days) following the last dose of 
study drug regardless of the subject’s participation in Part B (see Schedule of Assessments, APPENDIX 1). 
Part B  
The expected study duration for Part B for each participant is approximately 102 weeks, including a 4-week 
Rescreening period, if needed. This period does not include a potential hiatus between Parts A and B for some 
participants. Part B will commence after a participant completes Part A and opts to continue onto Part B. If a 
participant does not complete Part A or completes outside of the protocol defined window due to reasons other 
than treatment-emergent adverse event (TEAE) considered as study drug related by the investigator, meeting 
study discontinuation criteria, or withdrawal of the informed consent, Part B participation will be assessed and 
approved in discussion with the Sponsor.     
If a participant has completed Part A more than 56 days prior to the start of Part B, then a Rescreening visit will 
be required (see Schedule of Assessments, APPENDIX 1).  
If a Rescreening visit is not required prior to Part B start, then Visit 1B can be performed on the same day as 
Visit 5A and any assessments in Visit 5A that are also required in Visit 1B need to only be performed once. A 
repeat of rescreening is acceptable after discussion with and documented approval by the Sponsor’s Medical 
Monitor. 
A cardiac rhythm monitoring patch will be placed at Visit 1B, Visit 6B, Visit 8B, Visit 10B, and EOT (see 
Schedule of Assessments, APPENDIX 1).  
Individual participant doses for Part B will be based on 
 in Part A (Section 4.2). After the initiation 
of Part B dosing, the 
 at V2B and at V3B from the 
 at Part B baseline (V1B) will be assessed 
locally.  The dose titration may occur based on these 2 
 changes at Visit 3B (Section 4.2).  
High sensitivity troponin T (hsTnT), high sensitivity troponin I (hsTnI), and standard troponin I (TnI) will be 
evaluated multiple times throughout the study in Parts A and B in conjunction with a 12-lead ECG.  
In Part B, TnI (standard) results will be communicated to the study sites by the central laboratory, as they are 
available, and will be part of an algorithm to evaluate the significance of TnI increase in this patient population. 
Details of this process are provided in Section 11.4.6.  
Additional assessments in Part B include, but are not limited to: N-terminal pro-B-type natriuretic peptide 
(NT-proBNP) evaluation, activity monitoring, cardiac magnetic resonance (CMR) if considered as suitable 
condition, 6-Minute Walk Distance (6MWD), New York Heart Association (NYHA) Functional Classification 
assessments, and Kansas City Cardiomyopathy Questionnaire (23-item version) (KCCQ-23) measurements (see 
Schedule of Assessments, APPENDIX 1). 
If a participant did not opt to participate in Part B, an observational study without study drug treatment is 
available. A participant still needs to consent to the Part B observation study before receiving any study 
assessment.   
Number of Participants:  
Enrollment of total of approximately 40 completed participants (~12 participants with MYH7 variant, ~12 
participants with TTN variant, and ~16 participants with primary DCM not with MYH7 or TTN disease-causing 
variant) is planned. Note: The ratio of participants with known DCM-causing variants (other than MYH7 or TTN) 
and non-genetic cause will be approximately 1:1. 
Study Treatment: 
In Part A, study drug will consist of 5 and 25 mg 
 tablets and 5 mg, 25 mg, and 50 mg 
 tablets. In Part B, study drug will consist of 5, 25, 50, and 75 mg 
 tablets and 
 5 mg tablets.  
Part A: 
Study drug will be administered orally BID for at least 5 days and up to 8 days for each Treatment Period. Doses 
may occur ± 2 hours from scheduled dosing times as long as doses are separated by at least 10 hours and by no 
more than 14 hours. 
Treatment Period 1:  
Participants will receive 25 mg BID of study drug. On the last dosing day of Treatment Period 1, a TTE will be 
performed either in the afternoon of Day 5, 6, 7, or 8, and approximately 7 hours after the morning dose. The 
 
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change from Baseline observed on that TTE, measured locally at the site by the site sonographer, will determine 
the dose to be administered in Treatment Period 2.  
Treatment Period 2 (doses determined by site measurement of 
:  
• 
If at the end of Treatment Period 1 (Visit 3A), the 
 from Baseline (Visit 2A) to Visit 3A is 
 to 
 the participant will be instructed to skip one dose and then will be 
down-titrated to 10 mg BID. If a participant is down-titrating, then dosing will start in the morning following 
the last dose for Treatment Period 1 and will end between 5 to 8 days later.  
• 
If at the end of Treatment Period 1 (Visit 3A), the 
 from Baseline (Visit 2A) is 
, the participant will be up-titrated to 50 mg BID. If a participant is up-titrating, then dosing 
will start in the evening on the last dosing day for Treatment Period 1 and will end between 5 to 8 days later. 
NOTE: If at the end of Treatment Period 1 (Visit 3A), the 
 from Baseline (Visit 2A) is 
, then study drug should be permanently discontinued (Section 6.2). 
Part B: 
Initial individual participant doses will be based on centrally determined 
 in Part A, regardless of 
whether a participant has to be rescreened in Part B:  
• 
If one of the doses in Part A resulted in a 
 and 
, then that will be the dose 
for Part B (10, 25, or 50 mg BID) 
• 
If both doses in Part A resulted in a 
 and 
, then the dose for Part B is the 
lower of the 2 doses that the participant received in Part A 
• 
If both doses in Part A resulted in a 
 with 10 and 25 mg BID, then the 
Part B dose for that participant is 50 mg BID 
• 
If both doses in Part A resulted in a 
 with 25 and 50 mg BID, then the 
Part B dose for that participant is 75 mg BID 
• 
If both doses in Part A resulted in a 
 with 10 and 25 mg BID, then the 
Part B dose for that participant is 5 mg BID 
• 
If both doses in Part A resulted in a 
 with 25 and 50 mg BID, then the 
Part B dose for that participant is 10 mg BID 
• 
If 25 mg BID dose from Part A 
 and 10 mg BID dose from Part A 
 
 10 mg BID 
• 
 If 25 mg BID dose from Part A 
 and 50 mg BID dose from Part A r
 
 25 mg BID 
 
Participants who could not complete Part A or completed TTE assessments outside of the protocol defined 
window may participate in Part B after investigator discussion with the Sponsor. The reasons of incompletion of 
Part A should be due to reasons other than treatment-emergent adverse event (TEAE) considered as study drug 
related by the investigator, meeting study discontinuation criteria, or withdrawal of the informed consent.  Part B 
starting dose for such cases is described in following 2 bullets.  
• 
If 
 of both doses were unavailable or performed significantly outside of the assessment window 
(see Appendix 1. Part A SoA footnote g), then the Part B dose will be 50 mg BID.   
• 
If a 
 was only available with 25 mg BID (Treatment Period 1) and a 
 was 
 and 
, then 25mg BID is the dose for Part B. If a 
 was
, then the 
Part B dose is 50 mg BID.  If 25 mg BID dose 
 
 10 mg BID 
Part B dose adjustment:  
After the initiation of Part B dosing, a TTE will be performed at Visit 2B and Visit 3B to ensure adequate PD 
responses. 
 measured at these times from Part B Baseline (V1B) will dictate dose adjustments as 
follows: 
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• 
If there is a 
 of 
 on both TTEs at Visits 2B and 3B compared from Part B 
baseline (V1B), based on local assessments, the dose will be titrated up to the next dose level. If a participant 
is already receiving the highest dose (75 mg BID), per the Investigator’s discretion, the participant will 
continue the study at 75 mg BID as long as there are no safety concerns (Section 6.2). 
• 
If there is a 
 of 
 on both TTEs at Visits 2B and 3B compared from Part B 
baseline (V1B), based on local assessments, the dose will be titrated down to the next dose. If a participant is 
already receiving the lowest dose (5 mg BID), then the participant will be discontinued from the study 
(Section 6.2).  
• 
If there is a 
 on at least one of TTEs from Visits 2B and 3B, based 
on local assessments, no dose change is needed.  
• 
If 
 at Visit 2B and 3B are 
 at one visit and 
 at the other, no 
dose change is needed. 
Study Duration: 
The expected study duration of Part A for each participant ranges from approximately 4 to 11 weeks, including 2 
to 8 weeks for Screening, 9 to 16 days for treatment, and approximately 2 weeks for follow-up. 
The expected study duration for Part B for each participant is approximately 102 weeks, including a 4-week 
Rescreening period, if needed. This period does not include a potential hiatus between Parts A and B for some 
participants.  
The total duration of the study for Parts A and B for each participant is up to 115 weeks. 
Inclusion Criteria 
Part A: 
Each participant in Part A must meet the following criteria to be included in this study.  
I1. Able to understand and comply with the study procedures, understand the risks involved in the study, 
and provide written informed consent according to federal, local, and institutional guidelines before the 
first study-specific procedure. 
I2. Men or women 18 to 80 years of age (inclusive) at the Screening visit. 
I3. For MYH7 and TTN cohorts, diagnosis of primary DCM, clinically stable and due to probably disease-
causing variant of MYH7 or TTN as defined by (a) through (f) of the following. All study participants, 
regardless of the cohort, must meet (g) and (h) criteria: 
a. 
Primary DCM participants that have no identified etiology other than variant in MYH7 or TTN 
(e.g., coronary artery disease or severe valvulopathy), as determined by the Investigator. Participants 
with a diagnosis of heart failure with reduced ejection fraction should be on Guideline Directed 
Medical Therapy as tolerated. 
NOTE: Presence of coronary artery disease, functional mitral regurgitation, or mild-to-
moderate valvular disease may be allowed if not considered the primary cause of the heart 
failure based on evaluation by the Investigator. Moderate aortic stenosis should be excluded. 
b. Pathogenic or likely pathogenic variants submitted in the form of final official genetic laboratory 
reports will be reviewed centrally by the Sponsor and Coordinating Investigator for eligibility. Some 
variants designated variant of uncertain significance (VUS) may also be permitted upon central 
review. 
Note: Participants with titin variants in the Z-disk and I-band regions will be excluded from the 
study (even if regarded as Pathogenic or Likely Pathogenic). 
c. 
DCM is not secondary to long-standing MYH7- or TTN-related hypertrophic cardiomyopathy or left 
ventricular noncompaction cardiomyopathy, as determined by the Investigator.  
NOTE: Hypertrabeculation of the left ventricular myocardium is not, in and of itself, a criterion 
for exclusion. 
d. Participants with DCM related to pathogenic or likely pathogenic variants of TTN must not also 
have a diagnosis of peripartum DCM (defined by DCM diagnosed initially in the last month of 
pregnancy or the 6 months following delivery). 
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e. 
In participants with DCM related to pathogenic or likely pathogenic variants of TTN, DCM must not 
be secondary to significant exposure to cardiotoxic chemotherapy agents, as determined by the 
Investigator. 
f. 
In participants with DCM related to pathogenic or likely pathogenic variants of TTN, DCM must not 
be due to a history of significant alcohol abuse, as determined by the Investigator. 
g. Documented LVEF 15 to 45% (on 2 occasions), including at least once during Screening and 
confirmed by the Echo Core Laboratory.  
 
If a participant’s most recent prior TTE (within past 12 months) documents a LVEF ≤ 45%, 
then only a single Screening visit confirming LVEF ≤ 45% by the Echo Core Laboratory is 
required.  
 
If no prior documented LVEF ≤ 45% by TTE within the past 12 months is available, then 2 
Screening TTEs are needed at least one week (7 days) apart. 
 
In addition, the absolute difference between the 2 LVEF values qualifying the participant 
should be < 12%. 
h. Participant receives chronic medication for the treatment of heart failure reflecting current 
guidelines, including at least one of the following, unless not tolerated or contraindicated: β-blocker, 
angiotensin converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor 
neprilysin inhibitor. Such treatments should have been given at stable doses for ≥ 2 weeks with no 
plan to modify during the study. 
I4. Sinus rhythm or stable atrial or ventricular pacing or persistent atrial fibrillation that is adequately rate-
controlled to allow PD assessments by TTE. 
NOTE: Participants with implantable cardioverter defibrillator, pacing, or cardiac resynchronization 
therapy are eligible if provided device programming is unchanged starting 2 months prior to and 
throughout the dosing period. 
I5. If multiple members of a family meet eligibility criteria, a maximum of 3 eligible participants per family 
may enroll in the study. 
I6. Female participants of childbearing potential (Appendix 6) must not be pregnant or lactating and, if 
sexually active, must use one of the following highly effective birth control methods from the Screening 
visit through 3 months after the last dose of study drug: 
• 
combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulation or progestogen-only hormonal contraception associated with inhibition of ovulation by 
oral, implantable, or injectable route of administration 
• 
intrauterine device (IUD) 
• 
intrauterine hormone-releasing system (IUS) 
• 
Female subject is surgically sterile. Surgical sterilization includes documented hysterectomy, 
bilateral oophorectomy, bilateral salpingectomy, and/or bilateral tubal occlusion or ligation prior to 
Screening.  
• 
Female participant postmenopausal for 1 year. Female subjects are considered postmenopausal if 
they have had amenorrhea for at least 1 year or more following cessation of all exogenous hormonal 
treatments, and follicle-stimulating hormone (FSH) levels are in the postmenopausal range. 
• 
Male partners of female participants must also use a contraceptive (eg, barrier, condom, or 
vasectomy). 
I7. Male participants must use barrier method of contraception (whether or not the participant had 
vasectomy).  
I8. For the cohort of primary DCM due to other causalities than MYH7 and TTN, participant must meet the 
following criteria in addition to I1, I2, I3 (g) and (h), I4, I5, I6, and I7.  
a. 
The cause of DCM is not  related to MYH7 or TTN variants     
b. The cause of primary DCM is by variants of the other genes except MYH7 and TTN, or non-genetic 
cause  
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Note: The ratio of participants with known DCM-causing variants (other than MYH7 or TTN) and non-
genetic cause will be approximately 1:1.  
c. 
DCM is chronic; not due to acute or possibly reversible conditions (eg, hyper/hypothyroidism, 
infectious cause, tachyarrhythmia, iron overload) according to investigator’s determination.   
d. DCM is not attributed to pregnancy, alcohol abuse, substance abuse, amyloidosis, sarcoidosis, or 
any other secondary form of cardiomyopathy per the investigator’s determination.  
Part B: 
Each Part A participant who opts in for Part B must meet the following criteria.  
Note 1:  If  no Rescreening Visit is required, the following criteria must be evaluated   by or at Part B Baseline 
Visit prior to dosing.   
Note 2: I4 and I5 only applies to participants in Part B receiving danicamtiv,  not the participants in the 
observational study.  
I1. Able to understand and comply with the study procedures, understand the risks involved in the study, 
and provide written informed consent according to federal, local, and institutional guidelines before the 
first study-specific procedure. 
I2. Participant receiving chronic medication for the treatment of heart failure reflecting current guidelines, 
including at least one of the following, unless not tolerated or contraindicated: β-blocker, angiotensin 
converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor. 
Such treatments should have been given at stable doses for ≥ 2 weeks prior to the start of Part B. 
I3. Sinus rhythm or stable atrial or ventricular pacing or persistent atrial fibrillation that is adequately rate-
controlled to allow PD assessments by TTE.  
NOTE: Participants with implanted cardioverter defibrillator, pacing, or cardiac resynchronization therapy 
are eligible if provided device programming is unchanged starting 2 months prior to Part B.   
I4. Female participants of childbearing potential (Appendix 6) must not be pregnant or lactating and, if 
sexually active, must use one of the following highly effective birth control methods after participants 
signed Part B informed consent through 3 months after the last dose of study drug 
• 
combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulation or progestogen-only hormonal contraception associated with inhibition of ovulation by 
oral, implantable, or injectable route of administration 
• 
intrauterine device (IUD) 
• 
intrauterine hormone-releasing system (IUS) 
• 
Female participant is surgically sterile. Surgical sterilization includes documented hysterectomy, 
bilateral oophorectomy, bilateral salpingectomy, and/or bilateral tubal occlusion or ligation before 
and/or at the signing of the Part B informed consent execution.  
• 
Female participant postmenopausal for 1 year. Female subjects are considered postmenopausal if 
they have had amenorrhea for at least 1 year or more following cessation of all exogenous hormonal 
treatments, and follicle-stimulating hormone (FSH) levels are in the postmenopausal range. 
• 
Male partners must also use a contraceptive (eg, barrier, condom, or vasectomy). 
I5. Male participants must use barrier method of contraception (whether or not the participant had 
vasectomy). 
Part A Exclusion Criteria: 
Participants who meet any of the following criteria will be excluded from the study. 
E1. Inadequate echocardiographic acoustic windows. 
E2. A participant has a QTcF interval > 480 milliseconds not attributable to ventricular pacing or has 
prolonged QRS duration ≥ 120 milliseconds, average of triplicate ECGs. 
E3. a.  For MYH7 and TTN cohorts, participants with known pathogenic variant of another gene 
implicated in DCM at Screening. 
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b.  For the cohort of participants with primary DCM due to other causalities than MYH7 and TTN, 
known MYH7 or TTN variants implicated in DCM at Screening. 
E4. Heart failure with reduced ejection fraction considered to be caused primarily by ischemic heart 
disease, chronic valvulopathy, or another condition, as determined by the Investigator. 
E5. Recent (< 90 days) acute coronary syndrome or angina pectoris. 
E6. Coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft) 
within prior 90 days. 
E7. Recent (< 90 days) hospitalization for heart failure, use of intravenous diuretic or chronic 
intravenous inotropic therapy, or other cardiovascular events (eg, cerebrovascular accident) 
E8. Known aortic stenosis of moderate or greater severity. 
E9. Presence of disqualifying cardiac rhythms that would preclude echocardiographic assessments, as 
determined by the Investigator, including: (a) rapid, inadequately rate-controlled atrial fibrillation 
or (b) frequent premature ventricular contractions that might interfere with reliable 
echocardiographic measurements of left ventricular function.  
E10. Hypersensitivity to danicamtiv or any of the components of the danicamtiv formulation. 
E11. Active infection, indicated clinically as determined by the Investigator. In the case of SARS-CoV-2 
(COVID-19) infection within 4 weeks prior to and during Screening, symptoms must have 
completely resolved and based on Investigator assessment in consultation with the Clinical Trial 
Physician, there are no sequelae that would place the participant at a higher risk of receiving 
investigational treatment. The methods to assess SARS-CoV-2 (COVID-19) infection include PCR, 
antigen test and serology tests.  Each study site should follow requirements per local institutional or 
regulatory guidance if any. 
E12. History of malignancy of any type within 5 years prior to Screening, with the exception of the 
following surgically excised cancers occurring more than 2 years prior to Screening: in situ cervical 
cancer, nonmelanomatous skin cancers, ductal carcinoma in situ, and nonmetastatic prostate cancer. 
E13. Severe renal insufficiency (defined as current estimated glomerular filtration rate [eGFR] 
< 30 mL/min/1.73 m2 by simplified Modification of Diet in Renal Disease equation [sMDRD]). 
E14. Serum potassium < 3.5 or > 5.5 mEq/L. 
E15. Any persistent (2 or more) out-of-range laboratory parameters (chemistry, hematology) at 
Screening, considered by the Investigator and the Medical Monitor to be clinically significant. 
E16. History or evidence of any other clinically significant disorder, condition, or disease (including 
substance abuse) that, in the opinion of the Investigator or the Sponsor Physician would pose a risk 
to participant safety or interfere with the study evaluation, procedures, completion, or lead to 
premature withdrawal from the study. 
E17. History of advanced heart failure therapy (ie, a heart transplant or left ventricular assisted device 
[LVAD] therapy).  
E18. A life expectancy of < 6 months. 
E19. Participated in a clinical trial in which the participant received any investigational drug (or is 
currently using an investigational device) within 30 days prior to Screening, or at least 5 times the 
respective elimination half-life (whichever is longer). 
E20. WOCBP with a positive pregnancy test. 
E21. Is employed by or is a first-degree relative of someone employed by the Sponsor, the Investigator, 
or his/her staff or family. 
E22. Currently placed in hospital or facility due to legal or administrative order. 
E23. Not having an implantable cardioverter defibrillator despite meeting the conditions of Class I 
recommendation defined in the 2022 American Heart Association (AHA)/American College of 
Cardiology (ACC) heart failure (HF) guidelines (7.4.1) or the 2021 European Society of 
Cardiology (ESC) HF guideline, depending on the region where participants reside.  
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E24. Unstable or untreated severe ventricular arrythmia (e.g., ventricular tachycardia or ventricular 
fibrillation).  Participants with severe ventricular arrythmia who have not received an implantable 
cardioverter defibrillator. 
Part B Exclusion Criteria:  
Participants who meet any of the following criteria after Part A completion to Part B cannot participate in Part B 
of the study.  
Note1: If no Rescreening Visit is required, the following criteria must be evaluated  by or at Part B Baseline Visit 
prior to dosing.  
E1. Recent (< 90 days) acute coronary syndrome or angina pectoris. 
E2. Coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft) 
within prior 90 days. 
E3. Recent (< 90 days) hospitalization for heart failure, use of intravenous diuretic or chronic 
intravenous inotropic therapy or other cardiovascular events (eg, cerebrovascular accident). 
E4. Active infection, indicated clinically as determined by the Investigator. In the case of SARS-CoV-2 
(COVID-19) infection within 4 weeks prior to Part B Baseline Visit or Rescreening (if required), 
symptoms must have completely resolved and based on Investigator assessment in consultation 
with the Clinical Trial Physician, there are no sequelae that would place the participant at a higher 
risk of receiving investigational treatment. The methods to assess SARS-CoV-2 (COVID-19) 
infection include PCR, antigen test and serology tests.  Each study site should follow 
requirements per local institutional or regulatory guidance if any. 
E5. For participants who need Rescreening, severe renal insufficiency (defined as current eGFR 
< 30 mL/min/1.73 m2 by sMDRD). 
E6. For participants who need Rescreening, any persistent (2 or more) out-of-range safety laboratory 
parameters (chemistry, hematology), considered by the Investigator and the Medical Monitor to be 
clinically significant. 
E7. WOCBP with a positive pregnancy test. 
E8. History or evidence of any other clinically significant disorder, condition, or disease (including 
substance abuse) that, in the opinion of the Investigator or the Sponsor Physician, would pose a risk 
to participant safety or interfere with the study evaluation, procedures, completion, or lead to 
premature withdrawal from the study 
E9. Is employed by or is a first-degree relative of someone employed by the Sponsor, the Investigator, 
or his/her staff or family. 
E10. Currently placed in hospital or facility due to legal or administrative order. 
E11. Not have an implantable cardioverter defibrillator despite meeting the conditions of class I 
recommendation defined in 2022 AHA/ACC HF guidelines (7.4.1) or the 2021 ESC HF guideline, 
depending on the region where participants reside.   
E12. Unstable or untreated severe ventricular arrythmia (e.g., ventricular tachycardia or ventricular 
fibrillation).  Participants with severe ventricular arrythmia who have not received an implantable 
cardioverter defibrillator 
E13. History of advanced heart failure therapy (ie, a heart transplant or LVAD therapy)  
Study Endpoints: 
Primary: clinical safety and tolerability as assessed by the following: 
• 
Frequency of treatment-emergent adverse events and serious adverse events in Part A 
• 
Frequency of clinically significant abnormalities from vital signs, adverse events, physical examination, 
ECG recordings, and safety labs in Part A 
Secondary: change in the following PD parameters, as assessed by TTE from Baseline corresponding to Parts A 
and B of the study: 
• 
Left ventricular 
 
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• 
Parameters of left ventricular systolic function including but not limited to left ventricular stroke volume 
(LVSV), LVEF, left ventricular strain (LVGLS and LVGCS), and tissue Doppler imaging (TDI) of 
mitral valve annulus peak systolic velocity (s’) 
• 
Parameters of left ventricular dimensions including left ventricular end-systolic and end-diastolic 
diameters (LVESD, LVEDD), left ventricular end-systolic and end-diastolic volumes indexed for body 
surface area (LVEDVi, and LVESVi) 
• 
Parameters of left atrial volume and function including, but not limited to minimum and maximum left 
atrium (LA) volumes indexed for body surface area (LAmaxVi, LAminVi), left atrial emptying fraction 
(LAEF), and left atrial function index (LAFI) 
• 
Parameters of left ventricular diastolic function including, but not limited to, TDI of mitral valve annulus 
peak velocity in diastole (e’, lateral, septal), ratio of peak inflow velocities in early and late diastole 
(E/A), ratio of early mitral peak inflow velocity to early mitral peak annulus velocity (TDI) (E/e’) lateral, 
septal, and average 
Exploratory:  
• 
 will be summarized by the cohort (MYH7, TTN, and 
other DCM) using descriptive statistics. 
• 
Clinical safety and tolerability as assessed by the following:  
− 
Frequency of treatment-emergent adverse events and serious adverse events in Part B  
− 
Frequency of clinically significant abnormalities from vital signs, adverse events, physical 
examination, ECG recordings, and safety labs in Part B  
• 
Additional exploratory endpoints including concentration-PD effect and soluble biomarkers of cardiac 
physiopathology may be included. 
• 
Frequency of left ventricular reverse remodeling (LVRR) during Part B, defined by the following criteria 
(Escobar-Lopez et al. 2021):  
− 
either left ventricular normalization (LVEF improvement to ≥ 50% with a ≥ 5% LVEF increment on 
TTE at the last follow-up)  
− 
or an absolute increase in LVEF by ≥ 10% on TTE at the study visits from TTE at baseline 
Sample Size and Statistical Considerations:  
The sample size for Part A of approximately 40 completed participants (approximately 12 participants with 
MYH7 variant, 12 participants with TTN variant, and approximately 16 participants with primary DCM due to 
causalities other than MYH7 and TTN variants) has been selected empirically to assess the effect size of 
danicamtiv on the various PD measurements and to provide a preliminary assessment of safety and tolerability in 
this patient population. There is no target sample size for Part B because it is an optional part of the study. 
Treatment-emergent adverse events, ECGs, vital signs, and laboratory values will be analyzed using descriptive 
statistics. Formal statistical testing will not be performed. 
Clinical data will be summarized by cohort, MYH7-DCM, TTN-DCM, and primary DCM by other causalities, 
and by dose in Part A and Part B. For MYH7 and TTN cohorts, data may be summarized by variant type and the 
location. For DCM cohort, data will be further evaluated by genetic mutation-positive and genetic mutation-
negative variable.  If positive genetics are identified, additional analysis may be  performed by variant type. 
Descriptive summary statistics for continuous variables will include the number of participants, mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized using counts and 
percentages. 
Blood samples to measure the peak danicamtiv plasma concentration will be drawn. Plasma concentration data 
for danicamtiv will be summarized using descriptive statistics, including mean or geometric mean as appropriate, 
SD, median, minimum, and maximum values and coefficient of variation % (CV%). No PK analyses will be 
performed. 
TTE data including, but not limited to, LVEF, 
, LVSV, and LAFI will be analyzed by cohort and dose using 
descriptive statistics. Observations by timepoint and change from Baseline (either absolute or percent relative 
change) at each timepoint will be summarized by cohort and by dose in both Part A and Part B.  
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Change in 
 will be summarized using descriptive statistics. 
Compliance Statement: 
This study will be conducted in accordance with the International Council on Harmonisation (ICH) Good Clinical 
Practice (GCP) guidelines, US Title 21 Code of Federal Regulations (CFR) Parts 11, 50, 54, 56 and 312; 
European Union GCP and Good Manufacturing Practices (GMP); and the principles enunciated in the 
Declaration of Helsinki and all human clinical research regulations where the study is to be conducted. 
Additional Items for Consideration: 
Guidance on COVID-19 risk mitigation is outlined in APPENDIX 5. 
 
 
 
 
 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 5: .................................................3 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 5 .....................................3 
PROTOCOL SYNOPSIS.................................................................................................................6 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF TABLES .........................................................................................................................21 
LIST OF FIGURES .......................................................................................................................22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................23 
1 
INTRODUCTION ......................................................................................................26 
2 
DANICAMTIV ...........................................................................................................27 
2.1 
Overview of Pharmacological Properties and Animal Studies ...................................27 
3 
BACKGROUND ........................................................................................................27 
3.1 
Summary of Clinical Experience to Date with Danicamtiv .......................................27 
3.1.1 
Studies in Healthy Participants ..................................................................................27 
3.1.2 
Study in Heart Failure Patients ..................................................................................28 
3.2 
Known and Potential Risks and Benefits ....................................................................30 
4 
RATIONALE FOR THE STUDY AND FOR DOSE AND DOSING 
SCHEDULE ...............................................................................................................31 
4.1 
Rationale for the Study ...............................................................................................31 
4.2 
Rationale for Dose and Dosing Schedule ...................................................................32 
5 
STUDY OBJECTIVES ..............................................................................................34 
5.1 
Primary Objectives .....................................................................................................34 
5.2 
Secondary Objectives .................................................................................................34 
5.3 
Exploratory Objectives ...............................................................................................34 
6 
OVERALL STUDY DESIGN AND PLAN ...............................................................34 
6.1 
Study Design ...............................................................................................................34 
6.1.1 
Part A ..........................................................................................................................35 
6.1.2 
Part B ..........................................................................................................................38 
6.2 
Treatment Discontinuation .........................................................................................40 
6.2.1 
Temporary Treatment Discontinuation (or Treatment Interruption) .........................40 
6.2.2 
Permanent Treatment Discontinuation .......................................................................41 
6.2.3 
Data Reviews ..............................................................................................................42 
6.2.4 
Discontinuation of Study .............................................................................................42 
6.3 
Study Duration ............................................................................................................42 
7 
SELECTION OF STUDY POPULATION ................................................................43 
7.1 
Inclusion Criteria ........................................................................................................43 
7.2 
Exclusion Criteria .......................................................................................................46 
7.3 
Withdrawal and Replacement of Participants .............................................................49 
7.3.1 
Withdrawal from the Study .........................................................................................49 
7.3.2 
Follow-up Procedures After Early Withdrawal from Study .......................................49 
7.3.3 
Replacement of Participants .......................................................................................50 
8 
RANDOMIZATION AND BLINDING PROCEDURES .........................................50 
9 
STUDY TREATMENT ..............................................................................................50 
9.1 
Investigational Medicinal Product ..............................................................................50 
9.1.1 
Supply of Investigational Medical Product ................................................................50 
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9.1.2 
Storage and Handling Procedures .............................................................................51 
9.1.3 
Packaging and Labeling .............................................................................................51 
9.2 
Investigational Medicinal Product, Administration, and Schedule ............................51 
9.2.1 
Part A: ........................................................................................................................51 
9.2.2 
Part B: ........................................................................................................................52 
9.3 
Treatment Compliance ................................................................................................53 
9.4 
Guidelines for the Management of an Exaggerated Pharmacological Effect .............53 
9.5 
Overdose .....................................................................................................................53 
9.6 
Concomitant Therapy .................................................................................................54 
10 
RISKS AND PRECAUTIONS ...................................................................................54 
10.1 
General ........................................................................................................................54 
10.2 
Pregnancy ...................................................................................................................55 
10.2.1 
Avoidance of Pregnancy .............................................................................................55 
10.2.2 
Restrictions for Male Participants ..............................................................................55 
10.2.3 
Acceptable Forms of Contraception ...........................................................................56 
10.2.4 
Reporting and Follow-up of Pregnancies ...................................................................56 
11 
STUDY ASSESSMENTS AND PROCEDURES ......................................................56 
11.1 
Pharmacodynamic Assessments .................................................................................56 
11.1.1 
Transthoracic Echocardiography ...............................................................................56 
11.1.2 
Cardiac Magnetic Resonance Imaging ......................................................................58 
11.1.3 
6-Minute Walk Distance (6MWD) ..............................................................................58 
11.2 
Efficacy Assessments .................................................................................................59 
11.2.1 
Exploratory Assessments ............................................................................................59 
11.2.1.1 
New York Heart Association Functional Classification .............................................59 
11.2.1.2 
Kansas City Cardiomyopathy Questionnaire (23-item Version) ................................59 
11.3 
Plasma Concentration, Pharmacogenetic, and Biomarker Assessments ....................59 
11.3.1 
Plasma Concentration Assessments ...........................................................................59 
11.3.2 
Genetic/Genotype/Pharmacogenetic/Biomarker Assessment .....................................60 
11.4 
Safety Assessments .....................................................................................................60 
11.4.1 
Medical History ..........................................................................................................60 
11.4.2 
Vital Signs ...................................................................................................................60 
11.4.3 
Physical Examination .................................................................................................60 
11.4.4 
Electrocardiograms (12-Lead ECG) ..........................................................................61 
11.4.5 
Extended Cardiac Rhythm Monitoring .......................................................................61 
11.4.6 
Troponin Levels ..........................................................................................................61 
11.4.7 
Adverse Events ............................................................................................................62 
11.4.8 
Safety Laboratory Tests (Other Than Troponin) ........................................................62 
11.5 
Missed Evaluations .....................................................................................................62 
11.6 
Participant Restrictions During the Study ..................................................................63 
12 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS .....................................................................................................................63 
12.1 
Definitions ..................................................................................................................63 
12.1.1 
Adverse Event .............................................................................................................63 
12.1.2 
Serious Adverse Events ...............................................................................................64 
12.1.3 
Adverse Events of Special Interest ..............................................................................64 
12.2 
Events NOT Meeting the Definition of an Adverse Event .........................................64 
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12.3 
Reporting Period and Follow Up ................................................................................65 
12.3.1 
Recording and Assessing Adverse Events ...................................................................66 
12.3.1.1 
Description .................................................................................................................66 
12.3.1.2 
Relationship to Study Treatment .................................................................................66 
12.3.1.3 
Severity .......................................................................................................................67 
12.3.1.4 
Pregnancy ...................................................................................................................67 
12.3.1.5 
COVID-19 Vaccine .....................................................................................................67 
13 
STATISTICAL METHODS .......................................................................................67 
13.1 
Determination of Sample Size ....................................................................................67 
13.2 
Study Endpoints ..........................................................................................................68 
13.2.1 
Primary Endpoint .......................................................................................................68 
13.2.2 
Secondary Endpoints ..................................................................................................68 
13.2.3 
Exploratory Endpoints ................................................................................................68 
13.3 
Statistical Analysis ......................................................................................................69 
13.3.1 
Analysis Populations ..................................................................................................69 
13.3.2 
General Considerations ..............................................................................................69 
13.3.3 
Participant Disposition ...............................................................................................69 
13.3.4 
Demographics and Baseline Characteristics .............................................................70 
13.3.5 
Pharmacokinetic Analyses ..........................................................................................70 
13.3.6 
Pharmacodynamic Analyses .......................................................................................70 
13.3.7 
Safety Analyses ...........................................................................................................70 
13.3.7.1 
Adverse Events ............................................................................................................70 
13.3.7.2 
12-lead Electrocardiogram ........................................................................................70 
13.3.7.3 
Other Safety Analyses .................................................................................................71 
13.3.8 
Exploratory Analyses ..................................................................................................71 
14 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS .............................71 
14.1 
Compliance Statement ................................................................................................71 
14.2 
Informed Consent .......................................................................................................71 
14.3 
Ethics Committee ........................................................................................................72 
15 
ADMINISTRATIVE PROCEDURES .......................................................................72 
15.1 
Sponsor’s Responsibilities ..........................................................................................72 
15.1.1 
Participant Confidentiality .........................................................................................73 
15.1.2 
Study Supplies .............................................................................................................73 
15.1.3 
Investigator Training ..................................................................................................73 
15.1.4 
Ongoing Communication of Safety Information During the Study ............................74 
15.1.5 
Study Monitoring ........................................................................................................74 
15.1.6 
Study Auditing and Inspecting ....................................................................................74 
15.2 
Investigator’s Responsibilities ....................................................................................74 
15.2.1 
Study Data Definition .................................................................................................74 
15.2.2 
Screening Log .............................................................................................................74 
15.2.3 
Danicamtiv Accountability .........................................................................................75 
15.2.4 
Reporting and Recording of Study Data .....................................................................75 
15.2.5 
Source Data and Source Documents ..........................................................................75 
15.2.6 
Participant Identification Information .......................................................................76 
15.2.7 
Protocol Deviations ....................................................................................................76 
15.2.8 
Blood Sample Collection/Storage ...............................................................................76 
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15.2.9 
Records Retention .......................................................................................................76 
15.3 
Clinical Trial Insurance ..............................................................................................77 
15.4 
Protocol Amendments and Study Administrative Letters ..........................................77 
16 
DATA QUALITY ASSURANCE ..............................................................................77 
17 
ADMINISTRATIVE CONSIDERATIONS ..............................................................77 
17.1 
Use of Computerized Systems ....................................................................................77 
17.2 
Study Records .............................................................................................................78 
18 
PUBLICATION ..........................................................................................................78 
19 
REFERENCE LIST ....................................................................................................80 
APPENDIX 1 
SCHEDULE OF ASSESSMENTS ............................................................83 
APPENDIX 2 
LABORATORY ASSESSMENTS ...........................................................94 
APPENDIX 3 
POTENTIAL DRUG-INDUCED LIVER INJURY REPORTING 
AND ADDITIONAL ASSESSMENTS REPORTING .............................95 
APPENDIX 4 
INVESTIGATOR’S SIGNATURE ...........................................................97 
APPENDIX 5 
ALLOWANCES FOR STUDY OPERATIONS AFFECTED BY 
PANDEMIC PRECAUTIONS (INCLUDING COVID-19) .....................98 
APPENDIX 6 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS 
AND METHODS OF CONTRACEPTION ..............................................99 
APPENDIX 7 
PROTOCOL AMENDMENT SUMMARY OF CHANGE 
HISTORY ................................................................................................101 
 
 
 
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LIST OF TABLES 
Table 1: 
Study MYK-491-003: Placebo-corrected Change from Baseline in 
Selected TTE Parameters by Danicamtiv Plasma Concentration 
Group (MAD Cohorts) ...............................................................................29 
Table 2: 
New York Heart Association Functional Classification of Heart 
Failure ........................................................................................................59 
Table 3: 
Schedule of Assessments, Part A ...............................................................83 
Table 4: 
Schedule of Assessments, Part B (Active Cohort) .....................................88 
Table 5: 
Schedule of Assessments, Part B (Observational Cohort) .........................93 
Table 6: 
Safety Laboratory Parameters ....................................................................94 
 
 
 
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LIST OF FIGURES 
 
31 
Figure 2: 
Part A Study Schema .................................................................................38 
Figure 3: 
Part B Study Schema .................................................................................40 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
6MWD 
6-minute walk distance 
ACC 
American College of Cardiology 
AE 
Adverse event 
AESI 
Adverse events of special interest 
AHA 
American Heart Association 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
 
 
BID 
Twice daily 
BP 
Blood pressure 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
CHMP 
Committee for Medicinal Products for Human Use 
CK-MB 
Creatine kinase-MB fraction 
CM 
cardiomyopathy 
Cmax 
Maximum observed plasma concentration 
CMR 
Cardiac magnetic resonance 
COVID-19 
Coronavirus disease 19 
CV% 
Coefficient of variation % 
CTR 
Clinical Trials Regulation 
DCM 
Dilated cardiomyopathy 
DILI 
Drug-induced liver injury 
EC 
Ethics committee or International Ethics Committee or equivalent 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
E/e 
Ratio of early mitral peak inflow velocity to early mitral peak annulus velocity 
eGFR 
Estimated glomerular filtration rate 
ESC 
European Society of Cardiology 
ET 
Early Termination 
EU 
European Union 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HF 
Heart failure 
HfrEF 
Heart failure with reduced ejection fraction 
HR 
Heart rate 
HsTnI 
High sensitivity troponin I 
HsTnT 
High sensitivity troponin T 
IB 
Investigator’s Brochure 
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ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-release system 
KCCQ-23 
Kansas City Cardiomyopathy Questionnaire (23-item version) 
LAEF 
Left atrial emptying fraction 
LAFI 
Left atrial function index 
LAmaxVi 
Left atrial maximum volume, indexed for BSA 
LAminVi 
Left atrial minimum volume, indexed for BSA 
LAaEF 
left atrial active emptying fraction 
LArEF 
left atrial reservoir emptying fraction 
LVAD 
left ventricular assisted device 
LVEDD 
Left ventricular end diastolic diameter 
LVEDVi 
Left ventricular end diastolic volume, indexed for BSA 
LVEF 
Left ventricular ejection fraction 
LVESD 
Left ventricular end systolic diameter 
LVESVi 
Left ventricular end systolic volume, indexed for BSA 
LVFS 
Left ventricular fractional shortening 
LVGLS 
Left ventricular global longitudinal strain 
LVGCS 
Left ventricular global circumferential strain 
LVSV 
Left ventricular stroke volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MYH7 
Myosin Heavy Chain 7 
NT-proBNP 
N-terminal pro-B-type natriuretic peptide 
NYHA 
New York Heart Association 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
QTcF 
QT interval, corrected using Fridericia’s formula 
s’ 
Mitral valve annulus peak systolic velocity 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
 
 
sMDRD 
Simplified Modification of Diet in Renal Disease 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Mean terminal half life 
TBL 
Total bilirubin 
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TDI 
Tissue Doppler imaging 
TEAE 
Treatment-emergent adverse event 
TIBC 
Total iron-binding capacity 
Tmax 
Time of maximum observed plasma drug concentration 
TnI 
Troponin I 
TSH 
Thyroid-stimulating hormone 
TTE 
Transthoracic echocardiography, transthoracic echocardiogram 
TTN 
Titin 
ULN 
Upper limit of normal 
US 
United States 
V1B 
Part B baseline 
VUS 
Variant of uncertain significance 
 
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1 
INTRODUCTION 
Heart failure is a global pandemic, affecting about 26 million people worldwide (including about 
6.5 million people in the United States [US]) and its prevalence is increasing due to aging of the 
population. Despite therapeutic advances made over the past 10 to 20 years, heart failure remains 
a major source of morbidity and mortality, comparable to cancer, with about 50% of heart failure 
patients dying within 5 years. Heart failure is also the leading cause of hospitalization in patients 
aged 65 years or older in the US and represents a major financial burden to society (Braunwald 
2013; Yancy et al. 2013; Benjamin et al. 2017). Therefore, it is imperative that new, innovative 
therapies be developed for this condition. 
Dilated cardiomyopathy (DCM) is a disease of the myocardium defined by left ventricular 
enlargement and myocardial systolic and diastolic dysfunction in the absence of known abnormal 
loading condition or significant coronary artery disease.  Recently, hypokinetic non-dilated 
cardiomyopathy which is defined as left ventricular or biventricular global systolic dysfunction 
without dilatation in the absence of the same conditions for previously described DCM, has been 
considered as a part of DCM (McDonagh et al. 2021; Pinto et al. 2016). While DCM may affect 
up to 1 in 250 individuals worldwide, in some 20 to 30% of cases, the disorder is mediated by 
intrinsic variants in single genes in sarcomeric or structural proteins that can ultimately cause 
contractile dysfunction (Hershberger, Hedges, and Morales 2013).  
Myosin heavy chain 7 (MYH7) is a gene that encodes a β-myosin heavy chain protein. Certain 
variants identified in MYH7 have been shown to result in detrimental alterations in actomyosin 
that have been implicated in DCM (Ujfalusi et al. 2018).   
Titin (TTN) is a gene that encodes the protein titin, which is the largest protein in the human body 
that provides structure to the contractile elements of the cardiac sarcomere. Variants that truncate 
the protein have been implicated in the development of DCM (Herman et al. 2012), both alone and 
in concert with other provoking events, such as pregnancy (Ware, Seidman, and Arany 2016), 
anthracycline chemotherapy exposure (Linschoten et al. 2017), and chronic alcohol abuse (Ware, 
Seidman, and Arany 2016). These pathogenic variants are largely concentrated in the region of the 
protein termed the Aband where myosin is bound and may interfere with myosin heads’ ability to 
interact with actin (Roberts et al. 2015). However, rarer variants within the Z-disk and I-band that 
affect sarcomere assembly, structure, and integrity have been implicated in DCM as well (Herman 
et al. 2012). 
The Sponsor intends to develop danicamtiv (MYK 491; BMS‑986434) for the treatment of heart 
failure with reduced ejection fraction (HFrEF) and DCM, which together represent about 40% of 
heart failure. Contemporary medical therapy for systolic heart failure centers on counteracting the 
effects of maladaptive neurohormonal activation with β adrenergic blockers, diuretics, and 
modulators of the renin-angiotensin-aldosterone-system (Yancy et al. 2016). Although these drugs 
are effective and improve clinical outcomes, chronic, well-tolerated therapies that directly target 
the weakened myocardium and/or address the underlying cause of myocardial dysfunction are 
lacking. 
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2 
DANICAMTIV 
2.1 
Overview of Pharmacological Properties and Animal Studies  
Danicamtiv is a novel, orally active, small molecule in clinical development for HFrEF and DCM 
that binds selectively to cardiac myosin and improves cardiac contractility by directly increasing 
actomyosin cross-bridge formation. Binding of danicamtiv to myosin is reversible and does not 
inhibit subsequent cross-bridge detachment. In biochemical experiments, as well as in studies 
conducted in vivo in small and large animals (rats, dogs, and pigs), danicamtiv increased 
myocardial contractility with minimal impact on cardiac relaxation and without perturbing calcium 
homeostasis, unlike current standard inotropic drugs. Toxicology studies performed showed that 
observed toxicities were the result of exaggerated, on-target pharmacological effects consistent 
with the known mechanism of danicamtiv, without off-target effects (Section 9.4).  
Please refer to the Investigator’s Brochure (IB) for more detailed information on danicamtiv. 
3 
BACKGROUND 
3.1 
Summary of Clinical Experience to Date with Danicamtiv 
Four clinical studies with danicamtiv have been completed (3 in healthy participants, 1 in 
participants with HFrEF/DCM). A summary of the clinical experience to date is provided below. 
For more details, please refer to the latest IB.  
3.1.1 
Studies in Healthy Participants  
Three clinical studies with danicamtiv have been completed in healthy participants (MYK-491-001, 
MYK-491-002, 
). 
MYK-491-001: 
A 
single-ascending 
dose, 
double-blind, 
placebo-controlled, 
tolerance, 
pharmacokinetic (PK), and echocardiographic pharmacodynamic (PD) study in healthy participants. 
A total of 64 participants were enrolled across 8 cohorts. Dose levels studied were 
  
The PK profile showed 
 
Mean time to maximum observed plasma concentration (Tmax) was 
 and 
mean terminal half-life (t1/2) was 
 
 
 
 
 
  
Danicamtiv was generally well-tolerated at all doses. One participant, who received a single oral 
dose of 100 mg once daily (QD), experienced 3 short asymptomatic episodes of complete heart 
block (4 to 8 seconds each) during sleep, captured as a single adverse event (AE). This event was 
serious due to the need for in-hospital monitoring and was considered treatment-related by the 
Investigator, but no intervention was required. Three other participants exposed to danicamtiv, 
experienced brief asymptomatic episodes (2 to 3 beats) of ventricular arrhythmia. Such arrhythmias 
can occur in normal individuals undergoing continuous monitoring (Min et al. 2010).  
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 (25 and 75 mg 
 
 
 
 
 200 mg QD 
 
 
  
One participant experienced transient, asymptomatic, non-sustained, ventricular tachycardia 
lasting for approximately 10 beats and occurring at approximately 36 hours and at approximately 
82 hours postdose in a fasted state.  
3.1.2 
Study in Heart Failure Patients 
A single, Phase 1b/2a study with danicamtiv has been completed in heart failure participants. 
MYK-491-003: A randomized, double-blind, placebo-controlled, adaptive design evaluation of 
the safety, tolerability, preliminary PK, and echocardiographic PD of ascending single and 
multiple oral doses of danicamtiv in participants with stable, moderate HFrEF (ischemic or 
non-ischemic origin).  
In the single-ascending dose (SAD) portion of the study, 12 HFrEF participants received oral doses 
of danicamtiv (175 to 550 mg). In the multiple-ascending dose (MAD) portion of the study, 
40 HFrEF participants were randomized (30 danicamtiv, 10 placebo) and administered danicamtiv 
(50 to 100 mg twice daily [BID]) or placebo for 7 days; 7 of these 40 participants were enrolled in 
both the SAD and MAD portions of the study. In both parts of the study, danicamtiv was safe and 
generally well-tolerated. Mild transient troponin increases were observed with danicamtiv in both 
SAD and MAD cohorts. These increases were not associated with electrocardiogram (ECG) 
changes suggestive of ischemia and levels of troponin I and returned to normal or Baseline values 
by the end of the study. With the exception of one case where the troponin increase was deemed 
possibly related to myocardial injury and possibly related to study drug, all other troponin increases 
were asymptomatic. All instances of troponin elevation were transient and resolved without 
sequelae. In the MAD cohorts, mild asymptomatic, transient increases in troponin, meeting 
predefined criteria were observed in 4 participants (4/20 = 20%) exposed to danicamtiv versus 
none on placebo. There were no concomitant associated symptoms or ECG changes suggestive of 
ischemia (Voors et al. 2020). Of note, mild troponin elevation was also observed with omecamtiv 
mecarbil, another compound in this class of cardiac myosin activators currently being investigated 
in a large, Phase 3 cardiovascular outcome trial in HFrEF (Teerlink et al. 2016; Teerlink et al. 
2020). 
Single-Ascending Dose Portion 
 
 
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doses of danicamtiv were well-tolerated with exposure concentrations reaching 6000 to 
7000 ng/mL. One participant experienced the following AEs beginning 12 to 24 hours after dosing 
with the highest dose (550 mg) and lasting approximately 24 hours: dyspnea, cardiac discomfort, 
and elevated troponin levels. The troponin I level reached a maximum of 0.12ng/mL (4 times the 
upper limit of normal [ULN] for the assay of 0.03 ng/mL). The danicamtiv concentration during 
the AE was in the range of 4900 ng/mL. There were no concurrent ECG changes, and the 
participant recovered fully with no residual findings. 
Intermittent and mildly elevated levels of troponin occurred in several participants, though only 
the one described above was symptomatic. Elevated troponin levels than ULN were seen during 
active treatment with danicamtiv as well as predose and during placebo dosing, but Safety Review 
Committee-defined criteria for troponin increase were only seen during active danicamtiv dosing. 
There was no relationship of danicamtiv concentration to the presence of elevated troponin. This 
pattern of elevated troponin is similar to that reported with omecamtiv mecarbil (Teerlink et al. 
2016). The mechanism and significance of the troponin elevations in this class of drugs is currently 
unknown. 
Multiple-Ascending Dose Portion  
In the MAD portion of the study, 30 participants received danicamtiv at 50, 75, or 100 mg BID 
doses and 10 participants received matching placebo for 7 days. In general, danicamtiv was 
well-tolerated at all doses. There were neither drug-related serious adverse events (SAEs), nor 
drug-related AEs leading to treatment discontinuation. One SAE of hyperkalemia was reported, 
which resolved favorably and was not considered related to double-blind treatment. All observed 
AEs were of mild to moderate severity. There were no cardiac ischemic events or ventricular 
arrhythmia AEs that were significantly changed from Baseline. Mild, asymptomatic, transient 
elevations of troponin without concurrent ECG changes were observed in several participants at 
Baseline and during treatment with active danicamtiv, with no apparent relation to dose or plasma 
concentration.  
At steady-state, the PK data demonstrated a mean Tmax of approximately 6 hours with a broad peak 
lasting several hours and a mean terminal t1/2 of approximately 22 hours. The preliminary PD 
responses assessed by echocardiography were related to danicamtiv plasma concentrations as 
shown in Table 1. 
Table 1: 
Study MYK-491-003: Placebo-corrected Change from 
Baseline in Selected TTE Parameters by Danicamtiv Plasma 
Concentration Group (MAD Cohorts) 
 
 
 
MYK-491 Plasma Concentration (ng/mL) 
Parameter 
Statistic 
Baselinea 
(n = 40) 
< 2000 
(n = 30) 
2000-< 3500 
(n = 26) 
≥ 3500 
(n = 13) 
Plasma Concentration (ng/mL) 
Mean 
- 
1169 
2716 
4448 
 
SD 
- 
454 
425 
855 
 
Median 
- 
1220 
2740 
4290 
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Table 1: 
Study MYK-491-003: Placebo-corrected Change from 
Baseline in Selected TTE Parameters by Danicamtiv Plasma 
Concentration Group (MAD Cohorts) 
 
 
 
MYK-491 Plasma Concentration (ng/mL) 
Parameter 
Statistic 
Baselinea 
(n = 40) 
< 2000 
(n = 30) 
2000-< 3500 
(n = 26) 
≥ 3500 
(n = 13) 
LVEF (%) 
Mean changeb 
32.4 
-0.25 
1.12 
2.29 
 
SEc 
6.002 
0.872 
0.928 
1.158 
LVFS (%) 
Mean changeb 
18.18 
0.46 
0.78 
0.51 
 
SEc 
5.241 
0.537 
0.574 
0.725 
LVSV (mL) 
Mean changeb 
59.4 
3.1 
7.8** 
5.7* 
 
SEc 
12.9 
1.8 
2.0 
2.5 
LVESVi (mL/m2) 
Mean changeb 
60.0 
-0.9 
-1.3 
-4.6** 
 
SEc 
21.8 
1.3 
1.4 
1.7 
LVGLS (%) 
Mean changeb 
-11.2 
-0.3 
-0.9* 
-1.0* 
 
SEc 
2.3 
0.3 
0.4 
0.4 
LVGCS (%) 
Mean changeb 
-14.1 
-0.4 
-2.1** 
-3.3** 
 
SEc 
4.3 
0.6 
0.7 
0.8 
LVEF=left ventricular ejection fraction; LVESVi=left ventricular end systolic volume index; LVFS=left ventricular 
fractional shortening; LVGCS=left ventricular global circumferential strain; LVGLS=left ventricular global 
longitudinal strain;  
LVSV=left ventricular stroke volume; MAD=multiple-ascending dose; SE=standard error; 
 
 TTE=transthoracic echocardiogram 
P-values were computed using an analysis of covariance with fixed effects for group and covariate of baseline 
assessment and random effects for participant. 
* p<0.05. 
** p<0.01. 
a Absolute arithmetic mean values for the Baseline, where the Baseline was average value of measurements across 
all the predose values, excluding Screening. 
b LS mean difference (SE) between each plasma concentration bin (<2000, 2000-<3500 or ≥3500 ng/mL) and 
placebo (concentration=0) in TTE parameters change from Baseline. 
c SE=standard error of the LS mean difference. 
 
3.2 
Known and Potential Risks and Benefits 
There is no expectation of clinical benefit for participants who volunteer to participate in the study. 
Please see Section 10 for risks. 
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4 
RATIONALE FOR THE STUDY AND FOR DOSE AND DOSING 
SCHEDULE 
4.1 
Rationale for the Study 
In cases where MYH7 or TTN variants are implicated as the cause of DCM, biochemical studies 
have shown clear depression in actomyosin function culminating in reduced contractile force 
(Ujfalusi et al. 2018; Roberts et al. 2015). In further biochemical assays, danicamtiv has been 
shown to increase actomyosin ATPase rates in a variety of MYH7 variants and specifically 
 
 (internal data 
on file). This stands in contrast to omecamtiv mecarbil, which was shown in biochemical studies 
to have a reduced impact on ATPase activity in this particular mutant myosin F764L (Tang et al. 
2019). 
In cases of DCM related to TTN variants, the vast majority occur in the A-band of the final protein 
where myosin heads are attached. These variants truncate the final protein product and ostensibly 
decrease the number of myosin heads available to interact with actin. In human induced pluripotent 
stem cardiomyocyte tissues possessing known truncating variants of TTN, exposure to a 
compound closely related with similar activity to danicamtiv demonstrated significant increases in 
maximal twitch tension (Hinson et al. 2015). Based on this evidence, the hypothesis of this 
exploratory study is that MYH7-DCM and TTN-DCM patients may be particularly suited to 
treatment with danicamtiv since it appears to address the very defect exhibited in these patients 
that results in cardiac dysfunction. It is possible these patients may either demonstrate PD 
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responses at doses not expected to be effective in the general HFrEF population or may see greater 
and/or more consistent PD responses at doses shown to be effective in general HFrEF.  
Participants enrolled in the study will have primary DCM that is not explained by ischemic heart 
disease or other reasons such as valvulopathy, and a documented DCM-causing MYH7 or TTN 
variant. In the amended protocol, danicamtiv will also be assessed in the individuals with primary 
DCM not related to MYH7 or TTN variants to preliminarily evaluate generalizability of safety and 
PD responses in the broader DCM population.  Clinical relevance of genetic variants in DCM have 
been studied in several observational studies in DCM patients.  Accumulating data suggest 
different clinical course per etiology and the underlying affected gene (Escobar-Lopez et al, 2021; 
Anderson et al, 2020; Shah et al, 2021).  These studies also revealed different response to HFrEF 
GDMT by the presence of genetic-causality and the affected gene. A recent natural history study 
in MYH7-DCM patients observed only 28% of the 106 study participants achieved left ventricular 
remodeling (LVRR) by HFrEF GDMT during 4.5 years (median,  IQR: 1.7-8.0 years) follow up 
period (de Frutos et al, 2022), although LVRR is generally observed around 50% of DCM patients 
(Escobar-Lopez et al, 2021).  To date, there has been no approved therapy with the same MoA of 
Danicamtiv for DCM and HFrEF.  Preliminary PD effects of danicamtiv in DCM patients by 
different underlying causality will be explored.     
There is precedent in early development of novel heart failure therapies to conduct pilot studies in 
small numbers of patients with an open-label and baseline-controlled design in order to document 
a therapeutic effect prior to conducting larger, placebo-controlled trials (Gronda et al. 2014; 
Thomas, O’Gorman, and Sheridan 1993) 
4.2 
Rationale for Dose and Dosing Schedule 
In Part A, the choice of the initial dose (25 mg BID) and treatment duration (up to 5 to 8 days) have 
been selected as they are expected to lead to steady-state peak concentrations (1000 to 2000 ng/mL). 
This concentration range appears to be sub-therapeutic in the general HFrEF participant population 
based on Study MYK-491-003 MAD, but may be therapeutic in the genetic DCM population. The 
choice of the scheduling window for treatment duration is to accommodate weekends and holidays; 
the 2 treatment periods do not need to have the same duration. After Treatment Period 1, a 
transthoracic echocardiogram (TTE) will be performed for an initial evaluation of the PD response 
(based on 
) to determine dosing for Treatment Period 2, which will entail either a 
decrease to 10 mg BID (if participant responded to 25 mg BID and in order to assess possible 
response to a lower dose) or an increase to 50 mg BID (if participant had no substantial response 
with 25 mg BID and to assess response to a higher dose). 
In Part B, initial individual participant doses will be based on 
 in Part A, regardless of 
whether a participant has to be rescreened in Part B. The Part B starting dose can be either one of 
5 mg BID, 10 mg BID, 25 mg BID, 50 mg BID, or 75 mg BID:  
• 
If one of the doses in Part A resulted in a 
 and 
, then that 
is the dose for Part B (10, 25, or 50 mg BID) 
• 
If both doses in Part A resulted in a 
 and
, then the dose 
for Part B is the lower of the 2 doses that the participant received in Part A 
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• 
If both doses in Part A resulted in a 
 of 
 with 10 and 25 mg BID, 
then the Part B dose for that participant is 50 mg BID 
• 
If both doses in Part A resulted in a 
 of 
 with 25 and 50 mg BID, 
then the Part B dose for that participant is 75 mg BID 
• 
If both doses in Part A resulted in a 
 of 
 with 10 and 25 mg BID, 
then the Part B dose is 5 mg BID 
• 
If both doses in Part A resulted in a 
 of 
 with 25 and 50 mg BID, 
then the Part B dose for that participant is 10 mg BID 
• 
If 25 mg BID dose from Part A 
 and 10 mg BID dose from Part A 
 10 mg BID 
• 
If 25 mg BID dose from Part A 
 and 50 mg BID from Part A 
25 mg BID 
 
For participants who could not complete Part A or completed TTE assessments outside of the 
protocol defined window may participate in Part B after investigator discussion with the Sponsor. 
The reasons of incompletion of Part A should be due to reasons other than treatment-emergent 
adverse event (TEAE) considered as study drug related by the investigator, meeting study 
discontinuation criteria, or withdrawal of the informed consent.  Part B starting dose for such cases 
is described in following 2 bullets.  
• 
If 
 of both doses were unavailable or performed significantly outside of the 
assessment window (see Appendix 1. Part A SoA foot note g), then the Part B dose will be 50 
mg BID.   
• 
If a 
 was only available with 25 mg BID (Treatment Period 1) and a 
 
was 
 and 
, then 25 mg BID is the dose for Part B. If a 
 was 
, then the Part B dose is 50 mg BID.  If 25 mg BID dose resulted in a 
 
 then the Part B dose for that participant is 10 mg BID  
Part B dose adjustment:  
• 
After the initiation of Part B dosing, TTE will be performed at Visit 2B and Visit 3B to ensure 
adequate PD responses. The PD responses from these two TTEs compared to Part B baseline 
(V1B) will yield the following dose titrations at Visit 3B: 
• 
If there is a 
of 
 on both TTEs at Visits 2B and 3B compared 
from V1B, based on local assessments, the dose will be titrated up to the next dose level. If a 
participant is already receiving the highest dose (75 mg BID), per the Investigator’s discretion, 
the participant will continue the study at 75 mg BID or discontinue the study (Section 6.2.2). 
• 
If there is a 
 of 
 on both TTEs at Visits 2B and 3B compared 
from V1B, based on local assessments, the dose will be titrated down to the next dose. If a 
participant is already receiving the lowest dose (5 mg BID), the participant will be discontinued 
from the study (Section 6.2.2).  
• 
If there is a 
 and 
 on at least one of TTEs at Visits 2B or 
3B compared from V1B, no dose change is needed. 
• 
If 
 at Visit 2B and 3B are 
 at one visit and >
 at 
the other, no dose change is needed. 
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Results of this study will inform potential subsequent clinical development in a genetic DCM 
subpopulation. 
5 
STUDY OBJECTIVES 
5.1 
Primary Objectives 
The primary objective of this study is: 
• 
To establish preliminary safety and tolerability of treatment with danicamtiv in participants 
with MYH7-DCM or with TTN-DCM, or DCM by other causalities for Part A. 
5.2 
Secondary Objectives 
The secondary objective of this study is: 
• 
To establish the preliminary effect, compared with Baseline, of treatment with danicamtiv on 
cardiac PD, as determined by TTE in participants with MYH7-DCM or TTN-DCM, or DCM 
by other causalities. 
5.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
• 
To establish the preliminary effect of danicamtiv on overall activity level in participants with 
MYH7-DCM or TTN-DCM, or DCM of other causalities. 
• 
To determine long term preliminary safety and tolerability of treatment with danicamtiv in 
participants with MYH7-DCM or TTN-DCM, or DCM of other causalities Part B. 
• 
To determine the timeline and durability of effects of danicamtiv on cardiac structure and 
function in participants with MYH7-DCM or TTN-DCM, or DCM of other causalities utilizing 
cardiac magnetic resonance (CMR) as well as continuing serial TTE assessments for Part B.  
• 
To explore the exposure-response relationship between danicamtiv exposure and TTE 
parameters in participants with MYH7-DCM, TTN-DCM, and DCM of other causalities. 
• 
To explore the effect of danicamtiv on soluble biomarkers of cardiac physiopathology in 
participants with MYH7-DCM, TTN-DCM, and DCM by other causalities. 
• 
To explore the different effects of danicamtiv on safety and PD between the groups of MYH7-
DCM, TTN-DCM, and primary DCM not related to MYH7 or TTN   
• 
To explore the natural course of cardiac status in participants with MYH7-DCM or TTN-DCM, 
or DCM of other causalities who participate in the observational study  
6 
OVERALL STUDY DESIGN AND PLAN 
6.1 
Study Design 
This is a 3-cohort, baseline-controlled, sequential, 2-period, open-label study with an optional 
extension investigating the safety and efficacy of danicamtiv in stable, ambulatory participants 
with primary DCM due to either MHY7 or TTN variants, or primary DCM due to other causalities 
not related to MYH7 or TTN variants. Total enrollment of approximately 40 participants 
(approximately 12 participants with MYH7 variant, 12 participants with TTN variant, and 
approximately16 participants with DCM not caused by MYH7 or TTN variant) ages 18 to 80 years 
is planned.  
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Note: The ratio of participants with DCM-causing variants (other than MYH7 or TTN) and non-
genetic cause will be approximately 1:1. 
6.1.1 
Part A 
Screening 
After providing informed consent, the participant’s anonymized genetic information will be 
communicated to the Sponsor at the time of the first Screening visit. Eligibility for the study, based 
on specific MYH7 or TTN variant, and presence of DCM-causing variant of the other genes will 
be assessed centrally by the Sponsor and Coordinating Investigator (Section 7.1).  Pre-Screening 
using historical genetic report may be conducted prior to Screening visit (VA1.1) where allowed 
by local regulations (APPENDIX 1).   
Participants will undergo 1 or 2 Screening visits to assess qualification for study participation over 
within 56 days of the Baseline visit (see Schedule of Assessments Part A, APPENDIX 1). Samples 
for genetic testing will be collected at Screening and assessed at a central genetic laboratory, where 
available.  Genetic testing results will be submitted for central genetic reviewers for review and 
approval as described in the Central Genetic Review Charter.  For the participants who were 
enrolled based on genetic testing results that were not conducted at a central genetic laboratory, 
their genetic status will be confirmed retrospectively via genetic testing at a central genetic 
laboratory after being enrolled into the study. Screening will include, but not be limited to: medical 
history, physical examination, safety laboratory tests, 12-lead ECG (triplicate), and 1 to 2 TTEs. 
If a qualifying prior TTE, performed within the past 12 months, is available, then another TTE is 
required at the first Screening visit.  The absolute difference of the left ventricular ejection fraction 
(LVEF) between the qualifying prior TTE and the second TTE at Screening must be < 12%. If 
there is no prior TTE within the past 12 months, then 2 Screening TTEs are required. TTEs must 
be performed at least 7 days apart during the Screening period, and there should be < 12% 
difference between the 2 LVEF values. 
Abnormal findings from laboratory assessments performed at Visit 1.1A may be repeated once 
during Screening.  
If a qualifying prior TTE is being used to qualify the participant, a cardiac rhythm monitoring 
patch will be placed after a TTE In Screening. If 2 Screening TTEs are required, the patch will be 
placed at the conclusion of the second TTE. The duration of cardiac rhythm monitoring will be at 
least 5 days and a maximum of 14 days. If the patch becomes detached before 5 days, the 
participant will need to return to the clinic so that another patch is placed.  
 
In addition, the protocol-specified Screening window may be extended due to participant or site 
scheduling issues, shipment delays (ie, study drug or essential equipment), or other unforeseeable 
issues (ie, due to the COVID-19 pandemic or natural disasters). The decision to extend the 
Screening window and/or repeat any assessments will be made on a per participant basis at the 
discretion of the Sponsor in consultation with the site Investigator. 
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Guidance on COVID-19 risk mitigation is outlined in APPENDIX 5. 
Rescreening is acceptable upon discussion with and documented approval by the Sponsor’s 
Medical Monitor. If rescreening is conducted, repeat of genetic testing at Screening is not 
necessary. Up to one (1) rescreen per participant is permitted. 
A study schema depicting the design of Part A is provided in Figure 2.  
Open-label Treatment Periods:  
All enrolled participants will undergo 2 open-label treatment periods with active study drug. Both 
treatment periods will last 5 to 8 days (see Schedule of Assessments, APPENDIX 1) and do not 
need to have the same duration. 
Treatment Period 1 (5 to 8 days):  
Visit 2A (Day 1 of Treatment Period 1): Baseline assessments, including a TTE (see Schedule of 
Assessments, APPENDIX 1), will be completed prior to administration of the first dose of study 
drug which is to be taken by the Participant prior to leaving the study site. The participant will be 
given adequate study drug (25 mg BID for up to 8 days) as well as clear study drug administration 
instructions from the site (every day, BID, at each administration). On Day 1, if baseline 
assessments are completed in the afternoon, then study drug will only be administered once in the 
afternoon.  A cardiac rhythm monitoring patch will be placed at the conclusion of the visit. 
Duration of cardiac rhythm monitoring may be between 5 and 14 days. If the patch becomes 
detached before 5 days, the participant will need to return to the clinic so that another patch is 
placed prior to leaving the study site. 
Telehealth Visit (TH) 1A: 1 to 3 days before the end of Treatment Period 1, the participant will be 
contacted via telephone, two-way text message, or e-mail (APPENDIX 1) to ensure compliance 
with study drug administration, to check for new AEs and concomitant medications, to remind the 
participant of the next scheduled clinic visit, and to take study drug in the morning of the next visit 
approximately 7 hours prior to the scheduled time of the visit. 
Visit 3A – End of Treatment Period 1 (Day 5 or up to Day 8): Participants will return for a clinic 
visit in the afternoon on Day 5, 6, 7, or 8, approximately 7 hours after the morning dose, for 
assessments of safety, tolerability, study drug plasma concentration, and evaluation of the PD 
response. A TTE and other study assessments including, but not limited to, 12-lead ECG and 
cardiac rhythm monitoring will be completed (see Schedule of Assessments, APPENDIX 1). The 
Investigator will evaluate for the absence of permanent discontinuation criteria including, but not 
limited to, the absence of excessive prolongation of QTcF (Section 6.2.2) to confirm that the 
participant can continue with the study. The cardiac sonographer at each local site will carefully 
measure 
 (Section 11.1.1) and promptly communicate the 
 from Baseline value 
(change from 
 determined at Visit 2A) to the Study Coordinator and Investigator. This result 
will determine the dose for Treatment Period 2, either 50 mg BID beginning that evening or 10 
mg BID beginning the following morning (Section 6.1). 
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The Investigator and/or Study Coordinator will inspect the cardiac rhythm monitoring patch. If the 
adhesive appears intact, the existing patch should be left in place. If the adhesive appears to be 
failing or the patch has become detached, then a new patch should be applied at this time. 
Treatment Period 2 (5 to 8 days):  
From Visit 3A until Visit 4A: Danicamtiv must be taken BID either starting in the evening of Visit 
3A or the morning after Visit 3A, depending on the results of the 
 from the TTE performed at 
Visit 3A. Participants should continue taking study drug through Visit 4A (see below under Visit 
4A). 
Telehealth Visit (TH) 2A: 1 to 3 days before the end of Treatment Period 2 (Visit 4A), the 
participant should be contacted via telephone, two-way text messaging, or e-mail (APPENDIX 1) 
to ensure compliance with study drug administration, to check for new AEs and concomitant 
medications, to remind the participant of the next scheduled clinic visit, and to take study drug in 
the morning of the next visit approximately 7 hours prior to the scheduled time of the visit. 
Visit 4A – End of Treatment Period 2 (5 to 8 days after Visit 3A): Participants will return to the 
clinic for assessments of safety, tolerability, study drug plasma concentration, and evaluation of 
the PD response.  
The last dose of study drug will be taken in the morning, approximately 7 hours before the clinic 
visit 5 to 8 days after Visit 3A. A TTE and other study assessments including, but not limited to, 
laboratory and plasma concentration blood samples, 12-lead ECG (triplicate), and cardiac rhythm 
monitoring will be completed (see Schedule of Assessments, APPENDIX 1). 
Early Termination Visit: If, after enrollment and receipt of any danicamtiv treatment, a decision is 
made that the participant should discontinue, an Early Termination Visit should be conducted as 
soon as feasible to ensure participant safety. 
Part A Completion vs Part B Start:  
After Visit 4A in Part A, each participant will have the option to continue onto Part B or to only 
complete the remaining Part A study visits. If a participant opts to continue onto Part B, the 
participant will need to sign the Part B ICF (Section 6.1.2). If a participant does not opt to continue 
onto Part B of the study, then refer to the Part A Follow-up below. 
Part A Follow-up: 
Telehealth Visit (TH) 3A: 
The participant should be contacted (APPENDIX 1) 1 to 3 days following the last dose of study 
drug to assess safety.  
Visit 5A – A study clinic visit to assess participant safety will occur 14 days (+ 7 days) following 
the last dose of study drug regardless of the participant’s participation in Part B (see Schedule of 
Assessments, APPENDIX 1). 
Guidance on COVID-19 risk mitigation is outlined in APPENDIX 5. 
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Figure 2: 
Part A Study Schema 
 
BID = twice daily; DCM = dilated cardiomyopathy; LVEF = left ventricular ejection fraction; MYH7 = myosin heavy 
chain 7; 
; TTE = transthoracic echocardiogram; TTN = Titin; V = visit 
a  Each Part A Treatment Period will be between 5-8 days and the 2 periods need not be the same duration. 
b  Participant screening may include a preliminary consent to review existing genetic testing results and 1 to 3 visits 
to confirm eligibility with 2 TTEs (1 may be historic within the last 12 months). 
c  Participant should be contacted 1 to 3 days prior to Visit 3A and Visit 4A (telehealth) to check for any new or 
worsening adverse events and review concomitant medications, ensure compliance with study drug, and to remind 
participant to take study treatment on the morning of Visit 3A and Visit 4A (visits with a TTE scheduled in the 
afternoon 5-8 days after Visit 2A and 3A, and approximately 7 hours after dosing).  
d  If 
, then study drug should be discontinued permanently (Section 6.2). 
 
6.1.2 
Part B 
A study schema depicting the design of Part B is provided in Figure 3.  
The expected study duration for Part B for each participant is approximately 102 weeks, including 
a 4-week Rescreening period, if needed. This period does not include a potential hiatus between 
Parts A and B for some participants.  
Part B will commence after a participant completes Part A and consents to continue onto Part B. 
If a participant does not complete Part A or completed outside of the protocol defined window due 
to reasons other than treatment-emergent adverse event (TEAE) considered as study drug related 
by the investigator, meeting study discontinuation criteria, or withdrawal of the informed consent, 
Part B participation will be assessed and approved in discussion with the Sponsor.     
If a participant has completed Part A more than 56 days prior to the start of Part B, then a 
Rescreening visit is required (see Schedule of Assessments, APPENDIX 1). 
If a Rescreening visit is not required prior to Part B start, then Visit 1B can be performed on the 
same day as Visit 5A and any assessments in Visit 5A that are also required in Visit 1B need to only 
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be performed once. A repeat of rescreening is acceptable after discussion with and documented 
approval by the Sponsor Medical Monitor. 
A cardiac rhythm monitoring patch will be placed at Visit 1B, Visit 6B, Visit 8B, Visit 10B, and 
EOT (see Schedule of Assessments, APPENDIX 1) and will be mailed back to the site by the 
participant after 2 weeks or when it spontaneously detaches after at least 5 days of monitoring. If 
the patch becomes detached prior to 5 days since application, a new patch should be placed as soon 
as possible at the site. 
Individual participant doses for Part B will be based on 
 in Part A (Section 4.2), 
regardless of whether a participant requires rescreening for Part B. After the initiation of Part B 
dosing, a TTE will be performed at Visit 2B and Visit 3B to ensure adequate PD responses, based 
on local assessments, with the potential for dose titration at Visit 3B (Section 4.2).  Visit 2B, 3B, 
4B, 6B, 8B, 10B and EOT should be planned to perform a TTE and blood draw for study drug 
plasma concentration, etc. at approximately 7 hours after the morning dose.    
High sensitivity troponin T (hsTnT), high sensitivity Troponin I (hsTnI), and standard troponin I 
(TnI), will be evaluated multiple times throughout the study in Parts A and B in conjunction with 
a 12-lead ECG. 
During Part B, TnI (standard) results will be communicated to the study sites by the central 
laboratory, as they are available, and will be part of an algorithm to evaluate the significance of 
TnI increase in this participant population. Details of this process are provided in Section 11.4.6.  
In addition to routine safety evaluations, additional assessments in Part B will include, but not be 
limited to, N-terminal pro-B-type natriuretic peptide (NT-proBNP) evaluation, activity 
monitoring, CMR (for suitable study participant), 6-Minute Walk Distance (6MWD), New York 
Heart Association (NYHA) Functional Classification assessments, and Kansas City 
Cardiomyopathy Questionnaire (23-item version) (KCCQ-23) measurements (see Schedule of 
Assessments, APPENDIX 1). 
Early Termination Visit: If, after enrollment and receipt of any danicamtiv treatment, a decision is 
made that the participant should discontinue, then an Early Termination Visit should be conducted 
as soon as feasible to ensure participant safety. 
End of Study / Follow-up Visit: A study clinic visit to assess safety will be made 4 weeks 
(± 1 week) following the last dose of study drug (see Schedule of Assessments, APPENDIX 1).  
Participants who do not opt in for Part B have the option of participating in an observational study 
without study drug administration (Part B observational study). Limited study assessments at 
smaller number of study visits will be performed after participants consent to this observational 
study (see Schedule of Assessments, APPENDIX 1).     
 
 
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Figure 3: 
Part B Study Schema 
 
 
a For participants who did not complete Part A due to reasons other than treatment-emergent adverse event (TEAE) 
considered as study drug related by the investigator, meeting study discontinuation criteria, or withdrawal of the 
informed consent, Part B participation may be assessed and approved in discussion with the Sponsor. Part B initial 
dose for this case can be found in Sections 4.2 and 9.2.2. 
b Dose change may occur at Visit 3B.  
 
6.2 
Treatment Discontinuation 
6.2.1 
Temporary Treatment Discontinuation (or Treatment Interruption) 
In case permanent discontinuation criteria in Section 6.2.2 are not met, temporary treatment 
discontinuation (skipping one or several doses of study drug; doses may be skipped for additional 
days in agreement between Sponsor’s Medical Monitor and the Investigator) may be considered 
for the following situations: 
• 
Participant experiences an AE/SAE and upon Investigator’s opinion that a temporary treatment 
discontinuation should be applied. Every effort should be made to resume study drug after 
careful consideration by the Investigator and if the participant does not meet any permanent 
discontinuation criteria. The study drug may be resumed at the same or lower dose after 
discussion with the Sponsor’s Medical Monitor.  
• 
Part B only – participant has confirmed TnI levels which exceed 0.1 ng/mL. Treatment will be 
temporarily discontinued until a decision is reached by the Coordinating Investigator, the 
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consulting Safety Reviewer, and the Sponsor’s Medical Monitor, as described in 
Section 11.4.6. 
• 
For other reasons upon Investigator’s consideration 
• 
By the Investigator in cases of TnI increase > 0.1 ng/mL above Baseline as mentioned 
previously (Section 11.4.6) or from AE/SAE or other reason. In cases of TnI increase 
> 0.1 ng/mL with appropriate confirmation, treatment with danicamtiv will be discontinued 
until a decision is reached by the Coordinating Investigator, the consulting Safety Reviewer, 
and the Sponsor’s Medical Monitor, as described in Section 11.4.6. If a decision was not 
permanent discontinuation, the study drug will be resumed at the same or lower dose 
recommended by the Coordinating Investigator, the consulting Safety Reviewer, and the 
Sponsor’s Medical Monitor.  
6.2.2 
Permanent Treatment Discontinuation 
Permanent discontinuation of study drug should be applied for the following situations: 
• 
Part A – participant has a 
 at Visit 3A (End of Treatment 
Period 1) based on local site assessment (Section 11.1.1)  
• 
Part B – participant has a 
 of 
 at both Visit 2B and Visit 3B 
compared from Part B baseline 
, based on local site assessment, and is already receiving 
the lowest dose (5 mg BID). (Section 7.3.2 and 9.2.2)  
• 
Part B – a participant has a 
 of 
 at both Visits 2B and 3B 
compared from Part B baseline 
 based on local assessment, and is already receiving the 
highest dose (75 mg BID). Per the Investigator’s discretion, the participant will continue the 
study at 75 mg BID (Section 7.3.2 and 9.2.2) 
• 
Participant has drug-related coronary ischemia, as determined by the Investigator 
NOTE: The whole context (clinical symptoms, ECG, and cardiac biomarkers, such as troponin, 
creatine kinase-MB fraction [CK-MB], cardiac imaging, and coronary angiograms, if 
applicable) should be taken into account by the Investigator in making that determination since 
participants enrolled in the study are likely to have an abnormal ECG and/or elevated and/or 
fluctuating troponin at Baseline in relation to their heart failure condition. 
• 
Participant has a drug-related SAE 
• 
A participant has a QTcF interval > 500 milliseconds (corrected using Fridericia’s formula), 
average of triplicate ECGs) not attributable to ventricular pacing or prolonged QRS duration 
(≥ 120 milliseconds). 
• 
Participant fulfills the criteria for potential drug-induced liver injury (Hy’s Law), including: 
• 
Aminotransferases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) are 
> 3 times ULN with an associated elevation of total bilirubin (TBL) > 2 times ULN without 
evidence of hemolysis, or 
• 
ALT or AST activity that is > 5 times ULN, or 
• 
TBL > 3 times ULN 
• 
Participant request  
• 
If in the Investigator’s opinion, continuation of administration of study treatment would be 
detrimental to participant’s safety or well-being 
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• 
At the specific request from the Sponsor 
Investigators are strongly encouraged to discuss with the monitoring team and/or the Sponsor in 
case a treatment discontinuation (temporary or permanent) is being considered. 
In case of early permanent treatment discontinuation, an Early Termination Visit should be 
scheduled as early as possible to perform End of Study assessments, including, but not limited to, 
evaluations of clinical safety and tolerability, as well as a TTE (APPENDIX 1).  
6.2.3 
Data Reviews  
All collected data will be reviewed by the Coordinating Investigator and the Sponsor’s Medical 
Monitor after 4 participants have completed Part A in each of the 3 cohorts (MYH7 and TTN 
variants or other causalities). This review is primarily to assess safety, given the potential for an 
outsized clinical response in this mechanism of disease. The magnitude of clinical response will 
also be evaluated during these reviews – one for each cohort. Additional reviews may be conducted 
by the Sponsor at any time during Part A. During these reviews, enrollment may continue 
uninterrupted. If no safety signal is detected, complete data will be formally reviewed when all 
participants have completed dosing in Part A.  
For Part B, safety reviews will be performed by the Coordinating Investigator, the Sponsor’s 
Medical Monitor, and the consultant safety reviewer on regular basis (approximately every 3 to 6 
months) to ensure there are no safety concerns. Discontinuation of participants and dose 
adjustments may be considered based on the safety data.  
6.2.4 
Discontinuation of Study 
The Sponsor reserves the right to terminate the study at any time for any reason including, but not 
limited, safety, lack of efficacy, or for strategic reasons. 
6.3 
Study Duration 
The durations listed below are for each individual participant: 
Part A: The expected study duration for Part A ranges from approximately 4 to 11 weeks, including 
2 to 8 weeks for Screening, approximately 9 to 16 days (Note: Day 16 only applies to the case 
when the dose was down-titrated in Treatment Period 2.) for treatment, and approximately 2 weeks 
for follow-up.  
Part B: The expected study duration for Part B is approximately 102 weeks, including a 4-week 
Rescreening period, if needed. This period does not include a potential hiatus between Parts A and 
B for some participants.  
The total duration of the study for Parts A and B is up to 115 weeks.  
The end of study is defined as the last participant last visit (LSLV) date of Part B. 
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7 
SELECTION OF STUDY POPULATION 
7.1 
Inclusion Criteria 
Part A: 
Each participant in Part A must meet the following criteria to be included in this study.  
Informed Consent: 
I1. Able to understand and comply with the study procedures, understand the risks involved 
in the study, and provide written informed consent according to federal, local, and 
institutional guidelines before the first study-specific procedure. 
Age: 
I2. Men or women 18 to 80 years of age (inclusive) at the Screening visit. 
Type of Participant and Disease Characteristics:  
I3. For MYH7 and TTN cohorts, diagnosis of primary DCM, clinically stable and due to 
probably disease-causing variant of MYH7 or TTN as defined by (a) through (f) of the 
following.  All study participants must meet (g) and (h) criteria: 
a. Primary DCM participants that have no identified etiology other than variant in MYH7 
or TTN (e.g., coronary artery disease or severe valvulopathy), as determined by the 
Investigator. Participants with a diagnosis of heart failure with reduced ejection fraction 
should be on Guideline Directed Medical Therapy as tolerated. 
NOTE: Presence of coronary artery disease, functional mitral regurgitation, or mild-
to-moderate valvular disease may be allowed if not considered the primary cause of 
the heart failure based on evaluation by the Investigator. Moderate aortic stenosis 
should be excluded. 
b. Pathogenic or likely pathogenic variants submitted in the form of final official genetic 
laboratory reports will be reviewed centrally by the Sponsor and the Coordinating 
Investigator for eligibility. Some variants designated variant of uncertain significance 
(VUS) may also be permitted upon central review. 
Note: Participant s with titin variants in the Z-disk and I-band regions will be excluded 
from the study (even if regarded as Pathogenic or Likely Pathogenic). 
c. DCM is not secondary to long-standing MYH7- or TTN-related hypertrophic 
cardiomyopathy or left ventricular noncompaction cardiomyopathy, as determined by 
the Investigator.  
NOTE: Hypertrabeculation of the left ventricular myocardium is not, in and of itself, a 
criterion for exclusion. 
d. Participants with DCM related to pathogenic or likely pathogenic variants of TTN must 
not also have a diagnosis of peripartum DCM (defined by DCM diagnosed initially in 
the last month of pregnancy or the 6 months following delivery). 
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e. In participants with DCM related to pathogenic or likely pathogenic variants of TTN, 
DCM must not be secondary to significant exposure to cardiotoxic chemotherapy 
agents, as determined by the Investigator. 
f. In participants with DCM related to pathogenic or likely pathogenic variants of TTN, 
DCM must not be due to a history of significant alcohol abuse, as determined by the 
Investigator. 
g. Documented LVEF 15 to 45% (on 2 occasions), including at least once during 
Screening and confirmed by the Echo Core Laboratory.  
 If a participant’s most recent prior TTE (within past 12 months) documents a LVEF 
≤ 45%, then only a single Screening visit confirming LVEF ≤ 45% by the Echo 
Core Laboratory is required.  
 If no prior documented LVEF ≤ 45% by TTE within the past 12 months is available, 
then 2 Screening TTEs are needed at least one week (7 days) apart. 
 In addition, the absolute difference between the 2 LVEF values qualifying the 
participant should be < 12%. 
h. Participant receives chronic medication for the treatment of heart failure reflecting 
current guidelines, including at least one of the following, unless not tolerated or 
contraindicated: β-blocker, angiotensin converting enzyme inhibitor, angiotensin 
receptor blocker, or angiotensin receptor neprilysin inhibitor. Such treatments should 
have been given at stable doses for ≥ 2 weeks with no plan to modify during the study. 
I4. Sinus rhythm or stable atrial or ventricular pacing or persistent atrial fibrillation that is 
adequately rate-controlled to allow PD assessments by TTE. 
NOTE: Participants with implanted cardioverter defibrillator, pacing, or cardiac 
resynchronization therapy are eligible if provided device programming is unchanged 
starting 2 months prior to and throughout the dosing period. 
I5. If multiple members of a family meet eligibility criteria, a maximum of 3 eligible 
participants per family may enroll in the study. 
I6. Female participants of childbearing potential (Appendix 6) must not be pregnant or 
lactating and, if sexually active, must use one of the following highly effective birth control 
methods from the Screening visit through 3 months after the last dose of study drug 
• 
combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation or progestogen-only hormonal contraception associated with inhibition 
of ovulation by oral, implantable, or injectable route of administration 
• 
intrauterine device (IUD) 
• 
intrauterine hormone-releasing system (IUS) 
• 
Female participant is surgically sterile. Surgical sterilization includes documented 
hysterectomy, bilateral oophorectomy, bilateral salpingectomy, and/or bilateral tubal occlusion 
or ligation prior to Screening.  
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• 
Female participant postmenopausal for 1 year. Female subjects are considered postmenopausal 
if they have had amenorrhea for at least 1 year or more following cessation of all exogenous 
hormonal treatments, and follicle-stimulating hormone (FSH) levels are in the postmenopausal 
range. 
• 
Male partners must also use a contraceptive (eg, barrier, condom, or vasectomy). 
I7. Male participants must use barrier method of contraception (whether or not the participant 
had vasectomy). 
I8. For the cohort of primary DCM due to causalities other than MYH7 and TTN, participant 
must meet the following criteria in addition to I1, I2, I3-g & h, I4, I5, I6 and I7. 
a. The cause of DCM is not related to MYH7 or TTN variants.   
b. The cause of primary DCM is by variants of other genes except MYH7 and TTN, or 
non-genetic cause  
Note: The ratio of participants with known DCM-causing variants (other than MYH7 
or TTN) and non-genetic cause will be approximately 1:1.  
c. DCM is chronic; not due to acute or possibly reversible conditions (eg, 
hyper/hypothyroidism, infectious cause, tachyarrhythmia, iron overload) according to 
investigator’s determination.  
d. DCM is not attributed to pregnancy, alcohol abuse, substance abuse, amyloidosis, 
sarcoidosis, or any other secondary form of cardiomyopathy per the investigator’s 
determination. 
Part B: 
Each Part A participant who opts in for Part B must meet the following criteria.  
Note 1: If no Rescreening Visit is required, the following criteria must be evaluated by or at Part 
B Baseline Visit prior to dosing.  
Note 2: I4 and I5 only applies to participants in Part B receiving danicamtiv, not the participants 
in the observational study.  
I1. Able to understand and comply with the study procedures, understand the risks involved 
in the study, and provide written informed consent according to federal, local, and 
institutional guidelines before the first study-specific procedure. 
I2. Participant receiving chronic medication for the treatment of heart failure reflecting current 
guidelines, including at least one of the following, unless not tolerated or contraindicated: 
β-blocker, angiotensin converting enzyme inhibitor, angiotensin receptor blocker, or 
angiotensin receptor neprilysin inhibitor. Such treatments should have been given at stable 
doses for ≥ 2 weeks prior to the start of Part B. 
I3. Sinus rhythm or stable atrial or ventricular pacing or persistent atrial fibrillation that is 
adequately rate-controlled to allow PD assessments by TTE.  
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NOTE: Participants with implanted cardioverter defibrillator, pacing, or cardiac 
resynchronization therapy are eligible if provided device programming is unchanged 
starting 2 months prior to Part B.   
I4. Female participants of childbearing potential (Appendix 6) must not be pregnant or 
lactating and, if sexually active, must use one of the following highly effective birth control 
methods after participants signed Part B informed consent through 3 months after the last 
dose of study drug 
• 
combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation or progestogen-only hormonal contraception associated with inhibition 
of ovulation by oral, implantable, or injectable route of administration 
• 
intrauterine device (IUD) 
• 
intrauterine hormone-releasing system (IUS) 
• 
Female participant is surgically sterile. Surgical sterilization includes documented 
hysterectomy, bilateral oophorectomy, bilateral salpingectomy, and/or bilateral tubal occlusion 
or ligation before and/or at the signing of the Part B informed consent execution.  
• 
Female participant postmenopausal for 1 year. Female subjects are considered postmenopausal 
if they have had amenorrhea for at least 1 year or more following cessation of all exogenous 
hormonal treatments, and follicle-stimulating hormone (FSH) levels are in the postmenopausal 
range. 
• 
Male partners must also use a contraceptive (eg, barrier, condom, or vasectomy). 
I5. Male participants must use barrier method of contraception (whether or not the participant 
had vasectomy). 
7.2 
Exclusion Criteria 
Part A: 
Participants who meet any of the following criteria will be excluded from the study. 
E1. Inadequate echocardiographic acoustic windows. 
E2. A participant has a QTcF interval > 480 milliseconds not attributable to ventricular 
pacing or prolonged QRS duration ≥ 120 milliseconds, average of triplicate ECGs. 
E3. a. 
For MYH7 and TTN cohorts, participants with known pathogenic variant of 
another gene implicated in DCM at Screening. 
b. 
For the cohort of participants with primary DCM due to other causalities than 
MYH7 and TTN, known MYH7 or TTN variants implicated in DCM at Screening.   
E4. HFrEF considered to be caused primarily by ischemic heart disease, chronic 
valvulopathy, or another condition, as determined by the Investigator. 
E5. Recent (< 90 days) acute coronary syndrome or angina pectoris. 
E6. Coronary revascularization (percutaneous coronary intervention or coronary artery 
bypass graft) within prior 90 days. 
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E7. Recent (< 90 days) hospitalization for heart failure, use of intravenous diuretic or chronic 
intravenous inotropic therapy, or other cardiovascular event (eg, cerebrovascular 
accident). 
E8. Known aortic stenosis of moderate or greater severity. 
E9. Presence of disqualifying cardiac rhythms that would preclude echocardiographic 
assessments, as determined by the Investigator, including: (a) rapid, inadequately rate-
controlled atrial fibrillation or (b) frequent premature ventricular contractions that might 
interfere with reliable echocardiographic measurements of left ventricular function. 
E10. Hypersensitivity to danicamtiv or any of the components of the danicamtiv formulation. 
E11. Active infection, indicated clinically as determined by the Investigator. In the case of 
SARS-CoV-2 (COVID-19) infection within 4 weeks prior to and during Screening, 
symptoms must have completely resolved and based on Investigator assessment in 
consultation with the Clinical Trial Physician, there are no sequelae that would place the 
participant at a higher risk of receiving investigational treatment. The methods to assess 
SARS-CoV-2 (COVID-19) infection include PCR, antigen test and serology tests.  Each 
study site should follow requirements per local institutional or regulatory guidance if 
any.  
E12. History of malignancy of any type within 5 years prior to Screening, with the exception 
of the following surgically excised cancers occurring more than 2 years prior to 
Screening: in situ cervical cancer, nonmelanomatous skin cancers, ductal carcinoma in 
situ, and nonmetastatic prostate cancer. 
E13. Severe renal insufficiency (defined as current estimated glomerular filtration rate [eGFR] 
< 30 mL/min/1.73 m2 by simplified Modification of Diet in Renal Disease equation 
[sMDRD]). 
E14. Serum potassium < 3.5 or > 5.5 mEq/L. 
E15. Any persistent (2 or more) out-of-range laboratory parameters (chemistry, hematology) 
at Screening, considered by the Investigator and the Medical Monitor to be clinically 
significant. 
E16. History or evidence of any other clinically significant disorder, condition, or disease 
(including substance abuse) that, in the opinion of the Investigator or the Sponsor 
Physician would pose a risk to participant safety or interfere with the study evaluation, 
procedures, completion, or lead to premature withdrawal from the study. 
E17. History of advanced heart failure therapy (ie, a heart transplant or left ventricular assisted 
device [LVAD] therapy). 
E18. A life expectancy of < 6 months. 
Prior/Concurrent Clinical Study Experience: 
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E19. Participated in a clinical trial in which the participant received any investigational drug 
(or is currently using an investigational device) within 30 days prior to Screening, or at 
least 5 times the respective elimination half-life (whichever is longer). 
Other Exclusions: 
E20. WOCBP with a positive pregnancy test. 
E21. Is employed by or is a first-degree relative of someone employed by the Sponsor, the 
Investigator, or his/her staff or family. 
E22. Currently placed in hospital or facility due to legal or administrative order. 
E23. Not having an implantable cardioverter defibrillator despite meeting the conditions of 
class I recommendation defined in 2022 AHA/ACC HF guidelines (7.4.1) or the 2021 
ESC HF guideline, depending on the region where participants reside.   
E24. Unstable or untreated severe ventricular arrythmia (e.g., ventricular tachycardia or 
ventricular fibrillation).  Participants with severe ventricular arrythmia who have not 
received an implantable cardioverter defibrillator. 
Part B: 
Participants who meet any of the following criteria after Part A completion to Part B cannot 
participate in Part B of the study.  
Note 1: If no Rescreening Visit is required, the following criteria must be evaluated by or at Part 
B Baseline Visit prior to dosing.  
E1. Recent (< 90 days) acute coronary syndrome or angina pectoris. 
E2. Coronary revascularization (percutaneous coronary intervention or coronary artery 
bypass graft) within prior 90 days.  
E3. Recent (< 90 days) hospitalization for heart failure, use of intravenous diuretic or chronic 
intravenous inotropic therapy or other cardiovascular event (eg, cerebrovascular 
accident). 
E4. Active infection, indicated clinically as determined by the Investigator. In the case of 
SARS-CoV-2 (COVID-19) infection within 4 weeks prior to Part B Baseline Visit or 
Rescreening (if required), symptoms must have completely resolved and based on 
Investigator assessment in consultation with the Clinical Trial Physician, there are no 
sequelae that would place the participant at a higher risk of receiving investigational 
treatment.  The methods to assess SARS-CoV-2 (COVID-19) infection include PCR, 
antigen test and serology tests.  Each study site should follow requirements per local 
institutional or regulatory guidance if any.   
E5. For participants who need Rescreening, severe renal insufficiency (defined as current 
eGFR < 30 mL/min/1.73 m2 by simplified sMDRD). 
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E6. For participants who need Rescreening, any persistent (2 or more) out-of-range safety 
laboratory parameters (chemistry, hematology), considered by the Investigator and the 
Medical Monitor to be clinically significant. 
E7. WOCBP participants with a positive pregnancy test.  
E8. History or evidence of any other clinically significant disorder, condition, or disease 
(including substance abuse) that, in the opinion of the Investigator or the Sponsor 
Physician, would pose a risk to participant safety or interfere with the study evaluation, 
procedures, completion, or lead to premature withdrawal from the study. 
E9. Is employed by or is a first-degree relative of someone employed by the Sponsor, the 
Investigator, or his/her staff or family. 
E10. Currently placed in hospital or facility due to legal or administrative order. 
E11. Not have an implantable cardioverter defibrillator despite meeting the conditions of class 
I recommendation defined in 2022 AHA/ACC HF guidelines (7.4.1) or the 2021 ESC 
HF guideline, depending on the region where participants reside.   
E12. Unstable or untreated severe ventricular arrythmia (e.g., ventricular tachycardia or 
ventricular fibrillation).  Participants with severe ventricular arrythmia who have not 
received an implantable cardioverter defibrillator 
E13. History of advanced heart failure therapy (ie, a heart transplant or LVAD therapy). 
 
7.3 
Withdrawal and Replacement of Participants 
The Investigator will make every reasonable attempt to retain participants through completion of 
the study.   
7.3.1 
Withdrawal from the Study 
Participants may withdraw from participation in the study at any time and for any reason. The 
degree to which a participant withdraws can vary, and efforts will be made to collect important 
safety data if feasible and the participant agrees. 
Participants can: 
• 
Withdraw from treatment and agree to participate in the Early Termination Visit 
• 
Withdraw from treatment and all follow up 
See Section 6.2 for Permanent Treatment Discontinuation.  
In all cases, the reason(s) for study withdrawal will be recorded in the source document and on the 
appropriate electronic case report form (eCRF). 
7.3.2 
Follow-up Procedures After Early Withdrawal from Study 
The Investigator will make every effort to complete the protocol-specified follow-up procedures 
as specified in the Early Termination Visit in APPENDIX 1, including the follow-up of any 
unresolved AEs until the AE is resolved or stabilized. 
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In the case of early permanent treatment discontinuation, an Early Termination Visit should be 
scheduled as early as possible (same day, next day, or as best as possible) to perform End of Study 
assessments, including but not limited to evaluations of clinical safety and tolerability, as well as a 
TTE (APPENDIX 1). 
7.3.3 
Replacement of Participants 
Participants who withdraw/are withdrawn permanently due to a drug-related AE may not be 
replaced. Participants who discontinue Part A of the study after receiving study drug for reasons 
other than drug-related AEs or participants who are not evaluable for concentration-PD at steady 
state may be replaced at the discretion of the Sponsor in consultation with the Investigator. 
Participants that discontinue the study during Part B will not be replaced. 
8 
RANDOMIZATION AND BLINDING PROCEDURES 
This is an open-label and non-randomized study.  
9 
STUDY TREATMENT 
The study drug is defined as danicamtiv (MYK-491).  
9.1 
Investigational Medicinal Product 
Danicamtiv drug substance is a 
 with a molecular weight of 
435.4 g/mol. Danicamtiv is 
  
Danicamtiv will be provided as 
 (Part A and Part B) 
 
 (Part B) tablets. Danicamtiv tablets are manufactured according to current Good 
Manufacturing Practice (cGMP) regulations. 
9.1.1 
Supply of Investigational Medical Product 
The clinical study material for the MYK-491-006 study will be provided by the Sponsor. 
Part A:  
The Sponsor will provide: 
• 
 5 mg tablets (to support 10 mg BID and 25 mg BID doses) and 
25 mg 
tablets (to support the 50 mg BID doses). The tablets will be blistered and carded; each blister 
card will contain either only 5 mg or only 25 mg tablets. There will be no mixed strength blister 
cards. Each blister card will be labeled as required by local regulations and will be “open” in 
labeling (label will identify the contents of the blister card).  
• 
 tablets supplied in high-density polyethylene bottles with 
induction seals and child-resistant caps – each one of 3 strengths: 5 mg (to support the 10 mg 
BID dose), 25 mg, and 50 mg. 
Part B:  
The Sponsor will provide:  
• 
 5 mg tablets in blister cards (to support the 5 mg and 10 mg BID doses).  
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• 
 tablets supplied in high-density polyethylene bottles with 
induction seals and child-resistant caps of 4 strengths: 5 mg (to support the 5 mg BID and 10 
mg BID doses), 25 mg, 50 mg, and 75 mg.  
9.1.2 
Storage and Handling Procedures 
Danicamtiv must be stored in accordance with the labeled storage conditions in the packaging 
supplied by the Sponsor. At the investigational site, danicamtiv will be stored in a secure area with 
access limited to authorized study personnel. 
9.1.3 
Packaging and Labeling 
Danicamtiv will be shipped in appropriately labeled containers. All study drug will be labeled 
according to applicable local regulatory guidelines. 
9.2 
Investigational Medicinal Product, Administration, and Schedule 
Each dose of study drug should be ingested with a full meal. 
9.2.1 
Part A: 
In Treatment Period 1, participants will receive 25 mg BID (every 12 hours) of danicamtiv. Doses 
may occur ± 2 hours from scheduled dosing times as long as doses are: 
• 
separated by at least 10 hours and by no more than 14 hours, and  
• 
given for at least 5 days and up to 8 days, ie, with treatment starting on the morning (or 
afternoon if baseline assessments completed in the afternoon) of Day 1 and last dose taken in 
the morning, at the earliest on Day 5 and at the latest on Day 8 (corresponding to a total of 8 to 
15 doses for Period 1).  
On the last dosing day of Treatment Period 1 (Visit 3A), a TTE will be performed in the afternoon 
of Day 5, 6, 7, or 8, approximately 7 hours after the morning dose. The 
, observed 
between the Baseline (Visit 2A) TTE and the Visit 3A TTE, measured locally at the site by the site 
sonographer, will determine the dose to be administered in Treatment Period 2.  
Treatment Period 2 (doses determined by site measurement of 
):  
• If at the end of Treatment Period 1 (Visit 3A), the 
 from Baseline (Visit 2A) to 
Visit 3A is 
 to 
, the participant will be instructed to skip 
one dose and then will be down-titrated to 10 mg BID. Thus, if a participant is down-titrating, 
then dosing for Treatment Period 2 will begin the morning of the day after the last dose for 
Treatment Period 1, and end between 5 to 8 days later, ie, last dose in Treatment Period 2 will 
be taken in the morning.  
• If at the end of Treatment Period 1 (Visit 3A), the 
 from Baseline (Visit 2A) is 
 the participant will be up-titrated to 50 mg BID. If a participant is up-
titrating, then dosing will start in the evening on the last dosing day for Treatment Period 1 
(Visit 3A). 
NOTE: If at the end of Treatment Period 1 (Visit 3A), the 
 from Baseline (Visit 2A) 
is 
, then study drug should be permanently discontinued (Section 6.2). 
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9.2.2 
Part B: 
Initial individual participant doses will be based on 
 in Part A, regardless of whether 
a participant has to be rescreened in Part B. The Part B starting dose can be either one of 5 mg BID, 
10 mg BID, 25 mg BID, 50 mg BID, or 75 mg BID: 
• 
If one of the doses in Part A resulted in a 
 and
, then that 
will be the dose for Part B (10, 25, or 50 mg BID) 
• 
If both doses in Part A resulted in a 
 and 
, then the dose 
for Part B is the lower of the 2 doses that the participant received in Part A 
• 
If both doses in Part A resulted in a 
 of 
 with 10 and 25 mg BID, 
then the Part B dose for that participant is 50 mg BID 
• 
If both doses in Part A resulted in a 
 of 
 with 25 and 50 mg BID, 
then the Part B dose for that participant is 75 mg BID 
• 
If both doses in Part A resulted in a 
 of 
 with 10 and 25 mg BID, 
then the Part B dose for that participant is 5 mg BID  
• 
If both doses in Part A resulted in a 
 of 
 with 25 and 50 mg BID, 
then the Part B dose for that participant is 10 mg BID 
• 
If 25 mg BID dose from Part A 
 and 10 mg BID from Part A 
 10 mg BID 
• 
If 25 mg BID dose from Part A 
 and 50 mg BID dose from Part A 
 25 mg BID 
For participants who could not complete Part A or completed TTE assessments  outside of the 
protocol defined window  may  participate in Part B after  investigator discussion with the Sponsor. 
The reasons of incompletion of Part A should be due to reasons other than treatment-emergent 
adverse event (TEAE) considered as study drug related by the investigator, meeting study 
discontinuation criteria, or withdrawal of the informed consent.  Part B starting dose for such cases 
is described in following 2 bullets.  
• 
If 
 of both doses were unavailable or performed significantly outside of the 
assessment window (see Appendix 1. Part A SoA foot note g), then the Part B dose will be 
50mg BID.  
• 
If a 
 was only available with 25 mg BID (Treatment Period 1) and a 
 
was
 and 
, then 25mg BID is the dose for Part B. If a 
 was 
, then the Part B dose is 50 mg BID. If 25 mg BID dose resulted in a 
 
, then the Part B dose for that participant is 10 mg BID. 
Part B dose adjustment:  
After the initiation of Part B dosing, a TTE will be performed at Visit 2B and Visit 3B (2 weeks 
and 6 weeks after start of Part B dosing, respectively) to ensure adequate PD responses. 
 
 measured at these times from V1B will dictate dose adjustments as follows: 
• 
If there is a 
 of 
 on both TTEs at Visits 2B and 3B compared from 
V1B, based on local assessment, the dose will be titrated up to the next dose level. If a 
participant is already receiving the highest dose (75 mg BID), per the Investigator’s discretion, 
the participant will continue the study at 75 mg BID or discontinue from the study 
(Section 6.2). 
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• 
If there is a 
 of 
 on both TTEs from Visits 2B and 3B compared 
from V1B, based on local assessments, the dose will be titrated down to the next dose. If a 
participant is already receiving the lowest dose (5 mg BID), then the participant will be 
discontinued from the study (Section 6.2).   
• 
If there is a 
 and 
 on at least one of TTEs from Visits 2B 
and 3B compared from V1B, based on local assessments, no dose change is needed. 
• 
If 
 at Visit 2B and 3B are 
 at one visit and 
 at 
the other, no dose change is needed. 
9.3 
Treatment Compliance 
Danicamtiv compliance will be monitored during clinic visits when the drug is returned to the site 
(with count of remaining unused tablets). In addition, in between the clinic visits, participants will 
be contacted for Telehealth Visits (telephone, 2-way text messaging, or e-mail) to ensure 
compliance with study treatment. Periodic assessment of danicamtiv plasma concentrations will 
also ensure compliance. During Part B of the study, an investigational product diary will be used 
to ensure compliance.  
9.4 
Guidelines for the Management of an Exaggerated Pharmacological 
Effect 
Based on the nonclinical pharmacological characteristics, exaggerated effects of danicamtiv may 
lead to myocardial ischemia. Plasma peak concentration (Cmax) is anticipated to be achieved at 
approximately 4 to 6 hours postdose. After reaching Cmax, plasma concentrations declined in a 
mono-exponential manner with t1/2 of approximately 22 to 25 hours. The clinical signs and 
symptoms, which may include chest pain, lightheadedness, diaphoresis, and ECG changes should 
start to abate over a short period of time. Any participant with signs and/or symptoms suggestive 
of cardiac ischemia should be immediately evaluated by the Investigator for the potential diagnosis 
of cardiac ischemia. The entire context including clinical symptoms, ECGs and serial cardiac 
biomarkers (eg, troponin, CK-MB), and cardiac imaging (including coronary angiography, if 
applicable) should be taken into account by the Investigator, in making that determination, since 
participants enrolled in the study are likely to have abnormal ECGs and possibly elevated or 
fluctuating troponin levels at Baseline in relation to their heart failure condition. If evidence of 
cardiac ischemia is present, then the participant should receive standard therapy for ischemia as 
appropriate, including supplemental oxygen and nitrates. 
 
 
 In 
addition, the exaggerated pharmacological effect may increase myocardial oxygen demand, so 
agents that may increase myocardial oxygen demand further should be administered with caution. 
9.5 
Overdose 
There is no antidote for danicamtiv. Participants who receive a greater dose than planned should 
be supported as appropriate. If there is an exaggerated pharmacologic effect, the participants 
should be supported as described in Section 9.4. 
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Symptomatic and asymptomatic overdose is an adverse event of special interest (AESI; 
Section 12.1.3). If a participant experiences an overdose, the Investigator will report the overdose 
within 24 hours, even if there are no associated signs or symptoms. Follow up on the participant’s 
condition will be conducted. 
9.6 
Concomitant Therapy 
During the study, participants should continue to take medications for the treatment of heart failure 
and other medical conditions at the same doses and as close to the same times as usual, in order to 
maintain as best as possible similar preload and afterload conditions throughout the study and to 
minimize confounding factors for the assessment of the effects of danicamtiv.  
All prescription and over-the-counter medications must be reviewed by the Investigator and should 
be recorded in the eCRF. Over-the-counter medications may be taken at stable doses throughout 
the study (at Investigator’s discretion), and in amounts no greater than as directed per the label. 
Questions concerning enrollment or medications should be discussed with the Medical Monitor. 
Coadministration of danicamtiv with strong CYP3A4 inhibitors and strong CYP3A4 inducers 
should be avoided. 
 
 
 
 
 
 
 
 
 Use of biotin 
supplements should be avoided throughout the study. Multivitamins that contain biotin (vitamins 
B7, B8, or H) should be withheld for at least 24 hours prior to each study visit. Other 
investigational therapies must be discontinued at least 30 days prior to Screening or 5 half-lives 
(whichever is longer).  
COVID-19 vaccine is not prohibited. If possible, participants should avoid receiving the vaccine 
within 14 days prior to Screening visit and Baseline visits (both study Parts A and B), and during 
study Part A.  
If the participant has an AE requiring treatment (including the ingestion of acetaminophen or 
ibuprofen), the medication should be recorded in the appropriate section of the eCRF, including 
time of the administration (start/stop), date, dose, and indication.   
10 
RISKS AND PRECAUTIONS 
10.1 
General 
In previous clinical studies, single doses of danicamtiv administered to healthy participants and 
heart failure participants in the dose ranges planned for this study were well -tolerated 
(Section 3.1).  
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In Study MYK-491-003, multiple doses of danicamtiv were administered for 7 days to heart failure 
participants, with doses of up to100 mg BID, greater than those tested in the current study (5 to 
75 mg BID). This multiple-dose initial experience in heart failure has been taken into account for 
the selection of doses in the current MYK-491-006 trial (Section 4.2). 
Based on the clinical experience accumulated with danicamtiv in about 120 participants (healthy 
participants and heart failure participants with 7-day dosing, ranging in heart failure patients from 
50 to 100 mg BID, being generally well-tolerated), together with the favorable clinical experience 
observed with another agent from the same class in a large, cardiovascular outcome, Phase 3 study 
of ~8 000 HFrEF patients (Teerlink et al. 2021), the Sponsor considers it safe to administer 
danicamtiv at doses ranging from 5 to 75 mg BID for up to approximately 100 weeks in this study. 
The dose selected for Part B will be based on participants’ response to doses they will have been 
exposed to in Part A, as well as the additional TTEs performed at Visits 2B and 3B, which will be 
used for dose titration.  
Throughout the study, there will be regular interactions with participants, including serial 
assessments of clinical safety and tolerability, ECG, and laboratory evaluations. The Sponsor will 
closely monitor clinical safety (AEs and SAEs), as reported by Investigators. Treatment 
discontinuation criteria are described above (Section 6.2).  
10.2 
Pregnancy 
10.2.1 
Avoidance of Pregnancy 
Women of childbearing potential are allowed to participate if they are not currently pregnant and/or 
breastfeeding and agree to not become pregnant for up to 3 months after the last dose of study 
drug. Women must use highly effective methods of birth control as listed in Section 10.2.3. 
Women of nonchildbearing potential are defined as women who are permanently (surgically) 
sterilized or are postmenopausal. Permanent sterilization includes documented hysterectomy, 
bilateral oophorectomy, bilateral salpingectomy, and/or bilateral tubal occlusion or ligation prior 
to Screening. Women are considered postmenopausal if they have had amenorrhea for at least 
1 year following cessation of all exogenous hormonal treatments and FSH levels are in the 
postmenopausal range. Determination of WONCBP should be performed at Part A Screening and 
to be recorded in eCRF.  Pregnancy tests (urine or blood determined by local requirements [eg, 
only serum is acceptable in the United Kingdom]) should be performed on WOCBP. Pregnant or 
lactating women are excluded from study participation. 
10.2.2 
Restrictions for Male Participants 
There is no information about effects that danicamtiv could have on the development of the fetus 
in humans. Therefore, it is important that the partners of male participants do not become pregnant 
during the study and for a total period of 3 months after the male participant has taken the last dose 
of study drug. As a precaution, all male participants should avoid fathering a child by using 
appropriate methods of birth control, as listed in Section 10.2.3, for the duration of the study and 
for 3 months after the last dose of study drug to ensure a fetus is not potentially exposed to study 
drug in the ejaculate.  
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Due to the risk of danicamtiv being secreted in the ejaculate, male participants should be advised 
not to donate sperm during the study and for 3 months after the last dose of study drug.  
In addition, male participants with partners capable of becoming pregnant should use barrier 
methods for the duration of the study and for 3 months after the last dose of study drug, including 
male participants who have had vasectomies.  
10.2.3 
Acceptable Forms of Contraception 
Highly effective methods of birth control are defined as those that result in a low failure rate (< 1% 
per year) when used consistently and correctly. From the time of Screening through 3 months after 
the last dose of study drug, participants should practice true abstinence or use effective means of 
contraception as follows: 
• 
Hormonal contraception associated with inhibition of ovulation, IUD, or IUS plus barrier (eg, 
male using condom or female using diaphragm or cervical cap) 
• 
Vasectomy plus barrier  
• 
Female is surgically sterile or is postmenopausal for 1 year. Permanent sterilization includes 
documented hysterectomy, bilateral oophorectomy, bilateral salpingectomy, and/or bilateral 
tubal occlusion or ligation prior to Screening. Females are considered postmenopausal if they 
have had amenorrhea for at least 1 year or more following cessation of all exogenous hormonal 
treatments, and FSH levels are in the postmenopausal range. 
• 
Male partners of postmenopausal females 
10.2.4 
Reporting and Follow-up of Pregnancies 
All pregnancies in female participants and female partners of male participants receiving at least 
1 dose of study drug will be reported if they occur anytime from first dose to 3 months after the 
last dose of study drug. The Investigator is responsible for informing the Sponsor of the pregnancy. 
The participant will be asked to provide information on the outcome of the pregnancy, including 
premature termination, for 6 months after birth. Spontaneous miscarriages and congenital 
abnormalities will be collected as SAEs (Section 12.3).  
11 
STUDY ASSESSMENTS AND PROCEDURES 
The Investigator is responsible for ensuring that all staff involved in the study are familiar and 
comply with the content of this section. 
Procedures to be performed during the study are detailed in APPENDIX 1.  
11.1 
Pharmacodynamic Assessments 
11.1.1 
Transthoracic Echocardiography 
The PD effect of danicamtiv will be evaluated throughout this study by serial TTE examination in 
accordance with an echo analysis protocol. TTE examination will be performed by the certified 
sonographers at each study site in accordance with an TTE site instruction manual. Sonographers 
in the study will complete TTE protocol training and submit an example of a study to the echo 
core laboratory for evaluation. The echo core laboratory will certify that the sonographer is able 
to perform the TTEs at a level satisfactory for obtaining the required protocol data. 
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The participants should be at rest for 10 minutes before the TTEs are obtained.  
Transthoracic echocardiograms at all timepoints will be evaluated centrally by a core laboratory 
for research purposes. At Screening, each site will provide the protocol required images to the 
Echo Core Laboratory for echo eligibility assessments.  
Measurement of 
should be assessed locally at each site on Visit 2A, Visit 3A, Visit 1B, Visit 
2B, and Visit 3B. This result should be reported in real time to the Investigator who will determine 
dosing for Treatment Period 2 at Visit V3A and dose titration, if needed, at Visit 3B (Section 6.1). 
For acquisition of 
 measurement, please refer to the TTE site instruction Manual.  
The use of contrast is not recommended for this study and should only be used to optimize image 
quality in subjects that exhibit technically limited echo windows. If a participant is screened using 
contrast, then contrast must be administered for all subsequent study related TTE examinations, 
with the full protocol being obtained with and without contrast. 
If echo contrast is used, the sonographer should first obtain the full set of protocol required images 
without contrast, and then provide additional images after contrast is administered at the end of 
the study. The full set of images must be transferred to the echo core laboratory and the use of 
contrast must be noted on the transmittal form.  
Key TTE measurements will include, but not be limited to: 
• 
Change in left ventricular 
 
• 
Change in left ventricular systolic function parameters 
− Left ventricular stroke volume (LVSV) 
− LVEF 
− Left ventricular strain parameters: global longitudinal (LVGLS) and circumferential strain 
(LVGCS) 
− Tissue Doppler imaging (TDI) of mitral valve annulus peak systolic velocity (s’) 
• 
Change in left ventricular dimensions: 
− Left ventricular end-systolic and end-diastolic diameters (LVESD, LVEDD) 
− Left ventricular end-systolic and end-diastolic volumes indexed for body surface area 
(LVEDVi, LVESVi) 
• 
Change in left atrial volume and function: 
− Minimum and maximum LA volumes indexed for body surface area (LAminVi, 
LAmaxVi) 
− Left atrial emptying fraction (LAEF) 
− Left atrial function index (LAFI) 
• 
Change in left ventricular diastolic function: 
− TDI of mitral valve annulus peak velocity in diastole (e’, lateral, septal) 
− Ratio of peak inflow velocities in early and late diastole (E/A) 
− Ratio of early mitral peak inflow velocity to early mitral peak annulus velocity (TDI) (E/e’) 
lateral, septal and average 
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These parameters will be PD assessments at the timepoints indicated in APPENDIX 1 (with a 
window of ± 1 hour). 
11.1.2 
Cardiac Magnetic Resonance Imaging  
Part A: CMR will not be obtained in Part A. 
Part B: CMR will be obtained in suitable participants (as determined by the investigator) at sites 
able to perform the examinations at V1B, week 48 (V8B), and week 96 (EOT).  
The CMR image acquisition will be performed at each study site and transferred data will 
be analyzed at the CMR core lab as indicated in the instruction manual and the analysis manual, 
respectively. Subsequent examinations in those participants will be obtained at one-year intervals 
(within 4 weeks of each year anniversary on study). Each examination will follow a standard 
imaging protocol to include, but not be limited to, the following parameters:  
• 
Change in left ventricular systolic function parameters 
− LVSV by phase contrast imaging of LV outflow 
− LVEF by volumetric assessment of short axis stack images 
− LVGLS and LVGCS 
• 
Change in left ventricular dimensions: 
− LVEDVi and LVESVi 
• 
Change in left atrial volume and function: 
− LaminVi and LamaxVi 
− LAEF 
− left atrial reservoir emptying fraction (LarEF 
− left atrial active emptying fraction (LaaEF) 
CMR data at all timepoints will be evaluated by a CMR core lab. CMR technologists and devices 
at sites will undergo training per the specifications of the CMR core lab where they will then be 
certified to perform CMR for this study. 
11.1.3 
6-Minute Walk Distance (6MWD) 
Part A: The 6MWD will not be conducted in Part A. 
Part B: The distance that a participant can walk in 6 minutes (6MWD) will be assessed at Baseline 
(prior to dosing; within 2 weeks of beginning Part B) per the study-specific 6MWD manual and 
qualified course at the study sites. Thereafter, the same assessment at the same course will be 
obtained at approximately 24-week intervals throughout Part B.  
Personnel responsible for conducting the 6MWD at the study sites will undergo training and 
certification by a vendor provided by the Sponsor  
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11.2 
Efficacy Assessments 
11.2.1 
Exploratory Assessments 
11.2.1.1 
New York Heart Association Functional Classification 
The NYHA Functional Classification of heart failure assigns participants to 1 of 4 categories 
based on the participant’s symptoms (Table 2). Heart failure classification will be assessed by 
the Investigator as indicated in APPENDIX 1. 
Table 2: 
New York Heart Association Functional Classification of Heart 
Failure 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results 
in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less-than ordinary-activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at 
rest. If any physical activity is undertaken, discomfort increases. 
Source: http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-
Failure_UCM_306328_Article.jsp#.VrtuzPkrKUl 
 
11.2.1.2 
Kansas City Cardiomyopathy Questionnaire (23-item Version) 
The Kansas City Cardiomyopathy Questionnaire (23-item version) is a patient reported 
questionnaire that measures the impact of participants’ cardiovascular disease or its treatment on 
6 distinct domains using a 2-week recall: symptoms/signs, physical limitations, quality of life, 
social limitations, self-efficacy, and symptom stability (Green et al, 2000). In addition to the 
individual domains, 2 summary scores can be calculated from the KCCQ-23: the overall summary 
score (includes the total symptom, physical limitation, social limitations and quality of life scores) 
and the clinical summary score (combines the total symptom and physical limitation scales). 
Scores range from 0 to 100, with higher scores reflecting better health status. The KCCQ-23 will 
be administered to participants as indicated in APPENDIX 1. The KCCQ-23 assessments 
completed at visits (except at Screening) should be completed prior to any other study procedure 
taking place, where possible, and prior to any meaningful discussion about the study or study 
treatment with investigative site staff. 
11.3 
Plasma Concentration, Pharmacogenetic, and Biomarker Assessments 
11.3.1 
Plasma Concentration Assessments 
Blood samples will be collected for plasma concentration assessments as indicated in APPENDIX 
1. It is important that sampling occur as close as possible to the scheduled time. Unscheduled or 
additional samples may be collected, if appropriate in the opinion of the Investigator and/or 
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Sponsor. If an unscheduled TTE or visit to evaluate possible ischemia is performed by the 
Investigator, a plasma sample should also be collected at this timepoint. 
11.3.2 
Genetic/Genotype/Pharmacogenetic/Biomarker Assessment 
Beside genetic testing for variants associated with cardiomyopathies that is mandatory, all 
participants will have the option to provide consent for blood to be drawn for potential future 
analysis of circulating biomarkers or genetic markers in relation to efficacy, safety, PD, or plasma 
concentration, as determined by future studies through DNA genotyping, direct sequencing, or 
other genetic testing modalities, unless there are local regulations prohibiting these analyses. If 
genetic or pharmacogenetic studies are conducted, genetic information will not be returned to 
participants. Pharmacogenetic samples could be used as a source of DNA for genotyping or 
sequencing of cardiomyopathy genes.  
11.4 
Safety Assessments 
Safety will be assessed throughout the study as indicated in APPENDIX 1. Safety assessments 
include medical history, physical examinations, 
 as determined by TTE, triplicate 12-lead 
ECGs, vital signs, observed and participant-reported AEs, serum troponin concentrations, and 
safety laboratory tests.  
The Sponsor will closely monitor safety on an ongoing basis.  
Any abnormal findings judged by the Investigator to be clinically important (new or worsened 
from Baseline) will be recorded as an AE which will be reviewed by the Sponsor.  
11.4.1 
Medical History 
A complete medical history will be recorded at the Screening visit, which will include evaluation 
(past or present) of the cardiovascular and heart failure medical history as well as the following: 
general, head and neck, eyes, ears, nose, throat, chest/respiratory, gastrointestinal/liver, 
gynecological/urogenital, 
musculoskeletal/extremities, 
skin, 
neurological/psychiatric, 
endocrine/metabolic, hematologic/lymphatic, allergies/drug sensitivities, past surgeries, substance 
abuse, or any other diseases or disorders as well as participation in clinical studies (study drug 
and/or device or other therapy). 
11.4.2 
Vital Signs  
Vital signs will be assessed throughout the study as indicated in APPENDIX 1 and will include 
temperature, HR, and blood pressure (BP). HR and BP shall be the mean of 3 measurements taken 
with the participant in a supine position after resting for at least 5 minutes. 
11.4.3 
Physical Examination 
Height (cm) and weight (kg) will be measured at Screening and timepoints indicated in APPENDIX 
1.  
A complete physical examination will be conducted including a neurological examination (gross 
motor and deep tendon reflexes), and assessment of the following: general appearance, skin, head 
and neck, mouth, lymph nodes, thyroid, abdomen, musculoskeletal, cardiovascular, neurological, 
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and respiratory systems. At all other timepoints, an abbreviated physical examination (pulmonary, 
cardiac, abdominal, and other systems related to symptoms) will be conducted. 
11.4.4 
Electrocardiograms (12-Lead ECG) 
The triplicate 12-lead ECG should be obtained as indicated in APPENDIX 1. The Investigator may 
add extra 12-lead ECG assessments if there are any abnormal findings or if the Investigator 
considers it is required for any other safety reason. If the participant has a new troponin 
abnormality (Section 11.4.6) or any signs or symptoms suggestive of possible cardiac ischemia, 
additional ECGs should be obtained. These assessments should be recorded as unscheduled 
assessments. All study ECGs will be read locally and sent to an ECG core laboratory.  
The Investigator will judge the overall interpretation as (a) normal, (b) abnormal without clinical 
significance, or (c) abnormal with clinical significance. If clinically significant, the abnormality 
will be recorded. In addition, at each visit, the Investigator or sub-investigator should compare the 
available ECGs at the visit to those from the prior visit. If there are signs of ischemia, dosing 
should be withheld until there is full understanding of the possible ischemic changes.  
In addition, at Visit 3A and Visits in Part B, the Investigator should evaluate the triplicate 12-lead 
ECGs and confirm lack of QTcF prolongation (Section 6.2) to continue treatment with study drug. 
The Investigator will review the ECG and correlate abnormal findings with any other clinical 
findings, participant’s medical history, and laboratory data to determine the clinical importance of 
the finding. 
11.4.5 
Extended Cardiac Rhythm Monitoring 
Part A: If using historical LVEF to qualify a participant, a cardiac rhythm monitoring patch will 
be placed at the first Screening visit (Visit 1.1A). If using 2 Screening TTEs, the patch will be 
placed at the time of the second Screening visit (Visit 1.2A). A new patch will be placed at the 
start of Treatment Period 1, after dosing.  
Part B: A cardiac rhythm monitoring patch will be placed at Visits 1B, 6B, 8B, 10B, and EOT.  
The duration of monitoring will range from 5-14 days. If the patch becomes detached prior to 
5 days, a new patch should be placed as soon as possible. Once the patch detaches (after at least 
5 days), participants will be instructed to mail the patch back to the site. 
11.4.6 
Troponin Levels  
In Part A, hsTnT, TnI, and hsTnI samples will be collected at timepoints as indicated in 
APPENDIX 1. Samples will be analyzed at a central laboratory at all clinic visits after Part A 
Screening (Visits 1.1A to Visit 5A). There are no discontinuation criteria related to troponin levels 
in Part A. 
In Part B, TnI (standard and high-sensitivity) and hsTnT samples will be collected as described in 
APPENDIX 1 and analyzed by the central laboratory. 
In Part B, troponin increase will be defined as:    
1) If TnI (standard) level is below ULN at Baseline (value obtained at Visit 1B) and subsequently 
increases to more than 0.05 ng/mL on any assay after start of dosing 
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2) If the TnI (standard) level is above the ULN at Baseline and then subsequently rises by more 
than 0.05 ng/mL above the participant’s Baseline value (obtained at Visit 1B) on any assay 
after start of dosing. 
If either of these conditions are met from start of Visit 1B to Visit 6B (week 24) and the absolute 
TnI (standard) level is below 0.1 ng/mL, the totality of the clinical data will be reviewed by the 
Coordinating Investigator, the consulting Safety Reviewer, and the Sponsor’s Medical Monitor 
periodically to determine if any signs of ischemia are seen. During this time, the participant will 
continue to take danicamtiv at the same dose. Subsequent telehealth visits will be transitioned to 
in-person clinic visits with 12-lead ECGs and troponin tests until troponin levels are stable or 
declining.  
If the TnI (standard) level exceeds 0.1 ng/mL, at any time, the participant will be asked to return 
for repeat evaluation as soon as possible. If this level of TnI (standard) is confirmed, treatment 
with danicamtiv will be temporarily discontinued and an ad hoc review by the Coordinating 
Investigator, the consulting Safety Reviewer, and the Sponsor’s Medical Monitor will be triggered. 
Abnormal and/or rising troponin values (as per Investigator’s judgment and considering potential 
Baseline troponin elevation frequently observed in heart failure) should lead to the participant 
being clinically evaluated for possible myocardial ischemia. Also, if the participant has any signs 
or symptoms suggestive of possible cardiac ischemia, additional serial troponin (and other safety 
labs, including CK-MB samples) should be obtained and subsequent dosing should be withheld 
until there is full understanding of the possible ischemic event. The Investigator will evaluate the 
entire clinical context (eg, signs, symptoms, new ECG changes, new troponin, and CK–MB 
abnormalities) and correlate with any other relevant clinical findings, participant’s medical history, 
and laboratory data to determine the clinical significance of the findings. 
If the Investigator assessment is that an AE has occurred, the event should also be reported as an 
AE accordingly (Section 12).  
11.4.7 
Adverse Events 
Please see Section 12 for information on evaluating, recording, and reporting AEs. 
11.4.8 
Safety Laboratory Tests (Other Than Troponin) 
Samples will be drawn for safety laboratory tests at the timepoints indicated in APPENDIX 1. At 
Screening, assessments will be made by the central laboratory. If the Investigator has any questions 
regarding eligibility, the Sponsor should be contacted.  
Screening laboratory testing will include thyroid-stimulating hormone (TSH) and iron (Fe)/total 
iron-binding capacity (TIBC)/ferritin to exclude uncontrolled thyroid functions and Fe overload.  
11.5 
Missed Evaluations 
Evaluations should occur within the assessment window specified by the protocol. If an evaluation 
is missed, it should be performed as close as possible to the original time. 
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11.6 
Participant Restrictions During the Study 
Starting at Screening and throughout the study, participants should be instructed to maintain a 
stable lifestyle. This includes but is not limited to:  
• 
Concomitant medications: every effort should be taken to maintain stable doses of concomitant 
medications, and to take such medications at consistent times during the day; for 
cardiovascular drugs, this will allow to minimize variability in cardiac loading conditions. 
• 
Activity levels:  
− In Part A, from 72 hours prior to the first dose through the Follow-up visit, participants 
should not engage in unaccustomed intensive exercise.  
− In Part B, participants should follow their customary exercise regimen and not engage in 
unaccustomed intensive exercise. Any planned increase in the amount of regular physical 
exercise should be discussed with the Investigator prior to commencing.  
• 
Meals/food:  
− Abstain from grapefruit or grapefruit juice, Seville oranges, and quinine (eg, tonic water). 
• 
Fluid intake: maintain usual daily fluid intake and avoid excessive alcohol consumption.  
In addition, starting at Screening, participants will be required to abstain from blood or plasma 
donation until 3 months after the final study visit. 
Contraception requirements are discussed in Section 10.2. 
If participants are participating in Part B observational study, this restriction will not apply.  
12 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS 
12.1 
Definitions 
12.1.1 
Adverse Event 
An AE is any untoward medical occurrence, or the deterioration of a preexisting medical condition 
(other than the condition that is being treated by the study) associated with the use of a study drug 
in humans, whether or not it is considered related to the study drug. An AE (also referred to as an 
adverse experience) can, therefore, be any unfavorable and unintended sign (eg, tachycardia, 
enlarged liver, clinically important abnormal laboratory result or diagnostic procedure), 
participant-reported symptom (eg, nausea, chest pain), or evidence of any disease activity 
temporally associated with the use of a study drug, whether or not related to the study drug. 
In clinical studies, an AE can include an undesirable medical condition occurring at any time after 
the participant has signed informed consent, including run-in or washout periods, even if no 
specific treatment has been administered. 
Preexisting medical conditions (other than natural progression of the disease being studied) judged 
by the Investigator or participant to have worsened in severity or frequency or changed in character 
during the protocol-specified AE reporting period will be reported as AEs or SAEs as appropriate. 
Imaging-based assessments of decrease in contractility are not considered AEs unless associated 
with symptoms or signs of clinical concern on the part of the Investigator. Such events should be 
categorized as an AE defined in terms of those symptoms or signs. 
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An AE or SAE can also be a complication that occurs as a result of protocol-mandated procedures 
(eg, procedures such as blood draws). 
For the Sponsor to collect additional information about clinically important laboratory results or 
diagnostic tests (eg, blood, ECG, imaging), at a minimum, the following abnormalities should be 
captured on the AE eCRF: 
• 
Any test result that meets the definition of an AE. 
• 
Any clinically important test abnormality that suggests a disease and/or organ toxicity that has 
worsened or is new (eg, > 3 times deviation from the upper or lower limit of the analyzing 
laboratory reference range, or as otherwise specified in the protocol). 
• 
Any test abnormality that requires the participant to have study drug discontinued or 
interrupted or in the clinical judgment of the Investigator. 
• 
Any test abnormality that requires the participant to receive specific corrective therapy, close 
observation, more frequent follow-up assessment, or further diagnostic investigation. 
The term AE is used generally to include any AE whether serious or nonserious. 
12.1.2 
Serious Adverse Events 
An SAE is an AE that fulfills one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening (places the participant at immediate risk of death from the event 
as it occurred) 
• 
Requires in-participant hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity or substantial disruption of the ability 
to conduct normal life functions 
• 
Results in a congenital abnormality or birth defect 
• 
Is an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, it may require medical or surgical intervention to prevent 1 of the outcomes listed 
above 
12.1.3 
Adverse Events of Special Interest 
Overdose (asymptomatic and symptomatic) and increased troponin are considered AESI; AESIs 
are required to be reported by the Investigator to the Sponsor within 24 hours, irrespective of 
regulatory seriousness criteria. 
Increased troponin will be captured as an AESI under the following conditions: if the participant’s 
TnI (standard) level reaches a level greater than 0.1 ng/mL on any assay after the start of dosing. 
12.2 
Events NOT Meeting the Definition of an Adverse Event 
If an event is not an AE, then it cannot be an SAE, even if the event outcome meets the definition 
for seriousness defined by the criteria in Section 12.1.2. Instances where an event is not an AE 
include: 
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• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or hospital 
admission/extension for convenience). 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• 
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) that are present or 
detected at the start of the study that do not worsen. 
• 
Hospitalization for a preexisting condition, provided all of the following criteria are met: 
− The participant has not experienced an adverse event. 
− The hospitalization was planned prior to the study or was scheduled during the study when 
elective surgery or procedure became necessary because of the expected normal 
progression of the disease. 
12.3 
Reporting Period and Follow Up 
All AEs will be reported throughout the duration of the study. The duration of the study is defined 
from the time the participant provides informed consent until the End of Study Visit for the 
participant. Preexisting medical conditions that increase in severity from the first dose of study 
drug will be reported as AEs.  
Any AEs that are unresolved at the participant’s last visit in the study are to be followed by the 
Investigator until resolved or stabilized and are considered irreversible, or the participant has 
died/lost to follow up. Deaths and new SAEs are to be reported even after end of study if they 
occurred within 30 days after the last study drug administration for each participant. If death or 
new SAEs are considered related to study drug or study procedures by the investigator, they must 
be reported even after this term. All SAEs will be entered into the safety database and handled in 
the same manner as SAEs reported during the treatment-emergent period; that is, causality will be 
assessed by both Investigator and Sponsor and if the SAE is deemed a suspected unexpected 
serious adverse reaction (SUSAR) (related and unexpected), will be submitted to regulators (as 
applicable) in an expedited fashion. 
The Sponsor retains the right to request additional information for any participant with ongoing 
AE(s)/SAE(s) at the end of the study, if deemed necessary. 
All SAEs (and AESIs, regardless of seriousness), regardless of causality, will be reported by the 
Investigator or designee to the Sponsor or its designee immediately, without undue delay, under 
no circumstances later than 24 hours after learning of the event. All follow-up information for 
previously reported SAEs will also be reported to the Sponsor or its designee within 24 hours of 
knowledge.  
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12.3.1 
Recording and Assessing Adverse Events 
12.3.1.1 
Description 
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study personnel: “Have you had any health problems since you were last asked?” or 
revealed by observation will be collected and recorded in the eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list 
of signs and symptoms (eg, anemia, not low hemoglobin). However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis and 
each sign or symptom will be recorded separately. 
Death is an outcome and not the name of the event. Every effort should be made to determine the 
cause of death. 
12.3.1.2 
Relationship to Study Treatment 
The Investigator should assess causality by answering either “yes” or “no” to the question “Is there 
a reasonable possibility that the event may have been caused by the IMP/study medication?” 
The following factors can be used in consideration of causality assessment: 
• 
De-challenge/re-challenge: Did the event abate after study drug was reduced or interrupted? 
Did the event reappear after study drug was reintroduced? 
• 
Temporal relationship and time to onset plausibility 
• 
Confounding risk factors 
• 
Amount and duration of study drug exposure 
• 
Concomitant medications 
Adverse Drug Reaction (ADR): An ADR is any untoward medical occurrence, or the deterioration 
of a preexisting medical condition associated with the use of a study drug in humans, when the 
Investigator/Sponsor has a reason to assess it as at least possibly related to the study drug. An ADR 
can, therefore, be any unfavorable and unintended sign (e.g., tachycardia, enlarged liver, clinically 
important abnormal laboratory result, or diagnostic procedure), participant-reported symptom 
(e.g., nausea, chest pain), or evidence of any disease activity temporally associated with the use of 
a study drug which, is assessed by investigator/sponsor as related to the study drug. 
Serious Adverse Reaction (SAR): An SAR is an ADR that fulfills one or more of the following 
criteria in the opinion of the Investigator or the Sponsor: 
• 
Results in death 
• 
Is immediately life-threatening (places the participant at immediate risk of death from the event 
as it occurred) 
• 
Requires in-participant hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity or substantial disruption of the ability 
to conduct normal life functions 
• 
Results in a congenital abnormality or birth defect 
• 
Is an important medical event 
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12.3.1.3 
Severity 
The Investigator will assess the intensity of each AE and SAE reported during the study and assign 
it to one of the following categories: 
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
• 
Moderate: An event causing sufficient discomfort and interferes with normal everyday 
activities. 
• 
Severe: An event preventing normal everyday activities. An AE that is assessed as severe 
should not be confused with a SAE. Severe is a category utilized for rating the intensity of an 
event; and both AEs and SAEs can be assessed as severe. 
• 
An AE is defined as serious when it meets the regulatory definitions as outlined in Section 
12.1.2. An SAE can also be severe but not all severe AEs are SAEs.  
Note: It is important to distinguish between category (AE vs. SAE) and intensity (mild, moderate, 
or severe) of AEs. 
Severity is a measure of intensity, whereas seriousness is defined by the criteria stated above.  
An AE of severe intensity need not necessarily be considered serious. For example, nausea that 
persists for several hours may be considered severe nausea but not an SAE. On the other hand, a 
stroke that results in only a limited degree of disability may be considered a mild stroke but would 
be an SAE. 
12.3.1.4 
Pregnancy 
Pregnancy in a female participant or if the partner of a male participant becomes pregnant during 
the study or for a period of 3 months after the male participant has taken the last dose of study 
drug, is not an SAE, but must be reported within the same timelines as an SAE. Pregnancies will 
be followed until final outcome and live births will be followed for 6 months after birth. Pregnancy 
reporting instructions are provided in the Investigator Site File.  
Spontaneous miscarriages and congenital abnormalities will be collected as SAEs (see 
Section 10.2.4). 
12.3.1.5 
COVID-19 Vaccine 
Any AEs or suspected ADRs to the COVID-19 vaccine should be reported through the appropriate 
regulatory system(s). However, if an AE is considered to be the result of an interaction with the 
study drug in the trial then the safety assessment and reporting protocols should be followed (see 
Section 12.3). If the event is serious and considered related to both the COVID-19 vaccine and the 
study drug then it becomes a SAR. Expectedness will be assessed and SUSAR reporting will be 
initiated if the SAR is unexpected. 
13 
STATISTICAL METHODS 
13.1 
Determination of Sample Size 
The sample size for Part A of approximately 40 completed participants (approximately 12 
participants with MYH7 variant, approximately 12 participants with TTN variant, and 
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approximately 16 participants with DCM not related to MYH7 or TTN variant) has been selected 
empirically to assess the effect size of danicamtiv on the various PD measurements and to provide 
a preliminary assessment of safety and tolerability in this patient population. There is no target 
sample size for Part B because it is an optional part of the study. 
13.2 
Study Endpoints 
13.2.1 
Primary Endpoint 
Primary endpoints are clinical safety and tolerability as assessed by the following: 
• 
Frequency of AEs and SAEs in Part A 
• 
Frequency of clinically significant abnormalities from vital signs, AEs, physical examination, 
ECG recordings, and safety labs in Part A 
13.2.2 
Secondary Endpoints 
Change in the following PD parameters, as assessed by TTE from Baseline corresponding to Parts A 
and B of the study: 
• 
Left ventricular 
 
• 
Parameters of left ventricular systolic function including, but not limited to, LVSV, LVEF, left 
ventricular strain (LVGLS and LVGCS), and TDI of mitral valve annulus peak systolic 
velocity (s’) 
• 
Parameters of left ventricular dimensions including LVESD, LVEDD, LVEDVi, and LVESVi 
• 
Parameters of left atrial volume and function including, but not limited, to LAmaxVi, 
LAminVi, LAEF, and LAFI 
• 
Parameters of left ventricular diastolic function including, but not limited to, TDI of mitral 
valve annulus peak velocity in diastole (e’, lateral, septal), ratio of peak inflow velocities in 
early and late diastole (E/A), ratio of early mitral peak inflow velocity to early mitral peak 
annulus velocity (TDI) (E/e’) lateral, septal, and average. 
13.2.3 
Exploratory Endpoints 
The following are exploratory endpoints:  
• 
 will be summarized by the cohort (MYH7, 
TTN, and other DCM) using descriptive statistics 
• 
Clinical safety and tolerability as assessed by the following:  
− Frequency of treatment-emergent adverse events and serious adverse events in Part B  
− Frequency of clinically significant abnormalities from vital signs, adverse events, physical 
examination, ECG recordings, and safety labs in Part B  
• 
Additional exploratory endpoints, including concentration-PD effect and soluble biomarkers 
of cardiac physiopathology may be included 
• 
Frequency of left ventricular reverse remodeling (LVRR) during Part B, defined by the 
following criteria (Escobar-Lopez et al, 2021) by TTE and CMR (if any):  
− either LVEF normalization (LVEF improvement to ≥ 50% with a ≥ 5% LVEF increment 
from baseline )  
− or an absolute increase in LVEF by ≥ 10% at the study visits from  baseline.   
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• Frequency of improvements in LVEF  during Part A, defined by the following criteria: 
− either LVEF normalization (LVEF improvement to ≥ 50% with a ≥ 5% LVEF increment 
from baseline to each post-dose TTE) 
− or an absolute increase in LVEF by ≥ 10% from baseline to each post-dose TTE   
13.3 
Statistical Analysis 
Before database lock, a statistical analysis plan (SAP) for clinical data will be finalized that will 
contain full details of all planned analyses. Additional reviews may be conducted by the Sponsor 
at any time during Part A. The analyses presented here represent an outline of the intended 
methodology. 
13.3.1 
Analysis Populations  
Three analysis populations are defined in this study: the Safety population, the PD Analysis 
population, and the PK population. 
The Safety population is defined as participants who are enrolled and receive any amount of study 
drug (danicamtiv), including participants who prematurely withdraw from the study. Except as 
noted, all safety analyses, including demographic and baseline characteristics, will be performed 
based on the Safety population. The PD (Pharmacodynamic) population is defined as participants 
who receive any amount of study drug (danicamtiv), have any interpretable PD data, and have no 
critical or major protocol deviations related to the study drug (eg, incomplete ingestion of the drug, 
vomiting up to 8 hours after drug administration). The PD analyses will be performed based on 
the PD population.  
The PK (Pharmacokinetic) population is defined as participants who receive any amount of 
danicamtiv, have detectable plasma concentration data, and have no major or critical protocol 
deviations related to the study drug (e.g., incomplete ingestion of the drug, vomiting up to 8 hours 
after drug administration). Plasma concentration data for danicamtiv will be summarized for the 
PK population. 
13.3.2 
General Considerations 
Clinical data will be summarized by cohort (MYH7, TTN, and DCM by other causalities), and by 
dose in each Part, and combined. For MYH7 and TTN cohorts, data may be summarized by variant 
type and the location. For DCM cohort, data will be further evaluated by genetic mutation positive 
and genetic mutation negative variable. If positive genetics are identified, additional analysis may 
be performed by variant type. Depending on reports from central genetic testing laboratory, 
participant reallocation to adequate cohort and additional analysis may be performed. Descriptive 
summary statistics for continuous variables will include the number of participants, mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized using 
counts and percentages.  
13.3.3 
Participant Disposition 
The number and percentage of participants who complete or discontinue the study, as well as 
reasons for early discontinuation, will be presented separately for Part A and Part B. 
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13.3.4 
Demographics and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized descriptively. 
13.3.5 
Pharmacokinetic Analyses 
Plasma concentration data for danicamtiv will be summarized using descriptive statistics, 
including mean or geometric mean as appropriate, SD, median, minimum and maximum values, 
and coefficient of variation % (CV%). No PK analyses will be performed. 
13.3.6 
Pharmacodynamic Analyses 
Transthoracic echocardiography data including, but not limited to, 
 
, parameters of LV and LA structure and function, in addition to assessments 
of LV diastolic function will be analyzed by variant cohort using descriptive statistics. 
Observations by timepoint and change from Baseline (either absolute or percent relative change) 
at each timepoint will be summarized by cohort and by dose in both Part A and Part B.  
The parameters assessed at each timepoint and change from Baseline, which corresponds each Part 
of the study, will be summarized in the table. The data will be also presented in the figure and 
listings.  
13.3.7 
Safety Analyses 
All safety analyses, except 
 as determined by TTE, will be performed on the Safety Analysis 
population. Analyses of 
 as determined by TTE, will be performed on the PD Analysis 
population. 
The safety analysis will focus on the treatment-emergent period, which is defined as the time from 
the first administration of study drug to 14 days after the last administration of study drug. 
13.3.7.1 
Adverse Events 
Adverse events will be mapped to system organ classes and preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). Adverse events will be monitored during the 
study, and the data analyzed with respect to overall incidence as well as severity and potential 
relationship of AEs to study drug. AEs with onset on or after the first dose of study drug to 14 days 
after the last administration of study drug will be considered treatment-emergent AEs (TEAEs). 
AEs with an onset before the first dose of study drug that increase in severity on or after the first 
dose of study drug will also be monitored. Treatment-emergent AEs will be summarized by variant 
cohort, MedDRA system organ class and preferred term, and by severity and relationship to study 
drug. All TEAEs, all treatment-emergent SAEs, and all TEAEs leading to study withdrawal or 
treatment discontinuation, if any, will be presented in data listings. 
13.3.7.2 
12-lead Electrocardiogram 
The triplicate 12-lead ECG data will be utilized to measure RR, PR, QRS, and QT intervals in 
milliseconds, rounded to the nearest integer. HR will be calculated by the instrument per the device 
algorithm and rounded to the nearest integer. QT will be corrected for HR using Fridericia’s 
formula. 
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Changes in ECG wave morphologies and intervals from the Baseline tracing will be analyzed and 
reported. 
13.3.7.3 
Other Safety Analyses 
Safety laboratory data including hematology, chemistry, and vital signs will be evaluated by 
timepoint for the Safety Analysis population using descriptive statistics. Changes from Baseline 
at each post-Baseline timepoint will also be assessed. Listings of participants with laboratory 
and/or vital sign values that are observed to be out of the reference range will be produced. 
Abnormal physical examination results will be listed. Concomitant medications will be 
summarized. 
13.3.8 
Exploratory Analyses 
 will be summarized by variant cohort using 
descriptive statistics.  
Additional exploratory analyses may be performed. Detailed planned exploratory analyses will be 
specified in the SAP. 
14 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS 
14.1 
Compliance Statement 
This study will be conducted in compliance with the protocol and in accordance with the 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines; US Title 
21 Code of Federal Regulations (CFR) Parts 11, 50, 54, 56, and 312; European Union (EU) GCP; 
cGMP; EU Clinical Trials Regulation (CTR) 536/2014 for clinical studies (if applicable); the 
principles enunciated in the Declaration of Helsinki; and all human clinical research regulations in 
the countries where the study is to be conducted. 
14.2 
Informed Consent 
The ICF used for the study must comply with the Declaration of Helsinki, US 21 CFR Part 50, 
ICH GCP guidelines, and any other local regulations. The Investigator, or a person delegated by 
the Investigator, must explain the medical aspects of the study including the nature of the study 
and the treatment, orally and in writing, in such a manner that the potential participant is aware of 
potential benefits and risks. Potential participants must be informed that participation is voluntary 
and that they may withdraw from the study at any time, without prejudice. Participants must give 
informed consent in writing. 
Prior to participation in any study-related procedures, participants must sign and date an Ethics 
Committee (EC)-approved written ICF in a language the participant can understand. The informed 
consent process must be conducted, documented in the source document (including the date), and 
the form must be signed before the participant undergoes any study-specific- procedures. 
The language in the written information about the study should be as nontechnical as practical and 
should be understandable to the potential participant. Before informed consent is obtained, the 
Investigator should provide the potential participant ample time and opportunity to inquire about 
the study and to decide whether or not to participate. 
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All questions about the study should be answered to the satisfaction of the participant. The written 
ICF should be signed and personally dated by the participant and by the person who conducted the 
informed consent discussion. All participants will receive a copy of his/her signed and dated ICF. 
14.3 
Ethics Committee 
The term EC used in this document refers to an Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC) or equivalent. The EC must review and, if appropriate, approve the 
following documents, as applicable: 
• 
Study protocol and amendment(s) 
• 
Written ICF(s) and consent form updates 
• 
Participant recruitment procedures/documents (eg, advertisements) 
• 
Written information to be provided to participants 
• 
IB and available safety information (Note: ECs do not approve IBs but are responsible for 
acknowledging receipt) 
• 
Information about payments and compensation available to participants 
The EC approval must be in writing, clearly identifying the study (by protocol date and/or version), 
the documents reviewed (including informed consent), and the date of the review. The Investigator 
has the responsibility to provide the Sponsor with the written EC approval prior to initiating any 
study-related procedures. 
The Investigator also has the responsibility to inform the EC of the following according to the 
EC’s policy: 
• 
All SUSARs 
• 
Any new information that may affect adversely the safety of the participants or the conduct of 
the trial 
• 
Protocol deviations 
• 
A synopsis of the study report upon study completion 
Documentation of subsequent reviews of the study must also be forwarded to the Sponsor. 
15 
ADMINISTRATIVE PROCEDURES 
15.1 
Sponsor’s Responsibilities 
The Sponsor reserves the right to terminate the study at any time for any reason. The Sponsor and 
the Investigators will assure that adequate consideration is given to the protection of the 
participants’ interests. The Sponsor retains the right to terminate the study and remove all study 
materials from a clinical site at any time. Specific circumstances that may precipitate such 
termination include: 
• 
Request by Health Authority to terminate the study 
• 
Unsatisfactory participant enrollment with regard to quality or quantity 
• 
Significant or numerous deviations from study protocol requirements, such as failures to 
perform required evaluations on participants, maintain adequate study records or inaccurate, 
incomplete, or late data recording on a recurrent basis 
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• 
The incident or severity of AEs in this or other studies indicating potential health hazard caused 
by the study drug 
15.1.1 
Participant Confidentiality 
The processing of personal data in pursuit of this study will be limited to those data that are reasonably 
necessary to investigate the utility of the study drugs used in this study. These data will be processed 
with adequate precautions to ensure confidentiality according to applicable laws. 
The Sponsor ensures that the personal data are: 
• 
Collected for a specified and legitimate purpose 
• 
Processed fairly and lawfully 
• 
Accurate and up to date 
Explicit consent for the processing of personal data will be obtained prospectively from the 
participating participant. 
The Sponsor, whose responsibilities require access to personal data, agrees to keep the identity of 
participants confidential. This confidentiality will be maintained throughout the complete data 
processing. 
Participants will be entitled to request confirmation of the existence of personal data held by the 
Sponsor and will have the right to rectify erroneous or inaccurate data up until database lock. 
15.1.2 
Study Supplies 
The Sponsor will supply or ensure the coordination of sufficient quantities of the following 
materials to each clinical site: 
• 
Activity monitor 
• 
Cardiac rhythm monitoring patch 
• 
Danicamtiv (MYK-491) tablets 
• 
ECG equipment 
• 
IB for danicamtiv 
• 
Laboratory manual 
• 
Laboratory test kits 
• 
Pharmacy manual 
15.1.3 
Investigator Training 
A site-specific study initiation meeting and/or an Investigator Meeting will be held to ensure the 
center staff understands the protocol, study requirements, and data capture processes. This training 
will take place before the first participant is enrolled. The clinical site will be provided with 
information regarding GCP and regulations specific to the conduct of the clinical studies. The 
clinical site will be responsible for ensuring that new team members are adequately trained, and 
the training is documented. 
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15.1.4 
Ongoing Communication of Safety Information During the Study 
The Sponsor will provide the Investigator with documentation of SAEs from the study and other 
studies with danicamtiv that are unexpected, as appropriate. The Investigator must forward this 
documentation to the EC as described in Section 14.3.  
The Sponsor will also notify the Investigator about any other significant safety findings that could 
alter the safety profile of the study drug from what is described in the protocol and significantly 
affect the safety of participants, affect the conduct of the study, or alter the EC’s opinion about the 
continuation of the study. 
15.1.5 
Study Monitoring 
The Sponsor will monitor this clinical study through remote data checks and monitoring visits to 
check the adequacy of clinical site staff and facilities, and to ensure adherence to the protocol, 
study procedures, and applicable regulations. The clinical site monitor will also assess proper 
eCRF completion and source document retention. The Investigator and clinical site staff are 
expected to provide adequate space for monitoring visits and to allocate sufficient time to permit 
adequate review of the study’s progress. The Investigator will permit study-related monitoring, 
audits, EC review, and regulatory inspection(s), providing direct access to source data/documents 
and study-related facilities (eg, pharmacy, diagnostic laboratories). 
15.1.6 
Study Auditing and Inspecting 
The Sponsor may audit the study conduct, compliance with the protocol, and accuracy of the data. 
The Investigator(s)/institution(s) will permit study-related monitoring, audits, and inspections by 
the Sponsor, EC, government regulatory authority(ies), and the Sponsor’s quality assurance 
personnel or its designees by providing direct access to source data/documents after appropriate 
notification from the Sponsor. 
15.2 
Investigator’s Responsibilities 
15.2.1 
Study Data Definition 
“Study Data” refers to all participant clinical data, primary and summary, laboratory data, and 
associated imaging data that are generated in connection with the performance of conducting the 
study, and required to be compiled in CRFs and/or submitted to the Sponsor as a deliverable under 
the Protocol. Such “Study Data” shall include data collected or prepared by Institution or 
Investigator in determining whether a study participant satisfies the enrollment criteria for the 
study or in the performance of the study. These data may be contained in CRFs or electronic data 
records, as well as any other documents or materials created for the study (e.g., TTE, CMR, or 
other types of medical images, ECG, or other types of tracings/printouts, or data summaries) and 
all recorded original observations and notations of clinical activities. 
15.2.2 
Screening Log 
The Investigator must keep a record that lists all participants who signed an ICF and the reason for 
non-inclusion if the potential participant does not ultimately enroll and not receive study drug. 
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15.2.3 
Danicamtiv Accountability 
The Investigator must ensure that the study drug at the investigational site is kept secured and 
accounted for with access limited to only those individuals authorized by the Investigator. The 
Investigator, his/her designee, or pharmacist must also maintain adequate records of distribution, 
dispensing, and all study drug to be able to reconcile the study drug records (accountability or 
dispensing logs) at the end of the study.. The study medication records must be readily available 
for inspection by the (unblinded) site monitor and/or auditor. In general, no study medication can 
be returned to Sponsor/clinical site or disposed of at the clinical site until the clinical site monitor 
has verified the accuracy of the study medication records at the clinical site and indicated whether 
the medication should be destroyed at the clinical site or returned to Sponsor/designee 
15.2.4 
Reporting and Recording of Study Data 
Data will be captured and compiled using procedures developed by the Sponsor or designee. All 
requested study data must be clearly recorded on the eCRF and other forms as required. Whenever 
possible, the reason for missing data in the source document must be recorded. Only individuals 
who are identified on the study personnel responsibility/signature log and who have received 
appropriate training on the electronic data capture (EDC) system may enter or correct data in the 
eCRF. Incomplete or inconsistent data on the eCRF will result in data queries that require 
resolution by the Investigator or designee. Corrections to the eCRF, including the reason for 
change, will be documented. 
Participant source data must be maintained as original records or a certified copy (copy of original 
information that has been verified, as indicated by a dated signature, as an exact copy having all 
the same attributes and information as the original). The Investigator and affiliated institution 
should take measures to prevent accidental or premature destruction of documents. Data collected 
on the eCRF must match the source documents. 
An eCRF must be completed for each participant who signs the ICF. All entries into the eCRF are 
ultimately the responsibility of the Investigator. The Investigator is responsible for ensuring 
accurate, authentic, and complete records for each participant. 
An electronic copy of the eCRF casebooks will be sent to the clinical site for retention with other 
study documents after full completion of the study. 
15.2.5 
Source Data and Source Documents 
The nature and location of all source documents will be identified to ensure that all sources of 
original data required to complete the eCRF are known to the Sponsor and clinical site staff. The 
source documents are to be accessible for verification by the clinical site monitor. 
Source documents should at minimum include the following information for each participant: 
• 
Participant identification and contact information (name, date of birth, sex, address, phone) 
• 
Documentation verifying participant eligibility (i.e., medical history, physical examination) 
• 
Informed consent process documentation and ICF 
• 
Record of all visits and other contacts 
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• 
Record of all AEs and other safety parameters and all event attributes 
• 
Record of all concomitant therapy (including start/stop dates, indication for use, dose) 
• 
Date of study completion and reason for early discontinuation, if applicable 
The author of an entry in the source documents should be identifiable as well as the date of the 
entry. Direct access to source documentation must be allowed for the purpose of verifying that the 
data recorded in the eCRF are consistent with the original source data. The Investigator will 
provide certified copies of the participant’s medical records in the event the clinical site’s policy 
does not permit direct access to the electronic medical records. 
15.2.6 
Participant Identification Information 
To permit easy identification of the individual participant during and after the study, the 
Investigator is responsible for keeping an updated log that contains the participant identification 
information. This document will be reviewed by the clinical site monitor for completeness. 
However, to ensure the participant’s confidentiality, the document will be maintained at the 
clinical site and no copy will be made. 
15.2.7 
Protocol Deviations 
Unless there is a safety concern, there should be no deviations or violations of the study protocol. 
In the event of a safety concern, the Investigator or designee must document and explain the reason 
for any deviation from the approved protocol. The Investigator may implement a deviation from, 
or a change to, the protocol to eliminate an immediate hazard to participants, without prior EC 
approval. If required, immediately after the implemented deviation or change, the Investigator must 
submit a report explaining the reasons for the protocol deviation to the EC and the Sponsor. If a 
protocol deviation results in inadequate participant data, the Sponsor may determine that the 
participant should be replaced. The Medical Monitor will notify the study monitor of the decision. 
15.2.8 
Blood Sample Collection/Storage 
Blood samples that are collected as part of routine medical care or as part of protocol procedures 
may be stored and analyzed for danicamtiv plasma concentration or biomarker analyses. All 
participants will be asked to provide consent for blood to be drawn for potential future analyses in 
relation to efficacy, safety, PD, or plasma concentration, unless there are local regulations 
prohibiting such analyses. 
Samples will be used (if allowed per local regulations) in compliance with guidelines defined by 
the US Food and Drug Administration (FDA) Guidance on Informed Consent for In Vitro 
Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable 
(issued 25 April 2006) and the European Medicines Agency (EMA) Reflection Paper on 
Pharmacogenomic Samples, Testing and Data Handling (EMA/Committee for Medicinal Products 
for Human Use [CHMP] 2007). 
15.2.9 
Records Retention 
The Sponsor will inform the Investigator in writing when it is acceptable to dispose of any study 
records. To enable evaluation and/or audits from regulatory authorities or the Sponsor, the 
Investigator agrees to keep records, including the identity of all participants (eg, participant 
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identification code list and all source documents), all original signed ICFs, copies of all eCRFs, 
original laboratory reports, detailed records of study drug disposition, and all essential documents 
for the conduct of a clinical study. To comply with international regulations, the records should be 
retained by the Investigator for at least 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region, or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the study drug. However, the Investigator may need to retain these documents for 
a longer period, if required by the local regulatory requirements or by an agreement with the 
Sponsor. 
15.3 
Clinical Trial Insurance 
Clinical trial insurance has been undertaken according to the laws of the countries where the study 
will be conducted. An insurance certificate will be made available to the participating clinical sites 
upon request. 
15.4 
Protocol Amendments and Study Administrative Letters 
Study procedures will not be changed without the mutual agreement of the Investigator and the 
Sponsor. 
If there are any substantial changes to the study protocol, then these changes will be documented 
in a study protocol amendment and, where required, in a new version of the study protocol. 
The amendment should be approved by the EC and the appropriate regulatory authority(ies), before 
implementation, as appropriate. Local requirements should be followed for revised protocols. 
If a protocol amendment requires a change to the ICF, the EC will need to approve the revised ICF 
before the revised form is used. 
If there are nonsubstantial changes, such as clarification of statement or corrections to obvious 
errors/typographical errors/inconsistencies in the protocol, or change to logistical or administrative 
aspects, then the Sponsor may issue an Administrative Letter. If local regulations require, any 
administrative change will be communicated to or approved by the EC. 
16 
DATA QUALITY ASSURANCE 
Quality assurance and quality control systems will be implemented and maintained with Standard 
Operating Procedures by the Sponsor, as appropriate, to ensure that this clinical study is conducted 
and data are generated, documented (recorded), and reported in compliance with the protocol, ICH 
E6 Good Clinical Practice: Consolidated Guidance, and the applicable regulatory requirements. 
17 
ADMINISTRATIVE CONSIDERATIONS 
17.1 
Use of Computerized Systems 
This study will require the use of the following electronic data collection methods: 
• 
EDC system to capture protocol-required participant data: the clinical site will enter data from 
source documents onto eCRFs for each study timepoint using a web-based interface. Study 
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monitors and data management personnel will use this system to review data and generate 
queries and reports as needed. 
• 
Cardiac clinical data management systems will be used to analyze echocardiographic data from 
digital equipment used by clinical site personnel to collect participant data. 
In addition, other central data management systems/databases and software may be used to collect 
and analyze study data: 
• 
Laboratory Information Systems or proprietary systems will be used by laboratories for storing 
and/or analyzing bioanalytical laboratory data collected throughout the study. 
• 
Statistical software will be used for the statistical analysis of the study data as outlined in the 
SAP. 
Information on the above systems will be provided to the Investigator, clinical site personnel, and 
other personnel, as appropriate. Measures will be taken to ensure data security and accuracy, 
including, but not limited to, user training, granting of user accounts and privileges to trained and 
authorized personnel in a role-based manner, username/password/electronic signature 
requirements enforcement, programmed and manual edit checks as outlined in data validation 
specifications, computer generated audit trails, centralized data management, and routine study 
monitoring. The systems used will be compliant with US 21 CFR Part 11 and Annex 11 to the 
Rule Governing Medicinal Products in the EU, and the data collected will be archived (at 
minimum) for the period specified by applicable regulatory requirements. 
17.2 
Study Records 
The Investigator and affiliated institution shall maintain the study documents and records as 
specified in “Essential Documents for the Conduct of a Clinical Trial” (ICH E6, Good Clinical 
Practice, Section 8), and as required by the applicable regulatory requirement(s). This includes, 
but is not limited to, the protocol, eCRFs, AE reports, participant source data (original records or 
certified copies), correspondence with health authorities and EC, consent forms, Investigator’s 
curriculum vitae, monitor visit logs, laboratory reference ranges and laboratory certification or 
quality control procedures, and laboratory director curriculum vitae. 
The eCRF must be completed at the time of, or shortly after the participant’s visit or upon receipt 
of test results. Information will be provided to clinical site staff on the proper way to complete the 
eCRF. 
A copy of each participant’s eCRF will be maintained by the Investigator. 
18 
PUBLICATION 
The data and results of the study will be owned solely by the Sponsor and shall be confidential 
information of the Sponsor, participant to the Investigator’s publication rights, all as outlined in 
the agreement between the Investigator/institution and the Sponsor regarding the conduct of the 
clinical study (the “Clinical Study Agreement”). It is understood by the Investigator that the 
Sponsor may use the information developed in this study in connection with the development of 
the Sponsor’s proprietary study drug and, therefore, may disclose such information as necessary 
or useful to other clinical Investigators or regulatory agencies. To allow for the use of the 
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information derived from the study, the Investigator understands that he/she has an obligation to 
provide and disclose all study results and all data developed during this study to the Sponsor. 
Any publication or presentation of the results or data of this clinical study by the Investigator may 
only be made in strict compliance with the provision of the Clinical Study Agreement. The 
Investigator understands that it is not the Sponsor’s intention to prevent publication of the data 
generated in the study; rather, the Sponsor reserves the right to control the form and timing of such 
publication for commercial reasons and desires to confirm the scientific accuracy of such 
information prior to such publication or presentation. 
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19 
REFERENCE LIST 
Anderson, J.L,. G.B.Christensen, H. Escobar, et al. 2020. ‘Discovery of TITIN Gene Truncating 
Variant Mutations and 5-Year Outcomes in Patients with Nonischemic Dilated Cardiomyopathy’ 
The American Journal of Cardiology,137:97-102.  
Benjamin, E. J., M. J. Blaha, S. E. Chiuve, M. Cushman, et al. 2017Committee American Heart 
Association Statistics, and Subcommittee Stroke Statistics. . 'Heart Disease and Stroke Statistics-
2017 Update: A Report From the American Heart Association', Circulation, 135: e146-e603. 
Bozkurt, B., Colvin, M., Cook, J., et al. 2016. 'Current Diagnostic and Treatment Strategies for 
Specific Dilated Cardiomyopathies', Circulation, 134:e579-e646. 
Braunwald, E. 2013. 'Heart failure', JACC Heart Fail, 1: 1-20. 
De Frutos, F., J.P. Ochoa, M. Navarro-Pnealver, et al. 2022. ‘Natural history of MYH7-related 
Dilated Cardiomyopathy. Journal of American College of Cardiology, 80:1447-11461.   
Green, C.P, Porter, C.B, Bresnahan D.R., et al. 2000. ‘Development and Evaluation of the Kansas 
City Cardiomyopathy Questionnaire: a New Health Status Measure for Heart Failure’, J Am Coll 
Cardiol, 35(5):1245-55. 
Gronda, E., G. Seravalle, G. Brambilla, G. Costantino, A. Casini, A. Alsheraei, E. G. Lovett, G. 
Mancia, and G. Grassi. 2014. 'Chronic baroreflex activation effects on sympathetic nerve traffic, 
baroreflex function, and cardiac haemodynamics in heart failure: a proof-of-concept study', Eur J 
Heart Fail, 16: 977-83. 
Escobar-Lopez, L., Ochoa J.P., Mirelus J.G., et al. 2021 Association of Genetic Variants with 
Outcomes in Patients with Nonischemic Dilated Cardiomyopathy, J Am Coll Cardiol. 
78(17):1682-99. 
Herman, D. S., L. Lam, M. R. Taylor, L. Wang, P. et al. 2012. 'Truncations of titin causing dilated 
cardiomyopathy', N Engl J Med, 366: 619-28. 
Hershberger, R. E., D. J. Hedges, and A. Morales. 2013. 'Dilated cardiomyopathy: the complexity 
of a diverse genetic architecture', Nat Rev Cardiol, 10: 531-47. 
Hinson, J. T., A. Chopra, N. Nafissi,et al. 2015. 'HEART DISEASE. Titin mutations in iPS cells 
define sarcomere insufficiency as a cause of dilated cardiomyopathy', Science, 349: 982-6. 
Linschoten, M., A. J. Teske, A. F. Baas, A. Vink, D. Dooijes, H. F. Baars, and F. W. Asselbergs. 
2017. 'Truncating Titin (TTN) Variants in Chemotherapy-Induced Cardiomyopathy', J Card Fail, 
23: 476-79. 
McDonagh T.A., Metra M., Adamo M., et al. 2021. 2021 ESC Guidelines for the Diagnosis and 
Treatment of Acute and Chronic Heart Failure; Developed by the Task Force for the Diagnosis 
and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) 
with the Special Contribution of the Heart Failure Association (HFA) of the ESC. European Heart 
Journal, 42(36):3599-726.  
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Merlo, M., Cannata, A., Gobbo M, et al. 2018. 'Evolving Concepts in Dilated Cardiomyopathy', 
Eur J Heart Fail, 20(2): 228-39. 
Min, S. S., J. R. Turner, A. Nada, et al. 2010. 'Evaluation of ventricular arrhythmias in early clinical 
pharmacology trials and potential consequences for later development', Am Heart J, 159: 716-29. 
Pinto, Y.M., Elliott, P.M., Arbustini E., et al. 2016. ‘Proposal for a Revised Definition of Dilated 
Cardiomyopathy, Hypokinetic Non-dilated Cardiomyopathy, and its implications for Clinical 
Practice: a Position Statement of the ESC Working Group on Myocardial and Pericardial Diseases', 
Eur Heart J, 37: 1850-58. 
Roberts, A. M., J. S. Ware, D. S. Herman, et al. 2015. 'Integrated allelic, transcriptional, and 
phenomic dissection of the cardiac effects of titin truncations in health and disease', Sci Transl 
Med, 7: 270ra6. 
Shah, R.A., M.B. BChir, B. Asatryan et al. 2022. ‘Frequency, Penetrance, and Variable 
Expressivity of Dilated Cardiomyopathy-associated Putative Pathogenic Gene Variants in UK 
Biobank Participants’, Circulation, 145:110-124 
Tang, W., W. C. Unrath, R. Desetty, and C. M. Yengo. 2019. 'Dilated cardiomyopathy mutation 
in the converter domain of human cardiac myosin alters motor activity and response to omecamtiv 
mecarbil', J Biol Chem, 294: 17314-25. 
Teerlink, J.R., Rafael Diaz, and G. Michael Felker, et al. 2021. Cardiac Myosin Activation with 
Omecamtiv Mecarbil in Systolic Heart Failure, N Engl J Med 2021;384:105-16.  
Teerlink, J. R., R. Diaz, G. M. Felker, et al. 2020. 'Omecamtiv Mecarbil in Chronic Heart Failure 
With Reduced Ejection Fraction: Rationale and Design of GALACTIC-HF', JACC Heart Fail, 8: 
329-40. 
Teerlink, J. R., G. M. Felker, J. J. McMurray, S. D. Solomon, K. F. Adams, Jr., J. G. Cleland, J. 
A. Ezekowitz, A. Goudev, P. Macdonald, M. Metra, V. Mitrovic, P. Ponikowski, P. Serpytis, J. 
Spinar, J. Tomcsanyi, H. J. Vandekerckhove, A. A. Voors, M. L. Monsalvo, J. Johnston, F. I. 
Malik, N. Honarpour, and Cosmic-Hf Investigators. 2016. 'Chronic Oral Study of Myosin 
Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, 
randomised, placebo-controlled trial', Lancet, 388: 2895-903. 
Thomas, P., D. J. O'Gorman, and D. J. Sheridan. 1993. 'Acute and chronic effects of flosequinan 
on resting and exercise haemodynamics in congestive heart failure', Br J Clin Pharmacol, 36: 539-
46. 
Ujfalusi, Z., C. D. Vera, S. M. Mijailovich, M., et al. 2018. 'Dilated cardiomyopathy myosin 
mutants have reduced force-generating capacity', J Biol Chem, 293: 9017-29. 
Voors, A. A., J. F. Tamby, J. G. Cleland, et al. 2020. 'Effects of danicamtiv, a novel cardiac myosin 
activator, in heart failure with reduced ejection fraction: experimental data and clinical results from 
a phase 2a trial', Eur J Heart Fail, 22: 1649-58. 
Ware, J. S., J. G. Seidman, and Z. Arany. 2016. 'Shared Genetic Predisposition in Peripartum and 
Dilated Cardiomyopathies', N Engl J Med, 374: 2601-2. 
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Yancy, C. W., M. Jessup, B. Bozkurt, J., et al. 2016. '2016 ACC/AHA/HFSA Focused Update on 
New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline 
for the Management of Heart Failure: A Report of the American College of Cardiology/American 
Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of 
America', J Am Coll Cardiol, 68: 1476-88. 
Yancy, C. W., M. Jessup, B. Bozkurt, J., et al, Foundation American College of Cardiology, and 
Guidelines American Heart Association Task Force on Practice. 2013. '2013 ACCF/AHA 
guideline for the management of heart failure: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines', J Am Coll Cardiol, 
62: e147-239. 
 
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APPENDIX 1 
SCHEDULE OF ASSESSMENTS 
Table 3: 
Schedule of Assessments, Part A 
Period 
Pre-
Screen 
Screening 
Treatment Period 1 
(25 mg BID) 
Treatment Period 2  
(10 or 50 mg BID) 
Follow-Up 
Early 
Term 
Visit Day 
 
Day -56 to -1 
(Screening 1)t 
If needed 
(Screening 
2) 
Day 1  
(Baseline) 
1-3 
days 
before 
V3A 
Afternoon of 
Day 5, 6, 7, 
or 8 
(End Tx 1) 
1-3 
days 
before 
V4A 
Afternoon,  
5-8 days 
after V3A 
(End Tx 2) 
1-3 days 
after 
V4A 
14 days + 
7d after 
V4Aa 
 
Visit Number 
V0A 
V1.1A 
V1.2A 
V2A 
TH1A 
V3A 
TH2A 
V4A/ 
EOT 
(Part A) 
TH3A 
V5A/ 
EOS  
(Part A)a 
ETA 
Telehealth Visit 
 
 
 
 
Xs 
 
Xs 
 
X 
 
 
Informed consent 
 
X 
  
  
 
  
 
  
  
  
 
Medical history  
(General and CV) 
 
X 
  
 
  
 
  
  
  
 
Documentation of 
MYH7- or TTN-DCM 
Variant 
Xb  
X 
  
  
 
  
 
  
  
  
 
Pregnancy Testc  
 
X 
X - predose 
 
  
 
  
  
X 
 
FSH Levelw 
 
X 
  
  
 
  
 
  
  
  
 
Physical Examinationd  
 
X 
  
X 
 
  
 
 X 
  
X 
 
Height 
 
X 
 
 
 
  
 
  
  
  
 
Weight 
 
X 
  
X 
 
X 
 
X 
  
X 
X 
Vital Signs 
 
X 
  
X 
 
 X 
 
X 
  
X 
X 
TTEe  
 
Xr 
X– 
X - predose 
 
Xf,g(7h post-
AM dose) 
 
Xg(7h post-
AM dose) 
  
  
X 
12-lead ECGh 
 
X 
X - predose 
 
Xu 
 
X 
  
X 
X 
Cardiac Monitoring 
Patchj  
 
X 
 
 
 
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Table 3: 
Schedule of Assessments, Part A 
Period 
Pre-
Screen 
Screening 
Treatment Period 1 
(25 mg BID) 
Treatment Period 2  
(10 or 50 mg BID) 
Follow-Up 
Early 
Term 
Visit Day 
 
Day -56 to -1 
(Screening 1)t 
If needed 
(Screening 
2) 
Day 1  
(Baseline) 
1-3 
days 
before 
V3A 
Afternoon of 
Day 5, 6, 7, 
or 8 
(End Tx 1) 
1-3 
days 
before 
V4A 
Afternoon,  
5-8 days 
after V3A 
(End Tx 2) 
1-3 days 
after 
V4A 
14 days + 
7d after 
V4Aa 
 
Visit Number 
V0A 
V1.1A 
V1.2A 
V2A 
TH1A 
V3A 
TH2A 
V4A/ 
EOT 
(Part A) 
TH3A 
V5A/ 
EOS  
(Part A)a 
ETA 
Telehealth Visit 
 
 
 
 
Xs 
 
Xs 
 
X 
 
 
Evaluation of Patch 
 
 
 
 
 
X 
 
 
 
 
 
NYHA Functional 
Classification 
 
 
 
X 
 
 
 
X 
 
X 
 
KCCQ-23x 
 
 
 
X 
 
 
 
X 
 
X 
 
Adverse Eventsv 
 
Prior/concomitant 
Therapy 
 
Danicamtiv Plasma PK 
Samplek  
 
  
Xl -predose  
 
X (7h post-
AM dose) 
 
X (7h post-
AM dose) 
  
  
X 
hsTnT/TnI/hs-TnIm 
(Central) 
 
X 
 
Xl 
 
X 
 
X 
 
X 
X 
NT-proBNP (Central) 
 
X 
 
Xl 
 
X 
 
X 
 
X 
X 
Chemistry, Hematology 
(Central) 
 
Xn  
 
Xl 
 
X 
 
X 
 
X 
X 
Blood sample for 
Pharmacogenetic 
Testingo 
 
 
 
Xl 
 
 
 
 
 
 
 
Blood sample for 
Genetic Cardiomyopathy 
Testingy 
 
X 
 
 
 
 
 
 
 
 
 
Non-genetic Biomarker 
Sample 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
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Table 3: 
Schedule of Assessments, Part A 
Period 
Pre-
Screen 
Screening 
Treatment Period 1 
(25 mg BID) 
Treatment Period 2  
(10 or 50 mg BID) 
Follow-Up 
Early 
Term 
Visit Day 
 
Day -56 to -1 
(Screening 1)t 
If needed 
(Screening 
2) 
Day 1  
(Baseline) 
1-3 
days 
before 
V3A 
Afternoon of 
Day 5, 6, 7, 
or 8 
(End Tx 1) 
1-3 
days 
before 
V4A 
Afternoon,  
5-8 days 
after V3A 
(End Tx 2) 
1-3 days 
after 
V4A 
14 days + 
7d after 
V4Aa 
 
Visit Number 
V0A 
V1.1A 
V1.2A 
V2A 
TH1A 
V3A 
TH2A 
V4A/ 
EOT 
(Part A) 
TH3A 
V5A/ 
EOS  
(Part A)a 
ETA 
Telehealth Visit 
 
 
 
 
Xs 
 
Xs 
 
X 
 
 
Tx Period 1 Study Drug 
Administrationp  
 
 
 
 
 
 
 
 
 
Tx Period 2 Study Drug 
Administrationp 
 
 
 
 
 
 
 
 
 
 
Study Drug Compliance 
Checkq  
 
 
 
 
X 
X 
X 
X 
 
 
 
 
AE = adverse event; CV = cardiovascular; DCM = dilated cardiomyopathy; ECG = electrocardiogram; EOS = end of study; ET = early termination Part A FSH = 
follicle-stimulating hormone; hsTnI = high sensitivity troponin I; hsTnT = high sensitivity troponin T; IMP = investigational medicinal product; KCCQ-23 = 
Kansas City Cardiomyopathy Questionnaire (23-item version); MYH7 = Myosin Heavy Chain 7; NT-proBNP = N-terminal pro b-type natriuretic peptide; NYHA 
= New York Heart Association; PK = pharmacokinetic; SAE = serious adverse event; TH = telehealth; TTE = transthoracic echocardiography; TTN = titin; TX = 
treatment; V = visit. 
a If a Rescreening visit is not required prior to Part B start, then Visit 1B can be performed on the same day as Visit 5A and any assessments in Visit 5A that are 
also required in Visit 1B need to only be performed once.  
b Where allowed by local regulations, participants may consent to share results of previous genetic testing. These results will be shared with the Sponsor for 
assessing potential eligibility prior to Visit 1A (Screening). 
c Pregnancy tests, urine or serum, is based on the policy of the local institution or regulating Health Authority (eg, requirement for serum-based testing in the 
United Kingdom) should be performed on all females of child-bearing potential at Screening, Day 1, and Follow-up. 
d At Screening, a complete physical examination will be conducted including a neurological examination (gross motor and deep tendon reflexes), height and 
weight, and assessment of the following: general appearance, skin, head and neck, mouth, lymph nodes, thyroid, abdomen, musculoskeletal, cardiovascular, 
neurological, and respiratory systems. All other timepoints can be abbreviated physical examination (pulmonary, cardiac, abdominal, and other systems related 
to any symptoms). 
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e Participant should be at rest for at least 10 minutes prior to performance of any TTE. At least one full TTE must be performed at Screening. Eligibility to be 
determined by criteria in Section 7.1. 
f TTE at Visit 3A will be reviewed locally in real time to determine dosing of study drug for Treatment Period 2. 
g TTE at Visit 3A and Visit 4A should be performed 7 hours (±1 hour) after ingestion of morning study drug dose. 
h Triplicate 12-lead ECG evaluations (all obtained within a 20-minute window) will be performed in the supine position after 10 minutes of rest. The predose 
ECG on Day 1 should be performed before dosing. Additional ECGs (unscheduled assessments) should be obtained in cases of suspected ischemia. 
 
 
 
j Cardiac rhythm monitoring patch will be placed at the first Screening visit (Visit 1.1A) if using historical LVEF to qualify. If using 2 Screening TTEs, the patch 
will be placed at the time of the 2nd Screening visit (Visit 1.2A). The duration of initial monitoring may range from a minimum of 5 days to a maximum of 14 
days. If the patch should become detached prior to 5 days, a new patch should be placed as soon as possible. A new patch will be placed at the start of each 
Treatment Period, after dosing. The patch will be inspected by the Investigator at each encounter with the participant. If adhesive appears intact, the existing 
patch should be left in place. If the patch adhesive appears to be failing, a new patch should be placed at that time.  
k Plasma samples will be obtained within 3 hours predose at Visit 2A. At Visit 3A and Visit 4A, plasma concentration will be obtained at 7 hours (±1 hour) 
following the last dose (taken in the morning) of each Treatment Period. An unscheduled or additional plasma sample may be collected if appropriate in the 
opinion of the Investigator and/or Sponsor (eg, in the case of an AE/SAE) (Section 11.3.1). 
l Predose laboratory samples may be obtained on the day prior to Visit 2A. 
m All samples will be analyzed at a central laboratory. If the participant has any signs or symptoms suggestive of possible cardiac ischemia, additional troponin 
samples may be obtained as well as a simultaneous plasma concentration sample (Section 11.3.1). 
n Abnormal findings from laboratory assessments performed at Visit 1A may be repeated once during Screening after corrective treatment (eg, hemolysis of 
sample, abnormal potassium levels). Screening laboratory tests will include TSH and Fe/TIBC/ferritin to exclude uncontrolled thyroid functions and Fe overload.  
o All Participants have the option to provide consent for blood to be drawn for potential future analysis of pharmacogenetics, as permitted by local regulation. 
Additional samples for pharmacogenetic testing will be collected if needed (eg., samples determined as not adequate for DNA extraction) anytime during the 
study after participants provided consent for additional sample collection.     
p Participants will be dosed BID (every 12 hours). Doses may occur ± 2 hours from scheduled dosing times as long as doses are separated by at least 10 hours and 
by no more than 14 hours. For Treatment Period 1, the initial dose (Visit 2A) should be given after all assessments (cardiac rhythm monitoring patch application 
excepted) are completed. On Day 1, if baseline assessments are completed in the afternoon then study drug will only be administered once in the afternoon. The 
last dose for Treatment Period 1 (Visit 3A) and the last dose for Treatment Period 2 (Visit 4A) should be taken the morning of each visit and approximately 7 
hours prior to the afternoon visits for Visit 3A and 4A. 
q Study drug compliance check will entail tablet count at Visit 3A and Visit 4A. At Telehealth Visit 1A and Telehealth Visit 2A, participant will be contacted and 
interviewed. Acceptable methods of contact include, but are not limited to, telephone, two-way text messaging, and email. 
r If a participant’s most recent prior TTE (within the past 12 months) documents a LVEF ≤ 45%, then only a single Screening visit confirming LVEF ≤ 45% by 
the Echo Core Laboratory is required. If no prior documented LVEF ≤ 45% by TTE within the past 12 months is available, then 2 Screening TTEs are needed 
at least one week (7 days) apart. The absolute difference between the 2 LVEF values qualifying the participant should be < 12%. 
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s One to 3 days before the end of each Treatment Period, the participant will be contacted to assess any symptoms, ensure compliance with study drug, and to 
remind the participant about next visit (Visits 3A and 4A) and to take study drug in the morning of Visits 3A and 4A, about 7 h prior to the scheduled time of 
each visit. 
t Visit 3A (D5 to D8) and Visit 4A (5 to 8 days after Visit 3A, ie. Day 9 up to Day 15). This scheduling window is to accommodate weekends and holidays.  
u Triplicate 12-lead ECG obtained at Visit 3A will be reviewed by the Investigator to confirm lack of QTcF prolongation in order to continue with study drug 
treatment (Section 6.2) before being sent to the ECG core laboratory. 
v Changes in baseline conditions from once the ICF is signed will be recorded as an AE. All changes, unless otherwise specified, that occur after the administration 
of study drug will be considered treatment emergent AEs. 
w FSH level assessment done at Screening is only for women of non-childbearing potential. 
x Should be done before any other assessments. 
y If rescreening is conducted, repeat of genetic testing at Screening is not necessary. Up to 1 rescreen per participant is permitted. 
 
 
 
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Table 4: 
Schedule of Assessments, Part B (Active Cohort) 
 
End of  
Part A 
Part B, Year 1 
Visit Day 
14 days + 
7d after 
V4A 
Day -28 to -1 
(Rescreening, 
if needed) 
Day 1 
(Baseline) 
Week 2 
Week 6 
Week 12 
Week 
18  
Week 
24 
Week 30 
Week 36 
Week 
42 
Week 
48 
Visit Number 
V5Aa 
V0Bl 
V1Ba 
V2B 
V3B 
V4B 
V5B 
V6B 
TH1B 
V7B 
TH2B 
V8B 
Visit Windows 
 
-28 days 
 
± 2 days 
± 7 days 
± 7 days 
± 7 
days 
± 7 
days 
± 7 days 
± 7 days 
± 7 
days 
± 7 
days 
Telehealth Visit 
 
 
 
 
 
 
 
 
X 
 
X 
 
Informed Consent 
 
X 
X (if 
needed) 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
X (if 
needed) 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
Weight 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
Complete Physical Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
Symptom-directed Physical 
Exam 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
TTE 
 
 
Xd 
X c,e 
X c,e 
X c 
X c 
 
 
 
X c 
12-lead ECG 
X 
X 
X 
X 
 X 
X 
X 
X 
Xi 
X 
Xi 
X 
Cardiac Rhythm 
Monitoringf 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Activity Monitorg 
 
 
X 
 
 
 
 
X 
 
 
 
X 
CMRh 
 
 
Xd 
 
 
 
 
 
 
 
 
X 
6MWD (in clinic) 
 
 
Xd 
 
 
 
 
X 
 
 
 
X 
NYHA Functional 
Classification 
X 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
KCCQ-23  
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
hsTnT/TnI/hs-TnI (Central)b 
X 
 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
X 
Xj 
X 
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Table 4: 
Schedule of Assessments, Part B (Active Cohort) 
 
End of  
Part A 
Part B, Year 1 
Visit Day 
14 days + 
7d after 
V4A 
Day -28 to -1 
(Rescreening, 
if needed) 
Day 1 
(Baseline) 
Week 2 
Week 6 
Week 12 
Week 
18  
Week 
24 
Week 30 
Week 36 
Week 
42 
Week 
48 
Visit Number 
V5Aa 
V0Bl 
V1Ba 
V2B 
V3B 
V4B 
V5B 
V6B 
TH1B 
V7B 
TH2B 
V8B 
Visit Windows 
 
-28 days 
 
± 2 days 
± 7 days 
± 7 days 
± 7 
days 
± 7 
days 
± 7 days 
± 7 days 
± 7 
days 
± 7 
days 
Telehealth Visit 
 
 
 
 
 
 
 
 
X 
 
X 
 
NT-proBNP (Central)  
X 
 
X 
X 
 X 
X 
X 
X 
Xj 
X 
Xj 
X 
Chemistry, Hematology 
(Central) 
X 
Xo 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Pregnancy Testk 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
Danicamtiv Plasma PK 
Sample 
 
 
X (pre-
dose_ 
Xc 
Xc 
Xc 
X 
Xc 
 
X 
 
Xc 
Non-genetic Biomarker 
Sample 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Study Drug Administration 
 
 
 
Adverse Eventsm 
 
Concomitant Medications 
 
Study Drug Compliance 
Checkn 
 
 
 
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Table 4: 
Schedule of Assessments, Part B (Active Cohort) 
 
Part B, Year 2 
Visit Day 
Week 54 
Week 60 
Week 66 
Week 72 
Week 78 
Week 84 
Week 96 
Follow-up 
(Week 98) 
Early 
Termination 
Visit Number 
TH3B 
V9B 
TH4B 
V10B 
TH5B 
TH6B 
EOT 
EOS-B/ F/U 
ETB 
Visit Windows 
± 7 days 
± 7 days 
± 7 days 
±- 7 days 
± 14 days 
± 14 days 
± 14 days 
+2 weeks 
 
Telehealth Visit 
X 
 
X 
  
X 
X 
  
 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
 
X 
 
 
X 
X 
X 
Complete Physical Exam 
 
 
 
 
 
 
X 
X 
X 
Symptom-directed Physical Exam 
 
X 
 
X 
 
 
 
 
 
Weight 
 
 
 
 
 
 
X 
 
X 
TTE 
 
 
 
X c 
 
 
X c 
X  
X c 
12-lead ECG 
 
X 
 
X 
 
 
X 
X 
X 
Cardiac Rhythm Monitoringf 
 
 
 
X 
 
 
X 
 
 
Activity Monitorg 
 
 
 
X 
 
 
X 
 
 
CMRh 
 
 
 
 
 
 
X 
 
 
6MWD   
 
 
 
X 
 
 
X 
 
 
NYHA Functional Classification 
 
X 
 
X 
 
 
X 
X 
X 
KCCQ-23  
X 
X 
X 
X 
X 
X 
X 
X 
X 
hsTnT/TnI/hs-TnI (Central)b 
 
X 
 
X 
 
 
X 
X 
X 
NT-proBNP (Central)  
 
X 
 
X 
 
 
X 
X 
X 
Chemistry, Hematology (Central) 
 
X 
 
X 
 
 
X 
X 
X 
Non-genetic biomarker Samples 
 
X 
 
X 
 
 
X 
X 
X 
Pregnancy Testk 
 
 
 
X 
 
 
X 
 
X 
Danicamtiv Plasma PK Sample  
 
 
 
X c 
 
 
X c 
 
 
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Table 4: 
Schedule of Assessments, Part B (Active Cohort) 
 
Part B, Year 2 
Visit Day 
Week 54 
Week 60 
Week 66 
Week 72 
Week 78 
Week 84 
Week 96 
Follow-up 
(Week 98) 
Early 
Termination 
Visit Number 
TH3B 
V9B 
TH4B 
V10B 
TH5B 
TH6B 
EOT 
EOS-B/ F/U 
ETB 
Visit Windows 
± 7 days 
± 7 days 
± 7 days 
±- 7 days 
± 14 days 
± 14 days 
± 14 days 
+ 2 weeks 
 
Telehealth Visit 
X 
 
X 
  
X 
X 
  
 
 
Study Drug Administration 
 
 
Adverse Eventsm 
 
Concomitant Medications 
Study Drug Compliance Checkn  
 
 
 
AEs = adverse events; CMR = cardiac magnetic resonance; ECG = electrocardiogram; EOS-B/F/U = end of study-Part B follow-up; EOT = end of treatment; ETB 
= early termination Part B; hsTnI = high sensitivity troponin I; hsTnT = high sensitivity troponin T; ICF = informed consent form; IMP = investigational medicinal 
product; KCCQ-23 = Kansas City Cardiomyopathy Questionnaire (23-item version); NT-proBNP = N-terminal pro b-type natriuretic peptide; NYHA = New York 
Heart Association; PK = pharmacokinetic; TH = telehealth; TTE = transthoracic echocardiography; ULN = upper limit of normal 
a If a Rescreening visit is not required prior to Part B start, then Visit 1B can be performed on the same day as Visit 5A and any assessments in Visit 5A that are 
also required in Visit 1B need only be performed once. If Visits 5A and 1B are not performed on the same day, Part B Medical History assessment to be done 
on study participants who require Rescreening Visit for Part B (V0B) or sign the Part B ICF at V1B and are less than or equal to 56 days from completion of 
Part A. 
b If TnI (standard) is elevated, telehealth visits should be converted to clinic visits; see footnote j. 
c Perform a TTE and dani plasma PK sample collection at approximately 7 hours (± 1 hour) after the morning dose on every visit after Day 1.    
d Can be done within 7 days of the initial starting dose in Part B 
e 
 
f Cardiac rhythm monitoring patch will be placed at Visit 1B, 6B, 8B, 10B, and EOT. The duration of initial monitoring is for a maximum of 14 days. If the patch 
should become detached prior to 5 days, a new patch should be placed as soon as possible. Once patch detaches after at least 5 days, participants will be instructed 
to mail the patch back to the site. 
g 
 
 
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h. CMR to be scheduled prior to dosing (prior to Visit 5A/Visit 1B if combining visits) and then within 4 weeks of each 1 year anniversary on study. CMR will be 
obtained only in suitable participants. 
i A 12-lead ECG and vital signs will be performed if TnI (standard) is elevated by more than 0.05ng/mL (see footnote h).  
j If TnI (standard) level is below ULN at Baseline and subsequently increases to more than 0.05 ng/mL, or if TnI level is above ULN at Baseline and then 
subsequently increases by more than 0.05 ng/mL above the participant’s Baseline value (obtained at Visit 1B in Part B) until Visit 6B (Week 24), the totality of 
the clinical data will be reviewed by a panel of experts periodically to determine if any signs of ischemia are seen. During this time, the participant will continue 
danicamtiv at the same dose; subsequent telehealth visits will become in-person clinic visits with 12-lead ECGs, vital signs,  and collection of TnI, hsTnI, TnT, 
and NT-proBNP until troponin levels are stable or declining. If TnI (standard) level exceeds 0.1 ng/mL at any time, the participant will be requested to return 
for repeat evaluation as soon as possible. If this level of TnI (standard) is confirmed, treatment with danicamtiv will be temporarily discontinued and an ad hoc 
expert review will be triggered. If TnI (standard and high sensitivity) and hsTnT are collected at visits TH1B and TH2B, then NT-proBNP should also be 
collected in the same blood draws. 
k Pregnancy tests, urine or blood, is based on the policy of the local institution or regulating Health Authority (eg, requirement for serum-based testing in the 
United Kingdom). 
l Rescreening visit to be performed only if timeframe between completion of Part A to start of Part B is greater than 56 days. 
m Changes in baseline conditions from once the ICF is signed will be recorded as an AE. All changes, unless otherwise specified, that occur after the administration 
of study drug will be considered treatment-emergent AEs. 
n Study drug compliance check will entail table count at all Part B visits including telehealth visits. Acceptable methods of contact include, but are not limited to, 
telephone, two-way text messaging and email. 
o Screening laboratory tests will include TSH and Fe/TIBC/ferritin to exclude uncontrolled thyroid functions and Fe overload.  
 
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Table 5: 
Schedule of Assessments, Part B (Observational Cohort) 
 
Part A 
 
 
 
 
 
 
Visit Day 
14 days + 
7d after 
V4A 
Day -28 to -1 
(Rescreening, 
if needed) 
Day 1 
(Baseline) 
Week 
12 
Week 24 
Week 48 
Week 96  
Visit Number 
V5A 
V0Ob 
V1Oc 
V2O 
V3O 
V4O 
V5O 
Visit Windows 
 
-28 days 
 
± 14 
days 
± 14 days 
± 14 days 
± 14 days 
Telehealth Visit 
 
 
 
 
 
 
 
Informed Consent 
 
X 
X (if needed) 
 
 
 
 
Medical History 
 
X 
X (if needed) 
 
 
 
 
Vital Signs 
 
X 
X 
X 
X 
X 
X 
Weight 
 
X 
X 
 
X 
X 
X 
Symptom-directed 
Physical Exam 
 
 
X 
 
X 
X 
X 
TTE 
 
 
Xa 
X  
X  
X  
X 
12-lead ECG 
X 
 
X 
X 
 X 
X 
X 
6MWD (in clinic) 
 
 
X 
 
X 
X 
X 
NYHA Functional 
Classification 
X 
 
 
X 
X 
X 
X 
X 
KCCQ-23  
X 
 
X 
X 
X 
X 
X 
hsTnT/TnI/hs-TnI 
(Central) 
X 
 
X 
X 
X 
X 
X 
NT-proBNP (Central)  
X 
 
X 
X 
 X 
X 
X 
Chemistry, Hematology 
(Central) 
X 
X 
X 
 
X 
X 
X 
Non-genetic Biomarker 
Sample 
X 
 
X 
 
X 
X 
X 
Adverse Events 
 
Concomitant 
Medications 
 
 
X 
X 
X 
X 
X 
6MWD = 6-minute walk distance; ECG = electrocardiogram; hsTnT = high sensitivity troponin T; KCCQ-23 = Kansas 
City Cardiomyopathy Questionnaire (23-item version); NT-proBNP = N-terminal pro b-type natriuretic peptide; 
NYHA = New York Heart Association; TnI = standard troponin I; TTE = transthoracic echocardiography; V = visit. 
a Can be done within 7 days of V1O. 
b Rescreening visit to be performed only if timeframe between completion of Part A to start of Part B is greater than 
56 days. 
c If a Rescreening visit is not required prior to Part B start, then Visit 1O can be performed on the same day as Visit 
5A and any assessments in Visit 5A that are also required in Visit 1O need only be performed once. If Visits 5A 
and 1O are not performed on the same day, Part B Medical History assessment to be done on study participants 
who require Rescreening Visit for Part B (V0O) or sign the Part B ICF at V1O and are less than or equal to 56 days 
from completion of Part A. 
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APPENDIX 2 
LABORATORY ASSESSMENTS 
Table 6: 
Safety Laboratory Parameters 
Hematologya 
Serum Chemistrya 
• CBC, including differential count 
• Platelet count 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Creatinine 
• ALP 
• ALT 
• AST 
• Total bilirubin 
• Glucose 
• CK 
• BUN or urea (per local standards) 
• LDH 
• Inorganic phosphorus 
• Total cholesterol  
• eGFR 
• Uric acid 
• Amylase 
• Lipase 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; CBC = complete blood cell count; CK = creatine kinase; eGRF = estimated glomerular filtration rate; LDH 
= lactic acid dehydrogenase 
a All samples will be assayed in the central laboratory at all timepoints except when deemed necessary by 
Investigator’s judgement 
 
Troponins and NT-proBNP will also be assessed (APPENDIX 1). 
The following nonsafety laboratory parameters will be measured in this study:  
• 
FSH 
• 
Pregnancy, assessed in urine or blood, based on the policy of the local institution or regulating 
Health Authority (eg, requirement for serum-based testing in the United Kingdom and 
Germany) 
• 
TSH, Fe/TIBC/ferritin for Screening 
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APPENDIX 3 
POTENTIAL DRUG-INDUCED LIVER INJURY REPORTING AND 
ADDITIONAL ASSESSMENTS REPORTING 
To facilitate appropriate monitoring for signals of drug-induced liver injury (DILI), cases of 
concurrent AST/ALT and TBL elevation according to the criteria specified in Section 6.2 
(3 times ULN for AST/ALT and 2 times ULN for TBL in participants with no underlying liver 
disease and eligibility criteria requiring normal liver function at Baseline) require the following: 
• 
The event is to be reported to the Sponsor as an SAE within 24 hours of discovery or 
notification of the event (i.e., before additional etiologic investigations have been concluded). 
• 
The appropriate eCRFs (eg, adverse event eCRFs) that capture information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities are to be completed and sent 
to the Sponsor. 
Other events of hepatotoxicity and potential DILI are to be reported as SAEs if they meet the 
criteria for an SAE defined in Section 12.1.2.  
Additional Clinical Assessments and Observation 
All participants in whom investigational product(s) or protocol-required therapies is/are withheld 
(either permanently or conditionally) due to potential DILI or who experience AST/ALT 
elevations > 3 times ULN are to undergo a period of close observation until abnormalities return 
to normal or to the participant’s Baseline levels. Assessments that are to be performed during this 
period include the following: 
• 
Repeat liver chemistries within 24 to 48 hours (ALT, AST, alkaline phosphatase, TBL); in 
cases of TBL ≥ 2 times ULN or AST/ALT much greater than 3 times ULN, retesting is to be 
performed within 24 hours. 
− Participants are to be monitored at least twice weekly; testing frequency may decrease to 
once per week or less if laboratory abnormalities stabilize or the investigational product(s) 
or protocol-required therapies have been discontinued AND the participant is 
asymptomatic. 
• 
Obtain prothrombin time/international normalized ratio, fractionated bilirubin, and any other 
potentially relevant laboratory evaluations of liver function or disease. 
• 
Obtain complete blood count with differential to assess for eosinophilia. 
• 
Obtain appropriate blood sampling for determination of plasma concentration, if this has not 
already been collected. 
• 
Obtain a more detailed history of the following: 
− Prior and/or concurrent diseases or illness 
− Exposure to environmental and/or industrial chemical agents 
− Symptoms (if applicable) including right upper quadrant pain, hypersensitivity 
type- reactions, fatigue, nausea, vomiting, and fever 
− Prior and/or concurrent use of alcohol, recreational drugs, and special diets 
− Concomitant medications (including nonprescription medicines and herbal and dietary 
supplements) 
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• 
Initiate full viral and autoimmune hepatitis evaluation (serologies for hepatitis A, B, C, D, E, 
Epstein-Barr virus, herpes simplex virus, etc.); evaluate for other potential causes of DILI, 
including but not limited to: nonalcoholic steatohepatitis, hypoxic/ischemic hepatopathy, and 
biliary tract disease. 
• 
Obtain gastroenterology or hepatology consult. 
• 
Perform appropriate liver imaging or biopsy if clinically indicated; strongly consider these tests 
in cases of concurrent transaminase and TBL elevation, as specified in Section 6.2.2.  
• 
Follow the participant until all laboratory abnormalities return to Baseline or normal. The close 
observation period is to continue for a minimum of 4 weeks after investigational product(s) or 
protocol-required therapies discontinuation. 
The potential DILI event and additional information, such as medical history, concomitant 
medications, and laboratory results, must be captured in corresponding eCRFs. 
 
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APPENDIX 4 
INVESTIGATOR’S SIGNATURE 
MYK-491-006, Amendment 5 release date: 28 Aug 2023 
I have read and understand the contents of the clinical protocol, MYK-491-006, “An Open-Label, 
Exploratory Study of the Safety and Preliminary Efficacy of Danicamtiv in Stable Ambulatory 
Participants with Primary Dilated Cardiomyopathy due to either MYH7 or TTN Variants or Other 
Causalities,” and I agree to the following: 
• 
To assume responsibility for the proper conduct of this clinical study at this clinical site and to 
conduct the study in compliance with this protocol, any future amendments, and any other 
study conduct procedures provided by the Sponsor/designee 
• 
That I am aware of and will comply with the internationally recognized code of Good Clinical 
Practices (GCP) and all other applicable regulatory requirements to obtain written and dated 
approval for the Ethics Committee (EC) (eg, Institutional or Central Review Board [IRB] or 
Independent Ethics Committee [IEC]) for the study protocol, written informed consents, 
consent form updates, study participant recruitment procedures, and any other written 
information to be provided to the study participants before initiating this clinical study 
• 
Not to implement any changes to, or deviations from the protocol without prior agreement 
from the Sponsor and reviewed and documented approval from the EC, except to eliminate an 
immediate hazard to the study participants, or when change(s) involves only logistical or 
administrative aspects of the clinical study 
• 
To permit direct monitoring and auditing by the Sponsor or the Sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies) 
• 
That I am thoroughly familiar with the appropriate use of the Investigational Medicinal Product 
(IMP) and other study medication(s) (if applicable), as described in this protocol, and any other 
information provided by the Sponsor or designee, including, but not limited to the current 
Investigator’s Brochure (IB) or equivalent document and marketed prescription information 
(if applicable) 
• 
To provide sufficient time and adequate numbers of qualified staff and facilities for the 
foreseen duration of the clinical study to conduct the study properly, ethically, and safely 
• 
To ensure that all persons assisting in this study are adequately informed about the protocol, 
study drug, and their clinical study-related duties and functions 
 
Signed: ____________________________________ 
Date: 
___________________ 
(sign name with credentials) 
 
Printed Name: ______________________________ 
(print name with credentials) 
 
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APPENDIX 5 
ALLOWANCES FOR STUDY OPERATIONS AFFECTED BY 
PANDEMIC PRECAUTIONS (INCLUDING COVID-19) 
Recent developments worldwide have seen unprecedented alterations in the operations of clinical 
research. Additionally, it is recognized that the dilated cardiomyopathy (DCM) patient population 
is at increased risk of adverse outcomes because of their underlying disease state. Individual 
clinical sites have since evaluated benefits and risks to participants of reopening to clinical research 
and made decisions to restart such activities accordingly. In these cases, discussions shall begin as 
soon as a site is contemplating reopening to clinical studies and should include the Sponsor as well 
as the Contract Research Organization (CRO). The site will determine a workflow for participants 
to be assessed and move through the conduct of the study in as safe a manner and environment as 
possible, limiting the exposure of these participants as well as members of the site’s staff and study 
monitors. This workflow will be documented in the investigator site file and should include 
provisions for adequate remote source document verification (for example by access to the 
investigator site file).  
Participants may be tested for COVID-19 in accordance with site standard practices and local 
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APPENDIX 6 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION 
Appendix 5 provides general information and definitions related to Women of Childbearing 
Potential (WOCBP) and methods of contraception that can be applied to most clinical trials. For 
information specific to this study regarding acceptable contraception requirements for female and 
male participants, refer to Section 10.2.3 of the protocol. Only the contraception methods as 
described in Section 10.2.3 are acceptable for this study.  
 
DEFINITIONS 
Women of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy, and/or bilateral tubal occlusion or ligation.  
Women in the following categories are not considered WOCBP: 
Premenarchal 
Premenopausal female with 1 of the following:  
-Documented hysterectomy 
-Documented bilateral salpingectomy 
-Documented bilateral oophorectomy 
-Documented bilateral tubal occlusion or ligation 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.  
 
Postmenopausal female 
-A postmenopausal state is defined as 12 months of amenorrhea in a woman over the age of 45 
years in the absence of other biological or physiological causes. In addition, females under the age 
of 55 years must have a serum follicle-stimulating hormone (FSH) level >40mIU/mL to confirm 
menopause.  
 
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and my require a washout period in order to obtain a physiologic FSH level. 
The duration of the washout period is a function of the type of HRT used. Suggested guidelines 
for the duration of the washout periods for HRT types are presented below. Investigators should 
use their judgment in checking serum FSH levels.  
1-week minimum for vaginal hormonal products (ring, creams, gels) 
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4- week minimum for transdermal products 
8-week minimum for oral products 
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is >40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal. 
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APPENDIX 7 
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY 
Overall Rationale for the Protocol Amendment 4, 20-Dec-2022 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to reflect the change in the study design.  
(1) Addition of a cohort of primary DCM not related to MYH7 or TTN variants to assess safety 
and PD responses with danicamtiv.  Data assessment between the DCM cohort, the MYH7 and 
TTN cohorts will be explored.  
(2) To evaluate if MYH7 or TTN disease-causing variants are involved in DCM causality, genetic 
testing reports will be reviewed and approved for study eligibility by the central reviewers at 
Screening.  Genetic testing can be performed at a local or central genetic testing lab when available 
in the region to determine participant eligibility.  For participants who are enrolled using genetic 
testing reports from other than a central genetic laboratory, their genetic status will be confirmed 
via testing at a central genetic laboratory retrospectively.   
A summary of additional changes that were made to the protocol are included in the table below 
to add clarity, consistency in terminology, and accuracy throughout the document. 
Section Number & Title 
Description of Changes 
Brief Rationale 
Title page; Synopsis 
Added CV028005 for the protocol number; 
Changed the title to “An Open-Label, Exploratory 
Study of the Safety and Preliminary Efficacy of 
Danicamtiv in Stable Ambulatory Participants with 
Primary Dilated Cardiomyopathy due to either 
MYH7 or TTN Variants or Other Causalities.”  
Added CV028005, which is 
study ID at BMS.   
To reflect the new cohort added. 
Synopsis - Study Title; 
Primary Objective; 
Secondary Objective; 
Exploratory Objectives; 
Study Design; Section 5.1 
Primary Objective; Section 
5.2 Secondary Objectives; 
Section 5.3 Exploratory 
Objectives; Section 6.1 
Study Design 
Added a new cohort of primary DCM.  For this 
cohort, other causalities than MHY7 or TTN 
variants as eligibility to participate.  Primary and 
secondary objectives updated to reflect this new 
cohort.  Added an exploratory objective to explore 
the PD comparisons between the DCM and the two 
genetic variants 
The addition of this new cohort 
allows safety and PD assessments 
with danicamtiv in DCM 
participants due to other 
causalities than MYH7 or TTN 
variants.  Data assessment 
between those three cohorts, 
DCM and the two genetic 
variants, will be explored. 
Synopsis – Study Design; 
Section 6.1.1 Part A 
Added that the Pre-Screening using a historical 
genetic report may be conducted prior to Screening 
visit where allowed by local regulations 
 
 
Pre-Screening has been described 
in the Part A Schedule of 
Assessment in the previous 
version of the study protocols.  
Specified it in the main protocol 
for clarity.     
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Section Number & Title 
Description of Changes 
Brief Rationale 
Synopsis – Study Design; 
Section 6.1.2 Part B 
And  
Synopsis – Study 
Treatment; Section 4.2 
Rationale for Dose and 
Dosing Schedule; Section 
9.2.2 Part B 
 
 
 
 
Added participation criteria for Part B for those 
participants who did not complete Part A 
 
 
 
 
 
 
Deleted the word “always” from Part B doses will 
always be based on the 
 in Part A 
 
Allows treatment to continue 
except for participants who 
experience drug related TEAEs, 
met stopping criteria or withdrew 
consent. This may allow cases, 
such as COVID-19 infection to 
continue.  Participation is 
assessed by the sponsor and PI 
 
To accommodate the case in 
which the 
 is not available in 
Part A. Part B participation for 
such case is described above 
Synopsis – Study Design; 
Section 6.1.2 Part B 
Deleted “If Visits 5A and 1B are performed on the 
same day, Part B study drug dosing should not start 
for at least 14 days after the last dose of the study 
drug in Part A.”  
To reflect the changes in study 
design made in PA3. This 
information was removed since 
it’s no longer applicable    
Synopsis – Study Design; 
Section 6.1.2 Part B; 
Section 11.4.6 Troponin 
Levels 
Clarified that hsTnT, hsTnI, and TnI will be 
evaluated throughout Parts A and B.  
 
To specify types of troponin 
assessed in the study 
Section 4.1 Rationale for 
the Study 
Added rationale for the DCM cohort 
Reflects the change in study 
design by adding a new cohort 
Synopsis –Number of 
Participants; Sample Size 
and Statistical 
Considerations; Section 
13.1 Determination of 
Sample Size 
Updated participants to approximately 40 including 
16 participants with DCM not related to MYH7 or 
TTN variant 
Added DCM cohort 
Synopsis –Number of 
Participants; Part A 
Inclusion Criteria I8; 
Section 6.1 Study Design; 
Section 7.1 Inclusion 
Criteria – Only for Part A 
Added that the ratio of participants with DCM 
causing variants (other than MYH7 or TTN) and 
non-genetic cause will be approximately 1:1 
To clarify planned enrollment 
ratio 
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Section Number & Title 
Description of Changes 
Brief Rationale 
Synopsis - Study 
Treatment; Section 4.2 
Rationale for Dose and 
Dosing Schedule; Section 
9.2.2 Part B 
Figure 3: Part B Study 
Schema 
 
Added the following: 
• If both doses in Part A resulted in a 
 
of 
 with 10 and 25 
mg BID, then the Part B dose is 5 mg BID 
• If both doses in Part A resulted in a 
 
of 
 with 25 and 50 
mg BID, then the Part B dose for that 
participant was previously5 mg and has 
been changed to 10 mg BID with this 
amendment 
To be able to select the one dose 
lower than the doses 
administered in Part A.  To date, 
all participants have received 
25mg BID and 50mg BID in Part 
A.  Safety and tolerability of 
danicamtiv with those doses have 
been acceptable in this 
population. Based on previously 
conducted PK assessment in 
healthy volunteer, 
 
 
 
 
 
 
Furthermore, there will be 
 
assessments at 2weeks and 6 
weeks after starting 10mg in Part 
B.  Dose optimization at 6 weeks 
in Part B will be performed 
depending on 
  
Synopsis – Study 
Treatment; Section 4.2 
Rationale for Dose and 
Dosing Schedule; Section 
9.2.2 Part B 
Added the following:  
• If 
 of both doses were 
unavailable or performed significantly outside 
of the assessment window (see Appendix 1. 
Part A SoA footnote g), then the Part B dose 
will be 50 mg BID.   
• If a 
 was only available with 25 
mg BID (Treatment Period 1) and a 
 
 was 
 and 
, then 
25mg BID is the dose for Part B. If a 
 
was 
, then the Part B 
dose is 50 mg BID.  If 25 mg BID dose 
resulted in a 
, 
then the Part B dose for that participant is 10 
mg BID  
Part B starting dose for such case 
was indicated based on available 
 in Part A or 50mg 
BID, which all Part A participant 
have received in Part A treatment 
period 2 to date with acceptable 
safety and tolerability 
Synopsis – Study Design 
Part B, Study Duration; 
Section 6.1.2 Part B; 
Section 6.3 Study Duration 
Updated the expected Part B duration to 102 weeks 
if Rescreening is needed.  
To align with the updated 
Schedule of Activities 
Synopsis – Part A 
Inclusion Criteria I3; 
Section 7.1 Inclusion 
Criteria –Part A 
Clarified that for MYH7 and TTN cohorts, I3 
criteria (a) through (f), specific for these variant 
type, must be met.  Clarified that for all participants 
must meet I3 criteria of LVEF (g) and HF GDMT 
(h)  
To reflect the inclusion criteria 
for the primary DCM cohort of 
other causalities 
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Section Number & Title 
Description of Changes 
Brief Rationale 
Synopsis – Part A 
Inclusion Criteria I3; 
Section 7.1Inclusion 
Criteria –Part A 
Deleted inclusion for variants involving certain 
myosin residues 
To streamline genetic eligibility 
criteria. Based on reported data, 
it is unlikely to affect the listed 
myosin amino acid residues by 
disease causing variants in 
MYH7 gene.  
Synopsis – Part A 
Inclusion Criteria I6; 
Section 7.1 Inclusion 
Criteria –Part A; Section 
10.2.1 Avoidance of 
Pregnancy; Section 10.2.3 
Acceptable Forms of 
Contraception 
Changed to “documented” hysterectomy, bilateral 
oophorectomy, bilateral salpingectomy, and/or 
bilateral tubal occlusion “or ligation” prior to 
Screening 
To align with the standard 
contraception requirement. Also, 
clarified how to confirm those 
previous procedures 
Synopsis – Part A 
Inclusion Criteria I8; 
Section 7.1 Inclusion 
Criteria –Part A 
Added I8 criteria for cohort of DCM due to 
causalities other than MYH7 and TTN 
To clarify the eligibility criteria 
Synopsis – Inclusion 
Criteria Part B I; Section 
7.1 Inclusion Criteria –Part 
B 
Added inclusion criteria for Part B 
To clarify inclusion criteria for 
participants continuing to Part B 
to ensure their condition still 
meet for study participation  
Synopsis – Part A 
Exclusion Criteria E3; 
Section 7.2 Exclusion 
Criteria – Part A 
Clarified that MYH7 and TTN cohorts and DCM 
due to other causalities are mutually exclusive in 
E3 
To clarify the eligibility criteria 
Synopsis – Part A 
Exclusion Criteria E15; 
Section 7.2 Exclusion 
Criteria – Part A 
 
Section 11.4.8 Safety 
Laboratory Tests (Other 
than Troponin); Appendix 
2 Laboratory Assessments; 
Appendix 1. Schedule of 
Assessments, Part A; 
Appendix 1. Schedule of 
Assessments, Part B 
(Active Cohort) 
Clarified that the exclusion is for out-of-range 
laboratory parameters (safety and nonsafety) at 
Screening 
 
 
Added TSH, Fe/TIBC/ferritin for Screening 
 
To clarify the eligibility criteria. 
TSH and Fe/TIBC/ferritin will be 
assessed at Screen to evaluate 
cause of DCM is probably not 
due to abnormal thyroid function 
or Fe overload.  
Synopsis – Part A 
Exclusion Criteria E22, 
E23; Part B E11, E12; 
Section 7.2 Exclusion 
Criteria – Part A, Part B 
Added EC of requirement for an ICD in 
participants who meets class I recommendation in 
the HF guidelines (E22 Part A and E11 Part B) and 
severe ventricular arrythmia (E23 Part A and E12 
Part B). Individuals with unstable or untreated 
severe ventricular arrythmia is not eligible for 
study participation. 
To assure safety of study 
participants those who are with 
elevated risk of sudden cardiac 
death due to ventricular 
arrythmia. 
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Section Number & Title 
Description of Changes 
Brief Rationale 
Synopsis – Part A 
Exclusion Criteria E11; 
Section 7.2 Exclusion 
Criteria – Part A  
Synopsis – Part B 
Exclusion Criteria E4; 
Section 7.2 Exclusion 
Criteria – Part B 
EC of COVID-19 infection within 30 days from 
Screening (Part A) or Rescreening (Part B) was 
replaced by below EC.  
 
In the case of SARS-CoV-2 (COVID-19) infection 
within 4 weeks prior to and during Screening for 
Part A or within 4 weeks prior to Part B Baseline 
Visit or Rescreening , symptoms must have 
completely resolved and based on Investigator 
assessment in consultation with the Clinical Trial 
Physician, there are no sequelae that would place 
the participant at a higher risk of receiving 
investigational treatment.   
To update the COVID 19 related 
exclusion criteria for Parts A and 
B given notable changes 
associated with COVID-19 since 
previous EC was made in 2020. 
There have been available 
vaccines and treatments for 
COVID-19 and symptoms also 
varies per individual. Individual 
cases can be assessed by the PI 
and Sponsor Medical Monitor.   
Synopsis – Part A 
Exclusion Criteria E11, 
Part B Exclusion Criteria 
E4; Section 7.2 Exclusion 
Criteria – Part B 
PCR test to confirm positive COVID-19 infection 
was replaced by the tests including PCR, antigen 
test and serology tests 
 
To allow other types of COVID-
19 test to diagnose positive 
infection. Each study sites should 
follow requirement per local 
institution or regulatory guidance 
Synopsis – Part B 
Exclusion Criteria E5; 
Section 7.2 Exclusion 
Criteria – Part B 
Clarified that Part B E5 of renal insufficiency and 
E6 of clinically significant out-of-range safety lab 
apply to participants that need Rescreening only 
To clarify applicable criteria 
which require safety lab test 
results only performed for 
Rescreening 
Synopsis – Part B 
Exclusion Criteria; Section 
7.2 Exclusion Criteria – 
Part B 
Added Part B Exclusion Criteria E8, E9,  and E10.  
These are also Part A Exclusion criteria 
To clarify that these ECs required 
for Part A are also required for 
Part B   
Synopsis – Study 
Endpoints; Section 13.2.1 
Primary Endpoints 
Clarified that the primary endpoints are for Part A 
only 
Part B is an optional extension to 
the study. Part A is required for 
all participants, hence primary 
endpoints will be collected in 
Part A only.  
Synopsis – Study 
Endpoints; Section 13.2.2 
Secondary Endpoints; 
Section 11.1.1 
Transthoracic 
Echocardiography 
Clarified that the parameters of left ventricular 
diastolic function will include, but not be limited 
to, TDI of mitral valve annulus peak velocity in 
diastole (e’, lateral, septal), ratio of peak inflow 
velocities in early and late diastole (E/A), ratio of 
early mitral peak inflow velocity to early mitral 
peak annulus velocity (TDI) (E/e’) lateral, septal, 
and average 
To specify the Echo parameters 
to be assessed for diastolic 
dysfunction.  
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Section Number & Title 
Description of Changes 
Brief Rationale 
Synopsis – Study 
Endpoints; Section 13.2.3 
Exploratory Endpoints 
Updated Exploratory Endpoints as follows: 
 
• 
 
 will be summarized by the 
cohort (MYH7, TTN, and other DCM) using 
descriptive statistics 
 
• Clinical safety and tolerability in Part B 
 
 
• Additional exploratory endpoints, including 
concentration-PD effect and soluble 
biomarkers of cardiac physiopathology may be 
included 
 
• Frequency of left ventricular reverse 
remodeling (LVRR) during Part B, defined by 
the following criteria by TTE and CMR (if 
any) 
 
• Frequency of improvements in LVEF during 
Part A 
To clarify the planned 
exploratory endpoints  
 
To accommodate the new cohort 
of DCM 
 
 
To define safety and tolerability 
for Part B 
 
To assess the added exploratory 
objectives for biomarker for 
cardiac physiopathology  
 
 
To define assessment endpoint 
for the exploratory objective of 
effect of danicamtiv on cardiac 
structure and function in Part A 
and Part B 
 
To define assessment endpoint 
for the exploratory objective of 
effect of danicamtiv on cardiac 
structure and function in Part A 
and Part B 
Synopsis – Sample Size 
and Statistical 
Considerations; Section 
13.3.2 General 
Considerations 
Added that clinical data will be summarized by 
MYH7, TTN, and other DCM. For MYH7 and 
TTN cohorts, data may be summarized by variant 
type and the location. For DCM cohort, data will be 
further evaluated by genetic mutation-positive and 
genetic mutation-negative variable. If positive 
genetics are identified,  additional analysis may be 
performed by variant type. 
 
Added that Depending on reports from central 
genetic testing laboratory, participant reallocation 
to adequate cohort and additional analysis may be 
performed. 
To reflect statistical 
consideration for the added DCM 
cohort which will include genetic 
and non-genetic causes.  
 
 
 
 
To clarify participant reallocation 
and additional data analysis may 
be performed if there was 
significant discrepancy between 
the information used for genetic 
eligibility at Screening and 
reports from a central genetic 
laboratory 
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Section Number & Title 
Description of Changes 
Brief Rationale 
Section 1 Introduction 
Added definition of DCM as a disease of the 
myocardium defined by left ventricular 
enlargement and myocardial systolic and diastolic 
dysfunction in the absence of known abnormal 
loading condition or significant coronary artery 
disease.   
Added that recently, hypokinetic non-dilated 
cardiomyopathy (HNDC) which is defined as LV 
or biventricular global systolic dysfunction without 
dilatation in the absence of the same conditions for 
previously described DCM has been considered as 
a part of DCM. 
To add disease state background 
Figure 2: Part A Study 
Schema 
Updated to include the new cohort  
To reflect the new cohort  
Synopsis – Study Design; 
Section 6.1.2 Part B; 
Synopsis – Study 
Treatment; Appendix I 
Schedule of Assessments, 
Part B (Observational 
Cohort) 
Added as an option for those who did not opt to 
participate in Part B, an observational study 
without the study drug administration will be 
available (Part B observational study). The limited 
study assessments at the reduced study visits will 
be performed after participants consent to this 
observational study  
Allows patients who did not opt 
to Part B to participate in a new 
observational study which aims 
to observe natural course of 
cardiac status.   
Section 6.2.3 Data 
Reviews; Section 13.3 
Statistical Analysis 
Added that additional reviews may be conducted 
To clarify potential review which 
may be considered 
Section 6.2.3 Data Reviews Changed the section title to Data Reviews from 
Safety Review 
To generalize data type to be 
reviewed during study  
Section 9.1.1 Supply of 
Investigational Medical 
Product 
Added that 
 tablets 
will be supplied in high-density polyethylene 
bottles with induction seals and child-resistant caps 
of 3 strengths: 5 mg (to support the 5 mg BID and 
10 mg BID doses), 25 mg, and 50 mg for Part A 
To clarify the additional type of 
IMP will be provided for Part A 
Section 9.3 Treatment 
Compliance 
Added that during Part B, an investigational 
product diary will be used to ensure compliance 
A diary to record IMP 
administration will be used in 
Part B to ensure compliance  
Section 11.3.2 
Genetic/Genotype/Pharmac
ogenetic/Biomarker 
Assessment 
Added “circulating biomarkers” as potential future 
analysis 
 
Added “Beside genetic testing for variants 
associated with cardiomyopathies that is 
mandatory.” 
To clarify, genetic testing to 
assess variants associated with 
cardiomyopathy will be 
performed for all participants.  
Testing will be conducted 
prospectively at Screening or 
retrospectively after being 
enrolled.  
Section 11.6 Participant 
Restrictions During the 
Study 
Added that the restrictions will not apply to the 
participants of the Part B observational study  
Restriction to ensure adequate 
dosing and safety related to 
danicamtiv will not be required 
for Part B observational study 
since there will be no danicamtiv 
treatment 
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Section Number & Title 
Description of Changes 
Brief Rationale 
Section 12.1.2 Serious 
Adverse Events 
Removed treatment-emergent period from this 
section.  
Updated that the SAE collection period is from ICF 
signing to 30 days after the last study drug 
administration 
To update the SAE collection 
period 
Section 12.1.2 Serious 
Adverse Events; Section 
12.3 Reporting Period and 
Follow Up 
Clarified that SAEs will be collected whether or 
not the events are considered related to the study 
medication or study procedure 
To clarify that SAEs will be 
collected regardless of 
relatedness to the study 
medication or procedure 
Section 12.3 Reporting 
Period and Follow Up 
Deleted the statement that the AEs occurring after 
providing informed consent but before the study 
dose administration will be reported as AEs only if 
considered related to protocol or study procedures.  
To clarify that AEs occurring 
after signing ICF to be reported 
regardless of study drug or 
procedure relatedness 
Section 13.3.7.1 Adverse 
Events 
Moved the definition of TEAEs to this section. 
Added that TEAEs are defined as AEs with onset 
on or after the first dose of the study drug to 14 
days after the last study drug administration 
The same information was 
described in SAE section (12.1.2) 
in previous protocol. TEAE 
definition is moved to this 
section.   
6.2.1. Temporary 
Treatment Discontinuation 
(or Treatment Interruption)  
Change in protocol text: hsTnI (high sensitive 
Troponin I) was changed to TnI (standard 
Troponin I) 
To reflect protocol clarification 
letter (PCL) dated 30 June 2022. 
To correct a typographical error 
and to be consistent with Section 
11.4.6. 
Appendix 1. Schedule of 
Assessments, Part B 
(Active Cohort) 
If Visits 5A and 1B are not performed on the same 
day, Part B Medical History assessment to be done 
on study participants who require Rescreening 
Visit for Part B (V0B) or sign the Part B ICF at 
V1B and are less than or equal to 56 days from 
completion of Part A. 
To reflect PCL dated 30 June 
2022.  To clarify that Part B 
Medical History will also be 
assessed on study participants 
who sign the Part B ICF at V1B 
and are less than or equal to 56 
days from completion of Part A 
Protocol Synopsis-Study 
Duration 
Change in protocol text: The expected study 
duration of Part A for each participant ranges from 
approximately 4 to 11 weeks, including 2 to 8 
weeks for Screening, 9 to 16 days for treatment, 
and approximately 2 weeks for follow-up. 
To reflect protocol clarification 
letter date 03 May 2022. To 
correct a typographical error and 
to be consistent with Section 
6.1.1. and Appendix 1. Schedule 
of Assessments regarding Visit 
5A. 
Protocol Synopsis-Part A 
Exclusion Criteria 
Removed the comma following “pacing” in E2. A 
participant has a QTcF interval > 480 milliseconds, 
not attributable to ventricular pacing or has 
prolonged QRS duration ≥ 120 milliseconds, 
average of triplicate ECGs. 
To reflect protocol clarification 
letter date 03 May 2022. To 
correct a typographical error and 
to be consistent with Section 7.2. 
regarding exclusion criterion #2. 
Appendix 1. Schedule of 
Assessments, Part A 
Changed the TH3A visit to 1-3 days after V4A. 
 
To reflect protocol clarification 
letter date 03 May 2022. To 
correct a typographical error and 
to be consistent with Section 
6.1.1 regarding Part A telehealth 
visit (TH) 3A. 
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Section Number & Title 
Description of Changes 
Brief Rationale 
Appendix 1. Schedule of 
Assessments, Part A 
FSH level assessment done at Screening (V1.1A) is 
only for women of non-childbearing potential 
(WONCBP). 
To reflect protocol clarification 
letter date 03 May 2022. To 
clarify that FSH level assessment 
is only for WONCBP to 
determine if FSH levels meet 
postmenopausal level defined in 
Appendix 6. 
Appendix 1. Schedule of 
Assessments, Part A 
Added to footnote “o” for Blood sample for 
pharmacogenetic testing:  
Additional samples for 
pharmacogenetic testing will be 
collected if needed (eg., samples 
determined as not adequate for 
DNA extraction) anytime during 
the study after participants 
provided consent for additional 
sample collection.    
Appendix 1. Schedule of 
Assessments, Part A 
(Active Cohort) 
Added footnote “x” for KCCQ-23 
To indicate that this should be 
done before any other 
assessments 
Appendix 1. Schedule of 
Assessments, Part B 
(Active Cohort) 
Added 12-lead ECG to Rescreening Visit 
To evaluate any changes in ECG 
prior to participating in Part B  
Appendix 1. Schedule of 
Assessments, Part B 
(Active Cohort) 
Changed the Follow up visit to Week 98 
To align with the Follow up visit 
schedule in Part A  
Appendix 1. Schedule of 
Assessments, Part B 
(Active Cohort) 
Added ± 2 days visit window to V2B 
To allow for flexibility 
Appendix 1. Schedule of 
Assessments, Part B 
(Active Cohort) 
Added Medical history to V1B if needed 
To allow for medical history 
assessment if needed at Part B 
baseline 
Appendix 1. Schedule of 
Assessments, Part B 
(Active Cohort) 
Added footnote “o” to denote that screening 
laboratory tests will include TSH and 
Fe/TIBC/ferritin to V0B visit 
To exclude uncontrolled thyroid 
function and Fe overload 
Appendix 1 Schedule of 
Assessments, Part B 
(Observational Cohort) 
Added to list schedule of assessments for the 
observational study 
To clarify assessments during the 
study 
Appendix 6. Women of 
Childbearing Potential 
Definitions and Methods of 
Contraception 
Added “and/or bilateral tubal occlusion or ligation” 
and “documented bilateral tubal occlusion or 
ligation.” 
To update the contraception 
methodology by including an 
additional acceptable method 
 
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